Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
COMPOSITIONS FOR A ONCE A DAY TREATMENT OF
CYCLOOXYGENASE-2 MEDIATED DISEASES
5 BACKGROUND OF THE INVENTION
This invention relates to ph~ ceutical compositions for
the treatment of cyclooxygenase-2 me~ te~1 diseases, methods of
treatment thereof and the use of a compound in the manufacture of a
medicament.
In particular, this invention relates to a pharmaceutical
composition for the treatment of cyclooxygenase-2 mediated diseases,
said composition being suitable for once a day ~imini~tration, said
composition comprising
5 ,5 -dimethyl-3 -(3 -fluorophenyl)-4-(4-methylsulfonyl)
15 phenyl)-2-(5H)-furanone.
~ so2CH3
H3~
~ ~F
O ~
Non-steroidal anti-infl~mm~tory agents are normally
- ~lmini~tered 2 to 4 times daily. The relatively short half-life of mostnon-steroidal anti-infl~mm~tory agents means that once a day
~-lmini~tration is impractical and even twice a day ~rlmini~tration is
unusual. The relatively large doses needed to achieve once a day
treatment of conventional non-steroidal anti-infl~mm~tory agents would
also lead to side effects so that there is a general understanding that once
a day ~ ini~tration is unlikely to be achievable.
Surprisingly a compound has been identified which can be
employed on a once a day basis and which will not produce an
. .. .
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unacceptable level of side effects on such a regimen, and in particular
will not cause an Im~( ceptable level of gastric side effects.
US 5,474,995, issued December 12, 1995, WO 95/00501,
published January 5, 1995 and WO 95/18799, published July 13, 1995,
5 disclose 3,4-di-substituted furanones and derivatives thereof as potent,
selective inhibitors of cyclooxygenase-2. We have found that 5,5-
dimethyl-3-(3 -fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(SH)-
furanone, possesses a surprising combination of attributes that make it
possible to formulate and use the composition in a surprising manner.
10 Not only is the compound potent, safe and effective at modest oral
dosages of 2.5 to 250 mg of agent per day, but in addition this active
agent possesses a half-life in humans of sufficient length that a single
oral dose of 2.5 to 250 mg of agent per day will provide effective safe
anti-infl~mm~tory treatment over a 24 hour period. Such active agents
15 are particularly useful in the treatment of chronic indications, including
arthritis, pain, Alzheimer's disease and the like.
SUMMARY OF THE INVENTION
This invention is directed to a ph~rm~ce~ltical composition
20 for the treatment of cyclooxygenase-2 me~ te-l diseases, said
composition being suitable for once a day oral ~imini~tration, said
composition comprising 2.5 to 250 mgs of 5,5-dimethyl-3-(3-
fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(SH)-furanone.
The invention is also directed to a method of treating
25 cyclooxygenase-2 me li~te-l diseases comprising the once a day oral
lmini~tration of 2.5 to 250 mgs of 5,5-dimethyl-3-(3-fluorophenyl)-4-
(4-methylsulfonyl)phenyl)-2-(SH)-furanone .
The invention is also directed to the use of 5,5-dimethyl-3-
(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(SH)-furanone in the
30 manufacture of a medicament cont~inin~ 2.5 to 250 mgs of said
compound for once a day ~-lmini~tration for the treatment of
cyclooxygenase-2 mediated diseases.
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DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, this invention is directed to a
pharm~ce-ltical composition for the treatment of cyclooxygenase-2
me~ ted diseases, said composition being suitable for once a day oral
5 ~lmini~tration, said composition comprising 2.5 to 250 mg of 5,5-
dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-
furanone, and a pharmaceutical carrier therefor.
5,5 -Dimethyl-3-(3-fluorophenyl)-4-(4-
methylsulfonyl)phenyl)-2-(5H)-furanone, its utility and methods of
10 m~king them are disclosed in US 5,474,995, issued December 12, 1995,
WO 95/00501, published January 5, 1995 and WO 95/18799, published
July 13, 1995, which are hereby incorporated by reference.
