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. nitrogen or sulfur atom; In some embodiments, Xis O or NH, n is 0, and R 1 is: or a salt thereof. The invention also provides a compound wherein the com­ 10 pound of Formula A is a compound of Formula I: 0

(I) Y-(c,-c,J,"''~,

15

O H2N, ~~ Y-(C1-C6)alkyl'-.. "-T l I; ; Y-(C1-C6)alkyl ; 20 NH2 0 wherein Xis 0, NRa, or-S-NH-; Y-(C,-Co)•"''~ij~ Ra is Hor (C 1-C4 )alkyl; 1 R is -C(=O)-L-(CH2)cm-l)----CH3 , -(C=O)­ (CH2)m-Y; -(C=O)-L-(CH2)m-Y; -(C=O)­ 25 (C1-C6)alkyl-Y; (CHRX)-NHRY; -P(=O)(OH)2; an amino acid; or a linear or branched chain of two to five amino acids; Lis 0, NH, ---OCH2O-, or -C(=O)O----CH2O-; Rx is Hor -(CH2)mY; RY is H or----C(=O)----CH(NH2)-(CH2)mY; 30 mis 1-6;

each Y is independently -NH2, ----CO2H, -P(=O) 3 orR ; (OH)2, -PO(=O)(OH)2, Het, or a guanidine moiety; Het is a 5 or 6 membered heterocyclic ring comprising 1, 2, wherein or 3 heteroatoms selected from 0, N, S, or P, wherein the ring 35 Lis 0, NH, -OCH2O-, or ----C(=O)O----CH2O-; 3 optionally includes one or two sites of unsaturation and the R is an amino acid or a linear or branched chain oftwo to ring is optionally substituted with 1, 2, or 3 oxo, halo, nitro, or five amino acids, linked to X by a carbonyl or sulfur residue; methyl groups; or a salt thereof. 2 each R is independently H, hydroxy, (C 1 -C6 )alkyl, (C 1 ­ In any embodiment ofthe invention, each (C 1 -C6 )alkyl can C 6 )alkoxy, (C 1 -C6 )alkanoyl, (C 1 -C6 )alkanoyloxy, aryl, het­ 40 be independently -(CH2)-, -(CH2)2-, -(CH2)3-, eroaryl, carboxy, cyano, nitro, halo, trifluoromethyl, trifluo­ -(CH2)4-, -(CH2)5 -, or -(CH2)6-. 2 2 2 2 2 romethoxy, SR , SO2N(R ) 2, NR R , or COOR ; wherein The invention further provides compounds of the follow­ each R2 is independently H, (C1 -C6 )alkyl, (C1 -C6 )alkanoyl, ing formulas: US 8,937,151 B2 5 6

0 o'QI~ X # s:"<) j~ S; 0 0

wherein X is O or NH; carboxylic acid; statine; 1,2,3,4,-tetrahydroisoquinoline-3­ or a salt thereof. carboxylic acid; penicillamine; ornithine; citrulline; Additionally, a compound ofFormula I can be a compound a-methyl-alanine; para-benzoyl-phenylalanine; phenylgly­ of Formula II or Formula III: 40 cine; propargylglycine; sarcosine; and tert-butylglycine; or R3 is a combination of any two to five amino acids in a linear or branched configuration; and (II) R4 is a residue of a sulfur-containing amino acid linked to

45 Formula III by its sulfur atom shown as part of Formula III; or a salt thereof. When the sulfur-containing amino acid linked to Formula III is taurine, the sulfur of Formula III can be the sulfonyl group oftaurine (i.e., the sulfur bonded to R4 or can be a sulfonyl). (III) 50 The invention additionally provides a pharmaceutical com­ position comprising a compound of a formula as described herein and a pharmaceutically acceptable diluent or carrier. The pharmaceutical composition can be formulated for intra­ venous, subcutaneous, intracardiac, intramuscular, intrapera­ 55 toneal, or topical administration. Accordingly, the invention provides a method oftreating a disease or condition that is modulated by a matrix metallo­ proteinase (MMP) comprising administering to a patient in wherein need ofsuch treatment an effective amount ofa compound of Xis O or NH; 60 a formula described herein, so that the disease or condition is R3 is an amino acid moiety selected from Ala, Cys, Asp, treated. The matrix metalloproteinase (MMP) can be a gelati­ Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gin, Arg, Ser, nase (e.g., MMP-2, MMP-9, or MMP-13), a collagenase, a Thr, Val, Trp, Tyr, or taurine, optionally protected on any stromelysin, MMP-23, MMP-19, or matrilysin, and the activ­ nitrogen, sulfur, or carboxylic acid with a protecting group, or ity ofthe matrix metalloproteinase can be significantly inhib­ a non-natural amino acid, for example, selected from phos­ 65 ited. phoserine; phosphothreonine; phosphotyrosine; hydroxypro­ When the compounds, compositions, or methods of the line; y-carboxyglutamate; hippuric acid; octahydroindole-2- invention are used to inhibit MMPs, the inhibition may be US 8,937,151 B2 7 8 selective for one type of MMP over one or more others. In described herein below. The invention also provides for the some embodiments, a compound can selectively inhibit use of a compound or composition described herein for the MMP-2, MMP-9, and/orMMP-14. The manner ofinhibition manufacture of a medicament to treat such conditions, for n may also involve slow-binding inhibition with respect to k 0 example, conditions in a manimal, such as a human. The 5 and k 0ffparameters, as documented in Table 2 of Example 2. medicament can include a pharmaceutically acceptable dilu­ Accordingly, modulating a matrix metalloproteinase or ent, excipient, or carrier. The invention further provides for inhibiting a matrix metalloproteinase includes selectively the use of a compound or composition described herein to inhibiting a matrix metalloproteinase, such as MMP-2, prepare a medicament for treating such disorders in a mam­ MMP-9, and/or MMP-14, while other gelatinases, such as mal, such as a human. MMP-1, MMP-3, and/or MMP-7 are not inhibited. 