Note: Descriptions are shown in the official language in which they were submitted.
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PHOSPHATE TRANSPORT INHIBITORS
FIELD OF THE INVENTION
The present invention involves the treatment of chronic renal failure, uremic
bone disease and related diseases by inhibition of phosphate retention by
certain N-
aryl-2-sulfonamidobenzamides.
BACKGROUND OF THE INVENTION
When kidneys are injured, the adaptive mechanisms involved in restoring
homeostasis can lead to additional injury and an inexorable progression to end
stage
renal disease (ESRD) (Hostetter et al, Am. J. Physiol. 241:F85-F93 (1981)).
ESRD
affects more than 270,000 patients in the US. While the use of dialysis and
kidney
transplantation have dramatically improved the survival rate of patients with
ESRD, a
number of problems have appeared in these patients which complicates their
long term
management. Early and major contributors to the morbidity of patients with
ESRD are
abnormalities in mineral and bone metabolism induced by a progressive loss of
renal
excretory function. Among other factors, phosphate (Pi) retention has been
identified
as playing a major role in the progression of renal failure and in the
generation of
secondary hyperparathyroidism (HPTH) and uremic bone disease.
Evidence implicating a role for Pi retention in the progression of chronic
renal
failure (CRF) has come mainly from studies on experimental animals. Ibels et
al, N.
Engl. J. Med. 298:122-126, (1978), first demonstrated in a rat model of CRF
that
dietary Pi restriction prevented renal functional deterioration as assessed by
stabilization or improvement of serum creatinine levels, reduced proteinuria,
improved
histology and reduced mortality. Similar findings were obtained in a rat model
of
nephrotoxic serum nephritis (Karlinsky et al, Kidney Int. 17:293-302 ( 1980)).
However, these studies were criticized on the basis that a low Pi diet is
associated with
decreased food intake and thus protein intake which by itself can reduce the
progression of CRF. Therefore, Lumlertgul et al, Kidney Int. 29:658-666, (
1986)
placed 5/6th nephrectomized rats on a normal Pi diet but gave one group a Pi
binder.
All rats were pair fed and had similar caloric, protein, carbohydrate, vitamin
and
mineral intakes. At both 6 and 12 weeks rats ingesting the Pi binder showed a
lower
protein excretion, lower serum creatinine level, lower renal calcium content
and less
histologic scarring than rats not receiving the Pi binder. This study
demonstrated
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unequivocally that dietary Pi restriction can have beneficial effects on the
progression
of CRF independent of caloric and protein intake in experimental animals.
In addition to the beneficial effects of dietary Pi restriction on the
progression
of CRF discussed above, evidence has also been found that dietary Pi excess
can
accelerate the progression of CRF. A number of studies in rat models of CRF
(Kleinknecht et al, Kidney Int. 5:534-541, (1979); Haut et al, Kidney Int.
17:722-731,
( 1980); Gimenez et al, Kidney Int. 22:36-41, ( 1982)) have shown that diets
high in Pi
lead to a more rapid deterioration in renal function as assessed by serum
creatinine
levels and the severity of histologic lesions.
Some evidence also suggests that dietary Pi restriction may slow the
progression of CRF in patients. Maschio et al, Kidney Int., 22:371-376, (1982)
and
Maschio et al, Kidney Int., 24:S 273-S 277, (1983) placed patients with mild
or
moderate renal insufficiency on diets restricted in protein and Pi for up to
76 months.
They found that the rate of decline in renal function was slower in the
dietary restricted
group than in the control group, especially in patients with mild CRF.
Barsotti et al.,
Kidney Int. 24:S278-S284, (1983) and Barsotti et al., Clin. Nephrol. 21:54-59,
(1984)
placed CRF patients on either a low protein diet or on a low protein-low Pi
diet and
found that the rate of decline in renal function slowed after the institution
of dietary
restrictions in both groups. Importantly, they also observed a slower rate of
decline in
patients on the low protein-low Pi diet compared to the low protein diet
alone. In a
study of 4 children placed on a low Pi diet serum creatinine levels were
halved during
the 6 months on the restricted diet compared with a similar period on a normal
diet
(McCrory et al, J. Pediatr. 111:410-412, ( 1987). Furthermore, growth velocity
in these
children increased significantly on the low Pi diet compared with the control
period.