As discussed in US 5,474,995 compounds including 5,5-
dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-
15 furanone are useful for the relief of pain, fever and infl~mm~tion of avariety of conditions including rhe--m~tic fever, symptoms associated
with influenza or other viral infections, common cold, low back and
neck pain, dysmenorrhea, headache, toothache, sprains and strains,
myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis
20 degenerative joint diseases (osteoarthritis), gout and ankylosing
spondylitis, bursitis, burns, injuries following surgical and dental
procedures. In addition, such a compound may inhibit cellular
neoplastic transformations and metastic tumor growth and hence can be
used in the treatment of cancer. It is also useful for the treatment of
25 dementia including pre-senile and senile dementia, and in particular,
dementia associated with Alzheimer's Disease (ie Alzheimer's
dementia).
The compound will also inhibit prostanoid-induced smooth
muscle contraction by preventing the synthesis of contractile prostanoids
30 and hence may be of use in the treatment of dysmenorrhea, premature
labor and asthma.
By virtue of its potent inhibitory activity against
cyclooxygenase-2 (COX-2) and/or its selectivity for inhibiting COX-2
over cyclooxygenase-1 (COX-1) the specified compound is also useful
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as an alternative to conventional non-steroidal ~n~iinfl~mm~tory drugs
(NSAID'S) particularly where such NSAIDS may be contra-indicated
such as in patients with peptic ulcers, gastritis, regional enteritis,
ulcerative colitis, diverticulitis or with a recurrent history of
5 gastrointestinal lesions; GI blee.ling, coagulation disorders including
anemia such as hypoprothrombinemia, haemophilia or other blee(ling
problems (including those relating to reduced or impaired platelet
function); kidney disease (eg impaired renal function); those prior to
surgery or taking anticoagulants; and those susceptible to NSAID
10 induced ~thm~
For the treatment of any of these cyclooxygenase mediated
diseases the compound may be ~-lmini~tered orally.
As indicated above, ph~ ceutical compositions for
treating COX-2 me~ te~ e~es as defined may optionally include one
15 or more ingredients as listed above.
The ph~ ceutical compositions cont~inin~ the active
ingredient may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous or oily suspensions, dispersible
powders or granules, emulsions, hard or soft capsules, or syrups or
20 elixirs. The compositions are intended for oral use and may be
prepared according to any method known to the art for the manufacture
of ph~ eutical compositions and such compositions may contain one
or more agents selected from the group consisting of sweetening agents,
flavoring agents, coloring agents and preserving agents in order to
25 provide ph~ ceutically elegant and palatable ~reparations. Tablets
contain the active ingredient in ~lmixtllre with non-toxic
ph~ ceutically acceptable excipients which are suitable for the
manufacture of tablets. These excipients may be for example, inert
diluents, such as calcium carbonate, sodium carbonate, lactose, calcium
30 phosphate or sodium phosphate; gran~ tin~ and tii~integrating agents,
for example, corn starch, or alginic acid; binding agents, for example
starch, gelatin or acacia, and lubricating agents, for example,
magnesium stearate, stearic acid or talc.
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~ Other suitable formulations are set forth in U.S. Patent No.
5,474,995. However, in view of the uni~ue set of properties possessed
by 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-
(5H)-furanone, including long half-life, low solubility, high potency and
5 de minimi~ gastrointestinal (GI) side effects we have found the
following oral forrnulations to be of particular value:
Rapidisc(~) - In view of the above mentioned
characteristics, S,5-dimethyl-3-(3-fluorophenyl)-4-(4-
methylsulfonyl)phenyl)-2-(5H)-furanone is particularly well suited for a
10 rapid dissolving sublingual formulation. For example, due to the lack
of GI side-effects, the agent need not be taken with a large amount of
water. Suitable Rapidisc(~) formulations and methods of m~kin~ same
are disclosed in US 4,305,502, US 4,371,516, US 4,470,202, US
4,758,598, US 4,754,597, US 5,046,618 and US 5,188,882, all of which
15 are hereby incorporated by reference.
As mentioned in the Background section, we have found
5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-
furanone to possess a surprising combination of attributes. Not only are
these active agents potent safe and effective at modest oral dosages of
20 2.5 to 250 mg of agent per day, but in addition these active agents
possess a half-life in humans of sufficient length that a single oral dose
of 2.5 to 250 mg of active agent per day will provide effective safe anti-
infl~mm~tory treatment over a 24 hour period. Such agents are
particularly useful in the treatment of chronic indications, such as
25 rheumatoid and osteo allhl;tis as well as Alzheimer's Disease.
