U.S. patent application number 09/741213 was filed with the patent office on 2001-06-14 for crystalline form of 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonamide.
This patent application is currently assigned to G.D. Searle & Co.. Invention is credited to Gaud, Henry T, McLaughlin, Kathleen T., Medich, John R., Talley, John J., Yonan, Edward E..
Application Number | 20010003752 09/741213 |
Document ID | / |
Family ID | 21820280 |
Filed Date | 2001-06-14 |
United States Patent
Application |
20010003752 |
Kind Code |
A1 |
Talley, John J. ; et
al. |
June 14, 2001 |
Crystalline form of 4- [ 5-methyl-3-phenylisoxazol-4-yl ]
benzenesulfonamide
Abstract
A stable crystalline form of
4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulf- onamide is
described. This crystal structure, designated Form B, is more
stable, has favorable handling properties and is characterized by
its melting point, x-ray and other physical characterizations.
Inventors: |
Talley, John J.; (Brentwood,
MO) ; Medich, John R.; (Curnee, IL) ;
McLaughlin, Kathleen T.; (Arlington Heights, IL) ;
Gaud, Henry T; (Evanston, IL) ; Yonan, Edward E.;
(Carol Stream, IL) |
Correspondence
Address: |
James M. Warner
Pharmacia Corporation
Corporate Patent Department
P.O. Box 5110
Chicago
IL
60680
US
|
Assignee: |
G.D. Searle & Co.
P.O. Box 5110
Chicago
IL
60680
|
Family ID: |
21820280 |
Appl. No.: |
09/741213 |
Filed: |
December 19, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09741213 |
Dec 19, 2000 |
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09246276 |
Feb 8, 1999 |
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09246276 |
Feb 8, 1999 |
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08909512 |
Aug 12, 1997 |
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60024378 |
Aug 14, 1996 |
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Current U.S.
Class: |
514/378 ;
548/240 |
Current CPC
Class: |
H01L 23/4006 20130101;
H01L 23/427 20130101; A61P 43/00 20180101; A61P 25/02 20180101;
A61P 19/02 20180101; H01L 2924/0002 20130101; A61P 29/00 20180101;
C07D 261/08 20130101; H01L 2924/0002 20130101; H01L 2924/00
20130101 |
Class at
Publication: |
514/378 ;
548/240 |
International
Class: |
A61K 031/42 |
Claims
What is claimed is:
1. A form of 4-[5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide
having a melting point of about 170-174.degree. C.
2. A form of claim 1 having an IR spectrum with the following
peaks: 1170, 925, 844, and 729 cm.sup.-1.
3. A form of claim 1 having an IR spectrum without a significant
peak at 723 cm.sup.-1.
4. A form of claim 1 having an x-ray powder diffraction pattern
substantially as shown in FIG. 5.
5. A pharmaceutical composition comprising a
therapeutically-effective amount of crystalline Form B of
4-[5-methyl-3-phenylisoxazol-4-yl]benzene- sulfonamide in
association with at least one pharmaceutically-acceptable carrier,
adjuvant or diluent.
6. A method of treating or preventing a cyclooxygenase-2 associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of the crystalline Form B of
4-[5-methyl-3-phenylisoxazol-4-yl]benzenesul- fonamide.
7. The method of claim 6 for use in treatment of inflammation.
8. The method of claim 6 for use in treatment of arthritis.
9. The method of claim 6 for use in treatment of pain.
10. The method of claim 6 for use in treatment of fever.
11. A method of preparing crystals of claim 1 comprising
recrystallizing
4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide using an
alcohol based solvent system.
12. The method of claim 11 wherein the solvent system comprises one
or more solvents selected from methanol, isopropanol, aqueous
methanol and aqueous ethanol.
13. The method of claim 11 wherein the crystals are recrystallized
from a mixture of isopropanol and methanol.
Description
FIELD OF THE INVENTION
[0001] This invention is in the field of antiinflammatory
pharmaceutical agents and specifically relates to a crystalline
form of 4-[5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide,
methods of preparing the crystalline form, pharmaceutical
compositions and methods for treating cyclooxygenase-2 (COX-2)
associated disorders, including inflammation.
