EP0524979A1 - 2(5h)-furanones substituees dans les positions 5 et/ou 4, utilisees comme agents anti-inflammatoires - Google Patents

2(5h)-furanones substituees dans les positions 5 et/ou 4, utilisees comme agents anti-inflammatoires

Info

Publication number
EP0524979A1
EP0524979A1 EP91907029A EP91907029A EP0524979A1 EP 0524979 A1 EP0524979 A1 EP 0524979A1 EP 91907029 A EP91907029 A EP 91907029A EP 91907029 A EP91907029 A EP 91907029A EP 0524979 A1 EP0524979 A1 EP 0524979A1
Authority
EP
European Patent Office
Prior art keywords
compounds
alkyl
formula
hydrogen
compound
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP91907029A
Other languages
German (de)
English (en)
Other versions
EP0524979A4 (en
Inventor
Gary C. M. Lee
Michael E. Garst
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Allergan Inc
Original Assignee
Allergan 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
Application filed by Allergan Inc filed Critical Allergan Inc
Publication of EP0524979A1 publication Critical patent/EP0524979A1/fr
Publication of EP0524979A4 publication Critical patent/EP0524979A4/en
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/28—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/58—One oxygen atom, e.g. butenolide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/60—Two oxygen atoms, e.g. succinic anhydride
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring

