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„ 2012/062925 A2 (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 18 May 2012 (18.05.2012) 2012/062925 A2 (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, A61K 31/00 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (21) International Application Number: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, PCT/EP201 1/069986 ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (22) International Filing Date: NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, 11 November 201 1 ( 11. 1 1.201 1) RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (25) Filing Language: English ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 10190922.4 11 November 2010 ( 11. 1 1.2010) EP GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, (71) Applicant (for all designated States except US): AKRON RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, MOLECULES GMBH [AT/AT]; Campus-Vienna-Bio- DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, center 5, A-1030 Vienna (AT). LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, (72) Inventors; and GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (75) Inventors/ Applicants (for US only): PENNINGER, Josef [AT/AT]; Himmelhofgasse 62, A-1 130 Vienna Declarations under Rule 4.17 : (AT). NEELY, Graham Gregory [CA/AU]; 4/186-190 — as to the applicant's entitlement to claim the priority of Lawrence St, Alexandria, Sydney, 2015 (AU). MC- the earlier application (Rule 4.17(Hi)) MANUS, Shane [IE/AT]; Klimschgasse 5/5, A-1030 Vi enna (AT). — of inventorship (Rule 4.1 7(iv)) (74) Agent: SONN & PARTNER Patentanwalte; Riemer- Published: gasse 14, A-1010 Vienna (AT). — without international search report and to be republished (81) Designated States (unless otherwise indicated, for every upon receipt of that report (Rule 48.2(g)) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, < © o (54) Title: COMPOUNDS AND METHODS FOR TREATING PAIN o (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. Compounds and methods for treating 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 m e 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. It is a goal of the present invention to provide methods of treating, ameliorating or suppressing pain, in particular 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. These compounds are given in the claims, and especially include Tenofovir (PMPA) , dasatinib, AMG-706 ( motesanib ), BIRB 796 ( Doramapimod ), EKB-569 ( Pelitinib ), sorafenib , Vandetanib, CI-1033 ( Canertinib ) , NSC161613, N6- Benzyladenosine-5 '-phosphate, p-Aminobenzoly PAB-J acid, NSC47091, cilomilast , Nicotinamide ( Nicotinamide ) , IBMX, Roflumilast, Filaminast, Piclamilast, V11294, CC-10004 ( Apre- milast ), LAS31025 ( Arofylline ), CP80633 ( Atizoram ), Ca- tramilast/Atopik ( Catramilast ), BRL-61063 ( Cimpyfylline ), Daxalipram/mesopram ( Daxalipram ), Doxofylline, Drotaverine, Efloxate, Etamiphylline, Etazolate, Etofylline, Glaucine Hydro- bromide ( Broncholytine ) , GRC3886 ( oglemilast ) , oxtriphyllin ( Choline theophyllinate ), Pumaf entrine, Revamilast, Tofimi- last, Tolafentrine, Seoanin ( Trapidil ), GW 842470 (AWD 12- 281), CDP-840, YM-976, CI-1018, D-4418, Lirimilast, SCH-351591, RPL-554, IPL-455903 (HT-0712), GSK256066, Zardaverine, Varden- afil, OPC-6535 ( Tetomilast ) , IC485, L-826,141, ONO-6126, CI- 1044, MK-0873, T-2585, R1533 (MEM-1414), Ronomilast ( ELB-353 ) , UK-500,001, AN2728 , DE-103, Tofisopam, (R) -Tof isopam ( Dex- tofisopam ) , (S )-Tof isopam ( Levotof isopam (USAN) ) , EKB-568, SU-14813, LY-333531 ( Ruboxistaurin ) , CGP-52421, SKI-606 ( Bo- sutinib ), Roscovitine, Tenofovir (PMPA) , Methimazole, Adefovir dipivoxil (Bis-POM PMEA) ( Adefovir ), Acetazolamide, midostau- rin ( PKC-412 ) , tozasertib ( MK-0457, VX 680 ) or lestaurtinib ( CEP-701 ). A further compound is imatinib (STI-571), which is preferably used in the treatment on non-inflammatory pain, espe cially in the treatment of neuropathic pain. Alternative names or identification of the compounds are given in brackets. Chem i cal structures of some of these compounds are given as follows: V11294 - [(3-cyclopentyloxy-4- methoxyphenyl )methyl ]- N-ethyl-8-propan-2- ylpurin- 6-amine : In preferred embodiments the inventive compound is an inhib itor (i.e. an antagonist) or modulator of any one of FRK, PDE4D, LPAR3, CAMK1D, CSNK1G3 or FM03 . Inhibitors or ligands (i.e. binders) or modulators of FRK, PDE4D, LPAR3, CAMK1D, CSNK1G3 or FM03 can be used in the treatment of pain in a subject. In pre ferred embodiments the FRK, PDE4D, LPAR3, CAMK1D, CSNK1G3 or FM03 modulator is a selective FRK, PDE4D, LPAR3, CAMKID, CSNK1G3 or FM03 modulator. By "selective" it is meant that the affinity for one of FRK, PDE4D, LPAR3, CAMK1D or FM03 is at least 10- fold, preferably 25-fold, more preferred 100-fold, still pre ferred 150-fold higher than the affinity of the other targets selected from FRK, PDE4D, LPAR3, CAMK1D or FM03 . Surprisingly it has been shown that some of these targets, such as FRK, FM03, LPAR3 can be both activated, e.g. by an ago nist, or inhibited (e.g. by an inhibitor or antagonist) for an anti-pain effect in a patient. The group of agonists and antago nists is refered to herein as "modulators". Although in most cases an inhibitor is preferred for greater effect, it seems that modulation of activity of these targets in any direction reduces the pain or sensation of pain. Preferably the modulator is a strong binder to these targets, especially with a Kd of ΙΟΟΟηΜ or less or an IC50 of 1000 nM or less. Preferred lower values for Kd and IC50 are 800 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 50 nM or less or even 30 nM or less. In particular preferred are FM03 modulators or inhibitors for use in the treatment of pain. Such compounds are e.g. Tenofovir and Methimazole. In particular preferred are FRK modulators or inhibitors for use in the treatment of pain. Such compounds are e.g. dasatinib, motesanib, Doramapimod, Pelitinib, sorafenib, Vandetanib and Canertinib . Preferably the inhibitor is selected from compounds with a Kd of lower than 3000 nM, preferably lower than 2000 nM, espe cially preferred lower than 1000 nM. In particular, these com pounds can be selected from dasatinib (Kd 0.31 nM) , motesanib (Kd 99 nM) , Doramapimod (Kd 360 nM) , Pelitinib (Kd 190 nM) , so rafenib (Kd 440 nM) and Vandetanib (Kd 480 nM) . The Kd may also be up to 750 nM or up to 500 nM. Kd, K i or IC50 values of course relate to the binding or in hibiting capability of a given compound on a given target, such as one of FRK, PDE4D, LPAR3, CAMKID, CSNK1G3 or FM03, as associ ated herein. In preferred embodiments the FRK modulator is selected from compounds comprising a substituted pyridine, quinoline, isoquin- oline or pyridine group. In especially preferred embodiments the FRK modulator is an FRK inhibitor. An inhibitor or antagonist is a compound that lowers or inhibits the activity of a given target here FRK. This can be achieved by binding to the target, e.g. but not neces sarily to the catalytic center, and preventing the catalytic ac tivity of the target. Preferably an inhibitor or modulator, in particular of FRK, is selected from compounds comprising a substituted pyrimidine, quinoline, isoquinoline or pyridine group, such as from motesanib (AMG-706) , Pelitinib (EKB-569) , sorafenib (sorafenib), Vandetanib (Vandetanib) , canertinib ( CI-1033 ).
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