Note: Descriptions are shown in the official language in which they were submitted.
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FAT-BINDING POLYMERS, OPTIONALLY COMBINED WITH LIPASE INHIBITORS
BACKGROUND OF THE INVENTION
Human obesity is a recognized health problem with approximately 97
million people considered clinically overweight in the United States. The
accumulation or maintenance of body fat bears a direct relationship to caloric
intake.
Therefore, one of the most common methods for weight control to combat obesity
is
the use of relatively low-fat, low calorie diets, that is, diets containing
less fat and
calories than a "normal diet" or that amount generally consumed by the
patient.
The presence of fats in a great many food sources greatly limits the food
sources which can be used in a low-fat diet. Additionally, fats contribute to
the
flavor, appearance and physical characteristics of many foodstuffs. As such,
the
acceptability of low-fat diets and the maintenance of such diets are
difficult.
Various chemical approaches have been proposed for controlling obesity.
Anorectic agents, such as dextroamphetamine, the combination of the non-
amphetamine drugs phentermine and fenfluramine ("Phen-Fen") and
dexfenfluramine (Redux) alone, are associated with serious side effects.
Indigestible
materials such as OLESTRATM, mineral oil or neopentyl esters (see U.S. Patent
No.
2,962,419) have been proposed as substitutes for dietary fat. Garcinia acid
and
derivatives thereof have been described as treating obesity by interfering
with fatty
acid synthesis. Swellable crosslinked vinyl pyridine resins have been
described as
appetite suppressants via the mechanism of providing non-nutritive bulk, as in
U.S.
Patent 2,923,662. Surgical techniques, such as temporary ileal bypass surgery,
are
employed in extreme cases.
However, methods for treating obesity, such as those described above, have
serious shortcomings with controlled diet remaining the most prevalent
technique
for controlling obesity. As such, new methods for treating obesity are needed.
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SUMMARY OF THE INVENTION
The present invention relates to a method for treating obesity, a method for
reducing the absorption of dietary fat, and a method for treating
hypertriglyceridemia in a patient and to particular polymers for use in the
methods
or in a manufacture of a medicament. The methods comprise the step of orally
administering to a mammal, such as a human, a therapeutically effective amount
of a
fat-binding polymer. The administration of a fat-binding polymer of the
invention
facilitates the excretion of fat from the body without digestion, with minimal
side
effects and low toxicity. In a preferred embodiment, the fat-binding polymers
are
administered in combination with a therapeutically effective amount of a
lipase
inhibitor, such as the pancreatic lipase inhibitors described in U.S. Patent
No.
4,598,089 to Hadvary et al. The combination administration can reduce
undesirable
side effects often encountered when lipase inhibitors, in particular, the
pancreatic
lipase inhibitors lipstatin and tetrahydrolipstatin are administered alone.
For
example, a serious side effect resulting from the administration of a lipase
inhibitor
is steatorrhea, or fatty stools.
The fat-binding polymers of the invention comprise at least one fat-binding
region. A fat-binding region can include a region having a positive charge, a
region
which is hydrophobic or a region having a positive charge and which is
hydrophobic.
In one embodiment, the fat-binding polymer is an aliphatic polymer selected
from the group consisting of polyalkylacrylates, polyacrylamides,
polyalkylmethacrylates, polymethacrylamides, poly-N-alkylacrylamides, poly-N-
alkylmethacrylamides, substituted derivatives thereof and copolymers thereof.
For
example, the substituted derivatives of the polymers can be characterized by
one or
more substituents, such as substituted or unsubstituted, saturated or
unsaturated
alkyl, and substituted or unsubstituted aryl groups. Suitable substituents to
employ
on the alkyl or aryl groups include, but are not limited to, cationic or
neutral groups,
such as alkoxy, aryl, aryloxy, aralkyl, halogen, amine, and ammonium groups.
For
example, the polymer can be poly(dimethylamino propylacrylamide),
poly(trimethylammonium ethylacrylate), poly(trimethylammonium ethyl
methacrylate), poly(trimethylammonium propyl acrylamide), poly(dodecyl
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acrylate), poly(octadecyl acrylate), poly(octadecyl methacrylate) and
copolymers
thereof.
In another embodiment, the fat binding polymer is a synthetic amine polymer
and pharmaceutically acceptable salts thereof. Amine polymers (or salts
thereof)
suitable for use in the invention include, but are not limited to, substitued
or
unsubstituted polymers or copolymers of the following monomers: allylamine,
diallyldimethyl ammonium, ethyleneimine, vinylamine, diallylamine,
vinylimidazole and diallylmethylamine.
In another embodiment, the fat binding polymer is an amine derivative of an
anhydride containing polymer.
In yet another embodiment, the fat-binding polymer is a hydroxyl-containing
polymer, for example, poly(vinylalcohol).
In a specific embodiment, the fat-binding polymer is an amine-containing
polymer wherein one or more hydrophobic regions are bound to a portion of the
amine nitrogens of the amine polymer. In a particular embodiment, between
about 1
and about 60 percent of the amine nitrogens are substituted, preferably
between
about 1 and about 30 percent.
In another embodiment, the hydrophobic region of the fat-binding polymer
can include a hydrophobic moiety, for example, a substituted or unsubstituted,
normal, branched or cyclic alkyl group having at least four carbons. In a
particular
embodiment, the hydrophobic moiety is an alkyl group of between about four and
thirty carbons.
In another embodiment, the hydrophobic region is a quaternary amine-
containing moiety having a terminal hydrophobic substituent. Suitable
hydrophobic
regions which can include a hydrophobic moiety and/or a quaternary amine-
containing moiety are described herein and in U.S. Patent Nos. 5,607,669,
5,679,717
and 5,618,530, the entire contents of which are incorporated herein by
reference in
their entirety.
The polymers of the present invention offer desirable pharmacological
properties such as excellent fat binding properties and low toxicity. In
addition,
when the fat-binding polymers are administered in combination with lipase
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inhibitors, as described herein, undesirable side effects experienced, such as
steatorrhea, when the lipase inhibitors are administered alone can be
lessened.
DETAILED DESCRIPTION OF THE INVENTION
S The features and other details of the invention will now be more
particularly
described and pointed out below as well as in the claims. It will be
understood that
the particular embodiments of the invention are shown by way of illustration
and not
as limitations of the invention. The principle features of this invention can
be
employed in various embodiments without departing from the scope of the
invention.
In one aspect, the invention relates to a method for treating obesity
comprising the step of orally administering to a mammal a therapeutically
effective
amount of one or more fat-binding polymers. In a preferred embodiment, the fat-
binding polymer is administered in combination with a therapeutically
effective
1 S amount of a lipase inhibitor.
In another aspect, the invention relates to a method for reducing the
absorption of dietary fat comprising the step of orally administering to a
mammal a
therapeutically effective amount of one or more fat-binding polymers. In a
preferred
embodiment, the fat-binding polymer is administered in combination with a
therapeutically effective amount of a lipase inhibitor.
In yet another aspect, the invention relates to a method for treating
hypertriglyceridemia in a mammal comprising the step of orally administering
to a
mammal a therapeutically effective amount of one or more fat-binding polymers.
In a preferred embodiment, the fat-binding polymer is administered in
combination
with a therapeutically effective amount of a lipase inhibitor.
A particular aspect of the invention relates to a method for treating
steatorrhea comprising the step of orally administering to a mammal a
therapeutically effective amount of a fat-binding polymer. In a specific
embodiment, the steatorrhea is a result of the administration of a lipase
inhibitor.
, The invention also relates to fat-binding polymers useful in the method of
the
invention.
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"Lipases" as that term is used herein, are ubiquitous enzymes which hydrolyze
ester
bonds in neutral lipids. Examples of lipases include, but are not limited to,
pancreatic and gastric lipases. The preferred substrates of lipases are
insoluble in
water. Lipases exhibit maximal activity in the presence of lipid/water
interfaces.
For example, pancreatic lipase, which is the key enzyme of dietary
triglyceride
absorption, exerts it activity at the water/lipid interface, in conjunction
with bile salts
and co-lipase.
"Lipase inhibitor" as that term is used herein refers to compounds which are
capable of inhibiting the action of lipases, for example, gastric and
pancreatic
lipases. Lipstatin and its tetrahydro derivative, Tetrahydrolipstatin, as
described in
U.S. Patent No. 4,598,089 to Hadvary et al., the entire content of which is
hereby
incorporated by reference, are potent inhibitors of both gastric and
pancreatic
lipases, as well as cholesterol ester hydrolase. Lipstatin is a natural
product of
microbial origin, and tetrahydrolipstatin is the result of catalytic
hydrogenation of
lipstatin. Other lipase inhibitors include a class of compound commonly
referred to
as Panclicins. Panclicins are analogues of Tetrahydrolipstatin (See e.g.,
Mutoh, M.,
et al., "Panclicins, Novel Pancreatic Lipase Inhibitors, II. Structural
Elucidation,"
The Journal ofAntibiotics, 47(12): 1376-1384 (1994), the entire content of
which is
hereby incorporated by reference.)
"Fat-binding polymers", as that term is used herein, are polymers which
absorb, bind or otherwise associate with fat thereby inhibiting (partially or
completely) fat digestion, hydrolysis, or absorption in the gastrointestinal
tract
and/or facilitate the removal of fat from the body prior to digestion. The fat-
binding
polymers comprise one or more fat-binding regions. "Fat-binding regions", as
defined herein can include a positively charged region, a hydrophobic region,
or a
region which is both positively charged and hydrophobic.
"Fats", as that term is used herein, are solids or liquid oils generally
consisting of glycerol esters of fatty acids. Sources of fats include both
animal and
vegetable fats, for example, triglyceride esters of saturated and/or
unsaturated fatty
acids, free fatty acids, diglycerides, monoglycerides, phospholipids and
cholesterol
esters are fats, as defined herein.
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A variety of polymers can be employed in the invention described herein.
The polymers are synthetic polymers which can be aliphatic, or aromatic.
However,
aliphatic and synthetic polymers are preferred. A "synthetic polymer", as that
term
is employed herein, is a polymer which is not obtainable from a natural source
either
directly or through a minor derivatization of the naturally occurnng form.
Further,
the polymer can be hydrophobic, hydrophilic or copolymers of hydrophobic
and/or
hydrophilic monomers. Particularly preferred polymers comprise monomers having
both cationic and hydroxy functional groups, and/or comprise a combination of
separate monomers each having either a cationic or hydroxy functional group.
Other
preferred polymers comprise monomers having both cationic and hydrophobic
groups, and/or comprise a combination of separate monomers each having either
a
cationic or a hydrophobic functional groups. As used herein the term
"combination
of monomers" or "combination of repeat units" means that at least one of each
monomer or at least one of each repeat unit are present in the resulting
polymerized
polymer in any order. Many polymers can be conveniently manufactured from
olefinic or ethylenic monomers (such as vinylalcohol, allylamine or acrylic
acid) or
condensation polymers. Examples of the preparation of preferred polymers of
the
invention are included in Examples 1-98.
For example, the polymers can include substituted or unsubstituted
polyvinylalcohol, polyvinylamine, poly-N-alkylvinylamine, polyallylamine, poly-
N
alkylallylamine, polydiallylamine, poly-N-alkyldiallylamine, polyalkylenimine,
other polyamines, polyethers, polyamides, polyacrylic acids,
polyalkylacrylates,
polyacrylamides, polymethacrylic acids, polyalkylmethacrylates,
polymethacrylamides, poly-N-alkylacrylamides, poly-N-alkylmethacrylamides,
polystyrene, polyvinylnaphthalene, polyethylvinylbenzene, polyaminostyrene,
polyvinylbiphenyl, polyvinylanisole, polyvinylimidazolyl, polyvinylpyridinyl,
polydimethylaminomethylstyrene, polydiallylmethylammonium chloride,
polytrimethylammonium ethyl methacrylate, polytrimethylammonium ethyl
acrylate, and copolymers thereof. In addition, the polymers can be further
characterized by one or more substituents such as substituted and
unsubstituted,
saturated or unsaturated alkyl, and substituted or unsubstituted aryl groups.
Suitable
groups to employ include cationic or neutral groups, such as alkoxy, aryl,
aryloxy,
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aralkyl, halogen, amine, ammonium groups, substituted or unsubstituted
oxypolyethylene oxide, and mono, di or higher hydroxyalkyl groups .
Particularly preferred polymers (or salts thereof) include substituted or
unsubstituted polydiethylammonium chloride , polyvinylimidazole,
polyalkylacrylates, polyacrylamides, polyalkylmethacrylates,
polymethacrylamides,
poly-N-alkylacrylamides, poly-N-alkylmethacrylamides and copolymers thereof.
These polymers can be further characterized by one or more substituents such
as
those discussed above.
Other particularly preferred polymers include aliphatic amine polymers, such
as polyallylamine, polydiallylamine, polydiallylmethylamine, polyvinylamine,
polyethylenimine. In a specific embodiment, the amine polymer comprises one or
more hydrophobic regions which are bound to a portion of the amine nitrogens
of
the amine polymer. In a particular embodiment, between about 1 and about 60
percent of the amine nitrogens are substituted, preferably between about 1 and
about
30 percent.
Additional particularly preferred polymers include malefic anhydride and
malefic anhydride olefinic copolymers, itaconic anhydride, and amine
derivatives
thereof. The amine derivatives may preferably contain dimethyl amino groups.
In one embodiment, the hydrophobic region of the fat-binding polymer can
include a hydrophobic moiety, for example, a substituted or unsubstituted,
normal,
branched or cyclic alkyl group having at least four carbons. In a specific
embodiment, the hydrophobic moiety is an alkyl group of between about four and
thirty carbons.
In another embodiment, the hydrophobic region is a quaternary amine-
containing moiety having a terminal hydrophobic substituent.
In yet another embodiment, the fat-binding region comprises a nitrogen, for
example, the nitrogen of an amine, capable of possessing a positive charge
under
conditions present in the gastro-intestinal tract. For example, a quaternary
amine-
containing moiety, or the nitrogen of a polyamine.
In yet another embodiment, the fat-binding polymer is a hydroxyl-containing
polymer, for example, poly(vinylalcohol) which can comprise further fat-
binding
regions. For example, the polymer comprises a repeat unit having the formula
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_g_
-[CHz-CH-]
O
R
wherein R is a hydrophobic region.
Preferred polymers are copolymers that comprise both cationic monomers such as
those containing nitrogen, and monomers with hydroxy groups.
Other polymers and methods of preparation, which can be used in the
claimed invention have been reported in the patent literature in, for example,
United
States Patent Nos. 5,487,888, 5496,545, 5,607,669, 5,618,530, 5,624,963,
5,667,775, and 5,679,717 and co-pending U.S. Applications having Serial Nos
08/471,747, 08/482,969, 08/567,933, 08/659,264, 08/823,699, 08/835,857,
08/470,940, 08/461,298, 08/826,197, 08/777,408, 08/927,247, 08/964,956,
08/964,498, and 08/964,536, the entire contents of all of which are
incorporated
herein by reference.
The polymer can be linear or crosslinked. Crosslinking can be performed by
reacting the copolymer with one or more crosslinking agents having two or more
functional groups, such as electrophilic groups, which react with, for
example,
amine groups to form a covalent bond. Crosslinking in this case can occur, for
example, via nucleophilic attack of the polymer amino groups on the
electrophilic
groups. This results in the formation of a bridging unit which links two or
more
amino nitrogen atoms from different polymer strands. Suitable crosslinking
agents
of this type include compounds having two or more groups selected from among
acyl chloride, epoxide, and alkyl-X, wherein X is a suitable leaving group,
such as a
halo, tosyl or mesyl group. Examples of such compounds include, but are not
limited to, epichlorohydrin, succinyl dichloride, acryloyl chloride,
butanedioldiglycidyl ether, ethanedioldiglycidyl ether, pyromellitic
dianhydride, and
dihaloalkanes. These crosslinking agents are referred to herein as
multifunctional
crosslinking agents.
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The polymer composition can also be crosslinked by including a
multifunctional co-monomer as the crosslinking agent in the polymerization
reaction
mixture. A multifunctional co-monomer can be incorporated into two or more
growing polymer chains, thereby crosslinking the chains. Suitable
multifunctional
co-monomers include, but are not limited to, diacrylates, triacrylates, and
tetraacrylates, dimethacrylates, diacrylamides, and dimethacrylamides.
