CA2457876A1 - Process for the preparation of activated polyethylene glycols - Google Patents

Process for the preparation of activated polyethylene glycols Download PDF

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Publication number
CA2457876A1
CA2457876A1 CA002457876A CA2457876A CA2457876A1 CA 2457876 A1 CA2457876 A1 CA 2457876A1 CA 002457876 A CA002457876 A CA 002457876A CA 2457876 A CA2457876 A CA 2457876A CA 2457876 A1 CA2457876 A1 CA 2457876A1
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group
polyethylene glycol
chr1
activated polyethylene
containing heterocyclic
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CA002457876A
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French (fr)
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CA2457876C (en
Inventor
Marie-Pierre Faure
Michel Ibea
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RBA Pharma Inc
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2203/00—Applications
    • C08L2203/02—Applications for biomedical use

Abstract

The present invention relates to a process for the preparation of activated polyethylene glycols, or PEG(NPC)2s, comprising reacting polyethylene glycol with an activator while in the presence of an aromatic nitrogen containing heterocyclic base. The process is carried out at temperatures ranging from about 20 to about 30 ~C, more preferably at room temperature, and under stoichiometric conditions.

Claims (36)

1. A process for preparing activated polyethylene glycol comprising reacting a polyethylene glycol (PEG) substrate with an activator, either in the presence or absence of an aromatic nitrogen-containing heterocyclic base, as illustrated by Equation 1 below:
M-(O-CH2-CH2-)n-OM + 2 Y-Q-X + aW-T .fwdarw. Y-Q-O-(CH2-CH2-O)n-Q-Y + aW-T.MX
Equation 1 wherein M-(O-CH2-CH2-)n-OM is the polyethylene glycol substrate;
M is selected from the group consisting of H, Li, Na, K, Rb and Cs;
"n" is an integer ranging from 4 to 800;
Y-Q-X is the activator;
"X" and "Y" are either identical or different and are selected from the group consisting of H, Cl, Br, I, mesylates, tosylates and phenoxides;
"Q" is represented by the following general Formula 1:
Q = (U0)n0-[(Q0)n1(CHR1)n2-(Q1)n3]p-[(R2C-CR3)n4-(Q2)n5]m-[(CHR4)n6-(Q3)n7]q-(U1)n8 Formula 1 wherein Q0, Q1, Q2, and Q3 are either identical or different, and are selected from the group consisting of oxygen and sulfur atoms;
R1, R2, R3, and R4 are either identical or different and are selected from the group consisting of hydrogen atom, lower alkyl, lower branched alkyl, aryl and aralkyl;
n0, n1, n3, n5, n7, and n8 are integers selected from the group consisting of 0 and 1;

