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llIIlIlllIlIlIllIlIllIllIllIIIIIIIIIIIIIIIIIIIIllIllllIIlIllllllIIIlllIlIllIIIIIIIIIIIIIII US 20140275135A1 (») United States (12) Patent Application Publication (io) Pub. No.: US 2014/0275135 A1 GENOV et al. (43) Pub. Date: Sep. 18, 2014 (54) SAI.TS AND SOI.ID IJORVIS Olr (22) liiled: Msr. 13, 2014 ISOQUI Ij OLINONES AND COMPOSITION Ol'SIN('HE Related U.S. Application Data COMPRISIN(1 A'vD VIETIIODS SAME (60) Provisional application No. 61/789,740, lilcd on Mar. 15. 2013. (71) Applicant: Infinity Pharmaceuticals, Inc., Publication ('lsssilicstisn ('anibridge, MA (US) (51) Int. CL (72) Inventors Daniel G. GENOV, Boston. MA (US). Ct)7D 401//4 (2006.01) Louis GRENIER, Newton. )vLA (US). G/11N 31/16 (2006 01) Andrew u. IIA(IUI'., ( helmsford. MA (52) U.S. «L (J.JS); Alcsandcr Redvers 1(BERI.IN, CPC ............ Cd 7D 401//4 GP/Ãdh'168 ('anibridge (2013.01)1 ((iu); I.udouc Sylvsin (2013.01) Merc RENOU. Cambridge ((iB); 514/275: 544/324; 436/42 Susana DEL RIO GANCEDO, IJSV('......... Ctunbridgc (GB) (5 7) ABSTRACT Sohd fonus of chemical compounds that modulate kinase activity, including PI3 kinase activity, and compounds, phar- (73) Assigncc. Infinity Pharmaceuticslt, Inc., maceutical compositions, mid methods of treatment of dis- Ctunbridgc, MA ((JS) eases md conditions associated with kinase activity. includ- uig PL3 kinasc acuvity. arc descnbed hcrmn. Also providtxl hcrmn arc proccsscs for prcpanng compounds, solid fonna (21) Appl. No . 14/209,842 thereof, turd phannaccutwsl compositions thereof Patent Application Publication Sep. 18, 2014 Sheet 1 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 2 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 3 of 54 US 2014/0275135 A1 95 90 85 80 75 /0 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340'C FIG. 2A 1TA, 9.1880m9 Step -2.7575!, 100 -" '5'4m 95 =- 90= 85-. 25.9657K 2.385/mg 80~ 75 70 "I "I ' 9 . 9 7: 7 40 Ki 80 100 120 140 160 180 2i30 220~240 260 280 300 320 340'C FIG. 2B 04 12Ã00mo 40 60 80 100 120 140 160 180 200 220 240 260 280 'C FIG. 2C Patent Application Publication Sep. 18, 2014 Sheet 4 of 54 US 2014/027i135 A1 Wg -1 40 60 80 100 120 140 160 180 200 220 240 260 280 800 „20 340 C FIG. 3A Wq -1 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340'C FIG. 3B letegrel - 24.41mJ - novelized -12,67Jg I 0neet 21 8.42 'C Wg -1 0.0 40 60 80 100 120 140 160 180 200 220 240 260 280 *C FIG. 3C Patent Application Publication Sep. 18, 2014 Sheet 5 of 54 US 2014/0275135 A1 0. /0 0,60 E Ã 0. 50 ~ 0.40 4 0.30 Patent Application Publication Sep. 18, 2014 Sheet 6 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 7 of 54 US 2014/027i135 A1 C C R E CD CCt CG 1 ! ! 1 T ! ! l ! ! lm CD CO (2& ~ ~ M CO CD ~ ~ C3 CG eX& LC) CFl CB CA CC CC CF& QO CO CQ CQ CO j 0$ Patent Application Publication Sep. 18, 2014 Sheet 8 of 54 US 2014/027i135 A1 Form 1 .'=orrn 1A After 24 hours standing Li ~ Form 1A After filtration 'l0 20 2 —Theta — Scale Patent Application Publication Sep. 18, 2014 Sheet 9 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 10 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 11 of 54 US 2014/027i135 A1 C CN j i/3 p ~ C:i 93 t3 c& E lo o cudQ K V Patent Application Publication Sep. 18, 2014 Sheet 12 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 13 of 54 US 2014/027i135 A1 300 5 10 l5 20 25 30 35 40 8 -28Ideg) Patent Application Publication Sep. 18, 2014 Sheet 14 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 15 of 54 US 2014/0275135 A1 Patent Application Publication Sep. 18, 2014 Sheet 16 of 54 US 2014/027i135 A1 o ! ~ 8 8 8 8 g 8 8 8 8 ssmmwsIIIQN8IQQ88$8$88~ (""ivf103)v!) (SlLao0)93 Patent Application Publication Sep. 18, 2014 Sheet 17 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 18 of 54 US 2014/0278135 A1 ";0)iep -0.89? 