Specific
examples include ethylene glycol diacrylate, propylene glycol diacrylate,
butylene
glycol diacrylate, ethylene glycol dimethacrylate, butylene glycol
dimethacrylate,
methylene bis(methacrylamide), ethylene bis(acrylamide), ethylene
bis(methacrylamide), ethylidene bis(acrylamide), ethylidene
bis(methacrylamide),
pentaerythritol tetraacrylate, trimethylolpropane triacrylate, bisphenol A
dimethacrylate, and bisphenol A diacrylate. Other suitable multifunctional
monomers include polyvinylarenes, such as divinylbenzene.
The amount of cross-linking agent is typically between about 0.01 and about
1 S 10 weight % based on the combined weight of crosslinking agent and
monomers,
with 0.1-3% being preferred. Typically, the amount of cross-linking agent that
is
reacted with the polymer, when the crosslinking agent is a multifunctional
agent, is
sufficient to cause between about 0.1 and 6 percent of the nucleophiles
present on
the monomer, for example, an amine to react with the crosslinking agent.
The hydrophobic region or regions of the fat-binding polymers include but
are not limited to, for example, a hydrophobic moiety such as a substituted or
unsubstituted, normal, branched or cyclic alkyl group having at least about
four
carbons and preferably at least 6 carbons. For example, a hydrophobic moiety
such
as an alkyl group of at least four carbons and preferably at least 6 carbons
can be
bound to the fat-binding polymer, for example, through an amine of the fat-
binding
polymer.
A "hydrophobic moiety (group)", as the term is used herein, is a moiety
which, as a separate entity, is more soluble in octanol than water. For
example, the
octyl group (CBH,~) is hydrophobic because its parent alkane, octane, has
greater
solubility in octanol than in water. The hydrophobic moieties can be a
saturated or
unsaturated, substituted or unsubstituted hydrocarbon group. Such groups
include
substituted and unsubstituted, normal, branched or cyclic alkyl groups having
at
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least four carbon atoms, substituted or unsubstituted arylalkyl or
heteroarylalkyl
groups and substituted or unsubstituted aryl or heteroaryl groups. Preferably,
the
hydrophobic moiety includes an alkyl group of between about four and thirty
carbons. Specific examples of suitable hydrophobic moieties include the
following
alkyl groups n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-
dodecyl,
n-tetradecyl, n-octadecyl, 2-ethylhexyl, 3-propyl-6-methyl decyl, phenyl and
combinations thereof. Other examples of suitable hydrophobic moieties include
haloalkyl groups of at least six carbons (e.g., 10-halodecyl), hydroxyalkyl
groups of
at least six carbons (e.g., 11-hydroxyundecyl), and aralkyl groups (e.g.,
benzyl).
The positiviely charged region or regions of the fat binding polymers may
include primary, secondary, tertiary or quaternary amines. Optionally, the
positively
charged region or regions of the fat-binding polymers may include an amine
nitrogen capable of possessing a positive charge under conditions present in
the
gastro-intestinal tract and a quaternary amine-containing moiety. Suitable
quaternary amine-containing moieties used in conjunction with acrylate or
acrylamide polymers, for example, include alkyl trialkylammonium groups also
referred to as ammonioalkyl groups. The term, "ammonioalkyl", as used herein,
refers to an alkyl group which is substituted by a nitrogen bearing three
additional
substituents. Thus, the nitrogen atom is an ammonium nitrogen atom which bears
an alkylene substituent, which links the ammonium nitrogen atom to the
polymer,
and three additional terminal alkyl substituents having from about one to
about
twenty-four carbons. A "terminal substituent" of the quaternary amine-
containing
moiety, as the term is employed herein, is any one of the three substituents
on the
quaternary amine nitrogen. In a specific embodiment, the polymer is an amine
polymer and the alkylene group links the ammonium nitrogen atom to the
nitrogen
atom of the polymer. It is to be understood that multiple moieties can be
bound to
the same amine and/or different amines of the polymer composition.
In another embodiment, the quaternary amine-containing moiety can bear at
least one terminal hydrophobic alkyl substituent, such as an alkyl group
having
between about four and twenty-four carbons, thereby providing both a
hydrophobic
region and a positively charged region in combination.
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An ammonioalkyl group will further include a negatively charged
counterion, such as a conjugate base of a pharmaceutically acceptable acid.
Examples of suitable counterions include Cl-, P04 , Br , CH3S03~, HS04 , S042-
,
HC03-, C03Z-, acetate, lactate, succinate, propionate, butyrate, ascorbate,
citrate,
maleate, folate, tartrate, polyacrylate, an amino acid derivative, and a
nucleotide.
Suitable ammonioalkyl groups are of the general formula:
R'
-(CHZ)~-- N +--RZ
~ Y-
R3
wherein, R', RZ and R3 represent an alkyl group, wherein each R'-R',
independently,
is a normal or branched, substituted or unsubstituted alkyl group having a
carbon
atom chain length of between about one to about twenty-four carbon atoms, n is
an
1 S integer having a value of two or more and Y is a negatively charged
counterion. In a
particular embodiment, R', RZ and R3 are all methyl groups and n is an integer
between about 2 and about 12. Examples of preferred alkylene linking groups
are
ethyl, propyl, butyl, pentyl, hexyl, octyl, and decyl groups. Example of
suitable
quaternary amine-containing moieties include, but are not limited to:
3-(trimethylammonio)propyl;
4-(tr-imethylammonio)butyl;
6-(trimethylammonio)hexyl;
8-(trimethylammonio)octyl;
10-(trimethylammonio)decyl;
12-(trimethylammonio)dodecyl and combinations thereof. A particularly
preferred
amine-containing moiety is a 6-(trimethylammonio)hexyl group.
Alternatively, a quaternary amine-containing moiety and a hydrophobic
moiety are present in the same substituent, thereby providing both a
positively
charged and hydrophobic region in combination. For example, the quaternary
amine
nitrogen or ammonium nitrogen of the quaternary amine-containing moiety is
bound
to the polymer backbone by an alkylene having two or more carbons. However, at
least one of the three terminal substituents (R', RZ and R3) of the ammonium
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nitrogen is a hydrophobic alkyl group having from four to about twenty-four
carbons. The remaining terminal substituents are each independently a normal
or
branched, substituted or unsubstituted alkyl group having from one to about
twenty-
four carbons or a hydrogen atom. In another embodiment, at least two of the
three
terminal substituents can be hydrophobic alkyl groups having from four to
about
twenty-four carbons, the remainder having from one to about twenty-four
carbons or
a hydrogen atom. In a further embodiment, all three of the terminal
substituents can
be hydrophobic alkyl groups having from six to about twenty-four carbons.
A "hydrophobic alkyl group", as that term is employed herein, includes a
substituted or unsubstituted alkyl group having from four to about twenty-four
carbons and which is hydrophobic, as earlier defined. The hydrophobic alkyl
group
can be, for example, a normal or branched, substituted or unsubstituted alkyl
group
having from six to about twenty-four carbons.
Particular examples of quaternary amine-containing moieties, which provide
both a hydrophobic and quaternary amine-containing substituent, include, but
are
not limited to:
4-(dioctylmethylammonio)butyl;
3-(dodecyldimethylammonio)propyl;
3-(octyldimethylammonio)propyl;
3-(decyldimethylammonio)propyl;
5-(dodecyldimethylammonio)pentyl;
6-(dimethyldecylammonio)hexyl;
6-(decyldimethylammonio)hexyl;
3-(tridecylammonio)propyl;
3-(docosyldimethylammonio)propyl;
6-(docosyldimethylammonio)hexyl;
4-(dodecyldimethylammonio)butyl;
3-(octadecyldimethylammonio)propyl;
3-(hexyldimethylammonio)propyl;
3-(methyldioctylammonio)propyl;
3-(didecylmethylammonio)propyl;
3-(heptyldimethylammonio)propyl;
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3-(dimethylnonylammonio)propyl;
6-(dimethylundecylammonio)hexyl;
4-(heptyldimethylammonio)butyl;
4-(dioctylmethylammonio)butyl;
S 6-(octyldimethylammonio)hexyl;
12-(decyldimethylammonio)dodecyl;
3-(dimethylundecylammnio)propyl; and
3-(tetradecyldimethylammonio)propyl.
Other suitable quaternary amine-containing moieties include secondary and
tertiary analogs, such as 4-(dioctylmethylammonio)4-methylbutyl and 4-
(dioctylmethylammonio)-4,4-dimethylbutyl.
The fat-binding polymers of the invention can be formed, for example, by
reacting a polymer, which can be linear or crosslinked, with a suitable
alkylating
agent or by polymerizing an alkylated monomer.
1 S An "alkylating agent", as that term is employed herein, means a reactant
that,
when reacted with a monomer or a copolymer characterized by a repeat unit of
the
invention and having a nucleophilic site capable of reaction with the
alkylating
agent, causes a hydrophobic substituent, as described herein, to be covalently
bound
to one or more of sites on the fat-binding polymer, for example, the amine
nitrogen
atoms or hydroxyl oxygens of an amine-containing or hydroxyl-containing
monomer or polymer, respectively. Further, when multiple substituents are
employed, they can be bound to the same and/or different nucleophilic sites of
the
fat-binding polymer, for example, the same and/or different amine nitrogens of
an
amine-containing fat-binding polymer or hydroxyl oxygen of a hydroxyl-
containing
polymer.
Suitable alkylating agents are compounds comprising an alkyl group or alkyl
derivative, having at least four carbon atoms, which is bonded to a leaving
group
such as a halo (e.g., chloro, bromo or iodo), tosylate, mesylate or epoxy
group).
Examples of suitable alkylating agents which provide a hydrophobic moiety
include alkyl halides having at least four carbon atoms, such as n-hexyl
halide,n-
heptyl halide, n-octyl halide, n-nonyl halide, n-decyl halide, n-undecyl
halide, n-
dodecyl halide, n-tetradecyl halide, n-octadecyl halide, and combinations
thereof.
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Other examples include: a dihaloalkane that includes an alkyl group of at
least four
carbons (e.g., a 1,10-dihalodecane); a hydroxyalkyl halide having at least
four
carbon atoms (e.g., an 11-halo-1-undecanol); an aralkyl halide (e.g., a benzyl
halide); an alkyl epoxy ammonium salt having at least six carbons (e.g.,
glycidylpropyl-trimethylammonium salts) and epoxyalkylamides having at least
six
carbons (e.g., N-(2,3-epoxypropyl) butyramide or N-(2,3-epoxypropyl)
hexanamide). Preferred halogen components of the alkyl halides are bromine and
chlorine. Particularly preferred alkylating agents which, when reacted with
the
polymer composition, will cause formation of an amine polymer reaction product
that includes a first substituent, are 1-bromodecane and 1-chlorooctane.
Examples of suitable alkylating agents which can provide a quaternary
amine-containing moiety have the general formula:
R'
X-(CHZ)~ - N +--Rz (I)
I Y-
R3
wherein,
R', R2, and R3 represent an alkyl group, wherein each R independently is a
normal or branched, substituted or unsubstituted alkyl group
having a carbon atom chain length of between about one to
about twenty four carbon atoms,
n is an integer having a value of two or more,
X is a leaving group as earlier described, and
Y is a negatively charged counterion.
When at least one of the three terminal substituents of the quaternary amine
alkylating agent is a hydrophobic alkyl group having from four to about twenty-
four
carbons, the alkylating agent therefore provides both a hydrophobic moiety and
a
quaternary amine-containing moiety. The alkylene group in this instance is
three or
more carbon atoms in length.
Particular examples of quaternary ammonium compounds suitable as
alkylating agents include the following:
SUBSTITUTE SHEET (RULE 26)
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(4-bromobutyl)dioctylmethylammonium bromide;
(3-bromopropyl)dodecyldimethylammonium bromide;
(3-chloropropyl)dodecyldimethylammonium bromide;
(3-chloropropyl)decyldimethylammonium bromide;
(5-tosylpentyl)dodecyldimethylammonium bromide;
(6-bromohexyl)dimethyldecylammonium bromide;
(12-bromododecyl)decyldimethylammonium bromide;
(3-bromopropyl)tridecylammonium bromide;
(3-bromopropyl)docosyldimethylammonium bromide;
(6-bromohexyl)docosyldimethylammonium bromide;
(4-chlorobutyl)dodecyldimethylammonium bromide;
(3-chloropropyl)octadecyldimethylammonium bromide;
(3-bromopropyl)octyldimethylammonium bromide;
(4-iodobutyl)dioctylmethylammonium bromide;
(2,3-epoxy propyl)decyldimethylammonium bromide; and
(6-bromohexyl)docosyldimethyammonium bromide.
Other suitable alkylating agents include secondary and tertiary analogs, such
as (3-bromobutyl)dioctylmethylammonium bromide and (3-chloro-3,3-dimethyl
propyl)dioctylmethylammonium bromide.
Examples of suitable alkyl trimethylammonium alkylating agents include
alkyl halide trimethylammonium salts, such as:
(4-halobutyl)trimethylammonium salt;
(S-halopentyl)trimethylammonium salt;
(6-halohexyl)trimethylammonium salt;
(7-haloheptyl)trimethylammonium salt;
(8-halooctyl)trimethylammonium salt;
(9-halononyl)trimethylammonium salt;
(10-halodecyl) trimethylammonium salt;
(11-haloundecyl)trimethylammonium salt;
(12-halododecyl)trimethylammonium salt; and
combinations thereof. A particularly preferred quaternary amine-containing
alkylating agent is (6-bromohexyl)- trimethylammonium bromide.
SUBSTITUTE SHEET (RULE 26)
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The fat-binding polymers of the invention can be formed, for example, by
reacting a polymer, which can be linear or crosslinked, with a suitable
modifying
agent. A "modifying agent", as that term is employed herein, means a reactant
that,
when reacted with a monomer or a copolymer characterized by a repeat unit of
the
S invention and having a nucleophilic site capable of reaction with the
modifying
agent, causes a hydrophobic substituent, as described herein, to be covalently
bound
to one or more of sites on the fat-binding polymer, for example, the amine
nitrogen
atoms of an amine-containing polymer. Further, when multiple substituents are
employed, they can be bound to the same and/or different nucleophilic sites of
the
fat-binding polymer, for example, the same and/or different amine nitrogens of
an
amine-containing fat-binding polymer.
Suitable modifying agents are compounds comprising substituted alkyl
group or alkyl aromatic groups which is bonded to a leaving group such as a
halo
(e.g., chloro, bromo or iodo), tosylate, mesylate or epoxy group). Examples of
suitable modifying agents which provide a hydrophilic moiety include
haloalkanols,
(for example, 2-bromoethanol, 3-bromopropanol, 4-bromobutanol, 4-chlorobutanol
and 3-bromo-2-hydroxy propanol), haloalkanoic acids (for example chloracetic
acid,
bromoacetic acid, 3-bromo propionic acid and 4-bromobutyric acid, glycidol,
glycidyl trimethylammonium chloride, and ethylene oxide. Particularly
preferred
modifying agents which include glycidol, and 2-bromoethanol.
Preferred fat binding polymers, copolymers or salts thereof in accordance
with the invention are described in Examples 1-98.
Even more preferred fat binding polymers, copolymers (and/or salts thereof)
of the invention comprises at least one repeat unit or a combination of repeat
units
selected from the following group of repeat unit formulas, or combinations of
repeat
unit formulas.
