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WO 2013/063263 Al May 2013 (02.05.2013) W P O P C T

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WO 2013/063263 Al May 2013 (02.05.2013) W P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/063263 Al May 2013 (02.05.2013) W P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A01N 37/18 (2006.01) A61K 31/16 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, PCT/US20 12/06 1922 KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (22) International Filing Date: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 25 October 2012 (25.10.2012) NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (25) Filing Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (26) Publication Language: English ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/55 1,376 25 October 201 1 (25. 10.201 1) US kind of regional protection available): ARIPO (BW, GH, 61/619,405 2 April 2012 (02.04.2012) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 61/660,765 17 June 2012 (17.06.2012) us UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 61/665,296 27 June 2012 (27.06.2012) us TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicant: LYCUS LLC [US/US]; 4 Horace Court, Prin MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, ceton Junction, NJ 08550 (US). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventor; and (71) Applicant : SESHA, Ramesh [IN/US]; 4 Horace Court, Published: Princeton Junction, NJ 08550 (US). — with international search report (Art. 21(3)) (74) Agent: PROUT, William, F.; Prout International IP, LLC, — before the expiration of the time limit for amending the P.O. Box 761, Wayzata, MN 55391 (US). claims and to be republished in the event of receipt of (81) Designated States (unless otherwise indicated, for every amendments (Rule 48.2(h)) kind of national protection available): AE, AG, AL, AM, © (54) Title: PHARMACEUTICAL COMPOSITIONS FOR TREATING PAIN 2 7) Abstract: A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of a second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxi - some proliferator-activated receptors (PPAR) agonist; c) an opioid; or d) NSAID or pharmaceutically acceptable salts, isomers, or polymorphs thereof and optionally a pharmaceutically acceptable carrier useful for the prevention or treatment of pain and pain re - lated disorders is provided. The pharmaceutical compositions are useful in a method for treatment pain and pain related disorders, by administering the compositions to a patient in need thereof. PHARMACEUTICAL COMPOSITIONS FOR TREATING PAIN Related Applications This application claims priority under 35 U.S. C.§ 119 to U.S. Provisional Application No.: 61/551,376, filed on October 25, 201 1, U.S. Provisional Application No.: 61/660,765, filed on June 17, 2012, U.S. Provisional Application No.: 61/619,405, filed on April 2, 2012, and U.S. Provisional Application No.: 61/665,296, filed on June 27, 2012 the disclosures of which are incorporated by reference herein in their entirety. Field of the Invention [0001] The present invention provides pharmaceutical compositions, useful treating pain and pain related disorders. The invention further provides, methods for treating pain and pain related disorders using a therapeutically effective amount of the compounds and pharmaceutical compositions disclosed herein. Background of the Invention [0002] There are several types of pain. Various pain types include chronic pain, e.g., nociceptive, neuropathic, psychogenic pain, and mixed nociceptive and neuropathic pain. Examples of these types of pain include, but are not limited to, diabetic neuropathy, neurogenic pain, central pain, somatic pain, visceral and cancer pain, inflammatory pain, inflammatory bowel disease (IBD) pain, multiple sclerosis pain, post-operative pain, chronic low back pain, sciatica, cervical and lumbar pain, tension headaches, cluster headaches, chronic daily headaches, herpes neuralgia and post-herpetic neuralgia, facial and oral neuralgias and myofascial pain syndromes, phantom limb pain, stump pain and paraplegic pain, dental pain, opioid resistant pain, post-surgical pain including cardiac surgery and mastectomy, pain of labor and delivery, post-partum pain, post-stroke pain, angina pain, genitourinary tract pain including pelvic pain and cystitis and vulvar vestibulitis and orchialgia, irritable bowel syndrome, pre menstrual syndrome pain, pain resulting from burns or chemical injury or sunburn, and bone injury pain. [0003] Fibromyalgia (FM) is a chronic pain illness. Symptoms of the disease include muscle aches, pain and stiffness of joints and muscles, soft tissue tenderness, general fatigue, and sleep disturbances. Common sites of this widespread pain include: neck, shoulders, back, pelvic girdle, and hands. The disease and its progression can affect any