Definitions

  • the present invention is directed to novel 2(5H)- furanones substituted in the 5 position and or in the 4 position, which compounds are active as anti-inflammatory agents.
  • the present invention is also directed to
  • compositions which comprise one or more of the novel compounds of the invention, to the methods of using these pharmaceutical compositions, and to the chemical processes of making the novel compounds.
  • Manoalide is a compound isolated from a marine sponge [E. D. de Silva et al., Tetrahedron Letters 21:1611-1614 (1980)] which has anti-inflammatory, immunosuppressive and analgesic properties.
  • Manoalide (Compound 1) the
  • Manolide such as seco-manoalide (Compound 2) and dehydro-seco-manoalide (Compound 3) also have anti- inflammatory activity.
  • Compound 2 seco-manoalide
  • Compound 3 dehydro-seco-manoalide
  • United States Patent No. 4,855,320 discloses 5- arylalkyl-4-alkoxy-2(5H)-furanones as anti-convulsive and anti-epileptic agents.
  • R 1 is H, alkyl of 1 to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds;
  • R 2 is H, alkyl of 1 to 20 carbons, alkylene having one or more double bonds, alkyne having one or more triple bonds, arylalkyl, arylalkylene having one or more double bonds or arylalkyne having one or more triple bonds;
  • R 3 is H, alkyl of 1 to 20 carbons, arylalkyl, or halogene, and
  • X is H or alkyl of 1 to 20 carbons, CO-X*, CO-O-X*,,
  • the present invention also covers salts of the above- defined compounds, formed with pharmaceutically acceptable acids or bases, as applicable.
  • the present invention relates to pharmaceutical formulations comprising one or more
  • the compounds of the invention have anti-inflammatory, immunosuppressant and anti-proliferative activity. Therefore, the compounds are useful for treating in mammals (including humans) inflammation, rheumatoid arthritis, osteoarthritis, rheumatic carditis, ocular and dermal inflammatory
  • autoimmune diseases such as allergic diseases.
  • bronchial asthma and myasthenia gravis and for
  • the present invention relates to the processes of making the compounds of .
  • Formula 5 which is thereafter oxidized (typically with Jones reagent) to yield the corresponding R 1 -substituted 4-oxo-alkynoic acid of Formula 6.
  • the intermediate of Formula 6 is hydrogenated over a "poisoned" catalyst, typically Lindlar catalyst, to yield an alkenoic acid intermediate which cyclizes, usually spontanously, to provide compounds of Formula 2 where R 2 , R 3 and X are hydrogen.
  • a mild reducing agent such as sodium borohydride
  • condensation product of Formula 8 usually is not isolated because it cyclizes during the condition of the
  • a di-substituted maleic acid anhydride (Formula 9) is reacted with the lithium salt of an alkyne (Formula 10) to provide a 5-alkynyl substituted 5-hydroxy-2 (5H)- furanone derivative (Formula 11).
  • Formula 10 -CC- symbolizes such a precursor of the group R 1 which is readily converted by hydrogenation and or other reactions within the skill of the practicing organic chemist, into the group R 1 defined in connection with Formula 1 and Formula 2.
  • Reaction Scheme 4 shows a hydrogenation step in which the olephinic bond of the intermediate of Formula 11 is partially or fully saturated to provide compounds of Formula 2. Reduction of the compounds of Formula 2 with sodium borohydride provides compounds of Formula 1.
  • Another process of preparing compounds of the invention where neither R 2 nor R 3 are hydrogen involves the reaction a di-substituted maleic acid anhydride of Formula 9 with a Grignard reagent of the formula R 1 -MgBr to provide compounds of Formula 2 where X is hydrogen.
  • the processes leading to the compounds of the invention may involve performance of routine chemical reactions (such as esterification, saponification of esters, oxidation of alcohols to ketones or aldehydes, formation of acetals, ketals, and lactones from aldehydes or ketones, and the like) which are well known to the practicing synthetic organic chemist.
  • routine chemical reactions such as esterification, saponification of esters, oxidation of alcohols to ketones or aldehydes, formation of acetals, ketals, and lactones from aldehydes or ketones, and the like
  • esters are derived from the saturated aliphatic alcohols or acids of ten or fewer carbon atoms or from the cyclic or
  • saturated aliphatic cyclic alcohols and acids of 5 to 10 carbon atoms Particularly preferred aliphatic esters are those derived from lower alkyl acids or alcohols. Also preferred are the phenyl or lower alkylphenyl esters.
  • alkyl as used in the present description and claims includes straight chain alkyl. groups, branched chain alkyl groups, cycloalkyl groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. Unless the number of carbons is otherwise
  • alkyl groups but with the restriction that the group has 1 to 6 carbon atoms.
  • long chain alkyl also means the former broad definition of “alkyl” groups but with the restriction that the group has no less than 4 carbon atoms, and no more than approximately 25 carbon atoms.
  • preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms, or the cyclic or saturated aliphatic-cyclic radicals of 5 to 10 carbon atoms.
  • the compounds of the invention may be prepared as mixtures of enantiomeric compounds (where the enantiomers may or may not be present in equal
  • diastereomer itself may be a mixture of enantiomers in 1:1, or other, ratios. Alternatively, each diastereomeric compound may be sterically and optically pure. However, all of the above-noted forms, including optically pure enantiomers and mixtures thereof, as well as all