Oral dosage levels for agents 5,5-dimethyl-3-(3-
fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone are of the
order of from about 2.5 to 250 mg per patient per day.
The amount of active agent that may be combined with the
30 carrier materials to produce a single dosage form will vary depending
upon the host treated and the particular mode of ~tlmini~tration. For
example, a formulation intended for oral ~(lmini.~tration to humans may
contain from 2.5 to 250 mg of agent compounded with an a~l)ropliate
and convenient amount of carrier material which may vary from about
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5 to about 95 percent of the total composition. Dosage unit forms may
typically contain 2.5, S, 10, 12.5, 20, 25, 37.5, S0, 75, 100, 125, 150,
175 or 250 mg of active agent.
It will be understood, however, that the specific dose level
for any particular patient will depend upon a variety of factors
including the age, body weight, general health, sex, diet, time of
~-lmini.~tration, rate of excretion, drug combination and the type and
severity of the particular disease undergoing therapy. For many
patients, a dosage range of 2.5 to 125 or 10 to 75 mg per day is
preferred.
For long term therapy, such as in the treatment of chronic
diseases including rheumatoid arthritis, osteoarthritis or Alzheimer's
disease, a dosage of 10 to 75 or 5 to 125 mg per day is preferred. More
particularly, for the treatment of osteoallh~ilis~ a dosage of 10, 25 or 50
mg per day is preferred, whereas for the treatment of rheumatoid
arthritis, 25, 50 or 75 mg per day is preferred. For the treatment of
non-chronic indications such as headache or post-operative swelling and
pain, S, 10, 25 or 50 mg per day is preferred.
Accordingly, in one aspect this invention is directed to a
pharmaceutical composition for the treatment of COX-2 mediated
diseases, said composition being suitable for once a day oral
~tlmini~tration, said composition comprising a 2.5 to 250 mg of 5,5-
dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(SH)-
furanone, and a pharmaceutical carried therefor.
Within this aspect there is a first genus of compositions
comprising 5, 10 or 25 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-
methylsulfonyl)phenyl)-2-(SH)-furanone .
Within this aspect there is a second genus of compositions
comprising 10 to 125 mg of S,S-dimethyl-3-(3-fluorophenyl)-4-(4-
methylsulfonyl)phenyl)-2-(SH)-furanone.
Within this genus there is a class of compositions
comprising 10 to 75 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-
methylsulfonyl)phenyl)-2-(SH)-furanone.
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~ Within this genus there is a second class of compositions
comprising 10, 25, or 50 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-
methylsulfonyl)phenyl)-2-(5H)-furanone.
Within this genus there is a third class of compositions
S comprising 25, S0 or 75 mg of 5,S-dimethyl-3-(3-fluorophenyl)-4-(4-
methylsulfonyl)phenyl)-2-(SH)-furanone.
In another aspect the invention is directed to a unit dose
oral form which comprises from 5 to 22.5 mg of S,S-dimethyl-3-(3-
fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, for
10 example, 12.5 or 20 mg.
EXAMPLE 1
Wet ~ranulated tablet composition
lS Amount per tablet Ingredient
25 mg COX-2 Inhibitor
79.7 mg Microcrystalline cellulose
79.7 mg Lactose monohydrate
6 mg Hydroxypropyl cellulose*
8 mg Croscarrnellose sodium
1 mg Magnesium stearate
25 Tablet dose strengths of between 5 and 125 mg can be accomodated by
varying total tablet weight, and the ratio of the first three ingredients.
Generally it is preferable to maintain a 1:1 ratio for microcrystalline
cellulose: lactose monohydrate.
