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Steroidal Glycoside Compounds As Core 2 Glcnac-T Inhibitors

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Steroidal Glycoside Compounds As Core 2 Glcnac-T Inhibitors (19) TZZ_ZZ _T (11) EP 1 909 802 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/704 (2006.01) A61K 31/7048 (2006.01) 21.05.2014 Bulletin 2014/21 A61K 31/706 (2006.01) A61P 1/04 (2006.01) A61P 1/06 (2006.01) A61P 1/16 (2006.01) (2006.01) (2006.01) (21) Application number: 06755733.0 A61P 3/10 A61P 7/02 A61P 9/10 (2006.01) A61P 11/00 (2006.01) A61P 11/06 (2006.01) A61P 13/12 (2006.01) (22) Date of filing: 06.07.2006 A61P 17/06 (2006.01) A61P 31/18 (2006.01) A61P 19/02 (2006.01) (86) International application number: PCT/GB2006/002518 (87) International publication number: WO 2007/003957 (11.01.2007 Gazette 2007/02) (54) Steroidal glycoside compounds as core 2 GlcNAc-T inhibitors Steroidale Glycosid-Verbindungen als core 2 GlcNAc-T-Hemmer Glycosides steroïdiens en tant qu’inhibiteurs du core 2 GlcNAc-T (84) Designated Contracting States: WO-A-2004/062675 WO-A-2005/060977 AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A-2005/120535 WO-A2-01/32679 HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI WO-A2-02/069980 CN-A- 1 415 625 SK TR US-A- 4 602 003 US-A- 5 104 856 US-A1- 2003 148 962 (30) Priority: 06.07.2005 GB 0513881 • DATABASE WPI 7 January 2004 (2004-01-07), (43) Date of publication of application: Derwent Publications Ltd., London, GB; Class 16.04.2008 Bulletin 2008/16 042,page 3, AN 2004-239758 XP002409228 HUANG H, LIU Z: "Medicine composition for (60) Divisional application: treating myocardial ischemia, angina pectoris 11163561.1 / 2 382 979 and cardiac infarction" & CN 1 465 344 A 11163563.7 / 2 382 980 (CHENGDU DIAO PHARM GROUP CO LTD) 7 11163564.5 / 2 382 981 January 2004 (2004-01-07) • DATABASE WPI 2 March 2005 (2005-03-02), (73) Proprietor: BTG International Limited Derwent Publications Ltd., London, GB; Class London EC4M 7RD (GB) 054,page 4, AN 2005-426073 XP002409229 WANG JINGANG: "Dioscin oral disintegration tablet and (72) Inventor: CHIBBER, Rakesh its preparing method." & CN 1 586 493 A London WC2R 2LS (GB) (KEXINBICHENG MEDICINE SCIENCE) 2 March 2005 (2005-03-02) (74) Representative: Kirkham, Nicholas Andrew et al Graham Watt & Co. LLP St. Botolph’s House 7-9 St. Botolph’s Road Sevenoaks, Kent TN13 3AJ (GB) (56) References cited: EP-A1- 1 800 685 WO-A-02/03996 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 909 802 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 909 802 B1 • DATABASE WPI 12 January 2005 (2005-01-12), • BIENVENU JEAN-GUY ET AL: "Recombinant Derwent Publications Ltd., London, GB; Class soluble P-selectin glycoprotein ligand-1-Ig 062,page 9, AN 2002-751531 XP002409230 ZHU reduces restenosis through inhibition of platelet- DAYUAN ET AL.: "Furost saponine analogue and neutrophil adhesion after double angioplasty in its separation process and use" & CN 1 184 229 swine", CIRCULATION, vol. 103, no. 8, 27 C (SHANGHAI INST OF PHARMACOLOGY) 12 February 2001 (2001-02-27), pages 1128-1134, January 2005 (2005-01-12) -& CN 1 184 229 C ISSN: 0009-7322 (SHANGHAI INST OF PHARMACOLOGY [CN]) 12 • BUERKE MICHAEL ET AL: "Sialyl Lewis-x- January 2005 (2005-01-12) containing oligosaccharide attenuates • DATABASE WPI 18 May 2005 (2005-05-18), myocardial reperfusion injury in cats", JOURNAL Derwent Publications Ltd., London, GB; Class OF CLINICAL INVESTIGATION, vol. 93, no. 3, 056,page 5, AN 2005-631469 XP002409231 HAN 1994, pages 1140-1148, ISSN: 0021-9738 J. ET AL.: "Medicine for regulating blood fat and • MYERS DANIEL ET AL: "New and effective treating cardiocerehral disease and preparing treatment of experimentally induced venous method" & CN 1 615 896 A (YUNNAN PROV thrombosis with anti-inflammatory rPSGL-Ig", MEDICINE INST) 18 May 2005 (2005-05-18) THROMBOSIS AND HAEMOSTASIS, vol. 87, no. • DATABASE WPI 26 January 2000 (2000-01-26), 3, March 2002 (2002-03), pages 374-382, ISSN: Derwent Publications Ltd., London, GB; Class 0340-6245 003,page 9, AN 2000-443110 XP002409232 LI • MIMAKI YOSHIHIRO ET AL: "Inhibitory effects of PINGYA ET AL.: "Process for extracting steroidal saponins on 12-O- ginsenoside Re, and use of medicine thereof" & tetradecanoylphorbol-13-acetate CN 1 242 374 A (XINLIHENG PHARMACEUTICAL (TPA)-enhanced 32P-incorporation into SCIEN) 26 January 2000 (2000-01-26) phospholipids of HeLa cells and proliferation of • DATABASE WPI 1 January 1997 (1997-01-01), human malignant tumor cells", BIOLOGICAL Derwent Publications Ltd., London, GB; Class AND PHARMACEUTICAL BULLETIN, vol. 18, no. 980,page 9, AN 1998-087548 XP002409233 3, 1995, pages 467-469, ISSN: 0918-6158 JUNPENG PENG ET AL.: "Anti-thrombosis glucoside medicine" & CN 