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WO 2013/167743 Al 14 November 2013 (14.11.2013) P O P C T

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WO 2013/167743 Al 14 November 2013 (14.11.2013) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2013/167743 Al 14 November 2013 (14.11.2013) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/18 (2006.01) A61K 31/708 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/522 (2006.01) A61K 45/06 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/675 (2006.01) A61P 29/00 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, A61K 31/7068 (2006.01) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (21) International Application Number: NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, PCT/EP2013/059752 RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (22) International Filing Date: TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, 10 May 2013 (10.05.2013) ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 12167771 .0 11 May 2012 ( 11.05.2012) EP 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: AKRON MOLECULES GMBH [AT/AT]; MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Helmut-Qualtinger-Gasse 2, A-1030 Vienna (AT). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventors: NILSSON, Henrik; ReisnerstraBe 11/6, A- 1030 Vienna (AT). MCMANUS, Shane; Klimschgasse Declarations under Rule 4.17 : 5/15, A-1030 Vienna (AT). MUHAMED, Arif; Brunnl- — of inventorship (Rule 4.17(iv)) badgasse 13/12, A-1090 Vienna (AT). Published: (74) Agent: SONN & PARTNER PATENTANWALTE; Riemergasse 14, A-1010 Vienna (AT). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (54) Title: USE OF COMPOUNDS FOR THE TREATMENT OF PAIN (57) Abstract: The present invention relates to new therapies to treat pain and related diseases, as well as pharmaceutical com pounds for use in said therapies. Use of compounds for the treatment of pain The present invention relates to the field of method of treatment of pain and the provision of pharmaceutical compounds suitable for such treatments. Acute and chronic pain affects millions of people after in jury or surgery and those suffering from diseases like arthri tis, cancer, and diabetes. Nociception (the detection of noxious or damaging stimuli) serves a crucial biological purpose: it alerts living organisms to environmental dangers, inducing the sensation of pain, reflex withdrawal and complex behavioural and emotional responses, which protect the organism from further damage. Noxious stimuli are detected by specialized high thresh old primary sensory neurons (nociceptors) , which transfer sig nals to the spinal cord and then transmit them to the brain for higher level processing that results in the conscious awareness of the sensation called pain. The functional importance of pain perception is exemplified by individuals with defects in noci ception; patients with congenital insensitivity to pain do not survive past their twenties. Two basic types of pain can be distinguished - acute and chronic. Acute or nociceptive pain is generally self -limiting and serves a protective biological function by warning of on going tissue damage caused by noxious chemical, thermal and me chanical stimuli. Examples of nociceptive pain include: post operative pain, pain associated with trauma, and the pain asso ciated with arthritis. Chronic pain, on the other hand, serves no protective biological function, and reflects either poor res olution of the painful stimuli, or is itself a disease process. Chronic pain is unrelenting and not self -limiting and can per sist for years and even decades after the initial injury. Chron ic pain is predominantly neuropathic in nature and may involve damage either to the peripheral or central nervous systems. Chronic pain may, however, also be nociceptive, such as inflam matory in nature. Furthermore, chronic pain may also be mixed nociceptive and neuropathic. Finally, chronic pain may also be of a central origin, deriving from processes/conditions in the central or peripheral nervous system, such as e.g. post stroke pain or post-amputation pain/phantom limb pain, which may, how ever, also be considered neuropathic in nature. Currently available therapies for pain have a number of dis advantages, which warrant the development of new therapies for the treatment, prevention and/or reduction of pain. The disad vantages are different for the different classes of available drugs. Use of non-steroidal anti-inflammatory drugs (NSAIDs) in creases the risk