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FMO3 Inhibitors for Treating Pain

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FMO3 Inhibitors for Treating Pain (19) TZZ ___T (11) EP 2 674 161 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 18.12.2013 Bulletin 2013/51 A61K 31/675 (2006.01) A61K 31/4164 (2006.01) A61P 29/00 (2006.01) (21) Application number: 13174939.2 (22) Date of filing: 11.11.2011 (84) Designated Contracting States: • Neely, Graham Gregory AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Sydney, 2015 (AU) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • McManus, Shane PL PT RO RS SE SI SK SM TR 1030 Vienna (AT) Designated Extension States: • Nilsson, Henrik BA ME 1030 Vienna (AT) (30) Priority: 11.11.2010 EP 10190922 (74) Representative: Sonn & Partner Patentanwälte Riemergasse 14 (62) Document number(s) of the earlier application(s) in 1010 Wien (AT) accordance with Art. 76 EPC: 11781808.8 / 2 637 649 Remarks: •This application was filed on 03-07-2013 as a (71) Applicant: Akron Molecules GmbH divisional application to the application mentioned 1030 Vienna (AT) under INID code 62. •Claims filed after the date of receipt of the divisional (72) Inventors: application (Rule 68(4) EPC). • Penninger, Josef 1130 Vienna (AT) (54) FMO3 inhibitors for treating pain (57) The present invention relates to new therapies to treat pain and related diseases, as well as pharmaceutical compounds for use in said therapies. EP 2 674 161 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 674 161 A1 Description [0001] The present invention relates to the field of method of treatment of pain and the provision of pharmaceutical compounds suitable for such treatments. 5 [0002] Acute and chronic pain affects millions of people after injury or surgery and those suffering from diseases like arthritis, 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 threshold primary sensory neurons (nociceptors), which transfer signals to the spinal cord 10 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 nociception; patients with congenital insensitivity to pain do not survive past their twenties. [0003] 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 ongoing tissue damage caused by noxious chemical, 15 thermal and mechanical stimuli. Examples of nociceptive pain include: postoperative pain, pain associated with trauma, and the pain associated with arthritis. Chronic pain, on the other hand, serves no protective biological function, and reflects either poor resolution of the painful stimuli, or is itself a disease process. Chronic pain is unrelenting and not self-limiting and can persist for years and even decades after the initial injury. Chronic pain is predominantly neuropathic in nature and may involve damage either to the peripheral or central nervous systems. 20 [0004] 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. [0005] 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 ), 569EKB- ( Pelitinib ), sorafenib , Vandetanib, 1033CI- 25 ( Canertinib ), NSC161613, N6-Benzyladenosine-5’-phosphate, p-Aminobenzoly PAB-J acid, NSC47091, cilomilast , Nicotinamide ( Nicotinamide ), IBMX, Roflumilast, Filaminast, Piclamilast, V11294, CC- 10004 ( Apremilast ), LAS31025 ( Arofylline ), CP80633 ( Atizoram ), Catramilast/Atopik ( Catramilast ), BRL-61063 ( Cimpyfylline ), Daxalipram/meso- pram ( Daxalipram ), Doxofylline, Drotaverine, Efloxate, Etamiphylline, Etazolate, Etofylline, Glaucine Hydrobromide ( Broncholytine ), GRC3886 ( oglemilast ), oxtriphyllin ( Choline theophyllinate ), Pumafentrine, Revamilast, Tofimilast, 30 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, Vardenafil, 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)-Tofisopam ( Dextofisopam ), (S)-Tofisopam ( Levotofisopam (USAN) ), EKB-568, SU-14813, LY-333531 ( Ruboxistaurin ), CGP- 52421, SKI-606 ( Bosutinib ), Roscovitine, Tenofovir (PMPA), Methimazole, Adefovir 35 dipivoxil (Bis-POM PMEA) ( Adefovir ), Acetazolamide, midostaurin ( 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, especially in the