Other human studies (Barrientos et al, Electrolyte Metab. 7:127-133, (1982);
Ciadrella
et al, Nephron 42:196-199, (1986); Gin et al, Metabolism 36:1080-1085,
(1987)),
mainly of short duration, have failed to observe an effect of Pi restriction
on the course
of CRF. Nevertheless, the bulk of the animal studies discussed above together
with the
less well controlled human studies suggest that dietary restriction of Pi is
beneficial in
slowing the progression of CRF, especially in mild to moderate renal
insufficiency.
The mechanism by which Pi excess leads to an increase in the rate of renal
failure is unknown. However, most evidence supports an interaction between Pi
and
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cellular Ca2+ accumulation. In the failing kidney a rise in the filtered load
of Pi
together with a reduction in Pi reabsorption secondary to elevated levels of
parathyroid
hormone (PTH) results in an increase in tubular fluid Pi concentration. This
leads to
an increased transepithelial flux of Ca2+ and elevated cellular Ca2+ levels
resulting in
Ca2+-induced cell injury (Bode et al., Endocrinology 102:1725-1732, (1978).
Alternatively, or in addition, calcium-phosphate precipitation may occur
resulting in
renal calcification and nephrocalcinosis (Lau, K., Kidney Int. 36:918-937, (
1989)).
Finally, Shapiro et al., Am . J. Physiol. 258:F183-F188, (1990) suggested that
the renal hypermetabolism normally associated with the 5/6th nephrectomized
model
of CRF in rats may contribute to the progression of CRF in this model. Thus,
restriction of dietary Pi reduced renal oxygen consumption by 50 % and reduced
intracelluar Pi concentrations without altering the steady state concentration
of ATP as
assessed by 31 P-NMR in this model.
Chronic renal failure (CRF) affects more than 270,000 patients in the US alone
and costs an estimated $6.8 billion in annual heath care costs. Early and
major
contributors to the morbidity of CRF patients are abnormalities in electrolyte
and bone
metabolism induced by the progressive loss of renal excretory function.
Phosphate
(Pi) retention has been identified as playing a major role in the progression
of CRF and
in the development of uremic bone disease.
Studies in the literature have shown that dietary Pi restriction slows the
progression of CRF in animal models and in small patient studies; decreases
elevated
plasma PTH levels in CRF animal models and patients; and increases the
circulating
levels of 1, 25 (0H)2 vitamin D and intestinal Ca2+ absorption.
Thus, inhibition of Pi transport by the gut and kidney is considered
beneficial
in slowing the progression of CRF and uremic bone disease. Thus, inhibition of
Pi
transport by the gut and kidney is beneficial in slowing the progression of
CRF and
uremic bone disease.
Consequently, there exists a need to find an alternative means of reducing
phosphate retention, in mammals, in addition to diet restriction of phosphate
for the
treatment of renal diseases, and uremic bone disease.
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SUMMARY OF THE INVENTION
The present invention involves novel methods of using of N-aryl-2-
sulfonamidobenzamides as phosphate transport inhibitors for the selective
inhibition
of Pi transport in the kidney and/or the intestine as a therapeutic treatment
in chronic
renal failure and uremic bone disease.
DETAILED DESCRIPTION OF THE INVENTION
The present invention involves the use of inhibitors of phosphate transport,
for the treatment of chronic renal failure, and uremic bone disease, as well
as other
related diseases, such as hyperphosphatemia, vitamin D metabolism, and
secondary
hyperparathyroidism caused by the retention of phosphate. Preferably,
inhibitors for
use herein are those which selectively inhibit Na+-dependent Pi transport in
tissues,
preferably renal and intestinal tissue, from a number of species, including
human.
The present invention relates to the use of compounds that are inhibitors of
sodium-dependent phosphate transport, which are represented by the following
Formula (I):
R3v .O
..5,
O NH O
I (R2)m
N
(R~)n ~ ~ H
(I)
wherein:
R1 and R2 are independently selected from the group consisting of hydrogen,
alkyl,
alkenyl, arylalkyl, acyl, aroyl, haloalkyl, aryl, heteroaryl, halo, carboxy,
carboalkoxy, carbamyl, alkylcarbamyl, arylcarbamyl, cyano, alkoxy, hydroxyl,
phenylazo, amino, nitro, alkylamino, arylamino, arylalkylamino, acylamino,
aroylamino, alkylthio, arylalkylthio, arylthio, alkysulfinyl, arylsulfinyl,
arylalkylsulfinyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfamyl,
arylsulfonamido, and alkylsulfonamido;
or the R 1 and or the R2 moiety represents a fusing element forming a
benzothiophene, naphthalene, quinoline, or isoquinoline with the ring it
substitutes;
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or (R 1 )n and or (R2)m and the ring it substitutes represents a heterocycle
selected
from the group consisting of thiophene, furan, pyridine, pyrimidine, and
pyrazine,
and benzo analogs thereof; and
R3 is independently selected from the group consisting of alkyl, haloalkyl, R1
aryl
and R 1 aralkyl, and R 1 substituted heterocycles selected from the group
consisting
of thiophene, furan, pyridine, pyrimidine, pyrazine, imidazole, and thiazole,
and
benzo analogs thereof.