10 The disease or condition can include any disease, disorder, DETAILED DESCRIPTION or condition recited herein, including, but not limited to, cancer, stroke, a chronic wound, an ophthalmological disor­ The invention may be more fully appreciated by reference der, traumatic brain injury, spinal cord injury, subarachnoid to the following description, including the following glossary hemorrhage, tuberculosis, asthma, glaucoma, retinal 15 ofterms and the concluding examples. For the sake ofbrevity, ischemia, ischemic optic neuropathy, macular degeneration, sequalae of hyperhomocystinemia, convulsion, pain, aneur­ the disclosures ofthe publications, including patents, cited in ism, depression, anxiety, schizophrenia, muscle spasm, this specification are herein incorporated by reference. Ref­ migraine headache, urinary incontinence, drug withdrawal, erence is herein made to the subject matter recited by certain nicotine withdrawal, opiate tolerance or withdrawal, emesis, 20 claims, examples of which are illustrated in the accompany­ brain edema, tardive dyskinesia, AIDS-induced dementia, ing structures and formulas. While the exemplary subject ocular damage, retinopathy, a cognitive disorder, or a neu­ matter will be described, it will be understood that the exem­ ronal injury associated with HIV-infection; or a gelatinase­ plary descriptions are not intended to limit the claims. On the mediated neurodegenerative disorder comprising epilepsy, contrary, the inventive subject matter is intended to cover all Alzheimer's disease, Huntington's disease, Parkinson's dis­ 25 alternatives, modifications, and equivalents, which may be ease, multiple sclerosis, or amyotrophic lateral sclerosis; or a included within the scope of the presently disclosed subject combination thereof. matter as defined by the claims. In some embodiments, the condition is ischemic stroke or Introduction. hemorrhagic stroke. In another embodiment, the condition is The discovery and synthesis ofSB-3CT, the first prototype a neurological disorder or ophthalmological disorder. The 30 mechanism-based inhibitor for MMPs (K, 14±1 nM and neurological disorder or ophthalmological disorder can arise 600±200 nM for human MMP-2 and MMP-9, respectively) from at least one of trauma, ischemic or hypoxic conditions. was reported in 2000 (J. Amer. Chem. Soc. 2000, 122, 6799­ The neurological disorder can be a neurodegenerative disor­ 6800; J. Biol. Chem. 2000, 275, 41415-23). The K, values for der. In some embodiments, the disease, disorder, or condition other MMPs tested in the µM range at best. may arise from at least one ofpainful neuropathy, neuropathic 35 pain, diabetic neuropathy, drug dependence, drug with­ drawal, drug addiction, depression, anxiety, movement dis­ SB-3CT orders, tardive dyskinesia, cerebral infections that disrupt the blood-brain barrier, meningitis, meningoencephalitis, hypoglycemia, cerebral ischemia (stroke), cardiac arrest, spi­ 40 nal cord trauma, head trauma, perinatal hypoxia, or hypogly­ cemic neuronal damage. The administering ofa compound described herein can be carried out in combination with administering a thrombolytic agent. The thrombolytic agent can be, for example, tissue 45 The selectivity of SB-3CT for inhibition of gelatinases plasminogen activator (tPA). over all other MMPs is due to the ability of gelatinase to The invention provides for the use of a compound facilitate the requisite rate-limiting deprotonation event lead­ described herein to prepare a medicament to treat a disease or ing to thiirane-ring opening, giving tight-binding inhibition condition that is modulated by a matrix metalloproteinase by the thiolate generated within the active site. SB-3CT was (MMP). The medicament can include a physiologically 50 evaluated in a mouse transient ischemia model and found to acceptable diluent or carrier. reduce infarct volume to 30% of control and significantly