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Download File I 1111111111111111 11111 1111111111 111111111111111 11111 111111111111111 IIII IIII US008937151B2 c12) United States Patent (IO) Patent No.: US 8,937,151 B2 Chang et al. (45) Date of Patent: *Jan. 20, 2015 (54) GELATINASE INHIBITORS AND PRODRUGS (56) References Cited (75) Inventors: Mayland Chang, Granger, IN (US); U.S. PATENT DOCUMENTS Shahriar Mobashery, Granger, IN 2,965,651 A 12/1960 Kosmin et al. (US); Mijoon Lee, Mishawaka, IN (US) 4,797,218 A 1/1989 Steinberg et al. 5,288,722 A 2/ 1994 Kishimoto et al. (73) Assignee: University of Notre Dame du Lac, 5,981,763 A 1111999 Garapon et al. Notre Dame, IN (US) 6,703,415 B2 3/2004 Mobashery et al. 7,144,917 B2 12/2006 Mobashery et al. 7,928,127 B2 * 4/2011 Lee et al. ...................... 514/336 ( *) Notice: Subject to any disclaimer, the term ofthis 8,093,287 B2 1/2012 Lee et al. patent is extended or adjusted under 35 U.S.C. 154(b) by Odays. FOREIGN PATENT DOCUMENTS This patent is subject to a terminal dis­ WO WO 95/35275 Al 12/1995 claimer. WO WO 97/18231 Al 5/1997 WO WO 98/33788 Al 8/1998 (21) Appl. No.: 13/582,678 WO WO 2006/125208 Al 11/2006 WO WO 2006125208 Al * 11/2006 WO WO 2011/026107 Al 3/2011 (22) PCT Filed: Mar. 4, 2011 OTHER PUBLICATIONS (86) PCT No.: PCT/US2011/027282 Gooyit et al., "Selective water-soluble gelatinase inhibitor prodrugs," § 371 (c)(l), Journal of Medicinal Chemistry (2011) 54: 6676-6690. (2), ( 4) Date: Nov. 14, 2012 Ikejiri et al., "Potent mechanism-based inhibitors for matrix metal­ loproteinases," The Journal ofBiological Chemistry (2005) 280 (40): 33992-34002. (87) PCT Pub. No.: WO2011/109767 Lee et al., "A potent gelatinase inhibitor with anti-tumor-invasive PCT Pub. Date: Sep. 9, 2011 activity and its metabolic disposition," Chem Biol Drug Des (2009) 73: 189-202. Testero et al., "Sulfonate-containing thiiranes as selective gelatinase (65) Prior Publication Data inhibitors," ACS Medicinal Chemistry Letters (2011) 2: 177-181. International Search Report (Form PCT/ISA/210) for corresponding US 2013/0052184 Al Feb. 28, 2013 International Application No. PCT/US2011/027282 mailed Nov. 4, 2011. Written Opinion (Form PCT/ISA/237) for corresponding Interna­ Related U.S. Application Data tional Application No. PCT/US2011/027282 mailed Nov. 4, 2011. (60) Provisional application No. 61/310,607, filed on Mar. * cited by examiner 4, 2010. Primary Examiner - Marcela M Cordero Garcia (51) Int. Cl. Assistant Examiner - Kaipeen Yang A61K 38/00 (2006.01) (74) Attorney, Agent, or Firm - Haukaas Fish PLLC; C07K 2100 (2006.01) Michael H. Haukaas C07K 4100 (2006.01) C07K5/00 (2006.01) (57) ABSTRACT C07K 7100 (2006.01) The invention provides compounds, compositions, and meth­ C07K 14100 (2006.01) ods for the treatment ofdiseases, disorders, or conditions that C07K 16100 (2006.01) are modulated by matrix metalloproteinases (MMPs). The C07K 17100 (2006.01) disease, disorder, or condition can include, for example, C07D331/02 (2006.01) stroke, neurological disorders, or ophthalmological disor­ C07D 409112 (2006.01) ders. The treatment can include administering a compound or composition described herein, thereby providing a prodrug (52) U.S. Cl. compound that metabolizes to an active MMP inhibitor in CPC ............ C07D 331102 (2013.01); C07D 409112 vivo. The MMP inhibition can be selective inhibition, for (2013.01) example, selective inhibition of MMP-2, MMP-9, and/or USPC .......................................................... 530/300 MMP-14. Thus, the invention provides non-mutagenic pro­ (58) Field of Classification Search drug compounds ofthe formulas described herein that result CPC ..... A61K 38/00; A61K 31/38; A61K 38/005; in the inhibition of MMPs upon in vivo administration. A61K 31/195; A61K 31/336 See application file for complete search history. 16 Claims, No Drawings US 8,937,151 B2 1 2 GELATINASE INHIBITORS AND PRO DRUGS sulfur, and phosphorus, wherein the solubilizing group optionally includes one or more ester, amide, carboxylic acid, RELATED APPLICATIONS phosphate, carbonate, oxime, imine, carbamate, Mannich base (beta-amino ketone), or ether groups; This application is a National Stage Application of PCT/ 5 2 each R is independently H, hydroxy, (C 1 -C6)alkyl, (C 1 ­ US2011/027282, filed Mar. 4, 2011, which claims priority C6)alkoxy, (C 1 -C6)alkanoyl, (C 1-C6)alkanoyloxy, aryl, het­ under 35 U.S.C. §119(e) to U.S. Provisional Patent Applica­ eroaryl, carboxy, cyano, nitro, halo, trifluoromethyl, trifluo­ tion No. 61/310,607, filed Mar. 4, 2010, and which applica­ 2 2 2 2 2 romethoxy, SR , SO2 N(R ) 2 , NR R , or COOR ; wherein tions are incorporated herein by reference. A claim ofpriority 2 each R is independently H, (C 1 -C6)alkyl, (C 1 -C6)alkanoyl, to all, to the extent appropriate is made. 10 (CcC10)aroyl, aryl, aryl(C1 -C6)alkyl, heteroaryl, heteroaryl BACKGROUND OF THE INVENTION (C 1 -C6)alkyl, or optionally a nitrogen protecting