SUBSTITUTE SHEET (RULE 26)
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(II)
R R2
* rJn * ~Jn
O~NH O O
CI- \N~~ ~O~O~RS
wherein Rl = H, or CH3,
R2 = H, or CH3,
R5 = H, or an alkyl chain from C, to Cz2, m = 0 - 4, and p = 5 - 125
(III)
R1 R2
*~ * n * n
N'
O NH2 O NH
N + CI_ R4
R5
wherein R1 = H, or CH3,
R2 = H, or CH3,
R4 = a hydrophobic group and
R5 = H, or an alkyl chain from C, to Czz
(IV1
R R2 R3
* L '~n * T Jn * L Jn
O/J~~ NH O/I~NHZ O ~NH
CI- \N~~ R4
wherein R1 = H, or CH3,
R2 = H, or CH3,
R3 = H, or CH3,
R4 = a hydrophobic group, and
m=0-4
SUBSTITUTE SHEET (RULE 26)
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(V)
R R2 R3
* ~n * T Jn * L 'I' Jn
O NH O/~NHZ O/~N~RS
CI- ~N~ R4
wherein R1 = H, or CH3,
R2 = H, or CH3,
R3 = H, or CH3,
R4 = a hydrophobic group,
RS = an alkyl chain from C, to C2z and
m=0-4
(VI)
* Jn
HO ~ OH
HO~~~N~'~OH
CI
(VII)
* ~ Jn-*
HO + _
HO~~~N.RS CI
Wherein RS = H, or an alkyl chain from C, to C22
SUBSTITUTE SHEET (RULE 26)
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(VIII)
* n HCI
N~~OH
OH
HOJ
HO
(IX)
R5
m
R6
O N O
~N~R7
HCI
R8
wherein RS = H, or an alkyl chain from C, to Czz,
R6 = H, or an alkyl chain from C, to Czz
R7 = H, or an alkyl chain from C, to Czz
R8 = H, or an alkyl chain from C, to Czz
(X)
* l ~ !n
N\ X_
R5 R6
wherein RS = H, or an alkyl chain from C, to Czz,
R6 = H, or an alkyl chain from C, to Czz, and wherein
X = a pharmaceutically acceptable anion
Particularly preferred fat binding polymers, copolymers (and/or salts thereof)
of the
invention comprise the following:
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~ A polymer of Formula II wherein: R1 = H, R2 = H, R5 = CH3, m = 1, p =about
114 and wherein the resulting polymer may be expressed as Poly((3-
acrylamidopropyl)trimethylammonium chloride-co-O-acryloyl-O'-
methylpolyethyleneglycol 5000). Preferably, such polymer contains 11 wt% of
the PEG-containing monomer;
~ A polymer of Formula III wherein Rl = H, R2 = H, R4 = C,ZH25, R5 = CH3 and
wherein the resulting polymer may be expressed as Poly(3-methyl-1-
vinylimidazolium chloride-co-acrylamide-co-dodecyl acrylamide). Even more
preferably, such polymer has a monomer mole ratio of 35/70/5;
~ A polymer of Formula IV wherein R1 = H, R2 = H, R3 = H, R4 = C6H5
(phenyl),m = 1 and wherein the resulting polymer may be expressed as Poly((3-
acrylamidopropyl) trimethylammonium chloride-co-acrylamide-co-N-
phenylacrylamide). Even more preferably, such polymer has a Mol% monomer
composition of 25/70/5;
~ A polymer of Formula V wherein R1 = H, R2 = H, R3 = H, R4 = C,$H3~, R5 =
CH3, m = 1 and wherein the resulting polymer may be expressed as Poly((3-
acrylamidopropyl)trimethylammonium chloride-co-acrylamide-co-N-methyl-N-
octadecylacrylamide). Even more preferably such polymer has a Mol%
monomer composition of 25/70/5;
~ The polymer of Formula VI which may be expressed as Poly(N,N-diallyl-N,N-
di(2,3-dihydroxypropyl)ammonium chloride);
~ The polymer of Formula VII wherein R5=methyl and wherein such polymer may
be expressed as Poly(N,N-diallyl-N-methyl-N-(2,3-dihydroxypropyl)
ammonium chloride);
~ The polymer of Formula VIII which may be expressed as Poly(N,N-di(2,3-
dihydroxypropyl)allylamine) hydrochloride;
~ A polymer of Formula IX wherein, R5 = H, R6 = H, R7 = CH3, R8 = CH3 and
wherein such polymer may be expressed as Poly(N-(3-
dimethylaminopropyl)maleimide-co-ethylene) hydrochloride;
SUBSTITUTE SHEET (RULE 26)
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~ A Polymer of Formula X wherein RS = H, R6 = CH3, X = tartrate, and wherein
such polymer may be expressed as Poly(N-methyl-N,N-diallylammonium)
tartrate.
In addition, another particularly preferred polymer of the invention may be
expressed as Polyethyleneimine 80% ethoxylated, the structure of which is
understood in the art.
Exemplative synthetic schemes for each of the preferred and particularly
preferred polymers of the invention may be found in the Examples and
particularly
in Examples .
In another embodiment, the fat-binding polymer can have a lipase inhibitor
covalently bound to the polymer as described in PCT/LJS99/00195. In a further
embodiment, the fat-binding polymer can be administered in combination with a
lipase inhibitor which is convalently bound to a polymer as described in
PCT/US99/00195, the entire content of which is incorporated herein by
reference.
As used herein, the terms "therapeutically effective amount" and "therapeutic
amount" are synonymous. The terms refer to an amount which is sufficient to
treat
obesity, reduce the absorption of fat or treat hypertriglyceridemia. The
dosage of
fat-binding polymer administered to the patient will vary depending among
other
things on the weight of the patient and the general health of the patient. The
dosage
can be determined with regard to established medical practice. The amount of
fat-
binding polymer administered can be in the range of from about 0.01 mg/kg of
body
weight/day to about 1 g/kg of body weight/day. The amount of lipase inhibitor
which can be administered in combination with the fat-binding polymers of the
invention can be determined with regard to accepted medical practice (e.g. the
Physicians Desk Reference).
As disclosed above, in a preferred embodiment, the preferred and particularly
preferred fat-binding polymers in accordance with the invention are
administered in
combination with a lipase inhibitor, as described herein. The term "in
combination"
in this context includes both simultaneous or sequential administration
(either type
of compound first) of the fat-binding polymer and lipase inhibitor. The fat-
binding
polymer and lipase inhibitor, when used in combination, can be employed
together
SUBSTITUTE SHEET (RULE 26)
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in the same dosage form or in separate dosage forms taken at the same time or
within a time period, wherein both the fat-binding polymer and lipase
inhibitor are
present in a therapeutically effective amount.
The fat-binding polymers of the invention can be formulated using
conventional inert pharmaceutical adjuvant materials into dosage forms which
are
suitable for oral administration. The oral dosage forms include tablets,
capsules,
suspension, solutions, and the like. The identity of the inert adjuvant
materials
which are used in formulating the fat-binding polymers of the invention will
be
immediately apparent to persons skilled in the art. These adjuvant materials,
either
inorganic or organic in nature, include, for example, gelatin, albumin,
lactose,
starch, magnesium stearate, preservatives (stabilizers), melting agents,
emulsifying
agents, salts, and buffers.
In patients with hypertriglyceridemia it is to be understood that the patient
does not necessarily suffer from hypercholesterolemia.
EXAMPLES
Example 1. Poly((3-acrylamidopropyl)trimethylammonium chloride-co-
acrylamide-co-N-decylacrylamide) Mol% monomer composition: 25/70/5
A 250-mL round-bottomed flask was fitted with an overhead stirrer, a reflux
condenser, and a thermocouple probe. The following materials were placed into
the
flask in the order specified: a solution of decylacrylamide (2.83 g, 0.0134
mole) in
tert-butanol (45 mL), 3-acrylamidopropyltrimethylammonium chloride (18.45 g of
a
75 percent solution in water, 0.067 mole), deionized water (40 mL), and
acrylamide
(13.33 g, 0.1875 mole). The resulting mixture was stirred and heated to 50
°C. A
clear, slightly yellow solution resulted. The solution was sparged for at
least 30
minutes with a vigorous nitrogen flow from an 18-gauge syringe needle whose
tip
was placed below the surface of the stirring solution. The radical initiator
2,2'azobis(2-amidinopropane) dihydrochloride (0.363 g, 0.00134 mole) was then
added to the solution and the temperature was increased to 60 °C. The
solution was
stirred at 60 °C for 14-16 hours. The solution was then cooled to room
temperature
and poured into 3 L of isopropanol, resulting in precipitation of the
polymeric
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product as a colorless solid. This mixture was stirred for 1-3 hours, and the
isopropanol was decanted away from the polymer product. A fresh 3-L portion of
isopropanol was then added, and the mixture was stirred for 3-6 hours. Again,
the
isopropanol was decanted away, and another 3-L portion of fresh isopropanol
was
added to the polymer. The mixture was stirred for 6-14 hours and the
isopropanol
was decanted away from the polymer product. The polymer was placed on a glass
tray, and dried in a forced-air oven at 70 °C for 24-48 hours. The
dried solid was
then ground to a fine powder using a commercial coffee grinder. The fine
powder
was placed into a glass tray in a forced air oven at 70 °C for at least
24 hours. A
colorless solid (30.04 g) was obtained.
Example 2. Poly((3-acrylamidopropyl)trimethylammonium chloride-co
acrylamide-co-N-decylacrylamide) Mol% monomer composition: 25/65/10
The procedure of example 1 was followed substituting the following
materials and amounts: decylacrylamide (5.33 g, 0.0252 mole), 3-
acrylamidopropyltrimethylammonium chloride (17.37 g of a 75 percent solution
in
water, 0.063 mole), deionized water (40.5 mL), acrylamide (11.65 g, 0.1638
mole),
2,2'azobis(2-amidinopropane) dihydrochloride (0.342 g, 0.00126 mole). The
amount
of polymer obtained was 30.7 g.
Example 3. Poly((3-acrylamidopropyl)trimethylammonium chloride-co-
acrylamide-co-N-decylacrylamide) Mol% monomer composition: 25/60/15
The procedure of example 1 was followed substituting the following
materials and amounts: decylacrylamide (7.55 g, 0.0357 mole), 3-
acrylamidopropyltrimethylammonium chloride (16.4 g of a 75 percent solution in
water, 0.060 mole), deionized water (41 mL), acrylamide (10.15 g, 0.1428
mole),
2,2'azobis(2-amidinopropane) dihydrochloride (0.332 g, 0.00119 mole). The
amount
of polymer obtained was 25.6 g.
Example 4. Poly((3-acrylamidopropyl)trimethylammonium chloride-co-
acrylamide-co-N,N-didecylacrylamide) Mol% monomer composition: 25/70/5
The procedure of example 1 was followed substituting the following
materials and amounts: didecylacrylamide (3.69 g, 0.0105 mole) in tert-butanol
SUBSTITUTE SHEET (RULE 26)
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(37 mL), 3-acrylamidopropyltrimethylammonium chloride (14.48 g of a 75 percent
solution in water, 0.053 mole), deionized water (34.4 mL), acrylamide (10.15
g,
0.147 mole), 2,2'azobis(2-amidinopropane) dihydrochloride (0.285 g, 0.00105
mole). The amount of polymer obtained was 23.62 g.
S Example 5. Poly((3-acrylamidopropyl)trimethylammonium chloride-co-
acrylamide-co-N-phenylacrylamide) Mol% monomer composition: 75/20/5
The procedure of example 1 was followed substituting the following
materials and amounts: phenylacrylamide (1.04 g, 0.0071 mole) in tert-butanol
(37.5 mL), 3-acrylamidopropyltrimethylammonium chloride (29.27 g of a 75
percent solution in water, 0.106 mole), deionized water (30 mL), acrylamide
(2.01 g,
0.028 mole), 2,2'azobis(2-amidinopropane) dihydrochloride (0.192 g, 0.00071
mole). The amount of polymer obtained was 26.1 g.
Example 6. Poly((3-acrylamidopropyl)trimethylammonium chloride-co-
acrylamide-co-N-benzylacrylamide) Mol% monomer composition: 75/20/5
The procedure of example 1 was followed substituting the following
materials and amounts: benzylacrylamide (0.91 g, 0.0056 mole) in tert-butanol
(51 mL), 3-acrylamidopropyltrimethylammonium chloride (23.32 g of a 75 percent
solution in water, 0.085 mole), deionized water (40 mL), acrylamide (1.60 g,
0.023
mole), 2,2'azobis(2-amidinopropane) dihydrochloride (0.192 g, 0.00056 mole).
The
amount of polymer obtained was 17.8 g.
Example 7. Poly((3-acrylamidopropyl)trimethylammonium chloride-co-N-tert-
octylacrylamide) Mol% monomer composition: 90/10
The procedure of example 1 was followed using the following reagents: N-
tent-octylacrylamide (2.24 g, 0.0122 mole) in tert-butanol (50 g), 3-
acrylamidopropyltrimethylammonium chloride (30.25 g of a 75 percent solution
in
water, 0.110 mole), deionized water (50 mL), 2,2'azobis(2-amidinopropane)
dihydrochloride (0.166 g, 0.00061 mole). The amount of polymer obtained was
21.2 g.
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Example 8. Poly((3-acrylamidopropyl)trimethylammonium chloride-co- N-
butylacrylamide) Mol% monomer composition: 25/75
The procedure of example 1 was followed using the following reagents: N-
butylacrylamide (5.06 g, 0.04 mole) in tert-butanol (13.38 g), 3-
acrylamidopropyltrimethylammonium chloride (3.65 g of a 75 percent solution in
water, 0.013 mole), deionized water (8.9 mL), 2,2'azobis(2-amidinopropane)
dihydrochloride (0.072 g, 0.00027 mole). The amount of polymer obtained was
4.00 g.
Example 9. Poly(2-(Methacryloyloxy)ethyl-tert-butylamine hydrochloride)
The procedure of example 1 was followed using the following reagents:
2-(Methacryloxy)ethyl-tert-butylamine (30 g, 0.162 mole) in tert-butanol (68
mL),
deionized water (22 mL), 2,2'azobis(2-amidinopropane) dihydrochloride (0.220
g,
0.00081 mole). The solvent used for precipitation and washing of the polymer
was
hexane. The amount of polymer obtained was 21.9 g.
Example 10. Poly((3-acrylamidopropyl)trimethylammonium chloride-co-
styrene) Mol% monomer composition: 60/40
The procedure of example 1 was followed using the following reagents:
styrene (5.03 g, 0.048 mole) in ethanol (80 mL), 3-acrylamidopropyltrimethyl-
ammonium chloride (19.96 g of a 75 percent solution in water, 0.072 mole),
2,2'-
azobisisobutyronitrile (0.198 g, 0.0012 mole). The solvent used for
precipitation and
washing of the polymer was acetone. The amount of polymer obtained was 14.5 g.
Example 11. Poly((3-methacrylamidopropyl)trimethylammonium chloride-co-
poly(dimethylsiloxane)monomethacrylate) Wt% monomer composition: 90/10
The procedure of example 1 was followed using the following reagents:
poly(dimethylsiloxane)monomethacrylate (Mn = 9,000-12,000) (0.60 g) in
isopropanol (18.6 mL), 3-methacrylamidopropyltrimethylammonium chloride
(10.8 g of a 50 percent solution in water, 0.072 mole), 2,2'-
azobisisobutyronitrile
(0.030 g, 0.00018 mole). The solvent used for precipitation and washing of the
polymer was isopropanol. The amount of polymer obtained was 4.13 g.
SUBSTITUTE SHEET (RULE 26)
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Example 12. Poly((3-acrylamidopropyl)trimethylammonium chloride-co-
acrylamide-co-N-octadecylacrylamide) Mol% monomer composition: 60/35/5
The procedure of example 1 was followed substituting the following
materials and amounts: octadecylacrylamide (79.38 g, 0.2453 mole) in
isopropanol
(3081.2 g), 3-acrylamidopropyltrimethylammonium chloride (811.41 g of a 75
percent solution in water, 2.944 mole), deionized water (406 mL), and
acrylamide
(122.06 g, 1.717 mole), 2,2'-azobisisobutyronitrile (4.029 g, 0.0245 mole) in
tetrahydrofuran (46 g). The amount of polymer obtained was 815 g.
Example 13. Poly((3-acrylamidopropyl)trimethylammonium chloride-co-
acrylamide-co-N-phenylacrylamide) Mol% monomer composition: 25/70/5
The procedure of example 1 was followed substituting the following
materials and amounts: phenylacrylamide (33.82 g, 0.230 mole) in tert-butanol
(1000 g), 3-acrylamidopropyltrimethylammonium chloride (316.7 g of a 75
percent
solution in water, 1.149 mole), deionized water (921 mL), acrylamide (228.67
g,
3.217 mole), 2,2'azobis(2-amidinopropane) dihydrochloride (3.323 g, 0.0230
mole)
in deionized water (24 g). The amount of polymer obtained was 532 g.
Example 14. Poly((3-acrylamidopropyl)trimethylammonium chloride-co-
acrylamide-co-N-methyl-N-octadecylacrylamide) Mol% monomer composition:
25/70/5
The procedure of example 1 was followed using the following reagents: N-
methyl-N-octadecylacrylamide (134.96 g, 0.400 mole) in tert-butanol (1892 g),
3-
acrylamidopropyltrimethylammonium chloride (550.9 g of a 75 percent solution
in
water, 2.00 mole), deionized water (1754 mL), and acrylamide (397.83 g, 5.597
mole), 2,2'azobis(2-amidinopropane) dihydrochloride (6.163 g, 0.040 mole) in
deionized water (32 g). The amount of polymer obtained was 1046 g.
