Source: http://www.patentsencyclopedia.com/app/20130059970
Timestamp: 2016-07-31 02:55:54
Document Index: 639905160

Matched Legal Cases: ['Application No.\n61', '§119', 'Application No. 1115107', 'Application No.\n1119365', '§119', 'art 2']

BIOCOMPATIBLE MATERIAL - Patent application
Patent application title: BIOCOMPATIBLE MATERIAL
Michael Driver (Basingstoke, GB)
Brian Tarbit (Ashington, GB)
Alexander Gehre (Basingstoke, GB)
IPC8 Class: AC07F9572FI
Patent application number: 20130059970
Monomers of formula (I) which include a vinyl group, polymers and
articles, such as contact lenses, made therefrom, all of which are
biocompatible, are described.Claims:
1. A monomer of formula (I): ##STR00061## wherein: W is
(CR.sup.1.sub.2)n; X is O, S or NR2; Y is a linker group; Z is
a zwitterionic group; each R1 is independently selected from H,
halogen or C1-4 alkyl; R2 is H or C1-4 alkyl; n is an
integer from 0 to 6; and m is an integer from 0 to 6.
2. The monomer of claim 1, wherein Y is selected from the group
consisting of C1-10 alkylene, C2-10 alkenylene, C2-10
alkynylene, C3-10 cycloalkylene, C3-10 cycloalkenylene,
C1-10 heteroalkylene, C2-10 heteroalkenylene, C2-10
heteroalkynylene, arylene, heteroarylene, --C(O)--, --C(S)--, --C(O)O--,
--C(O)S--, --C(O)N(RM)--, --C(S)--, --C(S)O--, --C(S)S-- and
--C(S)N(RM)--, wherein RM is hydrogen or C1-4 alkyl and
wherein the alkylene, alkenylene, alkynylene, cycloalkylene,
cycloalkenylene, heteroalkylene, heteroalkenylene, heteroalkynylene,
arylene and heteroarylene groups may be optionally substituted with one
or more RN, wherein each RN is independently selected from the
group consisting of --H, --OH, --CN, --NO2, --CF3, --OCF3,
--CO2H, --NH2, C1-C10 alkyl, C2-C10
alkenyl, C2-C10 alkynyl, --O(C1-C10 alkyl),
--O(C2-C10 alkenyl), --O(C2-C10 alkynyl), halogen,
--C(O)H, --C(O)--(C1-C10 alkyl), --C(O)--O(C1-C10
alkyl), --NH(C1-C10 alkyl), --N(C1-C10 alkyl)2,
--C(O)--NH(C1-C10 alkyl), --C(O)--N(C1-C0
alkyl)2, --NH--C(O)--(C1-C10 alkyl), --NH(C1-C10
alkyl)-C(O)--(C1-C10 alkyl),
--NH--S(O)2--(C1-C10 alkyl), --NH--(C1-C10
alkyl)-S(O)2--(C1-C10 alkyl), --(C0-C10)--SH,
--S(O)--(C1-C10 alkyl), --S(O)2--(C1-C10 alkyl),
--S(O)2--NH2, --S(O)2--NH--(C1-C10 alkyl),
--S(O)2--N(C1-C10 alkyl)2 and ═O.
3. The monomer of claim 1, wherein X is O.
4. The monomer of claim 1, wherein X is NR.sup.2.
5. The monomer of claim 4, wherein R2, Y and the N atom to which
they are bonded taken together form a 5 to 7 membered heterocyclic ring,
wherein the heterocyclic ring may be optionally substituted with one or
more RN, wherein each RN is independently selected from the
--C(O)--NH(C1-C10 alkyl), --C(O)--N(C1-C10
6. The monomer of claim 5, wherein R2, Y and the N atom to which
they are bonded taken together from a 5-membered heterocyclic ring.
7. The monomer of claim 6, wherein the 5-membered heterocyclic ring is
substituted with ═O.
8. The monomer of claim 7, which has the formula (IA): ##STR00062##
wherein W, R1, R2 and Z as defined for formula (I).
9. The monomer of claim 8, wherein n is 0.
10. The monomer of claim 1, wherein Y is --C(O)O-- and m is 1 to 4.
11. The monomer of claim 10, wherein m is 2.
12. The monomer of claim 1, wherein m is 0.
13. The monomer of claim 1, wherein Z is a zwitterionic group selected
from the group consisting of (IIA), (IIB), (IIC), (IID) and (IIE),
wherein group (IIA) has the formula: ##STR00063## wherein each R3
and R3A is independently selected from hydrogen and C1-4 alkyl
and a is an integer from 2 to 4; group (IIB) has the formula:
##STR00064## wherein each R4 and R4A is independently selected
from hydrogen and C1-4 alkyl and b is an integer from 1 to 4; group
(IIC) has the formula: ##STR00065## wherein each R5 and R5C
is independently selected from hydrogen and C1-4 alkyl; R5A is
hydrogen or a group --C(O)B1R5B, wherein R5B is hydrogen
or methyl, B' is selected from the group consisting of a bond; C1-10
alkylene, C2-10 alkenylene, C2-10 alkynylene, C3-10
cycloalkylene, C3-10 cycloalkenylene, C1-10 heteroalkylene,
C2-10 heteroalkenylene, C2-10 heteroalkynylene, arylene,
heteroarylene, --C(O)RM--, --C(O)ORM--, wherein RM is
selected from the group consisting of C1-10 alkylene, C2-10
alkenylene and C2-10 alkynylene, and wherein the alkylene,
alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heteroalkylene,
heteroalkenylene, heteroalkynylene, arylene and heteroarylene groups may
be optionally substituted with one or more RN, wherein each RN
is independently selected from the group consisting of --H, --OH, --CN,
--NO2, --CF3, --OCF3, --CO2H, --NH2,
C1-C10 alkyl, C2-C10 alkenyl, C2-C10
alkynyl, --O(C1-C10 alkyl), --O(C2-C10 alkenyl),
--O(C2-C10 alkynyl), halogen, --C(O)H,
--C(O)--(C1-C10 alkyl), --C(O)--O(C1-C10 alkyl),
--NH(C1-C10 alkyl), --N(C1-C10 alkyl)2,
alkyl)2, --NH--C(O)--(C1-C0 alkyl), --NH(C1-C10
--S(O)--(C1-C10 alkyl), --S(O)2--(C1-C0 alkyl),
--S(O)2--N(C1-C10 alkyl)2 and ═O, and c is an
integer from 1 to 4, wherein if Z is directly bonded to an O or N atom, z
is O and otherwise z is 1; group (IID) has the formula: ##STR00066##
wherein each R6 and R6C is independently selected from hydrogen
and C1-4 alkyl; R6A is hydrogen or a group
--C(O)B2R6B, wherein R6B is hydrogen or methyl, B2 is
selected from the group consisting of a bond; C1-10 alkylene,
C2-10 alkenylene, C2-10 alkynylene, C3-10 cycloalkylene,
C3-10 cycloalkenylene, C1-10 heteroalkylene, C2-10
heteroalkenylene, C2-10 heteroalkynylene, arylene, heteroarylene,
--C(O)RM--, --C(O)ORM--, wherein RM is selected from the
group consisting of C1-10 alkylene, C2-10 alkenylene and
C2-10 alkynylene, and wherein the alkylene, alkenylene, alkynylene,
cycloalkylene, cycloalkenylene, heteroalkylene, heteroalkenylene,
heteroalkynylene, arylene and heteroarylene groups may be optionally
substituted with one or more RN, wherein each RN is
independently selected from the group consisting of --H, --OH, --CN,
--C(O)--NH(C1-C10) alkyl), --C(O)--N(C1-C10
--S(O)2--N(C1-C10 alkyl)2 and ═O, and d is an
is O and otherwise z is 1; group (IIE) has the formula: ##STR00067##
wherein each R7 and R7C is independently selected from hydrogen
and C1-4 alkyl; R7A is hydrogen or a group
--C(O)B2R7B, wherein R7B is hydrogen or methyl, B2 is
--S(O)2--N(C1-C10 alkyl)2 and ═O, and e is an
is O and otherwise z is 1;
14. The monomer of claim 13, wherein Z is a group (IIB).
15. The monomer of claim 14, wherein R4 is methyl and b is 2.
16. The monomer of claim 1, wherein n is O or 1.
17. The monomer of claim 16, wherein n is 0.
18. The monomer of claim 1, wherein n is 0; X is NR2; Y, R2 and
the N atom to which they are bonded together form a 5-membered
heterocyclic ring substituted with ═O; x is 2; and Z is a group of
formula (IIB), wherein each R4 is methyl and b is 2.
19. The monomer of claim 1 of formula (IB): ##STR00068## wherein W, X
and Z, R1, R2, n and m are as defined in connection with
formula (I) in claim 1, V is S or O; and A is selected from NRM, O
and S, wherein RM is hydrogen or C1-4 alkyl.
20. The monomer of claim 1 of formula (IC): ##STR00069## wherein W, X,
Y, R1, R2, m and n are as defined in claim 1, each R4 and
R4A is independently selected from hydrogen and C1-4 alkyl and
21. The monomer of claim 1 of formula (ID): ##STR00070## wherein W is
as defined in connection with formula (I), each R4 and R4A is
independently selected from hydrogen and C1-4 alkyl and b is an
integer from 1 to 4.
22. The monomer of claim 1, which has formula (IE): ##STR00071##
wherein W is as defined in connection with formula (I), each R4 and
23. A polymer obtainable by reacting the monomer of claim 1 with a
co-monomer system.
24. The polymer of claim 23, wherein the co-monomer system comprises a
siloxane group-containing monomer or macromer.
25. The polymer of claim 24, wherein the siloxane group-containing
monomer is a material of formula (A) or (B):
(T1-Y)k-G1(Y2--Z)1 (A)
[(T1)k-Y3(Z)u]v-G1-R24 (B) wherein
T1 is a polymerisable group; Y1 and Y2 are each
independently a linker group selected from the group consisting of a
bond, C1-12 alkylene, C2-12 alkenylene, C2-12 alkynylene,
C3-12 cycloalkylene, C3-12 cycloalkenylene, C2-12
heteroalkenylene, C2-12 heteroalkynylene, arylene, heteroarylene,
--C(O)--C1-12 alkylene, --C(S)--C1-12 alkylene,
--C(O)O--C1-12 alkylene, --C(O)S--C1-12 alkylene,
--C(O)N(RM)--C1-12 alkylene, --C(S)--C1-12 alkylene,
--C(S)O--C1-12 alkylene, --C(S)S--C1-12 alkylene,
--C(S)N(RM)--C1-12 alkylene,
--(CH2)qq(OCH2CH2)rr-- and
--(CH2CH2O)rr(CH2)qq--, wherein RM is
hydrogen or C1-4 alkyl, qq is an integer from 1 to 10, rr is an
integer from 1 to 10, wherein one or more carbon atoms in the C1-12
alkylene group may be optionally replaced with a heteroatom selected from
the group consisting of S and O and the alkylene, alkenylene, alkynylene,
cycloalkylene, cycloalkenylene, heteroalkenylene, heteroalkynylene,
alkyl)-C(O)--(C1-C10 alkyl), --NH--S(O)2--(C1-C0
alkyl), --NH--(C1-C10 alkyl)-S(O)2--(C1-C10
alkyl), --(C0-C10)--SH, --S(O)--(C1-C10 alkyl),
--S(O)2--(C1-C10 alkyl), --S(O)2--NH2,
--S(O)2--NH--(C1-C10 alkyl),
--S(O)2--N(C1-C10 alkyl)2 and ═O; Y3 is a
linker group; R24 is a C1-12 alkyl group which may be
optionally substituted with one or more RN; G1 is a siloxane
group-containing component; Z is a zwitterionic group; k is an integer
from 1 to 10; l is an integer from 1 to 3; u is an integer from 1 to 3;
and v is an integer from 1 to 3.
26. The polymer of claim 25, wherein the co-monomer system comprises a
monomer comprising a vinyl group.
27. The polymer of claim 25, which has an oxygen permeability of about 30
barriers or more.
28. The polymer of claim 25, which has an equilibrium water content in
the range from 30 to 50%.
29. The polymer of claim 25, which has a modulus of less than 3 MPa.
30. An article comprising the polymer of claim 25.
31. The article of claim 30, which is an ophthalmic lens.
32. The article of claim 31, which is a contact lens.
33. An article comprising a surface having coated thereon the polymer of
34. The article of claim 33, which is a contact lens.
35. A method of coating an article having a surface comprising applying
the polymer of claim 25 to the surface of the article.Description:
No. 61/530,120, filed Sep. 1, 2011, and U.S. Provisional Application No.
61/558,066, filed Nov. 10, 2011, under 35 U.S.C. §119(e), and UK
Application No. 1115107.3, filed on Sep. 1, 2011, and UK Application No.
1119365.3, filed on Nov. 10, 2011, under 35 U.S.C. §119(a), the
disclosures of each of which are incorporated by reference herein in
[0002] This invention relates to biocompatible materials, in particular
monomers and polymers and articles formed therefrom. The materials of the
present invention are useful for either coating surfaces of devices or
for forming devices from bulk materials where improved biocompatibility
is a requirement, for instance where protein adsorption is a concern. The
materials are particularly useful in the manufacture of ophthalmic
devices, such as contact lenses.
[0003] Materials used in the manufacture of devices which are to be used
in contact with protein-containing or biological fluids are selected on
the basis of acceptable chemical, physical and mechanical properties and
compatibility with the protein-containing or biological fluid. However,
it is often difficult to optimise all of these properties simultaneously
and so a compromise must be reached which often results in sub-optimal
performance. An example is in the manufacture of contact lenses and
intraocular lenses which will, in use, be in contact with biological
fluids. In particular, contact lenses will be in contact with tear
components. The adsorption of tear components onto contact lenses results
in deposit formation which is problematic.
[0004] In order to avoid these problems occurring, the focus has been on
the provision of biocompatible materials which can either be used to coat
or form the bulk of such devices to discourage protein adsorption.
Biocompatible materials should be capable of reproducible manufacture, be
capable of being coated onto surfaces or processed into a suitable form
without being degraded or adversely changed, have the requisite
mechanical and permeability properties required for the particular
application for which they are to be used, be sterilisable without
adverse changes in, for example, permeability and mechanical or surface
properties, be not damaged or degraded by the biological environment and
not be carcinogenic. It is important that such materials do not provoke
an unwanted biological response.
[0005] An area where biocompatible materials are particularly important is
in the manufacture of ocular devices, in particular ophthalmic lenses, in
particular contact lenses. This is a key example of a situation where a
balance of different properties is required.
