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    Wo 2020177744 A 1

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    Wo 2020177744 A 1

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    Wo 2020177744 a 1

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    Wo 2020177744 A 1

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    (12) 388 FE SY ATS 7 BY (19) HERA z TOMO TAA i B = 10) RASS (a3) BURG A45 8 = Baud 2020 9 10 A (10.09.2020) WIPO! PCT 02020 Taal GD EREHSRS CO7D 455/03 (2006.01) A61K 31/4375 (2006.01) Qt) BaRRIAS: 22) EaRIRA AGIK 31/04 (2006.01) AGIP 29/00 (2006.01) PCTICN2020/078049 2020 43: 5 (05.03.2020) QS) RiREE x 06 ARE a (30) HEAR 2oig1016x88I8 — 201983 Fs OSA HES HARBOR A (INSTITUTE OF MATERIA MEDICA ,CHINESE ACADEMY OF MEDICAL SCIENCES) [CNICN}; 'P FB le it PS Ik Be te Sac TOK OR, Beijing 100050 (CN). (05.03.2019) CN uty; Ai 1 PE TB FY. Beijing 100050 (CN). AA ALA, Zhinong): “PSL AGH is Ti #4 84 H2 5, Being 100080 (CN). ESC ARCWANG, Wenjiey, 11 BUC 1H BI #85172. Beijing 100050 (CN) 1) HEMATITE, HRA HOT NL OLN ‘BRB + AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ.CA, CH, CL, CX, CO, CR, CU CZ, DE, DI, DK, DM, DO, DZ, EC, EE, EG. ES, Fl, GB, GD. GE, GH, GM, GT, HIN, HR, HU, 1D, IL, IN, IRIS, 40, IP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC.LK. LR LS, LU, LY, MA, MD, ME, MG, MK, MN, MWW, MX. MY, MZ,NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK. SL, ST, SV, S¥, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. (72) BOA A: EHR CONN, Hany; LA 3 TT (KW £588 1125, Beijing 100050 (CN). BAKE (WU, Liangiay: Pcs BIRD a eb 2 NA, RW, SD, SL, ST, 82, TZ, UG, ZM, ZW), BH (AM, Beijing 100050 (CN). (LI, Jing; S14 xe AZ, BY, KG, KZ, RU, TJ, TM), Nii (AL, AT, BE, BG, TPS AMD, Beijing 100050 (CN). ik CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU SIE CHANG, Haijingy: PLAGE A TUDE HA! EIS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT 62, Beijing 100080 (CN). 3BSEIB(DENG, _RO.RS, SE, SI, SK, SM, TR), OAPI (BF. BI, CF, CG, Cl. Anjun); "PGI Ti PRD HAStRSHI2 S, Beijing CM, GA, GN, GO, GW, KM. ML, MR, NE, SN, TD. TG). 100050 (CN). AEBEAFICTANG, Niaonan); 2} (5-16 J TTGIREC HHH 2, Beijing 100080 (CN). 84) EMG ATTA, Behar HALLE (24): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, *EI EAB CLA, Kiang): “1 ALC HIB WB 293428 CGD) , Beijing 100050 (CN). HE xiang; PIG BS BC BH 2 Af CLO , Being 100080 (CN). ESE WANG, (G4) Title: SALICYLIC ACID BERBERINE-TYPE ALKALOID QUATERNARY AMMONIUM COMPOUND AND USE THERE- (OF FOR PREPARING MEDICINES (54) SEOR-RAR: ACIS ANAL Ah Sl SOO RQ __ (87) Abstract: Disclosed in the present invention area salicylic acd berberine-type alkaloid quater- nium compound as shown in general Formula (2), a preparation method therefor, solubility ke sal products. The salicylic acid berberine-.ype alkaloid quaterary ammonium compound as shown in 4 Re + general formula (1) may be prepared by an organic synthesis method, and shows obvious solubility of alcohol-water mixed solvents. The compound may be conveniently prepared on a large scale, and has Riz Rw significant amiculcerative colitis activity, with non-toxic or low toxicity characteristics, The compound may be used to prepare products for preventing, relieving and/or treating ulcerative colitis, GT MB: ARIMATE T MUL CL) Bia AN REALE OR HR th, SU ATTA, MEME TE. PGE De Ae SP NE. SACU ABI NSE BIE ya He Bk AIRY LIAL AHL Ae a SCE ast SE RACE CREAR, AE OORLAMSE MULTE la, 11 SLY MDL TEEN BRAY. Fl AC TEER ERE A, ARAL TTD. SEMB TUS Fry BUH EA Nae A WO 2020/177744 Al WO 2020177744 PCTICN2020/078049 RATE EDR A YR ee Be Sil 4 25 YO FI BRR ARB Be Lk AMR HG A AT LBL A A RELA A aS TNL As PLE WEE IME ED II Er SAA ERR Ay SABIE IT AL SD ARB MC As ntl Fa ES SATAN AC Ae th TL BAR TRAN LA BEA ZG YD FI 0 SAL NETL NEES i RATE I SP GE ARH SE BAT OCs AR AH ERIE? Se HD A A Be HER BMC AT YOTE 60% ZAP ATE CT TEA PLAT OL SP STEERER A AH EH AE FLAT SE AYE TE, PRUNE, ACR Cs NE 2 GS UM A SE EA SERIAL PY il 4 2 7 CRS I GF TIT AG PSA» ARAL A DO BARE S~DEK ER RHE 4-2 BEAK GBR HR OK Ha ARE Ak HP TR TRA TS FTC. UA 56-2 HE [cag PE NDE-7- BBS Yeah Sy SO BS EAT» PT A PRS NE RL DEE ALE, ARGS REAL Tl DG, DENRA BRITT TARA, REALE TUR. BRA HUAMLAGR (Ulcerative colitis, UC) fe AMERE. diResPTE, Act. IERIE EEA, HAE A EPI SALA BEAT ZAKS EL, TAT RENE EE TR AL ERE, SP PPTL ZAR EEN TRG EH HR DEB iy ANB TB SA 2 I EEE Hip JS APG SE: BEN RT SR as AE Pa 5 SEA BE NAL HR A IGOR SEAL AG WRT, LHR My RAR Re eA EA AA LAGI, BP PHT WPS VEPINMY A ATUL = A SEIS MOLT ASS SA AR ER SUES MLAS TREAR, HOB EAR EE AES GPE EE PE HE 6 FE SUA ML, Wik, 8, Ai, Seti eM de RD PS AB ASOT, AMIS RA 5 UM, AUR eS BIS ZE 5 KEL cb, HARA Sié 30 UA, BOW KIS, WE, AAT, ABLE I 385C. MEAP RMR, NHR, BIG. SESE: 1 1 WO 2020177744 PCTICN2020/078049 AS A Mh eM, UATE, MAMET IE AS Ak HEE WANA RES Le BIE RE, LPR IK, EFL. AML, EAL. HE. AIS. IE, BEMAIAE C2e RCE eA RHA I, BESTE, SIRS BE) . SAUL ARASE CLARE. ARRAS GRR, FE)» BURG AS RY A AUT AD, ETM REE IE. aE DAE REE ES AREA ELEN BREE PBL. ORE, ELLE FM BATE P 0 15%) RAL, ROME ATERL AE, Bera AABN ait FEMMES, RA. PR, SUPE, ZEA, OR aE 2 16 RS HH EE 47 3 EA [Russel MG. Changes in the incidence of inflammatory bowel disease: what does it mean?. Eur J Inter Med, 2000, 11: 191.5 Jiang XI, et al. An analysis of 10218 ulcerative colitis cases in China. World J Gastroenterol, 2002, 1:158]o PAM, iota ELEN I ke — Bb 2S Uf BR ARR PA FREE ME FENRIS, HE WHO BASE ME ‘Att TEI LEAH K (Acute severe ulcerative colitis, ASUC)/E 45 (EWE 26 UI, HATE PG SE>90 UI OA ET 3 7.8°C BP LAT AE A ACP<105 g/l ERP EL AML ME >30 moh. 15%~25% fi HI HE HH HE A BK ASUC fi2fE > A} ASUC YAGI AB MATE AT BZ ASAT EAS 2599, (ALO HLAHE 3-5 RIGA, WLR REA ET MULTE RBG FARE ROLE, Uv CREA ART, SRT RAE, Ae HT AR. DAT, ASUC EA FIRE HIS IR AEAE 8.5% ~48%[Hindryckx Petal. Acute