As used herein, "alkyl" refers to an optionally substituted hydrocarbon group
joined together by single carbon-carbon bonds. Preferred alkyl substituents
are as
indicated throughout. The alkyl hydrocarbon group may be linear, branched or
cyclic, saturated or unsaturated.
As used herein, "aryl" refers to an optionally substituted aromatic group with
at least one ring having a conjugated pi-electron system, containing up to two
conjugated or fused ring systems. "Aryl" includes carbocyclic aryl,
heterocyclic
~-yl and biaryl groups, all of which may be optionally substituted. Preferred
aryl
substituents are as indicated throughout.
The compounds of the present invention may contain one or more
asymmetric carbon atoms and may exist in racemic and optically active
forms. All of these compounds and diastereomers are contemplated to be
within the scope of the present invention.
Preferred compounds include, but are not limited to:
N-phenyl-2-(3-trifluoromethylphenylsulfonamido)benzamide;
5-Methoxy-N-(3-trifluoromethylphenyl)-2-(4-chlorophenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(5-chloro-2-thienylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(3,3,3-trifluoroethylsulfonamido)benzamide;
S-Bromo-N-(4-Bromophenyl)-2-(3-chloro-2-fluorophenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(3-chloropropylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(4-methoxyphenylsulfonamido)benzamide;
5-Bromo-N-(4-Bromophenyl)-2-(2-fluorophenylsulfonamido)benzamide;
N-(4-Chlorophenyl)-2-(2-fluorophenylsulfonamido)benzamide;
N-(4-Bromophenyl)-2-(3,3,3-trifluoroethylsulfonamido)benzamide;
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N-(4-Bromophenyl)-5-chloro-2-(3-chloro-2-fluorophenylsulfonamido)benzamide;
N-(4-Chlorophenyl)-2-(3,4-dichlorophenylsulfonamido)benzamide;
N-(4-Bromophenyl)-2-(2-thienylsulfonamido)benzamide;
N-(4-Bromophenyl)-2-(2-methoxycarbonyl-3-thienylsulfonamido)benzamide;
N-(3,4-Dichlorophenyl)-2-(2-fluorophenylsulfonamido)benzamide;
N-(4-Chlorophenyl)-2-(3-trifluoromethylphenylsulfonamido)benzamide;
5-Bromo-N-(4-chlorophenyl)-2-(3,4-dichlorophenylsulfonamido)benzamide;
N-(4-Bromophenyl)-2-(phenylsulfonamido)benzamide and
5-Methoxy-N-(4-chlorophenyl)-2-(3-trifluoromethylphenylsulfonamido)benzamide.
Pharmaceutically acceptable salts for use when basic groups are present
include acid addition salts such as those containing sulfate, hydrochloride,
fumarate,
maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate,
methanesulfonate,
ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and
quinate. Pharmaceutically acceptable salts can be obtained from acids such as
hydrochloric acid, malefic acid, sulfuric acid, phosphoric acid, sulfamic
acid, acetic
acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic
acid,
ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
cyclohexylsulfamic acid, fumaric acid, and quinic acid.
Pharmaceutically acceptable salts also include basic addition salts such as
those containing benzathine, chloroprocaine, choline, diethanolamine,
ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium,
potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional
groups, such as carboxylic acid or phenol are present.
The present invention provides compounds of Formula (I) above which can
be prepared using standard techniques. An overall strategy for preparing
preferred
compounds described herein can be carried out as described in this section.
Using
the protocols described herein as a model, one of ordinary skill in the art
can readily
produce other compounds of the present invention.
With appropriate manipulation and protection of any chemical functionality,
synthesis of the remaining compounds of Formula (I) is accomplished by methods
analogous to those above and to those described in the Experimental section.
