FR2771005A1 - Synergistic compositions containing a cyclooxygenase-2 inhibitor and a N-methyl-d-aspartate antagonist, used in the treatment of inflammation and pain - Google Patents
Synergistic compositions containing a cyclooxygenase-2 inhibitor and a N-methyl-d-aspartate antagonist, used in the treatment of inflammation and pain Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- 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
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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Abstract
Description
La présente invention a pour objet une nouvelle association pharmaceutique trouvant notamment application dans le traitement de la douleur et des phénomènes inflammatoires. The subject of the present invention is a new pharmaceutical association which finds particular application in the treatment of pain and inflammatory phenomena.
Plus précisément, l'invention concerne une composition pharmaceutique comprenant, à titre de principe actif, une association d'un inhibiteur de cyclooxygénase-2 et d'un composé antagoniste NMDA. More specifically, the invention relates to a pharmaceutical composition comprising, as active ingredient, a combination of a cyclooxygenase-2 inhibitor and an NMDA antagonist compound.
Les inhibiteurs sélectifs de la cyclooxygénase-2 (COX-2) constituent une nouvelle classe d'agents antalgiques et anti-inflammatoires non stéroidiens. Selective inhibitors of cyclooxygenase-2 (COX-2) are a new class of non-steroidal analgesic and anti-inflammatory agents.
De tels composés ont par exemple été décrits dans les documents WO 94/15932, WO 96/03388 par la société GD Searle, WO 95/00501 par la société
Merck & Frosst Canada Inc., WO 95/18799, WO 96/08482 par la société Merck &
Co. ou encore FR 2747123, FR 2747124 par la société demanderesse.Such compounds have for example been described in documents WO 94/15932, WO 96/03388 by the company GD Searle, WO 95/00501 by the company
Merck & Frosst Canada Inc., WO 95/18799, WO 96/08482 by the company Merck &
Co. or FR 2747123, FR 2747124 by the applicant company.
Parmi les composés particulièrement préférés qui ont été décrits dans l'état de la technique, on peut citer notamment
- le 5-bromo-2-[4-fluorophényl]-3[4-méthanesulfonylphényl]- thiophène connu sous le nom de code DuP 697;
- le 4-[5-(4-méthylphényl)-3-(trifluorométhyl)pyrazol-1-yl]- benzènesulfonamide connu sous la dénomination Celecoxib;
- la (Z)-3-[1-(4-chlorophényl)-1-(4-méthanesulfonylphényl)méthylène]- dihydrofuran-2-one connu sous le nom de code UP 454-21.Among the particularly preferred compounds which have been described in the state of the art, mention may be made in particular of
- 5-bromo-2- [4-fluorophenyl] -3 [4-methanesulfonylphenyl] - thiophene known under the code name DuP 697;
- 4- [5- (4-methylphenyl) -3- (trifluoromethyl) pyrazol-1-yl] - benzenesulfonamide known under the name Celecoxib;
- (Z) -3- [1- (4-chlorophenyl) -1- (4-methanesulfonylphenyl) methylene] - dihydrofuran-2-one known under the code name UP 454-21.
D'une façon générale, ces composés présentent des propriétés antiinflammatoires et analgésiques, ces dernières mises en évidence dans différents modèles expérimentaux de douleurs inflammatoires. In general, these compounds have anti-inflammatory and analgesic properties, the latter highlighted in various experimental models of inflammatory pain.
Cependant, on sait que les inhibiteurs sélectifs de la cyclooxygénase-2 sont inactifs ou très peu actifs dans les tests de douleurs aiguës non inflammatoires. However, it is known that selective inhibitors of cyclooxygenase-2 are inactive or very little active in acute non-inflammatory pain tests.
Ainsi, Gans et al. J. Pharm. Exp. Ther. 1990 ; (254): 180-187 ont montré que le produit DuP 697 précité est inactif dans le test à la phénylbenzoquinone chez la souns.Thus, Gans et al. J. Pharm. Exp. Ther. 1990 ; (254): 180-187 have shown that the abovementioned product DuP 697 is inactive in the phenylbenzoquinone test in souns.
