Note: Descriptions are shown in the official language in which they were submitted.
ESTERS AND AMIDES OF
SUBSTITUTED PHENYL ACETIC ACIDS
TECHNICAL FIELD
This invention relates to compositions and
methods for treatment or prevention of colonic polyps.
BACKGROUND OF THE INVENTION
Each year in the United States alone,
approximately 60,000 people die from colon cancer, and
over 150,000 new cases of colon cancer are diagnosed. For
the American population as a whole, individuals have a
six percent lifetime risk of developing colon cancer,
making it the second most prevalent form of cancer in the
country. Colon cancer is also prevalent in Western
Europe.
To date, little progress has been made in the
; prevention and treatment of colorectal cancer, as
reflected by the lack of change in the five-year survival
rate over the last few decades. The only cure for this
cancer is surgery at an extremely early stage.
Unfortunately, most of these cancers are discovered too
r late for surgical cure, because most victims do not
experience symptoms until the disease is advanced.
`'; - 1-
... ... . ..... .
--2--
The incidence of colon cancer increases with
age, particularly after the age of 40. Since the mean
ages of populations in America and Western Europe are
increasing, the prevalence of colorectal cancer should
increase in the future.
In view of these grim statistics, efforts in
recent years have concentrated on colon cancer
prevention. Colon cancer usually arises from pre-
existing benign growths known as polyps. Prevention
efforts have emphasized the identification and xemoval of
colonic polyps. Polyps are identified by x-ray and/or
colonoscopy, and usually removed by devices associated
with the colonoscope. The increased use of colo~ x-rays
and colonoscopies in recent years has detected clinically
significant precancerous polyps in four to six times the
number of individuals per year that acquire colon cancer.
During the past five years alone, an estimated 3.5 to 5.5
million people in the United States have been diagnosed
with adenomatous colonic polyps, and it is estimated that
many more people have or are susceptible to developing
this condition, but are as yet undiagnosed. In fact,
there are estimates that 10-12 percent of people over the
age of 40 will form clinically significant adenomatous
polyps.
Removal of polyps has been accomplished either
with surgery or fiber-optic endoscopic polypectomy --
procedures that are uncomfortable, costly (the cost of a
single polypectomy ranges between $1,000 and $1,500 for
endoscopic treatment and more for surgery), and involve a
small but significant risk of colon perforation.
Overall, about $2.5 billion is spent annually in the
United States in colon cancer treatment and prevention.
As indicated above, each polyp carries with it
a chance that it will develop into a cancer. The
--2
'~
.
. ~
20~ '~;
--3--
likelihood of cancer is diminished if a polyp is removed.
However, many of these patients demonstrate a propensity
for developing additional polyps in the future. They
must, therefore, be monitored periodically for the rest
of their lives for polyp reoccurrence.
In most cases (i.e. the cases of so-called
common sporadic polyps), polyp removal will be effective
to reduce the risk of cancer. In a small percent~ge of
cases (i.e. the cases of the so-called polyposis
syndromes~, removal of all or part if the colon is
indicated. The difference between common sporadic polyps
and polyposis syndromes is dramatic. Common sporadic
polyp cases are characterized by relatively few polyps,
each of which can usually be removed leaving the colon
intact. By contrast, polyposis syndrome cases can be
characterized by many (e.g. hundreds or more) of polyps -
- literally covering the colon in some cases, making safe
removal of the polyps impossible short of surgical
removal of the colon. Because each polyp carries with it
the palpable risk of cancerous development, polyposis
syndrome patients invariably develop cancer if left
untreated. Many of these patients have undergone a
severe change in lifestyle as a result of surgery.
Patients have strict dietary restrictions, and many must
wear ostomy appliances to collect their intestinal
wastes.
Recently, several non-steroidal anti-
inflammatory drugs ("NSAIDs"), originally developed to
treat arthritis, have shown effectiveness in lnhi~itlng
and eliminating polyps. Polyps virtually dlsappear when
the patient take the drug. However, the prophylactlc use
of currently available NSAIDs, even ln polyposis syndrome
patients, is marked by severe side reactions that lnclude
gastrointestinal irritations and ulcerations. Once NSAID
. .
3-
,,~ ., ;,
' . . ` 1
.
.:~. .:
~, :
--4~
treatment is terminated due to such complications, the
polyps return, particularly in syndrome polyposis
patients.
SUMMARY OF THE INVENTION
This invention is a novel class of compounds of
formula I below that are effective in eliminating and
inhibiting polyps, but are not characterized by the
severe side reactions of NSAIDs:
R'Co~
wherein Q is the deprotonated residue of a
polymer or macromolecular structure having a molecular
weight of at least 1000 containing at least two primary
and/or secondary amino groups and/or hydroxy groups;
n is an integer of at least 2;
R1 and R2 are independently sel~cted from the
group consisting of hydrogen, halogen, alkyl, alkenyl,
.` alkinyl or halo alkyl;
R3 is one or more selected from the group
consisting of halogen, alkyl, alkenyl or alkinyl,
cycloalkyl, oxo-su~stituted alkylcycloalkyl, haloalkyl,
alkoxy, alkenyloxy, alkinyloxy, alkylamino, alkenylamino,
alkinylamino, alkysulfonyl, alkenylsulfonyl,
alkinylsulfonyl, alkylsulfinyl, alkenylsulfinyl,
:
--4--
: ~ .
.
~ ' ~
2~:i
alkinylsulfinyl, alkylsulfenyl, alkenylsulfenyl,
alkinylsulfenyl, pyrrolyl, piperidinyl, ben~oyl,
imidazolpyridinyl, isoindolyl, oxo-substituted
isoindolyl, thionylcarbonyl, phenyl, phenoxy and halo-
substituted phenoxy.
This invention also is a method of treating
patients with common sporadic polyps and polyposis
syndrome to reduce or eliminate their polyps by
administering to a patient in need of such treatment a
physiologically effective amount of a compound of formula
I, wherein n and R1 - R3 are as defined above, and Q is
the deprotonated residue of a polyamino or polyhydroxy
compound.
DETAILED DESCRIPTION OF THE INVENTION
As discussed above, the present invention is a
class of compounds of formula I above, as well as a
method of treating individuals with common sporadic
polyps and polyposis syndromes by the administration of
such a compound. Preferred compounds of the present
invention are those of formula I:
[R, I
wherein R, is hydrogen, and R2 is alkyl. The
most preferred compounds are where R1 is hydrogen, R2 is
alkyl and R3 is a branched alkyl, alkenyloxy,
.