n2, n4 and n6 are integers selected such that 0 <= n2 <= 3, 0 <= n4 <= 1, and 0 <= n6 <= 3;
U0 and U1 are either identical or different and are selected from the group consisting of -CO-; -SO2-, and >P=O; and p m and q are integers selected such that 0 <= p <= 6, 0 <=
m <= 2, 0 <= q <= 6, and 0 <=
p + m. ltoreq. 8;
WT is the aromatic nitrogen-containing heterocyclic base;
"a" is an integer ranging from 0 to 6; and Y-O-O-(CH2-CH2-O)n-Q-Y-is the activated polyethylene glycol.
2. A process as defined in claim 1, wherein "n" is an integer preferably ranging from 65 to 800.
3. A process as defined in claim 1, wherein "a" is an preferably ranging from 0 to 2.
4. A process as defined in claim 1, wherein the aromatic nitrogen-containing heterocyclic base has the structure represented by the following general Formula 2:
wherein (NR5R6)c is located either in the ortho or para position; and R5 and R6 are either identical or different and are selected from the group consisting of lower straight alkyl chain, lower branched alkyl chain, aryl group and aralkyl group; and "c" is an integer selected from the group consisting of 0, 1 and 2.
5. A process as defined in claim 4, wherein Q is selected from the group consisting of ~SO2-, -CO(CHR1)t SO2-, -CO-, -SO2(CHR1)t SO2-, -SO2-O-(CHR1)t-O-SO2, >PO, -CO-O-(CHR1)t-CR2=CR3-(CHR4)t-O-CO-, and -SO2-O-(CHR1)t-CR2=CR3-(CHR4)t-O-SO2-, wherein "t" is an integer ranging from 1 to 3 and wherein R1, R2, R3 and R4 are either identical or different and are selected from the group consisting of hydrogen, lower alkyl, lower branched alkyl, aryl and aralkyl.
6. A process as defined in claim 5, wherein R1, R2, R3 and R4 are selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and propyl.
7. A process as defined in claim 6, wherein Q is selected from the group consisting of ~SO2-, -CO-O-CH2-CH=CH-CH2-O-CO-, COCH2SO2-, -CO-, and -SO2CH2CH2SO2-.
8. A process as defined in claim 7, wherein the activator has a structure represented by Cl-CO-O-Ph-NO2.
9. A process as defined in claim 7, wherein the activator has a structure represented by Cl-SO2-O-CH2-CH2-O-SO2-Cl.
10. A process as defined in claim 7, wherein the activator has a structure represented by Cl-SO2-O-CH2-CH2-O-CO-Cl.
11. A process as defined in claim 7, wherein the activator has a structure represented by Cl-CO-O-CH2-CH=CH-CH2-O-CO-Cl.
12. An aromatic nitrogen-containing heterocyclic base as defined in claim 4, wherein R5 or R6 is a solid support.
13. An aromatic nitrogen-containing heterocyclic base as defined in claim 12, wherein R5 or R6 is a solid support used in peptide synthesis.
14. An aromatic nitrogen-containing heterocyclic base as defined in claim 13, wherein R5 or R6 is a solid support selected from the group consisting of amino methyl resin, p-alkoxybenzyl alcohol resin, benzhydrylamine resin, hydroxymethyl resin, 4-hydroxymethyl-benzoyloxymethyl resin, Merrifield resin, Sasrin resin, 4-methyl-benzhydrylamine resin.
15. An aromatic nitrogen-containing heterocyclic base as defined in claim 12, wherein R5 or R6 is a solid support composed of polystyrene-divinylbenzene.
16. An aromatic nitrogen-containing heterocyclic base as defined in claim 12, wherein the base is used as a catalyst in mixtures comprising stoichiometric quantities of a tertiary amine base selected from the group consisting of TEA, TIA, DIEA and 4-methyl morpholine.
17. An aromatic nitrogen-containing heterocyclic base as defined in claim 16, wherein the base is used at reaction temperatures ranging from about 20 to about 30 °C.
18. An aromatic nitrogen-containing heterocyclic base as defined in claim 17, wherein the base is used at room temperature.
19. A process as defined in claim 1, wherein the process is carried out in an organic solvent.
20. A process as defined in claim 19, wherein said organic solvent is an aprotic solvent.
21. A process as defined in claim 20, wherein the aprotic solvent has a boiling point ranging from about 35 °C to about 230 °C.
22. A process as defined in claim 21, wherein said aprotic solvent selected is selected from the group consisting of: DMSO, DMF, acetonitrile, nitromethane, HMPA, acetone, acetic anhydride, pyridine, o-dichlorobenzene, chlorobenzene, benzene, toluene, xylene, methylene chloride, carbon tetrachloride, THF, dioxane, ethyl acetate, DME, and carbon disulfide.
23. A process as defined in claim 22, wherein the organic solvent is methylene chloride.
24. A process as defined in claim 1, wherein said process is carried out at temperatures ranging from about 20 to about 30 °C
under stoichiometric conditions.
25. A process as defined in claim 24, wherein said process is carried out at temperature.
26. An activated polyethylene glycol having a general structure as shown below:
Y-Q-O-(CH2-CH2-O)n-Q-Y
wherein Q is represented by the following general Formula 1:

