CA2254121A1 - Compositions for a once a day treatment of cyclooxygenase-2 mediated diseases - Google Patents
Compositions for a once a day treatment of cyclooxygenase-2 mediated diseases Download PDFInfo
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- CA2254121A1 CA2254121A1 CA002254121A CA2254121A CA2254121A1 CA 2254121 A1 CA2254121 A1 CA 2254121A1 CA 002254121 A CA002254121 A CA 002254121A CA 2254121 A CA2254121 A CA 2254121A CA 2254121 A1 CA2254121 A1 CA 2254121A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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Abstract
This invention is directed to a pharmaceutical composition for the treatment of cyclooxygenase-2 mediated diseases, said composition being suitable for once a day oral administration, said composition comprising 2.5 to 250 mgs of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone. The invention is also directed to a method of treating cyclooxygenase-2 mediated diseases comprising the once a day oral administration of 2.5 to 250 mgs of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone. The invention is also directed to the use of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a medicament containing 2.5 to 250 mgs of said compound for once a day administration for the treatment of cyclooxygenase-2 mediated diseases.
Description
CA 022~4121 1998-11-10 TITLE OF THE INVENTION
COMPOSITIONS FOR A ONCE A DAY TREATMENT OF
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 . .. .
CA 022~4121 1998-11-10 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.
CA 022~4121 1998-11-10 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 CA 022~4121 1998-11-10 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.
CA 022~4121 1998-11-10 ~ 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 __ , . . .
CA 022~4121 1998-11-10 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.
CA 022~4121 1998-11-10 ~ 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.
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 CA 022~4121 1998-11-10 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 35 Directly compressed tablet composition Amount per tablet Ingredient 25 mg COX-2 Inhibitor 106.9 mg Microcrystallinecellulose CA 022~4121 1998-11-10 ~ 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 ~ . . . . . . ..
CA 022~4121 1998-11-10 45 mg Microcrystalline cellulose 45 mg Lactose anhydrate 4 mg Croscarmellose sodium 1 mg Magnesium stearate 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.
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.
Oral suspension 40 Amount per 5 mL dose Ingredient CA 022~4121 1998-11-10 101 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.
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 CA 022~4121 1998-11-10 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 CA 022~4121 1998-11-10 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
COMPOSITIONS FOR A ONCE A DAY TREATMENT OF
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 . .. .
CA 022~4121 1998-11-10 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.
CA 022~4121 1998-11-10 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 CA 022~4121 1998-11-10 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.
CA 022~4121 1998-11-10 ~ 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 __ , . . .
CA 022~4121 1998-11-10 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.
CA 022~4121 1998-11-10 ~ 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.
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 CA 022~4121 1998-11-10 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 35 Directly compressed tablet composition Amount per tablet Ingredient 25 mg COX-2 Inhibitor 106.9 mg Microcrystallinecellulose CA 022~4121 1998-11-10 ~ 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 ~ . . . . . . ..
CA 022~4121 1998-11-10 45 mg Microcrystalline cellulose 45 mg Lactose anhydrate 4 mg Croscarmellose sodium 1 mg Magnesium stearate 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.
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.
Oral suspension 40 Amount per 5 mL dose Ingredient CA 022~4121 1998-11-10 101 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.
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 CA 022~4121 1998-11-10 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 CA 022~4121 1998-11-10 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
Claims
WHAT IS CLAIMED IS:
1. A pharmaceutical composition for the treatment of cyclooxygenase-2 mediated diseases, said composition being suitable for once a day oral administration, said composition comprising 2.5 to 250 mg of a compound is 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
2. A composition according to Claim 1 comprising 5, 10 or 25 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)-phenyl)-2-(5H)-furanone.
3. A composition according to Claim 1 comprising 10 to 125 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)-phenyl)-2-(5H)-furanone.
4. A composition according to Claim 1 comprising 10 to 75 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)-phenyl)-2-(5H)-furanone.
5. A composition according to Claim 1 comprising 10, 25, or 50 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)-phenyl)-2-(5H)-furanone.