'' :'
'
: ~ :
2~5
6-
alkenylamino, pyrroline, isoindolyl, meta- or p-phenoxy
or phenalkoxy, benzoyl or thionylcarbonyl.
Examples of compounds of this invention include
polyibuprofenylamidoethylcellulose, 4-polyisobutylphenyl
acetate conjugate with polyvinyl alcohol,
polypiroprofenyl chitosan, poly-~-(4-piperidinophenyl)-
acetyllysine, polyfeneloracyl me~hyl cellulose,
polyaclofsnacyl chitosan, polyindoprofenyl ester of
polyvinyl alcohol, poly-4-pyrrolinophenylacetamidoethyl
cellulose, polyfenoprofenyl ester of polyvinyl alcohol,
poly-3-phenoxyphenylacetyl chitosan, polys~profenyl
chitosan, polybutibufenylamidoethyl cellulose,
polyketoprofenyl chitosan, and poly-3-benzoyl phenyl
acetyl ester of methyl cellulose.
As used herein, the term "halo" or 'Ihalogen''
refers to chloro, bromo, fluoro and iodo groups. The
term "alkyl" refers to straight or branched chains or
cyclic groups, preferably having from one to four carbon
atoms. The term "alkoxy" refers to straight, branched or
cyclic groups, preferably having from one to four carbon
atoms. "Alkenyl" and "Alkinyl" refer to straight or
branched groups, preferably having from two to five
carbon atoms. The term "haloalkyl" refers to an alkyl
group substituted with one or more halogens. The term
"lower alkyl" refers to Cl-Cs alkyl groups. The term
"oxo-substituted alkyl cycloalkyl" refers to an alkyl
group that contains an oxo-substituted cyclo-alkyl group
linked to the phenyl moiety through an alkylene moiety.
As used herein, the term macromolecule,
macromolecular structure, or polymer refers to molecules
having at least two primary and/or secondary amino
groups, and/or hydroxy groups. Examples of such amino-
containing polymers or macromolecules are polyvinylamine,
polyallylamine, polyethyleneimine, chitosan, polyamino
20~65
--7--
acids, polyamine exchange resins (e.g. Amberlite),
polyaminoalkanes, and the like. Examples of hydroxy-
containing polymers or macromolecules are
polyhydroxyalkanes, polyvinylalcohols, carbohydrates
(e.g. sucrose), polyethylene glycols, and the like. The
term "deprotonated residue" includes the situation where
at least some, but not all, of the amino and/or hydroxy
groups are deprotonated on the macromolecule or polymer.
Compounds of this invention have unexpected
utility for suppression of colonic polyps in view of the
startling discovery that the effects of conventional
NSAID therapy on colonic polyps can be, in fact, achieved
via topical exposure to the agents. This effect was
discovered in a patient with familial polyposis, a
disease characterized by the presence of numerous colonic
polyps. In an attempt to avoid colon cancer, the patient
underwent surgical excision of the colon with formation
of a continent ileostomy, or Kock's pouch. By this
rarely performed surgical procedure, a pouch is
constructed from the terminal portion of the small
intestine. A colonic bacterial environment developed
within the pouch resulting in extensive adenomatous polyp
formation. Polyps also developed on the stoma, an
external outlet from the pouch constructed from a
contiguous portion of small intestine, and in the
duodenum, the beginning of the small intestine.
An NSAID, when administered in oral doses, led
to the disappearance of the numerous polyps located in
the pouch but not the polyps on the stoma or in the
duodenum. Given an understanding of the metabolic and
excretory patterns of the drug as well as of bacterial
enzyme activation of the agent, these rare findings
suggested that high local concentrations of the drug were
responsible for the effects in the pouch. It was
-7-
.
.
.
'
"
20~5
apparent from the lack of response of the polyps in the
other locations, particularly the stomal polyps which are
close to the pouch, that the effect was topical and that
blood-borne or systemic delivery of the drug was
ineffectual.
The topical effect is particularly surprising
since the cells believed to be responsible for polyp
growth and subsequent malignancy are not only epithelial
cells deep within the crypts of the intestine, but may
also include cells which modulate the local immunological
defense mechanisms in deeper mucosal and serosal layers
of the intestinal wall.
Compounds of this invention deliver ac~ive
agents to the colon via the large macromolecular
structure to which the active agent is conjugated.
Colonic bacterial enzymes (or other colonic enzymes)
cleave the active agent from the macromolecule, achieving
locally high concentrations of the active agent and
allowing the agent to contact the colon itself leading to
inhibition of polyp proliferation.
The advantage of this treatment is that the
active agent can be concentrated where it is effective,
but whatever systemic levels are achieved are minimized.
The systemic levels are particularly low because only
passive absorption in the colon is involved. The
negligible systemic levels are important in that the
maintenance of chronic systemic levels of NSAIDs is
complicated by a high incidence of gastric ulcers
rendering them useless in a long-term prophylactic
regimen.
Thus, contrary to prior approaches that relied
on the high systemic levels of active agent to achieve
the desired effect within the colon with the consequent
.
6S
gastric complications, the compounds of the present
invention afford a different and safer therapeutic
approach in light of the topical effect of these active
agents on the colon itself.
Compounds of Formula I may also be formulated
into compositions together with pharmaceutically
acceptable carriers for parenteral injection, for oral
administration in solid or liquid form, for rectal
administration, and the like, although oral
administration is most preferred.
Compositions according to the present invention
for parenteral injection may comprise pharmaceutically
acceptable sterile aqueous or nonaqueous solutions,
suspensions or emulsions. Examples of suitable
nonaqueous carriers, diluents, solvents or vehicles
include propylene glycol, vegetable oils, such as olive
oil, and injectable organic esters such as ethyl oleate.
Such compositions may also contain adjuvants such as
preserving, wetting, emulsifying and dispersing agents.
They may be sterilized, for example, by filtration
through a bacteria-retaining filter, or by incorporating
sterilizing agents into the compositions. They can also
be manufactured in the form of sterile solid compositions
which can be dissolved in sterile water, or some other
sterile injectable medium immediately before use.
Solid dosage forms for oral administration
include capsules, tablets, pills, powders, troches and
granules. In such solid dosage forms, the actlve
compound is admixed with at least one lnert dlluent such
as sucrose, lactose or starch. Such dosage forms can
also comprise, as is normal practice, additional
substances other than diluents, e.g., lubrlcatlng agents
such as magnesium stearate. In the case of capsules,
tablets, troches and pills, the dosage forms may also
., .
