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US 2003/0153694 A1Published application
Novel monofunctional polyethylene glycol aldehydes
OwnerPerry Rosen, Kwang Nhoinventors
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Abstract
Novel monofunctional polyethylene glycol aldehyde for pegylating therapeutically active proteins to produce pegylated protein conjugates which retain a substantial portion of their therapeutic activity and are less immunogenic than the protein from which the conjugate is derived and a new synthesis for preparing such aldehydes.
Claims58
An aldehyde having the formula:
- 30
- wherein R is hydrogen or lower alkyl;
- X and Y are individually selected from —O— or —NH— with the proviso that X is NH when m is 1 and Y is —O—;
- PAG is a divalent residue of polyalkylene glycol resulting from removal of the terminal hydroxy groups and having a molecular weight of from about 1,000 to about 100,000 Daltons;
- z is an integer of from 2 to 4, m is an integer of from 0 to 1;
- and w is an integer of from 2 to 8, wherein the aldehyde group is free or protected with a hydrolyzable aldehyde protecting group, or a hydrate thereof.
3 more elements
An aldehyde of the formula:
- 35
- wherein R is hydroxyl or lower alkyl;
- A is a polyethylene glycol residue with its two terminal hydroxy groups being removed having a molecular weight of from 1,000 to 100,000 Daltons and having a valence of from 1 to 5;
- n is an integer of from 1 to 5 which integer is the same as the valence of A;
- and w is an integer from 2 to 8.
2 more elements
An aldehyde of the formula:
- 36
- wherein PAG1 and PAG2 are independently divalent residues of poly lower alkylene glycol resulting from removal of the two terminal hydroxy groups with the PAG1 and PAG2 residues having a combined molecular weight of from 1,000 to 100,000 Daltons;
- R and R1 are individually lower alkyl or hydrogen and w is an integer from 2 to 8;
- p is an integer of from 1 to 5;
- z is an integer of from 2 to 4, wherein the aldehyde group is hydrated, free or protected by a hydrolyzable aldehyde protecting group.
2 more elements
A compound of the formula:
- 37
- wherein R is hydrogen or lower alkyl;
- R2 is CH(OH)CH2OH, X and Y are individually selected from —O— or —NH— with the proviso that X is NH when m is 1 and Y is —O—;
- PAG is a divalent residue of polyalkylene glycol resulting from removal of the terminal hydroxy groups and having a molecular weight of from about 1,000 to about 100,000 Daltons;
- z is an integer of from 2 to 4, m is an integer of from 0 to 1;
- and w is an integer of from 2 to 8.
3 more elements
A compound of the formula:
- 38
- wherein R is hydrogen or lower alkyl, R2 is CH(OH)CH2OH, A is a polyethylene glycol residue with its two terminal hydroxy groups being removed having a molecular weight of from 1,000 to 100,000 Daltons and having a valence of from 1 to 5;
- n is an integer of from 1 to 5 which integer is the same as the valence of A;
- and w is as integer for 2 and 8.
1 more element
A compound of the formula:
- 39
- wherein PAG1 and PAG2 are independently divalent residues of poly lower alkylene glycol resulting from removal of the two terminal hydroxy groups with the PAG1 and PAG2 residues having a combined molecular weight of from 1,000 to 100,000 Daltons;
- R and R1 are individually lower alkyl or hydrogen, R2 is —CH(OH)CH2OH, w is an integer from 2 to 8;
- p is an integer of from 1 to 5, and z is an integer of from 2 to 4.
1 more element
A compound of the formula:
- RO—PAG-O(CH2)z—O—CH2—(CH2)w—R2
- wherein R is lower alkyl or hydrogen, R2 is CH(OH)CH2OH, PAG is the divalent residue of polyethylene glycol resulting from removal of the two terminal hydroxy groups having a molecular weight of from 1,000 to 100,000 Daltons, z is a integer of from 2 to 4 and w is an integer of from 2 to 8.
A conjugate of the formula:
- 40
- wherein P is the residue of a protein with its amino group removed, R is hydrogen or lower alkyl;
- X and Y are individually selected from —O— or —NH with the proviso that X is NH when Y is —O—;
- PAG is a divalent residue of polyalkylene glycol resulting from removal of the terminal hydroxy groups, having a molecular weight of from 1,000 to 100,000 Daltons;
- z is an integer of from 2 to 4, m is an integer of from 0 to 1;
- and w is an integer of from 2 to 8.
3 more elements
A conjugate of the formula:
- 45
- wherein P is a residue of a protein with its amino group removed, R is hydrogen or lower alkyl, A is a polyethylene glycol residue with its two terminal hydroxy groups being removed having a molecular weight of from 1,000 to 100,000 Daltons and having a valence of from 1 to 5;
- n is an integer of from 1 to 5 which integer is the same as the valence of A, and which integer is the same as the number of proteins P, w is as above.