Par ailleurs, on sait que l'activation des récepteurs N-méthyl d aspartate (NMDA) par les acides aminés neuroexcitateurs (asparte, glutamate) est impliquée dans certains processus douloureux ; des antagonistes NMDA possèdent une activité antalgique mise en évidence sur de nombreux tests, y compris des tests de douleur chronique. Furthermore, it is known that the activation of the N-methyl aspartate receptors (NMDA) by the neuroexcitatory amino acids (aspart, glutamate) is involved in certain painful processes; NMDA antagonists have analgesic activity demonstrated on numerous tests, including chronic pain tests.
Il a été découvert, et ceci constitue le fondement de la présente invention, que l'association d'un inhibiteur de la cyclooxygénase-2 et d'un composé antagoniste NMDA présente un effet analgésique significatif, à des doses où chacun des produits constitutifs de cette association est inactif ou très peu actif. It has been discovered, and this forms the basis of the present invention, that the combination of a cyclooxygenase-2 inhibitor and an NMDA antagonist compound exhibits a significant analgesic effect, at doses where each of the constituent products of this association is inactive or very little active.
L'effet bénéfique de l'association conforme à la présente invention a été démontré aussi bien pour les modèles de douleur inflammatoire que pour les modèles de douleur aiguë non inflammatoire. The beneficial effect of the combination in accordance with the present invention has been demonstrated for both inflammatory pain models and for acute non-inflammatory pain models.
Les résultats obtenus ont montré que cette association présente une activité analgésique supérieure à celle de chacun de ces produits constitutifs utilisés seuls à la même dose. The results obtained have shown that this association has a greater analgesic activity than that of each of these constituent products used alone at the same dose.
L'effet de potentialisation ainsi démontré rend possible l'utilisation de faibles doses de chacun des produits constitutifs de l'association, en limitant ainsi leurs possibles effets secondaires. The potentiating effect thus demonstrated makes it possible to use low doses of each of the constituent products of the association, thereby limiting their possible side effects.
De plus cette association permet le traitementàedouTeurs drorigines très variées chez un plus grand nombre de patients. In addition, this association allows the treatment of a variety of origins in a larger number of patients.
Avantageusement, l'association pharmaceutique conforme à la présente invention se présentera sous une forme appropriée pour une administration:
- par voie orale, comme par exemple, sous forme de comprimés simples ou dragéifiés, de gélules ou de granulés;
- par voie rectale, comme par exemple, sous forme de suppositoires;
- par voie parentérale, comme par exemple, sous forme de préparations injectables;
- par voie oculaire, comme par exemple, sous la forme de collyres ou de solutions ophtalmiques;
- par voie transdermique;
- par voie nasale, comme par exemple sous forme d'aérosols et sprays;
- par voie auriculaire, comme par exemple sous forme de gouttes.Advantageously, the pharmaceutical combination in accordance with the present invention will be in a form suitable for administration:
- orally, as for example, in the form of simple or coated tablets, capsules or granules;
- rectally, as for example, in the form of suppositories;
- parenterally, for example, in the form of injections;
- by eye, as for example, in the form of eye drops or ophthalmic solutions;
- transdermally;
- nasally, such as in the form of aerosols and sprays;
- by ear, as for example in the form of drops.
Une telle composition peut être préparée, selon des méthodes connues en soi, en incorporant le principe actif, constitué par l'association précitée, à des excipients habituellement utilisés tels que le talc, la gomme arabique, le lactose, l'amidon, le stéarate de magnésium, la polyvidone, les dérivés de la cellulose, le beurre de cacao, les glycérides semi-synthétiques, les véhicules aqueux ou non, les corps gras d'origine animale ou végétale, les glycols, les agents mouillants, dispersants ou émulsifiants, les gels de silicone, certains polymères ou copolymères, les conservateurs, arômes et colorants. Such a composition can be prepared, according to methods known per se, by incorporating the active principle, constituted by the abovementioned combination, into excipients usually used such as talc, gum arabic, lactose, starch, stearate magnesium, polyvidone, cellulose derivatives, cocoa butter, semi-synthetic glycerides, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, glycols, wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavors and colors.