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Scheme 1
NHZ
COOCH3
R~ i , ' (CH3)3AI
NHZ O
O ~ NHZ \ II Rz
( N \ /
HN ~ O R2~ R' r H
~O
R' ~ ~ NaOH R3SOZC1
pyridine
R3v , O
.,S~
O NH O
R2
N \ /
Ri ~ ~ H
In order to use a compound of Formula (I) or a pharmaceutically acceptable
salt thereof for the treatment of humans and other mammals, it is normally
formulated in accordance with standard pharmaceutical practice as a
pharmaceutical
composition.
The present compounds can be administered by different routes including
intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical
(transdermal), or transmucosal administration. For systemic administration,
oral
administration is preferred. For oral administration, for example, the
compounds
can be formulated into conventional oral dosage forms such as capsules,
tablets, and
liquid preparations such as syrups, elixirs, and concentrated drops.
Alternatively, injection (parenteral administration) may be used, e.g.,
intramuscular, intravenous, intraperitoneal, and subcutaneous. For injection,
the
compounds of the invention are formulated in liquid solutions, preferably, in
physiologically compatible buffers or solutions, such as saline solution,
Hank's
solution, or Ringer's solution. In addition, the compounds may be formulated
in
solid form and re-dissolved or suspended immediately prior to use. Lyophilized
forms can also be produced.
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Systemic administration can also be by transmucosal or transdermal means.
For transmucosal or transdermal administration, penetrants appropriate to the
barrier
to be permeated are used in the formulation. Such penetrants are generally
known
in the art, and include, for example, for transmucosal administration, bile
salts and
fusidic acid derivatives. In addition, detergents may be used to facilitate
permeation. Transmucosal administration, for example, may be through nasal
sprays, rectal suppositories, or vaginal suppositories.
For topical administration, the compounds of the invention can be
formulated into ointments, salves, gels, or creams, as is generally known in
the art.
The amounts of various compounds to be administered can be determined by
standard procedures taking into account factors such as the compound IC50,
EC50,
the biological half-life of the compound, the age, size and weight of the
patient, and
the disease or disorder associated with the patient. The importance of these
and
other factors to be considered are known to those of ordinary skill in the
art.
Amounts administered also depend on the routes of administration and the
degree of oral bioavailability. For example, for compounds with low oral
bioavailability, relatively higher doses will have to be administered.
Preferably the composition is in unit dosage form. For oral application, for
example, a tablet, or capsule may be administered, for nasal application, a
metered
aerosol dose may be administered, for transdermal application, a topical
formulation
or patch may be administered and for transmucosal delivery, a buccal patch may
be
administered. In each case, dosing is such that the patient may administer a
single
dose.
Each dosage unit for oral administration contains suitably from 0.01 to 500
mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof, calculated as the free base. The
daily
dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal
routes
contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula (I). A
topical formulation contains suitably 0.01 to 5.0% of a compound of Formula
(I).
The active ingredient may be administered from 1 to 6 times per day,
preferably
once, sufficient to exhibit the desired activity, as is readily apparent to
one skilled in
the art.
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As used herein, "treatment" of a disease includes, but is not limited to
prevention, retardation and prophylaxis of the disease.
Composition of Formula (I) and their pharmaceutically acceptable salts
which are active when given orally can be formulated as syrups, tablets,
capsules
and lozenges. A syrup formulation will generally consist of a suspension or
solution
of the compound or salt in a liquid carrier for example, ethanol, peanut oil.
olive oil,
glycerine or water with a flavoring or coloring agent. Where the composition
is in
the form of a tablet, any pharmaceutical carrier routinely used for preparing
solid
formulations may be used. Examples of such carriers include magnesium
stearate,
terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
Where the
composition is in the form of a capsule, any routine encapsulation is
suitable, for
example using the aforementioned carriers in a hard gelatin capsule shell.
Where
the composition is in the form of a soft gelatin shell capsule any
pharmaceutical
carrier routinely used for preparing dispersions or suspensions may be
considered,
for example aqueous gums, celluloses, silicates or oils, and are incorporated
in a soft
gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of a
compound or salt in a sterile aqueous or non-aqueous carrier optionally
containing a
parenterally acceptable oil, for example polyethylene glycol,
polyvinylpyrrolidone,
lecithin, arachis oil or sesame oil.
