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WO 2017/178820 Al 19 October 2017 (19.10.2017) P O P C T

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WO 2017/178820 Al 19 October 2017 (19.10.2017) 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 2017/178820 Al 19 October 2017 (19.10.2017) P O P C T (51) International Patent Classification: (72) Inventors: VASUDEVAN, Dr. Sridhar; c/o Oxford Uni A61K 31/44 (2006.01) A61K 31/519 (2006.01) versity Innovation Limited, Buxton Court, 3 West Way, A61K 31/4439 (2006.01) A61K 31/53 (2006.01) Botley Oxford OX2 0JB (GB). JAGANNATH, Dr. Aarti; A61K 31/505 (2006.01) A61P 43/00 (2006.01) c/o Oxford University Innovation Limited, Buxton Court, 3 A61K 31/517 (2006.01) West Way, Botley Oxford OX2 0JB (GB). FOSTER, Prof Russell; c/o Oxford University Innovation Limited, Buxton (21) International Application Number: Court, 3 West Way, Botley Oxford OX2 0JB (GB). PCT/GB20 17/05 1029 (74) Agent: BARKER BRETTELL LLP; 100 Hagley Road, (22) International Filing Date: Edgbaston, Birmingham West Midlands B16 8QQ (GB). 12 April 2017 (12.04.2017) (81) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of national protection available): AE, AG, AL, AM, (26) Publication Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (30) Priority Data: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 1606622.7 15 April 2016 (15.04.2016) GB HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, (71) Applicant: OXFORD UNIVERSITY INNOVATION KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, LIMITED [GB/GB]; Buxton Court, 3 West way, Botley MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, Oxford OX2 0JB (GB). NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, [Continued on nextpage] (54) Title: ADENOSINE RECEPTOR MODULATORS FOR THE TREATMENT OF CIRCADIAN RHYTHM DISORDERS Figure 1 Figure 1 (57) Abstract: The present invention relates continued A to the use of adenosine receptor modulators to affect the circadian rhythm, in particular, "Λ to the use of such modulators for the treat ment of circadian rhythm disorders. In par ticular, the invention relates to a com posi hr) tion com prising at least one selective aden osine receptor modulator, wherein said composition modulates two or three, but not al 1of adenosine receptor subtypes Ai, A 2A , A 2B and/or A for use in the treatment of cir cadian rhythm disorders or for modulating a biological clock. 1 ° Figure 1 Π n continued a WO 2017/178820 Al III I II II 11 I I 11 III III III 11 I III lllll 11 111 llll 11llll RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, VN, ZA, ZM, ZW. SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, (84) Designated States (unless otherwise indicated, for every GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). kind of regional protection available): ARIPO (BW, GH, Published: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, — with international search report (Art. 21(3)) TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, ADENOSINE RECEPTOR MODULATORS FOR THE TREATMENT OF CIRCADIAN RHYTHM DISORDERS The present inventio n rel ates t o the use of adenosi ne receptor modulators t o affect the circad ian rhyth m, in particu lar, t o the use of such modulators for the treatm ent of circad ian rhyth m disorders. In particu lar, the inventio n rel ates t o a com positio n co mprisi ng at least one sel ective adenosi ne receptor modulator, wherei n sa id co mposition modulates two or t hree, but not all of adenosi ne receptor su btypes Ai, A2A, A2B and/or A3 for use in the treatm ent of circad ian rhyth m disorders or for modulati ng a biol ogica l clock. Almost all orga nism s on Ea rth apply an intern al biol ogica l tim er t o antici pate cha nges that acco mpany the daily sol ar cycl e. The possessio n of such an interna l tim er allows orga nism s t o inherently "know" where in the daily sol ar cycle they are, absent of externa l cues. Such intern ally generated daily rhyth ms are called "circad ian rhyth ms", and are endogenous t o the orga nism . The mecha nism s underlyi ng circad ian rhyth ms involve circad ian oscil latio ns in processes such as gene expression and protei n modificatio ns. A core clock control s t hese circad ian osci llations by sign al generation . The mammalia n circad ian clock in the bra in conveys 24-ho ur rhyth micity t o rest- activity cycl es, tem peratu re, sleep, and virtua lly all other behaviou ral and physiol ogica l processes. The impositio n of an interna l tem pora l fra mework is an essentia l part of an orga nism' s biol ogy; it allows all of t he interna l processes t o work in harmony, such as gene expressio n, cel l divisio n and meta bol ism. In order for su ch rhyth ms t o be ada ptive, they must be synch ron ised, or entra ined, t o the externa l environ ment, pred ominantly prod uced by the 24 hour light/d ark cycl e due t o the rotation of the Ea rth, and/or t o other entra ining sign als, known as "tim e givers" or zeitgebers. It is key that circad ian rhyth ms are generated intern ally by t he orga nism, and are not driven by the externa l environ ment. However, these endogenous circad ian rhyth ms are adj usted by environ menta l signa ls, such that they are synch ron ised t o t he externa l cycl e or clock. In the absence of externa l cues or sign als, the endogenous circad ian rhyth m in a human on average runs sl ightly longer t han 24 hours. Th is may be the case in tota lly blind su bjects who are lacki ng conscious light perception, where the com plete absence of detection of the light/d ark cycle may be sufficient f or the clock t o run free of adj ustm ent based on externa l signa ls. In these cases, the circad ian rhyth m may req uire rea lign ment, such that the interna l clock is running at the sa me tim e as the externa l one. The interna l circad ian clock has its own tim e, known as circad ian t ime (CT); w hich is a sta nda rd of t ime based on the free-ru nning period of a rhyth m (oscil latio n). Th is may or may not be align ed with the externa l/environ menta l t ime. CT is effectively the interna l tim e (either for the whol e clock or the rel eva nt tissue) . Time rel ative t o the externa l envi ron ment is denoted as ZT or Zeitgeber t ime. Under entra ined cond itio ns, CTO = ZTO = sta rt of the light phase (typ ica lly 6 or 7 am) and under free-ru nning co nditions, CTO in a human wou ld be the tim e at w hich the onset of activity occu rs. Determ ining the CT of a tissu e or ind ivid ual is possibl e via testing, as discu ssed later. The mecha nism underlyi ng the clock is a ubiq uito us cel l auto nom ous tra nscri ption- tra nsl ation feed back loop (TTF L) in w hich the tra nscri ption f actors CLOCK and BMALl drive the expression of Period (Perl/2) and Cryptochrome (Cryl/2), whose protei n prod ucts in t urn feed back t o inhibit CLOC K and BMALl resu lti ng in a negative feed back loop with in a 24 hou r period . Each individ ual cel l of an orga nism has an individ ual cel lular clock. Individ ual cel lula r clocks are mainta ined in synch rony by a master pacem aker in the su prach iasmatic nuclei (SCN ) in the hypotha lamus. In order t o ada pt t o the externa l 24 hour worl d, the clock must receive and respo nd t o signa ls that provide tem pora l cues (zeitgebers) . Zeitgebers modulate the tem pora l expression pattern of clock genes such as Perl/2 (Schwa rtz et al., Proc Natl Aca d Sci U S A 108, 17219-17 224, 20 11) t o set the phase, amplitude and period of oscil latio n of t he molecu lar clock. Light, w hich signa ls the dawn-d usk cycl e, drives cAM P response element binding factor (C EB)- mediated tra nscri ption of Per gen es. However, circad ian clocks t hrough out t he body receive inputs from numerous sou rces incl uding food, glucocorticoids and tem peratu re.
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