The invention thus provides novel compounds of Formula improvedneurobehavioral scores. Notably, administration of A and Formula I, intermediates for their synthesis, as well as SB-3CT at 6 hours after ischemia potently blocked histologi­ methods of preparing such compounds. The invention also cal damage. Furthermore, SB-3CT has been shown to be provides compounds ofthe formulas described herein that are 55 useful as intermediates for the synthesis ofother useful com­ effective for the treatment of viral-induced vascular leakage pounds. The invention further provides for the use of com­ in mice, a model of hemorrhagic fever, and in a rat model of pounds of Formula A and Formula I for the manufacture of subarachnoid hemorrhage, a type of hemorrhagic stroke. medicaments useful for the treatment of various conditions Thus, a selective gelatinase inhibitor can be used for treat­ modulated by matrix metalloproteinases, such as stroke in a 60 ment of both ischemic and hemorrhagic stroke. mammal. These studies indicate that MMP-9 and MMP-2 contribute Additionally, the invention provides compounds and com­ in the disease process of stroke. Gelatinase inhibitors can positions described herein for use in medical therapy. The protect the neurovascular integrity ofthe brain from ischemia medical therapy can be treating a neurological disorder or or exogenous tPA thrombolysis by blocking degradation of cancer, such as breast cancer, lung cancer, pancreatic cancer, 65 the basal membrane laminin and exerting anti-apoptotic prostate cancer, or colon cancer. Additional diseases, disor­ effects on neurons. Therefore, combined treatment with ders, and conditions that can be treated with such therapy are selective gelatinase inhibitors and tPA can minimize neuro­ US 8,937,151 B2 9 10 toxicity and hemorrhagic transformation associated with tPA The term "and/or" means any one of the items, any com­ use, thereby extending the window of treatment for reperfu­ bination ofthe items, or all ofthe items with which this term sion therapy oftPA. is associated. The phrase "one or more" is readily understood For this approach to effectively treat stroke patients, it by one ofskill in the art, particularly when read in context of requires delivery of the gelatinase inhibitors by intravenous 5 its usage. For example, one or more substituents on a phenyl administration. The prototype selective gelatinase inhibitor ring refers to one to five, or one to four, for example if the SB-3CT has poor aqueous solubility (2.45 µg/mL), therefore phenyl ring is disubstituted. it cannot be administered intravenously. In addition, SB-3CT The term "about" can refer to a variation of ±5%, ±10%, is rapidly metabolized by oxidation at the para position ofthe ±20%, or ±25% of the value specified. For example, "about terminal phenyl ring and at the a-position with respect to the 10 50" percent can in some embodiments carry a variation from sulfonyl group. The p-hydroxylated metabolite was a more 45 to 55 percent. For integer ranges, the term "about" can potent gelatinase inhibitor than the parent SB-3CT (K, 6±3 include one or two integers greater than and/or less than a nM and 160±80 nM for human MMP-2 and MMP-9, respec­ recited integer. Unless indicated otherwise herein, the term tively). More than 400 second-generation gelatinase inhibi­ "about" is intended to include values, e.g., weight percents, tors have been synthesized that are more water soluble, more 15 proximate to the recited range that are equivalent in terms of metabolically stable, and more potent inhibitors than the par­ the functionality of the individual ingredient, the composi­ ent SB-3CT. These second-generation gelatinase inhibitors tion, or the embodiment. contain functional groups that can be used in a prodrug strat­ As will be understood by the skilled artisan, all numbers, egy to improve the aqueous solubility and pharmacokinetic including those expressing quantities of ingredients, proper­ properties of the gelatinase inhibitors. 20 ties such as molecular weight, reaction conditions, and so A prodrug ( drug+pro-moiety or solubilizing group) is a forth, are approximations and are understood as being option­ chemical entity with little or no pharmacological activity that ally modified in all instances by the term "about." These undergoes transformation to the therapeutically active drug in values can vary depending upon the desired properties sought the body. Water-soluble prodrugs of second-generation to be obtained by those skilled in the art utilizing the teachings gelatinase inhibitors have been prepared as described herein. 