EP0785778A1 - Utilisation d'inhibiteurs de la cyclo-oxygenase dans le traitement de maladies neurodegeneratives - Google Patents

Utilisation d'inhibiteurs de la cyclo-oxygenase dans le traitement de maladies neurodegeneratives

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Publication number
EP0785778A1
EP0785778A1 EP95933509A EP95933509A EP0785778A1 EP 0785778 A1 EP0785778 A1 EP 0785778A1 EP 95933509 A EP95933509 A EP 95933509A EP 95933509 A EP95933509 A EP 95933509A EP 0785778 A1 EP0785778 A1 EP 0785778A1
Authority
EP
European Patent Office
Prior art keywords
cox
phenyl
treatment
agents
cyclooxygenase
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.)
Withdrawn
Application number
EP95933509A
Other languages
German (de)
English (en)
Inventor
Yves Ducharme
Jacques Yves Gauthier
Petpiboon Prasit
Yves Leblanc
Zhaoyin Wang
Serge Leger
Michel Therien
Raymond George Hill
Dalip Jaicaran Sastri Sirinathsinghji
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.)
Merck Frosst Canada and Co
Organon Pharma UK Ltd
Original Assignee
Merck Frosst Canada and Co
Merck Sharp and Dohme Ltd
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 Merck Frosst Canada and Co, Merck Sharp and Dohme Ltd filed Critical Merck Frosst Canada and Co
Publication of EP0785778A1 publication Critical patent/EP0785778A1/fr
Withdrawn legal-status Critical Current