of gastrointestinal (GI) bleeding and impaired renal function or renal failure as well as cardiovascular (CV) disease, µ -opioid receptor agonists (opioids and opiates) carry the risk of addiction, as well as respiratory depression and constipation. Anti-depressants (e.g. tricyclic anti-depressants (TCAs) , such as nortriptyline and desipramine, as well as the selective serotonin norepinephrine reuptake inhibitors (SSNRIs) , including e.g. venlaf axaine) may have a negative impact on car diac function or, as in the case of the SSNRI duloxetine, may induce nausea. Anti-convulsants , such as pregabalin and gapa- bentin, can induce somnolence. The disadvantage for any of the existing available drugs may also be related to limited efficacy in treating and/or preventing pain. It is a goal of the present invention to provide methods of preventing, treating, ameliorating or suppressing pain, in par ticular by the use of novel compounds for this purpose. The present invention therefore provides the use of new classes of compounds for the treatment, prevention or reduction of pain. The present invention also provides a method of treat ing pain in a subject comprising the administration of a thera peutic compound selected from the inventive compounds. In a re lated aspect the present invention provides the use of a com pound of the invention for the manufacture of an analgesic or a medicament for the treatment of pain in a subject. The invention is further defined by the subject matter of the claims. The com pounds of the invention are e.g. given in the claims and in the tables herein. The compounds according to the invention are contemplated to have advantages in that they have less side effects as deter mined by one or several of the side effects listed above for one or more of the available therapies. Less side effects can be as sessed e.g. either in terms of reduced severity and/or reduced frequency of side effects. Such reduced side effects can e.g. be less somnolence c.f. anti-convulsants, fewer or less frequent cardiovascular side effects c.f. anti-depressants, less addic- tion potential c.f. µ -opioid receptor agonists, less G I bleeding c.f. NSAIDs etc. Alternatively, the compounds according to the invention are contemplated to have improved efficacy c.f. the available thera pies. Improved efficacy can e.g. be determined as a greater num ber of responders or greater magnitude of efficacy c.f. one or several of the existing therapies. In a further embodiment, the compounds according to the in vention are contemplated to have both reduced side effects and improved efficacy c.f. available therapies. In particular, selected pain subtypes can be specifically treated by the inventive compounds. Example inventive compounds are selected from the groups of a ) nucleotide analogues, b ) nucleoside analogues, c ) compounds that interact with DNA polymerase, or d ) compounds that interact with DNA. In the following tables 1 , 2 and 3 the inventive com pounds or salts thereof are identified by their unique CAS num ber (Chemical Abstracts Service, www.cas.org). The invention in cludes any salt form of the given compounds, but preferably re lates to the exact salt form as given in the tables. Table 3 re fers to both table 3a and 3b. Further inventive compounds are defined as derivatives of a given formula as described below the tables . Table 1 : Adefovir and Tenofovir derivatives (CAS number) 1000271-66-8 1026368-64-8 118552-93-5 3768-14-7 1000271-70-4 1034684-26-8 182798-75-0 142341-05-7 1000272-10-5 1034684-27-9 184350-33-2 142341-04-6 1000272-12-7 1034684-29-1 184350-32-1 124076-74-0 1001254-18-7 1034684-30-4 182799-00-4 186345-42-6 1001254-20-1 1072095-06-7 113852-35-0 7292-42-4 1001254-60-9 1082741-23-8 147127-15-9 180587-75-1 1002339-71-0 1135389-73-9 441785-21-3 206646-04-0 1004956-31-3 1135389-75-1 182799-03-7 116384-53-3 1004956-37-9 1135389-79-5 135295-28-2 441785-25-7 1004956-38-0 1135389-83-1 182798-87-4 206184-49-8 1004956-39-1 1174936-58-3 147127-16-0 113852-37-2 1010415-54-9 1174936-59-4 402575-05-7 114088-58-3 1016647-2 6- 9 118553-04-1 147 127-17-1 444 805-2 8-1 1016647-27-0 11858 0-13-5 1827 98- 94-3 14 93 94- 66-1 1016647-2 8-1 12 0447 8- 99-8 1664 03- 66-3 123 961 8-1 9- 9 1016968-33-4 1245542-30- 6 1827 98-8 9- 6 123 961 8-2 0-2 102 98 65-7 0-0 1245542-31-7 1824 15-4 0-3 123 961 8-22-4 102 98 65-73-3 1245542-32-8 1827 98-8 8-5 123 961 8-24- 6 1030 137- 98-4 1245542-34-0 1827 98-7 6-1 123 961 8-25-7 10317 05-73-3
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