BACKGROUND OF THE INVENTION
[0002] Prostaglandins play a major role in the inflammation process
and the inhibition of prostaglandin production, especially
production of PGG.sub.2, PGH.sub.2 and PGE.sub.2, has been a common
target of antiinflammatory drug discovery. However, common
non-steroidal antiinflammatory drugs (NSAIDs) that are active in
reducing the prostaglandin-induced pain and swelling associated
with the inflammation process are also active in affecting other
prostaglandin-regulated processes not associated with the
inflammation process. Thus, use of high doses of most common NSAIDs
can produce severe side effects, including life threatening ulcers,
that limit their therapeutic potential. An alternative to NSAIDs is
the use of corticosteroids, which have even more drastic side
effects, especially when long term therapy is involved.
[0003] Previous NSAIDs have been found to prevent the production of
prostaglandins by inhibiting enzymes in the human arachidonic
acid/prostaglandin pathway, including the enzyme cyclooxygenase
(COX). The recent discovery of an inducible enzyme associated with
inflammation (named "cyclooxygenase-2 (COX-2)" or "prostaglandin
G/H synthase II") provides a viable target of inhibition which more
effectively reduces inflammation and produces fewer and less
drastic side effects related to inhibition of cyclooxygenase-1
(COX-1).
[0004] A group of substituted isoxazoles are described in U.S. Pat.
No. 5,633,272, to Talley et al., and International Application
WO96/25405. The compounds are described to be useful for the
treatment of inflammation and inflammation-associated disorders.
4-[5-Methyl-3-phenylisoxazol-4-yl]benzenesulfonamide shows
potential as a selective inhibitor of COX-2 over COX-1.
[0005] With all pharmaceutical compounds and compositions, the
chemical and physical stability of a drug compound is important in
the commercial development of that drug substance. Such stability
includes the stability at ambient conditions, especially to
moisture and under storage conditions. Elevated stability at
different conditions of storage is needed to anticipate the
different possible storage conditions during the lifetime of a
commercial product. A stable drug avoids the use of special storage
conditions as well as frequent inventory replacement. A drug
compound must also be stable during the manufacturing process which
often requires milling of the drug to achieve drug material with
uniform particle size and surface area. Unstable materials often
undergo polymorphic changes. Therefore, any modification of a drug
substance which enhances its stability profile provides a
meaningful benefit over less stable substances.
[0006] It has now been discovered that
4-[5-methyl-3-phenylisoxazol-4-yl]b- enzenesulfonamide can be
prepared in different crystal forms. An earlier material (Form "A")
is unstable after mechanical grinding (milling) and is also
thermally unstable. A recently determined crystalline form (Form
"B") is described which is more stable and has improved physical
properties.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 shows a differential scanning calorimetry (DSC)
profile of 4-[5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide
Form A.
[0008] FIG. 2 shows a differential scanning calorimetry (DSC)
profile of 4-[5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide
Form B.
[0009] FIG. 3a shows an infrared spectrum of
4-[5-methyl-3-phenylisoxazol-- 4-yl]benzenesulfonamide Form B.
[0010] FIG. 3b shows an infrared spectrum of
4-[5-methyl-3-phenylisoxazol-- 4-yl]benzenesulfonamide Form A.
[0011] FIG. 4 shows an X-ray diffraction pattern of
4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide Form A.
[0012] FIG. 5 shows an X-ray diffraction pattern of
4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide Form B.
DETAILED DESCRIPTION OF THE INVENTION
[0013] It has been discovered that
4-[5-methyl-3-phenylisoxazol-4-yl]benze- nesulfonamide can be
prepared in a crystalline form designated "Form B". Form B can be
characterized by the following methods.
Melting
[0014] Melting points were performed either on a Thomas Hoover
melting point apparatus or a Mettler FP900 Thermosystem melting
point apparatus. Melting ranges were determined by differential
scanning calorimetry on a TA Instruments Differential Scanning
Calorimeter (Model 2100 controller, Model 912 dual calorimeter).
The sample (1-2 mg) was placed in an unsealed aluminum pan and
heated at 10.degree. C./minute.
[0015] Form A showed an onset of melting at 160.2.degree. C. with
an imbedded exotherm at 170.9.degree. C. due to crystal
rearrangement (see FIG. 1). Form B showed an onset of melting at
170.9.degree. C. (peak 172.5.degree. C.). An example of the DSC of
Form B is shown in FIG. 2.
Infrared Spectroscopy
[0016] Infrared spectra were obtained with a Nicolet DRIFT
(diffused reflectance infrared fourier transform) Magna System 550
spectrophotometer. A Spectra-Tech Collector system and a 3 mm
sample cup were used. Samples (2%) were analyzed in KBr and scanned
from 400 to 4000 cm.sup.-1. An example of an infrared absorption
spectra of Form B is shown in FIG. 3a, and that of Form A is shown
in FIG. 3b. The Y-axis represents corrected reflectance in
Kubella-Munk units.
