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Home , Dihydroergocryptine, Ergosine, Ergostine, Metergoline

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 (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 , , 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 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 . 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 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 of an alkylene oxide with fatty acids, for example polyoxy the compounds, the age, body weight, general health, SeX Stearate, or condensation products of ethylene diet, mode and time of administration, rate of excretion, the oxide with long chain aliphatic , for example hep Severity of the particular condition and the host undergoing tadecaethyleneoxycetanol, or condensation products of eth therapy. However, dosage levels of etoricoxib on the order ylene oxide with partial esters derived from fatty acids and of about 0.01 mg/kg to about 100 mg/kg of body weight per a hexitol Such as polyoxyethylene Sorbitol monooleate, or day, typically about 0.1 to about 10 mg/kg, more particularly condensation products of ethylene oxide with partial esters about 0.2 to about 5 mg/kg and especially about 0.14 to derived from fatty acids and heXitol anhydrides, for example about 3 mg/kg per day are useful in the novel method of polyethylene Sorbitan monooleate. The aqueous Suspensions treatment. For the treatment of a migraine attack, the active may also contain one or more preservatives, for example ingredient may be administered orally, topically, parenter ethyl or n-propyl p-hydroxybenzoate, one or more coloring US 2004/O132780 A1 Jul. 8, 2004 agents, one or more flavoring agents, and one or more 0032 For topical use, creams, ointments, gels, Solutions, Sweetening agents, Such as Sucrose, Saccharin or aspartame. Suspensions and the like containing the compound are 0.025 Oily suspensions may be formulated by Suspending employed. (For purposes of this application, topical appli the active ingredient in a vegetable oil, for example arachis cation includes mouth washes and gargles, as well as trans oil, olive oil, Sesame oil or coconut oil, or in mineral oil Such dermal applications.) Topical formulations are comprised of as liquid paraffin. The oily Suspensions may contain a a pharmaceutical carrier, which may include, e.g., cosol thickening agent, for example beeswax, hard paraffin or vents, emulsifiers, penetration enhancers, preservatives or cetyl . Sweetening agents Such as those Set forth emollients. above, and flavoring agents may be added to provide a 0033. The active ingredient is combined with the carrier palatable oral preparation. These compositions may be pre to produce the dosage form. For example, a formulation Served by the addition of an anti-oxidant Such as ascorbic intended for oral administration may contain from as low as acid. about 0.7 mg of etoricoxib to as high as about 7 g of 0.026 Dispersible powders and granules suitable for etoricoxib per dose, compounded with an appropriate and preparation of an aqueous Suspension by the addition of convenient amount of carrier material which may vary from water provide the active ingredient in admixture with a about 5 to about 95 percent of the total composition. A dispersing or Wetting agent, Suspending agent and one or preferred pharmaceutical composition contains from about more preservatives. Suitable dispersing or wetting agents 10 mg to about 200 mg of etoricoxib or a salt thereof. and Suspending agents are exemplified by those already mentioned above. Additional excipients, for example Sweet 0034 Etoricoxib may also be administered in combina ening, flavoring and coloring agents, may also be present. tion with other agents for the treatment or . Such administration may either be in unit dosage 0027. The pharmaceutical compositions may also be in form or concomitantly. All conventional anti-migraine