_g _
' ~ . `` : ,
,
,`
2~
-10-
comprise buffering agents. Tablets, pills and granules
can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration
include pharmaceutically acceptable emulsions, solutions,
suspensions, syrups and elixirs containing inert diluents
commonly used in the art, such as water. Besides such
inert diluents, compositions can also include adjuvants
such as wetting agents, emulsifyinq and suspending
agents, and sweetening, flavoring and perfuming agents.
Compositions for rectal administration are
preferably suppositories which may contain, in addition
to the active substance, excipients such as cocoa butter
or a suppository wax.
Actual dosage levels of active ingredient in
the compositions of the invention may be varied so as to
obtain an amount of active ingredient effective to
achieve polyp-eliminating activity in accordance with the
desired method of administration. The selected dosage
level therefore depends upon the nature of the active
compound administered, the route of administration, the
desired duration of treatment, and other factors. If
desired, the daily dose may be divided into multiple
doses for administration, e.g. two to four times per day.
Compounds of this invention can be made by one
of the five general schemes below.
- 1 0 -
,
'' ` ,
'
. : :
20~5
u:~
~0~ COO~ 'rC~1~ 1
l~ ~ J= C~ R I ~G~ro~ I
~ l ~ ~
R"
chi~osQngel H o - O~C`R J~
This scheme is useful for cases, where Q is
water swellable polymer carrying aminogroups. The water
soluble carbodiimide allows acylation in the alcoholic-
aqueous phase, and the water soluble by-product urea can
be removed by water, from the acylated polymer. The
scheme allows acylation with carboxylic acid sensitive to
the conditions of acid chloride or acid anhydride
formation.
A chitosan gel (GlcN)~ is prepared from
chitosan, according to the method of S. Hirano et al.
~Carbohyd. Res. 201 (1990) pp. 145-149) where m is the
number of repeating units within the chitosan molecule.
The gel is stirred in 70% aqueous methanol solution, at
0-5 C, with the R-carboxylic acid (2 equivalents per
GlcN; where R is the group in the brackets in formula I
minus the attached carbonyl), and with a water-soluble
carbodiimide (R'-N=C=N-R"; 2 equivalents per GlcN) for
three days. (R' and R" are cycloalkyl or alkyl and the
like, containing also quaternary ammon~um or sulfonate
salt for solubilization of the carbodiimide.) The
resulting gel is homo~eniæed, washed well with distilled
water, stirred with NaOH (1.2 equivalents per GlcN) in
water (50 ml per g of chitosan) for five days. The
mixture is homogenized and washed to neutrality. The gel
is then dried to an amorphous powder.
--11--
.
2~X4g~s
-12-
SCHEME II
r_ ~ - , R Coo~ - X-
L ~a~ ~ sc~ ,"
t~ O ~ `R rr~
This scheme is useful for cases, where a salt
between R-COOH and a polyamine Q is swellable or soluble
in DMF. The carbodiimide is chosen, so that the by-
product urea is soluble in dichloromethane, and therefore
removable by extraction with it. Sodium hydroxide is
used to extract unreacted R-COOH, so this scheme is
useful for cases where acylation is difficult and
incomplete. The scheme especially allows acylation with
carboxylic acids that degrade under the conditions of
acid chloride or acid anhydride formation.
(GlcN)m "chitosan," polylysine or similar
polyamine "X" (0.01 mol-NH2 groups; where m is the number
of repeating amino-containing units per molecule of
polyamine) are rapidly stirred in dimethylformanide
(''DMF,I' 30 ml) at 50C until no further dissolution is
apparent. The cooled (0) mixture is treated with
carbodiimide (R'-N=C=N-R"; 0.011 mol) with continued
stirring for two days. The resultant solution or
suspension is poured into ice water. The precipitate is
filtered off and washed with water. It is purified by
being homogenized with and filtered from (a) CH2Cl2 (2x 50
ml); (b) 0.1 N-NaOH (2 x 50 ml); (c) 0.1N-HCl (2 x 50
ml); (d) H2O (2 x 50 ml); and (e) ether (2 x 50 ml). The
resultant powder is dried.
-12-
.. ~
205~9E;~i
-13-
SCHEME lII
CI~
,,. ~c~3),~ yst)
o-C~f-C(~ )3 ~-X- -J
--~ C ~J3 )3 ~ o ~C ~
This scheme is suitable for cases were Q is a
hydroxyl group-containing polymer that is soluble or
swellable in dimethyl formamide. The bulky t-butyl group
in pivalic acid prevents acylation by it, and
dimethylamino pyridine catalyzes the difficult O-
acylation. By-product pivalic acid is removable from the
acylated polymer by extraction with organic solvent (e.g.
toluene). The scheme is useful for carboxylic acids that
are sensitive to the conditions of acylchloride
synthesis.
Dry polyvinyl alcohol, methyl cellulose, or a
similar swellable carbohydrate ([X-OH]m; 0.01 mol-OH;
where "m" is the number of repeating hydroxy-containing
units in the polymeric compound) is rapidly stirred in
absolute dimethyl formamide ("DMF," 50 ml) at 50C until
no further dissolution is apparent. Separately the
carboxylic acid (RCOOH; 0.01 mol) is dissolved in
absolute tetrahydrofuran (30 ml). At -10C, pivaloyl
chloride (0.01 mol) is added, followed by drop wise
addition of a tertiary amine (R'3N) (0.01 mol, e.g.,
.
-13-
,, , ' ~ ' ' '
, ' '' ' ~
.
20/5~Y65
-14-
triethylamine, ethyl diisopropylamine). The precipitated
amine hydrochloride is filtered off. The solution is
added, drop by drop, to the stirred and cooled (-10C)
polyol or carbohydrate mixture. The combined mixture is
treated at -10C with p-dimethyl amino pyridine (0.0001
mol.), and is allowed to come to room temperature and
stay there for 15 hours. Toluene tlO0 ml) is added, with
stirring. The mixture is evaporated to dryness in a
rotary evaporator. The residue is homo~enized in and
filtered from (a) toluene (100 ml) and (b) water (2 x 100
ml). The filtercake is dried in vacuo at 40C to
constant weight.
SCHEME IV
SOcl2, ~
5 oz C I
~=
--~C l --C2 --~
Lr ~m~ R~ ~ ,/C-R7
.. ~
.~ ~ c~
~ R 3 ~ItCI ~~C - R 1
n~
This scheme is useful for cases where Q is a
polymer swellable in dimethyl formamide (DMF), and where
-14-
.