D'une façon générale, tout composé présentant une activité inhibitrice de la cyclooxygénase-2 peut être utilisé dans le cadre de la présente invention. De préférence, on utilisera des dérivés de diaryl méthylidène tétrahydrofurane tels que ceux décrits dans les demandes FR 2747123 et FR 2747124 de la société demanderesse incorporées ici par référence. In general, any compound exhibiting cyclooxygenase-2 inhibiting activity can be used in the context of the present invention. Preferably, diaryl methylidene tetrahydrofuran derivatives such as those described in applications FR 2747123 and FR 2747124 of the applicant company incorporated herein by reference will be used.
Un composé particulièrement préféré est la (Z)-3-[1-(4-chlorophényl)-1 (4-méthanesulfonylphényl)méthylène] -dihydrofuran-2-one connu sous le nom de code UP 454-21. A particularly preferred compound is (Z) -3- [1- (4-chlorophenyl) -1 (4-methanesulfonylphenyl) methylene] -dihydrofuran-2-one known under the code name UP 454-21.
Parmi les composés antagonistes NMDA susceptibles d'être utilisés dans le cadre de la présente invention, on citera en particulier le dextrométhorphane, la kétamine, la dizocilpine ou encore la phencyclidine. Among the NMDA antagonist compounds capable of being used in the context of the present invention, mention will be made in particular of dextromethorphan, ketamine, dizocilpine or even phencyclidine.
On préférera tout particulièrement le dextrométhorphane, composé peu toxique et connu de longue date. ~ ~~~
Avantageusement, les compositions pharmaceutiques selon l'invention se présenteront sous forme de dose unitaire.Particular preference will be given to dextromethorphan, a compound which is not very toxic and has been known for a long time. ~ ~~~
Advantageously, the pharmaceutical compositions according to the invention will be in the form of a unit dose.
Dans l'association pharmaceutique conforme à la présente invention, le rapport pondéral du composé inhibiteur de la cyclooxygénase-2 au composé antagoniste NMDA sera celui présentant la meilleure synergie entre les deux composés associés ; il sera compris pour la majorité des exemples entre 0,01 et 10 et sera de préférence de 0,1 à 3,5. In the pharmaceutical combination in accordance with the present invention, the weight ratio of the cyclooxygenase-2 inhibitor compound to the NMDA antagonist compound will be that exhibiting the best synergy between the two associated compounds; for the majority of examples, it will be between 0.01 and 10 and will preferably be from 0.1 to 3.5.
La dose journalière utilisable des différents composés constituant l'association pharmaceutique conforme à l'invention dépendra bien entendu, de l'état du patient à traiter. The daily usable dose of the various compounds constituting the pharmaceutical association in accordance with the invention will of course depend on the condition of the patient to be treated.
Une dose journalière appropriée d'inhibiteur de cyclooxygénase-2 sera généralement comprise entre environ 50 mg et environ 500 mg. An appropriate daily dose of cyclooxygenase-2 inhibitor will generally be between about 50 mg and about 500 mg.
Les compositions pharmaceutiques conformes à la présente invention conviennent au traitement des phénomènes inflammatoires ainsi qu'au traitement de la douleur. The pharmaceutical compositions in accordance with the present invention are suitable for the treatment of inflammatory phenomena as well as for the treatment of pain.
On peut citer par exemple leur utilisation dans le traitement de l'arthrite, notamment l'arthrite rhumatoïde, la spondylarthrite, l'arthrite de la goutte, l'ostéoartlrrite, l'arthrite juvénile, les maladies auto immunes, le lupus érythémateux. Mention may be made, for example, of their use in the treatment of arthritis, in particular rheumatoid arthritis, spondylarthritis, gout arthritis, osteoartlrritis, juvenile arthritis, autoimmune diseases, lupus erythematosus.
