EP0915850A1 - Carbocyclische diarylmethylen-derivate, verfahren zu ihrer herstellung und ihre verwendung für therapeutische zwecke - Google Patents

Carbocyclische diarylmethylen-derivate, verfahren zu ihrer herstellung und ihre verwendung für therapeutische zwecke

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Publication number
EP0915850A1
EP0915850A1 EP97936719A EP97936719A EP0915850A1 EP 0915850 A1 EP0915850 A1 EP 0915850A1 EP 97936719 A EP97936719 A EP 97936719A EP 97936719 A EP97936719 A EP 97936719A EP 0915850 A1 EP0915850 A1 EP 0915850A1
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
formula
lower alkyl
ring
radical
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
EP97936719A
Other languages
English (en)
French (fr)
Inventor
Eric Nicolai
Michèle Launay
Dominique Potin
Jean-Marie Teulon
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.)
UPSA SAS
Original Assignee
UPSA SAS
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 UPSA SAS filed Critical UPSA SAS
Publication of EP0915850A1 publication Critical patent/EP0915850A1/de
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/16—Masculine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/14—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated

Definitions

  • the present invention relates, as new products, to the diarylmethylene carbocychque de ⁇ vés of general formula (I).
  • cyclooxygenase route One of the biotransformation routes of arachidonic acid is the cyclooxygenase route; it allows the transformation of arachidonic acid into PGG2 and then into PGH2.
  • COX-1 isoenzymes cyclooxygenase 1
  • COX-2 cyclooxygenase 2
  • the former is a constitutive enzyme, expressed in most tissues, while the latter, which is expressed in some tissues such as the brain, is transferable in most tissues by many products, particularly by cytokines and mediators produced in during the inflammatory reaction.
  • Each enzyme plays a different role and the inhibition of
  • COX-1 or COX-2 will cause consequences that are not identical. Inhibition of COX-1 will cause a decrease in prostaglandins participating in homeostasis which can lead to side effects. Inhibition of COX-2 will cause a decrease in the prostaglandins produced in an inflamed situation. Thus the selective inhibition of COX-2 makes it possible to obtain a well-tolerated anti-inflammatory agent.
  • the compounds of the invention make it possible to obtain this selective inhibition. Consequently, the compounds in question have a very interesting pharmacological profile insofar as they are endowed with anti-inflammatory and analgesic properties while being remarkably well tolerated in particular at the gastric level. They will be particularly indicated for the treatment of inflammatory phenomena and for the treatment of pain.
  • They can also be used for the treatment of gastrointestinal inflammations, Crohn's disease, gastritis, ulcerative colitis, cancer prevention, in particular adenocarcmoma of the colon, prevention of neurodegenerative diseases, particularly Alzheimer's disease, prevention Stroke, epilepsy and the prevention of premature labor.
  • the present invention also relates to the process for the preparation of said products and their applications in therapy
  • these known molecules have two aryl groups directly linked to two adjacent carbon atoms of the cyclopentene radical.
  • the originality of the compounds of the invention resides on the one hand in the fact that they carry two .aryl groups directly linked to the same carbon atom and on the other hand in the fact that these two aryl groups are linked to a cyclopentane, cyclopentene or cyclopentadiene radical via a methylidene group.
  • These carbocyclic diarylmethylene derivatives are characterized in that they correspond to the general formula (I):
  • cycle A represents:
  • ring B represents a ring with five carbon atoms: - saturated
  • R 2 and / or R 4 are absent to respect the valences of the carbon atom
  • X, and X 2 independently represent
  • X, and X 2 represent a methylenedioxy group
  • R,, R 2 , R 3 and R 4 independently represent
  • R, R 2 or RR independently represent:
  • R represents
  • lower alkyl a hydrocarbon chain having from 1 to 6 carbon atoms, linear or branched.
  • a lower alkyl radical is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiobutyl, pentyl, isopentyl, hexyl, isohexyl radical.
  • lower halogenoalkyl radical is meant an alkyl radical of 1 to 6 carbon atoms of which 1 to 7 hydrogen atoms have been replaced by 1 to 7 halogen atoms.
  • a lower halogenoalkyl radical is for example a tnfluoromethyl radical, a radical 2 , 2,2-t ⁇ fluoroethyl, a pentafluoroethyle radical, a 2,2-d ⁇ fluoro-3,3,3-t ⁇ fluoro propyl radical, a heptafluoropropyie radical, a chloromethyl or bromomethyl radical