Example 15. Poly(3-methyl-1-vinylimidazolium chloride-co-acrylamide-co-
dodecylacrylamide) Monomer mole ratio: 35/70/5
In a 500-mL flask equipped with an overhead mechanical stirrer and a
thermocouple probe, 1-vinylimidazole (270 g, 2.869 mole) was dissolved in 2.7
L of
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anhydrous ethyl acetate. The solution was cooled to -10 °C, and methyl
iodide was
added (1425 g, 10.04 mole). Throughout the reaction the temperature was
maintained at -10 °C using an ice salt bath. After the addition was
complete, the
reaction mixture was stirred for 1 hour at -10 °C, then brought to room
temperature
and allowed to stir for 16 hours. During this time off white crystals formed
in the
solution. The mixture was filtered and the crystalline solid was washed with
10 L of
anhydrous diethyl ether. This off white solid was then recrystallized from n-
propanol (melting point 68 °C). The crystalline solid was then
dissolved in 2.4 L of
methanol to which was added 3.7 kg of Amberlite IRA-400 chloride ion exchange
resin. The slurry was stirred for 4 hours and then filtered. The filtrate was
then
concentrated under vacuum and then placed on a high vacuum pump to remove any
remaining solvent. The amount of 3-methyl-1-vinylimidazole chloride obtained
was
347.76 g. The procedure of example 1 was followed using the following
reagents:
dodecylacrylamide (104.1 g, 0.435 mole) in tert-butanol (856 g), 3-methyl-1-
1 S vinylimidazolium chloride (619 g of a 71.1 percent solution in water,
3.0434 mole),
deionized water (888.1 mL), acrylamide (370.9 g, 5.217 mole), 2,2'azobis(2-
amidinopropane) dihydrochloride (11.8 g, 0.04348 mole). The amount of polymer
obtained was 813 g.
Example 16. Poly((3-acrylamidopropyl)trimethylammonium chloride-co-
acrylamide) Mol% monomer composition: 50/50
A 5000-mL round-bottomed flask was fitted with an overhead stirrer, a
reflux condenser, and a thermocouple probe. The following materials were
placed
into the flask in the order specified: 3-acrylamidopropyltrimethylammonium
chloride (396.86 g of a 75 percent solution in water, 1.44 mole), deionized
water
(1500 mL), and acrylamide (102.35 g, 1.44 mole). The resulting mixture was
stirred
at approximately 23 °C. A clear, slightly yellow solution resulted. The
solution was
sparged for at least 60 minutes with a vigorous nitrogen flow from an 18-gauge
syringe needle whose tip was placed below the surface of the stirring
solution.
Potassium metabisulfite (0.213 g, 0.00096 mole) and potassium persulfate
(0.259,
0.00096 mole) were then each separately dissolved in a small amount of water
and
added individually to the solution. A$er 2-10 minutes, the temperature was
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increased to 60 °C. The solution was stirred at 60 °C for 5-6
hours. The flask was
then fitted with a distillation head and the solution was heated to 95
°C. The
vigorous nitrogen flow was resumed and 500 mL of water was distilled out of
the
flask in order to facilitate the work-up procedure. The polymer solution was
cooled
and poured into 22 L of isopropanol, resulting in precipitation of the
polymeric
product as a colorless solid. This mixture was stirred overnight, and the
isopropanol
was decanted away from the polymer product. A fresh portion of isopropanol was
then added, and the mixture was stirred for 48 hours and the isopropanol was
decanted away from the polymer product. The polymer was placed on a glass
tray,
and dried in a forced-air oven at 70 °C for 24-48 hours. The dried
solid was then
ground to a fine powder using a commercial coffee grinder. The fine powder was
placed into a glass tray in a forced air oven at 70 °C for 24-48 hours.
A colorless
solid (390.5 g) was obtained.
Example 17. Poly((3-acrylamidopropyl)trimethylammonium chloride)
The procedure of example 16 was followed using the following reagents: 3-
acrylamidopropyltrimethylammonium chloride (533.3 g of a 75 percent solution
in
water, 1.94 mole), deionized water (1467 mL), potassium metabisulfite (0.143
g,
0.00065 mole) and potassium persulfate (0.174, 0.00065 mole). The amount of
polymer obtained was 372 g.
Example 18. Poly((3-acrylamidopropyl)trimethylammonium chloride-co-N-
vinyl-2-pyrrolidinone) Mol% monomer composition: 80/20
A 1000-mL round-bottomed flask was fitted with an overhead stirrer, a
reflux condenser, and a thermocouple probe. The following materials were
placed
into the flask in the order specified: 3-acrylamidopropyltrimethylammonium
chloride (141.04 g of a 75 percent solution in water, 0.512 mole), deionized
water
(511 mL), and N-vinyl-2-pyrrolidinone (14.22 g, 0.128 mole). The resulting
mixture was stirred at approximately 23 °C. A clear, slightly yellow
solution
resulted. The solution was sparged for at least 60 minutes with a vigorous
nitrogen
flow from an 18-gauge syringe needle whose tip was placed below the surface of
the
stirring solution. The radical initiator 2,2'azobis(2-amidinopropane)
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dihydrochloride (1.20 g, 0.0044 mole) was then added to the solution and the
temperature was increased to 60 °C. The solution was stirred at 60
°C overnight.
The solution was cooled to room temperature and diluted with 600 mL of
deionized
water. The solution was then poured into a series of cellulose dialysis bags
(Spectra/Por, molecular weight cutoff = 6000 - 8000), and exhaustively
dialysed
against deionized water. The polymer solution was removed from the dialysis
bags,
placed in a glass tray, and dried in a forced-air oven at 70 °C for 24-
48 hours. The
dried solid was then ground to a fine powder using a commercial coffee
grinder.
The fine powder was placed into a glass tray in a forced air oven at 70
°C for 24-48
hours. A colorless solid (78 g) was obtained.
Example 19. Poly((3-acrylamidopropyl)trimethylammonium chloride-co-N-
ethylacrylamide) Mol% monomer composition: 50/50
A 250-mL round-bottomed flask was fitted with an overhead stirrer, a reflux
condenser, and a thermocouple probe. The following materials were placed into
the
flask in the order specified: 3-acrylamidopropyltrimethylammonium chloride
(19.36 g of a 75 percent solution in water, 0.065 mole), deionized water (80
mL),
and N-ethylacrylamide (6.48 g, 0.0654 mole). The resulting mixture was stirred
at
approximately 23 °C. A clear, slightly yellow solution resulted. The
solution was
sparged for at least 30 minutes with a vigorous nitrogen flow from an 18-gauge
syringe needle whose tip was placed below the surface of the stirring
solution. The
radical initiator 2,2'azobis(2-amidinopropane) dihydrochloride (0.177 g,
0.00065
mole) was then added to the solution and the temperature was increased to 60
°C.
The solution was stirred at 60 °C until it became a thick gel. The
solution was then
cooled to room temperature and poured into 3 L of isopropanol, resulting in
precipitation of the polymeric product as a colorless solid. This mixture was
stirred
overnight, and the isopropanol was decanted away from the polymer product. A
fresh 3-L portion of isopropanol was then added, and the mixture was stirred
for 6-8
hours. Again, the isopropanol was decanted away. The polymer was placed on a
glass tray, and dried in a forced-air oven at 70 °C for 24-48 hours.
The dried solid
was then ground to a fine powder using a commercial coffee grinder. The fine
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powder was placed into a glass tray in a forced air oven at 70 °C for
at least 24
hours. A colorless solid (15.5 g) was obtained.
Example 20. Poly(diallyldimethylammonium chloride-co-acrylic acid)
Monomer mole ratio: 90/10
The procedure of example 19 was followed using the following reagents:
diallyldimethylammonium chloride (1465.9 g of a 65 percent solution in water,
5.89
mole), deionized water (3486.9 mL), acrylic acid (47.19 g, 0.655 mole),
2,2'azobis(2-amidinopropane) dihydrochloride (8.88 g, 0.0327 mole). The amount
of polymer obtained was 632 g.
Example 21. Poly((3-acrylamidopropyl)trimethylammonium chloride-co-O-
acryloyl-O'-methylpolyethylene glycol 5,000) Wt% monomer composition:
89/11
A procedure similar to example 19 was followed using the following
reagents: 3-acrylamidopropyltrimethylammonium chloride (1187 g of a 75 percent
solution in water, 4.31 mole), deionized water (3703 mL), and O-acryloyl-O'-
methylpolyethylene glycol 5,000 (109.7 g, .022 mole), 2,2'azobis(2-
amidinopropane) dihydrochloride (5.869 g, 0.0216 mole) in deionized water (30
g).
The amount of polymer obtained was 928 g.
Example 22. Poly(3-methyl-1-vinylimidazolium chloride-co-acrylamide)
Monomer mole ratio: 50/50
The procedure of example 19 was followed using the following reagents: 3-
methyl-1-vinylimidazolium chloride (268.18 g, 1.855 mole), deionized water
(933 mL), acrylamide (131.8 g, 1.855 mole), 2,2'azobis(2-amidinopropane)
dihydrochloride (5.030 g, 0.0186 mole). The amount of polymer obtained was
382 g.
Example 23. Poly(N,N-diallyl-2-hydroxyethylamine
A 50-mL round-bottomed flask was fitted with a magnetic stirrer, a reflux
condenser, and a thermocouple probe. The following materials were placed into
the
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flask in the order specified: N,N-diallyl-2-hydroxyethylamine (10 g),
concentrated
HC1 (7 g), deionized water (3 mL). The solution was degassed for 30 minutes by
bubbling with nitrogen from an 18-gauge needle. 2,2'Azobis(2-amidinopropane)
dihydrochloride (0.095 g, 0.00035 mole) was then added and the solution was
heated
to 60 °C. The solution was stirred at 60 °C overnight. The
solution was then cooled
to room temperature and poured into 1 L of isopropanol, resulting in
precipitation of
the polymeric product as a colorless solid. This mixture was stirred. for 1-3
hours,
and the isopropanol was decanted away from the polymer product. A fresh 1-L
portion of isopropanol was then added, and the mixture was stirred for 3-6
hours.
Again, the isopropanol was decanted away, and another 1-L portion of fresh
isopropanol was added to the polymer. The mixture was stirred overnight and
the
isopropanol was decanted away from the polymer product. The polymer was placed
on a glass tray, and dried in a forced-air oven at 70 °C for 24-48
hours. The dried
solid was then ground to a fine powder using a commercial coffee grinder. The
fine
powder was placed into a glass tray in a forced air oven at 70 °C for
at least 24
hours. A colorless solid (8 g) was obtained.
No Examples 24 and 25
Example 26. Modification of poly(2-ethyl-2-oxazoline) by partial hydrolysis
A 250-mL flask was equipped with an overhead mechanical stirrer,
condenser and a thermocouple probe. The following materials were placed into
the
flask in the order specified: poly(2-ethyl-2-oxazoline) (25 g), deionized
water
(95 mL), concentrated HCl (9.8 g). The solution was heated to reflux with
stirring
for 8 hours. The solution was then poured into 1.5 L of acetone resulting in
the
precipitation of the polymeric product. The mixture was stirred for 1 hour.
The
acetone was then decanted away and a fresh 1.5-L portion of acetone was added.
After 2 hours of stirring, the acetone was decanted away, and the solid was
blended
in a commercial blender containing fresh acetone. The solid was collected by
filtration and suspended in fresh acetone overnight. The solid was then
collected
and placed on a glass tray, and dried in a forced-air oven at 70 °C for
24-48 hours.
The dried solid was then ground to a fme powder using a commercial coffee
grinder.
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The fine powder was placed into a glass tray in a forced air oven at 70
°C for at least
24 hours. A colorless solid (30.04 g) was obtained.
Example 27. Modification of poly(allylamine) HCI with 100 mol % Glycidol
Poly(allylamine) HCl (60g of 50 percent aqueous solution, 0.321 mole
monomer equivalents) was dissolved in 80 mL of water and was then heated to
50 °C in a 500-mL flask equipped with an overhead mechanical stirrer,
condenser
and a thermocouple probe. The pH of the solution was adjusted to 10 by the
addition of NaOH (50 percent solution). Glycidol (23.77g 0.321mo1) was added
slowly to the stirred solution. A large exotherm was observed during the
addition of
the glycidol. This mixture was then heated at 50 °C for 3 hours giving
a very
viscous solution. The reaction mixture was cooled and then poured into a
dialysis
bag (Spectra/Por; molecular weight cut off 6000-8000) and dialyzed against 19
liters
of deionized water. The dialysis solution was changed until a conductivity of
< 1 mS/cm was recorded. The contents of the dialysis bag were then placed in a
beaker and the pH of the solution adjusted to a value < 2 with concentrated
HCI.
This solution was then transferred to drying trays and placed in a convection
oven at
70 °C for 24 hours. The dried solid was ground to a fme powder using a
lab mill and
then passed through a sieve (80 mesh). The product was then replaced in a
convection oven at 70 °C for 48 hours to remove any residual solvent.
Yield = 47.28.
Example 28. Modification of poly(allylamine) HCI with 200 mol % Glycidol
The procedure of example 27 was followed using the following materials:
Poly(allylamine) HCl (60g of 50 percent aqueous solution, 0.321 mole monomer
equivalents), deionized water (80 mL), glycidol (47.54 g, 0.642 mole). The
amount
of polymer obtained was 66.8 g.
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Example 29. Modification of poly(allylamine) HCl with 300 mol % Glycidol
The procedure of example 27 was followed using the following materials:
Poly(allylamine) HCl (40g of 50 percent aqueous solution, 0.214 mole monomer
equivalents), deionized water (80 mL), glycidol (47.54 g, 0.642 mole). The
amount
of polymer obtained was 48.9 g.
Example 30. Modification of poly(diallylamine) HCl with Glycidol
The procedure of example 27 was followed using the following materials:
Poly(diallylamine) HCl (106.8 g of 28.1 percent aqueous solution, 0.225 mole
monomer equivalents), deionized water (43.2 mL), glycidol (41.57 g, 0.561
mole).
The amount of polymer obtained was 56.3 g.
Example 31. 40 Mol% modification of poly(diallylmethylamine) HCl with 2-
chloroaceticic acid
In a 500-mL flask equipped with an overhead mechanical stirrer, condenser
and a thermocouple probe, poly(diallylmethylamine), (120 g of a 44.22 percent
aqueous solution 0.359 mole monomer equivalents) was dissolved in 60 mL of
deionized water and 225 mL ethanol. The solution was heated to 70 °C.
The pH of
the solution was adjusted to 10 by the addition of NaOH (50 percent solution).
2-Chloroacetic acid (13.58 g, 0.144 mole) was then added in one portion. The
reaction mixture was stirred at 70°C for 16-18 hours. The pH of the
solution was
checked periodically during this time and was maintained at 10 by the addition
of 50
percent NaOH. The solution was then cooled to room temperature, transferred to
a
dialysis bag (Spectra/Por molecular weight cut off 6000-8000) and dialyzed
against
19 liters of deionized water. The dialysis solution was changed until a
conductivity
of < 1mS/cm was recorded. The contents of the dialysis bag was then placed in
a
beaker and the pH of the solution adjusted to a value < 2 with concentrated
HCI.
This solution was then transferred to drying trays and placed in a convection
oven at
70 °C for 24 hours. The dried solid was ground to a fine powder using a
lab mill and
then passed through a sieve (80 mesh). The product was then replaced in a
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convection oven at 70 °C for 48 hours to remove any residual solvent.
The amount
of polymer obtained was 55.5 g.
Example 32. 30 Mol% modification of poly(diallylmethylamine) HCl with 2-
chloroaceticic acid
The procedure of example 31 was followed using the following materials:
poly(diallylmethylamine) HCl (120 g of 44.22 percent aqueous solution, 0.359
mole
monomer equivalents), deionized water (60 mL), ethanol (225 mL), 2-
chloroacetic
acid (10.19 g, 0.108 mole). The amount of polymer obtained was 53.8 g.
Example 33. 20 Mol% modification of poly(diallylmethylamine) HCl with 2-
chloroaceticic acid
The procedure of example 31 was followed using the following materials:
poly(diallylmethylamine) HCl (62.9 g of 44.22 percent aqueous solution, 0.188
mole
monomer equivalents), deionized water (30 mL), ethanol (110 mL), 2-
chloroacetic
acid (3.56 g, 0.038 mole). The amount of polymer obtained was 13.53 g.