[0017] The infrared spectrum of Form B is characterized by
absorptions at about 3377, 1170, 1151, 925, 844, 745, 729, and 534
cm.sup.-1 which are different than that observed in the Form A
spectra. The infrared spectrum of Form A is characterized in part
by an absorption at about 723 cm.sup.-1 which is different than
that observed in the Form B spectra. Form B crystals of the present
invention preferably display an infrared spectrum substantially the
same as that shown in FIG. 3a.
X-ray Powder Diffraction
[0018] The analysis was performed with a Siemens D5000 powder
diffractometer. Raw data was measured for 2.theta. values from 2 to
50, with steps of 0.020 and step periods of 2 seconds.
[0019] Table I sets out the significant parameters of the main
peaks in terms of 2.theta. values and intensities for Form B. An
example of the x-ray diffraction pattern for Form A is shown in
FIG. 4. An example of the x-ray diffraction pattern for Form B is
shown in FIG. 5. Significant differences between Form A and Form B
are evident at 12.221, 15.447, 17.081, 19.798 and 23.861.
1TABLE I Peak Angle-2.theta. Peak I/Imax No. (deg) D spacing Cps
(%) 1 12.221 7.2361 502.38 63.29 2 13.693 6.4617 38.03 4.79 3
14.227 6.2203 51.46 6.48 4 15.447 5.7314 599.94 75.58 5 15.801
5.6039 793.79 100.00 6 16.678 5.3110 239.95 30.23 7 17.081 5.1868
331.31 41.74 8 18.165 4.8796 270.21 34.04 9 19.066 4.6510 73.16
9.22 10 19.400 4.5717 200.13 25.21 11 19.798 4.4807 789.23 99.43 12
20.578 4.3126 209.43 26.38 13 22.008 4.0354 691.33 87.09 14 22.540
3.9414 71.87 9.05 15 22.975 3.8678 137.23 17.29 16 23.580 3.7699
394.27 49.67 17 23.861 3.7261 602.27 75.87 18 24.553 3.6226 397.23
50.04 19 25.206 3.5302 192.44 24.24 20 25.560 3.4822 77.74 9.79 21
25.940 3.4320 31.47 3.96 22 26.200 3.3985 20.87 2.63 23 27.295
3.2646 151.54 19.09 24 28.595 3.1191 207.74 26.17 25 29.124 3.0636
161.44 20.34 26 29.656 3.0099 73.94 9.32
[0020] Form B can be prepared by the recrystallization of
4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide from a
suitable solvent. To prepare Form B,
4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulf- onamide is dissolved
in a volume of solvent and cooled until crystals form. Preferably,
the compound is added to a solvent at a temperature of at least
about 25.degree. C. More preferably, the temperature of the solvent
is between 30.degree. C. and the boiling point of the solvent. An
even more preferred temperature is in a range of about
65-75.degree. C.
[0021] Alternatively, hot solvent may be added to the compound and
the mixture can be cooled until crystals form. Preferably, the
solvent is at a temperature of at least 25.degree. C. More
preferably, the temperature of the solvent is at a temperature in
the range of about 50-80.degree. C. Even more preferred, the
temperature is in a range of about 65-75.degree. C.
[0022] Preferably, the compound is mixed with an amount of solvent
over about 3 times the weight of the compound. More preferred, the
solvent to compound ratio is about 7 to about 10 times.
[0023] Preferably the solution is cooled slowly to precipitate Form
B. More preferably, the solution is cooled at a rate slower than
about 0.5.degree. C./minute. Even more preferably, the solution is
cooled at a rate of about 0.3.degree. C./minute or slower.
[0024] A suitable solvent is a solvent or mixture of solvents which
dissolves the compound and any impurities at an elevated
temperature, but upon cooling, preferentially precipitates Form B.
A suitable solvent is selected from an alcohol, methyl tert-butyl
ether, methyl ethyl ketone and a combination of solvents selected
from alcohol, methyl tert-butyl ether, acetonitrile, water,
acetone, tetrahydrofuran and methyl ethyl ketone. An alcohol or
aqueous alcohol is preferred. A more preferred solvent is selected
from methanol, aqueous methanol, ethanol, aqueous ethanol,
isopropyl alcohol and aqueous isopropyl alcohol. Even more
preferred is aqueous methanol, methanol, ethanol 3A, aqueous
ethanol and a mixture of isopropanol/methanol.
