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US 2004/0106747 A1Published application
Polyalkylene glycol acid additives
AssigneeHoffmann-La Roche Inc.
InventorsPascal Sebastian Bailon, Chee-Youb Won
Life of this patent
Estimating the term…
Abstract
A new class of activated polyalkylene glycol acids and their active ester reagents for conjugation to biopharmaceuticals such as polypeptides, sugars, proteins and therapeutically active small molecules to produce biologically active conjugates of these pharmaceuticals and methods for producing these conjugates.
Claims67
A compound of the formula
- 40
- wherein R, R1 and R2 are individually hydrogen or lower alkyl;
- X is
- —O— or —NH—;
- PAG is a divalent residue of polyalkylene glycol resulting from removal of both of its terminal hydroxy groups, which residue has a molecular weight of from 1,000 to 50,000 Daltons;
- n is an integer of from 0 to 1;
- m is an integer of from 4 to 8;
- and A is a hydrogen or an activated leaving group which when taken together with its attached oxygen atom forms an ester or hydrolyzable esters thereof wherein A is hydrogen.
5 more elements
The compound of formula
- 43
- wherein R is hydrogen or lower alkyl;
- X is—O— or —NH—;
- PAG is a divalent residue of polyalkylene glycol resulting from removal of both of its terminal hydroxy groups, which residue has a molecular weight of from 1,000 to 50,000 Daltons;
- w is an integer of from 1 to 3;
- and one of R3 and R4 is lower alkyl and the other is hydrogen or lower alkyl;
- and A is a hydrogen or an activated leaving group which when taken together with its attached oxygen forms an ester;
- or hydrolyzable esters thereof wherein A is hydrogen.
5 more elements
The compound of formula
- 45
- wherein R is hydrogen or lower alkyl, X is —O— or —NH—, A is a hydrogen or an activated leaving group which when taken together with its attached oxygen atom forms an ester, PAG1 is a divalent residue of a polyalkylene glycol resulting from the removal of both of the terminal hydroxy groups, said residue having a molecular weight of from about 500 to about 25,000 Daltons, y is an integer from 0 to 3 and v is an integer from 1 to 3;
- and k is an integer from 1 to 2;
- or hydrolyzable esters thereof wherein A is hydrogen.
1 more element
A process for producing an activated ester of the formula:
- 47
- wherein R, R1 and R2 are individually hydrogen or lower alkyl;
- X is —O— or —NH—;
- PAG is a divalent residue of polyalkylene glycol resulting from removal of both of its terminal hydroxy groups, which residue has a molecular weight of from 1,000 to 50,000 Daltons;
- n is an integer of from 0 to 1;
- m is an integer of from 4 to 8;
- and A is a hydrogen or an activated leaving group which when taken together with its attached oxygen atom forms an ester
- comprising, condensing a compound of the formula:
- RO—PAG—V V
- wherein R, and PAG are as above, and V is —OH or —NH2,
- with the compound of the formula:
- 48
- wherein R5 forms a hydrolyzable ester protecting group and Y is halide and R1, R2, m, and n, are as above,
- to produce an ester of the formula
- 49
- wherein R, PAG, X, R1, R2, R5, m and n are as above, hydrolyzing said ester to form a free acid of the formula:
- 50
- wherein R, PAG, X, R1, R2, m and n are as above, and reacting said free acid with a halide of an activated leaving group in the presence of a coupling agent to produce said activated ester.
15 more elements
A process for producing an activated ester of the formula:
- 51
- wherein R is hydrogen or lower alkyl;
- X is —O— or—NH—;
- PAG is a divalent residue of polyalkyleneglycol resulting from removal of both of its terminal hydroxy groups, which residue has a molecular weight of from 1,000 to 50,000 Daltons;
- w is an integer of from 1 to 3;
- and one of R3 and R4 is lower alkyl and the other is hydrogen or lower alkyl;
- and A is a hydrogen or an activated leaving group which when taken together with its attached oxygen atom forms an ester
- comprising, condensing a compound of the formula:
- 52
- wherein w, Y, R3, R4 and R5 are as above, Y is halide and R5 forms a hydrolyzable protecting group
- with a compound of the formula:
- RO—PAG—V V
- wherein R, and PAG are as above, V is —OH or —NH2,
- to produce an ester of the formula:
- 53
- wherein w, R, PAG, X, R3, R4 and R5 are as above
- hydrolyzing said ester to form a free acid of the formula:
- 54
- wherein R, PAG, X, R3, R4 and R5 are as above, and reacting said free acid with a halide of an activated leaving group in the presence of a coupling agent to produce said activated ester.
16 more elements
A process for producing an activated ester of the formula:
- 55
- wherein R is hydrogen or lower alkyl, X is —O— or —NH, A is a hydrogen or an activated leaving group which when taken together with its attached oxygen atom forms an ester, PAG1 is a divalent residue of a polyalkylene glycol resulting from the removal of both of the terminal hydroxy groups, said residue having a molecular weight of from about 500 to about 25,000 Daltons, y is an integer from 0 to 3 and v is an integer from 1 to 3;
- and k is an integer from 1 to 2,
- comprising, condensing a compound of the formula:
- 56
- wherein Y is halide, y and v are as above, and R5 forms a hydrolyzable ester protecting group
- with a compound of the formula
- RO—PAG1—O—(CH2)k—V XXXVI
- wherein R, PAG1 and k are as above, V is —OH or —NH2,
- to produce an ester of the formula:
- 57
- wherein R, PAG1, X, R5, k, v and y are as above,
- hydrolyzing said ester to form a free acid of the formula:
- 58
- wherein R, PAG1, X, k, v and y are as above, and reacting said free acid with a halide of an activated leaving group in the presence of a coupling agent to produce said activated ester.
12 more elements
A conjugate of the formula
- 59
- wherein P is a residue of a biopharmaceutical having a terminal hydroxy group wherein the terminal hydroxy group is removed, R, R1 and R2 are individually hydrogen or lower alkyl;
- X is —O— or —NH—;
- PAG is a divalent residue of polyalkylene glycol resulting from removal of both of its terminal hydroxy groups, which residue has a molecular weight of from 1,000 to 50,000 Daltons;
- n is an integer of from 0 to 1;
- and m is an integer of from 4 to 8.
3 more elements
A conjugate of the formula
- 60
- wherein P is a residue of a biopharmaceutical having a terminal hydroxy group wherein the terminal hydroxy group is removed, R, R1 and R2 are individually hydrogen or lower alkyl;
- X is —O— or —NH—;
- PAG is a divalent residue of polyalkylene glycol resulting from removal of both of its terminal hydroxy groups, which residue has a molecular weight of from 1,000 to 50,000 Daltons;
- n is an integer of from 0 to 1;
- and m is an integer of from 4 to 8.
3 more elements
Dependencies are inferred from the claim text.