Example 34. Modification of poly(diallylmethylamine) HC1 with 3-
bromopropionic acid
In a 500-mL flask equipped with an overhead mechanical stirrer, condenser
and a thermocouple probe, poly(diallylmethylamine), (67.84 g of a 44.22
percent
aqueous solution 0.203 mole monomer equivalents) was dissolved in 60 mL of
deionized water and 120 mL ethanol. The solution was heated to 70 °C.
The pH of
the solution was adjusted to 10 by the addition of NaOH (50 percent solution).
3-
Bromopropionic acid (32.63 g, 0.213 mole) was then added in one portion. The
reaction mixture was stirred at 70 °C for 16-18 hours. The pH of the
solution was
checked periodically during this time and was maintained at 10 by the addition
of 50
percent NaOH. The solution was then cooled to room temperature, transferred to
a
dialysis bag (Spectra/Por molecular weight cut off 6000-8000) and dialyzed
against
19 liters of deionized water. The dialysis solution was changed until a
conductivity
of < 1mS/cm was recorded. The contents of the dialysis bag was then placed in
a
beaker and the pH of the solution adjusted to a value < 2 with concentrated
HC1.
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This solution was then transferred to drying trays and placed in a convection
oven at
70 °C for 24 hours. The dried solid was ground to a fine powder using a
lab mill and
then passed through a sieve (80 mesh). The product was then replaced in a
convection oven at 70 °C for 48 hours to remove any residual solvent.
The amount
of polymer obtained was 35 g.
Example 35. Modification of poly(diallylmethylamine) HCI with 4-
bromobutyric acid
The procedure of example 34 was followed using the following materials:
poly(diallylmethylamine) HCl (67.84g of 44.22 percent aqueous solution, 0.203
mole monomer equivalents), deionized water (60 mL), ethanol (130 mL), 4-
bromobutyric acid (35.63 g, 0.213 mole). The amount of polymer obtained was
73 g.
Example 36. Modification of poly(allylamine) HCl with 3-bromopropionic acid
The procedure of example 34 was followed using the following materials:
poly(allylamine) HCl (40 g of a 50 percent aqueous solution, 0.214 mole
monomer
equivalents), deionized water (SO mL), 3-bromopropionic acid (34.36 g, 0.225
mole). The amount of polymer obtained was 28.5 g.
Example 37. Modification of poly(allylamine) HCl with 4-bromobutyric acid
The procedure of example 34 was followed using the following materials:
poly(allylamine) HCl (40 g of a 50 percent aqueous solution, 0.214 mole
monomer
equivalents), deionized water (50 mL), 4-bromobutyric acid (39.4 g, 0.236
mole).
The amount of polymer obtained was 20.6 g.
Example 38. Modification of polyethylenimine with 3-bromopropionic acid
The procedure of example 34 was followed using the following materials:
polyethylenimine (30 g of a 50 percent aqueous solution, 0.348 mole monomer
equivalents), deionized water (45 mL), 3-bromopropionic acid (55.9 g, 0.365
mole).
The amount of polymer obtained was 37.3 g.
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Example 39. Polydiallylamine hydrochloride
Diallylamine (2000.3 g) was added slowly over a period of 2 days to
concentrated HCl (2035.6 g). The temperature of the reaction was maintained
below
°C by cooling the flask in an ice-salt-water bath, and by adjusting the
addition
5 rate. The room temperature pH of the resulting diallylamine hydrochloride
solution
(68.16 percent diallylamine hydrochloride) was 0.005.
To a 12-L 4-necked round-bottomed flask equipped with an overhead stirrer
and an air condenser, was added diallylamine hydrochloride (3667.8 g of a
68.16
percent solution), and deionized water (4665.5 g). The resulting solution had
pH
10 0.74. To the flask was added NaOH (66.8 g of a 50 percent aqueous
solution). The
resulting solution had pH 2.55. Nitrogen gas was bubbled through the solution,
via
a stainless steel needle, with stirring, and venting on top of the air
condenser for 2
hours. The nitrogen line was put on top of the air condenser with positive
pressure
from a mineral oil bubbler. To the flask was added 125.0 g of freshly made 20
percent 2,2'-azobis(2-amidinopropane) dihydrochloride in deionized water. This
was added via syringe through a septum. The 2,2'-azobis(2-amidinopropane)
dihydrochloride solution was not degassed with nitrogen. The solution was
heated
to 60 °C over a period of 1 hour 8 minutes., with a heating mantle
connected to a
J-Kem temperature controller. The solution was heated at 60 °C for 18
hours. The
reaction temperature rose to 64 °C, and slowly cooled back down to 60
°C over a 3
hours period. After the first 18-hour heating period, the reaction solution
was
allowed to cool down slowly to 49 °C, and to the flask was added 125.0
g of freshly
made 20 percent 2,2'-azobis(2-amidinopropane) dihydrochloride in deionized
water.
The solution was heated to 60 °C over a period of about 15 minutes,
with a heating
mantle connected to a J-Kem temperature controller. The solution was heated at
60
°C for 18 hours. The reaction temperature rose to 62 °C, and
slowly cooled back
down to 60 °C over a 1 hour period. After the second 18 hours heating
period, the
reaction solution was allowed to cool down slowly to 40 °C, and to the
flask was
added 125.0 g of freshly made 20 percent 2,2'-azobis(2-amidinopropane)
dihydrochloride in deionized water. The solution was heated to 60 °C
over a period
of about 15 minutes, with a heating mantle connected to a J-Kem temperature
controller. The solution was heated at 60 °C for 18 hours. The reaction
temperature
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rose to 63 °C, and slowly cooled back down to 60 °C over a 1
hour period. After
cooling to room temperature, the solution was a dark orange viscous, flowable,
clear
solution. The flask contents were combined with deionized water (4166.7 g).
The
resulting solution had pH 4.41. SEC analysis: Mw 61,500 Daltons;
polydispersity
2.43.
Example 40. Polydiallylmethylamine
Diallylmethylamine (361.0 g) was added slowly over a period of 2 hours,l0
minutes to concentrated HCl (320.3 g). The temperature of the reaction was
maintained below 10 °C by cooling the flask in an ice-salt-water bath,
and by
adjusting the addition rate. The room temperature pH of the resulting
diallylmethylamine hydrochloride solution was 6.492, and the solution had two
phases, a small oil phase (top) with a large aqueous phase (bottom). To 660.5
g of
this mixture was added concentrated HCl (22.6 g), and the pH of the final
solution
was 0.349. The final solution was a single phase, and contains 68.04 percent
diallylmethylamine hydrochloride by weight.
To a 500-mL three-necked round-bottomed flask equipped with an overhead
stirrer and a vigreux column, was added diallylmethylamine hydrochloride (73.5
g
of a 68.04 percent solution), and deionized water (26.5 g). The resulting
solution
had pH 0.871. To the flask was added 50 percent aqueous NaOH until the
resulting
solution had pH 2.53. Nitrogen gas was bubbled through the solution, via a
stainless
steel needle, with stirring, and venting on top of the vigreux column for 30
minutes
The nitrogen line was put on top of the vigreux column with positive pressure
from
a mineral oil bubbler. To the flask was added 2.5 g of freshly made 20 percent
2,2'-
azobis(2-amidinopropane) dihydrochloride in deionized water. This was added
via
a transfer pipette, through one of the flask necks with a strong nitrogen
flow. The
2,2'-azobis(2-amidinopropane) dihydrochloride solution was not degassed with
nitrogen. The reaction solution was heated to 60 °C over a period of 30
minutes,
with a heating mantle connected to a J-Kem temperature controller. The
reaction
solution was heated at 60 °C for 18 hours. After the first 18-
hourheating period, the
reaction solution was allowed to cool down slowly to room temperature, and to
the
flask was added 2.5 g of freshly made 20 percent 2,2'-azobis(2-amidinopropane)
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dihydrochloride in deionized water. The reaction solution was heated to 60
°C over
a period of about 30 minutes. The reaction solution was heated at 60 °C
for another
18 hours. After the second 18-hourheating period, the reaction solution was
allowed
to cool down slowly to room temperature, and to the flask was added 2.5 g of
freshly
made 20 percent 2,2'-azobis(2-amidinopropane) dihydrochloride in deionized
water.
The reaction solution was heated to 60 °C over a period of about 30
minutes. The
reaction solution was heated at 60 °C for another 18 hours. After
cooling to room
temperature, the reaction solution was a clear dark orange, viscous and
flowable
solution. The flask contents were combined with deionized water (150.0 g). The
resulting solution had pH 4.36. SEC analysis: Mw 54,100 Daltons;
polydispersity
2.13.
Example 41. Functionalization of polyethylene-alt-malefic anhydride) with 3-
(dimethylamino)propylamine.
To a solution of polyethylene-alt-malefic anhydride) (20.0 g) in N,N
dimethylformamide (180 mL) under a nitrogen atmosphere was added 3
(dimethylamino)propylamine (40 mL). The mixture was heated at 60 °C
overnight
and allowed to cool to room temperature. Concentrated HCl (47 g) was added and
the mixture was transferred to a Spectra/Por 1 dialysis membrane bag
(molecular
weight cutoff 6000 to 8000) and dialyzed against deionized water for at least
18
hours. The dialyzed polymer solution was dried in a forced-air oven at 70
°C for 48
hours to afford 37.8 g.
No Example 42
Example 43. Functionalization of poly(diallylmethylamine) with
polyoxyethylene(40) nonylphenyl glycidyl ether.
Polyoxyethylene(40) nonylphenyl glycidyl ether was synthesized by reacting
polyoxyethylene(40) nonylphenyl ether (100.0 g) with epichlorohydrin (60 mL)
in
the presence of deionized water (0.750 g), NaOH (6 g), and 3,5-di-tert-butyl-4-
hydroxyanisole (0.23 g) at 60 °C for 10 hours. After cooling to room
temperature,
methylene chloride (200 mL) was added, and this solution was extracted with a
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solution of deionized water (200 mL) and potassium dihydrogen phosphate (10
g).
The organic layer was washed four times with deionized water (100 mL per wash)
and concentrated on a rotary evaporator (60 °C bath temperature). The
residue was
triturated with diethyl ether (1 L) and dried under vacuum at 50 °C to
afford 83.0 g.
A basic solution of polydiallylmethylamine was prepared by mixing
polydiallylmethylamine hydrochloride (677 g of a 44.22 percent aqueous
solution),
deionized water (823 g) and NaOH (87 g of a 50 percent aqueous solution)
overnight.
To a portion of the polydiallylmethylamine basic solution (158.9.0 g) was
added polyoxyethylene(40) nonylphenyl glycidyl ether (3.0 g). After stirring
overnight, concentrated HC1 (25.0 g) was added. The reaction mixture was
transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff
6000
to 8000) and dialyzed against deionized water for at least 18 hours. The
dialyzed
polymer solution was dried in a forced-air oven at 70 °C for 48 hours
to afford
31.5 g.
Example 44. Functionalization of poly(diallylmethylamine) with
polyoxyethylene(40) nonylphenyl glycidyl ether.
To a portion of the polydiallylmethylamine basic solution (158.7 g; Example
43) was added polyoxyethylene(40) nonylphenyl glycidyl ether (6.0 g; Example
43).
After stirring overnight, concentrated HCl (18.0 g) was added. The reaction
mixture
was transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight
cutoff
6000 to 8000) and dialyzed against deionized water for at least 18 hours. The
dialyzed polymer solution was dried in a forced-air oven at 70 °C to
afford 33.4 g.
Example 45. Functionalization of poly(diallylmethylamine) with
polyoxyethylene(40) nonylphenyl glycidyl ether.
To a portion of the polydiallylmethylamine basic solution (158.7 g; Example
43) was added polyoxyethylene(40) nonylphenyl glycidyl ether (9.0 g; Example
43).
After stirring overnight, concentrated HCl (32.6 g) was added. The reaction
mixture
was transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight
cutoff
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6000 to 8000) and dialyzed against deionized water for at least 18 hours. The
dialyzed polymer solution was dried in a forced-air oven at 70 °C to
afford 37.3 g.
Example 46. Functionalization of poly(diallylmethylamine) with
S polyoxyethylene(40) nonylphenyl glycidyl ether.
To a portion of the polydiallylmethylamine basic solution (158.7 g; Example
43) was added polyoxyethylene(40) nonylphenyl glycidyl ether (12.0 g; Example
43). After stirring overnight, concentrated HC1 (24.2 g) was added. The
reaction
mixture was transferred to a Spectra/Por 1 dialysis membrane bag (molecular
weight cutoff 6000 to 8000) and dialyzed against deionized water for at least
18
hours. The dialyzed polymer solution was dried in a forced-air oven at 70
°C to
afford 40.6 g.
Example 47. Functionalization of poly(diallylmethylamine) with
polyoxyethylene(40) nonylphenyl glycidyl ether.
To a portion of the polydiallylmethylamine basic solution (158.7 g; Example
43) was added polyoxyethylene(40) nonylphenyl glycidyl ether (30 g; Example
43).
After stirring overnight, concentrated HCl was added until the pH of the
resulting
solution was less than 1Ø The reaction mixture was transferred to a
Spectra/Por 1
dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed
against
deionized water for at least 18 hours. The dialyzed polymer solution was dried
in a
forced-air oven at 70 °C to afford 60.0 g.
No Example 48
Example 49. Functionalization of poly(diallylmethylamine) with
polyoxyethylene(23) lauryl glycidyl ether.
Polyoxyethylene (23) lauryl glycidyl ether was synthesized by reacting
polyoxyethylene (23) lauryl ether (50.0 g) with epichlorohydrin (50 mL) in the
presence of deionized water (0.625 g), NaOH (5 g), and 3,5-di-tert-butyl-4-
hydroxyanisole (0.28 g) at 60 °C for 10 hours. After cooling to room
temperature,
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methylene chloride (100 mL) was added, and this solution was extracted with a
solution of deionized water (100 mL) and potassium dihydrogen phosphate (5 g).
The organic layer was washed four times with deionized water (100 mL per wash)
and concentrated on a rotary evaporator (60 °C bath temperature). The
residue was
triturated with diethyl ether (1 L) and dried under vacuum to afford 34.55 g.
A basic solution of polydiallylmethylamine was prepared by mixing
polydiallylmethylamine hydrochloride (677 g of a 44.22 percent aqueous
solution),
deionized water (823 g) and NaOH (87 g of a 50 percent aqueous solution)
overnight.
To a portion of the polydiallylmethylamine basic solution (158.7 g) was
added polyoxyethylene(23) lauryl glycidyl ether (3.0 g). After stirnng
overnight,
concentrated HCl (40.3 g) was added. The reaction mixture was transferred to a
SpectralPor 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and
dialyzed against deionized water for at least 18 hours. The dialyzed polymer
solution was dried in a forced-air oven at 70 °C to afford 31 g.
Example 50. Functionalization of poly(diallylmethylamine) with
polyoxyethylene(23) lauryl glycidyl ether.
To a portion of the basic solution of polydiallylmethylamine (158.7 g;
Example 49) was added polyoxyethylene(23) lauryl glycidyl ether (6.0 g;
Example
49). After stirnng for 24 hours at room temperature, concentrated HCl (21.6 g)
was
added. The reaction mixture was transferred to a Spectra/Por 1 dialysis
membrane
bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized
water
for at least 18 hours. The dialyzed polymer solution was dried in a forced-air
oven
at 70 °C to afford 30.0 g.
Example 51. Functionalization of poly(diallylmethylamine) with glycidol.
A basic solution of polydiallylmethylamine was prepared by mixing
polydiallylmethylamine hydrochloride (615.4 g of a 44.22 percent aqueous
solution), deionized water (745.2 g) and NaOH (78.0 g of a 50 percent aqueous
solution) overnight.
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To a portion of the basic solution of polydiallylmethylamine (158.7 g) was
added glycidol (26.9 mL). After stirring for 24 hours at room temperature,
concentrated HCl (14.2 g) was added. The reaction mixture was transferred to a
Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and
dialyzed against deionized water for at least 18 hours. The dialyzed polymer
solution was dried in a forced-air oven at 70 °C to afford 40.0 g.
Example 52. Functionalization of poly(diallylmethylamine) with glycidol.