[0006] Historically, early contact lenses were formed from
polymethylmethacrylate which were rigid and allowed very little oxygen
through to the cornea. Later, lenses incorporating silicones were made
which had improved gas permeability The hydrophobic nature of silicone
materials meant that the lenses were easily fouled with tear film
components and in certain cases had a tendency to stick to the eye.
Furthermore, while lenses formed from such silicones have a high oxygen
permeability, the low water content of such materials means that they can
be uncomfortable for the wearer. Hence, the focus then shifted to
hydrogel systems for the development of more comfortable lenses. Examples
of hydrogel systems are those comprising hydroxyethyl methacrylate
(HEMA), vinyl pyrrolidone and methacrylic acid or combinations thereof.
Such hydrogel systems have a much higher water content than the original
rigid gas permeable silicone lenses, and are more conformable and
generally less prone to fouling and on-eye dehydration and so are more
comfortable for the wearer. However, the oxygen permeability of these
materials is not as high as it is for silicones which can increase the
risk of corneal damage. In this regard, the oxygen permeability of these
lenses may be regarded as adequate for daily use but less suitable for
[0007] Therefore, more recent research, has been focused on balancing the
oxygen permeability associated with silicone materials, with the water
content and hydrophilicity (and hence comfort) associated with hydrogel
systems. This has led to the development of a class of materials known as
silicone hydrogels in which hydrophobic silicone monomers are combined
with hydrophilic materials without resulting phase separation which can
cause the derived polymer to become translucent or opaque. However, as
the contact lenses will be in contact with the surface of the eye, it is
also of utmost importance that the silicone hydrogels used to form
contact lenses do not elicit any unwanted biological response. As
silicone materials are inherently hydrophobic this is a particular
challenge because hydrophobicity can cause break up of the tear film on
the eye and to surface fouling, both of which can lead to discomfort.
Hence, there is a need for biocompatible materials which balance
biocompatibility with both high gas, in particular oxygen, permeability
and provide a suitably wettable surface
[0008] As described above, polymerisable vinyl components, such as
2-hydroxyethylmethacrylate and N-vinyl pyrrolidone, have been used to
manufacture ophthalmic lenses, and much effort has been devoted to
copolymerise such vinyl systems with co-monomers to produce lens
materials with improved properties. In particular,
2-(methacryloyloxyethyl)-2'(trimethylammonium ethyl)phosphate, inner salt
(MPC, hydroxyethyl methacrylate-phosphorylcholine, HEMA-PC), has been
used to form biocompatible polymers. These materials contain a
zwitterionic phosphorylcholine (PC) group and the biocompatibility of
these materials is derived from the fact that this PC group mimics the
zwitterionic structure of phospholipids such as phosphatidylcholine and
sphingomyelin which are the major components of the outer membrane of all
living cells. Contact lens materials incorporating MPC have been shown to
possess beneficial properties, including reduced dehydration on eye and
reduced deposition of tear film components. More generally, polymers
containing zwitterionic groups have been shown to improve
biocompatability by reducing protein deposition, blood activation,
inflammatory reactions, bacterial adhesion and inhibiting biofilm
[0009] A disadvantage of MPC is that is it a solid which has very limited
solubility. This places limitations on the utility of MPC as a component
in lens formulations.
[0010] Furthermore, while MPC has been shown to react with other
methacrylate compounds to form co- and ter-polymer systems, the reactions
with the other vinyl systems have not been straightforward. This is a
consequence of the mismatch in the relative reactivity rates of
methacrylate groups and vinyl groups, in addition to the insolubility of
MPC in other comonomers In this regard, it has been found that where a
mixture of vinyl and methacrylate monomers is polymerised, it will
predominantly result in mixtures of polymer derivatives comprising either
methacrylate components or vinyl components.
[0011] There is a need for new biocompatible materials. In particular,
there is a need for materials which impart biocompatibility suitable for
the synthesis of biocompatible polymers, particularly biocompatible
polymers further comprising residues derived from vinyl co-monomers.
Additionally, there is a need for biocompatible monomers which have an
improved solubility in, and/or reaction rates comparable with, vinyl
monomers, suitable for the synthesis of biocompatible copolymers,
particularly biocompatible copolymers useful in the manufacture of
devices which are in contact with protein-containing solutions and
biological fluids, such as ocular devices, such as contact lenses.
[0012] In the field of ocular devices and contact lenses specifically,
there is also a need for biocompatible materials which, when formed into
such devices, exhibit both a high gas permeability and a wettable
[0013] The present invention provides ethylenically unsaturated monomers
which include both a terminal vinyl group and a zwitterionic group.
[0014] Various embodiments of the invention are described herein. It will
be recognised that features specified in each embodiment may be combined
with other specified features to provide further embodiments.
[0015] In this regard, in a first aspect, the present invention provides a
monomer of formula (I):
wherein: [0016] W is (CR12)n;[0017] X is O, S or
NR2;[0018] Y is a linker group;[0019] Z is a zwitterionic group;
[0020] each R1 is independently selected from H, halogen, C1-4
alkyl or C1-4 haloalkyl;[0021] R2 is H or C1-4 alkyl;
[0022] n is an integer from 0 to 6; and[0023] m is an integer from 0 to
[0024] Advantageously, the monomers of the present invention include both
a zwitterionic functionality, to provide improved biocompatibility, and a
vinyl group. The presence and nature of the vinyl group means that, where
the monomers are to be used in a copolymerisation, a range of comonomers
become suitable co-reactants, with better matched reactivity, in
particular vinyl comonomers, such as N-vinyl pyrrolidone and
N-vinylcarbamates which are already known to be useful in the manufacture
of ocular devices, such as contact lenses. The monomers of the present
invention, having increased solubility in co-monomer systems can be
copolymerized with such co-monomer systems which include siloxane
co-monomers to form polymers which are particularly useful for forming
ocular devices, in particular ophthalmic lenses, in particular contact
lenses. This is a particular advantage as compared to the commonly used
material, MPC, which is known to be of very limited solubility.
[0025] The value of n may be 0, 1, 2, 3, 4, 5 or 6. In a preferred
embodiment, n is 0. In an alternative embodiment, n is 1. In a further
embodiment, n is 2. Where n is 0, the vinyl group is adjacent to the
heteroatom which means that the lone pair of electrons on the heteroatom
can interact with the electrons in the vinyl group which has the effect
of increasing the reactivity of the monomer.
[0026] In one embodiment, R1 is hydrogen. In an alternative
embodiment, R1 is C1-4 alkyl, in particular ethyl or methyl, in
particular methyl. In an alternative embodiment, R1 may be halogen,
in particular fluorine. In an alternative embodiment, R1 may be a
C1-4 haloalkyl group, wherein one or more of the hydrogen atoms in
the alkyl group is substituted with a halogen, in particular fluorine. An
example of a C1-4 haloalkyl group is CF3. Each R1 group
may be the same or different. In one embodiment, the R1 groups are
different. In one embodiment, the R1 groups are the same. For
example, when n is 1, each of the two R1 groups bound to the carbon
atom may be the same or different. Similarly, when n is 2, each of the
four R1 groups may be the same or different. Similarly, when n is 1
and m is 1, each of the four R1 groups may be the same or different.
[0027] In one embodiment, X is O. In alternative embodiment, X is S. In a
further embodiment, X is NR2. In one embodiment, R2 is
hydrogen. In one embodiment, R2 is C1-4 alkyl, in particular
ethyl or methyl, in particular methyl.
[0028] Y is a linker group which forms a link between the heteroatom X and
the (CR12)mZ group in the monomer of formula (I). The
nature of group Y is not particularly limited and in a preferred
embodiment, Y is selected from the group consisting of C1-10
heteroarylene, --C(O)--, --C(S)--, --C(O)O--, --C(O)S--,
--C(O)N(RM)--, --C(S)--, --C(S)O--, --C(S)S-- and
--C(S)N(RM)--, wherein RM is hydrogen or C1-4 alkyl. The
alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene,
heteroalkylene, heteroalkenylene, heteroalkynylene, arylene and
heteroarylene groups may be optionally substituted with one or more
RN, wherein each RN is independently selected from the group
consisting of --H, --OH, --CN, --NO2, --CF3, --OCF3,
[0029] In one embodiment, Y is a C1-10 alkylene, C2-10
alkenylene or C2-10 alkynylene optionally substituted with one or
more RN. In a further embodiment, Y is C1-6 alkylene, C2-6
alkenylene or C2-6 alkynylene optionally substituted with one or
more RN. In a further embodiment, Y is C1-10 alkylene, in one
instance C1-6 alkylene optionally substituted with one or more
[0030] In an alternative embodiment, Y is --C(═V)A-, wherein V is S or
O and A is selected from NRM, O or S, wherein RM is H or
C1-4 alkyl. In particular, in one embodiment, the present invention
provides a monomer of formula (IB):
wherein W, X and Z, R1, R2, n and m are as defined above in
connection with formula (I), V is S or O; and A is selected from
NRM, O and S. Where the monomer of the present invention has formula
(IB), preferably V is O and A is O such that Y as defined in formula (I)
is --C(O)O--.
[0031] In the compounds of formula (I) wherein X is selected from
NR2, then R2, Y and the N atom to which they are bonded taken
together may form a 5 to 7 membered heterocyclic ring optionally
substituted with one or more RN, particularly wherein RN is O.
In particular, R2, Y and the N atom to which they are bonded taken
together form a 5-membered heterocyclic ring be optionally substituted
with one or more RN, particularly wherein RN is O.
[0032] In one embodiment, the monomer has the formula (IA):
wherein W, R1 and Z are as defined above. In one embodiment, the
monomer has the formula (IA), wherein n is O and hence the group W is not
present. In one embodiment, the monomer had the formula (IA), wherein all
R1 are H and m is 2.
[0033] In alternative embodiment, the monomer has the formula (IAA)
wherein W, R1, m and Z are as defined above and K is selected from
the group consisting of C1-10 alkylene, C2-10 alkenylene,
C2-10 alkynylene, C3-10 cycloalkylene, C3-10
cycloalkenylene, C1-10 heteroalkylene, C2-10 heteroalkenylene,
C2-10 heteroalkynylene, arylene, heteroarylene, --C(O)--, --C(S)--,
--C(O)O--, --C(O)S--, --C(O)N(RM)--, --C(S)--, --C(S)O--, --C(S)S--
and --C(S)N(RM)--, wherein RM is hydrogen or C1-4 alkyl.
The alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene,
[0034] In the compounds of formula (I), the value of m may be 0, 1, 2, 3,
4, 5 or 6. In one embodiment, m is 0. In particular, preferably m is O
when Y is a group as defined above other than --C(O)--, --C(S)--,
--C(O)O--, --C(O)S--, --C(O)N(RM)--, --C(S)-- or --C(S)N(RM)--.
In an alternative embodiment, in particular where Y is --C(O)--,
--C(S)--, --C(O)O--, --C(O)S--, --C(O)N(RM)--, --C(S)-- or
--C(S)N(RM)--, m is 1 or 2.
[0035] Z is a zwitterionic group. A zwitterionic group is one which
carries both a positive charge and a negative charge located on different
atoms within the group such that the net charge of the group is zero. As
a consequence, zwitterionic groups have a high polarity and a natural
affinity for water. Phospholipids, such as phosphatidylcholine and
sphingomyelin, which are the major components of the outer membrane of
all living cells have a zwitterionic structure. Hence, because the
monomers of the present invention include a zwitterionic group, they can
be used to produce polymers which mimic the zwitterionic structure of
phospholipids. This improves the biocompatibility of the polymers which
the monomers of the present invention may be used to produce.
[0036] In one embodiment, Z is a zwitterionic group selected from the
group consisting of formula (IIA), (IIB), (IIC), (IID) and (IIE).
[0037] In one embodiment, Z is a zwitterionic group of formula (IIB).
[0038] Group (IIA) has the formula:
wherein each R3 and R3A is independently selected from hydrogen
and C1-4 alkyl and a is an integer from 2 to 4.
[0039] In one embodiment, both R3 groups are the same. In particular,
both R3 groups may be C1-4 alkyl, in one embodiment, methyl.
[0040] In one embodiment, both R3A groups are the same. In
particular, both R3A groups may be hydrogen.
[0041] In one embodiment, a is 2 or 3. In a further embodiment, a is 3.
[0042] In one embodiment of a monomer of formula (I), where Z is a group
of formula (IIA), m is 1 or 2.
[0043] Group (IIB) has the formula:
wherein each R4 and R4A is independently selected from hydrogen
and C1-4 alkyl and b is an integer from 1 to 4;
[0044] In one embodiment, all R4 groups are the same. In particular,
all R4 groups may be C1-4 alkyl, in one embodiment, methyl. In
one embodiment, at least one R4 group is C1-4 alkyl.
[0045] In one embodiment, the R4A groups are the same. In particular,
the R4A groups may be hydrogen.
[0046] In one embodiment, b is 2 or 3. In a further embodiment, b is 3.
Preferably b is 2.
[0047] In one embodiment of a monomer of formula (I), where Z is a group
of formula (IIB), m is 1 or 2.
[0048] In one embodiment, Z is a group of formula (IIB), wherein all
R4 groups are methyl groups and b is 2. In this embodiment, Z is a
phosphorylcholine (PC) group. PC groups occur naturally in the
phospholipids which form the membranes of all living cells. Therefore,
with a view to mimicking the zwitterionic properties of phospholipids, it
is particularly advantageous for Z to be a PC group.
[0049] Group (IIC) has the formula:
wherein each R5 and R5C is independently selected from hydrogen
and C1-4 alkyl; R5A is hydrogen or a group
--C(O)B1R5B, wherein R5B is hydrogen or methyl, B1 is
selected from the group consisting of a bond; C1-4 alkylene,
heteroalkenylene, heteroalkynylene, arylene, heteroarylene, wherein the
RN as defined previously, and c is an integer from 1 to 4, wherein
if Z is directly bonded to an O or N atom, z is O and otherwise z is 1.
[0050] In one embodiment, the R5 groups are the same. In particular,
the R5 groups may be C1-4 alkyl, in one embodiment, methyl. In
one embodiment, at least one R5 group is C1-4 alkyl.
[0051] In one embodiment, both R5C groups are the same. In
particular, the R5C groups may be hydrogen.
[0052] In one embodiment, c is 2 or 3. In a further embodiment, c is 3.
[0053] Group (IID) has the formula:
or more RN as defined previously, and d is an integer from 1 to 4,
wherein if Z is directly bonded to an O or N atom, z is O and otherwise z
is 1;
[0054] In one embodiment, the R6 groups are the same. In particular,
the R6 groups may be C1-4 alkyl, in one embodiment, methyl. In
one embodiment, at least one R6 group is C1-4 alkyl.
[0055] In one embodiment, both R6C groups are the same. In
particular, the R6C groups may be hydrogen.
