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Quaternary Ammonium Salts As Pain Modulating Agents Joseph R University of Kentucky UKnowledge Pharmaceutical Sciences Faculty Patents Pharmaceutical Sciences 10-13-2015 Use of Tris-Quaternary Ammonium Salts as Pain Modulating Agents Joseph R. Holtman University of Kentucky, [email protected] Peter Anthony Crooks University of Kentucky Linda P. Dwoskin University of Kentucky, [email protected] J. Michael McIntosh University of Kentucky Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/ps_patents Part of the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Holtman, Joseph R.; Crooks, Peter Anthony; Dwoskin, Linda P.; and McIntosh, J. Michael, "Use of Tris-Quaternary Ammonium Salts as Pain Modulating Agents" (2015). Pharmaceutical Sciences Faculty Patents. 40. https://uknowledge.uky.edu/ps_patents/40 This Patent is brought to you for free and open access by the Pharmaceutical Sciences at UKnowledge. It has been accepted for inclusion in Pharmaceutical Sciences Faculty Patents by an authorized administrator of UKnowledge. For more information, please contact [email protected]. 111111 1111111111111111111111111111111111111111111111111111111111111 US009155733B2 c12) United States Patent (10) Patent No.: US 9,155,733 B2 Holtman et al. (45) Date of Patent: Oct. 13, 2015 (54) USE OF TR/S-QUATERNARY AMMONIUM (56) References Cited SALTS AS PAIN MODULATING AGENTS U.S. PATENT DOCUMENTS (75) Inventors: Joseph R. Holtman, Lexington, KY 5,691,365 A 1111997 Crooks et al. (US); Peter Anthony Crooks, 2003/0225142 A1 12/2003 Crooks et al. Nicholasville, KY (US); Linda P. 2005/0261334 A1 1112005 Crooks et al. Dwoskin, Lexington, KY (US); J. 2006/0247270 A1 * 1112006 Mazurov eta!. .............. 514/305 Michael Mcintosh, Salt Lake City, UT 201110105556 A1 5/2011 Crooks et al. (US) 2013/0030018 A1 112013 Crooks et al. 2014/0080866 A1 3/2014 Crooks et al. (73) Assignees: University of Kentucky Research FOREIGN PATENT DOCUMENTS Foundation, Lexington, KY (US); University of Utah, Salt Lake City, UT wo WO 2007076112 A2 * 7/2007 (US) OTHER PUBLICATIONS ( *) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 Finnerup eta!. (Fundamental & Clinical Paramacology, 2007, 21, U.S.C. 154(b) by 623 days. 129-136).* Written Opinion (PCT/ISA/237) dated Sep. 25,2008 (six (6) pages). International Preliminary Report on Patentability dated Nov. 4, 2008 (21) Appl. No.: 12/576,300 (seven (7) pages). Itahara eta!., "Molecular assemblies ofbis- and tris-adenine deriva­ (22) Filed: Oct. 9, 2009 tives," Journal of Molecular Structure, 2002, pp. 213-220, vol. 616, Elsevier (eight (8) pages). (65) Prior Publication Data Levin eta!., "The nicotinic antagonist mecamylamine preferentially US 2010/0120857 Al May 13,2010 inhibits cocaine vs. food self-administration in rats," Physiology & Behavior, 2000, pp. 565-570, vol. 71, Elsevier (six (6) pages). Berge eta!., "Pharmaceutical Salts, Journal of Pharmaceutical Sci­ Related U.S. Application Data ences," 1977, pp. 1-19, vol. 66, No. 1, (nineteen (19) pages). (60) Provisional application No. 61/195,824, filed on Oct. 10, 2008. * cited by examiner (51) Int. Cl. Primary Examiner- Dennis Heyer A01N 43142 (2006.01) Assistant Examiner- Daniel M Podgorski A61K 31147 (2006.01) (74) Attorney, Agent, or Firm- Crowell & Moring LLP A61K 3114709 (2006.01) (52) U.S. Cl. (57) ABSTRACT CPC .................................. A61K 3114709 (2013.01) Provided are tris-quatemary ammonium compounds which (58) Field of Classification Search are modulators of nociception and pain. None See application file for complete search history. 7 Claims, 2 Drawing Sheets U.S. Patent Oct. 13, 2015 Sheet 1 of2 US 9,155,733 B2 Figure 1 GZ-556A 80 .---.. ..c 0 0 60 0. Q) .£ E 1.0 40 (j) <D ..c (.) c 20 lL 0 0 10 20 30 40 50 60 70 Time (min) ---Saline --tf-'- GZ-556A 90 meg/kg ---- GZ-55&'\ 135 meg/kg -ff- GZ-55&'\ 180 meg/kg U.S. Patent Oct. 13, 2015 Sheet 2 of2 US 9,155,733 B2 Figure 2 GZ-556A 1000 2500 pl?ase 1 phase 2 800 2000 c c: E E 600 1500 0 0 N (!) I d s N 400 -~ () () 1000 :J :J <( <:( 200 500 ... 0 0 0 90 135 180 D 90 135 180 Dose (meg/kg) Dose (meg/kg) Mean+/- SEM (n:::: 2-3 rats) US 9,155,733 B2 1 2 USE OF TR/S-QUATERNARY AMMONIUM pro fen) act by inhibition of the cyclo-oxygenase (Cox-1 ,2) SALTS AS PAIN MODULATING AGENTS enzyme. They are especially useful in nociceptive pain of inflammatory origin (eg. arthritis). However, the NSAID's FIELD OF THE INVENTION have limited efficacy when compared to the opioids. In addi­ tion, NSAID's have significant side effects (renal, gas­ The invention relates to the use of tris-quatemary ammo­ trointestinal, cardiovascular). The discovery of the Cox-2 nium salts for pain modulation. selective agents (eg. rofecoxib-Vioxx®; celecoxib-Cele­ brex®; valdecoxib-Bextra®) which have far less gastrointes­ BACKGROUND OF THE INVENTION tinal toxicity, was thought to be an advance in NSAID phar- 10 macology. Nonetheless, these agents still have low efficacy The treatment of