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WO1997044027A1 - Compositions de traitement journalier monodose de maladies a mediation cyclooxygenase-2 - Google Patents

Compositions de traitement journalier monodose de maladies a mediation cyclooxygenase-2 Download PDF

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Publication number
WO1997044027A1
WO1997044027A1 PCT/US1997/007985 US9707985W WO9744027A1 WO 1997044027 A1 WO1997044027 A1 WO 1997044027A1 US 9707985 W US9707985 W US 9707985W WO 9744027 A1 WO9744027 A1 WO 9744027A1
Authority
WO
WIPO (PCT)
Prior art keywords
treatment
methylsulfonyl
dimethyl
fluorophenyl
furanone
Prior art date
Application number
PCT/US1997/007985
Other languages
English (en)
Inventor
Bruno Hancock
Conrad Winters
Barry Gertz
Keith Gottesdiener
Original Assignee
Merck & Co., Inc.
Merck Frosst Canada Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9612065.4A external-priority patent/GB9612065D0/en
Application filed by Merck & Co., Inc., Merck Frosst Canada Inc. filed Critical Merck & Co., Inc.
Priority to AU31225/97A priority Critical patent/AU3122597A/en
Priority to CA002254121A priority patent/CA2254121A1/fr
Publication of WO1997044027A1 publication Critical patent/WO1997044027A1/fr

Links

Classifications

    • 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
    • A61K31/365—Lactones

Definitions

  • This invention relates to pharmaceutical compositions for the treatment of cyclooxygenase-2 mediated diseases, methods of treatment thereof and the use of a compound in the manufacture of a medicament.
  • this invention relates to a pharmaceutical composition for the treatment of cyclooxygenase-2 mediated diseases, said composition being suitable for once a day administration, said composition comprising
  • Non-steroidal anti-inflammatory agents are normally administered 2 to 4 times daily.
  • the relatively short half-life of most non-steroidal anti-inflammatory agents means that once a day administration is impractical and even twice a day administration is unusual.
  • the relatively large doses needed to achieve once a day treatment of conventional non-steroidal anti-inflammatory agents would also lead to side effects so that there is a general understanding that once a day administration is unlikely to be achievable.
  • 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-inflammatory treatment over a 24 hour period.
  • active agents are particularly useful in the treatment of chronic indications, including arthritis, pain, Alzheimer's disease and the like.
  • 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-(5//)-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-
  • the invention is also directed to the use of 5,5-dimethyl-3-
  • 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 mg of 5,5- dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)- furanone, and a pharmaceutical carrier therefor.
  • 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 dementia including pre-senile and senile dementia, and in particular, dementia associated with Alzheimer's Disease (ie Alzheimer's dementia).
  • 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 and hence may be of use in the treatment of dysmenorrhea, premature labor and asthma.
  • the specified compound is also useful as an alternative to conventional non-steroidal antiinflammatory 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 gastrointestinal lesions; GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding 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 induced asthma.
  • NSAID'S non-steroidal antiinflammatory drugs
  • the compound may be administered orally.
  • compositions for treating COX-2 mediated diseases as defined may optionally include one or more ingredients as listed above.
  • compositions containing 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 elixirs.
  • the compositions are intended for oral use and may be prepared according to any method known to the art for the manufacture of pharmaceutical 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 provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating 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.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents for example, corn starch, or alginic acid
  • binding agents for example starch, gelatin or acacia
  • lubricating agents for example, magnesium stearate, stearic acid or talc.
  • suitable formulations are set forth in U.S. Patent No. 5,474,995.
  • Rapidisc® In view of the above mentioned characteristics, 5,5-dimethyl-3-(3-fluorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5//)-furanone is particularly well suited for a 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 making 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 are hereby incorporated by reference.
  • Oral dosage levels for agents 5,5-dimethyl-3-(3- fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5/r)-furanone are of the order of from about 2.5 to 250 mg per patient per day.
  • a formulation intended for oral administration to humans may contain from 2.5 to 250 mg of agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms may typically contain 2.5, 5, 10, 12.5, 20, 25, 37.5, 50, 75, 100, 125, 150, 175 or 250 mg of active agent.
  • 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 administration, 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.
  • a dosage of 10 to 75 or 5 to 125 mg per day is preferred. More particularly, for the treatment of osteoarthritis, 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.
  • a dosage of 10 to 75 or 5 to 125 mg per day is preferred. More particularly, for the treatment of osteoarthritis, 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.
  • non-chronic indications such as headache or post-operative swelling and pain, 5, 10, 25 or 50 mg per day is preferred.
  • 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 administration, said composition comprising a 2.5 to 250 mg of 5,5- dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5/ ⁇ r )- furanone, and a pharmaceutical carried therefor.
  • a pharmaceutical composition for the treatment of COX-2 mediated diseases said composition being suitable for once a day oral administration, said composition comprising a 2.5 to 250 mg of 5,5- dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5/ ⁇ r )- furanone, and a pharmaceutical carried therefor.
  • a first genus of compositions comprising 5, 10 or 25 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(
  • compositions comprising 10 to 125 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5/f)-furanone.
  • compositions comprising 10 to 75 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5H)-furanone.
  • second class of compositions comprising 10, 25, or 50 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5//)-furanone.
  • compositions comprising 25, 50 or 75 mg of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5if)-furanone.
  • the invention is directed to a unit dose oral form which comprises from 5 to 22.5 mg of 5,5-dimethyl-3-(3- fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, for example, 12.5 or 20 mg.
  • 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.
  • microcrystalline cellulose lactose monohydrate.
  • 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.
  • 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. Generally it is preferable to maintain a 1 : 1 ratio for microcrystalline cellulose : lactose monohydrate.
  • Solution dose strengths of between 1 and 50 mg/5mL can be accomodated by varying the ratio of the two ingredients.
  • Suspension dose strengths of between 1 and 50 mg/5mL can be accomodated by varying the ratio of the first and last ingredients.
  • Step 1 Methyl 2-trimethylsilyloxyisobutyrate
  • Step 2 2-Trimethylsilyloxy-4'-(memylthioMsobutyrophenone 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 2 mL of THF was added. The mixture was stirred at -78°C for 2 h and then quenched with NH4OAC buffer.
  • Step 2 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 NH4OAC buffer. The product was extracted with EtOAc, dried over MgS ⁇ 4 and concentrated. The residue was purified by flash chromatography, eluting with 4: 1 hexane/EtOAc to give 25 mg of the title product.
  • Step 5 3-Fluorophenylacetic acid, l,l-dimethyl-2-(4- (methylsulfonyl > ,phenylV2-oxo-ethyl ester
  • 2-hydroxy-4'- (methylsulfonyl)isobutyrophenone (Step 4) (100 g), 3- fluorophenylacetic acid (83 g), l-cyclohexyl-3-(2- morpholinoethyl)carbodiimide metho-p-toluenesulfonate (225 g) and DMAP (25 g) in CH2CI2 (2 L) was mechanically stirred for 17 h at r.t..
  • Step 6 5,5-Dimethyl-3-(3-fluorophenyl)-4-(4- fmethylsulfonyl>phenyl > ))-2-r5/r)-furanone
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • DMAP 4-(dimethylamino)pyridine
  • TLMSC1 trimethylsilyl chloride