part of the body. The difficulty with fibromyalgia and pain levels the patient experiences can change over time. Sometime a patient will feel better and sometime a patient can feel worse since the pain waxes and wanes over time. [0004] Effective treatment options for fibromyalgia, particularly ones that are suitable for long-term use, are very limited. Non-limiting examples of drugs that have been used include, for example, alpha2delta agonists, such as pregabalin, gabapentin, or opioids such as tramadol, tapentadol, and tricyclic antidepressants such as nortriptytline. However all these medications have reported side effects. [0005] Another disorder, Irritable bowel disease (IBD) is typically characterized by cramping, abdominal pain, bloating, constipation, and diarrhea. IBD may cause a great deal of discomfort and distress, but it is not believed to cause permanently harm to the intestines or lead to a serious disease, such as cancer. Many patients can control their symptoms with diet, stress management, and prescribed medications. For some patients, however, IBD can be disabling. They may be unable to work, attend social events, or even travel short distances. As many as 20 percent of the adult population, or one in five Americans, have symptoms of IBD, making it one of the most common disorders diagnosed by doctors. [0006] Treatment options for irritable bowel disease (IBD) are limited. One medication available specifically to treat IBD is alosetron hydrochloride (Lotronex). Lotronex has been re- approved with significant restrictions by the U.S. Food and Drug Administration (FDA) for women with severe IBD who have not responded to conventional therapy and whose primary symptom is diarrhea. However, it is recommended that Lotronex should be used with great caution because it can cause serious side effects such as severe constipation or decreased blood flow to the colon. [0007] Another type of pain is the neuropathic pain. It is caused by a primary lesion or dysfunction in the nervous system. Neuropathic pains are divided into peripheral neuropathic pain due to lesion of the peripheral nervous system and central pain following lesions of the central nervous system. Neuropathic pain commonly is described as hot burning, throbbing, shooting, lancinating, stabbing, sharp, cramping, gnawing, aching, heavy, tender, splitting, tiring, exhausting, sickening, fearful, punishing, cruel, icy cold, tingling, pins and needles, intense and itch like. Medical descriptors are allodynia (pain due to a stimulus which does not normally provoke pain), hyperalgesia (an increased response to a stimulus which is normally painful), hyperaesthesia (increased sensitivity to stimulation, excluding the special senses), dysaesthesia (an unpleasant abnormal sensation, whether spontaneous or evoked), hyperpathia (a painful syndrome characterized by an abnormally painful reaction to astimulus, especially a repetitive stimulus, as well as an increased threshold) and neuralgia (pain in the distribution of a nerve or nerves not necessarily of paroxysmal quality). Neuropathic pain may be associated with mood changes, sleep disturbance, fatigue and may have an impact on physical and social functioning. The prevalence of neuropathic pain is estimated to be about 1%. [0008] The treatment options for neuropathic pain include alpha2deltaagonists such as pregabalin, gabapentin, opioids such as morphine, dextromethorphan, and tapentadol etc. [0009] Compounds of formula I, for example Agomelatine, A, a melatonergic agonist (MTi and MT2 receptors) and 5-HT2c antagonist are known for their antidepressant like properties. A Agomelatine and similar compounds were disclosed in U.S. Patent No. 5,194,614 and U.S. Patent No. 5,224,442. The patents disclose several compounds of naphthalene structure including agomelatine, their pharmaceutical compositions and methods for treating a living animal afflicted with treatable disorder of the melatoninergic system. Agomelatine has been reported to re-synchronize circadian rhythms, based on animal models of delayed sleep phase syndrome and other circadian rhythm disruptions. It has also been reported to increase noradrenaline and dopamine release specifically in the frontal cortex and has no known influence on the extracellular levels of serotonin and to provide an antidepressant-like effect in animal depression models (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm de-synchronization and in models related to stress and anxiety. In humans, agomelatine has been reported to provide positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset. Thus, it has been marketed for the treatment of major depressive disorders and reported to have a reduced level of sexual side effects, as well as discontinuation effects, compared to other antidepressants.
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