2054g65
-15-
it needs a highly reactive reagent for acylation. The
scheme is suitable for carboxylic acids that form stable
acid chlorides.
Carboxylic acid (R-COOH; 0.01 mol) is refluxed
with thionylchloride or oxalylchloride (20 ml) until
solution is complete and gas evolution ceases. Excess
reagent is removed by evaporation. The residual acid
chloride is diluted with tetrahydrofuran (10 ml) to give
solution A.
A polyamine (l-X-NH2]m) such as chitosan,
aminoethyl cellulose, polylysine (0.01 mol-NH2), or a
polyhydroxy compound ([-X-OH]m) such as polyvinyl alcohol
or a carbohydrate (e.g. methyl cellulose; 0.01 mol-OH)
are heated in absolute dimethyl formamide at 50C, until
no further dissolution is apparent. Pyridine (0.01 mol)
and p-dimethylaminopyridine (0.01 mol) are added. The
mixture is cooled to -10C, and solution A is added
slowly with stirring. After 15 hours at room
temperature, toluene (100 mol) is added, and the solution
is evaporated in vacuo. The residue is homogenized with
and filtered from ~a) water (2 x 100 ml); (b) ether (2 x
100 ml), and is dried.
-15-
.~
. .
20S4~
-16-
R-C~o~ Cl,~A", 1~.~4 ~,o~1"
- ~J ~ O~
R-~~ [
- R~
This scheme is useful, where Q is a polyamine
swellable or soluble in dimethylformamide. It is
especially suitable for cases where the removal of by-
products such as salts, acids, or bases) from the final
product is difficult, since in this case only carbon
dioxide and low molecular weight alcohol are produced as
by-products. The scheme is especially useful for
carboxylic acids that decompose under the conditions of
acid chloride synthesis.
Chitosan, amino ethyl cellulose, polylysine or
a similar polyamine ([-X-NHz]~; 0.01 mol -NH2 groups) is
rapidly stirred in dimethyl formamide (30 ml) at 50C
until no further dissolution is apparent. The carboxylic
acid (RCOOH; 0.01 mol) is dissolved in absolute
tetrahydrofuran (30 ml). At first trialkylamine (NR'3;
0.01 mol), and then alkylchlorocarbonate (Cl-COOR"; 0.01
mol, where R" is ethyl or isobutyl) is added. The
precipitated trialkylammonium chloride (R'3NHCl) ls
filtered off. The filtrate is added, with stirring, to
the cold (-30C) polyamine solution. After being stored
for 15 hours at -15C, the mixture is poured on ice (300
.. . .
:
2054~65
-17-
g), with stirring. After the ice has melted, the
precipitate is filtered off, is thoroughly washed with
water, and is dried.
The foregoing may be better understood from the
following examples, which are presented for purposes of
illustration and are not intended to limit the scope of
the invention. As used in the following examples, the
references to compounds such as (1), (2), (3) etc., and
to substituents such as R, R" R2 etc., refer to the
corresponding compounds and substituents in the foregoing
reaction schemes and in formula I.
EXAMPLE 1
Polyibuprofenyl Aminoethylcellulose
Ibuprofen (0.01 mol) is con~ugated to
aminoethylcellulose (O.Gl mol-NH2) according to Scheme IV.
Specifically, thionylchloride was used to prepare the
acid chloride of ibuprofen. With pyridine as the base,
the procedure yields the desired _~mp^und (R1= hydrogen;
R2= CH3; R3 = 4-isobutyl; Q = aminoethylcellulose; m 2 50;
n/m 2 0.8; n 2 40).
EXAMPLE 2
Poly [4-isobutylphenylacetyl]
Ester of Polyvlnyl Alcohol
a) 4-Isobutylphenyl acetic acid
4-isobutylacetophenone (49.4 g.), sulphur tl3.6
g.) and morpholine (38 ml.) are refluxed for 16 hours;
concentrated hydrochloric acid (344 ml.) and glacial
acetic acid (206 ml.) are added, and the mixture is
refluxed for a further 7 hours. The mixture is cooled,
diluted with water, and the oil that separates is
isolated with ether. The ethereal solution is extracted
into aqueous sodium carbonate from which the crude acid
is precipitated by adding hydrochloric acid. The crude
-17-
2054~65
-18-
acid is again isolated with ether, and the solution is
washed with water and evaporated to dryness to give a
crystalline residue. The residue is crystallized from
light petroleum (B.P. 40-60C) to give 4-
isobutylphenylacetic acid, M.P. 85.5-87.5C. (Found: C.
74.1; H. 8.5 Cl2H1sO2 requires C. 75.0; H. 8.3%.)
b) 4-Polyisobutylphenyl Acetate
Conjugate with Polyvinyl Alcohol
4-isobutylphenyl acetic acid (0.01 mol) is
conjugated to polyvinyl alcohol (0.01 mol -OH1 according
to Scheme IV. Specifically, oxalyl chloride is used to
prepare the acid chloride. With triethyl amine as the
base, the procedure yields the desired compound (R1, = R2
= H; R3 = 4-isobutyl; Q = polyvinyl alcohol; m 2 100; n/m
; > 0.9; m 2 90).
EXAMPLE 3
` PolyPirprofenvl chitosan
Pirprofen (0.01 mol) is conjugated to chitosan
according to Scheme I.
The procedure yields the desired product (R1 =
CH3; R2 = hydrogen; R3 = m-Cl and p-N-pyrrolyl; Q =
chitosan; m ~ 40; n/m 2 0.7; m 2 28).
EXAMPLE 4
Poly ~-(4-PiperidinoPhenYl)-AcetYllpolvlvsine
a) 4-piperidino acetophenone
A mixture of 4-fluoro-acetophenone (202 g.),
piperidine (225 g.) and dimethylsulfoxide (450 ml.) is
heated at a steam cone for 48 hours. After cooling, it
is poured into ice water, the precipitate formed is
filtered off, and recrystallized from hexane to yield the
4-piperidino-acetophenone melting at 85-86~.
b) (4-piperidinophenyl)-thioacetmorpholid
A mixture of 4-piperidino-acetophenone ~45 g.),
morpholine (200 ml.), sulfur (8.5 g.), and p-toluene
sulfonic acid (2 g.) is refluxed for 17 hours while
-18-
'
:
,"~:
20S~6S `
--19--
stirrin~. It is evaporated in vacuo, and the residue
recrystallized from ethanol, to yield the (4-piperidino-
phenyl)-thioacetmorpholid of the formula
CN ~CH2 - CSN S~
melting at 156-158
c) 4-piperidinophenyl) - acetic acid ^ HCI
A mixture of (4-piperidinophenyl)-thioacetic-
morpholid (42 g.) and concentrated hydrochloric acid (250
ml.) is slowly heated to reflux and refluxed for 3 hours.
