US008894970B2 (12) United States Patent (10) Patent No.: US 8,894,970 B2 Tomczuk et al. (45) Date of Patent: Nov. 25, 2014 (54) ARGINASE INHIBITORS AND METHODS OF 546/184, 133, 138, 139, 152; 548/560; USE THEREOF 540/484 See application file for complete search history. (75) Inventors: Bruce Edward Tomczuk, Collegeville, PA (US); Gary Lee Olson, (56) References Cited Mountainside, NJ (US); Richard Scott Pottorf, Belle Mead, NJ (US); Lijuan U.S. PATENT DOCUMENTS Jane Wang, Wildwood, MO (US); Bhask Rao Nall h 4.483,853. A 11/1984 Collins et al. naskara Kao Nalagancnu, 5,792,769 A * 8/1998 Lu et al. ...... 514,252.12 Hillsborough, NJ (US); Yanqun Zhang, 5,891,909 A * 4/1999 Soll et al. ...................... 514/517 East Brunswick, NJ (US) 6,037,356 A * 3/2000 Lu et al. ...... ... 514,349 6,133,315 A * 10/2000 Lu et al. ...... 514/517 6,204.263 B1* 3/2001 Lu et al. ...... 514,235.8 (73) Assignee: Corridor Pharmaceuticals, Inc., 6,225,302 B1* 5/2001 Lu et al. ......... ... 514, 183 Towson, MD (US) 6,235,778 B1* 5/2001 Tomczuk et al. 514/517 6,245,763 B1* 6/2001 Lu et al. ......... ... 514,247 (*) Notice: Subject to any disclaimer, the term of this 6,281.206 B1 : 8/2001 Lu et al. ...... ... 514, 183 patent is extended or adjusted under 35 6,326,492 B1* 12/2001 Wang et al. ..................... 544, 63 6,344,466 B2 * 2/2002 Soll et al. ....... ... 514,331 U.S.C. 154(b) by 356 days. 6,344,484 B1* 2/2002 Tomczuk et al. 514/565 6,344,486 B1* 2/2002 Soll et al. ....... ... 514,620 (21) Appl. No.: 13/191,160 6,350,764 B2* 2/2002 Lu et al. ...... ... 514,349 6,414,020 B2 * 7/2002 Lu et al. ...... 514/517 22) Filed: Jul. 26, 2011 6,417,161 B1* 7/2002 Lu et al. ....................... 514f13.6 (22) File l. A0. 6,472.399 B2 * 10/2002 Lu et al. ...... 514,255.05 6,476,016 B2 * 1 1/2002 Wang et al. .............. 514, 21108 (65) Prior Publication Data 6,514,978 B2 * 2/2003 Lu et al. ................... 514,255.06 6,518,310 B2 * 2/2003 Tomczuk et al. ............. 514,613 US 2012/O17111.6 A1 Jul. 5, 2012 6,521,663 B2 * 2/2003 Panet al. ....... ... 514,518 6,566,379 B1* 5/2003 Lu et al. ...... ... 514,345 6,635,637 B2 * 10/2003 Wang et al. ... ... 514,228.8 Related U.S. Application Data 6,638.931 B1 * 10/2003 Tomczuk et al. ... 514,238.2 6,706,021 B2 * 3/2004 Lu et al. ............. ... 604/244 (60) Provisional application No. 61/428,894, filed on Dec. 6,706,765 B2 * 3/2004 Tomczuk et al. .. ... 514,605 31, 2010, provisional application No. 61/450,804, 6,730,783 B2 * 5/2004 Tomczuk et al. .. ... 544,158 filed on Mar. 9, 2011 7,029,654 B2 * 4/2006 Lu et al. .. 424/91 • - s 7,402.586 B2 * 7/2008 Lu et al. .. ... 514,269 2004/OO57926 A1 3/2004 Ochoa et al. (51) Int. Cl. 2005/0176651 A1 8/2005 Madge et al. A6 IK5I/00 (2006.01) 2007/0185060 A1 8/2007 Wang A6M 36/14 (2006.01) 2010, O189644 A1 7/2010 Christianson et al. A6 IK3I/69 (2006.01) C07F 5/02 (2006.01) FOREIGN PATENT DOCUMENTS A61 K5 I/04 (2006.01) WO WO 2010/085797 T 2010 A61 K 49/00 (2006.01) WO WO 2011, 133653 10, 2011 (52) U.S. Cl. CPC ............... A6 IK3I/69 (2013.01); A61 K5 I/044 OTHER PUBLICATIONS (2013.01); A61K 49/0004 (2013.01); C07F 5/02 (2013.01) Busnel, O... et al., “Synthesis and evaluation of new omega-borono USPC ......... 424/1.69: 424/1.11: 424/1.65: 424/9.1: alpha-amino acids as rat liver arginase inhibitors. Bioorganic & s s Sf Medicinal Chemistry, 2005, 13(7):2373-2379. (58) Field of Classification Search (Continued) CPC ... A61K 51/08: A61 K51/0497; A61K 51/00; A61KAcik 51/04; 5/044. A61K 51/041:Asiks i?olac.A61K 51/044: Acik Primary Examiner DIJones 51/0453: A61K 51/0459; A61K 51/0463: (74) Attorney, Agent, or Firm — Saul Ewing LLP. Kathryn A61K 51/0465, A61K51/0468. A61K51/047. Doyle; Domingos J. Silva A61 K51/06; A61K 51/065; A61K 2123/00; A61K 2121/00; A61K 38/00; A61K 38/005; (57) ABSTRACT