4Ã CA 3,!930ma -29. 3883e-03ma 1GG Siep -12.48! &Xp -0.4110mg Siep 6.449'i8) 0.2'24mg 80 ~- -r 40 60 80 100 120 140 160 180 200 220 240 260 280 300 220 340'0 FIG. 13A S)ep -1.0667'1) ! 63) 'ace CA 81 -65 88PPe- 8.8046/ 90~ .!a Sma 85~ 80 -„! 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 0 FIG. 138 Step -0.6189!. lCA 11,2966)mg — 69.997, e — 03!ai] ', 00 g)" ~ Step -14 6637/ -1.6481mg 90 -„ 85-1 40 60 80 100 120 140 160 180 200 220 240 260 280 '0 FIG. 13C Patent Application Publication Sep. 18, 2014 Sheet 19 of 54 US 2014/027i135 A1 Wg -1 2,0 0 0',0 -0" 40 60 80 100 120 140 160 180 200 22G 240 260 280 300 220 340'"C FIG. 34A 40 60 80 100 12G 140 160 180 20G 220 240 260 280 00 32G 340'C FIG. 34B Wg -1; 0 09C'6200rlg -1- 2~ 'C 0 i.-e: 1 9 l.99 ~er'9 196 66'",. 40 6G 80 100 120 140 160 180 00 220 240 260 280 'C FIG. 14C Patent Application Publication Sep. 18, 2014 Sheet 20 of 54 US 2014/027i135 A1 0.60 ~ 0.40 E 5 0X 0.25 ~ 0,20 0.15 0 !0 20 30 40 50 60 70 80 90 x-RH(x) FIG. 15 Patent Application Publication Sep. 18, 2014 Sheet 21 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 22 of 54 US 2014/027i135 A1 1 Patent Application Publication Sep. 18, 2014 Sheet 23 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 24 of 54 US 2014/027i135 A1 cD co c) I cD CD cD CD CD cD cD CD cD cD '') C' ) Patent Application Publication Sep. 18, 2014 Sheet 25 of 54 US 2014/0275135 A1 Step -7./6?5,"r,. -0.393." Ii9 Step -9.9'i 842 -0.5'-2') — — — — — — — r r r 1--r r r r-T r" r r r i r,, ] ] T 9 7 ] g I 1 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340"C FIG. 18A 40 60 80 100 120 140 160 180 200 ?20 '?40 260 280 300 320 340'&: FIG. 38B Patent Application Publication Sep. 18, 2014 Sheet 26 of 54 US 2014/027i135 A1 Wq -1 0.0 OSC ! 40„"Oreg btagra[ -43.34mJ — 0.4- ( aorraa[iz.d -3[296.:g -1 -06 ([, a 7 I .-"'aak [85.':.! 'C -1. 1 -1.2 -1A -r--"--r-- --v--r -T'--[-- r--f--&--T- T- 7--i-- --i--T - --T -r--[-- — T--t"- [--r--[--'- - i-- ["- T 40 60 80 100 120 140 160 180 20G 220 240 260 280 300 320 340 C FIG. 39A 1[/g --1 1,0 0.6 0.4 0.2 0.0 -0.2 40 60 80 100 12Q 140 160 180 200 220 240 260 280 300 320 340"C FIG. 19B Patent Application Publication Sep. 18, 2014 Sheet 27 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 28 of 54 US 2014/027i135 A1 (DCJEDCD&C)NCJN\DcD(-JCJED'.DER3 ]"T''T', 'T$ 'I (-JCIC)&D(- at ( I;t, T T T T i i 7 7TT, ar n&awaanac~nnac acianamnaconHC'BMOOf (SDIIJw"MM CVMCOI CGi'3M WC% C lMCM (0/UllOJ) Ul ] Patent Application Publication Sep. 18, 2014 Sheet 29 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 30 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 31 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 32 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 33 of 54 US 2014/027i135 A1 a a C! c «L «D F I«l canQ c c) CCl 4C ) ID «W «& V I ID «D I: I n- Patent Application Publication Sep. 18, 2014 Sheet 34 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 35 of 54 US 2014/0275135 A1 Patent Application Publication Sep. 18, 2014 Sheet 36 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 37 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 38 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 39 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 40 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 41 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 42 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 43 of 54 US 2014/027i135 A1 Patent Application Publication Sep. 18, 2014 Sheet 44 of 54 US 2014/027i135 A1 so'vent Posed in poiyrnonph ee(een IP.I I I THT 1-II!eTHI I80E iL 4eT 20 2 —Theta — Scoie FllG.