25 of the descriptions herein. It is also understood that such These inhibitors rapidly generate the active drug in the blood­ values inherently contain variability necessarily resulting stream. The prodrugs are designed to release naturally occur­ from the standard deviations found in their respective testing ring non-toxic pro-moieties during the transformation to the measurements. therapeutically active drug. The prodrug gelatinase inhibitors As will be understood by one skilled in the art, for any and are at least 5000-fold more water soluble than SB-3CT and 30 all purposes, particularly in terms of providing a written are amenable to intravenous administration. This novel thera­ description, all ranges recited herein also encompass any and peutic strategy by itself or in combination with tPA would all possible sub-ranges and combinations of sub-ranges reduce injury and extend the time window for thrombolytic thereof, as well as the individual values making up the range, therapy in patients with stroke. particularly integer values. A recited range ( e.g., weight per­ 35 cents or carbon groups) includes each specific value, integer, DEFINITIONS decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the As used herein, the recited terms have the following mean­ same range being broken down into at least equal halves, ings. All other terms and phrases used in this specification thirds, quarters, fifths, or tenths. As a non-limiting example, have their ordinary meanings as one of skill in the art would 40 each range discussed herein can be readily broken down into understand. Such ordinary meanings may be obtained by a lower third, middle third and upper third, etc.As will also be reference to technical dictionaries, such as Hawley's Con­ understood by one skilled in the art, all language such as "up densed Chemical Dictionary 14th Edition, by R. J. Lewis, to," "at least," "greater than," "less than," "more than," "or John Wiley & Sons, New York, N.Y., 2001. more," and the like, include the number recited and such References in the specification to "one embodiment", "an 45 terms refer to ranges that can be subsequently broken down embodiment", etc., indicate that the embodiment described into sub-ranges as discussed above. In the same manner, all may include a particular aspect, feature, structure, moiety, or ratios recited herein also include all sub-ratios falling within characteristic, but not every embodiment necessarily includes the broader ratio. Accordingly, specific values recited for that aspect, feature, structure, moiety, or characteristic. More­ radicals, substituents, and ranges, are for illustration only; over, such phrases may, but do not necessarily, refer to the 50 they do not exclude other defined values or other values same embodiment referred to in other portions of the speci­ within defined ranges for radicals and substituents. fication. Further, when a particular aspect, feature, structure, One skilled in the art will also readily recognize that where moiety, or characteristic is described in connection with an members are grouped together in a common manner, such as embodiment, it is within the knowledge ofone skilled in the in a Markush group, the invention encompasses not only the art to affect or connect such aspect, feature, structure, moiety, 55 entire group listed as a whole, but each member ofthe group or characteristic with other embodiments, whether or not individually and all possible subgroups of the main group. explicitly described. Additionally, for all purposes, the invention encompasses not The singular forms "a", "an", and "the" include plural only the main group, but also the main group absent one or reference unless the context clearly dictates otherwise. Thus, more of the group members. The invention therefore envis­ for example, a reference to "a compound" includes a plurality 60 ages the explicit exclusion ofany one or more ofmembers of ofsuch compounds, so that a compound X includes a plurality a recited group. Accordingly, provisos may apply to any ofthe of compounds X. It is further noted that the claims may be disclosed categories or embodiments whereby any one or drafted to exclude any optional element. As such, this state­ more of the recited elements, species, or embodiments, may ment is intended to serve as antecedent basis for the use of be excluded from such categories or embodiments, for exclusive terminology, such as "solely," "only," and the like, 