# US 7,612,153 B2 · Heterobifunctional poly(ethylene glycol) and uses thereof

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- Number: US 7,612,153 B2
- Document ID: US7612153B2
- Status: Granted
- Kind: B2
- Application number: 11/256,735
- Filed: 2005-10-24
- Published: 2006-06-29
- Granted: 2009-11-03
- Earliest claimed: 2004-10-25
- Assignees: Intezyne Technologies, Inc.
- Inventors: Kurt Breitenkamp; Kevin Sill; Habib Skaff
- Web page: https://patentgrep.com/patent/US7612153B2

## CPC

- C07C 323/12: the carbon skeleton being acyclic and saturated
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- C07C 67/08: by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
- C07C 67/31: by introduction of functional groups containing oxygen only in singly bound form
- C07C 69/76: Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C 69/92: with etherified hydroxyl groups
- C07C 205/34: having nitro groups bound to carbon atoms of six-membered aromatic rings and etherified hydroxy groups bound to acyclic carbon atoms of the carbon skeleton
- C07C 213/08: by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
- C07C 247/10: and containing rings
- C07C 271/16: to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
- C07C 319/14: of sulfides
- C07D 207/452: with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
- C07D 209/48: with oxygen atoms in positions 1 and 3, e.g. phthalimide
- C07D 213/71: to which a second hetero atom is attached
- C07F 7/1892: {by reactions not provided for in C07F7/1876 - C07F7/1888}
- C08G 65/2612: {containing aromatic or arylaliphatic hydroxyl groups}
- C08G 65/2627: {containing aromatic or arylaliphatic amine groups}
- C08G 65/329: with organic compounds
- C08G 65/33337: {cyclic}
- C08G 65/33396: {having oxygen in addition to nitrogen}
- C08L 2203/02: for biomedical use
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)

## Abstract

The present invention provides bifunctional polymers, methods of preparing the same, and intermediates thereto. These compounds are useful in a variety of applications including the PEGylation of biologically active molecules. The invention also provides methods of using said compounds and compositions thereof.

## Claims

### Claim 1

A compound of formula I′:
wherein:
n is 10-2500;
R1 is —X(CH2CH2Y)m(CH2)n′R3, wherein:
X is —O—, —S—, —C≡C—, or —CH2—;
each Y is independently —O— or —S—;
m is 0-10;
n_′ is 0-10; and
R3 is —N3, —CN, a mono-protected amine, a di-protected amine, a protected aldehyde, a protected hydroxyl, a protected carboxylic acid, a protected thiol, a 9-30 membered crown ether, or an optionally substituted group selected from aliphatic, a 5-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a detectable moiety;
R2 is halogen, N3, CN, a mono-protected amine, a di-protected amine, a protected hydroxyl, a protected aldehyde, a protected thiol, —NHR4, —N(R4)2, —SR4, —O(CH2CH2O)q(CH2)rR5, —OC(O)R4, or —OS(O)2R4;
q and r are each independently 0-4;
each R4 is independently an optionally substituted group selected from aliphatic, a 5-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10-membered saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a detectable moiety, or:
two R4 on the same nitrogen atom are taken together with said nitrogen atom to form an optionally substituted 4-7 membered saturated, partially unsaturated, or aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
R5 is hydrogen, halogen, N3, CN, a mono-protected amine, a di-protected amine, a protected aldehyde, a protected hydroxyl, a protected carboxylic acid, a protected thiol, or an optionally substituted group selected from aliphatic, a 5-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a detectable moiety,
provided that:
(a) when either of R1 or R2 is (EtO)2CH—, then the other of R1 or R2 is not —S—S-pyridin-2-yl, —OBn, —OC(O)C(CH3)═CH2, or —OC(O)CH═CH—CH═CH-Ph;
(b) when either of R1 or R2 is —OBn, the other is not —OC(O)Cl;
(c) R1 and R2 are not simultaneously —OC(O)CH═CH2;
(d) when either of R1 or R2 is —CN, then the other is not -phthalimido; and
(e) when either of R1 or R2 is acetyl, then the other is not —CN or -phthalimido.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein the R1 and R2 groups of formula I′ are different from each other.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R3 is an optionally substituted group selected from aliphatic or aryl.