[0025] Alternatively, the compound is dissolved in one solvent and
a co-solvent is added to aid in the crystallization of the desired
form.
[0026] The crystals of Form B so formed are separated from the
solvent such as by filtration or centrifugation. Preferably, the
crystals are dried, and more preferably at a temperature in the
range of about 30.degree. C. to about 100.degree. C. Even more
preferably, the crystals are dried under vacuum.
[0027] Alternatively, Form B can be prepared by heating Form A at a
temperature sufficient to convert to Form B. Preferably, Form A is
heated at a temperature in the range of 50.degree. C. to about
140.degree. C.
Preparation
[0028] The following examples contain detailed descriptions of the
methods of preparation of Form B. These detailed descriptions fall
within the scope, and serve to exemplify the invention. These
detailed descriptions are presented for illustrative purposes only
and are not intended as a restriction on the scope of the
invention. All parts are by weight and temperatures are in degrees
Centigrade unless otherwise indicated.
[0029] 4-[5-Methyl-3-phenylisoxazol-4-yl] benzenesulfonamide was
prepared by the following method where ethanol 3A is an aqueous
ethanol (5% water) denatured with methanol:
EXAMPLE 1
[0030] Step 1. Preparation of deoxybenzoin oxime.
[0031] Sodium acetate trihydrate (152.5 g, 1.12 mole, 1.1 eq.) was
added to deoxybenzoin (200 g, 1.02 mole) and dissolved with ethanol
(3A, 0.8 L) and water (0.24 L) in a 5 L flask with mechanical
stirrer, reflux condenser, and thermometer. The solution was
stirred and heated to 70.+-.1.degree. C. Water (0.1 L) was added to
hydroxylamine hydrochloride (78.0 g, 1.12 mole, 1.1 eq.) in a
separate 500 ML flask with stirring. The hydroxylamine
hydrochloride solution was transferred to the deoxybenzoin
solution, while the reaction mixture was kept at about 70.degree.
C. The mixture was heated to boiling (about 84.degree. C.) and held
at this temperature for 40 minutes. The mixture was cooled to
40.degree. C. in two hours and charged water (10.5 L) into the
reaction mixture. The reaction mixture was cooled to 20.degree. C.
over another hour with stirring. Crystals of pure oxime formed
which were isolated by filtration (Buchner funnel, No. 1 Whatman
filter paper) using house vacuum, washed with a mixture of 50 mL of
3A ethanol and 100 mL of water, and with water (1 L). The solid was
dried with vacuum for 2 hours, and at 55.degree. C. under house
vacuum for 12 hours to yield pure deoxybenzoin oxime (213.2 g,
99%).
[0032] Step 2. Preparation of
5-hydroxy-5-methyl-3,4-diphenylisoxazoline.
[0033] The deoxybenzoin oxime (Step 1) was dissolved in anhydrous
THF (565 mL) under a nitrogen atmosphere. The solution was cooled
to -20.degree. C. The solution was treated with lithium
diisopropylamide (2 M, 800 mL, 1.60 mol) while allowing the
reaction temperature to warm to 10-15.degree. C. The reaction
mixture to was cooled to -10.degree. C. to -20.degree. C. and
anhydrous ethyl acetate (218 mL) was added to the solution while
allowing the reaction temperature to rise to a maximum of
25.degree. C. and held for 30 minutes at 25.degree. C. The reaction
mixture was cooled to about 0.degree. C. Water was added to a
quench flask and cooled to 0-5.degree. C. The pre-cooled reaction
mixture was transferred from the reaction flask to the quench flask
while maintaining the temperature of the quench mixture below
25.degree. C. The quenched mixture was cooled to 0-5.degree. C.
Hydrochloric acid (12 M). was added to the mixture, keeping the
temperature below 25.degree. C. during the addition by controlling
the addition rate and stirred until all the solids dissolve
(.about.5 minutes). The pH of the stirred mixture was measured to
be pH 3-4. The layers were separated and the organic layer was
removed. Heptane was added to the organic layer with stirring. The
organic layer was distilled until the pot temperature reached
90-91.degree. C. The solution was cooled to 5.degree. C. and
filtered. The solid was washed with two 300 mL portions of ethyl
acetate-heptane (20/80), cooled to 5.degree. C. The solid product
was dried on the funnel for several hours then dried at ambient
under vacuum with a nitrogen sweep over the weekend to yield the
isoxazoline (108.75 g, 57.7%).