65 example, as used in an explicit negative limitation. in connection with the recitation ofclaim elements or use of The term "contacting" refers to the act oftouching, making a "negative" limitation. contact, or of bringing to immediate or close proximity, US 8,937,151 B2 11 12 including at the cellular or molecular level, for example, to -continued bring about a physiological reaction, a chemical reaction, or a physical change, e.g., in a solution, in a reaction mixture, in vitro, or in vivo. The terms "comprising", "including", "having", and 5 "composed of' are open-ended terms as used herein. A "heterocycle" or "heterocycloalkyl" group refers to a The term "alkyl" refers to a straight- or branched-chain monocyclic, or fused, bridged, or spiro polycyclic ring struc­ alkyl group having from 1 to about 20 carbon atoms in the ture that is saturated or partially saturated and has from 3 to 12 chain. For example, the alkyl group can be a (C 1-C20)alkyl, a 10 ring atoms per ring structure selected from carbon atoms and up to three heteroatoms selected from nitrogen, oxygen, and (C 1-C12)alkyl, (C 1 -C 8 )alkyl, (C 1 -C 6 )alkyl, or (C 1-C4 )alkyl. Examples of alkyl groups include methyl (Me, which also sulfur. The ring structure may optionally contain up to two may be structurally depicted by a/ symbol), ethyl (Et), n-pro­ oxo groups on carbon or sulfur ring members, and can be pyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (t-Bu), optionally substituted or unsubstituted. Illustrative examples pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that 15 of heterocycle groups include the following entities, in the in light of the ordinary skill in the art and the teachings form of properly bonded moieties: provided herein would be considered equivalent to any one of the foregoing examples. Alkyl groups can be optionally sub­ H H stitutedor unsubstituted, and optionally partially unsaturated, 20 such as in an alkenyl group. [)o, OH, D, The term "alkenyl" refers to a straight- or branched-chain o. o. o. alkenyl group having from 2 to 20 carbon atoms in the chain. (The double bond of the alkenyl group is formed by two sp 2 hybridized carbon atoms.) Illustrative alkenyl groups include 25 (? (_; (il () Q HN-NH, S , N, N, NH , C1 -C 12 alkenyl groups, such as prop-2-enyl, but-2-enyl, but- 3-enyl, 2-methylprop-2-enyl, hex-2-enyl, and groups that in light ofthe ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the 30 CJ CJ (J NH NH O NH NH foregoing examples. Alkenyl groups can be optionally sub- stituted or unsubstituted. 0 0 0 0 ~# The term "cycloalkyl" refers to a saturated or partially )l )l saturated, monocyclic, fused polycyclic, or spiro polycyclic us, O· HN\__JNH, carbocycle having from 3 to 12 ring atoms per carbocycle, 35 and can be optionally substituted or unsubstituted. In some 0 0 0 embodiments, an alkyl group refers to a cycloalkyl group that accordingly includes a ring structure. Such alkyl groups include (cycloalkyl)-alkyl groups. Illustrative examples of cycloalkyl groups include the following entities, in the form 40 °CJ° Cr0 CI 0 0 of properly bonded moieties: II H ~# HN~O. O"() () () NH NH NH 45 V [>DOOQ 0 0 Ooooo,, Cr0(-2(2 (X)(X>C0 ,)--( ij__< 55 u lNH CX>COOO 60 bco/b (X>(X> 0 > CC) 0>£D£D~,, 65 The term "aryl" refers to an aromatic hydrocarbon group derived from the removal of at least one hydrogen atom from US 8,937,151 B2 13 14 a single carbon atom of a parent aromatic ring system. The oles, oxazoles, thiazoles, diazines, triazoles, and tetrazoles. In radical attachment site can be at a saturated or unsaturated one embodiment, Het specifically refers to 1,3,4-oxadiazoles, carbon atom of the parent ring system. The aryl group can 1,2,4-oxadiazoles, the isomeric 1,2,4-oxadiazoles, tetrazoles, have from 6 to 30 carbon atoms, for example, about 6-14 1,3,4-thiadiazoles, oxazoles, 1,2-diazines, thiazoles, and 1,3, carbon atoms, about 6-13 carbon atoms, or about 6-10 carbon 5 4-triazoles. In another specific embodiment, Het specifically atoms. The aryl group can have a single ring ( e.g., phenyl) or refers to 1,2-diazine, a thiazole, a 1,2,4-oxadiazole, a 1,3,4­ multiple condensed (fused) rings, wherein at least one ring is thiadiazole, a 1,3,4-triazole, or a tetrazole. In yet another aromatic ( e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or embodiment, Het specifically refers to a 1,2,4-oxadiazole, or anthryl). Typical aryl groups include, but are not limited to, a 1,3,4-thiadiazole. In other embodiments, Het can refer to a radicals derived from