[0056] In one embodiment, d is 1 or 2. In a further embodiment, d is 2.
[0057] Group (IIE) has the formula:
C3-10 cycloalkenylene, heteroalkylene, C2-10 heteroalkenylene,
C2-10 heteroalkynylene, arylene, heteroarylene, wherein the
RN as defined previously, and e is an integer from 1 to 4, wherein
if Z is directly bonded to an O or N atom, z is O and otherwise z is 1;
[0058] In one embodiment, the R7 groups are the same. In particular,
the R7 groups may be C1-4 alkyl, in one embodiment, methyl. In
one embodiment, at least one R7 group is C1-4 alkyl.
[0059] In one embodiment, both R7C groups are the same. In
particular, the R7C groups may be hydrogen.
[0060] In one embodiment, e is 1 or 2. In a further embodiment, e is 2.
[0061] Further zwitterionic groups are those of formula (IIF), (IIG) and
(IIH). These groups contain an alkyl or fluoroalkyl group capable of
binding to a surface by physisorption.
[0062] Group (IIF) has the formula:
wherein each R8 and R8C is independently selected from hydrogen
and C1-4 alkyl; R8A is a group --C(O)B3R8B, wherein
R8B is hydrogen or methyl, B3 is selected from the group
consisting of a bond; C1-10 alkylene, C2-10 alkenylene,
RN as defined previously; f is an integer from 1 to 4, wherein if Z
is directly bonded to an O or N atom, z is O and otherwise z is 1;
[0063] In one embodiment, the R8A groups are the same. In particular,
the R8A groups may be C1-4 alkyl, in one embodiment, methyl. In
one embodiment, at least one R8A group is C1-4 alkyl.
[0064] In one embodiment, both R8 groups are the same. In particular,
the R8 groups may be hydrogen.
[0065] In one embodiment, each R8B group is hydrogen.
[0066] In one embodiment, R8A is a group --C(O)B3R8B,
wherein B3 is a group of formula
--[(CR8D2)aaO]bb-- where the groups
--(CR8D2)-- are the same or different and in each group
--(CR8D2)--, the groups R8D are the same or different and
each group R8D is hydrogen, fluorine or C1-4 alkyl or
fluoroalkyl and aa is from 2 to 6, preferably 3 or 4 and bb is from 1 to
12, preferably 1 to 6. In an embodiment wherein all groups R8D are
hydrogen and in all the groups --[(CR8D2)aaO]--, aa is 2,
the residues of the monomer of formula (IIF) are not able to form strong
secondary valence interactions with hydrophobic surfaces. While residues
of such monomers may be included in the polymers of the invention, it is
usually also necessary to include residues of monomers which are capable
of forming strong secondary valence interactions if such interactions are
to bind a polymer to a surface. Monomers which have groups wherein dd is
higher than 2 can be used to provide strong secondary valence
interactions. In this regard, where B3 is a group of formula
--[(CR8D2)aaO]bb--, it is advantageous that aa is 2
in about 50 or less, about 70 or less, about 90 mol % or less of the
residues --[(CR8D2)aaO]bb--.
[0067] Group (IIG) has the formula:
wherein each R9 and R9C is independently selected from hydrogen
and C1-4 alkyl; R9A is a group --C(O)B4R9B, wherein
R9B is hydrogen or methyl, B4 is selected from the group
C2-10 alkynylene, C3-10 cycloalkylene, C3-40
RN as defined previously; g is an integer from 1 to 4, wherein if Z
[0068] In one embodiment, the R9A groups are the same. In particular,
the R9A groups may be C1-4 alkyl, in one embodiment, methyl. In
one embodiment, at least one R9A group is C1-4 alkyl.
[0069] In one embodiment, both R9 groups are the same. In particular,
the R9 groups may be hydrogen.
[0070] In one embodiment, each R9B group is hydrogen.
[0071] In one embodiment, R9A is a group --C(O)B4R9B,
wherein B4 is a group of formula
--[(CR9D2)ccO].sub.dd-- where the groups
--(CR9D2)-- are the same or different and in each group
--(CR9D2)--, the groups R9D are the same or different and
each group R9D is hydrogen, fluorine or C1-4 alkyl or
fluoroalkyl and cc is from 2 to 6, preferably 3 or 4 and dd is from 1 to
12, preferably 1 to 6. In an embodiment wherein all groups R9D are
hydrogen and in all the groups --[(CR9D2)ccO]--, cc is 2,
the residues of the monomer of formula (IIG) are not able to form strong
to bind a polymer to a surface. Monomers which have groups wherein cc is
interactions. In this regard, where B4 is a group of formula
--[(CR9D2)ccO].sub.dd--, it is advantageous that cc is 2
residues --[(CR9D2)ccO].sub.dd--.
[0072] Group (IIH) has the formula:
wherein each R10 and R10C is independently selected from
hydrogen and C1-4 alkyl; R10A is a group
--C(O)B5R10B, wherein R10B is hydrogen or methyl, B5
is selected from the group consisting of a bond; C1-10 alkylene,
or more RN as defined previously; h is an integer from 1 to 4,
[0073] In one embodiment, the R10A groups are the same. In
particular, the R10A groups may be C1-4 alkyl, in one
embodiment, methyl. In one embodiment, at least one R10A group is
C1-4 alkyl.
[0074] In one embodiment, both R10 groups are the same. In
particular, the R10 groups may be hydrogen.
[0075] In one embodiment, each R10B group is hydrogen.
[0076] In one embodiment, R10A is a group --C(O)B5R10B,
wherein B5 is a group of formula
--[(CR10D2)eeO].sub.ff-- where the groups
--(CR10D2)-- are the same or different and in each group
--(CR10D2)--, the groups R10D are the same or different
and each group R10D is hydrogen, fluorine or C1-4 alkyl or
fluoroalkyl and ee is from 2 to 6, preferably 3 or 4 and ff is from 1 to
12, preferably 1 to 6. In an embodiment wherein all groups R10D are
hydrogen and in all the groups --[(CR10B2)eeO]--, ee is 2,
the residues of the monomer of formula (IIH) are not able to form strong
to bind a polymer to a surface. Monomers which have groups wherein ee is
interactions. In this regard, where B5 is a group of formula
--[(CR10d2)eeO].sub.ff--, it is advantageous that ee is 2
residues --[(CR10D2)eeO].sub.ff--.
Exemplary Monomers of Formula (I)
[0077] In one embodiment, the present invention provides a monomer of
formula (I), which has the formula (IB):
wherein W, X, Z, A, R1, R2, n and m are as defined previously
in connection with formula (I).
[0078] In one embodiment, the present invention provides a monomer of
formula (IB), wherein X is O, particularly wherein A is O, particularly
wherein A is O and Z is a group of formula IIB, particularly wherein A is
O, n is O and Z is a group of formula IIB, particularly wherein A is O, n
is O and Z is a group of formula IIB, wherein each R4 is methyl and
b is 2.
[0079] In one embodiment, the present invention provides a monomer of
formula (IB), wherein X is NR2, particularly wherein A is O,
particularly wherein A is O and Z is a group of formula IIB, particularly
wherein A is O, n is O and Z is a group of formula IIB, particularly
wherein A is O, n is O and Z is a group of formula IIB, wherein each
R4 is methyl and b is 2.
[0080] In one embodiment, the present invention provides a monomer of
formula (IB), wherein X is O and A is NRM, particularly, wherein Z
is a group of formula IIB, particularly wherein Z is a group of formula
IIB and n is O, particularly wherein n is O and Z is a group of formula
IIB, wherein each R4 is methyl and b is 2.
[0081] In one embodiment, the present invention provides a monomer of
[0082] In one embodiment, the present invention provides a monomer of
formula (IB), wherein X is NR2 and A is NRM, particularly
wherein Z is a group of formula IIB, particularly wherein n is O and Z is
a group of formula IIB, particularly wherein n is O and Z is a group of
formula IIB, wherein each R4 is methyl and b is 2.
[0083] In one embodiment, the present invention provides a monomer of
formula (IC):
wherein W, X, Y, R1, R2, R4, R4A, m, n and b are as
[0084] In one embodiment, the present invention provides a monomer of
formula (IC), wherein X is O.
[0085] In one embodiment, the present invention provides a monomer of
formula (IC), wherein X is NR2.
[0086] In one embodiment, the present invention provides a monomer of
formula (IC), wherein X is NR2 and n is O, particularly wherein m is
2, particularly wherein m is 2 and Y, R2 and the N atom to which
they are bonded together form a 5 to 7-membered heterocyclic ring,
preferably a 5-membered heterocyclic ring.
[0087] In one embodiment, the present invention provides a monomer of
formula (IC), wherein X is NR2, n is O, m is 2 and Y, R2 and
heterocyclic ring, each R4 is methyl and b is 2.
[0088] In one embodiment, the present invention provides a monomer of
wherein W, R4, R4A and b are as defined previously.
[0089] In one embodiment, the present invention provides a monomer of
[0090] The monomers of the present invention may be prepared by
[0091] In general, there are three routes by which the monomers may be
synthesized, specifically: [0092] (i) reaction of a nucleophilic
zwitterionic derivative with a reactive vinyl derivative;[0093] (ii)
reaction of a nucleophilic vinyl compound with a reactive zwitterionic
derivative; or[0094] (iii) reaction of a nucleophilic vinyl compound
with a phospholane followed by ring opening with a trialkylamine.
[0095] The term "halogen" (or "halo") is used herein to refer to fluorine,
chlorine, bromine and iodine.
Carbonyl and Carboxy
[0096] The term "carbonyl" is used herein to refer to a carbon connected
with a double bond to an oxygen atom, and tautomeric forms thereof. A
carbonyl group may also be denoted as --C(O)--. Examples of moieties that
contain a carbonyl include but are not limited to aldehydes --C(O)H,
ketones --C(O)--(C1-C10 alkyl)-, carboxylic acids --CO2H
and amides --C(O)NH2, --C(O)--NH(C1-C10 alkyl),
--C(O)--N(C1-C10 alkyl)2, --NH--C(O)--(C1-C10
alkyl), --NH(C1-C10 alkyl)-C(O)--(C1-C10 alkyl) and
esters --C(O)--O(C1-C10 alkyl).
Thiocarbonyl and Thiocarboxy
[0097] The terms "thiocarbonyl" and "thiocarboxy" are used herein to refer
to a carbon connected via a double bond to a sulfur atom, and tautomeric
Alkyl, Alkenyl, Cycloalkyl etc.
[0098] The term "alkyl" is used herein to refer to monovalent straight
chain or branched, saturated, acyclic hydrocarbyl groups. In one
embodiment, alkyl is C1-10alkyl, in another embodiment
C1-6alkyl, in another embodiment C1-4alkyl, such as methyl,
ethyl, n-propyl, i-propyl or i-, n-, secondary or t-butyl groups.
[0099] The term "cycloalkyl" is used herein to refer to monovalent,
saturated, cyclic hydrocarbyl groups. In one embodiment, cycloalkyl is
C3-10cycloalkyl, in another embodiment, C3-6cycloalkyl, such as
cyclopentyl and cyclohexyl.
[0100] The term "alkenyl" is used herein to refer to monovalent straight
or branched, unsaturated, acyclic hydrocarbyl groups having at least one
carbon-carbon double bond and, in one embodiment, no carbon-carbon triple
bonds. In one embodiment alkenyl is C2-10alkenyl, in another
embodiment, C2-6alkenyl, in another embodiment C2-4alkenyl.
[0101] The term "cycloalkenyl" is used herein to refer to monovalent,
unsaturated, cyclic hydrocarbyl groups. In one embodiment, cycloalkenyl
is C3-10cycloalkyl, in another embodiment, C3-6cycloalkyl, such
as cyclopentenyl and cyclohexenyl.
[0102] The term "alkynyl" is used herein to refer to monovalent straight
carbon-carbon triple bond. In one embodiment alkynyl is
C2-10alkynyl, in another embodiment, C2-6alkynyl, in another
embodiment C2-4alkynyl.
Heteroalkyl, Heterocyclyl etc.
[0103] The term "heteroalkyl" is used herein to refer to monovalent alkyl
groups in which up to three carbon atoms, in one embodiment up to two
carbon atoms, in another embodiment one carbon atom, are each replaced
independently by O, S(O)q or N, provided at least one of the alkyl
carbon atoms remains. The heteroalkyl group may be C-linked or
hetero-linked, i.e. it may be linked to the remainder of the molecule
through a carbon atom or through O, S(O)q or N, wherein q is
[0104] The term "heterocyclyl" or "heterocyclic ring" is used herein to
refer to monovalent, cycloalkyl groups or divalent cycloalkylene groups
in which up to three carbon atoms, in one embodiment up to two carbon
atoms, in another embodiment one carbon atom, are each replaced
independently by O, S(O)q or N, provided at least one of the
cycloalkyl carbon atoms remains.
[0105] Examples of heterocyclyl groups include oxiranyl, thiaranyl,
aziridinyl, oxetanyl, thiatanyl, azetidinyl, tetrahydrofuranyl,
tetrahydrothiophenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl,
tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl,
1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl,
oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl,
1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thieazepanyl and 1,4-diazepanyl.
Other examples include cyclic imides, cyclic anhydrides and
thiazolidindiones. The heterocyclyl group may be C-linked or N-linked,
i.e. it may be linked to the remainder of the molecule through a carbon
atom or through a nitrogen atom.
Aryl etc.
[0106] The term "aryl" is used herein to refer to monovalent, aromatic,
cyclic hydrocarbyl groups, such as phenyl or naphthyl (e.g. 1-naphthyl or
2-naphthyl). In general, the aryl group may be a monocyclic or polycyclic
fused ring aromatic group. Preferred aryl groups are
C6-C14aryl.
[0107] Other examples of aryl groups are monovalent radicals derived from
aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,
chrysene, coronene, fluoranthene, fluorene, as-indacene, s-indacene,
indene, naphthalene, ovalene, perylene, phenalene, phenanthrene, picene,
pleiadene, pyrene, pyranthrene and rubicene.
Heteroaryl etc.
[0108] The term "heteroaryl" is used herein to refer to monovalent,
heteroaromatic, cyclic hydrocarbyl groups additionally containing one or
more heteroatoms independently selected from O, S, N and NRN,
wherein RN is preferably H, alkyl (e.g. C1-6alkyl) or
cycloalkyl (e.g. C3-6cycloalkyl).
[0109] In general, the heteroaryl group may be a monocyclic or polycyclic
(e.g. bicyclic) fused ring heteroaromatic group. In one embodiment,
heteroaryl groups contain 5-13 ring members (preferably 5-10 members) and
1, 2, 3 or 4 ring heteroatoms independently selected from O, S, N and
NRN. In one embodiment, a heteroaryl group may be 5, 6, 9 or 10
membered, e.g. 5-membered monocyclic, 6-membered monocyclic, 9-membered
fused-ring bicyclic or 10-membered fused-ring bicyclic.
