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(12) Patent Application Publication (10) Pub. No.: US 2004/0229803 A1 Stephenson Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2004/0229803 A1 Stephenson Et Al US 2004O2298.03A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0229803 A1 Stephenson et al. (43) Pub. Date: Nov. 18, 2004 (54) COMPOSITIONS OF A Related U.S. Application Data CYCLOOXYGENASE-2 SELECTIVE INHIBITOR AND A POTASSIUM ION (60) Provisional application No. 60/465,068, filed on Apr. CHANNEL MODULATOR FOR THE 24, 2003. Provisional application No. 60/464,775, TREATMENT OF PAIN, INFLAMMATION filed on Apr. 23, 2003. Provisional application No. OR INFLAMMATION MEDIATED 60/464,609, filed on Apr. 22, 2003. DSORDERS Publication Classification (75) Inventors: Diane T. Stephenson, Groton, CT (US); Duncan P. Taylor, Bridgewater, (51) Int. Cl.' ....................... A61K 38/17; A61K 31/415; NJ (US) A61K 31/50 (52) U.S. Cl. ............................ 514/12; 514/247; 514/406; Correspondence Address: 514/571 SENNIGER POWERS LEAVITT AND ROEDEL (57) ABSTRACT ONE METROPOLITAN SQUARE 16TH FLOOR The present invention provides compositions and methods ST LOUIS, MO 63102 (US) for the treatment of pain, inflammation or inflammation mediated disorders in a Subject. More particularly, the (73) Assignee: Pharmacia Corporation invention provides a combination therapy for the treatment of pain, inflammation or inflammation mediated disorders (21) Appl. No.: 10/828,734 comprising the administration to a Subject of a potassium ion channel modulator in combination with a cyclooxygenase-2 (22) Filed: Apr. 21, 2004 Selective inhibitor. US 2004/0229803 A1 Nov. 18, 2004 COMPOSITIONS OF A CYCLOOXYGENASE-2 pain-based receptors within the human body. For example, SELECTIVE INHIBITOR AND A POTASSIUM ION morphine and most other opioid analgesicS elicit an inhibi CHANNEL MODULATOR FOR THE TREATMENT tory neuronal effect within central nervous and gastrointes OF PAIN, INFLAMMATION OR INFLAMMATION tinal (GI) systems by interacting with areas of the brain MEDIATED DSORDERS receiving input from the Spinal pain-transmitting pathways containing opioid receptors. By Suppressing neuronal activ CROSS REFERENCE TO RELATED ity at these receptor points, opioid narcotics produce anal APPLICATION gesia and control the pain threshold within a human patient. 0001. This application claims priority from the following 0007 Opioid narcotics, however, have several negative Provisional Applications: Serial No. 60/465,068 filed on side effects that severely limit their therapeutic value. These Apr. 24, 2003, Serial No. 60/464,775 filed on Apr. 23, 2003, Side effects include drowsiness, lethargy, difficulty in being and Serial No. 60/464,609 filed on Apr. 22, 2003, all of mobile, respiratory depression, excessive central nervous which are hereby incorporated by reference in their entirety. System depression, weakness in the extremities, and dizzi neSS. In addition, patients being treated with opioids also FIELD OF THE INVENTION may develop tolerance to the agent, requiring higher doses, 0002 The present invention provides methods and com or addition of other opioids to the pain treatment regimen. positions related to the treatment of pain, inflammation or The larger effective dosage may in turn lead to the devel inflammation mediated disorders. More particularly, the opment of physical and psychological addiction. Further, invention is directed toward a combination therapy for the other typical Side effects of opioid analgesics include miosis, treatment of pain, inflammation or inflammation mediated or constriction of the pupils, nausea, vomiting, prolongation disorders comprising the administration to a Subject of a of Stomach emptying time, and decreased propulsive con potassium ion channel modulator in combination with a tractions of the Small intestine. cyclooxygenase-2 Selective inhibitor. 0008. Several studies demonstrate that potassium chan BACKGROUND OF THE INVENTION nels may contribute to Signal transmission in the brain and Spinal cord, and opioids action may be related to potassium 0.003 Pain is a sensory experience distinct from sensa channel function (Asano T, et al., (1996) Masui Novem tions of touch, preSSure, heat and cold. It is often described ber;45(11): 1342-6). In one study, for example, it was dem by Sufferers by Such terms as bright, dull, aching, pricking, onstrated that potassium ion channel modulator administra cutting or burning and is generally considered to include tion to mice showed significant anesthetic effect for the both the original Sensation and the reaction to that Sensation. treatment of chronic pain (Beekwilder M., et al., (2002) J. Pain Sensation is complex and variable. Often experiences Pharmacol. Exp. Ther. (304)(2):531-38). In another study, it considered painful by one Subject may not be equally painful was