Ces compositions peuvent également être utilisées dans le cadre du traitement de l'asthme bronchique, des dysménorrhées, des tendinites, des bursites, des inflammations dermatologiques telles que le psoriasis, l'eczéma, les brûlures, les dermatites. These compositions can also be used in the context of the treatment of bronchial asthma, dysmenorrhea, tendinitis, bursitis, dermatological inflammations such as psoriasis, eczema, burns, dermatitis.
Ces compositions peuvent également être utilisées dans le cadre du traitement des inflammations gastro-intestinales, de la maladie de Crohn, des gastrites, des colites ulcératives, la prévention du cancer, notamment l'adénocarcinome du colon, la prévention des maladies neurodégénératives, particulièrement la maladie d'Alzheimer, la prévention du l'ischémie cérébrale, l'épilepsie et la prévention du travail utérin prématuré. These compositions can also be used in the context of the treatment of gastrointestinal inflammations, Crohn's disease, gastritis, ulcerative colitis, the prevention of cancer, in particular colon adenocarcinoma, the prevention of neurodegenerative diseases, particularly Alzheimer's disease, prevention of cerebral ischemia, epilepsy and prevention of premature uterine labor.
Ces compositions peuvent enfin être utilisées dans le cadre du traitement des symptômes douloureux et en particulier des algies musculaires, articulaires ou nerveuses, des douleurs dentaires, des zonas, des migraines, des affections rhumatismales, des douleurs d'origine cancéreuses, ainsi qu'à titre de traitement complémentaire dans les états infectieux et fébriles. These compositions can finally be used in the context of the treatment of painful symptoms and in particular muscle, joint or nervous pain, dental pain, zonas, migraines, rheumatic affections, pain of cancerous origin, as well as title of complementary treatment in infectious and febrile states.
L'invention couvre encore un procédé de traitement thérapeutique des mammifères, caractérisée en ce qu'il consiste à administrer à ce mammifère une quantité thérapeutiquement efficace d'une association d'un inhibiteur de cyclooxygénase-2 et d'un composé antagoniste NMDA telle que définie précédemment. The invention also covers a method for the therapeutic treatment of mammals, characterized in that it consists in administering to this mammal a therapeutically effective amount of a combination of a cyclooxygenase-2 inhibitor and an NMDA antagonist compound such as previously defined.
Ce procédé permet notamment de traiter les phénomènes inflammatoires et la douleur. This process makes it possible in particular to treat inflammatory phenomena and pain.
Mise en évidence des propriétés analgésiques de l'association pharmaceutique conforme à l'invention
Pour mettre en évidence les propriétés analgésiques spécifiques de l'association pharmaceutique conforme à la présente invention, on a réalisé plusieurs essais pharmacologiques dont les protocoles expérimentaux et les résultats obtenus seront donnés ci-après.Demonstration of the Analgesic Properties of the Pharmaceutical Association According to the Invention
To demonstrate the specific analgesic properties of the pharmaceutical combination in accordance with the present invention, several pharmacological tests were carried out, the experimental protocols and the results of which will be given below.
Dans ces essais, le composé utilisé comme exemple d'inhibiteur sélectif de la cyclooxygénase-2 est le composé connu sous le nom de code UP 454-21 répondant à la formule générale suivante:
tandis que le composé utilisé comme antagoniste NMDA est le dextrométhorphane.In these tests, the compound used as an example of a selective inhibitor of cyclooxygenase-2 is the compound known under the code name UP 454-21 corresponding to the following general formula:
while the compound used as an NMDA antagonist is dextromethorphan.
Les résultats obtenus pour ces essais ont été exprimés en pourcentage d'inhibition de la réaction douloureuse par rapport à un groupe témoin. The results obtained for these tests were expressed as a percentage of inhibition of the painful reaction compared to a control group.
