(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 4 February 2010 (04.02.2010) WO 2010/013279 A3 (51) International Patent Classification: celle (AV) (IT). LA RANA, Giovanna [IT/IT]; Via M . A61K 47/48 (2006.01) A61P 29/00 (2006.01) Schipa, 64, 1-80122 Napoli (IT). SASSO, Oscar [IT/IT]; Corso Umberto I, 259, 1-80034 Marigliano (NA) (IT). (21) International Application Number: SARNELLI, Giovanni [IT/IT]; Via Napoli, 27, 1-80078 PCT/IT2009/000341 Pozzuoli (NA) (IT). RUSSO, Roberto [IT/IT]; Via del (22) International Filing Date: Priorato, 39, 1-80135 Napoli (IT). NIEDDU, Maria 29 July 2009 (29.07.2009) [IT/IT]; Via dei Mille, 3 1, 1-07100 Sassari (SS) (IT). CIRILLO, Carla [IT/IT]; Via Giuseppe Verdi, 40, (25) Filing Language: Italian 1-81030 Orta di Atella (CE) (IT). DE LUCIA, Salvatore (26) Publication Language: English [IT/IT]; Via Frazione Cagni, 12, 1-8201 1 Forchia (BN) (IT). (30) Priority Data: NA2008A000047 29 July 2008 (29.07.2008) rr (74) Agent: SARPI, Maurizio; Studio Ferrario, Via Collina, 36, 1-00187 Roma (IT). (71) Applicant (for all designated States except US): STEW¬ ART ITALIA SRL [IT/IT]; Corso G. Matteotti, 10, (81) Designated States (unless otherwise indicated, for every 1-2012 1 Milano (IT). kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (72) Inventors; and CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (71) Applicants : RIMOLI, Maria Grazia [IT/IT]; Via San DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, Nullo, 64, 1-80014 Giugliano (NA) (IT). CALIGNANO, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, Antonio [IT/IT]; Corso Amedeo di Savoia, 239, 1-801 36 KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, Napoli (NA) (IT). CUOMO, Rosario [IT/IT]; Via Martiri ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, delle Foibe, 11, 1-81 100 Caserta (IT). BOATTO, Gian- NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, piero [IT/IT]; Via delle Magnolie 43/B, 1-07100 Sassari SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, (IT). TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (72) Inventors; and (84) Designated States (unless otherwise indicated, for every (75) Inventors/ Applicants (for US only): ABIGNENTE, En¬ kind of regional protection available): ARIPO (BW, GH, rico [IT/IT]; Via Cilea, 112, 1-80127 Napoli (IT). GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, MELISI, Daniela [IT/IT]; Via Lago di Viverone, 71, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 1-74 100 Taranto (IT). CURCIO, Annalisa [IT/IT]; Via TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, Roma, 105, 1-80058 Torre Annunziata (NA) (IT). LUON- ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, GO, Elvira [IT/IT]; Via Piesco, 18, 1-83030 Torre Ie No- MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, [Continued on next page] (54) Title: GALACTOSYLATED PRO-DRUGS OF NON-STEROIDAL ANTI-INFLAMMATORIES WITH IMPROVED PHARMACOKINETIC CHARACTERISTICS AND REDUCED TOXICITY OF THE STARTING DRUG (57) Abstract: Pro-drugs of all non-steroidal anti-inf lammatories with free acid function derivatized with an ester group, which have the general structural formula given below (I) where A is: aspirin, diflunisal, benorylate, ibufenac, diclofenac, indomethacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclof enamic acid, flufenamic acid, niflumic acid, and where in the ester group R can be a sugar (amongst which aldose, or ketose pentose, or esose selected from a group of D- and L- enantioiuers of ribose, glucose, galactose, mannose, arabinose, xilose, allose, altrose, gulose, idose and talose and substituted derivatives thereof, such as glucosamine, galactosamine, iV-acetyl glucosamine, iV-acetyl galactosamine, N- acetyl ribosamine), a disaccharide, a trisaccharide or an oligosaccharide. τ < T T <J T n r \ , , , , — before the expiration of the time limit for amending the M MK I I . claims m d (o b e repubHshed in the event of rece t of Published: amendments (Rule 48.2(h)) — with international search report (Art. 21(3)) (88) Date of publication of the international search report: 6 May 2010 