US 20090253782A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0253782 A1 Ratan et al. (43) Pub. Date: Oct. 8, 2009 (54) COMPOUNDS FOR ENHANCING ARGINASE Related U.S. Application Data ACTIVITY AND METHODS OF USE (60) Provisional application No. 60/807,661, filed on Jul. THEREOF 18, 2006. (76) Inventors: Rajiv R. Ratan, Scarsdale, NY Publication Classification (US); Marie T. Filbin, New York, (51) Int. Cl. NY (US) A63L/352 (2006.01) A6IP 25/28 (2006.01) Correspondence Address: (52) U.S. Cl. ........................................................ 514/454 Irving N. Feit Hoffmann & Baron, LLP (57) ABSTRACT 6900 Jericho Turnpike The present invention relates to a method for enhancing argi Syosset, NY 11791 (US) nase activity in a damagedor injured cell. In other aspects, the invention provides a method for treating a disorder that can be (21) Appl. No.: 12/309,500 treated by enhancing arginase activity in a human in need thereof, the method comprising administering to the human (22) PCT Filed: Jul.18, 2007 an effective amount of a compound that enhances arginase activity. Such disorders include ischemia, hypoxia, neurode (86). PCT No.: PCT/US2007/016335 generative disease or condition, stroke or trauma of the ner Vous system. In yet another aspect, the invention provides S371 (c)(1), methods for promoting regeneration of a neural cell in a (2), (4) Date: Jun. 23, 2009 human in need thereof. Patent Application Publication Oct. 8, 2009 Sheet 1 of 33 US 2009/0253782 A1 Figure 1 J. An. Chen. Soc., 1940, 62:3512 J. Chem. Soc., 1959, 2679 Phytochem istry 1968, 7:70 Phytochen istry 1972, 1:1089 Patent Application Publication Oct. 8, 2009 Sheet 2 of 33 US 2009/0253782 A1 Dehydrovariabilin CH4O4 Phytochen istry 1978, 17:417 Chrysophanol Phytochem istry 1972, 11:222 Patent Application Publication Oct. 8, 2009 Sheet 3 of 33 US 2009/0253782 A1 C17H14O4 282.3 Dehydrovariabilin C17H14O4. 282.3 OO21,0658 4'-methoxychalcone C16H14O2 238.3 OD211475 5,7-dimethoxyisoflavone C17H14O4 as 26964-35 2 Retusin 7-methyl ether C17H1405 298.3 OO24O645 oozoss 2-hydroxyxanthone C13H8O3 soos. 5,74'-trimethoxyflavone C18H16O5 Patent Application Publication Oct. 8, 2009 Sheet 4 of 33 US 2009/0253782 A1 rom color easo as to or ento a ?ia octor |tio orotator to to O 1500473 also rear to a 2 f oisoarseO 50 2 1 98 Anisindone retario is O1504044 C15H1403 is acrossmoor Teimo I as f 120-46-7 a torm to a on to eatio to 101OOOO3 Biochanin a C16H12O5 284.3 Patent Application Publication Oct. 8, 2009 Sheet 5 of 33 US 2009/0253782 A1 Patent Application Publication Oct. 8, 2009 Sheet 6 of 33 US 2009/0253782 A1 Figure 3 te RT-PCR better than control x2 activity in Tillorone primary screen AO2 O23OOOO9 x2 activity in Phenirdione primary screen . AO3 O1500477 not quite 2x data O1501139 Pramoxine in primary hydrochloride Screers x2 activity in Indoprofen primary screen Phenazopyridine x2 activity in hydrochloride primary Screen O1 50 04 73 not quite 2x data in primary Piperine SCreefs AO7 O1500B73 x2 activity in 6,3'-dimethoxyflavone primary screen AO8 O1504132 x2 activity in Anisindione primary screen AO9 O1502198. not quite 2x data in primary 5,4'-dimethoxyflavone Sctees A1 O 00211227 x2 activity in Pinosylwin primary screen OO2O1066 x2 activity