Essai n" 1: test de l'arthrite au kaolin chez le rat
Une inflammation est induite par l'administration d'une suspension aqueuse de kaolin à 10 % dans l'articulation tibio-fémorale du rat.Trial # 1: Kaolin arthritis test in rats
Inflammation is induced by the administration of an aqueous suspension of 10% kaolin in the tibio-femoral joint of the rat.
Les composés et l'association étudiée sont administrés par voie orale 30 minutes après l'injection de kaolin. The compounds and the combination studied are administered orally 30 minutes after the injection of kaolin.
Le comportement douloureux spontané (gêne à la démarche) est alors coté 5 et 6 heures après l'injection de kaolin. Spontaneous painful behavior (discomfort with gait) is then rated 5 and 6 hours after the injection of kaolin.
Les résultats obtenus ont été représentés à la figure 1 qui montre l'effet de potentialisation exercé par le dextrométhorphane sur le composé inhibiteur de la cyclooxygénase-2 (UP 454-21). The results obtained have been represented in FIG. 1 which shows the potentiating effect exerted by dextromethorphan on the compound inhibiting cyclooxygenase-2 (UP 454-21).
Essai n" 2: test de pression de la patte dans le modèle d'hyperalgésie à la carragénine
L'inflammation est induite chez le rat par administration plantaire d'une suspension de carragénine à 2 %.Test No. 2: leg pressure test in the carrageenan hyperalgesia model
Inflammation is induced in rats by plantar administration of a suspension of 2% carrageenan.
3 heures après cette injection, une pression croissante est exercée sur la patte de l'animal. 3 hours after this injection, increasing pressure is exerted on the paw of the animal.
Le seuil douloureux, exprimé en grammes, est alors noté. The pain threshold, expressed in grams, is then noted.
Les composés et l'association étudiée sont administrés par voie orale une heure avant le test de pression de la patte. The compounds and the combination studied are administered orally one hour before the paw pressure test.
Les résultats obtenus ont été représentés à la figure 2 qui montre l'effet de potentialisation exercé par le dextrométhorphane sur le composé inhibiteur de cyclooxygénase-2 (UP 454-21). The results obtained are represented in FIG. 2 which shows the potentiating effect exerted by dextromethorphan on the inhibitor compound of cyclooxygenase-2 (UP 454-21).
On donnera maintenant plusieurs exemples de compositions pharmaceutiques selon l'invention:
EXEMPLES D'ASSOCIATIONS UP 454-21/DEXTROMÉTHORPHANE
Exemple 1: Gélule (taille n 1)
UP 454-21... 50 mg
Dextrométhorphane... . . ... ...20 mg
Cellulose microcristalline... . . .....100 mg
Hydroxypropylméthylcellulose ..... 10 mg Stéarate de magnésium . ... 5 mg pour une gélule
Exemple 2: Comprimé
UP 454-21... . ....50 mg
Dextrométhorphane . . .. ...20 mg
Cellulose microcristalline ..... 100 mg
Lactose.... . . ....100 mg
Hydroxypropylméthylcellulose ..... 10 mg
Stéarate de magnésium . ... ...5 mg
Hydroxypropylcellulose ...... 50 mg pour un comprimé
Exemple 3: Suppositoire
UP 454-21... . . .....100 mg Dextrométhorphane .. ... ... 40 mg
Glycéride semi-synthétique (suppocire)..1.900 mg pour un suppositoire
Exemple 4: Solution ophtalmique
UP 454-21... . . 0,1 %
Dextrométhorphane... ... ......0,06 %
Huile de ricin (Cremophor EL)...... .....5 %
Polysorbate 80......................................1 %