[0110] Monocyclic heteroaromatic groups include heteroaromatic groups
containing 5-6 ring members and 1, 2, 3 or 4 heteroatoms selected from O,
S, N or NRN.
[0111] In one embodiment, 5-membered monocyclic heteroaryl groups contain
1 ring member which is an --NRN-- group, an --O-- atom or an --S--
atom and, optionally, 1-3 ring members (e.g. 1 or 2 ring members) which
are ═N-- atoms (where the remainder of the 5 ring members are carbon
[0112] Examples of 5-membered monocyclic heteroaryl groups are pyrrolyl,
furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl,
isothiazolyl, thiazolyl, 1,2,3 triazolyl, 1,2,4 triazolyl, 1,2,3
oxadiazolyl, 1,2,4 oxadiazolyl, 1,2,5 oxadiazolyl, 1,3,4 oxadiazolyl,
1,3,4 thiadiazolyl and tetrazolyl.
[0113] Examples of 6-membered monocyclic heteroaryl groups are pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5 triazinyl, 1,2,4 triazinyl and
1,2,3 triazinyl.
[0114] In one embodiment, 6-membered monocyclic heteroaryl groups contain
1 or 2 ring members which are ═N-- atoms (where the remainder of the
6 ring members are carbon atoms).
[0115] Bicyclic heteroaromatic groups include fused-ring heteroaromatic
groups containing 9-13 ring members and 1, 2, 3, 4 or more heteroatoms
selected from O, S, N or NRN.
[0116] In one embodiment, 9-membered bicyclic heteroaryl groups contain I
ring member which is an --NRN-- group, an --O-- atom or an --S--
are ═N-- atoms (where the remainder of the 9 ring members are carbon
[0117] Examples of 9-membered fused-ring bicyclic heteroaryl groups are
benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl,
benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl,
pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl,
imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl,
pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl,
pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolyl,
indazolyl, purinyl, indolininyl, imidazo[1,2-a]pyridinyl,
imidazo[1,5-a]pyridinyl, pyrazolo[1,2-a]pyridinyl,
pyrrolo[1,2-b]pyridazinyl and imidazo[1,2-c]pyrimidinyl.
[0118] In one embodiment, 10-membered bicyclic heteroaryl groups contain
1-3 ring members which are ═N-- atoms (where the remainder of the 10
ring members are carbon atoms).
[0119] Examples of 10-membered fused-ring bicyclic heteroaryl groups are
quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl,
phthalazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl,
1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl,
pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl,
pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,
pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl,
pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl and
pyrimido[4,5-d]pyrimidinyl.
[0120] In some embodiments, a heterocyclyl group may be fused to an aryl
or heteroaryl group to form a bicyclic ring system containing 5 to 13
members. Examples of such groups include dihydroisoindolyl,
dihydroindolyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl or
2,3-dihydro-pyrrolyl-[2,3-b]pyridine.
[0121] The terms "alkoxy" and "alkyloxy" are used herein to refer to an
--O-alkyl group in which alkyl is as described above. Exemplary alkoxy
groups include methoxy (--OCH3) and ethoxy (--OC2H5).
[0122] The term "alkylene" is used herein to refer to a divalent
-alkyl-group in which alkyl is as defined previously. Exemplary alkylene
groups include --CH2--, --(CH2)2-- and
--C(CH3)HCH2--.
Alkenylene
[0123] The term "alkenylene" is used herein to refer to a divalent
-alkenyl-group in which alkenyl is as defined previously. Exemplary
alkenylene groups include --CH═CH--, --CH═CHCH2--, and
--CH2CH═CH--.
[0124] The term "alkynylene" is used herein to refer to a divalent
-alkynyl-group in which -alkynyl- refers to a straight or branched chain
hydrocarbon group having from 2 to 12, conveniently 2 to 6, carbon atoms
and one carbon-carbon triple bond in the chain. Exemplary alkynylene
groups include ethynyl and propargyl.
[0125] The term "arylene" is used herein to refer to a divalent
-aryl-group where aryl is as described above which is linked to two or
more other groups. Examples of arylene groups include phenylene.
[0126] "Phenylene" means a -phenyl-group. Exemplary groups are
1,3-phenylene and 1,4-phenylene.
Heteroarylene
[0127] The term "heteroarylene" is used herein to refer to a
-heteroaryl-group, where heteroaryl is as described above, which is
linked to two or more other groups. Exemplary groups include 2,5-furyl,
2,5-thienyl, 2,4-thiazolyl, 2,5-thiazolyl and 2,6-pyridyl.
[0128] As used herein, the term "nucleophilic" has its conventional
meaning and refers to a derivative which includes a group that forms a
bond with another species (an electrophile) by donating an electron pair.
[0129] The term "vinyl compound" refers to a compound which includes a
terminal --CH═CH2 group.
[0130] Examples of nucleophilic groups include alcohols, peroxides,
alkoxide anions, carboxylate anions, ammonia, amines, azides, nitrites,
thiols, (RSH), thiolate anions (RS.sup.-), anions of thiolcarboxylic
acids (RC(O)--S.sup.-), and anions of dithiocarbonates
(RO--C(S)--S.sup.-) and dithiocarbamates (R2N--C(S)--S.sup.-).
[0131] In the general reaction (i) described above, the reactive vinyl
derivative will include an electrophilic group which reacts with the
nucleophilic zwitterionic or zwitterionic precursor derivative. Hence,
the reactive vinyl derivative can be described by the general formula
C═C--W--X-E, wherein W and X are as defined for formula (I) and E is
an electrophilic group. The skilled person will be familiar with suitable
reagents which may be used as the reactive vinyl derivative. Examples of
suitable reactive vinyl derivatives include vinylchloroformate and vinyl
[0132] In one embodiment, the reactive vinyl derivative is an N-vinyl
lactam derivative. N-vinyl lactams have properties which are useful in
the preparation of contact lenses. For example, N-vinyl pyrrolidone is a
compound which is commonly used in the manufacture of contact lenses.
Hence, it would be advantageous to provide a biocompatible co-monomer
which is reactive with this compound.
[0133] The reactive vinyl derivative is reacted with a nucleophilic
derivative of a zwitterion or zwitterionic precursor which may be
depicted generally as having a structure A1-(CR1)m--Z,
wherein A1 is a nucleophilic group containing a heteroatom selected
from N, O and S. For example, A1 may be selected from the group
consisting of alcohols, peroxides, alkoxide anions, carboxylate anions,
ammonia, amines, azides, nitrites, thiols (RSH), thiolate anions
(RS.sup.-), anions of thiolcarboxylic acids (RC(O)--S.sup.-), and anions
of dithiocarbonates (RO--C(S)--S.sup.-) and dithiocarbamates
(R2N--C(S)--S.sup.-).
[0134] Examples of suitable nucleophilic derivatives of a zwitterion
include but are not limited to hydroxyethylphosphorylcholine and
aminoethylphosphorylcholine.
[0135] Examples of suitable nucleophilic derivatives of a zwitterionic
precursor include but are not limited to ethylene glycol or monoprotected
derivatives thereof and aminoethanol.
[0136] As described above, in one embodiment the zwitterionic group Z is a
group of formula (IIB), in particular a phosphorylcholine group.
Synthetic routes for adding a PC group to a monomer are known in the art.
For example, Chabrier et al. describes a two step reaction which involves
reacting a hydroxyl substituted starting material with a halophospholane
and then ring opening with a trialkylamine in FR-A-2270887 and Bul. Soc.
Chim de France (1974) 667-671. An analogous two stage reaction for
producing HEMA-PC was described by Nakaya et al in JP-A-58-154591 and
Makromol. Chem., Rapid Commun., 1982, 3, 457. A more recent synthetic
route is described in EP-A-0730 599.
[0137] Monomers of formula (IB) may be synthesized using reaction (i)
above, wherein the reactive vinyl derivative used has the formula (IIIA):
wherein W, X and R1 are as defined above and L is a leaving group
which, together with the carbonyl group, forms an electrophilic group
which reacts with the nucleophilic derivative of a zwitterion or
zwitterionic precursor. The skilled person will be familiar with suitable
leaving groups. Examples of suitable leaving groups include halogens,
amine moieties, alkoxy, allylthio, triflates, mesylates, tosylates and
fluorosulphonates.
[0138] Alternatively, where X in formula (IB) is N, a vinyl isocyanate,
i.e. a compound of formula (IIIB) or a vinyl isothiocyanate, i.e. a
compound of formula (IIIC), may be used as the reactive vinyl derivative:
[0139] With reference to the general reaction (ii) described above, the
nucleophilic vinyl compound is one which includes both a nucleophilic
group and a vinyl group. It has the general structure
C═C--W--X--Y--(CR1)m-Nuc, wherein "Nuc" is a nucleophilic
group. Examples of suitable nucleophilic groups include but are not
limited to --OH, --NH2, NHR, SH and suitable anions, including
carboxylate anions. In one embodiment, the nucleophilic vinyl compound is
an N-vinyl lactam derivative, in particular a derivative of N-vinyl
pyrrolidone. N-vinyl lactam derivatives may be formed by reacting an
N-vinyl lactam with a base to form an anion at position 3 on the ring
(adjacent to the carbonyl group) and then subsequently reacting the anion
with, for example, iodooethanol, to form a 3-hydroxyethyl-substituted
lactam.
[0140] In one embodiment, the nucleophilic vinyl derivative may have the
[0141] The nucleophilic vinyl compound is reacted with a reactive
zwitterionic derivative having the general formula Z-L, wherein L is a
leaving group as defined above in connection with reaction scheme (i).
Examples of suitable reactive zwitterionic derivatives include but are
not limited to those having a leaving group selected from the group
consisting of tosyl-, mesyl-, fluorosulphonate-, triflate-,
imidazolecarbonyloxy-, halo, amononiumalkyl, epoxyalkyl, alkoxycarbonyl,
alkylthiocarbonyl and alkylcarbonyloxycarbonylalkyl.
[0142] In one embodiment of the present invention, the zwitterionic group
in the monomers of the present invention is a group of formula (IIB),
specifically a phosphorylcholine type group.
[0143] Monomers of formula (IA), wherein Z is a group of formula (IIB) may
alternatively be formed by a reaction (iii), wherein a nucleophilic vinyl
compound, such as those described above in connection with reaction
scheme (ii), is reacted with a phospholane followed by ring opening with
a trialkylamine.
[0144] Monomers of formula (IC), wherein b is 2, may be synthesized by
reacting a nucleophilic vinyl derivative of formula (V):
with a phospholane reagent (VIA) or (VIB):
wherein each R4A is independently selected from the group consisting
of H and C1-4 alkyl and L' is a leaving group. The skilled person
will be familiar with suitable leaving groups. Examples of suitable
leaving groups include halogens, amine moieties, alkoxy, allylthio,
triflates, mesylates, tosylates and fluorosulphonates.
[0145] Reaction with a phospholane reagent (VIA) forms an intermediate
compound of formula (VII):
which can then be reacted with a trialkylamine reagent N(R4)3,
wherein each R4 is independently hydrogen or C1-4 alkyl to
produce a compound of formula (IC).
[0146] Phospholane reagents of formula (VIA) and (VIB) are commercially
available and methods for synthesizing phospholane reagents are known in
the art (N. Thung, M Chassignol, U. Asseline and P. Chalvier, Bull. Soc.
Chim. Fr. 1981 (Part 2) 51). The skilled person will also be familiar
with the fact that suitable substituted phosphorus compounds may also be
used in place of a phospholane reagent. In one embodiment, in the
phospholane reagent (VI), each R4A is hydrogen. In one embodiment,
the phospholane reagent is ethylenechlorophosphate (ECP) (CAS
6609-64-9,2-chloro-1,3,2-dioxaphospholane-2-oxide). It is advantageous to
minimise the presence of impurities in the phospholane reagent to avoid
side reactions and this can be monitored by 31P NMR.
[0147] Trialkylamine reagents are commercially available. Examples of
suitable trialkylamine reagents include trimethylamine and triethylamine.
In one embodiment, the trialkylamine reagent is trimethylamine i.e. each
[0148] In one embodiment, the first step may be carried out in a first
suitable solvent in which the compound of formula (V) and the phospholane
reagents (VIA) and (VIB) are soluble, and in which an acid scavenger is
insoluble. For the second step, a nitrile in particular, a nitrile
derivative of a C1-6 carboxylic acid, preferably acetonitrile may be
advantageously used or a nitrile solvent may be used for both the first
and second steps.
[0149] The monomers of the present invention are useful in producing
biocompatible polymers which can be used in biocompatible coatings and in
forming bulk materials and devices. Therefore, in a further aspect, the
present invention provides polymers derived from co-polymerizing a
monomer of formula (I) as defined herein with one or more co-monomers.
[0150] The polymers of the present invention are biocompatible and
advantageously can be used to produce articles which have both a high
gas, in particular oxygen permeability and a high water content.
[0151] The polymers of the present invention may be produced by
conventional polymerization reactions, for example by thermal or
photochemical polymerization. For thermal polymerisation, a temperature
in the range from 40 to 100° C., typically 50 to 80° C. may
be used. For a photochemical polymerisation, actinic radiation such as
gamma, UV, visible or microwave radiation may be use. Typically UV
[0152] The polymerisation is generally performed in a reaction medium,
which is for instance a solution or dispersion using a solvent with which
the groups present in the monomers will not react under the
polymerisation conditions used, for example water, alcohols, such as
ethanol, methanol and glycol, and furthermore carboxylic acid amides,
such as dimethylformamide, dipolar aprotic solvents, such as dimethyl
sulfoxide or methyl ethyl ketone, ketones for example acetone or
cyclohexanone, hydrocarbons, for example toluene, ethers, for example
THF, dimethoxyethane or dioxane and halogenated hydrocarbons, for example
trichloroethane and also mixtures of suitable solvents, for example
mixtures of water with an alcohol, for example a water/ethanol or
water/methanol mix. Any mixtures of these solvents may be used.
Alternatively the polymerisation may be carried out in the absence of a
solvent or where a co-monomer acts as the solvent.
[0153] The polymerisation may be carried out in the presence of one or
more polymerisation initiators, such as benzoyl peroxide,
2,2'-azo-bis(2-methylpropionitrile) or benzoin methyl ether. Other
polymerisation initiators which may be used are disclosed in "Polymer
Handbook", 3rd Edition, Ed. J. Brandrup and E. H. Immergut, Pub.
Wiley-Interscience, New York 1989.