It is evaporated in vacuo, the residue triturated with
chloroform and recrystallized from isoprop~nol, to yield
the (4-piperidinophenyl)-acetic acid hydrochloride of the
formula:
< ~ ; { ~ CH2-COOH-HC~
melting at 189-193.
d) Poly [~-(4-piperidinophenyl)-
acetyl]polylysine
(4-piperidinophenyl)acetic acid is prepared in
situ, in the DMF solution of poly-L-lysine with one
equivalent NET3. The synthesis proceeds according to
Scheme II to yield the desired product (R1 = R2 = H; R3 =
p-N-piperidyl; Q = polylysine; m 2 40; n/m 2 0.8; n 2
; 32)-
; EXAMPLE 5
Polyfencloracvl Met~y~ Cellulose
This product is synthesized from fenclorac and
methyl cellulose according to Scheme III. The procedure
yields the desired product (R1 = Cl; R2 = H; R3 =m-Cl and
p-cyclohexyl; Q = methylcellulose; m 2 50; n/m 2 0,7; m2
35).
EXAMPLE 6
Polyalclofenacyl Chitosan
Alclofenac (0.01 mol) is conjugated to chitosan
(0.01 mol-NH2) according to Scheme V. The procedure
--19--
2054~5
-20-
- yields the desired compound (R~ = H; R2 = H; R3 = p-
allyloxy-Cl; Q = chitosan; m 2 40; n/m 2 0.8; n 2 32).
EXAMPLE 7
PolvindoProfen~l Ester Of Polyvinyl Alcohol
Indoprofen (0.01 mol.) is conjugated to
polyvinyl alcohol (0.01 mol-OH) according to Scheme III.
Specifically, triethylamine is used as the base. The
procedure yields the desired compound (Rl = CH3; R2 = H; R3
= p-(l-oxo-2-isoindolinyl); Q = polyvinyl alcohol; m 2
100; n/m 2 0.8; n 2 80).
EXAMPLE 8
; Poly [4-PYrrolino PhenYlacetamido Ethyl] Cellulose
a) 4-pyrrolino phenyl acetic acid
A mixture of ethyl 4-amino-phenylacetate
hydrochloride (10.8 g.), 1,4-dibromo-2-butene (32.4 g.),
sodium bicarbonate (84 g.) and dimethylformamide (500
ml.) are refluxed for 6 hours while stirring, filtered
hot, and the filtrate evaporated in vacuo. The residue
is taken up in 25% aqueous sodium hydroxide (150 ml.),
the mixtures refluxed for one hour, cooled and washed
with diethyl ether. It is adjusted to pH 5 with
hydrochloric acid, extracted with diethyl ether, the
extract dried, filtered and evaporated, to yield the 4-
pyrrolino-phenylacetic acid of the formula.
G~CH3~OOH
melting at 162-165.
b) poly-4-pyrrollno phenylacetamido ethyl
cellulose
4-pyrrolino phenyl acetic acid is con~ugated to
amino ethyl cellulose accordin~ to Scheme V. The
, procedure yields the desired product ~Rl = R2 = H; R3 = P
N-pyrrolinyl; Q = ethyl cellulose; m 2 50; n/m 2 0.9; n 2
` 45).
.:;
~ -20-
~05496S
-21-
EXAMP~E 9
Polyfenoprofenyl-Ester Of Polyvinyl Alcohol
Fenoprofen (0.01 mol-OH) is conjugated to
polyvinyl alcohol (0.01 mol-OH) accordinq to Scheme IV.
Specifically, oxalyl chloride is used to prepare the acid
chloride of fenoprofen. Pyridine is the base. The
procedure yields the desired compound (R1 = CH3; R2 = H; R3
= meta-phenoxy; Q = polyvinyl alcohol; m 2 50; ntm 2 0.8;
n 2 40).
EXAMPLE 10
Poly [3-Phenoxvphenylace-tyll Chitosan
a) 2-(3-Phenoxyphenyl~ Acetic Acid
To morpholine (26 ml.) is added m-
phenoxyacetophenone (42.4 g.) and sulfur (9.6 g.). The
reaction mixture is refluxed with stirring for 20 hours.
To the reaction mixture is then added 15 percent aqueous
potassium hydroxide (700 ml.) and a small amount of ethyl
alcohol. The reaction mixture is refluxed with stirring
for an additional 20 hours. The solvent is distilled
out. The remaining reaction mixture is filtered while
hot, partially cooled with ice, and acidified with
concentrated hydrochloric acid, whereupon an oily
precipitate ~orms and then crystallized. The crystalline
precipate is filtered, washed several times with water,
and dried to yield 45.9 g. of crude product as a yellow-
orange solid. The crude product is suspended in boiling
hexane, and ethyl acetate is added until the product goes
into solution. The solution is then treated with carbon,
filtered and cooled, to yield 22.7 g. of white flakes of
2-(3-phenoxyphenyl) acetic acid, M.P. 84-86 C.;
pK'a=6.9.
Analysis-Calc for C14H~2O3 (percent): C, 73.66; H,
5.30. Found (percent); C, 73.85; H, 5.35.
20S4965 `
~-22-
b) Poly [3-phenoxyphenylacetyl] Chitosan
This product is synthesized from 3-
phenoxypllenyl acetic acid (0.01 mol) and chitosan (0.01
mol-NH2) according to Scheme II. The procedure yields the
clesired product (R1 = R2 = H; R3 = meta-phenoxy; Q =
chitosan; m 2 50; n/m 2 0.9; n 2 45).
EXAMPLE 11
..
Polysuprofenyl Chitosan
Suprofen (0.02 mol) is conjugated to chitosan
gel (0.01 mol-NH2) according to Scheme I. The procedure
yields the desired compound (R1 = CH3; R2 = H; R3 = p-2-
thienylcarbonyl; Q = chitosan; m 2 50; n/m 2 0.9; n 2
45),
EXAMPLE 12
Poly~butibufenYl AmidoethYll Cellulose
Butibufen (0.01 mol) is conjugated to
aminoethylcellulose according to Scheme IV.