benzene, naphthalene, anthracene, 10 5-membered heterocyclic ring wherein the ring includes three biphenyl, and the like. The aryl can be unsubstituted or heteroatoms independently selected from 0, S, P, and N. In optionally substituted. some embodiments, at least two ofthe heteroatoms are N. In The term "heteroaryl" refers to a monocyclic, fused bicy­ some embodiments, at least two of the heteroatoms are 0. In clic, or fused polycyclic aromatic heterocycle (ring structure 15 yet other embodiments, Het is specifically any 1, 2, 3, 4, 5, 6, having ring atoms selected from carbon atoms and up to four 7, or 8 groups selected from 1,3,4-oxadiazoles, 1,2,4-oxadia­ heteroatoms selected from nitrogen, oxygen, and sulfur) hav­ zoles, the isomeric 1,2,4-oxadiazoles, tetrazoles, 1,3,4-thia­ ing from 3 to 12 ring atoms per heterocycle. The heteroaryl diazoles, oxazoles, 1,2-diazines, thiazoles, and 1,3,4-triaz­ can be unsubstituted or optionally substituted. Illustrative oles. examples ofheteroaryl groups include the following entities, 20 The term "halogen" represents chlorine, fluorine, bromine in the form of properly bonded moieties: or iodine. The term "halo" represents chloro, fluoro, bromo or iodo. As to any ofthe groups or "substituents" described herein, each can further include one or more ( e.g., 1, 2, 3, 4, 5, or 6) 25 substituents. It is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. The term "substituted" means that a specified group or moiety can bear one or more (e.g., 1, 2, 3, 4, 5, or 6) substitu­ 30 ents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents. Where the term "substituted" is used to describe a structural system, the substitution is meant 35 to occur at any valency-allowed position on the system. In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any speci­ fied substituent, it is understood that such a moiety or group is 40 intended to be unsubstituted in some embodiments but can be substituted in other embodiments. Suitable substituent groups include, e.g., alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, aroyl, heteroaryl, het­ erocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alky­ 45 !amino, dialkylamino, trifluoromethylthio, difluoromethyl, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsul­ fonyl, arylsulfinyl, arylsulfonyl, heteroarylsulfinyl, heteroar­ ylsulfonyl, heterocyclesulfinyl, heterocyclesulfonyl, phos­ 50 phate, sulfate, hydroxylamine, hydroxyl (alkyl)amine, and/or cyano. In certain embodiments, any one ofthe above groups can be included or excluded from a variable or from a group of substituents. Specific values listed below for substituents (i.e., groups) 55 and ranges are for illustration only. They do not exclude other defined values or other values within defined ranges for the Those skilled in the art will recognize that the species of substituents. cycloalkyl, heterocycle, and heteroaryl groups listed or illus­ Specifically, (C 1-C6)alkyl can be, for example, methyl, trated above are not exhaustive, and that additional species ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, within the scope ofthese defined terms may also be selected. 60 3-pentyl, or hexyl;

As used herein, the term "Het" can refer to a 5 or 6 mem­ (C1-C6)alkoxy can be methoxy, ethoxy, propoxy, isopro­ bered heterocyclic ring comprising 1, 2, or 3 heteroatoms poxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or selected from 0, N, S, or P, wherein the ring optionally hexyloxy; includes one or two cites of unsaturation and the ring is (C2 -C6)alkenyl can be vinyl, ally!, 1-propenyl, 2-propenyl, optionally substituted with 1, 2, or 3 oxo, halo, nitro, or 65 1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl, 2-pentenyl, methyl groups. The Het group can be a heterocycle group or 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, a heteroaryl group. Examples include oxadiazoles, thiadiaz­ 4-hexenyl, or 5-hexenyl; US 8,937,151 B2 15 16

(C2 -C6)alkynyl can be ethynyl, 1-propynyl, 2-propynyl, tages resulting from greater metabolic stability, for example 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, increased in vivo half-life or reduced dosage requirements. 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, Isotopically labeled compounds of this invention and pro­ 4-hexynyl, or 5-hexynyl; drugs thereof can generally be prepared by carrying out the