Typical compositions for inhalation are in the form of a solution, suspension
or emulsion that may be administered as a dry powder or in the form of an
aerosol
using a conventional propellant such as dichlorodifluoromethane or
trichlorofluoromethane.
A typical suppository formulation comprises a compound of Formula (I) or a
pharmaceutically acceptable salt thereof which is active when administered in
this
way, with a binding and/or lubricating agent, for example polymeric glycols,
gelatins, cocoa-butter or other low melting vegetable waxes or fats or their
synthetic
analogs.
Typical dermal and transdermal formulations comprise a conventional
aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste
or
are in the form of a medicated plaster, patch or membrane.
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Preferably the composition is in unit dosage form, for example a tablet,
capsule or metered aerosol dose, so that the patient may administer a single
dose.
No unacceptable toxological effects are expected when compounds of the
present invention are administered in accordance with the present invention.
Sodium-dependent phosphate transport inhibition is determined by the
ability of the test compound to inhibit the uptake of radio-labeled inorganic
phosphate by proximal tubule cells. Appropriate cells from human, rabbit, or
rat
may be used.
Cell Preparation and phosphate uptake assay
Rabbit proximal tubule cells were isolated and cultured according to the
procedure of Sakhrani, L. M. et al., Am. J. Physiol. 246:F757-F764, (1984)
whose
disclosure is incorporated herein by reference in its entirety. Human proximal
tubule cells were purchased from Clonetics (San Diego, CA) and grown according
to the suppliers' instructions. On the day of the experiment, cells were
harvested
from culture plates with 0.5 mM EDTA in phosphate buffered saline. The cells
were
washed twice in uptake buffer (see below) and equilibrated at 37 C in the same
buffer for 30 minutes. Aliquots of cells ( 100 u1, 0.5 to 1 million cells)
were
distributed into glass test tubes. Fifty u1 of drug solution or buffer were
added
followed by 50 u1 of uptake buffer containing 100 uM [32P]-K2HP04 ( 0.5 to 1
uCi/tube).After varying periods of time (usually 4 minutes) at 37 C, uptakes
were
stopped with 4 ml of cold stop solution (see below) and the cells were washed
3
times in this solution by centrifugation. The pelleted cells were dissolved in
0.5 ml
1N NaOH and 32P was counted in a liquid scintillation counter. Phosphate
uptake is
expressed as pmol phosphate/mg cell protein.
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Stop solution Uptake Buffer pH 7.4
Mannitol 100mM NaCI 143 mM
NaCI 100 mM Hepes 15 mM
Na Arsenate 10 mM KCl 5.4 mM
Hepes 5 mM MgCl2 0.8 mM
CaCl2 1.8 mM
Glucose 0.1
In the above noted whole cell assay system for rabbit and human proximal
tubule cells the cells are harvested by filtration and 32P uptake is measured.
It is
also possible to use 33P rather than 32P. Using human proximal tubule cells
the
IC50 for 5-bromo-N-(4-bromophenyl)-2-(5-chloro-2-
thienylsulfonamido)benzamide, 5-bromo-N-(4-bromophenyl)-2-(2-
fluorophenylsulfonamido)benzamide, and 5-bromo-N-(4-bromophenyl)-2-(3-
chloropropylsulfonamido)benzamide are 12, 15, and 14 ~M respectively.
The following examples illustrate preparation of compounds and
pharmaceutical compositions that may be used in this invention. The examples
are
not intended to limit the scope of this invention as defined hereinabove and
as
claimed below.
Example 1
N-(4-Bromophenyl)-2-amino-5-bromobenzamide
A 11.6 ml portion of a 2.0 M solution of trimethylaluminum (23.2 mmol)
was added to a solution of 4.0 g (23.25 mmol) of 4-bromoaniline at Oo C. The
reaction mixture was held at ambient temperature for 45 min, and then cooled
to Oo
C. Methyl 2-amino-5-bromobenzoate (4.72 g, 23.25 mmol) was added in small
portions, and after a vigorous gas evolution ceased the reaction mixture was
held at
ambient temperature for 18 hr. The reaction mixture was then poured into 250
ml of
10% HCl (further gas evolution occurred) and the solid which formed collected
by
filtration. The solid was washed in turn with water and toluene and then dried
at
room temperature. TLC silica, CHCI3:MeOH 9:1 with a drop of formic acid, Rf
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0.80-0.90 and NMR identical with that of an authentic sample. This is a
general
procedure which works with a wide variety of aromatic and heteroaromatic
anthranilic acid and aniline analogs.