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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a method of treating Alzheimers disease and to the use of compounds in the preparation of a medicament for the treatment of Alzheimers disease.
  • US Patent No. 5,192, 753 states inter alia that dementia in human beings may be treated with compounds selected from the non-steroidal anti-inflammatory group of cyclooxygenase inhibitors.
  • the non-steroid anti-inflammatory drugs (NSAIDs) referred to in US Patent No. 5,192,753 are all agents which possess significant ability to inhibit cyclooxygenase type 1 (COX-1).
  • NSAIDs non-steroid anti-inflammatory drugs
  • COX-1 cyclooxygenase type 1
  • COX Cyclooxygenase
  • the present invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a human in need thereof a therapeutically effective amount of a non-steroid COX-II inhibitor. From antoher aspect this invention provides the use of a COX-II inhibitor in the manufacture of a medicament for the treatment of a neurodegenerative disease and in particular Alzheimers disease.
  • treating includes treatment of existing disease and prophylactic treatment of those at risk of developing the disease.
  • COX-II inhibitor means a compound able to inhibit human COX-II enzyme without causing relatively significant inhibition of human COX-I enzyme.
  • compounds which bind at least 10 times as well to COX-I receptors as to COX-II receptors are chosen for use in the invention, more aptly 20 times as well, favourably 50 times as well most favourably at least 100 times as well, and preferably at least 1000 times as well
  • the COX-II inhibitors for use in this invention are most aptly those which are highly brain penetrant so that the maximum concentration of COX-II inhibitor after administration of the anti-neurodegenerative for example the anti-alzheimer effective dose of COX-II inhibitor is at least the binding IC50 value and preferably at least 10 times that value for example at least 100 times the binding IC50 value.
  • the COX-II inhibitor may be of any structural type other than a steroid. However, most aptly the COX-II inhibitor employed in this invention is not a carboxylic acid or a salt thereof. Most favourably it will possess a S0 2 CH 3 , NHS0 2 CH 3 , S0 2 NH 2 , S0 2 NHCH 3 or like substituent on an aromatic ring especially on a phenyl ring. * o -
  • this invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a patient therapeuticaUy effective amount of a compound generically disclosed (and preferably a compound specifically described) in US Patent No 4,375,479; 4,590,205; 4,820,827; 5,344,991; EP 0418845; WO 91/19708; WO 94/15932 or WO 94/13635.
  • the invention also provides the use of such compounds in the manufacture of a medicament for the treatment of neurodegenerative disease and in particular Alzheimers disease.
  • Favourably the COX-II inhibitor employed is one described in
  • WO/94 26751 (published November 24, 1994); WO 94/20480 (published September 15, 1994), US 5,436,265 (issued July 25, 1995), WO 95/00501 (published January 5, 1995); WO 95/18799 (published July 13, 1995) and GB 2283745 (published May 17, 1995) all of which are included herein by cross-reference (ie may be read together with this Specification).
  • COX-II inhibitor employed is one described in WO 95/00501, especially these wherein R 1 is a SO2CH3 group.
  • Preferred compounds for use in this invention are compounds named in WO 95/00501.
  • the medicaments for treating neurodegenerative disease may be formulated as described in the aforementioned referenced documents.
  • the medicament may be employed in the doses and regimens set out in the aforementioned referenced documents with respect to the treatment of diseases which benefit from the administration of a COX-II inhibitor. It is a great advantage of this invention that treatment may be carried out without causing gastric side effects of the type that can occur when COX I inhibitors are used for prolonged periods. Since neurodegenerative diseases such as Alzheimers disease are generally progressive treatment may need to take place for a number of years. Thus the provision of medicaments which are surprisingly effective without any significant tendency to cause gastric side effects at the therapeutic dose is of great use particularly to the elderly.
  • medicaments of this invention for the treatment of patients who are assymptomatic is also envisaged especially in those cases where genetic information suggests that the patient is likely to develop Alzheimers disease or other neurodegenerative disease especially those which may be termed dementia, for example senile demintia or pre-senile dementia.
  • the invention encompasses the use of a novel compound of Formula I useful in the treatment of a neurodegenerative disease such as Alzheimers Disease:
  • X-Y-Z- is selected from the group consisting of:
  • R 1 is selected from the group consisting of (a) S(0) 2 CH 3>
  • P(0)(CH 3 )OH, and (h) P(0)(CH 3 )NH 2 ⁇ R2 is selected from the group consisting of (a) Ci-6alkyl, (b) C 3) C4, C5, C ⁇ , and C7, cycloalkyl,
  • heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, 0, or N, and optionally 1, 2, or 3 additionally N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of
  • halo including fluoro, chloro, bromo and iodo
  • R3 is selected from the group consisting of (a) hydrogen,
  • R5, R5' ( R6 ( R7 anc ⁇ R8 are each independently selected from the group consisting of
  • Ci-ealkyl or R5 and R ⁇ or R 7 and R& together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;
  • Q is C02H. C0 2 -C i-4alkyl, tetrazolyl-5-yl, C(R 7 )(R 8 )(OH), or C(R 7 )(R 8 )(0-C i-4alkyl);
  • R 4 and R 4 ' are other than CF 3 .
  • X-Y-Z- is selected from the group consisting of -C(0)-0-CR 5 (R 5 )- when side b is a double bond, and sides a and c are single bonds; and R 1 is selected from the group consisting of
  • R2 is selected from the group consisting of (a) C i-ealkyl,