  • Some of the compounds of the invention may have cis and trans stereoisomers.
  • the scope of the invention includes both pure stereoisomers as well as mixtures thereof.
  • a pharmaceutically acceptable salt may be prepared for any compound of this invention having a functionality capable of forming such salt, for examle an acid or an amine functionality.
  • a pharmaceutically acceptable salt may be any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
  • Such a salt may be derived from any organic or inorganic acid or base.
  • the salt may be a mono or
  • Organic amine salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or
  • alkylating agent such as methyl iodide.
  • Preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri-acid may also be used.
  • the preferred compounds of the present invention are, with reference to Formula 2 and with respect to the OX substituent in the 5-position of the furanone moiety, those where the substituent is hydroxy, methoxy or
  • acetyloxy (X is H, or CH 3 O or CH 3 CO).
  • the preferred compounds in accordance with the present invention are those where R 1 is hydrogen, long chain alkyl, or arylalkyl.
  • R 1 is hydrogen, long chain alkyl, or arylalkyl.
  • the R 1 group is long chain alkyl which is straight chained, or where the R 1 is arylalkyl containing a straight alkyl chain of 3 carbons.
  • the compounds of the invention are preferred where R 2 is hydrogen, or alkyl group, particularly straight chain alkyl.
  • R 3 is H, methyl or bromo.
  • R 3 CH 3 ;
  • the compounds of the present invention are useful in pharmaceutical compositions to produce anti-inflammatory, immunosuppressant and anti-proliferative activity.
  • compositions containing one or more compounds of the invention include: inflammation, rheumatoid arthritis, osteoarthritis, rheumatic carditis, ocular and dermal inflammatory diseases, autoimmune diseases such as allergic diseases, bronchial asthma and myasthenia gravis, unwanted immune responses and unwanted proliferation of cells, psoriasis, acne, atopic diseases and allergic conjunctivitis.
  • the activity of the compounds of this invention is demonstrated by inhibition of the enzyme phospholipase A 2 in vitro and by reduction of inflammation in the mouse ear anti-inflammatory assay in vivo.
  • Activity of compounds of this invention may also be demonstrated by inhibition of phosphoinositide-specific phospholipase C. This activity has been reported for manoalide and may indicate anti-inflammatory utility.
  • Activity of the compounds may also be demonstrated by inhibition of ornithine decarboxylase, a rate limiting enzyme in cellular growth, which indicates use in treating psoriasis and neoplasis.
  • the compounds also modify calcium homeostasis. This activity is shown by effect on intracellular calcium levels in experiments using gastric glands, spleen cells, epithelial cells, GH 3 cells, etc. Calcium is inhibited from entering through the plasma membrane calcium channels and calcium release from intracellular stores is also blocked. Modification of calcium homeostasis is expected to have application in diseases of the nervous system involving modification of membrane lipids or transmitter release (Parkinson's, Alzheimer's), diseases of the cardiovascular system involving application of cardiac or vascular smooth muscle contractility and platelet
  • Atherosclerosis diseases of the gastrointestinal tract such as ulcer disease, diarrhea, motility due to secretion of acid or Cl-, diseases of the kidney involving renal handling of fluid and electrolytes (metabolic acidosis, alkalosis), and disease of abnormal growth (neoplasia, psoriasis).
  • the compounds of this invention have activity which is similar to that of manoalide, that is the compounds appear to be devoid of the endocrine properties of the glucocorticoids while having anti-inflammatory and
  • the compounds of the invention are administered to mammals, including humans, in an effective amount to produce the desired activity, preferably in an amount of about 0.05 to 100 mg per day per kilogram of body weight.
  • the amount of the compound depends upon the disease or condition being treated, the severity thereof, the route of administration and the nature of the host.
  • the compounds may be
  • compositions of this invention are provided.
  • compositions of this type may be found in Remington's Pharmaceutical Sciences. Mack Publishing
  • the pharmaceutical composition may be in the form of a salve, cream,
  • compositions for topical administration will contain 0.05-5% of the active ingredient.
  • a typical cream formulation may contain the
  • a typical ointment formulation may contain the following:
  • suitable pharmaceutical carriers include mannitol, lactose, starch, magnesium stearate, talcum, glucose and magnesium carbonate.
  • Oral compositions may be in the form of tablets, capsules, powders, solutions, suspensions, sustained release formulations, and the like.
  • a typical tablet or capsule may contain the
  • Parenteral compositions are prepared in conventional suspension or solution forms, as emulsions or as solid forms for reconstruction. Suitable carriers are water, saline, dextrose. Hank's solution. Ringer's solution, glycerol, and the like. Parenteral administration is usually by injection which may be subcutaneous,
  • the compounds of this invention may be combined with other known anti-inflammatory/immunosuppressive agents such as steroids or non-steroidal anti-inflammatory agents (NSAID) in the pharmaceutical compositions and methods described herein.