group when R2 is covalently bonded to a nitrogen atom; and Evidence is accumulating that damage to neurons and apo­ each n is independently 0, 1, 2, 3, or 4; ptotic death of neurons play a role in the pathogenesis of 15 or a salt thereof; many conditions and disorders, including acute and chronic wherein the compound has an aqueous solubility ofat least neurologic disorders. These disorders range from acute about 5 mg/mL. stroke, head trauma, and epilepsy to more chronic conditions In some embodiments, the compound can have an aqueous such as Huntington's disease, Alzheimer's disease, HIV-as­ solubility ofat least about 2.5, at least about 5, at least about sociated dementia, multiple sclerosis, and glaucoma. A con­ 20 7.5, at least about 10, at least about 12.5, at least about 15, at tributing factor to several ofthese diseases is the activation of least about 20, at least about 25, at least about 30, or at least matrix metalloproteinases (MMPs) in the extracellular matrix. about 40 mg/mL. In some embodiments, the compound can MMPs constitute a family ofextracellular soluble or mem­ have an aqueous solubility ofat least 2, 4, 5, 10, 20, 25, or 30 brane-bound proteases that are prominently involved in mM. In yet other embodiments, the compound has an aque­ remodeling the extracellular matrix. MMP-9 in particular is 25 ous solubility of at least about 4000 times, or at least about significantly elevated in humans after stroke, which is the 5000 times that of SB-3CT, which has an aqueous solubility third leading cause ofdeath in the United States. It is also the ofabout 2.45 µg/mL. primary cause oflong-term disability. Acute ischemic stroke, The compounds ofthe invention can inhibit matrix metal­ the most common form of stroke, is caused by clotting in the loproteinases. For example, the compounds can inhibit cerebral arteries leading to brain oxygen deprivation and 30 cerebral infarction. Gelatinases (e.g., MMP-2 and MMP-9) MMP-2 and have a K, of less than about 3 µM. In some are known to be involved in neuronal cell death, blood-brain embodiments, the compound inhibits MMP-9 and has a K, of barrier breakdown and hemorrhage. The only FDA-approved less than 20 µM. 1 drug for the treatment of ischemic stroke is tissue plasmino­ The variable group R -X- can be ortho, meta or para gen activator (tPA), a thrombolytic agent. The administration with respect to the phenoxy moiety ofFormulaA, however, in of tPA has to be within three hours of the onset of stroke, 35 many embodiments, R 1-X-is meta or para with respect to resulting in its applicability to less than 5% ofstroke patients the phenoxy moiety of Formula A. (CNS Neural Disord Drug Targets 2008, 7, 243-53). The use In some embodiments, X can be 0, NH or -S-NH-, n oftPA is also limited by serious side effects, which include can be 0, and R 1 can be: neurotoxicity and thrombolysis-associated hemorrhagic transformation, and the use of tPA is contraindicated for 40 patients with evidence ofhemorrhage or those who are taking 0 0 anti-coagulant medication. Blood from stroke patients receiv­ ing tPA treatment shows elevated levels ofMMP-9, and tPA (C1-C6)alkyl-....._,.~~; ~~ was shown to activate MMP-9. Additionally, recent reports L' l Y-(C1-C6)alkyl' l; indicate that tPA upregulates MMP-9 in the brain and con­ 45 tributes to matrix degradation and brain damage. 0 0 Accordingly, there is a need for new therapies for the treatment of stroke, and for treatments of stroke that have Y-(C,-Co)•">''- H,N~ fewer and/or less severe side effects than currently used thera­ J,J pies. There is also a need for new gelatinase inhibitors, such r;- Y-(C1-C6)alkyl ; as selective geleatinase inhibitors, that do not have the side 50 l; effects of known therapies such as tPa. NH2 0 SUMMARY Y-(C,-Co)•">'~~~ The invention provides a compound of Formula A: 55 (C1-C6)alkyl-Y; (A) 60 3 orR ; wherein wherein Xis O,-S-NH-, NRawhereinRa is Hor(C1-C4 )alkyl; 65 Lis 0, NH, -OCH2O-, or ----C(=O)O----CH2 O-; 1 R is a solubilizing group comprising 5-30 atoms, in addi­ each Y is independently -NH2 , ----CO2 H, -P(=O) tion to hydrogen, selected from carbon, oxygen, nitrogen, (OH)2 , -PO(=O)(OH)2 , Het, or a guanidine moiety; US 8,937,151 B2 3 4 Het is a 5 or 6 membered heterocyclic ring comprising 1, 2, (CcC10)aroyl, aryl, aryl(C1 -C6 )alkyl, heteroaryl, heteroaryl or 3 heteroatoms selected from 0, N, S, or P, wherein the ring (C 1 -C6 )alkyl, or optionally a nitrogen protecting group when optionally includes one or two sites of unsaturation and the covalently bonded to a nitrogen atom; and ring is optionally substituted with 1, 2, or 3 oxo, halo, nitro, or each n is independently 0, 1, 2, 3, or 4; methyl groups; and 5 or a salt thereof; and R3 is an amino acid or a linear or branched chain oftwo to 1 wherein the compound has an aqueous solubility ofat least five amino acids, linked to X or the carbonyl of R by a 5mM.
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