[0034] Step 3. Preparation of
4-[(5-methyl-3-phenyl)-4-isoxazolyl]benzenes- ulfonamide.
[0035] 5-Hydroxy-5-methyl-3,4-diphenylisoxazoline (Step 2) (142 g,
0.56 mol) was dissolved in dichloromethane (568 mL) in a 3 L
roundbottom flask equipped with a heating mantle, mechanical
stirrer, cold water condenser, J-KEM temperature controller and
thermocouple, forming a slurry. The slurry was stirred and cooled
to <10.degree. C. Chlorosulfonic acid (335 mL, 586.3 g, 5.04
mol) was added to the slurry, keeping the temperature of the flask
below 20.degree. C. by controlling the addition. The mixture was
heated to reflux (ca. 40.degree. C.), maintained for 5 hours, then
cooled to 0-5.degree. C. The cooled reaction solution was slowly
transferred to a 3 L 3-necked roundbottom flask (mechanical stirrer
and thermocouple) containing water (1000 ml) previously cooled to
0-5.degree. C., using vigorous agitation and keeping the pot
temperature below 10.degree. C. The mixture was stirred for an
additional 5 minutes. The layers were separated. In a separate 3 L
flask (mechanical stirrer, external ice/salt bath, thermocouple)
28% ammonium hydroxide (700-mL) was cooled to 0-5.degree. C. The
methylene chloride solution was transferred to the stirred ammonium
hydroxide solution, keeping the temperature below 10.degree. C. The
mixture was stirred at ambient temperature for 60 minutes. The
resulting slurry was filtered and the solid was washed with water
(200 ml) and dried, yielding the
4-[(5-methyl-3-phenyl)-4-isoxazoly- l]benzenesulfonamide as a white
solid (94.3 g, 53.5%).
[0036] Step 4. Recrystallization of
4-[(5-methyl-3-phenyl)-4-isoxazolyl]be- nzenesulfonamide
[0037] The 4-[(5-methyl-3-phenyl)-4-isoxazolyl] benzenesulfonamide
from Step 3 was dissolved in 300 mL of boiling methyl ethyl ketone
(2-butanone) and diluted with 10% aqueous isopropyl alcohol (300
mL, (270 mL anhydrous isopropyl alcohol and 30 mL of water)). The
material was cooled to room temperature, whereupon crystals formed.
The crystals were isolated by filtration and dried in a vacuum
drying oven (10 mm Hg, 100.degree. C.) to afford pure Form B
(112.95 g, 65%): mp 172-173.degree. C.
EXAMPLE 2
[0038] 5-Methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (Example
1, step 3) (3 g) was combined with 80% ethanol 3A/20% water (9 ml)
and heated until solids dissolved. The flask was cooled with a tap
water bath and held for 1 hour to form a precipitate. The solid was
filtered off and washed with ethanol 3A. The material was heated to
dryness under vacuum (50-60.degree. C., 20 in Hg). The material
formed was identified as Form B.
EXAMPLE 3
[0039] 5-Methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (Example
1, step 3) (10 g) was combined with ethanol 3A (100 ml) and heated
until the solids dissolved (about 70 .degree. C.). The flask was
cooled to 20-25.degree. C. over 1.5 hours and held for 30 minutes
to form a precipitate. The solid was filtered off (Whatman #1
filter paper) and washed with water. The material was heated to
dryness under vacuum (90.degree. C., 50-100 mm Hg). The material
formed was identified as Form B.
EXAMPLE 4
[0040] 5-Methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (Example
1, step 3) (9.8 g), methanol (73.5 mL) and water (24.5 mL) were
combined and heated to 65-70.degree. C. The solution was held for
about 10 minutes and filtered while hot to remove any particulate
matter. The solution was cooled slowly to 50.degree. C. (about
0.3.degree. C./min) and held at 50.degree. C. for 1 hour
(crystallization begins during the hold period). The solution was
further cooled to 5.degree. C. (about 0.3.degree. C./min) and held
at 5.degree. C. for 1 hour. The product was isolated by filtration
and washed with 10 mL of cold methanol/water (75/25). The product
was dried at 95-100.degree. C. for 4 hours to give 8.55 g of Form
B.