the form of oil-in-water emulsions. The oily phase may be agents are used in conjunction with the etoricoxib at con a vegetable oil, for example olive oil or arachis oil, or a ventional doses that are determined by the skilled clinician. mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring These compounds are known and normal daily dosages are phosphatides, for example Soybean, lecithin, and esters or well established. Typically, the individual daily dosages for partial esters derived from fatty acids and hexitol anhy these combinations may range from about one-fifth of the drides, for example Sorbitan monooleate, and condensation minimally recommended clinical dosages to the maximum products of the Said partial esters with ethylene oxide, for recommended levels for the entities when they are given example polyoxy-ethylene Sorbitan monooleate. The emul alone. Precise dosages are left to the discretion of the Sions may also contain Sweetening and flavoring agents. physician Thus, in further aspects, the invention encom passes pharmaceutical compositions for treating or prevent 0028 Syrups and elixirs may be formulated with Sweet ing migraines comprising etoricoxib and one or more agents ening agents, for example glycerol, propylene glycol, Sor Selected from the group consisting of rofecoxib, indometha bitol or Sucrose. Such formulations may also contain demul cin, Sulindac, etodolac, , , cents, preservatives, flavorants and coloring agents. , , etofenamic acid, tolmetin, 0029. The pharmaceutical compositions may be in the ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen, form of a sterile injectable aqueous or oleaginous Suspen ketoprofen, oxaprozin, piroXicam, meloxicam, tenoxicam, Sion. This Suspension may be formulated according to the lornoxicam, cinnoxicam, Sudoxicam, tenoxicam, phenylb known art using those Suitable dispersing or wetting agents utaZone, OxyphenbutaZone, apaZone, azapropaZone, nime and Suspending agents which have been mentioned above. Sulide, diflunisal, nabumetone, aspirin, Sodium Salicylate, choline, magnesium trisalicylate, Salsalate, diflunisal, Sali 0.030. Injectable compositions are typically in the form of cylsalicyclic acid, SulfaSalazine olSalazine, , Sterile Solutions or Suspensions, which include the active ergonovine, ergonovine, meSylates, , methyler ingredient in a parenterally acceptable diluent. Among these gonovine, methylsergide, , meSylate, are sterile water, dextrose 5% in water (D5W), Ringer's , , dihydroergocris Solution and isotonic Saline, as well as mixtures thereof. tine, , dihydro-O-, dihydro CoSolvents Such as ethanol, propylene glycol or polyethyl fi-ergocryptine, ergotoxine, , , ergoc ene glycols may also be used. Sterile, injectable oil is ryptine, C-ergocryptine, fi-ergocryptine, , , occasionally employed as a Solvent or Suspending medium in intramuscular preparations. A representative example is , , , , peanut oil. In addition, fatty acids Such as oleic acid, , , and , preservatives, buffers and local anesthetics find use in the in combination with a pharmaceutically acceptable carrier. preparation of intramuscular injectables. In a preferred embodiment, the invention encompasses a pharmaceutical composition comprising etoricoxib and 0031. The combination of active ingredients may also be metoclopramide, in combination with a pharmaceutically administered rectally or intravaginally as Suppositories. acceptable carrier. These can be prepared by mixing the drug with a Suitable non-irritating excipient which is Solid at ordinary room 0035) In another aspect, the invention encompasses a temperature but molten at normal or elevated body tempera method for treating or preventing migraines in a mammalian ture. Examples of Such materials include cocoa butter and patient in need of Such treatment or prevention comprising polyethylene glycols. administering to Said patient a compound of Formula A: US 2004/O132780 A1 Jul. 8, 2004