pain is a critical health issue. Acute (eg. postoperative pain) and chronic (eg. arthritis, low back, can­ and evidence is now available linking them to significant cer) pain affects tens of millions of people annually in the US. cardiovascular events including stroke and myocardial inf­ Each year some 30 million people visit a physician with a arction following chronic use. This has resulted in the complaint of a painful condition. Some 10% of these patients 15 removal of both rofecoxib and valdecoxib from the market. are seen with chronic pain as their main complaint. The finan­ No suitable agent exists for the treatment of neuropathic pain. cialloss due to pain has been estimated to exceed 100 billion GABA-pentin (Neurontin®), an anticonvulsant, has found dollars a year as a result of medical fees, decreased produc­ use for some neuropathic pain syndromes (eg. diabetic tivity, litigation and the cost of drugs. New therapeutic agents peripheral neuropathy, postherpetic neuralgia), but it still has with greater efficacy, in particular for chronic neuropathic 20 limited efficacy. Duloxetine (Cymbalta®), an antidepressant, pain syndromes (eg. complex regional pain syndrome), and has recently been approved for the treatment of diabetic with fewer side effects would result in significant societal peripheral neuropathy. However, it has limited efficacy and benefit. usefulness for other neuropathic pain states. TheN-methyl­ Pain can be broadly divided into two categories: nocicep­ d-aspartate (NMDA) receptor antagonists (eg. ketamine) tive and neuropathic pain. Nociceptive pain occurs as a result 25 have been proposed for the treatment of neuropathic pain. of activation of peripheral nociceptors, actually free nerve Their general use is impractical given the marked side effects endings by noxious stimuli (heat, pressure, inflannnatory including sedation, psychosis and motor impairment. The mediators). Examples of nociceptive pain include postsurgi- limitations of the currently available therapies clearly dem­ cal pain, inflammatory pain ( eg. arthritis) and low back pain. onstrate the need for a broad spectrum new class of effica- Such a pain is often described as "a constant, dull, aching 30 cious and safe analgesic drugs for the treatment of nocicep­ pain". Neuropathic pain occurs as a result of damage to the tive and neuropathic pain. peripheral or central nervous system. Examples of neuro­ Given the need for more effective, less toxic, analgesic pathic pain include radiculopathy (eg. disc impingement on a drugs, a great deal of emphasis has been placed on identifying nerve), complex regional pain syndrome (CRPS I, II), dia­ novel molecular targets that could form the basis for new betic peripheral neuropathy or central pain (stroke, spinal 35 analgesics. cord injury, multiple sclerosis). Patients typically describe neuropathic pain as "burning and tingling" in nature. It is SUMMARY OF INVENTION characterized by hyperalgesia (increased painful response to a noxious stimulus) and allodynia (pain to a previously non­ In one embodiment, compounds corresponding to the fol­ noxious stimulus). lowing structure are provided. (I) 50 In many patients, in particular those with chronic pain The three side chains attached to the phenyl ring can be conditions of malignant (cancer-related pain) and non-malig­ connected to the 1, 2, and3 positions; the 1, 2, and4 positions; nant (arthritis, low back pain, CRPS) origin, pain is inad­ or the 1, 3 and 5 positions of the phenyl ring. equately managed with currently available drugs. Available The values for m1, m2 and m3 are each independently 0, 1, drugs are simple modifications ( eg. extended release) of 2, 3, 4 or 5. 55 The values for n1, n2, and n3 are each independently 1, 2, drugs from classes which have been available for decades 3, 4 or 5. including the opioids, nonsteroidal anti-inflammatory agents 18 28 38 X , X , and X are each independently an organic or (NSAID's) or various adjuvants (antidepressants, anticonvul­ inorganic anion. 1 2 3 sants) initially approved for other uses besides pain. Opioids L , L and L are each independently chosen from the ( eg. morphine, oxycodone) are often successfully used for the 60 group consisting of ---CH2 ---CH2-, cis -CH=CH-, treatment of moderate to severe nociceptive pain. Chronic trans ---CH=CH-, -C C-, ---CH2-S-, neuropathic pain is much less responsive to opioids. Use of -S-CH2-, -Se-CH2-, ---CH2-Se-, ---CH2---0-, opioid analgesics is associated with a broad range of signifi­ ---O-CH2-, -CH2-NH-, -NH---CH2-, ---CH2- cant side effects including cognitive impairment, respiratory NR- where R is a branched or straight chain alkyl group of depression and constipation. In addition, long-term opioid 65 one to four carbons, -NR---CH2- where R is a branched or dosing results in the development oftolerance to the analgesic straight chain alkyl group of one to four carbons, effect, drug abuse and dependence.
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