A. CLASSIFICATION OF SUBJECT MATTER INV. A61K47/48 A61P29/00 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K A61P Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practical, search terms used) EPO-Internal , WPI Data, COMPENDEX, EMBASE, BIOSIS C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No WO 98/35973 A (OREAL [FR]; DALKO MARIA 3,9-17 [FR]; GALEY JEAN BAPTISTE [FR]) 20 August 1998 (1998-08-20) the whole document figure 1 ; example 1 1,2 HANESSIAN S ET AL: "One-step 3,10-17 stereocontrolled synthesis of [alpha]-anomeric carboxylic acid esters from unprotected glycosyl donors: A water-soluble aspirin pro-drug analogue" SYNTHESIS 2002 GEORG THIEME VERLAG DE, no. 14, 2002, pages 1959-1968, XP002527135 the whole document page 1962; compound 11 / Further documents are listed in the continuation of Box C See patent family annex Special categories of cited documents later document published after the international filing date or priority date and not in conflict with the application but ' document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention Ξ' earlier document but published on or after the international document of particular relevance, the claimed invention filing date cannot be considered novel or cannot be considered to . ' document which may throw doubts on priority cla ιm(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance, the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu¬ other means ments, such combination being obvious to a person skilled " document published prior to the international filing date but in the art later than the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 26 October 2009 24/03/2010 Name and mailing address of the ISA/ Authorized officer European Patent Office, P B 5818 Patentlaan 2 NL - 2280 HV Rijswijk TeI (+31-70) 34 0-2040, Fax (+31-70) 340-3016 Orl ando , Michel e Form PCT/ISA/210 (second sheet) (April 2005) C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. WO 2004/002457 A (A & D BIOSCIENCE INC 1-3,7-17 [US]; HOLICK MICHAEL F [US]; RAMANATHAN HALASYA [) 8 January 2004 (2004-01-08) the whole document paragraphs [0048] - [0059] US 2005/215487 A l (HOLICK MICHAEL F [US] 1-3,7-17 ET AL) 29 September 2005 (2005-09-29) the whole document paragraphs [0077] - 10088] CN 1 513 861 A (UNIV CHINA OCEANOGRAPHY) 1-3,7-17 21 OuIy 2004 (2004-07-21) abstract & DATABASE WPI Week 200470 Thomson Scientific, London, GB; AN 2004-710642 & CN 1 513 861 A (UNIV CHINA OCEANOGRAPHY) 2 1 July 2004 (2004-07-21) abstract ZHAO ET AL: "A facile enzymatic process 1-3,7-17 for the preparation of ibuprofen ester prodrug in organic media" JOURNAL OF MOLECULAR CATALYSIS. B , ENZYMATIC, ELSEVIER, AMSTERDAM, NL, vol. 36, no. 1-6, 1 November 2005 (2005-11-01), pages 47-53, XP005105115 ISSN: 1381-1177 the whole document page 48; figure SCHEMEl ZHAO X ET AL: "Pharmacological activity 1-3,7-17 and hydrolysis behavior of novel ibuprofen glucopyranoside conjugates" EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 41, no. 11, 1 November 2006 (2006-11-01), pages 1352-1358, XP024993925 ISSN: 0223-5234 [retrieved on 2006-11-01] the whole document page 1353; figure SCHEMEl V- Form PCT/ISA/21 0 (continuation of second sheet) (April 2005) C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim N o Y NA WANG ET AL: "Regi oselective Enzymatic 1-3 ,7-17 Synthesi s of Non-Steroidal Ant i -Infl ammatory Drugs Containing Glucose i n Organic Media" BIOTECHNOLOGY LETTERS , KLUWER ACADEMIC PUBLISHERS, DO, vol . 27, no . 11 , 1 June 2005 (2005-06-01 ) , pages 789-792 , XP019230862 ISSN: 1573-6776 the whole document page 790; figure SCHEMEl Y MISHRA ASHUTOSH ET AL: "Synthesi s , 7 characterization and pharmacological eval uati on of ami de prodrugs of ketorol ac" EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol . 43, no. 1 1 , 26 September 2007 (2007-09-26) , pages 2464-2472, XP002527136 ISSN : 0223-5234 abstract Y TSUNEMATSU H ET AL: "SYNTHESIS AND THE 8 STEREOSELECTIVE ENZYMATIC HYDROLYSIS OF FLURBIPROFEN-BASIC AMINO ACID ETHYL ESTERS" JOURNAL OF DRUG TARGETING, HARWOOD ACADEMIC PUBLISHERS GMBH , DE , vol .