* Klucel(~)LF~)from Aqualon
EXAMPLE la
Wet ~ranulated tablet composition
35 Amount per tablet Ingredient
12.5 mg COX-2 Inhibitor
86 mg Microcrystalline cellulose
86 mg Lactose monohydrate
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6 mg Hydroxypropyl cellulose
8 mg Croscarmellose sodium
1 mg Magnesium stearate
s
EXAMPLE lb
Wet granulated tablet composition
~0 Amount per tablet Ingredient
10 mg COX-2 Inhibitor
87.2 mg Microcrystalline cellulose
87.2 mg Lactose monohydrate
6 mg Hydroxypropyl cellulose
8 mg Croscarmellose sodium
1 mg Magnesium stearate
EXAMPLE lc
Wet granulated tablet composition
Amount per tablet Ingredient
5 mg COX-2 Inhibitor
89.7 mg Microcrystalline cellulose
89.7 mg Lactose monohydrate
6 mg Hydroxypropyl cellulose
8 mg Croscarmellose sodium
1 mg Magnesium stearate
EXAMPLE 2
35 Directly compressed tablet composition
Amount per tablet Ingredient
25 mg COX-2 Inhibitor
106.9 mg Microcrystallinecellulose
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~ 106.9 mg Lactose anhydrate
7.5 mg Croscarmellose sodium
3.7 mg Magnesium stearate
S Tablet dose strengths of between 5 and 125 mg can be accomodated by
varying total tablet weight, and the ratio of the first three ingredients.
Generally it is preferable to maintain a 1:1 ratio for microcrystalline
cellulose: lactose monohydrate.
EXAMPLE 2a
Directly compressed tablet composition
Amount per tablet Ingredient
12.5 mg COX-2 Inhibitor
113.2 mg Microcrystalline cellulose
113.2 mg Lactose anhydrate
7.5 mg Croscarmellose sodium
3.7 mg Magnesiumstearate
EXAMPLE 2b
Directly compressed tablet composition
Amount per tablet Ingredient
10 mg COX-2 Inhibitor
42.5 mg Microcrystalline cellulose
42.5 mg Lactose anhydrate
- 4 mg Croscarmellose sodium
1 mg Magnesium stearate
EXAMPLE 2c
Directly compressed tablet composition
Amount per tablet Ingredient
S mg COX-2 Inhibitor
~ . . . . . . ..
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- 10-
45 mg Microcrystalline cellulose
45 mg Lactose anhydrate
4 mg Croscarmellose sodium
1 mg Magnesium stearate
EXAMPLE 3
Hard gelatin capsule composition
Amount per capsule Ingredient
25 mg COX-2 Inhibitor
37 mg Microcrystalline cellulose
37 mg Lactose anhydrate
1 capsule Hard gelatin capsule
1 mg Magnesium stearate
Capsule dose strengths of between 1 and 50 mg can be accomodated by
varying total fill weight, and the ratio of the first three ingredients.
20 Generally it is preferable to maintain a 1:1 ratio for microcrystalline
cellulose: lactose monohydrate.
EXAMPLE 4
Oral solution
Amount per 5 mL dose Ingredient
50 mg COX-2 Inhibitor
To 5 mL with Polyethylene oxide 400
Solution dose strengths of between 1 and 50 mg/SmL can be
accomodated by varying the ratio of the two ingredients.
EXAMPLE 5
Oral suspension
40 Amount per 5 mL dose Ingredient
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101 mg COX-2 Inhibitor
150 mg Polyvinylpyrrolidone
2.5 mg Poly oxyethylene sorbitan monolaurate
10 mg Benzoic acid
To 5 mL with sorbitol solution (70%)
Suspension dose strengths of between 1 and 50 mg/5mL can be
accomodated by varying the ratio of the first and last ingredients.
EXAMPLE 6
Intravenous infusion
Amount per 200mL dose Ingredient
1 mg COX-2 inhibitor
0.2 mg Polyethylene oxide 400
1.8 mg Sodium chloride
to 200mL Purified water
STARTING MATERIALS
5.5.-Dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-
furanone
Step 1: Methyl 2-trimethylsilyloxyisobutyrate
To a solution of 1.2 mL (10.4 mmol) of methyl 2-hydroxy-
isobutyrate in 50 mL of CH2C12 were added 1.2 g (17.6 mmol) of
imidazole and 2.1 mL (16.6 mmol) of TMSCl. The mixture was stirred
at r.t. for 1.5 h and quenched with 20 mL of H2O. The organic layer
was dried over MgSO4, concentrated and passed through a short plug of
silica gel eluted with 9: 1 hexane/EtOAc. Evaporation of solvent
afforded 1.27 g of the title compound as a colorless oil.
lH NMR (CD3COCD3) o 0.08 (9H, s), 1.38 (6H, s), 3.67 (3H, s).