EXAMPLE 5
[0041] Methanol/isopropanol (80/20, 120 ml) was added to
5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (Example 1, step
3) (25 g) and heated to about 68.degree. C. The solution was held
for about 15 minutes and filtered with a glass filtering funnel,
while hot, to remove any particulate matter. The solution was
cooled slowly to 5.degree. C. over 3.3 hours (about 0.3.degree.
C./min) and held at 5.degree. C. for 2 hours. The product was
isolated by filtration and washed with 10 mL of cold
methanol/isopropanol (80/20). The product was dried at
95-100.degree. C. for 3 hours to give 11 g of Form B.
COMPARATIVE EXAMPLE 6
[0042] 5-Methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (Example
1, step 3)(10 g) was combined with 20 mL of water:methanol (25:75),
and heated until the solids dissolved. The flask containing the
solution was set in ice and the mixture cooled rapidly to
<10.degree. C. with no crystallization observed on cooling. A
few crystals were observed forming on bottom of flask, and soon
crystallization was rapid. Let stand for about 10 minutes. The
solid was filtered off and washed with 75% aqueous methanol. The
material was heated to dryness under vacuum w/nitrogen bleed
(50-60.degree. C., 20 in Hg). Material formed was identified as
Form A.
[0043] The present invention also comprises a method of treating or
preventing a cyclooxygenase-2 associated disorder such as
inflammation in a subject, the method comprising treating the
subject having or susceptible to such inflammation or disorder with
a therapeutically-effective amount of crystalline Form B of
4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide.
[0044] Form B of 4-[5-methyl-3-phenylisoxazol-4-yl]
benzenesulfonamide would be useful for, but not limited to, the
treatment of inflammation in a subject, and for treatment of other
cyclooxygenase-2 mediated disorders, such as, as an analgesic in
the treatment of pain and headaches, or as an antipyretic for the
treatment of fever. For example, Form B would be useful to treat
arthritis, including but not limited to rheumatoid arthritis,
spondyloarthropathies, gouty arthritis, osteoarthritis, systemic
lupus erythematosus and juvenile arthritis. Form B would be useful
in the treatment of asthma, bronchitis, menstrual cramps, preterm
labor, tendinitis, bursitis, liver disease including hepatitis,
skin-related conditions such as psoriasis, eczema, burns and
dermatitis, and from post-operative inflammation including from
ophthalmic surgery such as cataract surgery and refractive surgery.
Form B also would be useful to treat gastrointestinal conditions
such as inflammatory bowel disease, Crohn's disease, gastritis,
irritable bowel syndrome and ulcerative colitis. Form B would be
useful for the prevention or treatment of cancer, such as
colorectal cancer, and cancer of the breast, lung, prostate,
bladder, cervix and skin. Form B would be useful in treating
glaucoma, angiogenesis and retinopathies. Form B would be useful in
treating inflammation in such diseases as vascular diseases
including atherosclerosis, migraine headaches, periarteritis
nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,
sclerodoma, rheumatic fever, type I diabetes, neuromuscular
junction disease including myasthenia gravis, white matter disease
including multiple sclerosis, sarcoidosis, nephrotic syndrome,
Behcet's syndrome, polymyositis, gingivitis, nephritis,
hypersensitivity, swelling occurring after injury, myocardial
ischemia, and the like. Form B would also be useful in the
treatment of ophthalmic diseases, such as retinitis,
conjunctivitis, retinopathies, uveitis, ocular photophobia, and of
acute injury to the eye tissue. Form B would also be useful in the
treatment of pulmonary inflammation, such as that associated with
viral infections and cystic fibrosis. Form B would also be useful
for the treatment of certain central nervous system disorders, such
as cortical dementias including Alzheimer's disease, and central
nervous system damage resulting from stroke, ischemia, seizures and
trauma. Form B is useful as antiinflammatory agents, such as for
the treatment of arthritis, with the additional benefit of having
significantly less harmful side effects. Form B would also be
useful in the treatment of allergic rhinitis, respiratory distress
syndrome, endotoxin shock syndrome, osteoporosis and inhibiting
bone resorption. Form B also would be useful in the treatment of
pain, but not limited to postoperative pain, dental pain, muscular
pain, and pain resulting from cancer. Form B would be useful for
the prevention of cardiovascular disease, such as atherosclerosis,
liver disease and dementias, such as Alzheimer's Disease.
[0045] Besides being useful for human treatment, this form is also
useful for veterinary treatment of companion animals, exotic
animals and farm animals, including mammals, rodents, and the like.
More preferred animals include horses, dogs, and cats.