Specifically, thionylchloride is used to prepare the acid
chloride of butibufen with pyrridine as the base. The
procedure yields the desired compound (R1 = ethyl; R2 = H;
R3 = p-isobutyl; Q = aminoethylcellulose; m 2 50; n/m 2
0.8; n 2 40).
EXAMPLE 13
Polvketo~rofenyl Chitosan
Ketoprofen (0.01 mol) is conjugated to chitosan
according to Scheme II. The procedure yields the desired
product (R1 = CH3; R2 = H; R3 = meta-benzoyl; Q = chitosan
m 2 50; n/m 2 0.8; n 2 40).
EXAMPLE 14
Poly-~3-Benzoylphenyl Acetyl]
Ester Of Methyl Cellulose
a) 3-Benzoyl Phenylacetic Acid
A mixture of (3-benzoylphenyl)acetonitrile (30
g.), concentrated sulphuric acid (60 cc.) and water (60
cc.) is heated under reflux under nitrogen for 10
-22-
. -
: ; , ~:. . .:
~ .. . .
2054965```
-23-
minutes. Water (180 cc.) is added, and a product
crystallizes, which is separated by filtration and washed
with water (100 cc.). There is obtained 24 g. of a
product, which is dissolved in diethyl ether (150 cc).
The ethereal solution is extracted with N sodium
hydroxide (200 cc.), and the alkaline solution is treated
with decolorizing charcoal (1 g.), and then acidified
with concentrated hydrochloric acid (25 cc.). An oil
separates out, which is extracted with methylene chloride
(450 cc.), washed with water (100 cc.) and dried over
anhydrous sodium sulphate. The product is concentrated
to dryness under reduced pressure (20.mm. Hg~ to give a
white crystalline residue (18 g.), M.P. 114-115 C.,
which is recrystallized from a mixture of benzene t120
cc) and petroleum ether (130 cc.) to yield 3-
benzoylphenylacetic acid (17.3 g.), M.P. 114-115 C.
(3-benzoylphenyl) acetonitrile employed as the
starting material is prepared as follows:
3-bromomethylbenzophenone (160 g.) is dissolved
in dicxane (300 cc.), and a solution of sodium cyanide
(125 g.) in water (300 cc.) is added. The mixture is
heated under reflux for three hours, and then treated
with charcoal (10 g.) and extracted with methylene
chloride (800 cc.). The methylene chloride solution is
dried over anhydrous sodium sulphate and concentrated to
dryness under reduced pressure (20 mm. Hg) to give a
brown oil (119 g.), which is dissolved in methylene
chloride (300 cc.) and chromatographed through alumina
(450 g.) Elution is effected with methylene chloride,
and there is collected a fraction of 4 liters, which is
concentrated to dryness under reduced pressure (20 mm.
Hg) to yield (3-benzoylphenyl) acetonitrile (109 g~) in
the form of an oil.
2054~6S -
-24-
3-bromomethylbenzophenone is prepared by
dissolving 3-methylbenzophenone (95 g.) in ethylene
bromide (200 cc.), heating the solution under reflux, and
adding a solution of bromine (79 g.) in ethylene bromide
(60 cc.) over a period of 3 hours in the presence of
ultra-violet light. Heating under reflux is continued
for 30 minutes, and the product is concentrated to
dryness under reduced pressure (20 mm. Hg) to give 3-
bromomethylbenzophenone in the form of an oil in
quantitative yield.
3-methylbenzophenone is prepared in accordance
with E. Ador and A.A. Rilliet, Ber., 12, 2298 (1879).
b) Poly-3-Benzoylphenyl Acetyl
Ester Of Methyl Cellulose
The ester is prepared from 3-benzoylacetic acid
(0.01 mol) and methyl cellulose (0.01 mol-OH), according
to Scheme IV, with oxalylchloride for the preparation of
the acid chloride, and triethylamine for the preparation
of the ester. The desired product is obtained (Rl = R2 =
H; R3 = m-benzoyl; Q = methylcellulose; m 2 40; n/m 2 0.7;
n ~ 35)-
EXAMPLE 15
PolY _urbiprofenYl Chitosan
Flurbiprofen (0.01 mol.) is conjugated tochitosan (0.01 mol-HN2) according to Scheme IV.
Specifically, oxalylchloride is used to prepare the acid
chloride of flurbiprofen. Triethylamine is the base.
The procedure yields the desired compound R1 = hydrogen;
R2 = methyl; R3 = m-Cl and p-phenyl; Q = chitosan; m ~ 50;
n/m > 0.2; n > 10.)
EXAMPLE 16
Polvfenclofenacyl~olylYsine
Fenclofenac (0.01 mol.) is con~ugated to
polylysine (0.01 mol-~NH2) according to Scheme IV.
-24-
2(~5496S
Specifically, thionylchloride is used to prepare the acid
chloride of fenclofenac. Triethylamine is the base. The
procedure yields the desired compound (R1 = hydrogen; Rz =
hydrogen; R3 = o-(2,4 dichlorophenoxy); Q = polylysine; m
> 50; n/m > 0.2; n > 20.)
EXAMPLE 17
Polyxenbucinyl Ester Of Polyvinyl Alcohol
Xenbucin is conjugated to polyvinyl alcohol
according to Scheme III. Specifically, triethylamine is
used as the base. The procedure yields the desired
compound (Rl = hydrogen; R2 = ethyl; R3 = phenyl; Q =
polyvinyl alcohol; m 2 100; n/m 2 0.2; n ? 20.)
EXAMPLE 18
Polyloxoprofenyl Chitosan
Loxoprofen is conjugated to chitosan (0.01 mol-
NH2) according to Scheme V. The procedure yields the
desired compound (R1 = hydrogen; R2 = methyl; R3 = p-(2-
oxocyclopentyl methylene; Q = chitosan; m > 50; n/m >
0.2; n > 10.)
EXAMPLE 19
PolymiroprofenvlpolylYsine
Miroprofen (0.01 mol.) is conjugated to
polylysine (0.01 mol-NH2) according to Scheme IV.
Specifically, thionylchloride is used to prepare the acid
chloride of miroprofen. Triethylamine is the base. The
procedure yields the desired compound ~R1 = hydrogen; R2 =
methyl; R3 = p-imidazol[1,2-a]pyridinyl; Q = polylysine; m
> 50; n/m > 0.2; n > 10.)
