Patent SG-11201901199W-A (SG)
Title: Substituted azole derivatives for generation, proliferation and differentiation of hematopoietic stem and progenitor cells
Inventor: BARI SUDIPTO
IPC: C12N5/0789
Filed: 2017-08-18
Abstract: Expandwith IM- & cytokines Pre-expansion HSC2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date 15 March 2018 (15.03.2018) WIP0 I PCT oimitia °nolo oloim mil Inv Hs (10) International Publication Number WO 2018/048346 Al (51) International Patent Classification: CO7D 401/04 (2006.01) Cl 2N 5/0789 (2010.01) CO7D 413/04 (2006.01) A61P 7/06 (2006.01) A61K 35/28 (2015.01) A61P 37/00 (2006.01) A61K 35/51 (2015.01) (21) International Application Number: PCT/SG2017/050409 (22) International Filing Date: 18 August 2017 (18.08.2017) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 10201606886V 18 August 2016 (18.08.2016) SG (71) Applicants: NATIONAL UNIVERSITY OF SINGA- PORE [SG/SG]; 21 Lower Kent Ridge Road, Singapore 119077 (SG). SINGAPORE HEALTH SERVICES PTE LTD [SG/SG]; 31 Third Hospital Avenue, #03-03 Bowyer Block C, Singapore 168753 (SG). (72) Inventors: BARI, Sudipto; c/o National University of Sin- gapore, Faculty of Science / Department of Pharmacy, 21 Lower Kent Ridge Road, Singapore 119077 (SG). CHAI, Christina Li Lin; c/o National University of Singapore, Faculty of Science / Department of Pharmacy, 21 Lower Kent Ridge Road, Singapore 119077 (SG). CHIU, Gigi Ngar Chee; c/o National University of Singapore, Facul- ty of Science / Department of Pharmacy, 21 Lower Kent Ridge Road, Singapore 119077 (SG). HWANG, William Ying Khee; c/o National University of Singapore, Duke- NUS Medical School, 21 Lower Kent Ridge Road, Sin- gapore 119077 (SG). LOW, Joo Leng; c/o National Uni- (54) Title: SUBSTITUTED AZOLE DERIVATIVES FOR GENERATION, PROLIFERATION AND DIFFERENTIATION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS CD45 - CD45+ CD34+CD38— CD45RA— (HPC) CD90+ (HSC1) CD49f+ (115C.2) 1-1 cc O cc O C Post-expansion Population Percentage (%) Population Pre-expansion 40 - 70 Post-expansical l > 90 CD45+ (WBC) CD45+CD34+CD38-CD45RA- (HPC) 0.5 - 2 60 - 80 CD45+CD34+CD38-CD45RA-CD90+ (HSC1) 0.1- 0.2 0.4 -1.0 CD45+CD34+CD3E-CD45RA-CD9O+CD49f+ (fiSC2) J 0.0 - 0.1 0.3 - 0.6 FIGURE 5 (57) : The present invention relates to substituted azole derivatives in combination with cytokines in the ex vivo expansion of CD34+ hematopoietic stem and progenitor cells (HSPC) in a biological sample, more particularly the expansion of these cells obtained from non-enriched, i.e., the mononuclear fraction of the biological sample. The present invention further describes the transplantation regimen of the expanded hematopoietic graft developed through xenotransplantation studies. In a preferred embodiment, the combina- tion comprising the azole based compounds and cytokines selected from SCF, TPO, FLT-3L and IGFBP-2 and results in the expansion of expansion of CD45+CD34+CD38-CD45RA-CD90+ hematopoietic stem cells and/or CD45+CD34+CD38-CD45RA-CD9O+CD49f + hematopoietic stem cells and/or CD45+CD34+CD38-CD45RA- hematopoietic progenitor cells from the mononucleated cells isolated [Continued on next page] WO 2018/048346 Al MIDEDIMOMOIDEIREEMOMIHNOMOMEHOIMIE versity of Singapore, NUS Graduate School for Integrative Sciences and Engineering (NGS), 21 Lower Kent Ridge Road, Singapore 119077 (SG). ZHONG, Qixing; c/o Na- tional University of Singapore, Faculty of Science / Depart- ment of Pharmacy, 21 Lower Kent Ridge Road, Singapore 119077 (SG). (74) Agent: MATTEUCCI, Gianfranco; Marks & Clerk Sin- gapore LLP, Tanjong Pagar, P 0 Box 636, Singapore 910816 (SG). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, 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, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, 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, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Declarations under Rule 4.17: — of inventorship (Rule 4.17(iv)) Published: — with international search report (Art. 21(3)) from umbilical cord blood.