To a portion of the basic solution of polydiallylmethylamine (158.7 g;
Example 51) was added glycidol (13.5 mL). After stirring for 24 hours at room
temperature, concentrated HCl (13.5 g) was added. The reaction mixture was
transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff
6000
to 8000) and dialyzed against deionized water for at least 18 hours. The
dialyzed
polymer solution was dried in a forced-air oven at 70 °C to afford 40.0
g.
Example 53. Functionalization of poly(diallylmethylamine).
To a portion of the basic solution of polydiallylmethylamine (158.7 g;
Example 51) was added bromoethane (30.30 mL). After stirnng for 24 hours at
room temperature, concentrated HCl (10.9 g) was added. The reaction mixture
was
transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff
6000
to 8000) and dialyzed against deionized water for at least 18 hours. The
dialyzed
polymer solution was dried in a forced-air oven at 70 °C to afford 31.0
g.
Example 54. Polyethylenimine, 80% ethoxylated.
A solution of polyethylenimine, 80 percent ethoxylated (269.1 g of a 35-40
percent solution in water; Aldrich Chemical Company) was transferred to a
Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and
dialyzed against deionized water for at least 18 hours. The dialyzed polymer
solution was dried in a forced-air oven at 70 °C to afford the desired
compound.
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Example 55. Copoly(N-[3-(dimethylamino)propyl]acrylamide/acrylamide/N-
dodecylacrylamide) (48:48:5).
A solution of N-[3-(dimethylamino)propyl]acrylamide (30.0 g), acrylamide
(13.6 g), and N-dodecylacrylamide (4.6 g) in deionized water (SO mL) and
ethanol
(SO mL) was heated to 60 °C under a nitrogen atmosphere. When the
solution
reached 60 °C, 2,2'-azobis(2-amidinopropane) dihydrochloride (2.4 g of
a 20
percent aqueous solution) was added. Heating was continued for 18 hours under
a
nitrogen atmosphere. After cooling to room temperature, the reaction solution
was
dissolved in isopropanol (150 mL), and concentrated HC1 (29.5 g) was added
with
stirring. The solution was decanted from the precipitated polymer. The polymer
was
suspended in isopropanol (500 mL), stirred for at least 15 minutes, and
allowed to
settle. After decanting, the polymer was similarly washed an additional 3
times with
isopropanol. The washed polymer was dried in a forced-air oven at 70 °C
to afford
81.1 g.
Example 56. Copoly(N-[3-(dimethylamino)propyl]acrylamide/acrylamide)
(50/50).
A solution of N-[3-(dimethylamino)propyl]acrylamide (30.0 g) and
acrylamide (13.6 g) in deionized water (40 mL) and ethanol (40 mL) was heated
to
60 °C under a nitrogen atmosphere. When the solution reached 60
°C, 2,2'-
azobis(2-amidinopropane) dihydrochloride (2.2 g of a 20 percent aqueous
solution)
was added. Heating was continued for 18 hours under a nitrogen atmosphere.
After
cooling to room temperature, the reaction solution was dissolved in
isopropanol
(150 mL), and concentrated HC1 (31.5 g) was added with stirring. The solution
was
decanted from the precipitated polymer. The polymer was suspended in
isopropanol
(500 mL), stirred for at least 15 minutes, and allowed to settle. After
decanting, the
polymer was similarly washed an additional 3 times with isopropanol. The
washed
polymer was dried in a forced-air oven at 70 °C to afford 68.2 g.~
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Example 57. Copoly(N-[3-(dimethylamino)propyl]acrylamide/acrylamide/N-
dodecylacrylamide) (75/20/5).
A solution of N-[3-(dimethylamino)propyl]acrylamide (22.5 g), acrylamide
(2.7 g), and N-dodecylacrylamide (2.3 g) in deionized water (30 mL) and
ethanol
(30 mL) was heated to 60 °C under a nitrogen atmosphere. When the
solution
reached 60 °C, 2,2'-azobis(2-amidinopropane) dihydrochlorzde (1.4 g of
a 20
percent aqueous solution) was added. Heating was continued for 18 hours under
a
nitrogen atmosphere. After cooling to room temperature, the reaction solution
was
dissolved in isopropanol (150 mL), and concentrated HC1 (29.2 g) was added
with
stirring. The solution was decanted from the precipitated polymer. The polymer
was
suspended in isopropanol (500 mL), stirred for at least 15 minutes, and
allowed to
settle. After decanting, the polymer was similarly washed an additional 3
times with
isopropanol. The washed polymer was dried in a forced-air oven at 70 °C
to afford
34.7 g.
Example 58. Functionalization of polydiallylamine with (6-bromohexyl)
trimethylammonium bromide.
A solution of polydiallylamine hydrochloride (106.8 g of a 28.09 percent
aqueous solution), deionized water (400 g), NaOH (9.6 g of a 50 percent
aqueous
solution), and (6-bromohexyl) trimethylammonium bromide (51.1 g) was heated to
60 °C for 18 hours. After 1 hour at 60 °C, NaOH (4.5 g of a 50
percent aqueous
solution) was added. After 1.5 hours at 60 °C, NaOH (4.5 g of a 50
percent aqueous
solution) was added. After 2 hours at 60 °C, NaOH (4.5 g of a 50
percent aqueous
solution) was added. Concentrated HCl was added until the reaction solution
had a
pH < 1. The solution was then poured into isopropanol (4 L) and stirred for at
least
15 minutes. The solution was decanted from the precipitated polymer. The
polymer
was suspended in isopropanol (4 L), stirred for at least 15 minutes, arid
allowed to
settle. After decanting, the polymer was similarly washed an additional time
with
isopropanol. The washed polymer was dried in a forced-air oven at 70 °C
to afford
69.4 g.
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Example 59. Functionalization of poly(diallylmethylamine) with polyethylene
glycol) diglycidyl ether.
A basic solution of polydiallylmethylamine was prepared by mixing
polydiallylmethylamine hydrochloride (615.4 g of a 44.22 percent aqueous
solution), deionized water (745.2 g) and NaOH (78.0 g of a 50 percent aqueous
solution) overnight. To a portion of the polydiallylmethylamine basic solution
(158.6 g) was added polyethylene glycol) diglycidyl ether (9.0 g, Average Mn
ca.
526, from Aldrich Chemical Co.). After stirnng overnight, concentrated HCl
(10 mL) was added. The reaction mixture was transferred to a Spectra/Por 1
dialysis
membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against
deionized water for at least 18 hours. The dialyzed polymer solution was dried
in a
forced-air oven at 70 °C to afford 9.3 g.
Example 60. Poly[bis(2-chloroethyl)ether-alt-1,3-bis[3-(dimethylamino)
propyl]urea], quaternized.
A solution of poly[bis(2-chloroethyl)ether-alt-1,3-bis[3-(dimethylamino)
propyl]urea], quaternized (566.7 g of a 62 percent solution in water; from
Aldrich
Chemical Co.) was transferred to a Spectra/Por 1 dialysis membrane bag
(molecular
weight cutoff 6000 to 8000) and dialyzed against deionized water for at least
18
hours. The dialyzed polymer solution was dried in a forced-air oven at 70
°C to
afford the desired compound.
Example 61. Functionalization of polyethylenimine with glycidol.
A solution of polyethylenimine (60.0 g), deionized water (240 g), and
glycidol (46.2 mL) was heated at 50 °C under a nitrogen atmosphere for
18 hours.
After cooling to room temperature, concentrated HCl (50 mL) was added. The
reaction was transferred to a Spectra/Por 1 dialysis membrane bag (molecular
weight cutoff 6000 to 8000) and dialyzed against deionized water for at least
18
hours. The dialyzed polymer solution was dried in a forced-air oven at 70
°C to
afford the desired compound.
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Example 62. Functionalization of polyethylenimine with 2-bromoethanol.
A solution of polyethylenimine (60.0 g), deionized water (240 g), and 2-
bromoethanol (49.4 mL) was heated at 50 °C under a nitrogen atmosphere
for 18
hours. After 1.5 hours at 50 °C, NaOH (31.9 g of a SO percent aqueous
solution)
was added. After cooling to room temperature, concentrated HCl (30 mL) was
added. The reaction mixture was transferred to a SpectralPor 1 dialysis
membrane
bag (molecular weight cutoff 6000 to 8000) and dialyzed against deionized
water for
at least 18 hours. The dialyzed polymer solution was dried in a forced-air
oven at
70 °C to afford the desired compound.
Example 63. Protonation of polydiallylmethylamine with L-tartaric acid.
A basic solution of polydiallylmethylamine was prepared by mixing
polydiallylmethylamine hydrochloride (615.4 g of a 44.22 percent aqueous
solution), deionized water (745.2 g) and NaOH (78.0 g of a SO percent aqueous
solution) overnight.
To a portion of the polydiallylmethylamine basic solution (158.6 g) was
added L-tartaric acid (30.8 g). After stirring overnight, the solution was
poured into
isopropanol (3 L) and stirred for at least 15 minutes. The solution was
decanted
from the precipitated polymer. The polymer was suspended in isopropanol (3 L),
stirred for at least 15 minutes, and allowed to settle. After decanting, the
polymer
was similarly washed an additional time with isopropanol. The washed polymer
was dried in a forced-air oven at 70 °C to afford 45.2 g.
Example 64. Polydiallyldimethylammonium chloride.
Polydiallyldimethylammonium chloride (526.8 g of a 20 percent aqueous
solution, average MW 200,000-350,000, from Aldrich Chemical Co.) was poured
into isopropanol (12 L) and stirred for at least 15 minutes. The solution was
decanted from the precipitated polymer. The washed polymer was dried in a
forced-
air oven at 70 °C to afford 90.8 g.
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Example 65. Functionalization of poly(diallylmethylamine) with
polyoxyethylene(2,000) methyl glycidyl ether.
NaH (3.28 g; 60 percent in oil from VWR) was weighed out in a three-
necked 1-L round-bottomed flask and washed 3 times with 200 mL of hexane. The
hexane was removed and the NaH was suspended in 350 mL of anhydrous dioxane.
Polyoxyethylene(2,000) methyl glycidyl ether (130 g; average Mn 2,000,
obtained
from Aldrich Chemical Co.) was dissolved in 250 mL of dioxane and then added
to
the above stirred solution at room temperature under a nitrogen atmosphere.
The
solution was stirred for a further hour at room temperature. The reaction
mixture
was heated to 45 °C and then 12.03 g of epichlorohydrin was added to
this solution
and the reaction mixture was heated overnight. The reaction was allowed to
cool to
room temperature and was then filtered. The filtered solution was concentrated
using a rotary evaporator to give a white solid. The solid was dissolved in
500 mL
of methylene chloride and the polymer was precipitated in 4 L of diethyl
ether. The
polymer was dissolved in 500 mL of methylene chloride and the polymer was
precipitated in 4 L of diethyl ether and filtered. The polymer was dried in a
vacuum
oven at room temperature over 72 hours to afford 110.9 g of polyoxyethylene
(2,000) methyl glycidyl ether.
A solution of polydiallylmethylamine hydrochloride (67.7 g of a 44.22
percent aqueous solution), deionized water (82.3 g) and NaOH (8.7 g of a 50
percent
aqueous solution) was heated at 60 °C for 3.5 hours. Polyoxyethylene
(2,000)
methyl glycidyl ether (1.5 g) was then added and the solution was heated at 60
°C
for an additional 8 hours. After cooling to room temperature, the reaction
mixture
was poured into acetone (4 L) and stirred for at least 15 minutes. The
solution was
decanted from the precipitated polymer. The polymer was suspended in acetone
(2 L), stirred for at least 15 minutes, and allowed to settle. After
decanting, the
polymer was similarly washed an additional time with acetone. The washed
polymer was dried in a forced-air oven at 70 °C to afford 26.4 g.
No Example 66
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Example 67. Functionalization of poly(diallylmethylamine) with
polyoxyethylene(2,000) methyl glycidyl ether
A solution of polydiallylmethylamine hydrochloride (67.7 g of a 44.22
percent aqueous solution), deionized water (82.3 g) and NaOH (8.7 g of a 50
percent
aqueous solution) was heated at 60 °C for 3.5 hours.
Polyoxyethylene(2,000)
methyl glycidyl ether (3.0 g) was then added and the solution was heated at 60
°C
for an additional 8 hours. After cooling to room temperature, the reaction
mixture
was poured into acetone (4 L) and stirred for at least 15 minutes. The
solution was
decanted from the precipitated polymer. The polymer was suspended in acetone
(2
L), stirred for at least 15 minutes, and allowed to settle. After decanting,
the
polymer was similarly washed an additional time with acetone. The washed
polymer was dried in a forced-air oven at 70 °C to afford 23.2 g.
Example 68. Copoly(diallylmethylamine/acrylamide) (50:50).
A solution of diallylmethylammonium chloride was prepared by adding
diallylmethylamine (250 g) dropwise to a solution that was cooled in an ice-
water
bath to 10 °C, of deionized water (192.3 g) and concentrated HCl (222.2
g).
A solution of diallylmethylammonium chloride (59.1 g of the 50 percent aqueous
solution), acrylamide (14.2 g), and 2,2'-azobis(2-amidinopropane)
dihydrochloride
(2.7 g of a 20 percent aqueous solution) in deionized water (14.2 g) was
heated to 60
°C for 18 hours under a nitrogen atmosphere. After cooling to room
temperature, the
reaction solution was transferred to a Spectra/Por 1 dialysis membrane bag
(molecular weight cutoff 6000 to 8000) and dialyzed against deionized water
for at
least 18 hours. The dialyzed polymer solution was dried in a forced-air oven
at 70
°C to afford 25.2 g.
Example 69. Copoly(diallyldimethylammonium chloride/acrylamide) (50:50).
A solution of diallyldimethylammonium chloride (49.8 g of a 65 percent
solution in water), acrylamide (14.2 g), and 2,2'-azobis(2-amidinopropane)
dihydrochloride (2.7 g of a 20 percent aqueous solution) in deionized water
(91.1 g)
was heated to 60 °C for 18 hours under a nitrogen atmosphere. After
cooling to
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room temperature, the reaction solution was transferred to a Spectra/Por 1
dialysis
membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against
deionized water for at least 18 hours. The dialyzed polymer solution was dried
in a
forced-air oven at 70 °C to afford 27.8 g.
Example 70. Functionalization of polydiallylmethylamine with
epichlorohydrin.
To a solution of polydiallylmethylammonium hydrochloride (67.8 g of a
44.22 percent aqueous solution), deionized water (82.8 g), and NaOH (8.7 g of
a 50
percent aqueous solution) was added epichlorohydrin (0.159 mL). The reaction
was
heated under a nitrogen atmosphere at 45 °C overnight. After 30 minutes
of heating,
the solution gelled. After the heating period, the reaction was allowed to
cool to
room temperature, and concentrated HCl (10.9 g) and deionized water (250 mL)
were added. The resulting slurry was transferred to a Spectra/Por 1 dialysis
membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against
deionized water for at least 18 hours. The dialyzed polymer solution was dried
in a
forced-air oven at 70 °C to afford 26.8 g.
Example 71. Copoly(diallyldimethylammonium chloride/poly(ethylene glycol)
methyl ether acrylate).
A solution of diallyldimethylammonium chloride (41.5 g of a 65 percent
solution in water), polyethylene glycol) methyl ether acrylate (3.0 g, Average
Mn
454, obtained from Aldrich Chemical Co.), and 2,2'-azobis(2-amidinopropane)
dihydrochloride (0.3 g) in 2-methyl-2-propanol (60 g) and deionized water (60
g)
was heated to 60 °C for 16.5 hours under a nitrogen atmosphere. After
cooling to
room temperature, the reaction solution was poured into isopropanol (2 L) and
stirred for at least 15 minutes. The solution was decanted from the
precipitated
polymer. The polymer was suspended in isopropanol (2 L), stirred for at least
15
minutes, and allowed to settle. After decanting, the polymer was suspended in
isopropanol (2 L), stirred for at least 15 minutes, and allowed to settle. The
washed
polymer was dried in a forced-air oven at 70 °C to afford 16.3 g.
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Example 72. Copoly(diallyldimethylammonium chloride/poly(propylene
glycol) methyl ether acrylate).