[0154] Generally, the copolymerisation is performed for 0.1 to 72 hours,
in one embodiment, 0.1 to 1 hours, in an alternative embodiment, 8 to 48
hours, for instance 16 to 24 hours and under an inert atmosphere of, for
example, nitrogen or argon.
[0155] The polymer is generally purified by dialysis, precipitation in a
non-solvent (e.g. diethyl ether or acetone) or ultrafiltration. The
resulting polymer is generally dried under vacuum e.g. for 5 to 72 hours
and has a molecular weight from 10,000 to 10 million, in one instance,
from 20,000 to 1 million, in an alternative instance, from 50,000 to
750,000, in an alternative instance, from 50,000 to 500,000.
[0156] Where the aim is to provide a biocompatible coating and co-monomers
capable of producing cross-linking are present in the monomer mixture,
the polymerisation conditions are set such that cross-linking does not
occur during polymerisation. For example, actinic radiation would not be
used to prepare polymer containing a co-monomer which can form crosslinks
by exposure to actinic radiation.
[0157] The precise nature of the co-monomer system with which the monomers
of the present invention are co-polymerized will depend on the intended
use of the polymer which is produced.
[0158] Advantageously, where the polymer is intended for use in forming
ocular devices such as contact lenses, the monomers of the present
invention are reacted with a co-monomer system which includes a siloxane
group-containing monomer or macromer.
[0159] A siloxane group-containing component is one which includes the
residue having the general structure --[Si(R)2O]--, wherein R is
hydrogen or a C1-10 alkylene, C2-10 alkenylene, C2-10
heteroalkynylene, arylene, heteroarylene group. Preferably R is a
C1-10 alkylene group, preferably a C1 alkylene group.
Preferably, the Si and attached 0 are present in the siloxane
group-containing monomer or macromer in an amount greater than 20 weight
percent, and more preferably greater than 30 weight percent of the total
molecular weight of the siloxane group-containing monomer or macromer.
[0160] Useful siloxane group-containing monomer or macromer may comprise
polymerizable functional groups such as acrylate, methacrylate,
acrylamide, methacrylamide, N-vinyl lactam, N-vinylamide, and styryl
functional groups. Examples of siloxane group-containing components which
may be included in the co-solvent system are described in U.S. Pat. No.
3,808,178, U.S. Pat. No. 4,120,570, U.S. Pat. No. 4,136,250, U.S. Pat.
No. 4,153,641, U.S. Pat. No. 4,740,533, U.S. Pat. No. 5,034,461, U.S.
Pat. No. 5,070,215 and EP 080539. All of the patents cited herein are
hereby incorporated in their entireties by reference.
[0161] In one embodiment of the present invention, the siloxane
group-containing monomer may be a polysiloxanylalkyl(meth)acrylic monomer
represented by the following formula X:
wherein: T denotes H or lower alkyl and in certain embodiments H or
methyl; Q denotes O or NR14; each R14 independently denotes
hydrogen or methyl, each R11, R12 and R13 independently
denotes a lower alkyl radical or a phenyl radical, and j is 1 or 3 to 10.
Examples of these polysiloxanylalkyl (meth)acrylic monomers include
methacryloxypropyl tris(trimethylsiloxy) si lane, pentamethyldisiloxanyl
methylmethacrylate, and methyldi(trimethylsiloxy)methacryloxymethyl
[0162] An alternative class of siloxane group-containing components which
may form a part of the co-solvent system are poly(organosiloxane)
prepolymers represented by Formula XI:
wherein: each A' independently denotes an activated unsaturated group,
such as an ester or amide of an acrylic or a methacrylic acid or an alkyl
or aryl group (providing that at least one A' comprises an activated
unsaturated group capable of undergoing radical polymerization); each of
R16, R17, R18 and R19 are independently selected from
the group consisting of a monovalent hydrocarbon radical or a halogen
substituted monovalent hydrocarbon radical having 1 to 18 carbon atoms
which may have ether linkages between carbon atoms; R15 denotes a
divalent hydrocarbon radical having from 1 to 22 carbon atoms, and n' is
O or an integer greater than or equal to 1, in one embodiment n' is 5 to
400, in another embodiment n' is 10 to 300. One specific example is
α,ω-bismethacryloxypropyl poly-dimethylsiloxane. Another
example is mPDMS (monomethacryloxypropyl terminated mono-n-butyl
terminated polydimethylsiloxane).
[0163] Another useful class of siloxane group-containing components
includes silicone-containing vinyl carbonate or vinyl carbamate monomers
of the following formula XII:
wherein: X' denotes O, S or NH; RSi denotes a silicone-containing
organic radical; T denotes hydrogen or lower alkyl, in certain
embodiments H or methyl; t is 1, 2, 3 or 4; and q' is O or 1. Suitable
silicone-containing organic radicals RSi include the following:
wherein R20 denotes
wherein p' is 1 to 6; or an alkyl radical or a fluoro-alkyl radical
having 1 to 6 carbon atoms; r' is 1 to 200, t' is 1, 2, 3 or 4; and s is
[0164] The siloxane group-containing vinyl carbonate or vinyl carbamate
monomers specifically include:
1,3-bis[4-(vinyloxycarbonyloxy)but-1-yl]tetramethyl-isiloxane
3-(vinyloxycarbonylthio) propyl-[tris (trimethylsiloxysilane];
3-[tris(trimethylsiloxy)wilyl]propyl vinyl carbamate; trimethylsilylethyl
vinyl carbonate; trimethylsilylmethyl vinyl carbonate, and
[0165] Another class of silicone-containing components includes compounds
of the following formulae:
(*D*L*D*G)aa*D*D*E1;
E(*D*G*D*L)aa*D*G*D*E1 or;
E(*D*L*D*G)aa*D*L*D*E1 (Formulae XIII-XV)
wherein: D denotes an alkyl diradical, an alkyl cycloalkyl diradical, a
cycloalkyl diradical, an aryl diradical or an alkylaryl diradical having
6 to 30 carbon atoms, G denotes an alkyl diradical, a cycloalkyl
diradical, an alkyl cycloalkyl diradical, an aryl diradical or an
alkylaryl diradical having 1 to 40 carbon atoms and which may contain
ether, thio or amine linkages in the main chain; * denotes a urethane or
ureido linkage; aa is an integer of at least 1; L denotes a divalent
polymeric radical of formula XVI:
in which R21 independently denotes an alkyl or fluoro-substituted
alkyl group having 1 to 10 carbon atoms which may contain ether linkages
between carbon atoms; r is at least 1; and p provides a moiety weight of
400 to 10,000; each of E and E1 independently denotes a
polymerizable unsaturated organic radical represented by formula XVII:
wherein R22 is hydrogen or methyl; R23 is hydrogen, an alkyl
radical having 1 to 6 carbon atoms, or a --CO--V'--R25 radical
wherein V' is --O--, --S-- or --NH-- and R24 is hydrogen or an alkyl
radical having 1 to 6 carbon atoms; R24 is a divalent radical having
1 to 12 carbon atoms; Y' denotes --CO-- or --OCO--; W' denotes --O-- or
--NH--; Ar denotes an aromatic radical having 6 to 10 carbon atoms; a' is
O to 6; b' is O or 1; c' is O or 1; and d' is O or 1.
[0166] A preferred silicone-containing component is represented by the
following formula XVIII:
wherein R26 is a diradical of a diisocyanate after removal of the
isocyanate group, such as the diradical of isophorone diisocyanate.
Another preferred silicone containing macromer is compound of formula XIX
(in which x+y is a number in the range of 10 to 30) formed by the
reaction of fluoroether, hydroxy-terminated polydimethylsiloxane,
isophorone diisocyanate and isocyanatoethylmethacrylate.
[0167] In an alternative embodiment of the present invention, the siloxane
group-containing monomer may be a material of formula (A) or (B):
(T1-Y1)k-G1(Y2--Z)l (A)
[(T1)k-Y3(Z)u]v-G1-R24 (B)
wherein [0168] T1 is a polymerisable group;[0169] Y1 and
Y2 are each independently a linker group selected from the group
consisting of a bond, C1-12 alkylene, C2-12 alkenylene,
C2-12 alkynylene, C3-12 cycloalkylene, C3-12
cycloalkenylene, C2-12 heteroalkenylene, C2-12
heteroalkynylene, arylene, heteroarylene, --C(O)--C1-12 alkylene,
--C(S)--C1-12 alkylene, --C(O)O--C1-12 alkylene,
--C(O)S--C1-12 alkylene, --C(O)N(RM)--C1-12 alkylene,
--C(S)--C1-12 alkylene, --C(S)O--C1-12 alkylene,
--C(S)S--C1-12 alkylene, --C(S)N(RM)--C1-12 alkylene,
alkyl), --NH(C1-C10 alkyl), --N(C1-C10alkyl)2,
--S(O)2--N(C1-C10 alkyl)2 and ═O;[0170] Y3
is a linker group;[0171] R24 is a C1-12 alkyl group which may
be optionally substituted with one or more RN;[0172] G1 is a
siloxane group-containing component;[0173] Z is a zwitterionic group;
[0174] k is an integer from 1 to 10;[0175] l is an integer from 1 to 3;
[0176] u is an integer from 1 to 3; and[0177] v is an integer from 1 to
[0178] In such embodiments of the present invention, the siloxane
group-containing monomer includes a polymerisable group, siloxane
functionality and a zwitterionic functionality within the same molecule.
This is advantageous because any phase separation may be at a molecular
level and so will not be visible to the naked eye. Furthermore, combining
the functionalities on a molecular level makes it possible to provide
materials which have a higher oxygen permeability than might be expected
for a given water content.
[0179] Although formula (A) and formula (B) (and the chemical formulae
which follow herein) are represented without any indication of specific
stereochemistry, the skilled person will understand that a number of
isomers are possible. In this regard, the present invention includes
within its scope, all possible stereoisomers of the chemical structures
[0180] The polymerisable group T1 is not limited and it may be any
group which is capable of reaction under polymerisation conditions to
form a polymer. It is the presence of the polymerisable group in the
materials of the present invention which means that it is possible to
form polymers and, ultimately, contact lenses from the materials of the
present invention. In certain embodiments, the polymerisable group
includes at least one carbon-carbon unsaturated bond. In such
embodiments, the group is capable of addition polymerisation reactions.
Alternatively, or in addition, the group which is capable of reaction to
form a polymer is a multi-functionalised derivative which is capable of
condensation polymerisation. This includes, for example, materials such
as diols, diamines, diacids and derivatives thereof.
[0181] In one embodiment, the siloxane group-containing monomer is a
material of formula (A). In an alternative embodiment, the siloxane
group-containing monomer is a material of formula (B).
[0182] In one embodiment, the polymerisable group T1 includes a group
which is selected from the group consisting of acrylates, methacrylates,
acrylamides, methacrylamides, styrenic and vinylic groups. Examples of
suitable vinylic groups include allyl derivatives, N-vinyl lactam
derivatives, such as suitably substituted N-vinyl pyrrolidone derivatives
and N- and O-vinyl derivatives.
[0183] In one embodiment, the polymerisable group T1 is a
methacrylate or acrylate group. Preferably, the polymerisable group
T1 is a methacrylate group.
[0184] With reference to formula (A) and formula (B) above, k is an
integer which defines the number of polymerisable groups, T1,
present in the polymerisable material. k may be 1, 2, 3, 4, 5, 6, 7, 8, 9
or 10. Preferably, k is 1 or 2.
[0185] Y' is a linker group which forms a link between the polymerisable
group T' and the siloxane group-containing component, G1, in a
polymerisable material of formula (A). Y2 is a linker group which
forms a link between the siloxane group-containing component, G1 and
the zwitterionic group, Z in a polymerisable material of formula (A).
Y1 and Y2 are each independently selected from the group
--S(O)2--N(C1-C10 alkyl)2 and ═O. Y1 and
Y2 may be the same or different. In one embodiment, Y1 and
Y2 are the same. In an alternative embodiment, Y1 and Y2
[0186] In one embodiment, Y1 and Y2 are each independently a
C1-12 alkylene group. In an alternative embodiment, Y1 is a
group of formula --(CH2)q(OCH2CH2)r-- and
Y2 is a group of formula
--(CH2CH2O)rr(CH2)qq--, wherein rr is an integer
in the range from 1 to 10, preferably 4 to 6 and qq is an integer in the
range from 1 to 10, in one embodiment, 2 to 4, preferably 3.
[0187] Y3 is a linker group which forms a link between the
polymerisable group, T1 and the siloxane group, G1, in
polymerisable material of formula (B). In this embodiment of the present
invention, the zwitterionic group, Z, is a substituent on the linker
group, Y3. The nature of Y3 is not particularly limited and in
a preferred embodiment, Y3 is selected from the group consisting of
a bond, C1-12 alkylene, C2-12 alkenylene, C2-12
alkynylene, C3-12 cycloalkylene, C3-12 cycloalkenylene,
C1-12 heteroalkylene, C2-12 heteroalkenylene, C2-12
--S(O)2--N(C1-C10 alkyl)2 and ═O. The position of
the group Z as a substituent of the linker group Y3 is not limited.
In this regard, the group Z may be a substituent on any one of the carbon
atoms which form a part of the backbone of the linker group, Y3.
[0188] In one embodiment, Y3 is a C1-12 alkylene or
heteroalkylene group, in particular a heteroalkylene group of formula
--(CH2)qq(OCH2CH2)rr-- or
--(CH2CH2O)rr(CF12)qq--, wherein qq is an
integer from 1 to 10 and rr is an integer from 1 to 10. In a preferred
embodiment, Y3 is --(CH2)3--O--(CH2)3--. In a
preferred embodiment of the present invention, the position of
substitution of the Z group on the Y3 group is such that the group
--Y3(Z)-- is --(CH2CH(Z)CH2)--O--(CH2)3--.
[0189] G1 is the siloxane group-containing component of the
siloxane-group containing monomer of this embodiment. As described
previously, it is the inclusion of the siloxane functionality in the
siloxane group-containing monomer which provides a material which has
good gas permeability. The nature of the siloxane group-containing
component is not particularly limited and the skilled person will be
familiar with suitable components. A siloxane group is one which includes
the residue having the general structure --[Si(R)2O]--, wherein each
R is independently selected from hydrogen or a C1-12 alkylene,
C2-12 alkenylene, C2-12 alkynylene, C3-12 cycloalkylene,
C3-12 cycloalkenylene, C1-12 heteroalkylene, C2-12
heteroalkenylene, C2-12 heteroalkynylene, arylene, heteroarylene
group, optionally substituted with one or more RN, wherein each
RN is independently selected from the group consisting of --H, --OH,
--CN, --NO2, --CF3, --OCF3, --CO2H, --NH2,
--S(O)2--N(C1-C10 alkyl)2 and ═O. The R groups
may be the same or different. In one embodiment all of the R groups are
the same. In an alternative embodiment, the R groups are different.