  • Halogen means a chlorine, bromine, iodine or fluorine atom.
  • saturated hydrocarbon cycle having 3 to 6 carbon atoms is intended to denote cyclopropane, cyclobutane, cyclopentane or cyclohexane.
  • the invention covers racemates, mixtures of cis and trans compounds but also optically active products, cis de ⁇ vés and trans p ⁇ s independently. These pure products will be obtained according to the methods known to those skilled in the art, in particular by chromatography in particular on chiral columns when it is a question of optical isomers.
  • the derivatives in accordance with the invention are the derivatives of formula (I) mentioned above in which: the cycle A represents:
  • ring B represents a ring with five carbon atoms
  • R 2 and / or R 4 are absent to respect the valences of the carbon atom
  • X, and X 2 independently represent:
  • halogen atom - a lower alkyl radical of 1 to 6 carbon atoms
  • R ,, R 2 , R 3 and R 4 independently represent the hydrogen atom
  • R 5 , R 6 independently represent a lower alkyl radical of 1 to 6 carbon atoms
  • R represents:
  • - ring A represents a phenyl nucleus or a pyridyl nucleus
  • ring B represents a cyclopentane or a cyclopentadiene
  • - X represents a fluorine atom, a chlorine atom, a methyl radical, a methoxy radical or a dimethylamino radical
  • - X 2 represents a hydrogen atom or a fluorine atom
  • R - R ,, R 2 , R 3 and R 4 independently represent the hydrogen atom, or R, and R 3 represent the hydrogen atom and R 2 and R 4 are absent,
  • - R represents a methyl radical or an NH 2 group.
  • the particularly preferred compounds of the invention are the derivatives:
  • the compounds of formula (I) can be synthesized as follows: By a Friedel and Craft reaction of the acid chloride of formula (II)
  • Another way of preparing the compounds of formula (I) consists in treating 4-fluorobenzonitrile with benzylmercaptan in dimethylformamide or 2-butanone for example in the presence of potassium carbonate to lead to 4-benzylthiobenzonitrile, according to the scheme:
  • benzophenones of formula (VII) may be treated with a cyclopentanone in the presence of lithium and titanium chloride or with the lithiated derivative of a cyclopentadiene according to the references already cited to lead to the compounds of formula (VIII)
  • A, X ,, X 2 , R h R, R 3 , R, B and Ph have the same meaning as above.
  • a solvent such as an alcohol or an aromatic solvent such as toluene or xylene for example.
  • the compounds of formula (I) as defined above are inhibitors of cyclooxygenase-2 and are endowed with a very good anti-inflammatory and analgesic activity associated with an excellent tolerance in particular gastric. These prop ⁇ are justifying their application in therapy and the invention also relates, as medicaments, to the products as defined by formula (I) above.
  • the invention also covers a pharmaceutical composition, caracté ⁇ see in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) as previously defined optionally incorporated in a pharmaceutically acceptable excipient, vehicle or support
  • compositions can be administered by the oral, rectal, parenteral, transdermal, ocular, nasal or au ⁇ uscular route.
  • compositions may be solid or liquid and may be in the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, capsules, granules, suppositories, injectables, transdermal systems, eye drops, aerosols and sprays and droplets. They are prepared according to the usual methods.
  • the active ingredient consisting of a pharmaceutically effective amount of at least one compound of formula (I) defined as above, can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose pulp, cocoa butter, semi-synthetic glycates, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable nature, glycols, various wetting, dispersing or emulsifying agents, cone gels, certain polymers or copolymers, preservatives, flavors and colors.
  • excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose pulp, cocoa butter, semi-synthetic glycates, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable nature, glycols, various wetting, dispersing or emuls
  • the invention also covers a pharmaceutical composition with anti-inflammatory and analgesic activity allowing in particular to favorably treat inflammatory phenomena and pain characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I ) mentioned above possibly incorporated in an excipient, vehicle or support pharmaceutically acceptable.
  • a pharmaceutical composition with anti-inflammatory and analgesic activity is prepared, making it possible in particular to favorably treat the various inflammations and pain.