(C 1-C6)alkanoyl can be acetyl, propanoyl or butanoyl; 5 procedures disclosed in the schemes or in the examples and (C2 -C6)alkanoyloxy can be acetoxy, propanoyloxy, preparations described below by substituting a readily avail­ butanoyloxy, isobutanoyloxy, pentanoyloxy, orhexanoyloxy; able isotopically labeled reagent for a non-isotopically

(C3 -C8)cycloalkyl can be cyclopropyl, cyclobutyl, cyclo­ labeled reagent. pentyl, cyclohexyl, cycloheptyl, or cyclooctyl; When referring to any formula given herein, the selection aryl can be phenyl, indenyl, 5,6,7,8-tetrahydronaphthyl, or 10 of a particular moiety from a list of possible species for a naphthyl; and specified variable is not intended to limit the definition ofthe bicyclic aryl can be indenyl or naphthyl. moiety for the variable appearing elsewhere. In other words, Het can be heteroaryl, monocyclic heteroaryl, bi cyclic het­ where a variable appears more than once, the choice of the eroaryl, or a non-aromatic heterocycle. Heteroaryl can be species from a specified list is independent ofthe choice ofthe fury!, imidazolyl, tetrazolyl, pyridyl (or its N-oxide), thienyl, 15 species for the same variable elsewhere in the formula, or pyrimidinyl (or its N-oxide), indolyl, orquinolyl (or its N-ox­ elsewhere in a different formula. ide); monocyclic heteroaryl can be fury!, imidazolyl, triaz­ The term "amino acid" includes but is not limited to the olyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, following 20 naturally-occurring proteogenic amino acid pyrazolyI, pyrrolyI, pyrazinyI, tetrazolyI, pyridy I ( or its N-ox­ residues: ~~~~r~:f~~n°:e ~?~~i~%~ &~rJ~~:d~);i~:~b~~tct~cr~~ 20 can be decahydroquinoline or decahydronaphthalene (cis or SYMBOL: DEFINITION SYMBOL: DEFINITION trans). The Het group can optionally include, for example, one ortwo cites ofunsaturation, and the ring can optionally be Ala Alanine Met Methionine substituted with 1, 2, 3, or 4 substituents, for example, oxo, Cys Cysteine Asn Asparagine halo, nitro, or methyl groups. 25 Asp Aspartic Acid Pro Praline Glu Glutarnic Acid Gln Glutarnine Any formula given herein is intended to represent com­ Phe Phenylalanine Arg Arginine pounds having structures depicted by the structural formula Gly Glycine Ser Serine as well as certain variations or forms. In particular, com­ His Histidine Thr Threonine pounds of any formula given herein may have asymmetric Ile Isoleucine Val Valine Lys Lysine Trp Tryptophan centers and therefore exist in different enantiomeric and/or 30 Leu Leucine Tyr Tyrosine diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope ofthe formula. Thus, Thus, an "amino acid" can be a natural amino acid residue any formula given herein is intended to represent a racemate, (e.g., Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, Hy!, Hyp, one or more enantiomeric forms, one or more diastereomeric 35 Be, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D forms, one or more atropisomeric forms, and/or mixtures or L form, taurine, or an unnatural amino acid ( e.g., phospho­ thereof. Furthermore, certain structures may exist as geomet­ serine; phosphothreonine; phosphotyrosine; hydroxyproline; ric isomers (i.e., cis and trans isomers), as tautomers, or as gamma-carboxyglutamate; hippuric acid; octahydroindole­ atropisomers. Additionally, any formula given herein is 2-carboxylic acid; statine; 1,2,3,4-tetrahydroisoquinoline-3­ intended to embrace hydrates, solvates, and polymorphs of carboxylic acid; penicillamine; ornithine; citrulline; a-me­ such compounds, and mixtures thereof. 40 thyl-alanine; para-benzoylphenylalanine; phenylglycine; The invention also specifically includes the racemic, scale­ propargylglycine; sarcosine; and tert-butylglycine) residue mic, R, and S mixtures and forms at the thiirane moiety of having one or more open valences. The term also comprises compounds of Formula A, Formula I, and their associated natural and unnatural amino acids bearing amino protecting formulas. Accordingly, in some embodiments, the stere­ groups ( e.g. acetyl, acyl, trifluoroacetyl, or benzyloxycarbo­ ochemistry ofthe thiirane chiral center is in the R configura­ 45 nyl), as well as natural and unnatural amino acids protected at tion, and in some embodiments, the stereochemistry of the carboxy with protecting groups ( e.g., as a (C1-C6)alkyl, phe­ thiirane chiral center is in the S configuration. Compounds of nyl or benzyl ester or amide). Other suitable amino and car­ both configurations actively inhibit MMPs. boxy protecting groups are known to those skilled in the art Any formula given herein is also intended to represent (See for example, T. W. Greene, Protecting Groups In unlabeled forms as well as