  • R5, R5' and R ⁇ are each independently selected from the group consisting of
  • Ci- ⁇ alkyl, or R ⁇ and R ⁇ together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms.
  • alkyl is defined to include Hnear, branched, and cyclic structures, with Ci-6alkyl including including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1, 1- dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C i-6alkoxy is intended to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration.
  • lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
  • Ci-6alkylthio is intended to include alkylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration.
  • lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc.
  • the propylthio group signifies -SCH CH 2 CH .
  • Heteroaryl includes furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, 1,2,3-oxadiazole, 1,2,3- thiadiazole, 1,2,3-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,4- triazole, 1,2,5-oxadiazole, 1,2,5-thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, and the like.
  • Benzoheteroaryl includes the above heteroaryl rings to which it is possible to fuse a benzene ring.
  • Exemplifying the invention are: (a) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2- hydroxy-2-propyl)thiophene, (b) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene, (c) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2- propyl)thiophene,
  • Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomericaUy pure forms and pharmaceutically acceptable salts thereof.
  • the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase and for treating cyclooxygenase mediated diseases as disclosed herein comprising a pharmaceuticaUy acceptable carrier and a non-toxic therapeuticaUy effective amount of compound of formula I as described above.
  • the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase-2 and for treating cyclooxygenase-2 mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeuticaUy effective amount of compound of formula I as described above.
  • the invention encompasses a method of inhibiting cyclooxygenase and treating cyclooxygenase mediated diseases, advantageously treated by an active agent that selectively inhibits COX-2 in preference to COX- 1 as disclosed herein comprising: administration to a patient in need of such treatment of a non-toxic therapeuticaUy effective amount of a compound of Formula I as disclosed herein.
  • a preferred compound is said to selectively inhibit COX-2 in preference to COX- 1 if the ratio of the IC50 concentration for COX-1 inhibition to COX-2 inhibition is 100 or greater.
  • compositions used in the present invention comprise a compound of Formula I as an active ingredient or a pharmaceuticaUy acceptable salt, thereof, and may also contain a pharmaceuticaUy acceptable carrier and optionaUy other therapeutic ingredients.
  • pharmaceuticalaUy acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, Hthium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the Uke. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceuticaUy acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturaUy occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, chohne, N,N_-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorphoHne, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • references to the compounds of Formula I are meant to also include the pharmaceuticaUy acceptable salts.
  • compounds of formula I may be administered orally, topicaUy, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceuticaUy acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • 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.
  • Compositions intended for oral use 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 pharmaceuticaUy elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceuticaUy 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.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4, 166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert sohd dUuent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or an oU medium, for example peanut oil, liquid paraffin, or oUve oU.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethyl-ceUulose, methylceUulose, hydroxy-propylmethyceUulose, sodium alginate, polyvinyl-pyrroUdone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally-occ
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n- propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • OUy suspensions may be formulated by suspending the active ingredient in a vegetable oU, for example arachis oU, oUve oU, sesame ofl or coconut oU, or in mineral oU such as liquid paraffin.
  • the oUy suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oU, for example olive oil or arachis oil, or a mineral oU, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterUe injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenteraUy-accep table diluent or solvent, for example as a solution in 1,3-butane diol.
  • oUs oleic acid
  • oleic acid find use in the preparation of injectables.
  • Compounds of formula I may also be administered in the form of a suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but Uquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non- irritating excipient which is solid at ordinary temperatures but Uquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • topical use creams, ointments, jelfies, solutions or suspensions, etc., containing the compound of Formula I are employed.
  • topical apphcation shaU include mouth washes and gargles.
  • Dosage levels of the order of from about 0.01 mg to about 140 mg kg of body weight per day are useful in the treatment of the above- indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day.
  • inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per l ⁇ logram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form wiU vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active 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 wiU generaUy contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