  • the invention also covers a pharmaceutical composition useful in the prevention of cancer, in particular colon adenocarcinoma, the prevention of neurodegenerative diseases, particularly Alzheimer's disease, the prevention of Stroke, epilepsy, the prevention of uterine labor. premature.
  • a composition is prepared formulated in the form of capsules or tablets dosed from 1 mg to 1000 mg or in the form of injectable preparations dosed from 0.1 mg to 500 mg.
  • Formulations in the form of suppositories, ointments, creams, gels, aerosol preparations, transdermal preparations or plasters may also be used.
  • the invention also covers a method of therapeutic treatment of mammals, characterized in that a therapeutically effective amount of at least one compound of formula (I) as defined above is administered to this mammal.
  • the compound of formula (I), either alone or in combination with a pharmaceutically acceptable excipient is formulated in capsules or tablets dosed from 1 mg to 1000 mg for administration by orally, or in the form of injectable preparations dosed from 0.1 mg to 500 mg or also in the form of suppositories, ointments, creams, gels or aerosol preparations.
  • This process allows in particular to favorably treat inflammatory phenomena and pain.
  • the compounds of formula (I) can be administered alone or in combination with a physiologically acceptable excipient in any form, in particular orally in the form of capsules or tablets or parenterally in the form of an injectable solution .
  • the compounds according to the invention can be administered in human therapy in the abovementioned indications orally in the form of tablets or capsules dosed from 1 mg to 1000 mg or parenterally in the form of injections dosed from 0.1 mg to 500 mg in one or more daily doses for an adult of average weight 60 to 70 kg.
  • the daily dose usable is between 0.1 mg and 100 mg per kg.
  • A 3-pyridyl
  • B cyclopent.ane
  • R, R 2 ⁇
  • R CH 3
  • X, 6-C1
  • X 2 H
  • Example 3 Prepared according to the procedure of Example 3. starting from the derivative of Example 5. Purified by chromatography on silica gel in an isopropyl ether / acetone mixture (95/5). Melting point crystals 86-88 ° C.
  • Example 3 Prepared according to the procedure of Example 3 starting from the derivative of Example 9. Purified by chromatography on silica gel in toluene. Melting point crystals 105 ° C.
  • A phenyl
  • B cyclopentane
  • R NH 2
  • X, 3-F
  • X 2 4-CH 3
  • A phenyl
  • B cyclopentadiene
  • R CH 3
  • X, 4-F
  • X 2 H.
  • R 2 and R 4 are absent
  • A 3 -pyridyl
  • B cyclopentane
  • R CH 3
  • X, 6-N (CH 3 ) 2
  • X 2 H
  • A phenyl
  • B cyclopentadiene
  • R 2 and R 4 are absent
  • X, 4-OCH 3
  • X 2 H
  • the anti-inflammatory activity of the compounds of the examples was evaluated according to the method of edema with carragenine and the analgesic activity according to the method of arthritis with kaolin.
  • the anti-inflammatory activity is evaluated in the rat by the carragenine edema test.
  • the edema is induced by plantar subcutaneous injection of a 2% aqueous solution of carragenine.
  • the percentage inhibition of the volume of the edema is calculated at 3 hours by measuring the volume of the paw using a mercury plethysmograph.
  • Example Anti-inflammatory activity Analgesic activity
  • the studied molecule is preincubated for 10 minutes at 25 ° C with 2U of COXl (purified enzyme from seminal vesicles of ram) or 1U of COX2 (purified enzyme from sheep placenta).
  • Arachidonic acid (6 ⁇ M for COXl, 4 ⁇ M for COX2) is added to the reaction medium and an incubation of 5 minutes at 25 ° C is carried out. At the end of the incubation, the enzymatic reaction is stopped by adding HC1 IN and the PGE2 produced is assayed by E1A.
  • results are expressed as a percentage of inhibition of the COXl and COX2 enzymatic activities. and correspond to means ⁇ standard deviations from the mean of 4 determinations.
  • the first toxicology studies carried out show that the products of the examples do not induce any deleterious effect after oral abso ⁇ tion in rats of doses up to 300 mg / kg.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP97936719A 1996-08-01 1997-07-31 Carbocyclische diarylmethylen-derivate, verfahren zu ihrer herstellung und ihre verwendung für therapeutische zwecke Ceased EP0915850A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9609742A FR2751964B1 (fr) 1996-08-01 1996-08-01 Nouveaux derives diarylmethylene carbocycliques, leurs procedes de preparation, et leurs utilisations en therapeutique
FR9609742 1996-08-01
PCT/FR1997/001431 WO1998005643A1 (fr) 1996-08-01 1997-07-31 Nouveaux derives diarylmethylene carbocycliques, leurs procedes de preparation et leurs utilisations en therapeutique