A61 K38/02: A61K 38/03: A61K 38/04; Th ion includ inhibi A61K 49/0002: A61K 49/0004: A61K 49/00; e present invention includes arginase enzyme inhibitors, A61K 49/001: A61K 49/0013: A61K 49/0015: compositions comprising these arginase inhibitors, and meth A61K 49/OO17: A61 K 49/OO.19 A61K ods of treating or diagnosing conditions characterized either 49/0021: A61K 49/005: A61 K31 (00: A61 K by abnormally high arginase activity or abnormally low nitric s 31f89: Co7F 5/O2: C07F 5/OO oxide levels in a mammal, comprising administering compo USPC 424/1.11, 1.65, 9.19.2, 9.3, 9.4, 9.5 sitions of the invention to the mammal. 424/9.6, 9.7, 9.8, 1.69: 514/1, 1.1; 530/300: 544/336, 98, 59, 105,349; 546/255, 2 Claims, 13 Drawing Sheets US 8,894,970 B2 Page 2 (56) References Cited N-hydroxy-I-homoarginine from I-glutamate.” ARKIVOC, 2003, 8:180-187. Hey, C., et al., “Inhibition of arginase in rat and rabbit alveolar OTHER PUBLICATIONS macrophages by Nomega-hydroxy-D.L-indospicine, effects on Moali, C., et al., “Recognition of alpha-Amino acids Bearing Various L-arginine utilization by nitric oxide synthase.” British Journal of Pharmacology, 1997, 121(3):395-400. C:NOH Functions by Nitric Oxide Synthase and Arginase Involves Reddy, V.J., et al., “Concise synthesis of omega-borono-alpha-amino Very Different Structural Determinants.” Biochemistry, 2000, acids.” Organic & Biomolecular Chemistry, 2007, 5(6):889-891. 39(38):8208-8218. Colleluori. D., et al., “Classical and Slow-Binding Inhibitors of Collet, S., et al., “Synthesis and evaluation of omega-borono-alpha Human Type II Arginase.” Biochemistry, 2001, 40:9356-93.62. amino acids as active-site probes of arginase and nitric oxide International Search Report for PCT/US2010/022090, mailed Sep. synthases.” J. Chem. Soc., Perkin Trans. 1, 2000, 2:177-182. 14, 2010. Kabasawa, H., et al., “Divergent synthesis of N-hydroxy-I- indospicine, the carbon isostere of N-hydroxy-l-arginine, and * cited by examiner U.S. Patent Nov. 25, 2014 Sheet 1 of 13 US 8,894,970 B2 chnur PhC=NH DCM 2a-C O R = Me, Et, tBu Phe-N sus R Ph 4a-C O Brulls-R R = Me, Et, tBu Ph2C=NH DEA 3a-C CH3CN R = Me, Et, tBu U.S. Patent Nov. 25, 2014 Sheet 2 of 13 US 8,894,970 B2 Fig. 2 B1N1OH 2-butanOne R 85 °C HO N1-a-Nsu1SN HN N-R \ / 7 6 R = Boc, alkyl, aralkyl aryl, heteroary 1)NH 8 Na(OAc)3BH3 N N HO o DCM/TMOF n-N-NsuN 12 R O 10 \ , / H R 9 12, imidazole 1N-R 7 Or 10 E - N-1-Nu 11 U.S. Patent Nov. 25, 2014 Sheet 3 of 13 US 8,894,970 B2 Phsen ork Se:O Ph 21 r (cod) Cl2 N DCMS’ \O--6 C-N D C) N 13 14 U.S. Patent Nov. 25, 2014 Sheet 5 of 13 US 8,894,970 B2 Fig. 6 Ph N Y Y O lk 1. 1 NHC/THF Cbz Rul-kO Ph 2. Cbz-C, DEA 25% TFA/DCM THF -e- ON N Oa N O C)N ; ()N BOC BOC 14 19 () H 20 RNCO DEA RC(=O)Cl DMF DEA DMF 21 22 23 U.S. Patent Nov. 25, 2014 Sheet 6 of 13 US 8,894,970 B2 Fig. 7 Ph. iN -k Ph N-N ul-k 1. Base 2 O 1. Base 2 2. Br(CH2)3OTBS Ph 2. Br11 4C OTBS 24 NH4OHaqueous N k Cbz-Cl Ph Nen -k THF DEA/THF Ph 21 21 OTBS OTBS 25 26 S.BH Cbz-NH O -k HC/THF Cbz NukO O Or TBAF/THF -e- r(COC) Cl2 21 DCMDPPM op OTBS OTBS O 27 28 12, imidazole lk O -k PhP-resin Cbz1 O FSNH DCM -e- R" -e- K2CO3 OH OSBA. op DMF O O 29 3O C bz1 Rul-kO O 1N O 31 U.S. Patent Nov. 25, 2014 Sheet 7 of 13 US 8,894,970 B2 H2N lukO Boc1 NRuk O Sie H (Boc)2O, DIEA O 21 - F - 21 5.5. Cl2 OTBS OTBS DCM 26 32 H -k 1. HC/THF H -k Boc O 2. lg, imidazole -N O R"a ---PhP-resin R" O X B OTBS op DMF O O 33 34 35 U.S. Patent Nov. 25, 2014 Sheet 8 of 13 US 8,894,970 B2 Fig. 9 Phe-N O O lk HF Oyo Citric acid BOC -NH O -k Ph 2. (Boc)2O, DEA 21 THF-> 21 OTBS OTBS 25 32 2. (Boc)2O, DEA Ph THF 21 3. TBSCL DMAR- 21 OTBS OTBS 25 32 U.S. Patent Nov. 25, 2014 Sheet 9 of 13 US 8,894,970 B2 Fig. 10 H 1. He, Pd/C N HCI, THF OH Cbz 2. TFA/DCM 3. PhB(OH)2 1 NHC, ether -e- HOS R R" OSBf O HO 31 H N OH BOC 1.