Preferably R is a C1-12 alkylene group, preferably a C1-6
alkylene group. Preferably, the Si and attached O are present in the
siloxane group in an amount greater than 20 weight percent, and more
preferably greater than 30 weight percent of the total molecular weight
of the siloxane group-containing component.
[0190] In one embodiment, the siloxane group-containing component has the
wherein R is as defined previously and w is an integer from 1 to 500.
[0191] In one embodiment, the siloxane group-containing component has the
wherein R is as defined previously and w1 and w2 are
independently an integer in the range from 1 to 500.
[0192] In one embodiment, the siloxane group-containing component has the
wherein R is as defined previously and w3, w4 and w5 are
each independently an integer in the range from 1 to 500.
[0193] In one embodiment, the siloxane group-containing component has the
wherein R is as defined previously and w6, w7, w8 and
w9 are each independently an integer in the range from 1 to 500.
[0194] Z is a zwitterionic group as defined previously. Where the siloxane
group-containing monomer has formula (A), Z is bonded to Y2. Where
the siloxane group-containing monomer has formula (B), Z is a substituent
on the linker group Y3.
[0195] Preferably, Z is a group of formula (IIB), in particular, a group
of formula (IIB), wherein all R4 groups are methyl groups and b is
2. In this embodiment, the zwitterionic group is a phosphorylcholine (PC)
[0196] l is an integer which defines the number of zwitterionic groups
which are present in the siloxane group-containing monomer of formula
(A). I may be 1, 2 or 3. Preferably, 1 is 1 or 2.
[0197] u is an integer which defines the number of zwitterionic groups
(B). u may be 1, 2 or 3. Preferably, u is 1 or 2.
[0198] v is an integer which defines the number of
[(T1)k--Y3(Z)u] groups which are present in the
siloxane group-containing monomer of formula (B). u may be 1, 2 or 3.
Preferably, u is 1 or 2.
Exemplary Siloxane Group-Containing Monomers of Formula (A)
[0199] In one embodiment, the siloxane group-containing monomer of the
present invention has the formula (AA):
wherein "OPC" is a zwitterionic group of formula (IIB), wherein all
R4 groups are methyl and b is 2, w is an integer from 1 to 500, r'
and r'' may be the same or different and are each independently an
integer from 0 to 10, preferably 4 to 6.
[0200] Accordingly, in one embodiment, the siloxane group-containing
monomer is a material of formula (A), wherein T1 is a methacrylate
group, Y1 is (CH2CH2O)r'(CH2)3, G1 is
a group of formula (c), w is an integer from 1 to 500, Y2 is
(CH2)3(CH2CH2O)rr'', Z is a group of formula
(IIB) wherein all R4 groups are methyl and b is 2, k is 1, 1 is 1
and r' and r'' may be the same or different and are each independently an
integer between 0 and 10, preferably 4 to 6.
[0201] In one embodiment of the invention, the polymerisable material is a
material of formula (AB):
R4 groups are methyl and b is 2 and w is O to 15.
[0202] Accordingly, in one embodiment, the siloxane group-containing
group, Y1 is (CH2)3, w is O to 15, preferably 2 to 4,
Y2 is (CH2)3, Z is a group of formula (IIB) wherein all
R4 groups are methyl and b is 2, k is 1 and 1 is 2.
Exemplary Siloxane Group-Containing Monomers of Formula (B)
[0203] In one embodiment of the present invention, the polymerisable
monomer of the present invention has the formula (BB):
R4 groups are methyl and b is 2.
[0204] Accordingly, in one embodiment, the siloxane group-containing
monomer is a material of formula (B), wherein T1 is a methacrylate
group, Y3 is --(CH2)3--O--(CH2)3--, Z is a group
of formula (JIB) wherein all R4 groups are methyl and b is 2, W is a
group of formula (c), R24 is methyl, u is 1 and v is 1.
[0205] In an alternative embodiment of the present invention, the siloxane
group-containing monomer has the formula (BC).
[0206] Accordingly, in one embodiment, the siloxane group-containing
of formula (IIB), wherein all R4 groups are methyl and b is 2,
G1 is a group of formula (a), R24 is (CH2)4CH3,
u is 1 and v is 1.
[0207] In one embodiment the siloxane group-containing monomer has the
formula (BD):
wherein "OPC" is a zwitterionic group of formula (JIB), wherein all
R4 groups are methyl and b is 2 and w is an integer from 1 to 500.
[0208] Accordingly, in one embodiment, the siloxane group-containing
monomer is a material of formula (B), wherein T' is an acrylate group,
Y3 is --(CH2)--(CH(OZ))--CH2--O--(CF12)3--, Z is
a group of formula (IIB), wherein all R4 groups are methyl and b is
2, G1 is a group of formula (a), R24 is methyl, u is 1 and v is
[0209] Other silicone-containing components suitable for use in this
invention include those described in WO 96/31792 such as macromers
containing polysiloxane, polyalkylene ether, diisocyanate,
polyfluorinated hydrocarbon, polyfluorinated ether and polysaccharide
groups. U.S. Pat. No. 5,321,108, U.S. Pat. No. 5,387,662 and U.S. Pat.
No. 5,539,016 all describe polysiloxanes with a polar fluorinated graft
or side group having a hydrogen atom attached to a terminal
difluoro-substituted carbon atom. Such polysiloxanes may also be used as
the siloxane group-containing monomer in the co-solvent system.
[0210] Alternatively, the siloxane group-containing monomer may be a
hydroxyl-functionalised siloxane group-containing monomer. Examples
include 2-methyl-2-hydroxy-3-[3-[1,3,3,3-tetramethyl-1-[trimethylsilyl)ox-
y]disiloxanyl]propoxy]propyl ester (which can also be named
(3-methacryloxy-2-hydroxypropyloxy)propylbis(trimethylsiloxy)methylsilane-
), 3-methacryloxy-2-hydroxypropyloxy)propyltris(trimethylsi loxy)silane,
bis-3-methacryloxy-2-hydroxypropyloxypropyl polydimethylsiloxane,
3-methacryloxy-2-(2-hydroxyethoxy)propyloxy)propylbis(trimethylsiloxy)met-
hylsilane, N-2-methacryloxyethyl-O-(methyl-bis-trimethylsiloxy-3-propyl)si-
lyl carbamate and
N,N,N',N'-tetrakis(3-methacryloxy-2-hydroxypropyl)-[alpha],[omega]-bis-3--
aminopropyl-polydimethylsiloxane and mixtures thereof.
[0211] In one embodiment, the siloxane group-containing monomer is
3-[Tris(trimethylsiloxy)silyl]propyl methacrylate, methacryloxypropyl
terminated polydimethylsiloxane; monomethacryloxypropyl functional
polydimethylsiloxane; monomethacryloxypropyl terminated
polytrifluoropropylmethyl-siloxane-symmetric,
2-hydroxy-3-[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]pr-
opoxy]propyl methacrylate and tristrimethylsiloxysilyl propylvinyl
[0212] In one embodiment, the polymers of the present invention are
obtainable by reacting about 1 to 100 mol % monomer of formula (I) with
about 1 to about 95 mol % siloxane monomer and other diluent monomers to
a total of 100%. The diluent monomers may be monomers which comprise a
vinyl group, including but not limited to acrylates, methacrylates such
as methacrylic acid, methylmethacrylate, hydroxyethylmethacrylate,
acrylamides such as dimethylacrylamide, N-vinyl lactams, such as
N-vinylpyrrolidone, and N- and O-vinyl derivatives such as
hydroxyethylvinylcarbamate, hydroxyethylvinylcarbonate
[0213] In the polymers of the present invention, a monomer of formula (I)
preferably accounts for about 1 to 100%, alternatively about 1 to about
80%, alternatively about 2 to about 70%, alternatively about 3 to about
60%, alternatively about 4 to about 50%, alternatively about 5 to about
40% by weight based on the total polymer.
[0214] In one embodiment, the co-monomer system with which the monomers of
the present invention are reacted comprises a co-monomer which comprises
a vinyl group. In one embodiment, the co-monomer which comprises a vinyl
group is one in which the vinyl group is directly attached to a
[0215] Advantageously, for a copolymerisation reaction to be effective,
the reactivity rates of the two co-monomers need to be closely matched.
Thus, as the monomers of the present invention include a terminal vinyl
group, it is possible to generate a whole new class of polymers which
include a zwitterionic functionality, because it enables vinyl systems of
differing reactivity, which are useful in ophthalmic applications, to be
used as co-monomers in place or together with acrylic monomers. These
polymer products cannot be produced using the presently used methacrylate
monomers, such as MPC, due to solubility issues and the difference in
reaction rate between methacrylate and vinyl systems.
[0216] Where the polymers of the present invention have been obtained by
reaction with a comonomer system which includes a siloxane monomer, as a
consequence of the presence of the terminal vinyl group, the zwitterionic
group and the siloxane functionality, the polymers of the present
invention are particularly useful in the manufacture of ophthalmic
lenses, in particular contact lenses.
[0217] Therefore, in a further aspect, the present invention provides an
article, in particular an ocular device, comprising a polymer as defined
herein. Preferably, the ocular device is an ophthalmic lens, preferably a
[0218] An ophthalmic lens is a lens which, in use, will be placed in
intimate contact with the eye or tear fluid. The term "ophthalmic lens"
is intended to include contacts lenses for vision correction, contact
lenses for changing eye colour, ophthalmic drug delivery devices and
ocular tissue protective devices.
[0219] The ophthalmic lenses of the present invention may be manufactured
by applying an appropriate amount of a mixture of a monomer of the
present invention and the co-monomer system with which it is to be
reacted to a lens mold cavity and initiating polymerization. Initiators,
including photoinitiators, which are commercially available may be added
to the mixture to aid initiation of the polymerization. As described
previously, polymerization may be initiated by a number of well known
techniques depending on the exact nature of the mixture. Examples of
suitable techniques include application of radiation such as microwave,
e-beam or ultraviolet. Alternatively, polymerization may be initiated by
[0220] In contrast to other tissues which receive oxygen from blood flow,
the cornea receives oxygen primarily from the corneal surface which is
exposed to the environment. Therefore, an ophthalmic lens which is
intended to be worn on the eye for extended periods of time must allow
sufficient oxygen to permeate through the lens in order to sustain
corneal health. It is possible to detect when the cornea has received an
inadequate supply of oxygen because it will swell. Preferably, the oxygen
permeability of the ophthalmic lenses of the present invention is
sufficient to prevent any clinically significant swelling of the cornea
from occurring. In one embodiment, the extent of corneal swelling
observed is about 10% or less over at least 8 hours, about 8% or less
over at least 8 hours, about 6% or less over at least 8 hours, about 4%
or less over at least 8 hours, about 2% or less over at least 8 hours,
about 1% or less over at least 8 hours.
[0221] In this regard, preferably an ophthalmic lens of the present
invention is suitable for extended wear. Advantageously, the ophthalmic
lenses of the present invention may be worn by a user for up to 4 days or
more, in one embodiment 7 days or more, in one embodiment 14 days or
more, in one embodiment 30 days or more, without causing substantial
corneal damage or user discomfort.
[0222] Accordingly, in one embodiment, the article of the present
invention has an oxygen permeability of about 20 barriers or more,
alternatively about 30 barriers or more, alternatively about 40 barriers
or more, alternatively about 50 barriers or more, preferably about 60
[0223] In one embodiment, the polymer of the present invention has an
equilibrium water content of 10% or more, 15% or more, 20% or more, 25%
or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more,
55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or
more, 85% or more, 90% or more, 95% or more. In one embodiment, the water
content of the polymer is in the range from about 20 to about 60%,
preferably about 30 to about 50%.
[0224] Alternatively or in addition, the polymers of the present invention
may have a tensile modulus (modulus of elasticity, E) of less than about
3 MPa. In one embodiment, the tensile modulus is in the range from 0.2 to
about 2.5 MPa, in one instance about 0.3 to 1.5 MPa, preferably about 0.4
to about 1 MPa.
[0225] Alternatively or in addition, the articles of the present invention
may have an optical transmission of about 80% or more, about 85% or more,
about 90% or more, about 95% or more, about 99% or more. In a preferred
embodiment, the articles of the present invention are transparent and/or
clear which is particularly advantageous where the article is an ocular
[0226] Alternatively or in addition, the articles of the present invention
may have a % of scattered visible light (haze) of <100%, in one
embodiment, <80%, in one embodiment, <60%, in one embodiment
<50%, measured according to the standard ASTM D 1003.
[0227] In one embodiment, the polymers of the present invention may be
used to biocompatibilise a surface. Thus, in a further aspect, the
present invention provides a process for biocompatibilising a surface
comprising coating the surface with a polymer of the present invention.
The invention further provides an article comprising a surface having
coated thereon a polymer as defined herein. The polymers of the present
invention may be used to coat many different surfaces, depending on the
nature of the groups which are present in the polymer and capable of
binding it to the surface.
[0228] Coating of a surface with the polymer may generally be carried out
by coating the surface with a solution or dispersion of the polymer,
generally in an alcoholic, aqueous, organic or halogenated solvent or a
mixture thereof. Examples of suitable solvents include methanol, ethanol,
dichloromethane and freon. Coating may be carried out at room temperature
or at an elevated temperature. Generally, coating is carried out at a
temperature in the range from 5 to 60° C.
[0229] Surfaces may be coated with the polymers of the present invention
by known techniques, such as dip-coating, spray-coating, web-coating or
[0230] In one embodiment, the polymer is coated onto the surface in the
form of a microdispersion, such as a microemulsion.
[0231] After coating, where the polymer of the present invention includes
cross-linkable groups, it may be subjected to a cross-linking reaction.
The cross-linking may be carried out by known methods, for example
thermally, using actinic radiation, using reactive gases, for example
ammonia, by changing the pH, using difunctional additives or by using
activation chemistries, for example by known methods as described in
"Methods in Enzymology, volume 135, Immobilised Enzymes and Cells, part
B", Ed. K. Mosbach, Academic Press Inc., New York, 1987. In cases where
crosslinking is achieved thermally or by gas treatment, the treatment may
be carried out on the dried coating. Alternatively, where the pH needs to
be changed or additives need to be included, treatment may be performed
on the coated material in a solution which does not remove the coating.
In some embodiments, crosslinking may be carried out with the coating
hydrated which facilitates the crosslinking reaction.