  • other known anti-inflammatory/immunosuppressive agents such as steroids or non-steroidal anti-inflammatory agents (NSAID) in the pharmaceutical compositions and methods described herein.
  • steroids non-steroidal anti-inflammatory agents
  • PMNa Polymorphonuclear leukocytes
  • gastric glands gastric glands, GH 3 cells, A431 cells, spleen cells, human keratinocytes corneal cells, etc. were loaded with the Ca 2+ sensitive fluorescent dye, Fura-2.
  • the appropriate cell type was chosen and the potency and efficacy of the anti- inflammatory furanones on calcium mobilization, calcium channel inhibition was quantitated.
  • the methods used for A431 cells listed below are representative of those used for other cells.
  • A431 cells were detached using a 5-10 min trypsin- EDTA treatment whereas GH 3 cells were treated 2 to 5 min with a 1% pancreatin solution. Cells were immediately washed twice in a 20mM HEPES buffer (pH 7.4) containing 120mM NaCl, 6 mM KC1, 1 mM MgSO 4 , 1 mg/ml glucose and 1 mg/ml pyruvate and 1.4mM calcium (medium A).
  • F was the relative fluorescence measurement of the sample.
  • F max was determined by lysing the cells with digitonin (100ug/ml) in DMSO. After F max was determined the pH was adjusted to 8, with NaOH and Ca 2+ chelated with 3mM EGTA to totally quench the fura-2 signal and obtain F min .
  • Test compound and phorbol myristate acetate are topically applied simultaneously to the pinnae of the left ears of mice. PMA alone is applied to the right ear.
  • mice Three hours and 20 minutes after application, the mice are sacrificed, left and right ears removed, and standard sized bores taken. Edema (inflammation) is measured as the difference in weight between left and right ears [Van Annan, C.G., Clin Pharmacol Ther (1974) 16:900-904].
  • phosphoinositide-specific phospholipase C may be
  • the compounds of the present invention can be made by the synthetic chemical pathways which are illustrated above in general terms, and in the specific examples as well.
  • the synthetic chemist will readily appreciate that the conditions described here in general terms, and specifically, can be generalized to any and all compounds represented by Formula 1 or by Formula 2, as applicable.
  • the synthetic chemist will readily appreciate that the herein described synthetic steps may be varied or adjusted by those skilled in the art without departing from the scope and spirit of the invention. Therefore, the following examples of specific compounds of the invention, and specific examples of the synthetic steps in which the compounds and certain intermediates are made. are set out to illustrate the invention, not to limit its scope.
  • n-Butyl lithium (a 1.6 M solution in hexane; 6.7 ml, 10.7 mmol) was added dropwise to a solution of ethyl propiolate (1.04 g, 10.6 mmol) in tetrahydrofuran (10 ml) at -78° under argon. After 10 minutes, a solution of hydrocinnamaldehyde (1.42 g, 10.6 mmol) in tetrahydrofuran (5 ml) was added. Stirring was continued at -78°C for 2 hours and acetic acid (1 ml) was added. On warming up to 0°, the reaction mixture was poured into water.
  • Methylmagnesium bromide (a 3M solution in tetrahydrofuran; 7.8 ml, 23.4 mmol) was added dropwise to a solution of ethyl propiolate (Compound 4, 2.25 g, 22.9 mmol) in tetrahydrofuran (10 ml) at -78° under argon.
  • n-Butyl lithium (a 1.6 M solution in hexane; 6.78 ml, 10.9 mmol) was added dropwise to a solution of 1-octyne (1.13 g, 10 mmol) in tetrahydrofuran (7 ml) at -78° under argon. After 20 minutes, the solution was cannulated dropwise, under argon, to a solution of 2,3-dimethylmaleic anhydride (1.30 g, 10.3, mmol) in tetrahydrofuran (15 ml) cooled at -78°. Stirring was continued for 2 hours while the cooling bath attained room temperature. The mixture was quenched with dilute hydrochloric acid, diluted with water (10 ml) and extracted with ethyl acetate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Rheumatology (AREA)
  • Molecular Biology (AREA)
  • Pain & Pain Management (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés de la formule (1), et composés de la formule (2), dans lesquelles R1 représente H, alkyle contenant 1 à 20 atomes de carbone, alkylène comportant une ou plusieurs liaisons doubles, alkyne comportant une ou plusieurs liaisons triples, arylalkyle, arylalkylène comportant une ou plusieurs liaisons doubles ou arylalkyne comportant une ou plusieurs liaisons triples, R2 représente H, alkyle contenant 1 à 20 atomes de carbone, alkylène comportant une ou plusieurs liaisons doubles, alkyne comportant une ou plusieurs liaisons triples, arylalkyle, arylalkylène comportant une ou plusieurs liaisons doubles ou arylalkyne comportant une ou plusieurs liaisons triples; R3 représente H, alkyle contenant 1 à 20 atomes de carbone, arylalkyle ou halogène, et X représente H ou alkyle contenant 1 à 20 atomes de carbone, CO-X*, CO-O-X*,, CO-NH-X*,, ou PO(OX*,)2 ou PO(OX*,)X*,, où X*, représente indépendamment H, alkyle contenant 1 à 20 atomes de carbone, phényle ou phényle substitué. Toutefois, dans les composés de l'invention illustrés par la formule (2), R1 et R3 ne peuvent pas représenter tous les deux de l'hydrogène. Les composés ont une une activité anti-inflammatoire.
EP19910907029 1990-04-17 1991-03-25 2(5h)-furanones substituted in the 5 and or in the 4 position, as anti-inflammatory agents Ceased EP0524979A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US51036490A 1990-04-17 1990-04-17
US510364 1990-04-17