A conjugate with the formula:
- 46
- wherein P is a residue of a protein with its amino group being removed, PAG1 and PAG2 are independently divalent residues of poly lower alkylene glycol resulting from removal of the two terminal hydroxy groups and with the PAG1 and PAG2 residues having a combined molecular weight of from 1,000 to 100,000 Daltons;
- R and R1 are individually lower alkyl or hydrogen, w is an integer of from 2 to 8, p is an integer of from 1 to 5, and z is an integer of from 2 to 4.
A conjugate of the formula
- RO—PAG-O(CH2)zO—CH2—(CH2)wCH2N HP III-D
- wherein P is a residue of a protein with an amino group being removed, PAG is a divalent residue of a poly lower alkylene glycol resulting from removal of the two terminal hydroxy groups having a molecular weight of from 1,000 to 100,000 Daltons, R is lower alkyl or hydrogen, w is an integer from 2 to 8 and z is an integer from 2 to 4.
A process for producing an aldehyde of the formula:
- RO—PAG-O—(CH2)3—O—CH2—(CH2)w—CHO
- wherein R is lower alkyl, PAG is a divalent residue of polyalkylene glycol resulting from removal of the terminal hydroxy groups, having a molecular weight of from 1,000 to 100,000 Daltons;
- z is an integer of from 2 to 4, and w is an integer of from 2 to 8;
- from a hydroxy compound of the formula
- RO—PAG-O—(CH2)z—OH
- wherein 3, R, PAG and z are as above
- comprising esterifying said hydroxy compound to form an ester of the formula
- RO—PAG-O—(CH2)z—OL
- wherein R and PAG are as above,
- by reacting said hydroxy compound with a sulfonating agent having the formula:
- HaloL
- wherein L is a sulfonate leaving group and Halo is a halogen,
- to form said sulfonate ester, and reacting said ester with an acetonide of the formula:
- 47
- wherein w is as above and B is an alkali metal
- to form a polymeric acetonide of the formula
- 48
- wherein R, P, PAG, z and w are as above
- and thereafter hydrolyzing said polymeric acetonide under acid conditions to remove the acetonide group, and thereafter subjecting said hydrolyzed acetonide to oxidation with a periodate oxidizing agent to form said aldehyde.
16 more elements
A process for producing an aldehyde of the formula:
- RO—PAG-O—(CH2)z—O—CH2—(CH2)w—CHO
- wherein R is lower alkyl, PAG is a divalent residue of polyalkylene glycol resulting from removal of the terminal hydroxy groups, having a molecular weight of from 1,000 to 100,000 Daltons;
- z is an integer of from 2 to 4, and w is an integer of from 2 to 8;
- from a hydroxy compound of the formula
- RO—PAG-O—(CH2)z—OH
- wherein R, PAG and z are as above
- comprising halogenating said hydroxy compound to form a halide of the formula
- RO—PAG-O—(CH2)z—X
- by reacting said hydroxy compound with a halogenating agent having the formula:
- X2SO
- wherein X is a halogen,
- to form said halide, and reacting said halide with an acetonide of the formula:
- 49
- wherein w is as above and B is an alkali metal
- to form a polymeric acetonide of the formula
- 50
- wherein R, PAG, z and w are as above
- and thereafter hydrolyzing said polymeric acetonide under acid conditions to remove the acetonide group, and thereafter subjecting said hydrolyzed acetonide to oxidation with a periodate oxidizing agent to form said aldehyde.
15 more elements
A process for producing an aldehyde of the formula:
- RO—PEG-O—(CH2)2—O—CH2—(CH2)w—CHO
- wherein PEG is a divalent residue of polyethylene glycol resulting from removal of the terminal hydroxy groups, having a molecular weight of from 1,000 to 100,000 Daltons;
- and w is an integer of from 2 to 8;
- from an acetonide of the formula
- 51
- wherein B is an alkali metal, and w is as above
- comprising reacting said acetonide with ethylene oxide by passing liquid ethylene oxide into an organic solution containing the acetonide under polymerization conditions to form the hydroxy acetonide compound of the formula.
- 52
- wherein PEG and w are as above,
- etherifying said hydroxy acetonide with a lower alkyl halide to form a polymeric acetonide of the formula
- 53
- wherein PEG, R and w are as above,
- and thereafter hydrolyzing said polymeric acetonide under acid conditions to remove the acetonide group, and thereafter subjecting said hydrolyzed acetonide to oxidation with a periodate oxidizing agent to form said aldehyde.
10 more elements
A process for producing an aldehyde of the formula
- RO—PEG-O—(CH2)z—O—CH2—(CH2)w—CHO
- wherein PEG is a divalent residue of polyethylene glycol resulting from removal of the terminal hydroxy groups, having a molecular weight of from 1,000 to 100,000 Daltons;
- z is an integer of from 2 to 4, and w is an integer of from 2 to 8, preferably 2 to 4;
- from a polymeric acetonide of the formula
- 54
- wherein PEG, R, w and z are as above.
- and thereafter hydrolyzing said polymeric acetonide under acid conditions to remove the acetonide group, and thereafter subjecting said hydrolyzed acetonide to oxidation with a periodate oxidizing agent to form said aldehyde.
4 more elements
Dependencies are inferred from the claim text.