4. The method for treating migraines in a mammalian patient in need of Such treatment comprising administering A. SOCH to Said patient a compound of Formula A:

C N SOCH3

4 N C N 2 N CH 2 N N

2 0.036 or a pharmaceutically salt, hydrate or N-oxide N CH thereof, in combination with one or more agents Selected from the group consisting of rofecoxib, indomethacin, Sulindac, etodolac, mefenamic acid, meclofenamic acid, or a pharmaceutically acceptable Salt, hydrate or N-oxide flufenamic acid, tolfenamic acid, etofenamic acid, tolmetin, thereof, in an amount that is effective to treat migraines in ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen, accordance with claim 1. ketoprofen, oxaprozin, piroXicam, meloxicam, tenoxicam, 5. The method for preventing migraines in a mammalian lornoxicam, cinnoxicam, Sudoxicam, tenoxicam, phenylb utaZone, OxyphenbutaZone, apaZone, azapropaZone, nime patient in need of Such prevention comprising administering Sulide, diflunisal, nabumetone, aspirin, Sodium Salicylate, to Said patient a compound of Formula A: choline, magnesium trisalicylate, Salsalate, diflunisal, Sali cylsalicyclic acid, SulfaSalazine olSalazine, ergotamine, ergonovine, ergonovine, meSylates, ergometrine, methyler gonovine, methylsergide, metergoline, ergoloid meSylate, SOCH3 dihydroergotamine, dihydroergocornine, dihydroergocris tine, dihydroergocryptine, dihydro-O-ergocryptine, dihydro Cl N C-ergocryptine, ergotoxine, ergocornine, ergocristine, ergocryptine, C.-ergocryptine, fi-ergocryptine, ergosine, 2 ergostine, bromocriptine, amitriptyline, methySergide, pro N N pranolol, Valproate, Verapamil, metoclopramide and prochlorperazine, in amounts that are effective to treat or 2 prevent migraines. A preferred agent is metoclopramide. N CH or a pharmaceutically acceptable Salt, hydrate or N-oxide What is claimed is: thereof, in an amount that is effective to prevent migraines 1. A method for treating or preventing migraines in a in accordance with claim 1. mammalian patient in need of Such treatment or prevention 6. The method according to claim 1 further comprising comprising administering to Said patient a compound of administering to Said patient one or more agents Selected Formula A: from the group consisting of rofecoxib, indomethacin, Sulindac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, etofenamic acid, tolmetin, SOCH3 ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, oxaprozin, piroXicam, meloxicam, tenoxicam, lornoxicam, cinnoxicam, Sudoxicam, tenoxicam, phenylb C N utaZone, OxyphenbutaZone, apaZone, azapropaZone, nime Sulide, diflunisal, nabumetone, aspirin, Sodium Salicylate, 2 N N choline, magnesium trisalicylate, Salsalate, diflunisal, Sali cylsalicyclic acid, SulfaSalazine olSalazine, ergotamine, 2 ergonovine, ergonovine, meSylates, ergometrine, methyler N CH gonovine, methylsergide, metergoline, ergoloid meSylate, dihydroergotamine, dihydroergocornine, dihydroergocris or a pharmaceutically acceptable Salt, hydrate or N-oxide tine, dihydroergocryptine, dihydro-O-ergocryptine, dihydro thereof, in an amount that is effective to treat or prevent fi-ergocryptine, ergotoxine, ergocornine, ergocristine, ergoc migraines. ryptine, C-ergocryptine, fi-ergocryptine, ergosine, ergostine, 2. The method according to claim 1 wherein the com bromocriptine, amitriptyline, methySergide, propranolol, pound of Formula A is administered at a dose ranging from Valproate, Verapamil, metoclopramide and prochlorperazine, about 10 to about 200 mg. in an amount that is effective to treat or prevent migraines. 3. The method according to claim 1 wherein the mam 7. The method according to claim 6 wherein agent is malian patient is human. metoclopramide. US 2004/O132780 A1 Jul. 8, 2004

8. A pharmaceutical composition comprising a compound goline, ergoloid meSylate, dihydroergotamine, dihydroergo of Formula A: cornine, , dihydroergocryptine, dihydro C-ergocryptine, dihydro-3-ergocryptine, ergotoxine, ergocornine, ergocristine, ergocryptine, C.-ergocryptine, fi-ergocryptine, ergosine, ergostine, bromocriptine, amitrip SOCH3 tyline, methySergide, propranolol, Valproate, Verapamil, metoclopramide and prochorperazine, in combination with a C pharmaceutically acceptable carrier. N 9. The pharmaceutical composition according to claim 8 2 comprising a compound of Formula A: N N

2 N CH SOCH and one or more agents Selected from the group consisting C N of rofecoxib, indomethacin, Sulindac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, 2 etofenamic acid, tolmetin, ketorolac, diclofenac, ibuprofen, N N naproxen, fenoprofen, ketoprofen, oxaprozin, piroXicam, meloxicam, tenoxicam, lornoxicam, cinnoxicam, Sudoxi 2 cam, tenoxicam, phenylbutaZone, oxyphenbutaZone, apa N CH Zone, azapropaZone, nimeSulide, diflunisal, nabumetone, aspirin, Sodium Salicylate, choline, magnesium trisalicylate, and metoclopramide in combination with a pharmaceuti Salsalate, diflunisal, Salicylsalicyclic acid, SulfaSalazine cally acceptable carrier. olsalazine, ergotamine, ergonoVine, ergonoVine, meSylates, ergometrine, methylergonovine, methylsergide, meter