### Claim 4 (depends on 3)

The compound according to claim 3, wherein R3 is an aliphatic group substituted with one or more groups independently selected from CN, N3, trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, N-methyl propiolamido, N-methyl-4-acetylenylanilino, N-methyl-4-acetylenylbenzoamido, bis-(4-ethynyl-benzyl)-amino, dipropargylamino, di-hex-5-ynyl-amino, di-pent-4-ynyl-amino, di-but-3-ynyl-amino, propargyloxy, hex-5-ynyloxy, pent-4-ynyloxy, di-but-3-ynyloxy, N-methyl-propargylamino, N-methyl-hex-5-ynyl-amino, N-methyl-pent-4-ynyl-amino, N-methyl-but-3-ynyl-amino, 2-hex-5-ynyldisulfanyl, 2-pent-4-ynyldisulfanyl, 2-but-3-ynyldisulfanyl, or 2-propargyldisulfanyl.

### Claim 5 (depends on 3)

The compound according to claim 3, wherein R3 is an aryl group substituted with one or more groups independently selected from CN, N3, NO2, —CH3, —CH2N3, —CH═CH2, —C≡CH, Br, I, F, bis-(4-ethynyl-benzyl)-amino, dipropargylamino, di-hex-5-ynyl-amino, di-pent-4-ynyl-amino, di-but-3-ynyl-amino, propargyloxy, hex-5-ynyloxy, pent-4-ynyloxy, di-but-3-ynyloxy, 2-hex-5-ynyloxy-ethyldisulfanyl, 2-pent-4-ynyloxy-ethyldisulfanyl, 2-but-3-ynyloxy-ethyldisulfanyl, 2-propargyloxy-ethyldisulfanyl, bis-benzyloxy-methyl, [1,3]dioxolan-2-yl, or [1,3]dioxan-2-yl.

### Claim 6 (depends on 2)

The compound according to claim 2, wherein R3 is a group suitable for Click chemistry.

### Claim 7 (depends on 6)

The compound according to claim 6, wherein R3 is an azide-containing group or an alkyne-containing group.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein said compound has a polydispersity index of about 1.0 to about 1.2.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein n is about 200 to about 250.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein n is about 100 to about 150.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein n is about 400 to about 500.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein said compound is selected from the group consisting of:

### Claim 13 (depends on 1)

The compound according to claim 1, wherein R3 is a mono-protected or di-protected amino group.

### Claim 14 (depends on 13)

The compound according to claim 13, wherein R3 is a mono-protected amino group.

### Claim 15 (depends on 14)

The compound according to claim 14, wherein R3 is a mono-protected amino group selected from t-butyloxycarbonylamino, ethyloxycarbonylamino, methyloxycarbonylamino, trichloroethyloxy-carbonylamino, allyloxycarbonylamino, benzyloxocarbonylamino, allylamino, benzylamino, fluorenylmethylcarbonyl, formamido, acetamido, chloroacetamido, dichioroacetamido, trichloroacetamido, phenylacetamido, trifluoroacetamido, benzamido, and t-butyldiphenylsilylamino.

### Claim 16 (depends on 13)

The compound according to claim 13, wherein R3 is a di-protected amino group.

### Claim 17 (depends on 16)

The compound according to claim 16, wherein R3 is a di-protected amino group selected from di-benzylamine, di-allylamine, phthalimide, maleimide, succinimide, pyrrole, 2,2,5,5-tetramethyl-[1,2,5]azadisilolidine, and azide.

### Claim 18 (depends on 13, 14, 15, 16, 17)

The compound according to any one of claims 13-17, wherein R2 is —OS(O)2R4, wherein R4 is an optionally substituted aliphatic group, or an optionally substituted 5-8-membered aryl ring.

### Claim 19 (depends on 18)

The compound according to claim 18, wherein R2 is p-toluenesulfonyloxy or methanesulfonyloxy.

### Claim 20 (depends on 13, 14, 15, 16, 17)

The compound according to any one of claims 13-17, wherein R2 is a group suitable for Click chemistry.

### Claim 21 (depends on 20)

The compound according to claim 20, wherein R2 is —N3.

### Claim 22 (depends on 1)

The compound according to claim 1, wherein R2 is selected from the group consisting of:

### Claim 23 (depends on 1)

The compound according to claim 1, wherein R1 is selected from the group consisting of:
R1 Groups
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
t
u
v
w
x
y
z
aa
bb
cc
dd
ee
ff
gg
hh
ii
jj
kk
ll
mm
nn
oo
pp
qq
rr
ss
tt
uu
vv
ww
xx
yy
zz
aaa
bbb
ccc
ddd
eee
fff
ggg
hhh
iii
jjj
kkk
lll
mmm
nnn
ooo
ppp
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rrr
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and uuu.