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  • Pharmacology & Pharmacy (AREA)
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  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
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  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de traitement de troubles neurodégénératifs tels que la maladie d'Alzheimer, dans lequel on utilise un inhibiteur de COX-2.
EP95933509A 1994-10-12 1995-10-09 Utilisation d'inhibiteurs de la cyclo-oxygenase dans le traitement de maladies neurodegeneratives Withdrawn EP0785778A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9420616 1994-10-12
GB9420616A GB9420616D0 (en) 1994-10-12 1994-10-12 Method, compositions and use
PCT/GB1995/002382 WO1996011676A1 (fr) 1994-10-12 1995-10-09 Utilisation d'inhibiteurs de la cyclo-oxygenase dans le traitement de maladies neurodegeneratives

Publications (1)

Publication Number Publication Date
EP0785778A1 true EP0785778A1 (fr) 1997-07-30

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EP95933509A Withdrawn EP0785778A1 (fr) 1994-10-12 1995-10-09 Utilisation d'inhibiteurs de la cyclo-oxygenase dans le traitement de maladies neurodegeneratives

Country Status (6)

Country Link
EP (1) EP0785778A1 (fr)
JP (1) JPH10507445A (fr)
GB (1) GB9420616D0 (fr)
IL (1) IL115505A (fr)
WO (1) WO1996011676A1 (fr)
ZA (1) ZA958558B (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5840746A (en) * 1993-06-24 1998-11-24 Merck Frosst Canada, Inc. Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases
US6515014B2 (en) 1995-06-02 2003-02-04 G. D. Searle & Co. Thiophene substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6184248B1 (en) * 1996-09-05 2001-02-06 Robert K. K. Lee Compositions and methods for treatment of neurological disorders and neurodegenerative diseases
US5985930A (en) 1996-11-21 1999-11-16 Pasinetti; Giulio M. Treatment of neurodegenerative conditions with nimesulide
EP1138324A1 (fr) * 1996-11-21 2001-10-04 The Mount Sinai School of Medicine of New York University Traitement de pathologies neurodégénératives par du nimesulide
BR9807920A (pt) * 1997-04-03 2000-02-22 Searle & Co Processos para tratamento de uma demência em um sujeito e para prevenção de uma demência
BR0309014A (pt) 2002-04-08 2005-01-11 Glaxo Group Ltd ácido(2-((2-alcóxi)-fenil)-ciclopent-1-enil)carbo e heterocìclico aromático e derivados
GB0225548D0 (en) 2002-11-01 2002-12-11 Glaxo Group Ltd Compounds

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3103372A1 (de) * 1981-01-27 1982-09-02 Schering Ag, 1000 Berlin Und 4619 Bergkamen Neue indanyl-derivate, ihre herstellung und verwendung
ATE17480T1 (de) * 1982-03-03 1986-02-15 Du Pont Entzuendungshemmende und/oder schmerzstillende 2,3-diaryl-5-halo thiophene.
PH27357A (en) * 1989-09-22 1993-06-21 Fujisawa Pharmaceutical Co Pyrazole derivatives and pharmaceutical compositions comprising the same
GB9012936D0 (en) * 1990-06-11 1990-08-01 Fujisawa Pharmaceutical Co Thiophene derivatives,processes for preparation thereof and pharmaceutical composition comprising the same
DE4219154C2 (de) * 1992-06-11 1995-04-20 Ford Werke Ag Rollen- oder Klemmkörper-Freilauf mit seitlicher zusätzlicher Wälzlagerung
US5604260A (en) * 1992-12-11 1997-02-18 Merck Frosst Canada Inc. 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2
ATE160345T1 (de) * 1993-01-15 1997-12-15 Searle & Co 3,4-diarylthiophene und analoga davon, sowie deren verwendung als entzündungshemmende mittel
US5409944A (en) * 1993-03-12 1995-04-25 Merck Frosst Canada, Inc. Alkanesulfonamido-1-indanone derivatives as inhibitors of cyclooxygenase
WO1994026731A1 (fr) * 1993-05-13 1994-11-24 Merck Frosst Canada Inc. Inhibiteurs de la cyclogenase
TW416958B (en) * 1993-05-14 2001-01-01 Pfizer Enantioselective oxazaborolidine catalysts
US5474995A (en) * 1993-06-24 1995-12-12 Merck Frosst Canada, Inc. Phenyl heterocycles as cox-2 inhibitors
US5436265A (en) * 1993-11-12 1995-07-25 Merck Frosst Canada, Inc. 1-aroyl-3-indolyl alkanoic acids and derivatives thereof useful as anti-inflammatory agents
US5344991A (en) * 1993-10-29 1994-09-06 G.D. Searle & Co. 1,2 diarylcyclopentenyl compounds for the treatment of inflammation
SG43841A1 (en) * 1994-01-10 1997-11-14 Merck Frosst Canada Inc Phenyl heterocycles as cox-2 inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9611676A1 *

Also Published As

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ZA958558B (en) 1997-04-04
IL115505A0 (en) 1996-01-19
IL115505A (en) 1999-12-31
GB9420616D0 (en) 1994-11-30
WO1996011676A1 (fr) 1996-04-25
JPH10507445A (ja) 1998-07-21

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