Publications (1)

Publication Number Publication Date
EP0915850A1 true EP0915850A1 (de) 1999-05-19

Family

ID=9494744

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97936719A Ceased EP0915850A1 (de) 1996-08-01 1997-07-31 Carbocyclische diarylmethylen-derivate, verfahren zu ihrer herstellung und ihre verwendung für therapeutische zwecke

Country Status (7)

Country Link
US (1) US5686460A (de)
EP (1) EP0915850A1 (de)
JP (1) JP2000515161A (de)
AU (1) AU729453B2 (de)
CA (1) CA2262223A1 (de)
FR (1) FR2751964B1 (de)
WO (1) WO1998005643A1 (de)

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WO1998043966A1 (en) * 1997-04-02 1998-10-08 Merck Frosst Canada & Co. Alpha-methylene gamma lactones as selective cyclooxygenase-2 inhibitors
US20040072889A1 (en) * 1997-04-21 2004-04-15 Pharmacia Corporation Method of using a COX-2 inhibitor and an alkylating-type antineoplastic agent as a combination therapy in the treatment of neoplasia
US6649645B1 (en) * 1998-12-23 2003-11-18 Pharmacia Corporation Combination therapy of radiation and a COX-2 inhibitor for treatment of neoplasia
KR100793668B1 (ko) 1999-12-08 2008-01-10 파마시아 코포레이션 강화된 생체이용률을 지닌 고체상 형태의 셀레콕시브
JP2004503601A (ja) * 2000-07-13 2004-02-05 ファルマシア・コーポレーション 眼のｃｏｘ−２媒介疾患の処置及び予防におけるｃｏｘ−２阻害剤の使用法
US7115565B2 (en) * 2001-01-18 2006-10-03 Pharmacia & Upjohn Company Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability
WO2002062391A2 (en) * 2001-02-02 2002-08-15 Pharmacia Corporation Method of using a cyclooxygenase-2 inhibitor and sex steroids as a combination therapy for the treatment and prevention of dismenorrhea
PE20021017A1 (es) 2001-04-03 2002-11-24 Pharmacia Corp Composicion parenteral reconstituible
UA80682C2 (en) * 2001-08-06 2007-10-25 Pharmacia Corp Orally deliverable stabilized oral suspension formulation and process for the incresaing physical stability of thixotropic pharmaceutical composition
AR038957A1 (es) 2001-08-15 2005-02-02 Pharmacia Corp Terapia de combinacion para el tratamiento del cancer
EP1622630B1 (de) * 2003-05-07 2012-08-29 Osteologix A/S Strontium-kombinationsbehandlung zur prophylaxe/behandlung von knorpel- und knochenzuständen
ES2275218T3 (es) * 2003-05-07 2007-06-01 Osteologix A/S Sales de estroncio hidrosolubles para el tratamiento de afecciones de cartilagos y/o huesos.
EP1667955A2 (de) 2003-07-28 2006-06-14 SmithKline Beecham Corporation Cycloalkylidenverbindungen als modulatoren des östrogenrezeptors
EP2148666A4 (de) * 2007-05-03 2013-05-01 Univ Emory Fulven- und fulvalen-analoge sowie ihre verwendung bei der krebsbehandlung
IL305573A (en) 2021-03-15 2023-10-01 Saul Yedgar HYALURONIC ACID-CONJUGATED DIPALMITOYL PHOSPHATIDYL ETHANOLAMINE IN COMBINATION WITH NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) FOR TREATING OR ALLEVIATING INFLAMMATORY DISEASES

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EP0311899A3 (de) * 1987-10-14 1990-06-27 Air Products And Chemicals, Inc. Alpha, beta-ungesättigte Alkenyl Bis-aryldiamine zur Verwendung in der Herstellung eines quer-verbindenden Kondensations-polymers
US5344991A (en) * 1993-10-29 1994-09-06 G.D. Searle & Co. 1,2 diarylcyclopentenyl compounds for the treatment of inflammation
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WO1995030652A1 (en) * 1994-05-04 1995-11-16 G.D. Searle & Co. Substituted spirodienes for the treatment of inflammation

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Also Published As

Publication number Publication date
CA2262223A1 (en) 1998-02-12
AU3944397A (en) 1998-02-25
AU729453B2 (en) 2001-02-01
US5686460A (en) 1997-11-11
FR2751964B1 (fr) 1998-10-30
FR2751964A1 (fr) 1998-02-06
WO1998005643A1 (fr) 1998-02-12
JP2000515161A (ja) 2000-11-14

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