EX~MPLE 20
Polyflurbi~rofenvl PolyethYleneimine
a) Flurbiprofen acid chloride
Thionyl chloride 1.64 ml (0.023 mol) was added
to a suspended solution of 5 g (0.02 mol) flurbiprofen in
30 ml of toluene. The reaction mixture was refluxed
-25-
2054~6S
-26-
under nitrogen for 60 minutes. The solvent was removed in
vacuo to give flurbiprofen acid chloride as a grey oil.
IR (neat) 2938, 2987, 3034, 3061, 1797, 1779, 1582, 1484,
1455, 1450 cm~~.
b) Polyflurbiprofenyl polyethyleneimine
Flurbiprofen acid chloride 2.98 g ~0.011 mol)
was dissolved in 25 ml pyridine. To this stirred
solution was added 0.98 g (0.54 mmol) of
polyethyleneimine (purity 99~ and average molecular
weight 1800). The reaction mixture was refluxed for one
hour. Concentration in_vacuo gave a viscous residue,
which was washed with 100 ml of concentrated sodium
bicarbonate solution. The aqueous part was decanted, and
the residue oil was washed with five 200 ml portions of
water to remove pyridine. The product was dried over
phosphorus pentoxide (P2Os) in a vacuum desiccator at room
temperature for 12 days. It gave 3.4 g of -
polyflurbiprofenyl polyethyleneimine as a solid.
IR (film) 3432, 3304, 2951, 2857, 1721, 1667,
1601, 1583, 1521, 1490, 1450, 1375, 1336, 1163 cm~1.
Elementary analysis calculated for C36~37N3O2F2,
FW 581;
% Theory: C, 67.66; H, 5.79; N, 6.57; F, 5.95. % Found :
C, 67.49; H, 6.05; N, 6.58; F, 5.98.
The procedure yields the desired compound R1 =
hydrogen; R2 = methyl; R3 = m-F and p-phenyl; Q =
polyethyleneimine; n/m = 0.66.
EXAMPLE 21
Polyflurbiprofen Ester Of PolYvlnyl Alcohol
Flurbiprofen acid chloride (0.02 mol, 5.24 g)
was prepared by the procedure of Example 20a and
dissolved in 20 ml pyridine. To this solution was added
1.75 g (0.035 mmol) of polyvinyl alcohol ("PVA"; average
molecular weight 50,000). The reaction mixture was
-26-
. ~ , . .,
..
.
: . .
. .
205496S
-27-
slowly heated until all PVA dissolved and then refluxed
for one hour. The clear solution was concentrated in
vacuo then washed with 100 ml of concentrated sodium
bicarbonate solution. The aqueous part was decanted and
the residue oil was washed with five 200 ml portions of
water to remove pyridine and unreacted PVA. The product
was dried over phosphorus pentoxide (P2Os) in a vacuum
desiccator at room temperature for 12 days. It gave 6.04
g of the polyflurbiprofen ester of polyvinyl alcohol as a
solid.
IR (film~ 3432, 2977, 2925, 1732, 1624, 1583,
1560, 1818, 1485, 1415 cm~l.
Elemental analysis calculated for ClgH19O3F-~H2O;
FW 320;
% Theory: C, 71.25; H, 6.25; F, 5.93. % Found : C,
70.99; H, 5.72; F, 5.45.
The procedure yields the desired compound R1 =
hydrogen; R2 = methyl; R3 = m-F and p-phenyl; Q =
polyvinyl alcohol;
n/m = 0.50.
EXAMPLE 22
Polyindoprofen Ester Of Polvvinyl Alcohol
a) Indoprofen acid chloride
Thionyl chloride (1.43 ml, 0.019 mol) was added
to a suspended solution of 5 g (0.018 mol) of indoprofen
in 30 ml toluene. The mixture was refluxed under
nitrogen for 60 minutes. Toluene was removed in vacuo.
The yellow oil was purified by crystallization ln a
solvent mixture of toluene/petroleum ether to give 4.14 g
of indoprofen acid chloride as a white powder: mp 125-
128C. IR(Nujor Mull) 2948, 2912, 1770, 1623, 1460, 1377
-i
-27-
2os496s `
-28-
b) Polyindoprofen ester of polyvinyl alcohol
Indoprofen acid chloride 4.14 g (0.014 mol) was
dissolved in 20 ml pyridine. To this solution was added
1.22 g (0.024 mol) of polyvinyl alcohol ("PVA", average
molecular weight of 50,000). The reaction mixture was
slowly heated until all PVA dissolved and then refluxed
for 90 min. The clear solution was concentrated in vacuo
then washed with 100 ml of concentrated sodium
bicarbonate solution. The agueous part was decanted and
the residual oil was washed with five 200 ~l portions of
water to remove pyridine and unreacted PVA. The product
was dried over phosphorus pentoxide (P2Os) in a vacuum
desiccator at room temperature for 12 days. It gave 5.25
g of polyindoprofen ester of polyvinyl alcohol as a
yellow solid.
IR (film) 3442, 3061, 2927, 1731, 1689, 1518,
1386, 1307 cm~1.
Elemental analysis calculated for C21H21NO4-~ H2O,
FW 378; % Theory: C, 66.84; H, 5.97; N, 3.71. ~ Found :
C, 66.34; H, 6.23; N, 4.56.
The procedure yields the desired compound R1 =
methyl; R2 = hydrogen; R3 = p~ oxo-2-isoindolinyl); Q =
polyvinylalcohol; n/m = 0.50.
EXAMPLE 23
PolvsuProfen Ester Of PolyvinYl Alcohol
a) Suprofen acid chloride
Thionyl chloride tl.55 ml, 0.021 mol) was added
to a suspended solution of 5 g (0.019 mol) of suprofen in
30 ml toluene. The mixture was refluxed under nitrogen
for 90 minutes. Toluene was removed in vacuo to give
suprofen acid chloride as a yellow solid; IR(Nujor Mull)
Z948, 2912, 1779, 1623, 1460, 1377, 477 cm~l.
.
-28-
.
205496S;
-29-
b) Polysuprofen ester o~ polyvinyl alcohol
Suprofen acid chloride (5.43 g.) was dissolved
in 20 ml pyridine. To this solution was added 1.66 g
(0.033 mol) of polyvinyl alcohol ("PVA", average
molecular weight of 50,000). The reaction mixture was
slowly heated until all PVA dissolved and then refluxed
for 90 min. The clear solution was concentrated in vacuo
then washed with 100 ml of concentrated sodium
bicarbonate solution. The aqueous part was decanted, and
the residual oil was washed with five 200 ml portions of
water to remove pyridine and unreacted PVA. The product
was dried over phosphorus pentoxide (P2Os) in a vacuum
desiccator at room temperature for 12 days. It gave 5.27
g of polysuprofen ester of polyvinyl alcohol as a solid.