A solution of diallyldimethylammonium chloride (41.5 g of a 65 percent
solution in water), polypropylene glycol) methyl ether acrylate (3.0 g,
Average Mn
202, obtained from Aldrich Chemical Co.), and 2,2'-azobis(2-amidinopropane)
dihydrochloride (0.3 g) in 2-methyl-2-propanol (60 g) and deionized water (60
g)
was heated to 60 °C for 16.5 hours under a nitrogen atmosphere. After
cooling to
room temperature, the reaction solution was poured into isopropanol (2 L) and
stirred for at least 15 minutes. The solution was decanted from the
precipitated
polymer. The polymer was suspended in isopropanol (2 L), stirred for at least
1 S
minutes, and allowed to settle. After decanting, the polymer was suspended in
isopropanol (2 L), stirred for at least 15 minutes, and allowed to settle. The
washed
polymer was dried in a forced-air oven at 70 °C to afford 18.2 g.
Example 73. Copoly(diallyldimethylammonium chloride/vinyl alcohol) (50:50).
A solution of diallyldimethylammonium chloride (32.6 g of a 65 percent
solution in water), vinyl acetate (10.53 g), and 2,2'-azobis(2-amidinopropane)
dihydrochloride (0.64 g) in 2-methyl-2-propanol (60 g) and deionized water (60
g)
was heated to 60 °C for 21 hours under a nitrogen atmosphere. After
cooling to
room temperature, the reaction solution was poured into isopropanol (2 L) and
stirred for at least 15 minutes. The solution was decanted from the
precipitated
polymer. The polymer was suspended in isopropanol (2 L), stirred for at least
15
minutes, and allowed to settle. After decanting, the polymer was suspended in
isopropanol (2 L), stirred for at least 15 minutes, and allowed to settle. The
washed
polymer was dried in a forced-air oven at 70 °C to afford 11.5 g. To a
solution of a
portion of the washed polymer (5.5 g) in deionized water (100 mL) was added
NaOH (0.15 g of a SO percent aqueous solution). The solution was heated at 60
°C
with stirring for 23.5 hours. The reaction solution was transferred to a
Spectra/Por 1
dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed
against
deionized water for at least 18 hours. The dialyzed polymer solution was dried
in a
forced-air oven at 70 °C to afford 4.5 g.
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Example 74. Copoly(diallyldimethylammonium chloride/poly(ethylene glycol
acrylate).
A solution of diallyldimethylammonium chloride (36.9 g of a 65 percent
solution in water), polyethylene glycol) methyl ether acrylate (6.0 g, Average
Mn
375, obtained from Aldrich Chemical Co.), and 2,2'-azobis(2-amidinopropane)
dihydrochloride (0.3 g) in deionized water (120 g) was heated to 60 °C
for 18 hours
under a nitrogen atmosphere. After cooling to room temperature, the reaction
solution was poured into acetone (2 L) and stirred for at least 15 minutes.
The
solution was decanted from the precipitated polymer. The polymer was suspended
in
acetone (2 L), stirred for at least 15 minutes, and allowed to settle. After
decanting,
the polymer was suspended in acetone (2 L), stirred for at least 15 minutes,
and
allowed to settle. The washed polymer was dried in a forced-air oven at 70
°C to
afford 20.0 g.
Example 75. Copoly(diallyldimethylammonium chloride/acrylic acid) (90:10).
A solution of diallyldimethylammonium chloride (73.29 g of a 65 percent
solution in water), acrylic acid (2.36 g) and 2,2'-azobis(2-amidinopropane)
dihydrochloride (0.444 g) in deionized water (175 mL) was heated to 60
°C for 18
hours under a nitrogen atmosphere. After cooling to room temperature, the
reaction
solution was poured into isopropanol (2 L) and stirred for at least 15
minutes. The
solution was decanted from the precipitated polymer. The polymer was suspended
in
isopropanol (2 L), stirred for at least 15 minutes, and allowed to settle.
After
decanting, the polymer was suspended in isopropanol (2 L), ground in a blender
for
at least 5 minutes, stirred for at least 15 minutes, and allowed to settle.
The washed
polymer was dried in a forced-air oven at 70 °C to afford 35.0 g.
Example 76. Copoly(diallyldimethylammonium chloride/acrylic acid) (75:25).
A solution of diallyldimethylammonium chloride (66.97 g of a 65 percent
solution in water), acrylic acid (6.47 g) and 2,2'-azobis(2-amidinopropane)
dihydrochloride (0.487 g) in deionized water (175 mL) was heated to 60
°C for 18
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hours under a nitrogen atmosphere. After cooling to room temperature, the
reaction
solution was poured into isopropanol (2 L) and stirred for at least 15
minutes. The
solution was decanted from the precipitated polymer. The polymer was suspended
in
isopropanol (2 L), stirred for at least 15 minutes, and allowed to settle.
After
decanting, the polymer was suspended in isopropanol (2 L), ground in a blender
for
at least 5 minutes, stirred for at least 15 minutes, and allowed to settle.
The washed
polymer was dried in a forced-air oven at 70 °C to afford 38.9 g.
Example 77. Functionalization of poly(diallylmethylamine) with 3-
bromopropionic acid.
A basic solution of polydiallylmethylamine was prepared by mixing
polydiallylmethylamine hydrochloride (615.4 g of a 44.22 percent aqueous
solution), deionized water (745.2 g) and NaOH (78.0 g of a 50 percent aqueous
solution) overnight.
To a portion of the basic solution of polydiallylmethylamine (158.6 g) was
added deionized water (141.4 g) and 3-bromopropionic acid (15.5 g). This
solution
was heated to 50 °C, and then NaOH (16.2 g of a 50 percent aqueous
solution) was
added. The reaction solution was heated at 50 °C for 18.5 hours. After
cooling to
room temperature, the reaction solution was transferred to a Spectra/Por 1
dialysis
membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed against
deionized water for at least 18 hours. The dialyzed polymer solution was dried
in a
forced-air oven at 70 °C to afford 29.2 g.
Example 78. Functionalization of poly(diallylmethylamine) with 4-
bromobutyric acid.
To a portion of the basic solution of polydiallylmethylamine (158.6 g;
Example 77) was added deionized water (141.4 g) and 3-bromobutyric acid (17.0
g).
This solution was heated to 50 °C, and then NaOH (16.2 g of a 50
percent aqueous
solution) was added. The reaction solution was heated at 50 °C for 18.5
hours. After
cooling to room temperature, the reaction solution was transferred to a
Spectra/Por 1
dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed
against
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deionized water for at least 18 hours. The dialyzed polymer solution was dried
in a
forced-air oven at 70 °C to afford 20.0 g.
Example 79. Functionalization of poly(diallylmethylamine) with 2-
bromoethanesulfonic acid.
To a portion of the basic solution of polydiallylmethylamine (158.6 g;
Example 77) was added deionized water (141.4 g) and 2-bromoethanesulfonic acid
(21.4 g). This solution was heated to SO °C, and then NaOH (16.2 g of a
50 percent
aqueous solution) was added. The reaction solution was heated at 50 °C
for 19
hours. After cooling to room temperature, the reaction solution was
transferred to a
Spectra/Por 1 dialysis membrane bag (molecular weight cutoff 6000 to 8000) and
dialyzed against deionized water for at least 18 hours. The dialyzed polymer
solution was dried in a forced-air oven at 70 °C to afford 28.8 g.
Example 80 . Functionalization of poly(diallylmethylamine) with 1,3-propane
sultone.
To a portion of the basic solution of polydiallylmethylamine (158.6 g;
Example 77) was added deionized water (141.4 g) and 1,3-propane sultone (12.4
g).
This solution was heated to 50 °C, and then NaOH (16.2 g of a 50
percent aqueous
solution) was added. The reaction solution was heated at 50 °C for 19
hours. After
cooling to room temperature, the reaction solution was poured into isopropanol
(2 L)
and stirred for at least 15 minutes. The solution was decanted from the
precipitated
polymer. The polymer was suspended in isopropanol (2 L), stirred for at least
15
minutes, and allowed to settle. After decanting, the polymer was suspended in
isopropanol (2 L), ground in a blender for at least S minutes, stirred for at
least 15
minutes, and allowed to settle. The washed polymer was dried in a forced-air
oven
at 70 °C to afford 38.8 g.
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Example 81. Functionalization of poly(diallylmethylamine) with 2-
bromoethanol.
To a portion of the basic solution of polydiallylmethylamine (158.6 g;
Example 77) was added deionized water (150 mL) and 2-bromoethanol (40.06 g).
This solution was heated to 45 °C, and then NaOH (16.2 g of a 50
percent aqueous
solution) was added. The reaction solution was heated at 45 °C for 21
hours. After
cooling to room temperature, the reaction solution was transferred to a
Spectra/Por 1
dialysis membrane bag (molecular weight cutoff 6000 to 8000) and dialyzed
against
deionized water for at least 18 hours. The dialyzed polymer solution was dried
in a
forced-air oven at 70 °C to afford 40.2 g.
Example 82. Functionalization of poly(diallylamine) with 2-bromoethanol.
A basic solution of polydiallylamine was prepared by mixing
polydiallylamine hydrochloride (519.03 g of a 28.9 percent aqueous solution),
deionized water (230.97 g) and NaOH (48.0 g of a 50 percent aqueous solution)
overnight.
To a portion of the polydiallylamine basic solution (133.62 g) was added 2-
bromoethanol (65.77 g). This solution was heated to 45 °C, and then
NaOH (16.2 g
of a 50 percent aqueous solution) was added. The reaction solution was heated
at 45
°C for 18 hours. After 3 hours at 45 °C, NaOH (50 percent
aqueous solution) was
added to bring the pH from 8.5 to 9.6. After cooling to room temperature, the
reaction solution was transferred to a Spectra/Por 1 dialysis membrane bag
(molecular weight cutoff 6000 to 8000) and dialyzed against deionized water
for at
least 18 hours. The dialyzed polymer solution was dried in a forced-air oven
at 70
°C to afford 41.0 g.
Example 83. Copoly[(3-acrylamidopropyl)trimethylammonium
chloride]/acrylic acid](90:10).
A solution of (3-acrylamidopropyl)trimethylammonium chloride (64.2 g of a
75 percent solution in water), acrylic acid (1.86 g) and 2,2'-azobis(2-
amidinopropane) dihydrochloride (0.351 g) in deionized water (190 mL) was
heated
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to 60 °C for 8 hours under a nitrogen atmosphere. After cooling to room
temperature, the reaction solution was poured into isopropanol (2 L) and
stirred for
at least 15 minutes. The solution was decanted from the precipitated polymer.
The
polymer was suspended in isopropanol (2 L), stirred for at least 15 minutes,
and
allowed to settle. After decanting, the polymer was suspended in isopropanol
(2 L),
stirred for at least 15 minutes, and allowed to settle. The washed polymer was
dried
in a forced-air oven at 70 °C to afford 44.8 g.
Example 84. Copoly[(3-acrylamidopropyl)trimethylammonium
chloride]/acrylic acid](75:25).
A solution of (3-acrylamidopropyl)trimethylammonium chloride (59.7 g of a
75 percent solution in water), acrylic acid (5.21 g) and 2,2'-azobis(2-
amidinopropane) dihydrochloride (0.392 g) in deionized water (190 mL) was
heated
to 60 °C for 8 hours under a nitrogen atmosphere. After cooling to room
temperature, the reaction solution was poured into isopropanol (2 L) and
stirred for
at least 15 minutes. The solution was decanted from the precipitated polymer.
The
polymer was suspended in isopropanol (2 L), stirred for at least 15 minutes,
and
allowed to settle. After decanting, the polymer was suspended in isopropanol
(2 L),
stirred for at least 1 S minutes, and allowed to settle. The washed polymer
was dried
in a forced-air oven at 70 °C to afford 47.1 g.
Example 85. Copoly(diallyldimethylammonium chloride/poly(ethylene glycol)
methyl ether acrylate).
A solution of diallyldimethylammonium chloride (50.0 g of a 50 percent
solution in water), polyethylene glycol) methyl ether acrylate (25.0 g,
Average Mn
454, obtained from Aldrich Chemical Co.), and 2,2'-azobis(2-amidinopropane)
dihydrochloride (0.5 g) in deionized water (190 mL) was heated to 60 °C
for 16
hours under a nitrogen atmosphere. After cooling to room temperature,
deionized
water (200 mL) was added and after thoroughly mixing, the reaction solution
was
transferred to a Spectra/Por 1 dialysis membrane bag (molecular weight cutoff
6000
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to 8000) and dialyzed against deionized water for at least 18 hours. The
dialyzed
polymer solution was dried in a forced-air oven at 70 °C to afford 31.0
g.
Example 86. Copoly[(3-acrylamidopropyl)trimethylammonium chloride
/poly(ethylene glycol) methyl ether acrylate].
A solution of polyethylene glycol) methyl ether (10.0 g, Average Mn 2,000,
obtained from Aldrich Chemical Co.), triethylamine (5.06 g), and 3,5-di-tert-
butyl-
4-hydroxyanisole (0.06 g) in tetrahydrofuran (250 mL) was cooled in an ice-
water
bath. While maintaining the temperature of the reaction solution at S-15
°C, a
solution of acryloyl chloride (4.53 g) in tetrahydrofuran (30 mL) was added
slowly.
Following the addition, the reaction solution was heated at 40 °C for
24 hours and
then stored at 4 °C for 72 hours. The upper liquid layer was decanted
from the
precipitate, and concentrated on a rotary evaporator to remove most of the
tetrahydrofuran. The concentrated solution was then poured into diethyl ether,
and
the light yellow precipitate was filtered and dried under vacuum to afford 2.5
g of
solid polyethylene glycol) methyl ether acrylate. Additional material was
isolated
from the initial precipitate by mixing it with tetrahydrofuran (250 mL) and
heating
at 35 °C for 2 hours. The mixture was filtered through celite, and the
filtered
solution was concentrated on a rotary evaporator to remove most of the
tetrahydrofuran. The concentrated solution was poured into diethyl ether, and
the
light yellow precipitate was filtered and dried under vacuum to afford 3.2 g
of solid
polyethylene glycol) methyl ether acrylate.
A solution of (3-acrylamidopropyl)trimethylammonium chloride (18.0 g of a
75 percent solution in water), polyethylene glycol) methyl ether acrylate (1.5
g),
and 2,2'-azobis(2-amidinopropane) dihydrochloride (0.15 g) in deionized water
(60.0 g) was heated to 60 °C for 4 hours under a nitrogen atmosphere.
After cooling
to room temperature, the reaction solution was poured into isopropanol (2 L)
and
stirred for at least 15 minutes. The solution was decanted from the
precipitated
polymer. The polymer was suspended in isopropanol (2 L), stirred for at least
15
minutes, and allowed to settle. After decanting, the polymer was suspended in
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isopropanol (2 L), stirred for at least 15 minutes, and allowed to settle. The
washed
polymer was dried in a forced-air oven at 70 °C to afford 14.5 g.
Example 87. Preparation of a copolymer of diallyamine HCL (50% and
acylamide (50%)
Diallylamine (60 g, 617 mmole) was suspended in water (200 mL) which
was acidified with concentrated HCl to pH 1.5 at 10-15 '~C. Acrylamide (43.85
g,
617 mmol) was added and the reaction mixture was purged with nitrogen for 10
minutes, followed by the addition of 2,2'-azobisisobutyronitrile (500 mg). The
reaction mixture was slowly heated to 65 ~C and the heating was continued for
16
hours under nitrogen. The reaction contents were poured into isopropanol (2 L)
and
the polymer precipitated. The supernatant was removed and replaced with fresh
isopropanol (2 L). This process was repeated 2 more times. The polymer was
finally
collected by filtration and the material was dried under vacuum at 45 ~C. The
polymer was ground, passed through an 80 mesh sieve, and dried again in a
vacuum
oven to yield 100 g of product.
Example 88. Preparation of a copolymer of (3-acrylamidopropyl)
trimethylammonium choloride (75 mole %) and acrylamide (25 mole%)
A 30-L reaction vessel was charged with (3-acrylamidopropyl)
trimethylammonium chloride (2481 g of 50 percent solution, 6 moles) and
acrylamide (142.16 g, 2 moles). Isopropanol (6 L) was added and the vessel was
purged with nitrogen for 10 minutes prior to the addition of 2,2'-
azobisisobutyronitrile (5.28g). The reaction mixture was heated to 70 ~C for
21
hours under nitrogen. The reaction mixture was collected in a bucket, the
supernatant was decanted, and the material was suspended in boiling
isopropanol
(3 L). The mixture was stirred with overhead stirrer for 20 minutes. The
solvent was
replaced with fresh boiling isopropanol (3 L) and the process was repeated 3
more
times. Finally the material was suspended in isopropanol (4 L) at room
temperature
for 1 day. The polymer became slightly brittle and was ground in a blender.