Eau ppi..................................... q.s.p. 100 %
ExempleS : Préparation injectable UP 454-21 ........................................... 0,1 %
Dextrométhorphane 0,06 %
PEG 400........................30 %
Alcool éthylique .. ........ ...10 %
Eau ppi........ . . ......q.s.p. 100 % Several examples of pharmaceutical compositions according to the invention will now be given:
EXAMPLES OF UP 454-21 / DEXTROMETHORPHANE ASSOCIATIONS
Example 1: Capsule (size n 1)
UP 454-21 ... 50 mg
Dextromethorphan .... . ... ... 20 mg
Microcrystalline cellulose .... . ..... 100 mg
Hydroxypropylmethylcellulose ..... 10 mg Magnesium stearate. ... 5 mg for one capsule
Example 2: Tablet
UP 454-21 .... .... 50 mg
Dextromethorphan. . .. ... 20 mg
Microcrystalline cellulose ..... 100 mg
Lactose ..... . .... 100 mg
Hydroxypropylmethylcellulose ..... 10 mg
Magnesium stearate. ... ... 5 mg
Hydroxypropylcellulose ...... 50 mg for one tablet
Example 3: Suppository
UP 454-21 .... . ..... 100 mg Dextromethorphan .. ... ... 40 mg
Semi-synthetic glyceride (suppocire) .. 1,900 mg for a suppository
Example 4: Ophthalmic solution
UP 454-21 .... . 0.1%
Dextromethorphan ... ... ...... 0.06%
Castor oil (Cremophor EL) ...... ..... 5%
Polysorbate 80 ...................................... 1%
Water ppi ..................................... qs 100%
EXAMPLES: UP 454-21 injectable preparation .......................................... 0.1%
Dextromethorphan 0.06%
PEG 400 ........................ 30%
Ethyl alcohol .. ........ ... 10%
Water ppi ......... . ...... qs 100%
Claims (6)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9714428A FR2771005B1 (en) | 1997-11-18 | 1997-11-18 | NEW PHARMACEUTICAL ASSOCIATION WITH ANALGESIC ACTIVITY |
| AU16716/99A AU1671699A (en) | 1997-11-18 | 1998-11-17 | Pharmaceutical combination of a cyclooxygenase-2 inhibitor |
| PCT/EP1998/007537 WO1999025382A1 (en) | 1997-11-18 | 1998-11-17 | Pharmaceutical combination of a cyclooxygenase-2 inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9714428A FR2771005B1 (en) | 1997-11-18 | 1997-11-18 | NEW PHARMACEUTICAL ASSOCIATION WITH ANALGESIC ACTIVITY |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2771005A1 true FR2771005A1 (en) | 1999-05-21 |
| FR2771005B1 FR2771005B1 (en) | 2002-06-07 |
Family
ID=9513481
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR9714428A Expired - Lifetime FR2771005B1 (en) | 1997-11-18 | 1997-11-18 | NEW PHARMACEUTICAL ASSOCIATION WITH ANALGESIC ACTIVITY |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU1671699A (en) |
| FR (1) | FR2771005B1 (en) |
| WO (1) | WO1999025382A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004039371A2 (en) * | 2002-10-29 | 2004-05-13 | Pharmacia Corporation | Compositions of cyclooxygenase-2 selective inhibitors and nmda receptor antagonists for the treatment or prevention of neuropathic pain |
| 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 |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6180651B1 (en) * | 1996-04-04 | 2001-01-30 | Bristol-Myers Squibb | Diarylmethylidenefuran derivatives, processes for their preparation and their uses in therapeutics |
| JP2002538078A (en) * | 1998-11-12 | 2002-11-12 | アルゴス ファーマシューティカル コーポレーション | COX-2 inhibitor combined with NMDA-blocker to treat pain |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996013483A1 (en) * | 1994-10-27 | 1996-05-09 | Merck Frosst Canada Inc. | Stilbene derivatives useful as cyclooxygenase-2 inhibitors |