in Der Tustone primary screen 1O O1401419 X x2 activity in 4,7-dimethoxyflavone primary screen O0210554 x2 activity in Daidzeir primary screen B04 O0200789 X x2 activity in 4'-methoxychalcone primary screen O02.11475 x2 activity in Tranilast primary screen B x2 activity in Biochanin a diacetate primary screen BO7 OO3OOSO1 Resveratrol 4'-methyl 7 BO8 O1504O44 Patent Application Publication Oct. 8, 2009 Sheet 7 of 33 US 2009/0253782 A1 ether primary screen x4 activity in Dertubone primary screen BO9 OO2O1650 x2 activity in Chlorpropham primary screen OO330051 x2 activity in . primary screen O0210296 x2 activity in Dehydrovariabilin primary Screen CO2 OO210658 X x2 activity in Retusin 7-methyl ether primary screen CO3 OO24. x2 activity in Xanthone primary screen CO4 OO200523 x2 activity in Pinosylwin methyl ether primary screen COS O02O1067 x2 activity in Chrysophanol primary screen CO6 OO30054 55 x2 activity in Apigenin primary screen CO7 OO020O846 not quite 2x data in primary 2-methoxyxanthone SCeeS 27 C08 O024O736 x2 activity in Apigenin triacetate primary screen C09 OO2005O2 x2 activity in Fenbendazole primary screen 10 O150.1016 x2 activity in Dibenzoylmethane primary screen C11 x2 activity in Methoxyvone primary screen O14006.66 x4 activity in Ginkgetin, k salt primary screen OO200436 x4 activity in Methyl robustone primary screen Dolotovo not quite 2x data Liquinitigenin dimethyl in primary ether SCsees oO 1 6O O x2 activity in primary screen O14O1406 Patent Application Publication Oct. 8, 2009 Sheet 8 of 33 US 2009/0253782 A1 channan x2 activity in Biochanin a primary screen 5,7- x2 activity in dimethoxyisoflavone primary screen x2 activity in For Thononetin primary screen not quite 2x data in primary 4'-methoxyflavone SCees x2 activity in Acacetin diacetate primary screen Patent Application Publication Oct. 8, 2009 Sheet 9 of 33 US 2009/0253782 A1 Figure 4 | Patent Application Publication Oct. 8, 2009 Sheet 10 of 33 US 2009/0253782 A1 Patent Application Publication Oct. 8, 2009 Sheet 11 of 33 US 2009/0253782 A1 Figure 6 GN CN u C) All O a r OE a V2 G S CO CS s St E CD Co S2 co s OV) o h CC r up 3 W-e aq opeze u Jo N Se Ae WNu e Seuf. We A3ee Patent Application Publication Oct. 8, 2009 Sheet 12 of 33 US 2009/0253782 A1 Figure 7 92 as CO E S 9 S. itg 9 S5 SR E5 2 5 9. C w Cyd upoW-eed opezeu ON Sieme WNueseufv empele Patent Application Publication Oct. 8, 2009 Sheet 13 of 33 US 2009/0253782 A1 92 s S RSN to 9 S C 3. S. E SR2 53 O) h CC r u3 W-e eq Opezleu, ON Se Ae WNu e Seufu We A3 ele Patent Application Publication Oct. 8, 2009 Sheet 14 of 33 US 2009/0253782 A1 Figure 9 O) w aE 9 9 to g it N5 2 O did O. (9 S V CP ... O 9 C V cy uoV-eled OpezieuoN SeAe VNu e Seufv empbee Patent Application Publication Oct. 8, 2009 Sheet 15 of 33 US 2009/0253782 A1 Figure 10 Overcoming MAG inhibition in vitro Post-treatment Acetaminphen Resveratol 4-methyl ether Chrysophanol (low dose) 7 11 Epicatechin pentaacetate N/A Patent Application Publication Oct. 8, 2009 Sheet 16 of 33 US 2009/0253782 A1 Figure 11 se .2 Patent Application Publication Oct. 8, 2009 Sheet 17 of 33 US 2009/0253782 A1 Figure 12 Patent Application Publication Oct. 8, 2009 Sheet 18 of 33 US 2009/0253782 A1 Figure 13 Overcoming MAG inhibition