treatment of neuropathic pain. Alternative names or identification of the compounds are given in brackets. Chemical structures of some of these compounds are given as follows: 40 V11294 -[(3-cyclopentyloxy-4-methoxyphenyl) methyl]-N-ethyl-8-propan-2-ylpurin-6- amine: 45 50 55 2 EP 2 674 161 A1 (continued) GW 842470 (AWD 12-281) N-(3,5-dichloropyridin-4-yl)-2-[1-[(4- fluorophenyl)methyl]-5-hydroxyindol-3- 5 yl]-2-oxoacetamide 10 15 CDP-840 4- [(2R) -2- [3-(Cyclopentyloxy)-4- methoxyphenyl]-2-phenylethyl]-pyridine hydrochloride 20 25 YM-976 4-(3-Chlorophenyl)-1,7-diethylpyrido [2,3-d]pyrimidin-2(1H)-one 30 35 CI-1018 N-[9-Methyl-4-oxo-1-phenyl-3,4,6,7- tetrahydro-pyrrolo[3,2,1-jk][1,4] benzodiazepin-3(R)-yl]pyridine-4- carboxamide 40 D-4418 -(3,5-Dichloro-4-pyridinyl)-8- methoxyquinoline-5-carboxamid 45 50 55 3 EP 2 674 161 A1 (continued) SCH-351591 3,5-dichloro-4-(8-methoxy- 2-(trifluorome-thyl)quinolin-5-ylcarbox- 5 amido)pyridine-1-oxide 10 SCH 351591 RPL-554 N-{2-[(2E)-2-(mesitylimino)-9,10- 15 dimethoxy-4-oxo-6,7-dihydro-2H- pyrimido[6,1-a]-isoquinolin-3(4H)-yl] ethyl}urea 20 25 IPL-455903 (HT-0712) (3R,5R)-5-(3-(cyclopentyloxy)-4- methoxyphenyl)-3-(3-methylbenzyl) piperidin-2-one 30 35 GSK256066 6-[[3-[(Dimethyla-mino)carbonyl]phenyl] su lfonyl]-4-[(3-methoxyphenyl)amino]- 8-methyl-3-quinolinecarboxamide 40 OPC-6535 6-[2-(3,4-diethoxyphenyl)-1,3-thiazol-4- 45 yl]pyridine-2-carboxylic acid 50 55 4 EP 2 674 161 A1 (continued) L-826,141 4-[2-[3,4-Bis(difluoromethoxy)phe nyl]- 2-[4-[2,2,2-trifluoro-1-hydroxy- 5 1-(trifluorome-thyl)ethyl]phenyl]ethyl ]- 3-methylpyridine N-oxide 10 L-826,141 (Enantiomer 1) CI-1044 N-(9-amino-4-oxo-1-phenyl-3,4,6,7- tetrahydro(1,4)diazepin o(6,7,1-hi)indol- 15 3-yl)nicotinamide 20 MK-0873 (-)-trans-2-(3’-(3-(N-Cycloprpropylcarbamoyl)-4-oxo-1,4-dihydro-1,8-naphthyridin-1- yl)-3-fluorobiphenyl-4-yl) cycloprpanecarboxylic acid T-2585 25 30 AN2728 5-(4-cyanophenoxy)-2,3-dihydro-1- hydroxy-2,1-benzoxaborole 35 40 SU-14813 (S,Z)-5-((5-fluoro-2-oxoindolin-3- ylidene)methyl)-N-(2-hydroxy-3- morpholinopropyl)-2,4-dimethyl-1H- pyrrole-3-carboxamide 45 50 55 5 EP 2 674 161 A1 (continued) CGP-52421 5 10 15 NSC161613 2-[[2-[(2-aminoacetyl)amino]-3-(2,4- dinitrophenyl)sulfanylp ropanoyl]amino] 20 pentaned ioic acid 25 30 NSC47091 2-(3-carboxyprop-2-enoylamino)- 6-[[(2)-3-carboxyprop-2-enoyl]amino] benzoic acid 35 40 [0006] In preferred embodiments the inventive compound is an inhibitor (i.e. an antagonist) or modulator of any one of FRK, PDE4D, LPAR3, CAMK1D, CSNK1G3 or FMO3. Inhibitors or ligands (i.e. binders) or modulators of FRK, PDE4D, LPAR3, CAMK1D, CSNK1G3 or FMO3 can be used in the treatment of pain in a subject. In preferred embodiments the FRK, PDE4D, LPAR3, CAMK1D, CSNK1G3 or FMO3 modulator is a selective FRK, PDE4D, LPAR3, CAMK1D, 45 CSNK1G3 or FMO3 modulator. By "selective" it is meant that the affinity for one of FRK, PDE4D, LPAR3, CAMK1D or FMO3 is at least 10-fold, preferably 25-fold, more preferred 100-fold, still preferred 150-fold higher than the affinity of the other targets selected from FRK, PDE4D, LPAR3, CAMK1D or FMO3. [0007] Surprisingly it has been shown that some of these targets, such as FRK, FMO3, LPAR3 can be both activated, e.g. by an agonist, or inhibited (e.g. by an inhibitor or antagonist) for an anti-pain effect in a patient. The group of agonists 50 and antagonists 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 1000nM 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. 55 [0008] In particular preferred are FMO3 modulators or inhibitors for use in the treatment of pain. Such compounds are e.g. Tenofovir and Methimazole. [0009] In particular preferred are FRK modulators or inhibitors for use in the treatment of pain. Such compounds are 6 EP 2 674 161 A1 e.g. dasatinib, motesanib, Doramapimod, Pelitinib, sorafenib, Vandetanib and Canertinib. [0010] Preferably the inhibitor is selected from compounds with a Kd of lower than 3000 nM, preferably lower than 2000 nM, especially preferred lower than 1000 nM.
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