6. A composition according to Claim 1 comprising 25, 50 or 75 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)-phenyl)-2-(5H)-furanone.
7. A pharmaceutical composition according to Claim 1, 2, 3, 4, 5, or 6 further comprising (a) Microcrystalline cellulose, (b) Lactose monohydrate, (c) Hydroxypropyl cellulose, (d) Croscarmellose sodium, and (e) Magnesium stearate; or further comprising (a) Microcrystalline cellulose, (b) Lactose anhydrate, (c) Croscarmellose sodium, and (d) Magnesium stearate; or further comprising Polyethylene oxide 400; or further comprising (a) Sorbitol solution, (b) Polyvinylpyrrolidone, (c) Poly oxyethylene sorbitan monolaurate, and (d) Benzoic acid.
8. A method of treating an inflammatory disease susceptible to treatment with an non-steroidal anti-inflammatory agent comprising:
administration orally once a day to a patient in need of such treatment 2.5 to 250 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
9. A method according to Claim 8 comprising:
administration orally once a day to a patient in need of such treatment 5, 10 or 25 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
10. A method according to Claim 8 comprising:
administration orally once a day to a patient in need of such treatment 10 to 125 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
11. A method according to Claim 8 comprising:
administration orally once a day to a patient in need of such treatment 10 to 75 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)-phenyl)-2-(5H)-furanone.
12. A method according to Claim 8 comprising:
administration orally once a day to a patient in need of such treatment 10, 25 or 50 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
13. A method according to Claim 8 comprising:
administration orally once a day to a patient in need of such treatment 25, 50 or 75 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
14. A method of treating an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent comprising:
administration orally once a day to a patient in need of such treatment a composition according to Claim 7.
15. A method according to Claim 9 for the treatment of non-chronic headache, pain or swelling.
16. A method according to Claim 12 for the treatment of osteoarthritis.
17. A method according to Claim 13 for the treatment of rheumatoid arthritis..
18. Use of 2.5 to 250 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
20. Use according to Claim 18 of 5, 10 or 25mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
21. Use according to Claim 18 of 10 to 125 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
22. Use according to Claim 18 of 10 to 75 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
23. Use according to Claim 18 of 10, 25 or 50 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
24. Use according to Claim 18 of 10, 25 or 50 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of osteoarthritis.
25. Use according to Claim 18 of 25, 50 or 75 mg of 5,5 -dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
26. Use according to Claim 18 of 25, 50 or 75 mg of 5,5 -dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of rheumatoid arthritis.
27. Use according to Claim 18 of 5, 10 or 25mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of non-chronic headache, pain or swelling.
28. A unit dose oral form which comprises from 5 to 22.5 mg of dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
29. A unit dosage form according to Claim 28 which comprises 12.5 or 20 mg of dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
1. A pharmaceutical composition for the treatment of cyclooxygenase-2 mediated diseases, said composition being suitable for once a day oral administration, said composition comprising 2.5 to 250 mg of a compound is 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
2. A composition according to Claim 1 comprising 5, 10 or 25 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)-phenyl)-2-(5H)-furanone.
3. A composition according to Claim 1 comprising 10 to 125 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)-phenyl)-2-(5H)-furanone.
4. A composition according to Claim 1 comprising 10 to 75 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)-phenyl)-2-(5H)-furanone.
5. A composition according to Claim 1 comprising 10, 25, or 50 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)-phenyl)-2-(5H)-furanone.
6. A composition according to Claim 1 comprising 25, 50 or 75 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)-phenyl)-2-(5H)-furanone.
7. A pharmaceutical composition according to Claim 1, 2, 3, 4, 5, or 6 further comprising (a) Microcrystalline cellulose, (b) Lactose monohydrate, (c) Hydroxypropyl cellulose, (d) Croscarmellose sodium, and (e) Magnesium stearate; or further comprising (a) Microcrystalline cellulose, (b) Lactose anhydrate, (c) Croscarmellose sodium, and (d) Magnesium stearate; or further comprising Polyethylene oxide 400; or further comprising (a) Sorbitol solution, (b) Polyvinylpyrrolidone, (c) Poly oxyethylene sorbitan monolaurate, and (d) Benzoic acid.