in vitro Pretreatent Post treatment 1 Acetaminphen None Chrysophanol (low dose) 5 None 6 methoxyvone S None 7 dehydrovariabilin 8 Phenethyl caffeate (CAPE) 11 Epicatech in pentaacetate Yes Patent Application Publication Oct. 8, 2009 Sheet 19 of 33 US 2009/0253782 A1 Figure 14 12) 10) Ev SO 3 e Co Daidzein 2. is on MAG s p up 40 2 methoxyvone or dadzeina AG tarcoprazero on A. MAG Lanzoprazole 20ty on fi AG Neurite outgrowth assay Patent Application Publication Oct. 8, 2009 Sheet 20 of 33 US 2009/0253782 A1 Figure 15 Arginase Actin Patent Application Publication Oct. 8, 2009 Sheet 21 of 33 US 2009/0253782 A1 Figure 16 2-hydroxyxanthoneto Irm2-hydroxy- 9H in xanther- 9- one 2-methoxyxanthone 2-methoxy- 9H xanthen- 9- one 3 3-methyl-1,2- methylcholanthrene dihydrocyclopentaijtetr aphene 4,7- 7-methoxy-2-(4- dimethoxyflavone methoxyphenyl)-4H chotel-4-One (IUPAC) 4'- (2E)-1-(4- methoxychalcone methoxyphenyl)-3- phenylprop-2-en-1-one (IUPAC), 1-(4- methoxyphenyl)-3- phenylprop-2-en-1-one (IUPAC) Patent Application Publication Oct. 8, 2009 Sheet 22 of 33 US 2009/0253782 A1 4'-methoxyflavone 2-(4-methoxyphenyl)- 4H-chromen-4-one (IUPAC), 5,4'- 5-methoxy-2-(4- dimethoxyflavone methoxyphenyl)-4H chronen-4-One (IUPAC) 5,7,4'- 5,7-dimethoxy-2-(4- trimethoxyflavone methoxyphenyl)-4H chromen-4-one (IUPAC) 5,7- 5,7-dimethoxy-3- dimethoxyisoflavon phenyl-4H-chromen-4- e one (IUPAC) 6,3'- 6-methoxy-2-(3- dimethoxyflavone methoxyphenyl)-4H chromen-4-One (IUPAC) Acacetin diacetate 2-(4-methoxyphenyl)-4- oxo-4H-chromene-5,7- diyl diacetate Patent Application Publication Oct. 8, 2009 Sheet 23 of 33 US 2009/0253782 A1 MOLENAME ar. In Anisindione 2-(4-methoxyphenyl)- 1H-indene-1,3(2H) - dione 4,5,7-trihydroxyflavone (chemical), 4H-1- benzopyran-4- one, 5,7-dihydroxy-2- (4-hydroxyphenyl)- (chemical), 5,7,4'- trihydroxy- flavone (chemical), 5,7- dihydroxy-2-(4- hydroxyphenyl) - 4H chromen- 4- one (IUPAC), 83244 (NSC), apigenin (common, vendor, MeSH, primary common), apigenine (common), apigenol (common), C. l. natural yellow 1 (common), flavone,4',5,7- trihydroxy- (chemical), NP-OOO448 (extract), pelargidenon 1449 (common), spigenin (common), versulin (common) Apigenin triacetate 2- (4-acetoxyphenyl)- 4-oxo- 4H- chronene 5,7-diyl diacetate Patent Application Publication Oct. 8, 2009 Sheet 24 of 33 US 2009/0253782 A1 Biochanin a 5,7-diydroxy-3-(4- methoxyphenyl)- 4H chromen- 4- one Biochanin a 3-(4-methoxyphenyl)-4- diacetate oxo-4H-chromene-5,7- diyl diacetate Chlorpropham isopropyl (3- chlorophenyl) Carbamate Chrysophanol 1,8-dihydroxy-3-methyl 9,10-anthraquinone Patent Application Publication Oct. 8, 2009 Sheet 25 of 33 US 2009/0253782 A1 Daidzein 4,7-dihydroxy-iso flavone (chemical), 4,7- dihydroxyisoflavone (chemical), 4H-1- benzopyran-4-one,7- hydroxy-3-(4- hydroxyphenyl)- (chemical), 7,4'- dihydroxyisoflavone (chemical), 7-hydroxy 3-(4-hydroxyphenyl)-4- benzopyrone (chemical), 7-hydroxy 3-(4-hydroxyphenyl)- 4H-1-benzopyrian-4- one (chemical), 7 hydroxy-3-(4- hydroxyphenyl)-4H chromen-4-one (IUPAC), 7-hydroxy-3- (4-hydroxyphenyl) chromen-4-one (chemical), daidzein (common, vendor, MeSH, primary common), daidzeol (common) Dehydrovariabilin 3,9-dimethoxy-6H 1)benzofuro3,2- cchromene Patent Application Publication Oct.