severe ulcerative colitis: from pathophysiology to clinical management. Nat Rev Gastro Hepat, 2016, 13: 654-664], “FI9M(7E 15%[Ungaro R, et al, Ulcerative colitis, Lancet, 2017, 389: 1756-1770]. Hst:, A&A an di a ILE TAT MPEP T CRORE AT ATE EUG RAS, UA Bis LEE TED RINE LAB RSP LS EZ — HEH BE SB HA Ph EL | 8 FIL 3.7%[Thorsteinsdottir S, et al. Pathogenesis and biomarkers of carcinogenesis in ulcerative colitis, Nat Rev Gastro Hepat, 2011, 8: 395-404]. SERIE DI TEL His FR FS BA A os LH AR EP CR EB ER PENOLA BUR ASE Ste, Sure RR, AR EAT K[Baumgart DC, 2 WO 2020177744 PCTICN2020/078049 et al. Inflammatory bowel disease: cause and immunobiology. Lancet, 2007; 369: 1627]. MAL ASUS MB Hk PGP, 5-2 IE rh PAS 2 Ws BU Ra (Salazosulfapyridine, SASP) jéit144'3] NF-KB AGUS HAART ETE A . BeaT SEE AITE FE ACI, 15 yah e820 dS A PP SEI AL SB HE BR AF X-box-binding protein | (xbp 1) NRE FEA 5 RTE MG A IAAT IR, BURNER ATE LE xbpl BAER, Mii RIA ROR RR. Xbpl A iA AIGA EIR Ze RUE HGRA TE BE M3 SA TGR EA PH PALE, ESM xbpl FU REN AHI 7 TM Ai FS EN SE ALBE ni. JESS, STAT3 BSE Ca Sie) RSH IL-23 a SRR, MU AE RIVE LAB IY 22H PS EE fF Al [Anderson CA, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nature genetics, 2011, 43: 246; Rovedatti L, et al, Differential regulation of interleukin-17 and Interferon-gamma production in inflammatory bowel disease. Gut., 2009, 58: 1629]. LAD. RACHA TENS DA Dre SE NS es EA ATT FB, BARS Rt VELEN IS BIBT PEM NVZT YD. MEP A BOIL, RA RA UTE EEE FESTA TET T AOI ITI, BD BRS Bsa EA A ED FF, UDR ae AT ESA TAT MEE, PRATHER, FROHE. Hae AG A eo LS EC PS AE APP PRY A I 77 T S, AERIS. IPAS PT AEWA 25 AHEM LL, BAR I RS BY EEE TR. CAN RTE IE MR EAS KB Cnuclear factor kappa-B, NF-KB) 4M SR UR A RSE DLIA, PDP RPAIL AS 0. (tumor necrosis factor-alpha, TNFa) fi Fi sé Redit Cit TNFa fi) . AWA ‘WE Janus kinases, JAK) ‘061A, SF, (EL A AYSrt Tot Pett 2 i 25 YR SERIE HS ATM. CEGRE ALG De EEA TEAC OTL BF Pe BETAIE PAGED ATH AVE nF WN WS Ha 8 2G HE — RTL, in AE AS Hl FLA} Zl FEA TTA. 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C1-C4 ee AURETT Ruy $5 Riz REBECA TERE RE UR, 2b Rox Rios Rury Raz P/M C1-C4 ek Ae AA BAR, Z.aE. AES FE PASE, Ta: Roy Rio Rus Riz PATRAY C2-C4 bei SUE & A BAH Ze UE, PARE. TRUE. TGR: Ro. Rios Ruy Rio PATMY C1-C4 SERGE S AAR IEE A PRE, ZAR, BE. RPI GUE. TUE: Ro Rios Ray Rio PATHE EE — RE hE UE, WE UE ak, WT AH. ARCA SR LAR Yk AR A RI a Ae eH A Ae 1-21: R, Rs Ro Rio Rin Rez -OCH,O- -OCH,O- HOH -OCH,O- H -OCH,O- 1H OMe OMe OMe OMe H H -OCH,0- OMe OMe H H H_ -OCH,CH,O- H -OCH;O- OMe OMe OMe H ~OCH,0- Me Me H H -OCH,O- H OMe OMe H -OCH,0- H OMe OMe Ob 10 -OCH,O- -OCHCH2O- HH 11 -OCH,CH,O- H = -OCH,O-H 12 -OCH,CH;0- H_-OCH,CH;O- H 43 -OCH,CH;0- -OCH,CH,0- HH 8 3 6 PCTICN2020/078049 WO 2020177744 A 5 fn Ro coo =o, ao PV ng + Re Rie Ru NH Re Rs Re Ri Ry Riz 14 -OCH,O- -OCH,O. =H OH 45 -OCH,O. 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