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(12) Patent Application Publication (10) Pub. No.: US 2004/0132780 A1 Allen Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2004/0132780 A1 Allen Et Al US 2004O132780A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0132780 A1 Allen et al. (43) Pub. Date: Jul. 8, 2004 (54) METHOD AND COMPOSITIONS FOR (52) U.S. Cl. .............................................................. 514/334 TREATING MIGRAINES (76) Inventors: Christopher P. Allen, Doylestown, PA (57) ABSTRACT (US); Phyllis W. Stone, Somerset, NJ (US); Sean Harper, Gwynedd Valley, The present invention relates to a method for treating or PA (US) preventing migraines in a mammalian patient in need of Such treatment or prevention comprising administering to Correspondence Address: Said patient a compound of Formula A or a pharmaceutically MERCKAND COINC Salt, hydrate or N-oxide thereof, in an amount that is PO BOX 2000 effective to treat or prevent migraines. RAHWAY, NJ 070650907 (21) Appl. No.: 10/476,753 (A) SOCH (22) PCT Filed: Apr. 30, 2002 (86) PCT No.: PCT/US02/13750 C N (30) Foreign Application Priority Data 4. N May 4, 2001 (US).......................................... 60/288623 2 Publication Classification (51) Int. Cl." ............................................ A61K 31/444 US 2004/O132780 A1 Jul. 8, 2004 METHOD AND COMPOSITIONS FOR TREATING DETAILED DESCRIPTION MIGRAINES 0007. The present invention encompasses a method for BACKGROUND OF THE INVENTION treating or preventing migraines in a mammalian patient in need of Such treatment or prevention comprising adminis 0001 Migraines are recurrent, often familial, symptom tering to Said patient a compound of Formula A: complexes of periodic attacks of vascular headache. The condition is characterized by intermittent attacks of head ache, preceded by an aura in approximately 15% of patients. The headache is often accompanied by associated Symp SOCH3 toms, most commonly nausea, vomiting, photophobia and phonophobia. Migraines affect approximately 17% of adult C women and 6% of adult men (Stewart et al., Neurology, 1994, 44 (suppl. 4), 517-523). 0002 Cyclooxygenase (COX), also known as prostag N landin H Synthase, is an enzyme implicated in the mediation 2 of pain, fever and inflammation. It catalyzes the oxidative conversion of arachidonic acid into prostaglandin H, a key intermediate in the biosynthetic pathway of prostaglandins, prostacyclins and thromboxanes, which in turn mediate a 0008 in an amount that is effective to treat or prevent variety of physiological effects both beneficial and patho migraines. logical. 0009. The compound of Formula A, which has the 0003) Recently it was discovered that two COX isoforms exist: COX-1, expressed constitutively in many tissues, and generic name etoricoxib, is a Selective inhibitor of cyclooxy COX-2, an induced isoform having elevated levels of genase-2. Etoricoxib is disclosed as Example 23 in U.S. Pat. expression in inflamed tissues. COX-1 is thought to be No. 5,861,419, issued on Jan. 19, 1999, which is hereby involved in ongoing “housekeeping functions, for example, incorporated by reference in its entirety. gastric cytoprotection, while COX-2 is implicated in the 0010. In an embodiment of the invention the compound pathological effects mentioned above. of Formula A is administered at a dose ranging from about 0004 Current cyclooxygenase inhibitors such as aspirin, 10 mg to about 200 mg. In another embodiment of the ibuprofen and indomethacin, used as non-Steroidal anti invention the mammalian patient is human. inflammatory drugs (NSAIDs), inhibit both COX-1 and 0011) Another embodiment of the invention encompasses COX-2 and have associated Side effects, Such as gastrotox a method for treating migraines in a mammalian patient in icity, which may be manifested as ulcer formation. COX-2 Selective inhibitors act as effective NSAIDs without Sub need of Such treatment comprising administering to Said Stantial gastrotoxic Side effects. For purposes of this disclo patient a compound of Formula A: sure only, a COX-2 selective inhibitor is defined as a COX inhibitor having a selectivity for the COX-2 isoform relative to the COX-1 isoform. SOCH3 SUMMARY OF THE INVENTION C N 0005 The present invention relates to a method for treating or preventing migraines in a mammalian patient in 2 need of Such treatment or prevention comprising adminis N N tering to Said patient a compound of Formula A: 2 N CH SOCH3 0012 or a pharmaceutically acceptable salt, hydrate or N-oxide thereof, in an amount that is effective to treat C N migraines. 0013 For purposes of this specification, treating 4 N migraines means relieving both the headache and the con Sequent associated Symptoms of migraine. Treating 2 migraines is Synonymous with the acute treatment of migraines. 