[0046] The present Form B may also be used in co-therapies,
partially or completely, in place of other conventional
antiinflammatories, such as together with steroids, NSAIDs,
5-lipoxygenase inhibitors, LTB.sub.4 receptor antagonists and
LTA.sub.4 hydrolase inhibitors.
[0047] Suitable LTA.sub.4 hydrolase inhibitors include RP-64966,
(S,S)-3-amino-4-(4-benzyloxyphenyl)-2-hydroxybutyric acid benzyl
ester (Scripps Res. Inst.),
N-(2(R)-(cyclohexylmethyl)-3-(hydroxycarbamoyl)prop-
ionyl)-L-alanine (Searle), 7-(4-(4-ureidobenzyl)phenyl)heptanoic
acid (Rhone-Poulenc Rorer), and
3-(3-(1E,3E-tetradecadienyl)-2-oxiranyl)benzoi- c acid lithium salt
(Searle).
[0048] Suitable LTB.sub.4 receptor antagonists include, among
others, ebselen, linazolast, ontazolast, Bayer Bay-x-1005, Ciba
Geigy compound CGS-25019C, Leo Denmark compound ETH-615, Merck
compound MAFP, Terumo compound TMK-688, Tanabe compound T-0757,
Lilly compounds LY-213024, LY-210073, LY223982, LY233469, and
LY255283, LY-293111, 264086 and 292728, ONO compounds ONO-LB457,
ONO-4057, and ONO-LB-448, Shionogi compound S-2474, calcitrol,
Lilly compounds Searle compounds SC-53228, SC-41930, SC-50605 and
SC-51146, Warner Lambert compound BPC 15, SmithKline Beecham
compound SB-209247 and SK&F compound SKF-104493. Preferably,
the LTB.sub.4 receptor antagonists are selected from calcitrol,
ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo
Denmark compound ETH-615, Lilly compound LY-293111, Ono compound
ONO-4057, and Terumo compound TMK-688.
[0049] Suitable 5-LO inhibitors include, among others, Abbott
compounds A-76745, 78773 and ABT761, Bayer Bay-x-1005, Cytomed
CMI-392, Eisai E-3040, Scotia Pharmaceutica EF-40, Fujirebio
F-1322, Merckle ML-3000, Purdue Frederick PF-5901, 3M
Pharmaceuticals R-840, rilopirox, flobufen, linasolast, lonapolene,
masoprocol, ontasolast, tenidap, zileuton, pranlukast, tepoxalin,
rilopirox, flezelastine hydrochloride, enazadrem phosphate, and
bunaprolast.
[0050] The present form also may be used in combination therapies
with opioids and other analgesics, including narcotic analgesics,
Mu receptor antagonists, Kappa receptor antagonists, non-narcotic
(i.e. non-addictive) analgesics, monoamine uptake inhibitors,
adenosine regulating agents, cannabinoid derivatives, Substance P
antagonists, neurokinin-1 receptor antagonists and sodium channel
blockers, among others. More preferred would be combinations with
compounds selected from morphine, meperidine, codeine, pentazocine,
buprenorphine, butorphanol, dezocine, meptazinol, hydrocodone,
oxycodone, methadone, Tramadol [(+) enantiomer], DuP 747,
Dynorphine A, Enadoline, RP-60180, HN-11608, E-2078, ICI-204448,
acetominophen (paracetamol), propoxyphene, nalbuphine, E-4018,
filenadol, mirfentanil, amitriptyline, DuP631, Tramadol [(-)
enantiomer], GP-531, acadesine, AKI-1, AKI-2, GP-1683, GP-3269,
4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742, SNX-111,
ADL2-1294, ICI-204448, CT-3, CP-99,994, and CP-99,994.
[0051] The present invention comprises a pharmaceutical composition
comprising a therapeutically-effective amount of crystalline Form B
of 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide in
association with at least one pharmaceutically-acceptable carrier,
adjuvant or diluent.
[0052] Also embraced within this invention is a class of
pharmaceutical compositions comprising crystalline Form B in
association with one or more non-toxic, pharmaceutically-acceptable
carriers and/or diluents and/or adjuvants (collectively referred to
herein as "carrier" materials) and, if desired, other active
ingredients. Form B of the present invention may be administered by
any suitable route, preferably in the form of a pharmaceutical
composition adapted to such a route, and in a dose effective for
the treatment intended. The active Form B and compositions may, for
example, be administered orally, intravascularly,
intraperitoneally, subcutaneously, intramuscularly or
topically.