8. A method of treating an inflammatory disease susceptible to treatment with an non-steroidal anti-inflammatory agent comprising:
administration orally once a day to a patient in need of such treatment 2.5 to 250 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
9. A method according to Claim 8 comprising:
administration orally once a day to a patient in need of such treatment 5, 10 or 25 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
10. A method according to Claim 8 comprising:
administration orally once a day to a patient in need of such treatment 10 to 125 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
11. A method according to Claim 8 comprising:
administration orally once a day to a patient in need of such treatment 10 to 75 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)-phenyl)-2-(5H)-furanone.
12. A method according to Claim 8 comprising:
administration orally once a day to a patient in need of such treatment 10, 25 or 50 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
13. A method according to Claim 8 comprising:
administration orally once a day to a patient in need of such treatment 25, 50 or 75 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
14. A method of treating an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent comprising:
administration orally once a day to a patient in need of such treatment a composition according to Claim 7.
15. A method according to Claim 9 for the treatment of non-chronic headache, pain or swelling.
16. A method according to Claim 12 for the treatment of osteoarthritis.
17. A method according to Claim 13 for the treatment of rheumatoid arthritis..
18. Use of 2.5 to 250 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
20. Use according to Claim 18 of 5, 10 or 25mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
21. Use according to Claim 18 of 10 to 125 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
22. Use according to Claim 18 of 10 to 75 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
23. Use according to Claim 18 of 10, 25 or 50 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
24. Use according to Claim 18 of 10, 25 or 50 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of osteoarthritis.
25. Use according to Claim 18 of 25, 50 or 75 mg of 5,5 -dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
26. Use according to Claim 18 of 25, 50 or 75 mg of 5,5 -dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of rheumatoid arthritis.
27. Use according to Claim 18 of 5, 10 or 25mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone in the manufacture of a once a day oral dosage form of a medicament for the treatment of non-chronic headache, pain or swelling.
28. A unit dose oral form which comprises from 5 to 22.5 mg of dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
29. A unit dosage form according to Claim 28 which comprises 12.5 or 20 mg of dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1789196P | 1996-05-17 | 1996-05-17 | |
| US60/017,891 | 1996-05-17 | ||
| GB9612065.4 | 1996-06-10 | ||
| GBGB9612065.4A GB9612065D0 (en) | 1996-06-10 | 1996-06-10 | Compositions for a once a day treatment of cyclooxtgenase-2 mediated diseases |
| PCT/US1997/007985 WO1997044027A1 (en) | 1996-05-17 | 1997-05-13 | Compositions for a once a day treatment of cyclooxygenase-2 mediated diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2254121A1 true CA2254121A1 (en) | 1997-11-27 |
Family
ID=26309473
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002254121A Abandoned CA2254121A1 (en) | 1996-05-17 | 1997-05-13 | Compositions for a once a day treatment of cyclooxygenase-2 mediated diseases |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU3122597A (en) |
| CA (1) | CA2254121A1 (en) |
| WO (1) | WO1997044027A1 (en) |
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|---|---|---|---|---|
| EP1061908A4 (en) * | 1998-03-13 | 2007-01-24 | Merck & Co Inc | Combination therapy and composition for acute coronary ischemic syndrome and related conditions |
| CO5280224A1 (en) * | 2000-02-02 | 2003-05-30 | Univ Florida State Res Found | SUBSTITUTED TAXANS WITH ESTER IN C7, USEFUL AS ANTITUMOR AGENTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| AU2004237439B2 (en) | 2003-05-07 | 2009-09-10 | Osteologix A/S | Treating cartilage/bone conditions with water-soluble strontium salts |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5474995A (en) * | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
-
1997
- 1997-05-13 AU AU31225/97A patent/AU3122597A/en not_active Abandoned
- 1997-05-13 WO PCT/US1997/007985 patent/WO1997044027A1/en active Application Filing
- 1997-05-13 CA CA002254121A patent/CA2254121A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU3122597A (en) | 1997-12-09 |
| WO1997044027A1 (en) | 1997-11-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |