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WO 2011/083304 Al (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 14 July 2011 (14.07.2011) WO 2011/083304 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61P 25/04 (2006.01) C07D 489/00 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/55 (2006.01) C07C 271/58 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/485 (2006.01) C07D 489/08 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, C07D 223/04 (2006.01) C07D 211/22 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, C07D 401/12 (2006.01) HN, HR, HU, ID, J , IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (21) International Application Number: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, PCT/GB20 10/0522 11 NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (22) International Filing Date: SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 23 December 2010 (23.12.2010) TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English ( 4) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Langi English GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, (30) Priority Data: ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 61/292,362 5 January 2010 (05.01 .2010) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (71) Applicant (for all designated States except US): SHIRE LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, LLC [US/US]; 9200 Brookfield Court, Florence, Ken SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, tucky KY 41042 (US). GW, ML, MR, NE, SN, TD, TG). (72) Inventors; and Declarations under Rule 4.17 : (75) Inventors/Applicants (for US only): FRANKLIN, — as to the applicant's entitlement to claim the priority of Richard [GB/GB]; 3 Rosedene Gardens, Fleet, Hamp the earlier application (Rule 4.17(Hi)) shire GU5 1 4NQ (GB). GOLDING, Bernard [GB/GB]; 42 Dukesfield, Shiremoor, Newcastle upon Tyne, Tyne — of inventorship (Rule 4.1 7(iv)) and Wear NE27 0EZ (GB). SWIFT, Karl [GB/GB]; 30 Published: Chasewood Corner, Stroud, Gloucestershire GL6 8JS (GB). TYSON, Robert [GB/GB]; Holly Lodge, Whites- — with international search report (Art. 21(3)) mocks, Durham DH1 4LH (GB). (74) Agent: HARRISON GODDARD FOOTE; Belgrave Hall, Belgrave Street, Leeds LS2 8DD (GB). (54) Title: PRODRUGS OF OPIOIDS AND USES THEREOF ∞ 3 4 o Ti e (ho u (57) Abstract: The present invention concerns prodrugs of opioid analgesics and pharmaceutical compositions containing such prodrugs. Methods for providing more consistent pain relief by increasing the bioavailability of the opioid analgesic with the aforementioned prodrugs are provided. The invention also provides for decreasing the adverse GI side effects of opioid analgesics. PRODRUGS OF OPIOIDS AND USES THEREOF FIELD OF THE INVENTION [01] The present invention relates to opioid prodrugs, their synthesis and use, and other subject matter. The invention provides amongst other things opioid prodrugs which aim to improve the opioid's systemic availability and/or minimize the adverse gastrointestinal (Gl) side-effects associated with the administration of the parent compound. [02] BACKGROUND OF THE INVENTION [03] Appropriate treatment of pain continues to represent a major challenge for both patients and healthcare professionals. Optimal pharmacologic management of pain requires selection of the appropriate analgesic drug that achieves rapid efficacy with minimal side effects. Opioid analgesics offer perhaps the most important option in the treatment of nociceptive pain and remain the gold standard of treatment. [04] A major shortcoming of many of the opioids is that they suffer from poor oral bioavailability due to first pass glucuronidation of the commonly present phenolic function. This has been shown, for example, with oxymorphone (Sloan et al. (2005). Supp Care Cancer 13 , 57-65), meptazinol (Norbury et al. ( 1983). Eur J Clin Pharmacol 25, 77-80) and buprenorphine (Kintz and Marquet (2002). pp 1- 11 in Buprenorphine Therapy in Opiate Addiction, Humana press). Such poor oral bioavailability results in variable blood levels of the respective opioid, and therefore, variable patient response - a highly undesirable feature in the treatment of pain where rapid and reliable relief is demanded. [05] Various types of prodrugs have historically been proposed to minimize first pass metabolism and so improve the oral bioavailability of opioids. These have included simple ester conjugates which are frequently hydrolyzed by plasma esterases extremely quickly. Such rapid hydrolysis by plasma esterases limits the utility of ester linked prodrugs and denies the necessary transient protection of the opioid against first past metabolism. [06] The rapidity of hydrolysis of ester conjugates is illustrated by work on the morphine ester prodrug morphine-3-propionate. Morphine has a poor oral bioavailability due to extensive first pass glucuronidation at the 3 and the 6 positions, resulting in much inter and intra subject variability in analgesic response after an oral dose of the drug (Hoskin ( 1989). Br. J. Clin Pharmacol 27, 499-505). The plasma and tissue stability of the 3-propionate prodrug was investigated, and it was found to be hydrolyzed in human plasma with a half- life of less than 5 minutes (Goth et al. ( 1997). International Journal of Pharmaceutics 154, 149-1 55). [07] Meptazinol is another opioid with poor oral bioavailability (< 10%). The low oral bioavailability has been attributed to high first pass glucuronidation (Norbury et al. ( 1983) Eur. J. Clin. Pharmacol. 25, 77-80). Attempts have been made to overcome this problem by the use of ester linked meptazinol prodrugs (Lu et al. (2005). Biorg. and Med. Chem Letters 15 , 2607-2609 and Xie et al. (2005). Biorg. and Med. Chem. Letters 15 , 493-4956). However, only one of these prodrugs - ((Z)-3-[2-(propionyloxy) phenyl]-2-propenoic ester) showed a significant increase in bioavailability over meptazinol itself, when tested in a rat model. However, to the Applicants knowledge, no further data has been published on this prodrug. These workers did subsequently publish on the utility of a phenyl carbamate derivative of (-)meptazinol but only with the aim of increasing the inherent in vitro potency of the compound as an inhibitor of acetyl choline esterase and not as a prodrug (Chou Z et al (2007) Chinese Patent Application Number 20071 0038209.7). [08] An alternative strategy for creating a prodrug from the hydroxylic/phenolic function present in the opioids is the formation of O-alkyI (alkyl ether) or aryl ether conjugates. However, such derivatives appear to be very resistant to hydrolysis and metabolic activation. This is best illustrated by the 3-methyl ether prodrug of morphine - codeine. While codeine was not originally developed as a prodrug of morphine, it was subsequently found to give rise to small quantities of morphine. It has been estimated that less than 5% of an oral dose of codeine is converted to morphine - reflecting the slowness with which O-dealkylation takes place (Vree et al. ( 1992). Biopharma Drug Dispos. 13 , 445-460 and Quiding et al. ( 1993). Eur. J. Clin. Pharmacol. 44, 3 19-323). The same phenomenon was observed for the corresponding dihydromorphine prodrug - dihydrocodeine, with less than 2% of an oral dose of dihydrocodeine being converted to dihydromorphine (Balikova et al. (2001 ). J. Chromatog. Biomed. Sci. Appl. 752, 179-1 86). [09] A further disadvantage of the O-alkyI ether prodrugging strategy is that the dealkylation of these opioids is effected by cytochrome P450 2D6 (Cyp2D6), a polymorph ically expressed enzyme (Schmidt et al. (2003). Int. J. Clin. Pharmacol. Ther. 4 1, 95-1 06). This polymorphic enzyme expression inevitably results in substantial variation in patient exposure to the respective active metabolite (e.g. , morphine and dihydromorphine). For example, low/negligible exposure to morphine derived from codeine has been reported amongst a large group of patients deficient in Cyp2D6 activity, potentially impacting the analgesic efficacy of codeine (Poulsen et al. ( 1998). Eur. Clin. Pharmacol. 54, 451 -454). [01 0] An ideal prodrug moiety and linkage for a particular opioid would afford the optimal balance of protection against first pass metabolism and subsequent efficient release of the active drug . There therefore remains a real need in the treatment of severe pain with opioids for products which retain all the inherent pharmacological advantages of the opioids, but which avoid or reduce their principal limitations of ( 1) low and erratic systemic availability after oral dosing and (2) induction of adverse Gl side effects, including emesis and chronic constipation. SUMMARY OF THE INVENTION [01 1] According to one aspect, the present invention provides a method of treating a disorder in a subject in need thereof with an opioid . The method comprises orally administering a therapeutically effective amount (e.g. , an analgesically effective amount) of an opioid prodrug or a pharmaceutically acceptable salt thereof to the subject, wherein the opioid prodrug comprises an opioid analgesic covalently bonded via a carbamate or thiocarbamate linkage, preferably via a carbamate linkage, to an amino benzoic acid (ABA) or an analogue thereof. The disorder may be one treatable with an opioid. For example, the disorder may be pain, e.g. neuropathic pain or nociceptive pain. [012] According to another aspect, the present invention provides a method for increasing the oral bioavailability of an opioid analgesic which has a significantly lower bioavailability when administered in its underivatized form.
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