Water-soluble polymer alkanals
View Patent ↗The present invention is directed to alkanal derivatives of water-soluble polymers such as poly(ethylene glycol), their corresponding hydrates and acetals, and to methods for preparing and using such polymer alkanals. The polymer alkanals of the invention are prepared in high purity and exhibit storage stability.
1. A polymer conjugate having the structure:
where
“NH-biologically active agent” represents a biologically active agent comprising from 1 to 5 amino groups;
POLY is a water-soluble polymer segment;
X′ is a linker moiety;
z′ is an integer from 3 to 12;
R 1 , in each occurrence, is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl;
R 2 , in each occurrence, is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl,
and further where the following apply:
when POLY is linear:
(a) the total number of carbonyls present in said polymer is 0 or 2 or greater except when X′ comprises one or more contiguous (—CH 2 CH 2 O—) segments,
(b) and further wherein X′ is oxygen or comprises at least one (—CH 2 CH 2 O—) segment, then at least one of R 1 or R 2 in at least one occurrence is an organic radical as defined above or said polymer is heterobifunctional, where POLY comprises a reactive group at one terminus that is not hydroxy, and
when POLY is branched:
(c) either (i) at least one of R 1 or R 2 in at least one occurrence is an organic radical as defined above or (ii) X′ includes —(CH 2 CH 2 O) b — where b is from 1 to about 20 in the instance where POLY comprises a lysine residue,
(d) and further wherein said POLY has 2 polymer arms, then neither polymer arm comprises oxygen as the only heteroatom in the instance where POLY comprises “C—H” as a branch point.
2. The polymer conjugate of claim 1 , having the structure:
where:
“NH-biologically active agent” represents a biologically active agent comprising from 1 to 3 amino groups and the remaining variables are as previously defined.
3. The polymer conjugate of claim 1 , wherein the biologically active agent is selected from the group consisting of small molecules, polypeptides, proteins, nucleotides, oligonucleotides, and polynucleotides.
4. The polymer conjugate of claim 3 , wherein the biologically active agent is a protein.
5. The polymer conjugate of claim 4 , wherein at least one “—NH— biologically active agent” represents the N-terminus of said protein.
6. The polymer conjugate of claim 1 having the structure:
wherein POLY, X′, each R 1 , each R 2 and R 3 are as previously defined.
7. The polymer conjugate of claim 6 , wherein the R 1 attached to C 2 is alkyl, and all other R 1 and R 2 variables are H.
8. The polymer conjugate of claim 7 , wherein the R 1 attached to C 2 is lower alkyl.
9. The polymer conjugate of claim 1 , wherein X′ comprises a moiety corresponding to the structure:
—(CH 2 ) c -D e -(CH 2 ) f — or —(CH 2 ) p -M r -C(O)—K s —(CH 2 ) q —
wherein:
c is zero to 8,
D is O, NH, or S,
e is 0, 1
f is zero to 8,
p is zero to 8,
M is —NH, O
K is NH, O
q is from zero to 8, and
r and s are each independently 0, 1.
10. The polymer conjugate of claim 1 , wherein X′ includes a moiety corresponding to the structure —CH 2 CH 2 O) b — or —(CH 2 CH 2 NH) g —, and b and g are each independently an integer ranging from 1 to 20.
11. The polymer conjugate of claim 1 , wherein said X′ comprises —C (O)NH—(CH 2 ) 1-6 NH—C(O)— or —NHC(O)NH—(CH 2 ) 1-6 NH—C(O)—.
12. The polymer conjugate of claim 1 , wherein POLY is selected from the group consisting of poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, poly(acryloylmorpholine), and poly(oxyethylated polyol).
13. The polymer conjugate of claim 12 , wherein POLY is a poly(ethylene glycol).
14. The polymer conjugate of claim 12 , wherein the poly(ethylene glycol) is terminally capped with an end-capping moiety.
15. The polymer conjugate of claim 13 , wherein the poly(ethylene glycol) has a nominal average molecular mass of from about 100 daltons to about 100,000 daltons.
16. The polymer conjugate of claim 13 , wherein said poly(ethylene glycol) has a structure selected from the group consisting of linear, branched and forked.
17. The polymer conjugate of claim 14 , having, a structure selected from the group consisting of:
wherein PEG is terminally-capped poly(ethylene glycol), b and g are each independently an integer ranging from 0 to 20, a is an integer ranging from 0 to 6, and the remaining variables are as previously defined.
18. The polymer conjugate of claim 17 , having the structure:
wherein the variables are as previously defined.
19. The polymer conjugate of claim 17 , having the structure:
20. The polymer conjugate of claim 19 , wherein “PEG” is a poly(ethylene glycol) having a structure corresponding to:
wherein n in each occurrence is independently an integer ranging from about 10 to about 4000, and Z is a moiety selected from the group consisting of hydroxy, ester, carbonate, aldehyde, alkenyl, acrylate, methacrylate, acrylamide, sulfone, thiol, carboxylic acid, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, alkoxy, benzyloxy, silane, phospholipid, biotin, and fluorescein.
21. The polymer conjugate of claim 20 , wherein Z is alkoxy, and n in each occurrence is the same and is an integer ranging from about 100-600.