IR (film) 3407, 3061, 2928, 1737, 1729, 1624,
1582, 1484, 1450, 1331 cm~1.
Elemental analysis calculated for C1BH18O4S, FW
330; % Theory: C, 65.64; H, 5.45; S, 9.69. % Found : C,
64.81; H, 5.47; S, 9.10.
The procedure yields the desired compound R1 =
methyl; R2 = hydrogen; R3 = p-2-thienylcarbonyl; Q =
polyvinylalcohol; n/m = 0.50.
EXAMPLE 24
.
PolysuDrofenyl Polvethvleneimine
a) Suprofen acid chloride
Thionyl chloride 1.55 ml (0.021 mol) was added
to a suspended solution of 5 g (0.019 mol) suprofen in 30
ml of toluene. The reaction mixture was refluxed under
nitrogen for 60 minutes. ~he solvent was removed in vacuo
to give suprofen acid chloride as a powder. IR (Nu~or
Mull) 2948, 2912, 1779, 1623, 1~60, 1377, 477 cm~1.
b) Polysuprofenyl polyethyleneimine
Polyethyleneimine (purity 99~ and average
molecular weight 1800) 1.011 g was dissolved in 30 ml of
-29-
:
20S4~6S`'
-30-
pyridine. To this stirred solution was added 3.27 g
(0.12 mol) of suprofen acid chloride. The reaction
mixture was refluxed for one hour. Concentration in
acuo gave a viscous residue, which was washed with 200
ml of 1 N sodium hydroxide solution. The aqueous part
was decanted, and the residue oil was washed with five
200 ml portions of water to remove pyridine. The product
was dried over phosphorus pentoxide (P2Os) in a vacuum
desiccator at room temperature for 12 days. It gave 1.5
g of polysuprofenyl polyethyleneimine as a solid.
IR (film) 2971, 2870, 1724, 1640, 1600, 1460,
1381, 1295 cm~1.
Elemental analysis calculated for C16H1sNO2S-H2O;
FW 346;
~ Theory: C, 63.36; H, 5.61; N, 4.62; S, 10.56 % Found :
C, 63.25; H, 5.42; N, 4.78; S, 9.41.
The procedure yields the desired compound R1 =
methyl; R2 = hydrogen; R3 = p-2-thienylcarbonyl; Q =
polyethyleneimine; n/m = 1Ø
EXAMPLE 25
PolvindoProf ~ thyleneimine
a) Indoprofen acid chloride
Thionyl chloride 1.51 ml (0.021 mol) was added
to a suspended solution of 5.3 9 (0.019 mol) indoprofen
in 30 ml of toluene. The reaction mixture was refluxed
under nitrogen for 60 minutes. The solvent was removed in
vacuo to give indoprofen acid chloride as a white powder;
mp 128 C. IR (Nujor Mull) 2964, 2915, 1775, 1666, 1519,
1461, 1457, 1377 cm~1.
b) Polyindoprofenyl polyethyleneimine
Polyethyleneimine (purity 99~ and average
molecular weight 1800) 1.44 g was dissolved in 30 ml of
pyridine. To this stirred solution was added 5.0 g
~0.017 mol) of indoprofen acid chloride. The reaction
.
.
2Q~i496S
-31-
mixture was refluxed for two hours. Concentration in
vacuo gave a viscous residue, which was washed with 200
ml of 1 N sodium hydroxide solution. The aqueous part
was decanted, and the residue oil was washed with five
200 ml portions of water to remove pyridine. The product
was dried over phosphorus pentoxide (P2Os) in a vacuum
desiccator at room temperature for 12 days. It gave 6.09
g of polyindoprofenyl polyethyleneimine as a yellow
solid.
IR (film) 3456, 3314, 2971, 2870, 1691, 1645,
1608, 1516, 1458, 1381, 1304, 1223 cm~1.
Elemental analysis calculated for C40H4~N5O5~1.5
H2O; FW 682. % Theory: C, 70.38; H, 6.30; N, 10.26.
Found : C, 70.15; H, 6.03; N, 9.66.
The procedure yields the desired compound R1 =
methyl; R2 = hydrogen; R3 = p-(1-oxo-2-isoindolinyl); Q =
polyethyleneimine n/m = 0.5.
EXAMPLE 26
PolyketoProfenyl PolYethyleneimine
a) Ketoprofen acid chloride
Thionyl chloride 2.0 ml was added to a
suspended solution of 5.9 g (0.023 mol) ketoprofen in 50
ml of toluene. The reaction mixture was refluxed under
nitrogen for 60 minutes. The solvent was removed in_vacuo
to give ketoprofen acid chloride as a yellow liquid; IR
(neat) 3009, 2927, 1784, 1661, 1598, 1448, 1461, 1381,
1281, 958, 719 cm~1.
b) Polyketoprofenyl polyethyleneimine
Polyethyleneimine (purity 99% and average
molecular weight 1800; 1.89 g) was dissolved in 50 ml o~
pyridine. To this stirred solution was added the
solution of 6.0 g ~0.022 mol) of ketoprofen acid
chloride. The reaction mixture was refluxed for one
hour. Concentration in vacuo gave a viscous residue,
-31-
.
,
-~ 205496S'
-32-
which was washed with 200 ml of 1 N sodium hydroxide
solution. The aqueous part was decanted, and the residue
oil was washed with five 200 ml portions of water to
remove pyridine. The product was dried over phosphorus
pentoxide (P2O5) in a vacuum desiccator at room
temperature for 12 days. It gave 2.0 g of
polyketoprofenyl polyethyleneimine as a solid.
IR (Nujor mull) 3301, 2954, 2927, 1654, 1595,
1460, 1377, 1282, 721, 703 cm~~.
Elemental analysis calculated for C33H39N3O4-H2O;
FW 619. % Theory: C, 73.66; H, 6.62; N, 6.78. ~ Found :
C, 73.86; H, 6.23; N, 6.62.
The procedure yields the desired compound R1 =
methyl; R2 = hydrogen; R3 = meta-benzoyl; Q =
polyethyleneimine; n/m = 0.666.
It will be understood that various changes and
modifications can be made in the details of procedure,
formulation and use without departing from the spirit of
the invention, especially as defined in the following
claims.
.
.
~, , . , ~ . ~ .. . . .