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    Acute Myeloid Leukemia SUPPLEMENTARY APPENDIX Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia Heikki Kuusanmäki, 1,2 Aino-Maija Leppä, 1 Petri Pölönen, 3 Mika Kontro, 2 Olli Dufva, 2 Debashish Deb, 1 Bhagwan Yadav, 2 Oscar Brück, 2 Ashwini Kumar, 1 Hele Everaus, 4 Bjørn T. Gjertsen, 5 Merja Heinäniemi, 3 Kimmo Porkka, 2 Satu Mustjoki 2,6 and Caroline A. Heckman 1 1Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki; 2Hematology Research Unit, Helsinki University Hospital Comprehensive Cancer Center, Helsinki; 3Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland; 4Department of Hematology and Oncology, University of Tartu, Tartu, Estonia; 5Centre for Cancer Biomarkers, De - partment of Clinical Science, University of Bergen, Bergen, Norway and 6Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland ©2020 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol. 2018.214882 Received: December 17, 2018. Accepted: July 8, 2019. Pre-published: July 11, 2019. Correspondence: CAROLINE A. HECKMAN - [email protected] HEIKKI KUUSANMÄKI - [email protected] Supplemental Material Phenotype-based drug screening reveals an association between venetoclax response and differentiation stage in acute myeloid leukemia Authors: Heikki Kuusanmäki1, 2, Aino-Maija
  • WHO Drug Information Vol

    WHO Drug Information Vol

    WHO Drug Information Vol. 26, No. 4, 2012 WHO Drug Information Contents International Regulatory Regulatory Action and News Harmonization New task force for antibacterial International Conference of Drug drug development 383 Regulatory Authorities 339 NIBSC: new MHRA centre 383 Quality of medicines in a globalized New Pakistan drug regulatory world: focus on active pharma- authority 384 ceutical ingredients. Pre-ICDRA EU clinical trial regulation: public meeting 352 consultation 384 Pegloticase approved for chronic tophaceous gout 385 WHO Programme on Tofacitinib: approved for rheumatoid International Drug Monitoring arthritis 385 Global challenges in medicines Rivaroxaban: extended indication safety 362 approved for blood clotting 385 Omacetaxine mepesuccinate: Safety and Efficacy Issues approved for chronic myelo- Dalfampridine: risk of seizure 371 genous leukaemia 386 Sildenafil: not for pulmonary hyper- Perampanel: approved for partial tension in children 371 onset seizures 386 Interaction: proton pump inhibitors Regorafenib: approved for colorectal and methotrexate 371 cancer 386 Fingolimod: cardiovascular Teriflunomide: approved for multiple monitoring 372 sclerosis 387 Pramipexole: risk of heart failure 372 Ocriplasmin: approved for vitreo- Lyme disease test kits: limitations 373 macular adhesion 387 Anti-androgens: hepatotoxicity 374 Florbetapir 18F: approved for Agomelatine: hepatotoxicity and neuritic plaque density imaging 387 liver failure 375 Insulin degludec: approved for Hypotonic saline in children: fatal diabetes mellitus