Publications (2)

Publication Number Publication Date
EP0524979A1 true EP0524979A1 (fr) 1993-02-03
EP0524979A4 EP0524979A4 (en) 1993-03-10

Family

ID=24030446

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19910907029 Ceased EP0524979A4 (en) 1990-04-17 1991-03-25 2(5h)-furanones substituted in the 5 and or in the 4 position, as anti-inflammatory agents

Country Status (6)

Country Link
EP (1) EP0524979A4 (fr)
JP (1) JPH05506215A (fr)
AU (1) AU7559691A (fr)
CA (1) CA2078771A1 (fr)
IE (1) IE911267A1 (fr)
WO (1) WO1991016055A1 (fr)

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US5268387A (en) * 1992-04-24 1993-12-07 Allergan, Inc. Pharmaceutical compositions and method for administering 3 and 4-substituted 2(5H)-furanones to a mammal for inhibiting bone loss
US6492413B2 (en) 1993-01-15 2002-12-10 G.D. Searle & Co. 3.4-diaryl thiophenes and analogs thereof having use as antiinflammatory agents
GB9602877D0 (en) * 1996-02-13 1996-04-10 Merck Frosst Canada Inc 3,4-Diaryl-2-hydroxy-2,5- dihydrofurans as prodrugs to cox-2 inhibitors
US5474995A (en) 1993-06-24 1995-12-12 Merck Frosst Canada, Inc. Phenyl heterocycles as cox-2 inhibitors
KR960703901A (ko) * 1993-08-19 1996-08-31 로즈 암스트롱 치환된 2(5H)푸라논, 2(5H)티오페논 및 2(5H)피롤론 유도체, 그의 제조 방법 및 엔도텔린 길항제로서의 그의 용도(Substituted 2(5H)Furanone, 2(5H)Thiophenone and 2(5H)Pyrrolone Derivatives, Their Preparation and Their Use as Endothelin antagonists)
WO1995018799A1 (fr) * 1994-01-10 1995-07-13 Merck Frosst Canada Inc. Heterocycles phenyliques utilises comme inhibiteurs de cox-2
US5451686A (en) * 1994-04-15 1995-09-19 Allergan, Inc. 3 and 5 alkyl and phenyl 4-(hydroxy or acyloxy)-alkyl substituted 2(5H)-furanones as anti-inflammatory agents
US5639468A (en) * 1995-06-07 1997-06-17 University Of Southern California Method for reducing or preventing post-surgical adhesion formation using manoalide and analogs thereof
US5922759A (en) * 1996-06-21 1999-07-13 Warner-Lambert Company Butenolide endothelin antagonists
US5998468A (en) * 1995-08-24 1999-12-07 Warner-Lambert Company Furanone endothelin antagonists
US6020343A (en) * 1995-10-13 2000-02-01 Merck Frosst Canada, Inc. (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors
US5981576A (en) * 1995-10-13 1999-11-09 Merck Frosst Canada, Inc. (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors
GB9615867D0 (en) * 1996-07-03 1996-09-11 Merck & Co Inc Process of preparing phenyl heterocycles useful as cox-2 inhibitors
US5891892A (en) * 1996-10-29 1999-04-06 Warner-Lambert Company Small molecule biaryl compounds as inhibitors of endothelin converting enzyme
US6080876A (en) * 1997-10-29 2000-06-27 Merck & Co., Inc. Process for making phenyl heterocycles useful as COX-2 inhibitors
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Also Published As

Publication number Publication date
IE911267A1 (en) 1991-10-23
CA2078771A1 (fr) 1991-10-18
EP0524979A4 (en) 1993-03-10
JPH05506215A (ja) 1993-09-16
WO1991016055A1 (fr) 1991-10-31
AU7559691A (en) 1991-11-11

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