1 138 984 A (RADIOMEDICINE INST MILITARY ME) 1 January 1997 (1997-01-01) • ZHANG, JIANYING ET AL: "Effect of six steroidal saponins isolated from Anemarrhenae rhizoma on platelet aggregation and hemolysis in human blood" CLINICA CHIMICA ACTA , 289 (1-2), 79-88 CODEN: CCATAR; ISSN: 0009-8981, 1999, XP002409220 • DATABASE WPI 6 April 2006 (2006-04-06), Derwent Publications Ltd., London, GB; Class 062,page 8, AN 2006-272298 XP002409234 FU T. ET AL.: "Steroidal saponin pharmaceutical composition, its preparation method and use." & WO 2006/034655 A (CHENGDU DIAO PHARM GROUP CO LTD) 6 April 2006 (2006-04-06) -& WO 2006/034655 A (CHENGDU DI AO PHARMACEUTICAL G [CN]; LIU ZHONGRONG [CN]; QI WEI [CN];) 6 April 2006 (2006-04-06) 2 EP 1 909 802 B1 Description [0001] The present invention relates to the use of known and novel compounds as pharmaceutical actives against diseases susceptible to treatment by modulation, eg. inhibition, of the enzyme Core 2 GlcNAc- transferase (EC 2.4.1.102), 5 also known as UDP-GlcNAc:Galβ1,3GalNAc-R (GlcNAc to GalNAc) β-1,6-N-acetylglucosaminyl transferase (core 2 β- 1,6 N-acetylaminotransferase, hereinafter referred to as Core 2 GlcNAc-T, as defined in the claims. [0002] Inhibitors of Core 2 GlcNAc-T are known but none are in clinical development as isolated actives for pharma- ceutical use. Examples of known compounds are disclosed in WO0187548, Kuhns et al., Glycoconjugate Journal 10 381-394 (1993), Hindsgaul et al., J Biol Chem. 266(27):17858-62 (1991), and Toki et al, Biochem Biophys Res Commun. 10 198(2):417-23 (1994). [0003] Applicant’s co-pending application WO05/060977 discloses known and novel steroidal glycosides that have therapeutic use as Core GlcNAc-T inhibitors, discusses the basis for use of such inhibitors in therapy and discloses published documents detailing the basis for Core 2 GlcNAc-T involvement in a number of diseases. The present appli- cation discloses further steroidal glycoside compounds that are inhibitors of core 2 GlcNAc-T and additional conditions 15 in which these compounds have a therapeutic use. [0004] Some of the presently disclosed steroidal glycosides have been tested previously in a limited number of disease paradigms. For example in protection against gastric mucosal lesions in rats (Matsuda H et al Bioorg Med Chem Lett. 24;13(6):1101-6, 2003), in mouse ear edema tests for anti inflammatory activity (Kim et al Arch Pharm Res. 22(3):313-6 (1999)), in treatment of dementia (US6593301) as "immuno-modulators" and spermatogenesis and ovulation stimulators 20 (Vasil’eva and Paseshnichenko Adv. Exp. Med. Biol. 404, 15-22 (1996)) and as adjuvants (Oda et al Biol Chem. 381(1):67-74 (2000)). Compounds of the invention have also been used in cytotoxicity assays (e.g. Hu et al Planta Medica, 63(2), 161-165 (1997), Mimaki et al Phytochemistry 37(1):227-32 (1994), Akhov et al Proc. Phytochem. Soc. Euprope 45, 227-231 (2000)), however cytotoxic concentrations are several orders of magnitude higher than those currently disclosed for inhibition of Core 2 GlcNAc-T activity. None of the aforementioned publications discloses that 25 certain steroidal glycosides are inhibitors of Core 2 GlcNAc-T. [0005] CN 1586493 A discloses a dioscin oral disintegration tablet ands its preparing method. CN 1415625 A discloses a method for preparing yam saponin, medical preparation and new usage in medication [0006] Certain plant sterol compounds, some of which are used as dietary supplements, impede the uptake of cho- lesterol from the gut and consequently lower plasma LDL cholesterol. However these compounds are generally used 30 in doses of several grams per day and are not known to be inhibitors of Core 2 GlcNAc-T. [0007] In a first aspect the present invention provides a compound of formula III as defined in the claims or a phar- maceutically acceptable salt, ether or ester thereof for use in the treatment of a subject in need of therapy for a condition involving detrimental activity of the enzyme core 2 GlcNAc-T, particularly raised activity, wherein the condition is selected from the group consisting of ischemia reperfusion injury, restenosis and thrombosis. 35 [0008] The prior art associates Core 2 GlcNAc-T (particularly through its involvement with branched oligosaccharide synthesis) with inter alia, vascular diseases, (including complications of diabetes), autoimmune and inflammatory con- ditions. Particular conditions associated with this enzyme and thus subject to treatment by the present invention are myopathy, retinopathy, nephropathy, atherosclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease, trans- plant rejection, ischemia reperfusion injury (eg stroke, myocardial ischemia, intestinal reperfusion e.g.
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