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique de traitement de maladies à médiation cyclooxygénase-2, cette composition pouvant être administrée une fois par jour par voie orale et contenant de 2,5 à 250 mg de 5,5 -diméthyl-3-(3 fluorophényl)-4-(4-méthylsulfonyl)phényl)-2-(5H)-furanone. L'invention concerne également une méthode pour traiter les maladies à médiation cyclooxygénase-2 comprenant l'administration d'une dose quotidienne de 2,5 à 250 mg de 5,5 -diméthyl-3-(3 fluorophényl)-4-(4-méthylsulfonyl)phényl)-2-(5H)-furanone. L'invention concerne également une utilisation de 5,5 -diméthyl-3-(3 fluorophényl)-4-(4-méthylsulfonyl)phényl)-2-(5H)-furanone dans la production d'un médicament contenant entre 2,5 et 250 mg dudit composé à administrer à raison d'une dose quotidienne pour le traitement de maladies à médiation cyclooxygénase-2.
PCT/US1997/007985 1996-05-17 1997-05-13 Compositions de traitement journalier monodose de maladies a mediation cyclooxygenase-2 WO1997044027A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU31225/97A AU3122597A (en) 1996-05-17 1997-05-13 Compositions for a once a day treatment of cyclooxygenase-2 mediated diseases
CA002254121A CA2254121A1 (fr) 1996-05-17 1997-05-13 Compositions de traitement journalier monodose de maladies a mediation cyclooxygenase-2

Applications Claiming Priority (4)

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

Publications (1)

Publication Number Publication Date
WO1997044027A1 true WO1997044027A1 (fr) 1997-11-27

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CA (1) CA2254121A1 (fr)
WO (1) WO1997044027A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1061908A4 (fr) * 1998-03-13 2007-01-24 Merck & Co Inc Therapie associee destinee au syndrome ischemique coronarien aigu ainsi qu'a des troubles connexes
CZ298484B6 (cs) * 2000-02-02 2007-10-17 Florida State University Research Foundation, Inc. Taxan a farmaceutická kompozice s jeho obsahem
US7320996B2 (en) 2001-08-15 2008-01-22 Sugen, Inc Indolinone protein kinase inhibitors and cyclooxygenase inhibitors for use in combination therapy for the treatment of cancer
US8541471B2 (en) 2003-05-07 2013-09-24 Osteologix A/S Water-soluble strontium salts for use in treatment of cartilage and/or bone conditions

Citations (1)

* Cited by examiner, † Cited by third party
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

Patent Citations (1)

* Cited by examiner, † Cited by third party
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

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1061908A4 (fr) * 1998-03-13 2007-01-24 Merck & Co Inc Therapie associee destinee au syndrome ischemique coronarien aigu ainsi qu'a des troubles connexes
CZ298484B6 (cs) * 2000-02-02 2007-10-17 Florida State University Research Foundation, Inc. Taxan a farmaceutická kompozice s jeho obsahem
US7320996B2 (en) 2001-08-15 2008-01-22 Sugen, Inc Indolinone protein kinase inhibitors and cyclooxygenase inhibitors for use in combination therapy for the treatment of cancer
US8541471B2 (en) 2003-05-07 2013-09-24 Osteologix A/S Water-soluble strontium salts for use in treatment of cartilage and/or bone conditions

Also Published As

Publication number Publication date
CA2254121A1 (fr) 1997-11-27
AU3122597A (en) 1997-12-09

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