A mixture of 12.1 g (50 mmol) of 5-bromoisatoic anhydride, 9.4 g (55
mmol) of 4-bromoaniline, and 0.2 g (5 mmol) of NaOH in 150 ml of dioxane was
refluxed for 18 hr. The cooled reaction mixture was filtered and concentrated
under
vacuum. The residue crystallized on addition of 95% EtOH. The solid was
collected by filtration and washed with ethanol. A sample purified by thick
layer
chromatography (silica, 15 % EtOAc in hexane) gave the expected NMR, MS, and
elemental analysis.
A similar procedure starting from 5-chloroisatoic anhydride and 4-
bromoaniline gave N-(4-bromophenyl)-2-amino-5-chlorobenzamide which gave the
expected NMR, MS, and elemental analysis.
Example 2
5-Bromo-N-(4-Bromophenyl)-2-(4-chlorophenylsulfonylamino)benzamide
A solution of N-(4-Bromophenyl)-2-amino-5-bromobenzamide (8.64 g, 23.3
mmol), 4-chlorobenzenesulfonyl chloride (4.98 g, 23.6 mmol), and 7.37 g (93.2
mmol) in 300 ml of CH2Cl2 was allowed to stand at room temperature for 2 days.
The reaction mixture was concentrated under vacuum and the residue dissolved
in
EtOAc. The solution was washed twice with 10% HCI, water, 5% NaHC03, water,
and dried over MgS04. Concentration and recrystallization from 10% EtOAc in
hexane gave product which had satisfactory NMR, MS, and elemental analysis.
Example 3
5-Bromo-N-(4-Bromophenyl)-2-(4-bromophenylsulfonylamino)benzamide
A solution of 31.5 mg (85 ~mol) of N-(4-Bromophenyl)-2-amino-5-
bromobenzamide, 32.5 mg (127.5 ~mol) of 4-bromobenzenesulfonyl chloride, and
28 ~1 (340 ~mol) of pyridine in 1 ml of CH2C12 was agitated for 18 hr. Then
84.5
mg (382 ~mol) of polyamine resin HL (Nova Biochem, 4.53 mmol/g) was added,
the mixture agitated for 18 hr, and the solids removed by filtration.
Concentration
under vacuum and purification by preparative HPLC (C 18, 20 - 95% acetonitrile
-
0.1 % aqueous TFA) gave product which gave a satisfactory HPLC-MS analysis.
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Using procedures similar to those in Examples 2 and 3, the products from
reaction of 5-bromo-N-(4-bromophenyl)-2-(4-chlorophenylsulfonylamino)
benzamide with the following sulfonyl chlorides were obtained: 3-chlorophenyl-
, 4-
chlorophenyl-, 3,4-dichlorophenyl-, 3-chloro-4-fluoro-, 2-fluorophenyl-, 2,5-
dimethoxyphenyl-, 3,4-dimethoxyphenyl-, 4-n-butoxyphenyl-, 2-
trifluoromethylphenyl-, 4-phenylazophenyl-, 4-trifluoromethylphenyl-, 3,5-bis-
trifluoromethylphenyl-, 2-methylphenyl-, 2,4,6-trimethylphenyl-, 2-naphthyl-,
methane-, trifluoromethane-, 2-thienyl-, 5-chloro-2-thienyl-, 4-biphenylyl-, 3-
chloropropyl-, 4-cyanophenyl-, 3,5-dichlorophenyl-, styryl-, 2-methoxycarbonyl-
3-
thienyl-, 4-iodophenyl-, 2,6-dichlorophenyl-, 4-t-butylphenyl-, and 2,2,2-
trifluoroethyl-. The products gave satisfactory results on HPLC-MS analyses.
All publications, including but not limited to patents and patent
applications,
cited in this specification are herein incorporated by reference as if each
individual
publication were specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
The above description fully discloses the invention including preferred
embodiments thereof. Modifications and improvements of the embodiments
specifically disclosed herein are within the scope of the following claims.
Without
further elaboration, it is believed that one skilled in the are can, using the
preceding
description, utilize the present invention to its fullest extent. Therefore
the
Examples herein are to be construed as merely illustrative and not a
limitation of the
scope of the present invention in any way. The embodiments of the invention in
which an exclusive property or privilege is claimed are defined as follows.
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