The
polymer was collected by filtration and washed with isopropanol (2 x 3 L). The
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polymer was dried under vacuum at 60 ~C for 2 days. The polymer was ground and
passed through an 80 mesh sieve to yield 1260 g of product.
Example 89. Preparation of a copolymer of (3-acrylamidopropyl)
trimethylammonium chloride (75 mole%), crylamide (20 mole%) and N-
octoylacrylamide (5 mole%)
A three-necked round-bottomed flask (1 L) was charged with (3-
acrylamidopropyl) trimethylammonium chloride (62 g of 50 percent solution,
150 mmol), acrylamide (2.84 g, 40 mmol), octylacrylamide (1.83 g, 10 mmol) and
isopropanol 160 mL. The mixture was purged with nitrogen for 10 minutes prior
to
the addition of 2,2'-azobisisobutyronitrile (132 mg). The reaction mixture was
heated to 70 '~C for 16 hours. At the end of reaction, the solvent was removed
from
the reaction mixture and the precipitated polymer was poured into boiling
isopropanol (1 L). The solvent was replaced with fresh boiling isopropanol.
The
process was repeated 3 more times. Finally, the polymer was suspended in
isopropanol (1 L) at room temperature for 6 hours. The polymer was collected
and
dried under vacuum at 60 °C. The polymer was ground and passed through
an 80
mesh sieve to yield 30 g of product.
Example 90. Preparation of the methylenebisacrylamide (1 mole%) cross-
linked copolymer of (3-acrylamidopropyl) trimethylammonium choloride
(75%)), acrylamide (20 mole%) and N-dodecylacrylamide (5 mole%)
A three-necked round-bottomed flask (1L) was charged with (3-
acrylamidopropyl) trimethylammonium chloride (124 g of 50 percent solution,
300 mmole), acrylamide (5.68 g, 80 mmole), dodecylacrylamide (4.78 g, 20
mmole)
and methylenebisacrylamide (616.7 mg, 4 mmole). Water (80 mL) and ethanol
80 mL were added. The mixture was purged with nitrogen for 10 minutes prior to
the addition of 2,2'-azobis (2-amidinopropane) dihydrochloride (400 mg). The
reaction mixture was heated to 65 °C for 16 hours. The reaction was
gelled within 2
hours. At the end of reaction, the solvent was removed from the reaction
mixture.
The precipitated polymer gel was suspended in boiling isopropanol (1 L). The
solvent was replaced with fresh boiling isopropanol. The process was repeated
3
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more times. Finally, the polymer was suspended in isopropanol (1 L) and ground
in
a blender. The polymer was collected and dried under vacuum at 60 °C.
The
polymer powdered, suspended in water (2.5 L), and filtered. The gel was washed
with water (4 x 2.5 L) followed by isopropanol (3 x 4 L). The polymer was
dried in
a vacuum oven to yield 60 g of product.
Example 91. Preparation of poly[(n-vinylimidazole-co-(1-vinyl-3-
methylimidazole-co-(1-vinyl-3-dodecylimidazole)] 20/75/5
To a 5 liter flask with mechanical stirrer, nitrogen purge, and temperature
controller was added: n-vinylimidazole (500 g; 5.31 moles), deionized water
(250 mL), and enough HCl to make the pH=0.8 (approximately 500 mL of 37
percent solution). Enough water was added to make the reaction solution 25
percent
solids and this was degassed via nitrogen purge for 1 hour. The reaction was
heated
to 60 °C at which point was added 2,2'-azobis (2-amidinopropane)
dihydrochloride
(2.5 g) dissolved in ~2 mL of water. A small exotherm of 7 °C was noted
and after
105 minutes an additional charge of 2,2'-azobis (2-amidinopropane)
dihydrochloride
(2.5 g of) in 2 mL of water was added. Total heating time at 60 °C was
8 hours.
After the reaction was cooled to room temperature, the pH was adjusted to 13.2
with
aqueous sodium hydroxide and the clear liquid was poured away from the gummy
solid. The gummy solid was taken up in enough deionized water to make 12
percent
of n-vinylimidazole homopolymer .
To a 1 liter flask with mechanical stirrer and temperature controller was
added: 300 g n-vinylimidazole homopolymer solution and enough concentrated HCl
to make the pH=8.25. To this was added 4.768 g dodecyl bromide (0.0191 moles)
and the reaction mixture was heated to 80 °C for 20 hours (the solution
became
cloudy after a few minutes). The reaction was allowed to cool to 40 °C
and
dimethyl sulfate was added in 5 mL portions (0.287 moles total). NaOH (5 mL of
50
percent) was added and the reaction mixture was allowed to stir at room
temperature
for 20 hours (pH 13.5). The reaction mixture was heated to 45 °C for 3
hours to
kill any unreacted dimethyl sulfate. The pH was adjusted to 1.2 with HCl and
the
mixture was triterated into isopropanol. The liquid was poured off, the
polymer was
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re-dissolved in deionized water and re-triterated into isopropanol. The
polymer was
dissolved in 300 mL of deionized water and 125 mL of Amberlite Cl- ion
exchange
resin beads for 4 hours. The polymer was filtered off, the beads were rinsed
with
water and the polymer solution was allowed to dry in a convection oven at 60
°C to
yield 51.2 g of solid.
Example 92. Preparation of poly[(diallyl dimethyl ammonium chloride)-co-(n-
vinyl glycine)] 70/30
To a 500-mL flask with mechanical stirrer, nitrogen purge, and temperature
controller was added: diallyldimethyl ammonium chloride (66.85 g of 65 percent
solution in water, 43.45 g solids, 0.2687 moles), allylamine HC1 (24.12 g of
27.16
percent solution based on allylamine charged in water, 0.1149 moles), and
deionized
water (75.69 mL) to make 30 percent solids (based on un-protonated monomers
charged). The reaction mixture was degassed via nitrogen purge for 1 hour and
then
heated to 60 °C at which time 2,2'-azobis (2-amidinopropane)
dihydrochloride
(0.25 g) in ~l mL of water was added. This was followed 30 minutes later with
an
additional charge of 2,2'-azobis (2-amidinopropane) dihydrochloride (0.25 g in
~1 mL of water). Further additional charges were made at 5 hours, 20 hours,
and 28
hours. At 48 hours the temperature was raised to 80 °C for 1 hour and
then turned
off and the reaction was allowed to cool to room temperature. To this polymer
solution was added chloroacetic acid (10.846 g; 0.1149 moles) and the pH was
adjusted to 10 with 50 percent NaOH solution in water. This mixture was heated
at
40 °C for 24 hours. The heat was then turned off and the polymer was
triterated into
acetone. The liquid was poured off and the polymer was re-dissolved into
deionized
water, the pH adjusted to ~2 with HCl (37 percent) and triterated again into
acetone.
The polymer was dissolved into deionized water once more and triterated into
acetone. The polymer was then dissolved into water and placed in a 60
°C
convection oven to dry to 55.1 g of amber glassy solid.
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Example 93. Preparation of Poly[(diallyl dimethyl ammonium chloride)-co-(n-
allyl pentylamine)-co-(n-allyl glycine)
To a 500-mL flask with mechanical stirrer, nitrogen purge, and temperature
controller was added: diallyldimethylammonium chloride (891 g of 65 percent
solution in water; 579.1 S g solids; 3.58 moles), allylamine HCl (321.5 g of
27.16
percent solution based on allylamine charged in water, 1.53 moles), and
deionized
water (454 mL) to make 40 percent solids (based on un-protonated monomers
charged). The reaction mixture was degassed via nitrogen purge for 1 hour and
then
heated to 60 °C at which time 1.67 g of 2,2'-azobis (2-amidinopropane)
dihydrochloride in ~2 mL of water was added. This was followed 15 minutes
later
with an additional charge of 2,2'-azobis (2-amidinopropane) dihydrochloride
(1.67 g). Additional charges were made at 16 hours, and 24 hours. At 40 hours
the
temperature was raised to 80 °C for 1 hour and then turned off and the
reaction was
allowed to cool to room temperature.
To a 500 mL flask with mechanical stirrer and temperature controller was
added: 250 g of the reaction mixture above (40 percent, 100 g solids based on
un-
protonated monomers charged). The pH was adjusted to 10 with 50 percent NaOH
in water. The temperature was raised to 70 °C and the reaction was
subsequently
charged with n-chlorodecane (9.32 mL; 0.046 moles) and allowed to stir for 20
hours. The reaction was allowed to cool to room temperature before adding
chloroacetic acid (30 g ; 0.3177 moles) and the pH was readjusted to 10. The
reaction was allowed to stir at 40 °C for 20 hours. The polymer was
then
precipitated into acetone and the liquid was decanted. The polymer was
redissolved
in deionized water and re-triterated into acetone; this procedure was repeated
once
more. The polymer was then dissolved in deionized water and the pH was
adjusted
to ~2 with HCl (37 percent) and the triteration into acetone procedure was
repeated
three more times. The polymer was dissolved in water and placed in a
convection
oven at 60 °C to dry to 36.9 g of glassy solid.
No Example 94
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Example 95. Preparation of Poly[((3-acrylamidopropyl) trimethylammonium
chloride)-co-(acrylamide)-co-(n-octadecylacrylamide)] 60/35/5
To a 500-mL flask with mechanical stirrer, temperature controller, and
nitrogen purge was added: (3-acrylamidopropyl) trimethylammonium chloride
(25.04 g of 75 percent in water; 18.78 g solids; 0.091 moles), acrylamide
(3.77 g ;
0.053 moles), n-octadecylacrylamide (2.45 g; 0.0076 moles), deionized water
(12.52 mL), and isopropanol (121 mL). This mixture was degassed for 1 hour
prior
to heating to 70 °C. 2,2'-Azobisisobutyronitrile (0.1 g) was added when
the
temperature reached 62 °C and all of the reactants were dissolved. The
reaction was
allowed to heat with stirring and nitrogen purge for 4 hours. Isopropanol (200
mL)
was added to the flask and the heat was turned off. The precipitated polymer
was
stirred in the hot isopropanol for ten minutes before pouring off the liquid.
The
polymer was scraped out of the flask and dried in a 60 °C convection
oven to yield
21.2 g of solid.
Example 96. Preparation of Poly[(diallyl ammonium choloride)-co-
(acrylamide)] 25/75
To a 500-mL flask with mechanical stirrer, temperature controller, and
nitrogen purge was added: diallylamine (8.88 g; 0.092 moles), and deionized
water
(20 mL). The mixture was cooled in an ice bath and 50 percent concentrated HCL
in water was slowly added dropwise until the pH reached 0.86. Acrylamide
(19.49 g;
0.2749 moles), 2,2'-azobis (2-amidinopropane) dihydrochloride (0.31 g), and
deionized water (20 mL) were added. The reaction mixture was degassed with
nitrogen for 30 minutes and the temperature was raised to 55 °C at
which point the
flask was placed in an ice bath to control the exotherm (maximum temperature
78 °C). The temperature was maintained at 60 °C for 4 hours. The
polymer was
precipitated into acetone and washed twice with more acetone. The polymer was
dried in a 70 °C convection oven to yield 25.1 g of solid.
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Example 97. Preparation of Poly((diallyl ammonium chloride)-co-
(acrylamide)J 75/25
To a 500-mL flask with mechanical stirrer, temperature controller, and
nitrogen purge was added: diallylamine (20.69 g; 0.213 moles), and deionized
water
(20 mL). The mixture was cooled in an ice bath and 50 percent concentrated HCL
in water was added dropwise until the pH reached 0.9. Acrylamide (5.05 g;
0.0711
moles), 2,2'-azobis (2-amidinopropane) dihydrochloride (0.335 g), and
deionized
water (20 mL) were added. The reaction mixture was degassed with nitrogen for
30
minutes and the temperature was raised to 65 °C. An additional charge
of 2,2'-
azobis (2-amidinopropane) dihydrochloride (0.335 g) was made at 24 hours and
another at 48 hours. At 72 hours the polymer was precipitated into acetone and
washed twice with more acetone. The polymer was dried in a 70 °C
convection
oven to yield 24.6 g of solid.
Example 98. Preparation of Poly[((3-acrylamidopropyl) trimethylammonium
chloride)-co-(acrylamide)-co-(n-octadecylacrylamide)J 50/45/5
To a 500-mL flask with mechanical stirrer, temperature controller, and
nitrogen purge was added: (3-acrylamidopropyl) trimethylammonium chloride
(22.7 g of 75 percent in water; 17.0 g solids), acrylamide (5.3 g), n-
octadecylacrylamide (2.7 g), deionized water (11.4 mL), and isopropanol (132
mL).
This mixture was degassed for 1 hour prior to heating to 70 °C.
2,2'-
Azobisisobutyronitrile (0.11 g) was added when the temperature reached 62
°C and
all of the reactants were dissolved. The reaction was allowed to heat with
stirring
and nitrogen purge for 4 hours. Isopropanol (200 mL) was added to the flask
and
the heat was turned off. The precipitated polymer was stirred in the hot
isopropanol
for ten minutes before pouring off the liquid. The polymer was scraped out of
the
flask and dried in a 60 °C convection oven to yield 18.3 g of solid.
Fat-Binding Evaluation via Paper Staining
The model consists of male, Sprague Dawly rats, 160 g, housed individually
in wire mesh cages. They were acclimated to the facility for six days, during
which
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time they were fed a chow based diet supplemented with 15 percent lard by
weight.
Feed and water were provided ad libitum. The animals were then randomly
assigned
to groups of four and fed test diets for three days. The test diet was also a
chow
based feed. A lipase inhibitor (Orlistat) was added at 0.04 percent by weight
and the
polymer was added at 0.30 percent by weight. They were mixed in the feed as a
powder followed by the addition of the supplemented fat in the form of lard at
15
percent by weight. During the final 24 hours of the treatment period an 8.5" x
11"
sheet of white paper was placed beneath each cage. One inch squares were drawn
on
the paper creating a grid of 80 squares. When oil in the form of unabsorbed
dietary
triglyceride seeps from the stool, it stains the paper. This can be readily
discerned
from urine if the papers were allowed to dry for six hours. The oil stains
confer
translucence to the paper. The squares that contain these oil stains were
counted and
expressed as a percentage of total area stained.
Some of the examples described above were tested in this model, and the
following results were obtained:
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Test Pol mer Percenta a of Pa er Stained
Control 1: 0
S no lipase inhibitor
no of mer
Control 2: 39 6
no polymer avera a of 24 ex eriments
Exam 1e 1 9
2 17
3 8
4 9
5 7
6 10
7 7
8 13
9 11
10 11
11 19
12 7
13 11
14 12
15 7
16 8
17 4
18 7
19 4
20 7
21 9
22 17
23 9
24 20
25 8
26 18
27 41
28 9
29 7
30 12
31 17
32 14
33 13
34 9
35 15
36 17
37 22
38 18
39 28
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Test Pol mer Percenta a of Pa er Stained
40 4
41 19
42 no exam 1e
43 13
44 7
45 12
46 10
47 21
48 no exam 1e
49 10
50 16
51 10
52 5
53 6
54 11
55 13
56 13
57 18
58 19
59 4
60 11
61 11
62 12
63 6
64 6
65 18
66
67 18
68 15
69 13
70 14
71 10
72 15
73 7
74 6
75 7
76 13
77 15
78 22
79 8
80 21
81 9
82 8
83 9
84 13
SUBSTITUTE SHEET (RULE 26)
CA 02379308 2002-O1-14
WO 01/05408 PCT/US99/15958
-67-
Test Pol mer Percenta a of Pa er Stained
85 6
86 14
87 12
88 9
89 7
90 5
91 18
92 13
93 11
94 no exam 1e
95 9
96 12
97 13
98 2
While this invention has been particularly shown and described with
references to preferred embodiments thereof, it will be understood by those
skilled
in the art that various changes in form and details may be made therein
without
departing from the spirit and scope of the invention as defined by the
appended
claims. Those skilled in the art will recognize or be able to ascertain using
no more
than routine experimentation, many equivalents to the specific embodiments of
the
invention described specifically herein. Such equivalents are intended to be
encompassed in the scope of the claims
SUBSTITUTE SHEET (RULE 26)