[0232] The polymers of the present invention may be used to coat a surface
of materials which can be used as a construction material for implants or
prostheses for the human or animal body, particularly where these
implants or prostheses have direct physical contact with blood and where
biocompatibility and haemocompatibility are required. They can also be
used in the construction of membranes and other devices that are to be
brought into contact with blood or other body fluids on an
extra-corporeal basis, for example in heart-lung machines or artificial
[0233] The polymers of the present invention may also be used to coat
materials used in processing applications, for example separation
membranes and process equipment and tubing. In particular, the polymers
of the present invention may be used to modify the surface properties of
biofiltration membranes in bioreactors and fermentation systems where the
membranes come into direct contact with complex biological solutions
containing e.g. proteins, polysaccharides, fats and whole cells. The
polymers of the present invention may be useful in reducing membrane
fouling by components of a process solution.
[0234] When the polymers of the present invention are used to coat the
surface of a material which is then used in the construction coat of
finished devices, it may be necessary to take precautionary steps to
ensure that the coated surface is not damaged and the effectiveness of
the treatment reduced before the finished device is produced.
[0235] The polymers of the present invention may be used to coat finished
implants, prostheses, membranes, catheters, contact lenses, intraocular
lenses, and other devices to impart biocompatibility to the article.
[0236] Therefore, in a further aspect, the present invention provides an
article comprising a surface having a coating thereon of a polymer of the
[0237] In one embodiment, the article is an ocular device, in particular
an ophthalmic lens, in particular a contact lens.
[0238] Several illustrative embodiments of the invention are described by
the following enumerated clauses: [0239] 1. A monomer of formula (I):
[0239] ##STR00042## [0240] wherein:[0241] W is
(CR12)n;[0242] X is O, S or NR2;[0243] Y is a
linker group;[0244] Z is a zwitterionic group;[0245] each R1 is
independently selected from H, halogen or C1-4 alkyl;[0246] R2
is H or C1-4 alkyl;[0247] n is an integer from 0 to 6; and[0248] m
is an integer from 0 to 6. [0249] 2. A monomer according to clause 1,
wherein Y is selected from the group consisting of C1-10 alkylene,
--C(O)--, --C(S)--, --C(O)O--, --C(O)S--, C(O)N(RM)--, --C(S)--,
--C(S)O--, --C(S)S-- and --C(S)N(RM)--, wherein RM is hydrogen
or C1-4 alkyl and wherein the alkylene, alkenylene, alkynylene,
--S(O)2--N(C1-C10 alkyl)2 and ═O.[0250] 3. A
monomer according to clause 1, wherein X is O.[0251] 4. A monomer
according to clause 1, wherein X is NR2.[0252] 5. A monomer
according to clause 4, wherein R2, Y and the N atom to which they
are bonded taken together form a 5 to 7 membered heterocyclic ring,
--S(O)2--N(C1-C10 alkyl)2 and ═O.[0253] 6. A
monomer according to clause 5, wherein R2, Y and the N atom to which
[0254] 7. A monomer according to clause 6, wherein the 5-membered
heterocyclic ring is substituted with ═O.[0255] 8. A monomer
according to clause 7, which has the formula (IA):
[0255] wherein W, R1, R2 and Z as defined for formula (I).
[0256] 9. A monomer according to clause 8, wherein n is 0.[0257] 10. A
monomer according to any one of clauses 1 to 4, wherein Y is --C(O)O--
and m is 1 to 4.[0258] 11. A monomer according to clause 10, wherein m
is 2.[0259] 12. A monomer according to any one of clauses 1 to 8,
wherein m is 0.[0260] 13. A monomer according to any preceding clause,
wherein Z is a zwitterionic group selected from the group consisting of
(HA), (IIB), (IIC), (IID) and (IIE), wherein group (IIA) has the formula:
[0260] ##STR00044## [0261] wherein each R3 and R3A is
independently selected from hydrogen and C1-4 alkyl and a is an
integer from 2 to 4; [0262] group (IIB) has the formula:
[0262] ##STR00045## [0263] wherein each R4 and R4A is
integer from 1 to 4; [0264] group (IIC) has the formula:
[0264] ##STR00046## [0265] wherein each R5 and R5C is
independently selected from hydrogen and C1-4 alkyl; R5A is
or methyl, B1 is selected from the group consisting of a bond;
C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene,
C3-10 cycloalkylene, C3-10 cycloalkenylene, C1-10
heteroalkylene, C2-10 heteroalkenylene, C2-10 heteroalkynylene,
arylene, heteroarylene, --C(O)RM--, --C(O)ORM--, wherein
RM is selected from the group consisting of C1-10 alkylene,
C2-10 alkenylene and C2-10 alkynylene, and wherein the
is O and otherwise z is 1; [0266] group (IID) has the formula:
[0266] ##STR00047## [0267] wherein each R6 and R6C is
independently selected from hydrogen and C1-4 alkyl; R6A is
hydrogen or a group --C(O)B2R6B, wherein R6B is hydrogen
or methyl, B2 is selected from the group consisting of a bond;
is O and otherwise z is 1; [0268] group (HE) has the formula:
[0268] ##STR00048## [0269] wherein each R7 and R7C is
independently selected from hydrogen and C1-4 alkyl; R7A is
hydrogen or a group --C(O)B2R7B, wherein R7B is hydrogen
C3-10 cycloalkylene, C3-10 cycloalkenylene, heteroalkylene,
is O and otherwise z is 1;[0270] 14. A monomer according to any
preceding clause, wherein Z is a group (JIB).[0271] 15. A monomer
according to clause 14, wherein R4 is methyl and b is 2.[0272] 16.
A monomer according to any preceding clause, wherein n is O or I.[0273]
17. A monomer according to clause 16, wherein n is 0.[0274] 18. A
monomer according to clause 1, wherein n is 0; X is NR2; Y, R2
and the N atom to which they are bonded together form a 5-membered
heterocyclic ring substituted with =0; x is 2; and Z is a group of
formula (IIB), wherein each R4 is methyl and b is 2.[0275] 19. A
monomer according to clause 1 of formula (IB):
[0275] ##STR00049## [0276] wherein W, X and Z, R1, R2, n
and m are as defined in connection with formula (I) in clause I, V is S
or O; and A is selected from NRM, O and S, wherein RM is
hydrogen or C1-4 alkyl.[0277] 20. A monomer according to clause 1
of formula (IC):
[0277] ##STR00050## [0278] wherein W, X, Y, R1, R2, m and n
are as defined in clause 1, each R4 and R4A is independently
selected from hydrogen and C1-4 alkyl and b is an integer from 1 to
4.[0279] 21. A monomer according to clause of formula (ID):
[0279] ##STR00051## [0280] wherein W is as defined in connection with
formula (I), each R4 and R4A is independently selected from
hydrogen and C1-4 alkyl and b is an integer from 1 to 4.[0281] 22.
A monomer according to clause 1, which has formula (IE):
[0281] ##STR00052## [0282] wherein W is as defined in connection with
hydrogen and C1-4 alkyl and b is an integer from 1 to 4.[0283] 23.
A polymer obtainable by reacting a monomer as defined in any preceding
clause with a co-monomer system.[0284] 24. A polymer according to clause
23, wherein the co-monomer system comprises a siloxane group-containing
monomer or macromer.[0285] 25. A polymer according to clause 24, wherein
the siloxane group-containing monomer is a material of formula (A) or
[0285] (T1-Y1)k-G1(Y2--Z)l (A)
[0286] wherein[0287] T1 is a polymerisable group;[0288] Y1
and Y2 are each independently a linker group selected from the group
--C(O)S--C1-12 alkylene, --C(O)N(R1'')--C1-12 alkylene,
--S(O)2--N(C1-C10 alkyl)2 and ═O;[0289] Y3
is a linker group;[0290] R24 is a C1-12 alkyl group which may
be optionally substituted with one or more RN;[0291] G1 is a
siloxane group-containing component;[0292] Z is a zwitterionic group;
[0293] k is an integer from 1 to 10;[0294] l is an integer from 1 to 3;
[0295] u is an integer from 1 to 3; and[0296] v is an integer from 1 to
3. [0297] 26. A polymer according to clause 24 or clause 25, wherein
the co-monomer system comprises a monomer comprising a vinyl group.
[0298] 27. A polymer according to any one of clauses 24 to 26, which has
an oxygen permeability of about 30 barriers or more.[0299] 28. A polymer
according to any one of clauses 24 to 27, which has an equilibrium water
content in the range from 30 to 50%.[0300] 29. A polymer according to
any one of clauses 24 to 28, which has a modulus of less than 3 MPa.
[0301] 30. An article comprising a polymer as defined in any one of
clauses 24 to 29.[0302] 31. An article according to clause 30, which is
an ophthalmic lens.[0303] 32. An article according to clause 31, which
is a contact lens.[0304] 33. An article comprising a surface having
coated thereon a polymer as defined in any one of clauses 24 to 29.
[0305] 34. An article according to clause 33, which is a contact lens.
[0306] 35. A method of coating an article having a surface comprising
applying a polymer as defined in any one of clauses 24 to 29 to the
surface of the article.
[0307] The Young's modulus of the lens materials were determined using a
TA-XT2 Texture Analyser, and the value was obtained by drawing a tangent
to the initial linear portion of the stress-strain curve, and dividing
the tensile stress by the corresponding strain. Measurements were
performed on films of 500 μm thickness prepared from the formulations
and cut into 10 mm×50 mm samples.
[0308] The Equilibrium Water Contents (EWC) of the prototype hydrogel
lenses produced according to the present invention were determined by
gravimetric means. The wet weight of lenses after equilibration in water
at room temperature overnight was first measured. The lenses were then
dried in an oven at 70° C. to a constant weight, which was the dry
weight. The EWC of the lenses was then calculated as follows.
EWC(wt %)=[(wet weight-dry weight)/wet weight]*100
[0309] The oxygen permeability (in barriers) of prototype lenses produced
according to the method of the present invention was determined by the
polargraphic method generally described in ISO 9913-1:1996(E).
[0310] The following examples describe the syntheses of monomers of
formula (I). These examples are intended to illustrate the invention and
are not to be construed as being limitations thereon.
2-(3-oxyethyl-1-vinylpyrrolidin-2-one)-2'-(trimethylammonium)-ethyl
phosphate, inner salt (HEVP-PC)
[0311] The reactions carried out in Example 1 are summarised in scheme I
(i) Preparation of (2-iodoethoxy)-tert-butyldimethylsilane
[0312] To a stirred solution of 2-iodoethanol (17.2 g; 100 mmol) and
imidazole (8.17 g; 120 mmol) in dichloromethane (100 mL) was added
tert-butyldimethylsilyl chloride (15.83 g; 105 mmol) at such a rate that
the reaction temperature did not rise above 30° C. Upon complete
addition the solution was left stirring for 17 h, then washed with water
(2×50 mL) and brine (50 mL) and dried over MgSO4. Evaporation
of the solvent afforded the target compound (28.0 g; 97.8 mmol; 98%) as a
[0313] 1H-NMR (400 MHz) (CDCl3): δ=3.83 (t, 2H, J=7.0 Hz),
3.83 (t, 2H, J=7.0 Hz), 3.20 (t, 2H, J=7 Hz), 0.90 (s, 9H), 0.08 (s, 6H)
(ii) Preparation of
3-[2-(tert-butyldimethylsilanyloxy)-ethyl]-1-vinylpyrrolidin-2-one
(TBSE-VP)
[0314] To a stirred ice-cold solution of diisopropylamine (0.46 mL; 3.3
mmol; 1.1 equiv.) in dry tetrahydrofuran (20 mL) was dropwise added a
2.5m solution of n-butyllithium (1.32 mL; 3.3 mmol; 1.1 equiv.) under an
argon atmosphere. Upon complete addition the solution was left stirring
for 10 min and then cooled to around -80 to -70° C.
1-vinylpyrrolidin-2-one (0.32 mL; 3.0 mmol) was added dropwise and the
solution was left stirring for 20 min. Hexamethylphosphoramide (0.57 mL;
3.3 mmol; 1.1 equiv.) was added and the solution left stirring for
further 20 min. To the solution was dropwise added
(2-iodoethoxy)-tert-butyldimethylsilane (859 mg; 3.0 mmol) and the
solution was left stirring at around -80 to -70° C. for 17 h. The
reaction mixture was warmed to ambient temperature and quenched with a
saturated aqueous solution of NH4Cl (15 mL). The aqueous phase was
extracted with diethyl ether (2×15 mL), the combined organic
extracts were dried over MgSO4 and concentrated under reduced
pressure. Column chromatography (ethyl acetate/petroleum ether (b.p.
40-60° C.)=1:9) afforded by-product
3,3-bis-[2-(tert-butyldimethylsilanyloxy)-ethyl]-1-vinylpyrrolidin-2-one
([TBSE] 2-VP) (49 mg; 0.115 mmol; 4%) as a colourless liquid. Further
elution with ethyl acetate/petroleum ether (b.p. 40-60° C.) (1:4)
afforded the target compound
(TBSE-VP) (621 mg; 2.30 mmol; 77%) as a colourless liquid.
[0315] 1H-NMR (400 MHz) (CD3OD): δ=7.01 (dd, 1H,
--CH═CH2, Jcis=9.1 Hz, Jtrans=16.0 Hz), 4.53 (d, 1H,
═CH2, Jtrans=16.0 Hz), 4.49 (d, 1H, ═CH2,
Jcis=9.1 Hz), 3.83-3.70 (m, 2H, --CH2O--), 3.57 (td, 1H,
--CHIN--, J=9.9 Hz, 3.0 Hz), 3.48-3.40 (m, 1H, --CH2N--),
2.76-2.65 (m, 1H, --CH--(C═O)--), 2.39-2.28 and 1.90-1.79 (2×m,
2H, --CH2--CH2N--), 2.10-2.00 and 1.63-1.52 (2×m, 2H,
--CH2--CH2O--), 0.90 (s, 9H, --C(CH3)3), 0.07 (s, 6H,
--Si(CH3)2--) ppm.
(iii) Preparation of 3-(2-hydroxyethyl)-1-vinylpyrrolidin-2-one (HE-VP)
[0316] To a stirred and ice-cold solution of
(TBSE-VP) (269 mg; 1.0 mmol) in dry tetrahydrofuran (10 mL) was dropwise
added a 1.0m solution of tetrabutylammonium fluoride (2.0 mL; 2.0 mmol;
2.0 equiv.) under an argon atmosphere. Upon completion of the addition
the reaction mixture was left stirring at 0° C. for 5 min, allowed
to warm to ambient temperature over 5 min and left stirring for another
40 min. The reaction mixture was partitioned between water (5 mL) and
ethyl acetate (10 mL) and the aqueous phase was extracted with ethyl
acetate (3×5 mL). The combined organic extracts were dried over
MgSO4 and concentrated under reduced pressure. Column chromatography
(ethyl acetate) afforded the target compound (135 mg; 0.87 mmol; 87%) as
a pale yellow liquid.