Q= (U0)n0-[(Q0)n1(CHR1)n2-(Q1)n3]p-[(R2C-CR3)n4-(Q2)n5]m-[(CHR4)n6-(Q3)n7]q-(U1)n8 Formula 1 wherein Q o, Q1, Q2, and Q3 are either identical or different, and are selected from the group consisting of oxygen and sulfur atoms;
R1, R2, R3, and R4 are either identical or different and are selected from the group consisting of hydrogen atom, lower alkyl, lower branched alkyl, aryl and aralkyl;
n0, n1, n3, n5, n7, and n8 are integers selected from the group consisting of 0 and 1;
n2, n4 and n6 are integers selected such that 0 <= n2 <= 3, 0 <= n4 <= 1, and 0 <= n6 <= 3;
U0 and U1 are either identical or different and are selected from the group consisting of -CO-; -SO2-, and >P=O; and p m and q are integers selected such that 0 <= p <= 6, 0 <=
m <= 2, 0 <= q <= 6, and 0 <=
p + m <= 8;
"n" is an integer preferably ranging from 4 to 800 and more preferably ranging from 65 to 800; and "Y" is selected from the group consisting of H, Cl, Br, I, mesylates, tosylates and phenoxides.
27. An activated polyethylene glycol as defined in claim 26, wherein Q is selected from the group consisting of ~SO2-, -CO(CHR1)t SO2-, -CO-, -SO2(CHR1)t SO2-, -SO2-O-(CHR1)t-O-SO2, >PO, -CO-O-(CHR1)t-CR2=CR3-(CHR4)t-O-CO-, and -SO2-O-(CHR1)t-CR2=CR3-(CHR4)t-O-SO2-, wherein "t" is an integer ranging from 1 to 3 and wherein R1, R2, R3 and R4 are either identical or different and are selected from the group consisting of hydrogen, lower alkyl, lower branched alkyl, aryl and aralkyl.
28. An activated polyethylene glycol as defined in claim 27, wherein Q is selected from the group consisting of -SO2-, -CO-O-CH2-CH=CH-CH2-O-CO-, COCH2SO2-, -CO-, and -SO2CH2CH2SO2-.
29. An activated polyethylene glycol as defined in claim 28, having the structure shown below by Formula 4:
wherein "n" is an integer ranging from 4 to 800.
30. An activated polyethylene glycol as defined in claim 28, having the structure shown below by Formula 5:
wherein "n" is an integer ranging from 4 to 800.
31. An activated polyethylene glycol as defined in claim 28, having the structure shown below by Formula 6:
wherein "n" is an integer ranging from 4 to 800.
32. An activated polyethylene glycol as defined in claim 28, having the structure shown below by Formula 7:
wherein "n" is an integer ranging from 4 to 800.
33. An activated polyethylene glycol as defined in any one of claims 26 to 32, having a molecular weight ranging from 200 to 35 000 Da.
34. An activated polyethylene glycol as defined in claim 33, susceptible of reacting with functional groups selected from the group consisting of hydroxyl groups, amine groups and thiol groups, resulting in the formation of bio-polymers.
35. An activated polyethylene glycol as defined in claim 34, wherein said functional groups are derived from the group consisting of peptides, proteins, saccharides, polysaccharides, and oligonucleotides.
36. An activated polyethylene glycol as defined in claim 34, wherein the bio-polymers are used in chemical, food, cosmetical, cosmeceutical, pharmaceutical and dermopharmaceutical applications.
CA2457876A 2001-08-22 2002-08-22 Process for the preparation of activated polyethylene glycols Expired - Fee Related CA2457876C (en)

Applications Claiming Priority (3)

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US31380101P 2001-08-22 2001-08-22
US60/313,801 2001-08-22
PCT/CA2002/001306 WO2003018665A1 (en) 2001-08-22 2002-08-22 Process for the preparation of activated polyethylene glycols

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CA2457876C CA2457876C (en) 2011-10-11

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US (1) US7125558B2 (en)
EP (1) EP1419191B1 (en)
AT (1) ATE376020T1 (en)
CA (1) CA2457876C (en)
DE (1) DE60223047T2 (en)
WO (1) WO2003018665A1 (en)

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Publication number Priority date Publication date Assignee Title
WO2005085322A1 (en) * 2004-03-05 2005-09-15 Bioartificial Gel Technologies Inc. Process for the preparation of activated polyethylene glycols

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EP1419191A1 (en) 2004-05-19
EP1419191B1 (en) 2007-10-17
DE60223047D1 (en) 2007-11-29
US7125558B2 (en) 2006-10-24
WO2003018665A1 (en) 2003-03-06
ATE376020T1 (en) 2007-11-15
DE60223047T2 (en) 2008-07-24
US20050080206A1 (en) 2005-04-14
CA2457876C (en) 2011-10-11

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