0014) Another embodiment of the invention encompasses 0006 or a pharmaceutically acceptable salt, hydrate or a method for preventing migraines in a mammalian patient N-oxide thereof, in an amount that is effective to treat or in need of Such prevention comprising administering to Said prevent migraines. patient a compound of Formula A: US 2004/O132780 A1 Jul. 8, 2004 ally, by inhalation, Spray, rectally or intravaginally in for mulations containing pharmaceutically acceptable carriers. A. SOCH 0020. The term parenteral as used herein includes Sub cutaneous injections, intravenous, intramuscular, intracister C N nal injection or infusion techniques. 0021 Etoricoxib may be in a form suitable for oral use, 4 N for example, tablets, troches, lozenges, aqueous or oily Suspensions, dispersible powders or granules, emulsions, 2 hard or Soft capsules, Solutions, Syrups and elixirs. Compo N CH Sitions intended for oral use may be prepared according to any method known to the art for the manufacture of phar maceutical compositions and typically Such compositions 0.015 or a pharmaceutically acceptable salt, hydrate or contain one or more agents Selected from the group con N-oxide thereof, in an amount that is effective to prevent Sisting of Sweetening agents, flavoring agents, coloring migraines. agents and preservatives in order to provide pharmaceuti 0016 For purposes of this specification, prevention of cally elegant and palatable preparations. These excipients migraines means reducing the Severity, the frequency or both may be for example, diluents Such as lactose, calcium the Severity and frequency of migraine attackS. Preventing carbonate, Sodium carbonate, calcium phosphate or Sodium migraines is Synonymous with migraine prophylaxis or the phosphate, granulating and disintegrating agents, for chronic treatment of migraines. example, corn Starch or alginic acid; binding agents, for example Starch, gelatin or acacia, and lubricating agents, for 0017 For purposes of this specification, migraine is example, magnesium Stearate, Stearic acid or talc. meant to include migraine without aura, migraine with aura, migraine with typical aura, migraine with prolonged aura, 0022. The tablets may be uncoated or they may be coated. familial hemiplegic migraine, basilar migraine, migraine Coating can be included to delay disintegration and absorp aura without headache, migraine with acute onset aura, tion in the gastrointestinal tract and thereby provide a ophthalmoplegic migraine, retinal migraine, childhood peri sustained action over a longer period. For example, a time odic Syndromes that may be precursors to or associated with delay material Such as glyceryl monoStearate or glyceryl migraine, benign paroxySmall vertigo of childhood, alternat distearate may be employed. They may also be coated by the ing hemiplegia of childhood, Status migrainoSuS and technique described in the U.S. Pat. Nos. 4,256,108; 4,166, migrainous infarction. Reference is made to the following: 452; and 4,265,874 to form osmotic therapeutic tablets for Headache Classification Committee of the International control release. Headache Society: Classification ad diagnostic criteria for 0023 Formulations for oral use may also be presented as headache disorders, cranial neuralgias and facial pain. Ceph hard gelatin capsules wherein the active ingredient is mixed alalgia. 1988;8(suppl 7): 1-96, which is hereby incorporated with an inert Solid diluent, for example, calcium carbonate, by reference in its entirety. calcium phosphate or kaolin, or as Soft gelatin capsules 0.018. Etoricoxib has a shorter time to maximum concen wherein the active ingredient is mixed with water or mis tration and longer half-life as compared to traditional cible Solvents Such as propylene glycol, PEGs and ethanol, NSAIDs such as naproxen and will therefore have greater or an oil medium, for example peanut oil, liquid paraffin or efficacy in the acute treatment of migraine. Etoricoxib is also olive oil. better Suited than traditional NSAIDs for chronic adminis 0024 Aqueous Suspensions contain the active material in tration. admixture with excipients Suitable for the manufacture of 0.019 For purpose of this specification, an amount that is aqueous Suspensions. Such excipients are Suspending effective to treat or prevent migraines is that amount that will agents, for example Sodium carboxymethylcellulose, meth relieve the Subject being treated of the Symptoms of the ylcellulose, hydroxy-propylmethycellulose, Sodium algi migraine attack and the Specific dose level and frequency of nate, polyvinyl-pyrrollidone, tragacanth and acacia, disperS dosage may vary and will depend upon a variety of factors ing or wetting agents may be a naturally-occurring including the activity of the Specific compounds used in phosphatide, for example lecithin, or condensation products combination, the metabolic Stability and length of action of
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