demonstrated that potassium ion channels provide a to another and may vary in the same Subject depending on common link between numerous neurotransmitter receptors the circumstances presented. This range of Sensations, as and the regulation of Synaptic transmission (Blednov et al., well as the variation in perception of pain by different (2003) PNAS January:(100)(1):277-82). individuals, renders a precise definition of pain difficult, however, many individuals Suffer with Severe and continu 0009. As an alternative to opioid analgesics, a number of ous pain. non-narcotic based drugs may be utilized to treat mild to moderate pain. Generally Speaking, non-narcotic drugs can 0004 Pain can be caused by the stimulation of nocicep be given over longer periods of time compared to opioid tive receptors and transmitted over intact neural pathways, analgesics because of their lower central nervous System and in which case the pain is termed “nociceptive' pain. Gen respiratory depressive effects. Examples of non-narcotic erally Speaking, there are two different types of nociceptive drugs employed to treat pain include acetylsalicylic acid Stimuli that are intense enough to be perceived as pain. One (aspirin), centrally acting alpha antiadrenergic agents, diflu type, Somatic pain, consists of an intense, localized, Sharp or Sinal, Salsalate, acetaminophen, and nonsteroidal anti-in Stinging Sensation. Somatic pain is mediated by fast-con flammatory agents Such as ibuprofen, naproxen, and feno ducting, lightly myelinated A-delta fibers that have a high profen. These agents all generally relieve pain through threshold (i.e. require a strong mechanical Stimulus to sense prostaglandin Synthesis inhibition resulting in a decrease in pain) and enter into the spinal cord through the dorsal horn pain receptor Stimulation. of the central nervous System where they terminate in the Spinal cord. 0010 Non-narcotic drugs also have several negative side effects that Severely limit their therapeutic value. Aspirin, for 0005 The second type of pain, sometimes referred to as example, has been shown through epidemiological data to Visceral pain, is characterized as a diffuse, dull, aching or be a factor in the occurrence of Reye's Syndrome. In burning Sensation. Visceral pain is mediated largely by addition, Salicylates have been shown to cause gastrointes unmyelinated, slower-conducting C-fibers that are poly tinal upset, gastrointestinal hemorrhage, and anti-platelet modal (i.e., mediate mechanical, thermal, or chemical effects. Acetaminophen has been linked to liver damage, Stimuli). C-fibers also enter the spinal cord through the kidney damage, and hematological effects Such as hemolytic dorsal horn of the central nervous System where they ter anemia, neutropenia, and leukopenia. Moreover, nonsteroi minate in the Spinal cord. Both Somatic and Visceral pain can dal anti-inflammatory agents also exhibit numerous negative be sensed centrally and peripherally within the human body Side effects as well, ranging from gastrointestinal distress, and may be either acute or chronic. gastrointestinal hemorrhage, and kidney damage when 0006. A number of analgesics reduce both central and administered at a therapeutically effective dosage for the peripheral Sensitization through interaction with the various treatment of pain. US 2004/0229803 A1 Nov. 18, 2004 SUMMARY OF THE INVENTION 0.011 Among the several aspects of the invention is provided a method for the treatment of pain, inflammation or inflammation-mediated disorders in a Subject. The method comprises administering to the Subject a cyclooxygenase-2 Selective inhibitor or an isomer, a pharmaceutically accept able Salt, ester, or prodrug thereof in combination with a potassium channel modulator or pharmaceutically accept able Salt or prodrug thereof. 0012. In one embodiment, the cyclooxygenase-2 selec tive inhibitor is a member of the chromene class of com 0024 wherein pounds. For example, the chromene compound may be a 0025 A is selected from the group consisting of partially compound of the formula: unsaturated or unsaturated heterocyclyl and partially unsat urated or unsaturated carbocyclic rings, 0026) R' is selected from the group consisting of hetero (I) cyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R is optionally Substituted at a Substitutable position with one or more radicals Selected from alkyl, haloalkyl, cyano, car boxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkdxyalkyl, alkyl Sulfinyl, halo, alkoxy and alkylthio; 0027 R is selected from the group consisting of methyl 0013 wherein: or amino; and 0.014) n is an integer which is 0, 1, 2, 3 or 4; 0028) R is selected from the group consisting of a radical Selected from H, halo, alkyl, alkenyl, alkynyl, OXO, cyano, 0015) G is O, S or NR; carboxyl, cyanoalkyl, heterocyclyloxy,
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