| US5521213A (en) * | 1994-08-29 | 1996-05-28 | Merck Frosst Canada, Inc. | Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2 |
| WO1996019469A1 (en) * | 1994-12-21 | 1996-06-27 | Merck Frosst Canada Inc. | Diaryl-2-(5h)-furanones as cox-2 inhibitors |
| US5552422A (en) * | 1995-01-11 | 1996-09-03 | Merck Frosst Canada, Inc. | Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents |
| WO1996031509A1 (en) * | 1995-04-04 | 1996-10-10 | Glaxo Group Limited | IMIDAZO[1,2-a]PYRIDINE DERIVATIVES |
| WO1996036623A1 (en) * | 1995-05-18 | 1996-11-21 | Merck Frosst Canada Inc. | Diaryl-5-oxygenated-2-(5h)-furanones as cox-2 inhibitors |
| WO1997014691A1 (en) * | 1995-10-13 | 1997-04-24 | Merck Frosst Canada Inc. | (methylsulfonyl)phenyl-2-(5h)-furanones as cox-2 inhibitors |
| US5639780A (en) * | 1995-05-22 | 1997-06-17 | Merck Frosst Canada, Inc. | N-benzyl indol-3-yl butanoic acid derivatives as cyclooxygenase inhibitors |
| US5677318A (en) * | 1996-07-11 | 1997-10-14 | Merck Frosst Canada, Inc. | Diphenyl-1,2-3-thiadiazoles as anti-inflammatory agents |
-
1997
- 1997-11-18 FR FR9714428A patent/FR2771005B1/en not_active Expired - Lifetime
-
1998
- 1998-11-17 AU AU16716/99A patent/AU1671699A/en not_active Abandoned
- 1998-11-17 WO PCT/EP1998/007537 patent/WO1999025382A1/en active Application Filing
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5521213A (en) * | 1994-08-29 | 1996-05-28 | Merck Frosst Canada, Inc. | Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2 |
| WO1996013483A1 (en) * | 1994-10-27 | 1996-05-09 | Merck Frosst Canada Inc. | Stilbene derivatives useful as cyclooxygenase-2 inhibitors |
| WO1996019469A1 (en) * | 1994-12-21 | 1996-06-27 | Merck Frosst Canada Inc. | Diaryl-2-(5h)-furanones as cox-2 inhibitors |
| US5552422A (en) * | 1995-01-11 | 1996-09-03 | Merck Frosst Canada, Inc. | Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents |
| WO1996031509A1 (en) * | 1995-04-04 | 1996-10-10 | Glaxo Group Limited | IMIDAZO[1,2-a]PYRIDINE DERIVATIVES |
| WO1996036623A1 (en) * | 1995-05-18 | 1996-11-21 | Merck Frosst Canada Inc. | Diaryl-5-oxygenated-2-(5h)-furanones as cox-2 inhibitors |
| US5639780A (en) * | 1995-05-22 | 1997-06-17 | Merck Frosst Canada, Inc. | N-benzyl indol-3-yl butanoic acid derivatives as cyclooxygenase inhibitors |
| WO1997014691A1 (en) * | 1995-10-13 | 1997-04-24 | Merck Frosst Canada Inc. | (methylsulfonyl)phenyl-2-(5h)-furanones as cox-2 inhibitors |
| US5677318A (en) * | 1996-07-11 | 1997-10-14 | Merck Frosst Canada, Inc. | Diphenyl-1,2-3-thiadiazoles as anti-inflammatory agents |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2004039371A2 (en) * | 2002-10-29 | 2004-05-13 | Pharmacia Corporation | Compositions of cyclooxygenase-2 selective inhibitors and nmda receptor antagonists for the treatment or prevention of neuropathic pain |
| WO2004039371A3 (en) * | 2002-10-29 | 2004-06-17 | Pharmacia Corp | Compositions of cyclooxygenase-2 selective inhibitors and nmda receptor antagonists for the treatment or prevention of neuropathic pain |
Also Published As
| Publication number | Publication date |
|---|---|
| AU1671699A (en) | 1999-06-07 |
| WO1999025382A1 (en) | 1999-05-27 |
| FR2771005B1 (en) | 2002-06-07 |
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