[0053] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are tablets or capsules.
The active ingredient may also be administered by injection as a
composition wherein, for example, saline, dextrose or water may be
used as a suitable carrier.
[0054] The amount of therapeutically active compound that is
administered and the dosage regimen for treating a disease
condition with the compound and/or compositions of this invention
depends on a variety of factors, including the age, weight, sex and
medical condition of the subject, the severity of the disease, the
route and frequency of administration, and the particular compound
employed, and thus may vary widely. The pharmaceutical compositions
may contain active ingredients in the range of about 0.1 to 2000
mg, preferably in the range of about 0.5 to 500 mg and most
preferably between about 1 and 100 mg. A daily dose of about 0.01
to 100 mg/kg body weight, preferably between about 0.5 and about 20
mg/kg body weight and most preferably between about 0.1 to 10 mg/kg
body weight, may be appropriate. The daily dose can be administered
in one to four doses per day.
[0055] In the case of psoriasis and other skin conditions, it may
be preferable to apply a topical preparation of Form B to the
affected area two to four times a day.
[0056] For inflammations of the eye or other external tissues,
e.g., mouth and skin, the formulations are preferably applied as a
topical ointment or cream, or as a suppository, containing the
active ingredients in a total amount of, for example, 0.075 to 30%
w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w.
When formulated in an ointment, the active ingredients may be
employed with either paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream
with an oil-in-water cream base. If desired, the aqueous phase of
the cream base may include, for example at least 30% w/w of a
polyhydric alcohol such as propylene glycol, butane-1,3-diol,
mannitol, sorbitol, glycerol, polyethylene glycol and mixtures
thereof. The topical formulation may desirably include a compound
which enhances absorption or penetration of the active ingredient
through the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethylsulfoxide and related
analogs.
[0057] Form B can also be administered by a transdermal device.
Preferably topical administration will be accomplished using a
patch either of the reservoir and porous membrane type or of a
solid matrix variety. In either case, the active agent is delivered
continuously from the reservoir or microcapsules through a membrane
into the active agent permeable adhesive, which is in contact with
the skin or mucosa of the recipient. If the active agent is
absorbed through the skin, a controlled and predetermined flow of
the active agent is administered to the recipient. In the case of
microcapsules, the encapsulating agent may also function as the
membrane.
[0058] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier, it may comprise a mixture
of at least one emulsifier with a fat or an oil or with both a fat
and an oil. Preferably, a hydrophilic emulsifier is included
together with a lipophilic emulsifier which acts as a stabilizer.
It is also preferred to include both an oil and a fat. Together,
the emulsifier(s) with or without stabilizer(s) make-up the
so-called emulsifying wax, and the wax together with the oil and
fat make up the so-called emulsifying ointment base which forms the
oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
present invention include Tween 60, Span 80, cetostearyl alcohol,
myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,
among others.
[0059] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties, since the
solubility of the active compound in most oils likely to be used in
pharmaceutical emulsion formulations is very low. Thus, the cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters may be used. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used.
[0060] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredients are dissolved
or suspended in suitable carrier, especially an aqueous solvent for
the active ingredients. The antiinflammatory active ingredients are
preferably present in such formulations in a concentration of 0-5
to 20%, advantageously 0.5 to 10% and particularly about 1.5%
w/w.
[0061] For therapeutic purposes, Form B is ordinarily combined with
one or more adjuvants appropriate to the indicated route of
administration. If administered per os, the compound may be admixed
with lactose, sucrose, starch powder, cellulose esters of alkanoic
acids, cellulose alkyl esters, talc, stearic acid, magnesium
stearate, magnesium oxide, sodium and calcium salts of phosphoric
and sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted
or encapsulated for convenient administration. Such capsules or
tablets may contain a controlled-release formulation as may be
provided in a dispersion of active compound in hydroxypropylmethyl
cellulose. Formulations for parenteral administration may be in the
form of aqueous or non-aqueous isotonic sterile injection solutions
or suspensions. These solutions and suspensions may be prepared
from sterile powders or granules having one or more of the carriers
or diluents mentioned for use in the formulations for oral
administration. The crystalline Form B may be dissolved in water,
polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, and/or various buffers. Other adjuvants and modes of
administration are well and widely known in the pharmaceutical
art.
[0062] All mentioned references are incorporated by reference as if
here written.
[0063] Although this invention has been described with respect to
specific embodiments, the details of these embodiments are not to
be construed as limitations.
* * * * *