[0317] 1H-NMR (400 MHz) (CD3OD): δ=7.02 (dd, 1H,
--CH═CH2, Jcis=9.1 Hz, Jtrans=16.0 Hz), 4.54 (d, 1H,
═CH2, Jtrans=16.0 Hz), 4.50 (d, 1H, ═CH2,
Jcis=9.1 Hz), 3.75-3.62 (m, 2H, --CH2O--), 3.59 (td, 1H, J=9.8
Hz, 3.0 Hz), 3.44 (dt, 1H, J=10.2 Hz, 8.2 Hz), 2.70 (qd, 1H,
--CH--(C═O)--, J=9.1 Hz, 5.0 Hz), 2.36 (dddd, 1H,
--CH2--CH2N--, J=15.7 Hz, 8.8 Hz, 7.9 Hz, 2.9 Hz), 2.06 (dddd,
1H, --CH2--CH2O--, J=19.1 Hz, 7.8 Hz, 6.6 Hz, 5.0 Hz), 1.80
(ddd, 1H, --CH2--CH2N--, J=17.8 Hz, 12.8 Hz, 9.2 Hz), 1.56
(ddt, 1H, --CH2--CH2O--, J=13.8 Hz, 9.2 Hz, 5.7 Hz) ppm.
(iv) Preparation of
[0318] To a stirred and chilled (-10° C.) solution of
2-chloro-2-oxo-1,3,2-dioxaphospholane (4.58 g; 32.1 mmol; 1.04 equiv.) in
acetonitrile (3 g) was dropwise added a solution of
3-(2-hydroxyethyl)-1-vinylpyrrolidin-2-one (4.80 g; 30.9 mmol) and
N,N,N',N'-tetramethylethylenediamine (1.98 g; 17.1 mmol; 0.55 equiv.) in
acetonitrile (7 g). Upon completion of the addition the reaction mixture
was left stirring for 15 min, filtered under an argon atmosphere and the
N,N,N',N'-tetramethylethylenediaminedihydrochloride precipitate washed
with dry acetonitrile (7 g) to give a filtrate comprising a solution of
2-(3-oxyethyl-1-vinylpyrrolidin-2-one)-2-oxo-1,3,2-dioxaphospholane in
[0319] To the stirred and chilled phospholane solution was added
4-methoxyphenol (4 mg; 0.029 mmol), acetonitrile (30 g) and
trimethylamine (3.7 g; 62.6 mmol; 2.02 equiv.) and the reaction mixture
was heated in a closed system (water condenser fitted with balloon) at
70° C. for 19 h. The reaction mixture was concentrated (ca. 10 to
20 mL of acetonitrile and excess trimethylamine removed) under vacuum and
the product allowed to crystallise out of solution at 5° C. and
allowed to warm to ambient temperature. The crystalline product was
filtered under argon atmosphere, successively washed with acetonitrile (6
mL) and ethyl acetate (3×6 mL) and dried in vacuo at ambient
temperature to afford 2.95 g of a white powder comprising the target
compound (2.83 g; 8.83 mmol; 29%) and residual acetonitrile (0.12 g; 2.94
[0320] 1H-NMR (400 MHz) (CD3OD): δ=7.01 (dd, 1H,
Jcis=9.1 Hz), 4.31-4.23 (m, 2H, --OCH2--CH2N+--),
4.10-3.93 (m, 2H, --CH--CH2--CH2O--), 3.67-3.62 (m, 2H,
--CH2N+--), 3.62-3.55 and 3.49-3.40 (2×m, 2H,
--CH2N--), 3.23 (s, 9H, --N+(CH3)3), 2.81-2.72 (m,
1H, --CH--(C═O)--), 2.39-2.28 and 1.90-1.79 (2×m, 2H,
--CH2--CH2N--), 2.10-2.00 and 1.63-1.52 (2×m, 2H,
--CH--CH2--CH2O--) ppm. 13C-NMR (100 MHz) (CD3OD):
δ=176.39 (--(C═O)--), 129.38 (--CH═CH2), 95.00
(═CH2), 66.69 (--CH2N+--), 63.86 and 63.80
(--CH--CH2--CH2O--), 59.56 and 59.51
(-0CH2--CH2N+--), 53.91, 53.87 and 53.81
(--N+(CH3)3), 43.47 (--CH2N--), 39.90
(--CH--(C═O)--), 32.51 and 32.42 (--CH--CH2--CH2O--), 24.82
(--CH2--CH2N--) ppm. 31P-NMR (162 MHz) (CD3OD):
δ=-0.14 ppm. HRMS (ESI) for C13H26N2O5P
[M+H]+: calculated: 321.1574
Preparation of 2-(trimethylammonium)ethyl-2-(vinyloxycarbonylamino)ethyl
phosphate, inner salt (HEVC-PC)
[0321] The reactions carried out in Example 2 are summarised in scheme 2
[0322] To a stirred and chilled (-10° C.) solution of
2-chloro-2-oxo-1,3,2-dioxaphospholane (5.00 g; 35.1 mmol) in acetonitrile
(3 g) was dropwise added a solution of N-hydroxyethyl-O-vinylcarbamate
(HEVC) (4.60 g; 35.1 mmol) and N,N,N',N'-tetramethylethylenediamine (2.24
g; 19.3 mmol; 0.55 equiv.) in acetonitrile (7.5 g). Upon completion of
the addition the reaction mixture was left stirring for 1 h, filtered
under an argon atmosphere and the N,N,N',N'-tetramethylethylenediamine
dihydrochloride precipitate washed with dry acetonitrile (8 g) to give a
filtrate comprising a solution of
2-(N-oxyethyl-O-vinylcarbamate)-2-oxo-1,3,2-dioxaphospholane in
[0323] To the stirred and chilled phospholane solution was added
4-methoxyphenol (20 mg; 0.161 mmol), acetonitrile (35 g) and
trimethylamine (3.67 g; 61.4 mmol; 1.75 equiv.) and the reaction mixture
70° C. for 17 h. The reaction mixture was concentrated (ca. 10 mL
of acetonitrile and excess trimethylamine removed) under vacuum and the
product allowed to crystallise out of solution at around -25° C.
[0324] The crystalline product was rapidly filtered and dried in vacuo at
ambient temperature to afford the target compound (1.08 g; 3.65 mmol;
10%) as an off-white solid.
[0325] 1H-NMR (400 MHz) (CD3OD): δ=7.16 (dd, 1H,
--CH═CH2, Jcis=6.3 Hz, Jtrans=14.0 Hz), 4.71 (dd, 1H,
═CH2, Jgem=1.4 Hz, Jtrans=14.0 Hz), 4.41 (dd, 1H,
═CH2, Jgem=1.4 Hz, Jcis=6.3 Hz), 4.32-4.23 (m, 2H,
--OCH2--CH2N+--), 3.93 and 3.91 (2×t, 2H,
--NH--CH2--CH2O--, J=5.5 Hz), 3.68-3.60 (m, 2H,
--CH2N+--), 3.37 (t, 2H, --NH--CH2--, J=5.5 Hz), 3.22 (s,
9H, --N+(CH3)3) ppm. 31P-NMR (162 MHz) (CD3OD):
δ=-0.12 ppm.
Preparation of 2-(trimethylammonium)ethyl-2-(vinylaminocarbonyloxy)ethyl
phosphate, inner salt (VAC-PC)
[0326] The reaction carried out in Example 3 is summarised in Scheme 3
[0327] Hydroxyethylphosphorylcholine (0.11 g, 0.4 mmol) as a suspension in
dimethylsulphoxide (1.2 g) with tris(2-(2-methoxyethoxy)ethyl)amine (0.04
g, 0.1 mmol) was stirred under a nitrogen atmosphere while
vinylisocyanate (0.04 g, 0.6 mmol) was added portion wise over 15
minutes. The mixture was stirred at room temperature for 3 days and then
the solution was added to MEK (30 g) under nitrogen and stirred for 30
minutes. The white solid that separated was collected by filtration,
washed with MEK and dried under vacuum (0.09 g, 0.3 mmol, 63%).
[0328] 1H-NMR (400 MHz) (d6DMSO): δ=6.55 (1H, m), 4.52
(1H, d), 4.15 (1H, d), 4.10 (2H, m), 4.02 (2H, m), 3.78 (2H, m), 3.52
(2H, m) and 3.15 (9H, s) ppm, 13C-NMR (100 MHz) (d6DMSO):
δ=157.2, 130.9, 92.9, 65.5, 62.3, 62.3, 58.2 and 53.1 ppm,
31P-NMR (162 MHz) (d6DMSO): δ=-0.12 ppm.
Polymer Systems were Made Using the Following General Procedure
[0329] Monomer components indicated in table 1 were mixed, degassed using
argon and heated to 70° C. for 1 hr. to give the cross-linked
polymer systems derived from the monomer feedstocks.
NVP- HEVC-
Formulation PC PC HEMA VP DMA SC1 SC6 EGDMA PD16
LN007/2/201 14.74 0 49.14 0 0 0 34.40 0.74 0.98
LN007/2/202 19.66 0 44.23 0 0 0 34.40 0.74 0.98
LN007/2/203 9.83 0 58.97 0 0 0 29.48 0.74 0.98
LN007/2/204 4.91 0 63.88 0 0 0 29.48 0.74 0.98
LN007/2/205 9.83 0 68.8 0 0 0 19.66 0.74 0.98
LN007/2/206 4.91 0 73.71 0 0 0 19.66 0.74 0.98
LN007/2/292 14.74 0 24.57 18.67 10.81 29.48 0 0.74 0.98
LN007/2/207 9.83 0 88.45 0 0 0 0 0.74 0.98
LN007/2/208 19.66 0 78.62 0 0 0 0 0.74 0.98
LN007/2/213 15.71 0 83.05 0 0 0 0 0.75 0.49
LN007/2/369 15.71 0 83.05 0 0 0 0 0.75 0.49
LN007/2/354 9.83 0 58.97 0 0 29.48 0 0.74 0.98
LN007/2/355 19.66 0 49.14 0 0 29.48 0 0.74 0.98
LN007/2/214 8.85 0 24.57 24.57 10.81 29.48 0 0.74 0.98
LN007/2/215 7.85 0 90.91 0 0 0 0 0.75 0.49
LN007/2/370 8.85 0 24.57 24.57 10.81 29.48 0 0.74 0.98
LN007/2/393 0 7.37 90.91 0.00 0.00 0.00 0.00 0.74 0.98
[0330] This example describes the general procedure for preparing
polymerisable materials and corresponding contact lenses (Table 2).
Unless otherwise stated, all the materials were used as received.
[0331] Each component of the polymerisable system including the monomers,
cross linker (EGDMA) and initiator (PD16) was weighed and added to a
glass vial. The vials were sealed with a cap and then placed on a roller
mixer at room temperature until all components were fully dissolved.
After dissolution, the mixture was filtered through a 0.45 micron filter
and the solution was de-oxygenated by gently bubbling dry argon gas
through the formulation.
[0332] Polypropylene contact lens molds were cleaned by rinsing with 20%
Decon 90 in water followed by drying in an oven at 70° C. for 30
min. The female molds were filled with the formulation and the male molds
were added to the female molds. The molds were then placed in an oven
preheated to 70° C. for 1 hour.
[0333] After cooling, the molds were immersed in purified water overnight
to de-mold the lenses.
1. Mixing weigh components used to form the polymerisable
solution into a glass vial
seal the vial with a lid
place on a roller-mixer at room temperature until fully
dissolved, filter through 0.45 micron membrane and de-
2. Preparation and rinse the plastic molds with 20% Decon 90 in water
filling the molds dry the molds in an oven at 70° C. for 30 min
fill the molds with the polymerisable solution and close
3. Polymerization preheat the oven to 70° C.
place the material-containing molds in the oven for 1 hr
and then allow to cool for 30 mins
4. Hydration and place the lenses/molds in purified water
Demolding open the molds and leave overnight
remove the lenses from the molds
[0334] The monomers were mixed with other components as listed in table 3
below and used to form contact lenses according to the methodology set
out in table 2. The abbreviations and corresponding full names of the
components are listed in Table 4.
Components (wt %) Water
NVP- HEVC- Hydrogel content
Formulation PC PC HEMA VP DMA SC1 EGDMA PD16 appearance (%)
LN007/2/207 9.83 0 88.45 0 0 0 0.74 0.98 clear nd
LN007/2/208 19.66 0 78.62 0 0 0 0.74 0.98 clear nd
LN007/2/213 15.71 0 83.05 0 0 0 0.75 0.49 clear 58.3
LN007/2/354 9.83 0 58.97 0 0 29.48 0.74 0.98 clear 32.6
LN007/2/355 19.66 0 49.14 0 0 29.48 0.74 0.98 clear 42.6
LN007/2/214 8.85 0 24.57 24.57 10.81 29.48 0.74 0.98 clear 38.5
LN007/2/215 7.85 0 90.91 0 0 0 0.75 0.49 clear 47.7
LN007/2/370 8.85 0 24.57 24.57 10.81 29.48 0.74 0.98 clear 40.9
LN007/2/393 0 7.37 90.91 0 0 0 0.74 0.98 slightly 37.0
NVP-PC 2-(3-Oxyethyl-1-vinylpyrrolidin-2-one)-
2'-(trimethylammonium)-ethyl phosphate, inner salt
HEVC-PC 2-(Trimethylammonium)ethyl-
2-(vinyloxycarbonylamino)ethyl phosphate, inner salt
VP N-Vinylpyrrolidone
SCI (3-Methacryloxy-2-hydroxypropoxy)-
propylbis(trimethylsiloxy)-methylsilane
SC6 Poly(dimethylsiloxane), monomethacryloxypropyl
substituted, di-hydroxypropyl terminated
EGDMA Ethyleneglycoldimethacrylate
PD16 Bis(tert-butylcyclohexyl) peroxydicarbonate
[0335] The equilibrium water content (EWC) of certain of the prototype
lenses was determined by gravimetric means. The wet weight of the lens
after equilibration in water at room temperature overnight was first
measured. The lens was then dried in an oven at 70° C. to a
constant weight, which was the dry weight. The water content of the
lenses was calculated as follows.
[0336] The EWC of certain of the polymers of example 6 are shown in table
2010-08-05Resin composition blended with starchy material
2012-05-03Biodegradable and biocompatible waterborne polyurethane
2008-11-06Flexible hydrogel-based functional composite materials
2009-12-10Fibre-reinforced thermoplastic material
2010-06-03Fiber reinforced composite material
2013-07-04Methods for using allylic oxidation catalysts to perform oxidation reactions
2013-06-13Compositions, methods and articles produced by compounding polyamides with olefin-maleic anhydride polymers
2013-05-16Polymerisable material
2013-03-07Methods for producing biocompatible materials