Step 2: 2-Trimethylsilyloxy-4'-(methylthio)isobutyrophenone
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- 12 -
A solution of 204 mg (1.0 mmol) of 4-bromothioanisole in
2.5 mL of THF was cooled to -78~C and treated with 0.42 mL of 2.5 M
n-BuLi solution in hexane. After stirring at -78~C for 1 h, a solution of
380 mg (2.0 mmol) of methyl 2-trimethylsilyloxyisobutyrate (Step 1) in
5 2 mL of THF was added. The mixture was stirred at -78~C for 2 h and
then quenched with NH40Ac buffer. The product was extracted with
EtOAc, dried over MgSO4 and concentrated. The residue was puri~led
by flash chromatography, eluting with 19:1 hexane/EtOAc to give 95
mg of the title product.
lH NMR (CD3COCD3) ~ 0.05 (9H, s), 1.52 (6H, s), 2.53 (3H, s), 7.33
(2H, d), 8.12 (2H, d).
Step 3: 2-Hydroxy-4'-(methylthio)isobutyrophenone
To a solution of 40 mg (0.14 mmol) of 2-trimethylsilyloxy-
4'-(methylthio)isobutyrophenone (Step 2) in 2 mL THF was added 0.2
mL of 1 M n-Bu4NF in THF. The resulting mixture was stirred for 30
min and then quenched with 10 mL of NH40Ac buffer. The product
was extracted with EtOAc, dried over MgSO4 and concentrated. The
residue was purified by flash chromatography, eluting with 4:1
hexane/EtOAc to give 25 mg of the title product.
lH NMR (CD3COCD3) o 1.50 (6H, s), 2.54 (3H, s), 4.68 (lH, s), 7.30
(2H, d), 8.15 (2H, d).
Step 4 2-hydroxy-4'-(methylsulfonyl)isobutyrophenone
To a solution of 2-hydroxy-4'-
(methylthio)isobutyrophenone (Step 3) (45 g) in t-BuOH (500 mL) and
CH2Cl2 (200 mL) was added a solution of OXONETM (194 g) in H20
(1.4 L). The reaction mixture was stirred for 18 h at r.t. and then
extracted with EtOAc (3 x 500 mL). The organic extracts were
combined and dried over Na2SO4 and the solvent was evaporated . The
residue was swished in Et2O/hexane to give the title compound as a
yellow solid (47.4 g).
Step 5 3-Fluorophenylacetic acid, 1,1-dimethyl-2-(4-
(methylsulfonyl)phenyl)-2-oxo-ethyl ester
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A mixture of 2-hydroxy-4'-
(methylsulfonyl)isobutyrophenone (Step 4) (100 g), 3-
fluorophenylacetic acid (83 g), 1-cyclohexyl-3-(2-
S morpholinoethyl)carbo~liimi~le metho-p-toluenesulfonate (225 g) and
DMAP (25 g) in CH2Cl2 (2 L) was mechanically stirred for 17 h at r.t..
A solution of lN HCl (1 L) was then added and the organic phase was
separated, washed with a saturated solution of Na2CO3 (0.4 L) and
dried over MgSO4. After concentration, the residue was purified by
10 silica gel chromatography, eluting with 30% EtOAcAlexane to give the
title compound as a white solid (133 g).
Step 6 5,5-Dimethyl-3-(3-fluorophenyl)-4-(4-
(methylsulfonyl)phenyl))-2-(SH)-furanone
A solution of the product from Step 5 (120 g) in CH2Cl2 (1
L) was treated with DBU (81.6 g) and stirred for 1 h at r.t.. The
reaction mixture was then treated with lN HCl (550 mL) and the
organic phase was separated, washed with saturated NaHCO3 and dried
over MgSO4. After concentration, the crude was swished with 20%
EtOAc/hexane (450 mL), and filtered to give the title compound as a
white solid (108.4 g, m.p. 172.7~C).
Analysis Calculated C 63.32; H 4.75
Found: C 63.50;H4.79
- ABBREVIATIONS
DBU = 1,8-diazabicyclo~5.4.0]undec-7-ene
DMAP = 4-(dimethylamino)pyridine
OXONETM = 2KHSO5.KHSO4.K2SO4
~ THF = tetrahydrofuran
TLMSCl = trimethylsilyl chloride