isotopically labeled forms of the 50 Organic Synthesis; Wiley: New York, 1981; D. Voet, Bio­ compounds. Isotopically labeled compounds have structures chemistry, Wiley: New York, 1990; L. Stryer, Biochemistry, depicted by the formulas given herein except that one ormore (3rd Ed.), W.H. Freeman and Co.: New York, 1975; J. March, atoms are replaced by an atom having a selected atomic mass Advanced Organic Chemistry, Reactions, Mechanisms and or mass number. Examples of isotopes that can be incorpo­ Structure, (2nd Ed.), McGraw Hill: New York, 1977; F. Carey rated into compounds of the invention include isotopes of 55 and R. Sundberg, Advanced Organic Chemistry, Part B: hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, Reactions andSynthesis, (2nd Ed.), Plenum: New York, 1977; and chlorine such as 2 H 3 H 11C 13C 14C 15N 180 170 31p and references cited therein). According to the invention, the 32P, 35S, 18F: 36Cl, 125I,'res;ecti~ely.' ' ' ' ' ' amino or carboxy protecting group can also comprise a radio­ Such isotopically labeled compounds are useful in meta­ nuclide (e.g., Fluorine-18, Iodine-123, orlodine-124). bolic studies (preferably with 14C), reaction kinetic studies Modified and protected amino acid residues, as well as (with, for example 2 H or 3 H), detection or imaging techniques 60 peptido-mimetics, are also intended to be encompassed [ such as positron emission tomography (PET) or single-pho­ within the definition of "amino acid" or a linear or branched ton emission computed tomography (SPECT)] including chain oftwo to five amino acids. As would be readily recog­ drug or substrate tissue distribution assays, or in radioactive nized by one skilled in the art, the amino acid can be linked to treatment of patients. In particular, an 18F or 11C labeled the remainder ofthe compound through its carbonyl residue, compound may be particularly preferred for PET or SPECT 65 its amino residue, orthrough a sulfur residue ifthe amino acid studies. Further, substitution with heavier isotopes such as includes a thiol group. A linear or branched chain of two to deuterium (i.e., 2 H) may afford certain therapeutic advan­ five amino acids can include any combination of two to five US 8,937,151 B2 17 18

Ala, Cys, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, C5 _7 cycloalkyl, phenyl, and phenyl(C1_6 alkyl) esters. Pre­ Pro, Gin, Arg, Ser, Thr, Val, Trp, or Tyr, optionally protected ferred esters include methyl esters. Prodrugs may also be on nitrogen, sulphur, or a carboxylic acid with protecting prepared by derivatizing free hydroxy groups using groups groups. including hemisuccinates, phosphate esters, dimethylami­ A combination oftwo to five amino acids can be referred to 5 noacetates, and phosphoryloxy-methyloxycarbonyls, follow­ as a "peptide". A peptide can also be a sequence of2 to about ing procedures such as those outlined in Adv. Drug Delivery 10 amino acids (e.g., as defined hereinabove) or peptidic Rev. 1996, 19, 115. Carbamate derivatives of hydroxy and residues having an open valences to link to a formula amino groups may also yield prodrugs. Suitable transforma­ described herein. The sequence may be linear or cyclic. For tions well know to those of skill in the art are described by example, a cyclic peptide can be prepared or may result from 10 Greg T. Hermanson in Bioconjugate Techniques, Academic the formation ofdisulfide bridges between two cysteine resi­ Press, San Diego, Calif. (1996). Other useful transformations dues in a sequence. A peptide can be linked through the are described in U.S. Patent Publication No. 2009/0005420 carboxy terminus, the amino terminus, or through any other (Lee et al.). convenient point ofattachment, such as, for example, through Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization the sulfur ofa cysteine. Peptide derivatives can be prepared as 15 described in U.S. Pat. No. 4,612,302 (Szabo et al.); U.S. Pat. of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl No. 4,853,371 (Coy et al.); and U.S. Pat. No. 4,684,620 ethers, wherein the acyl group may be an alkyl ester, option­ (Hruby et al.). ally substituted with one or more ether, amine, or carboxylic Prodrugs and Metabolites acid functionalities, or where the acyl group is an amino acid The invention also relates to pharmaceutically acceptable ester as described above, is also useful to yield prodrugs. prodrugs of SB-3CT, and treatment methods using such pro­ 20 Prodrugs ofthis type may be prepared as described inJ. Med. drugs. The term "prodrug" refers to a precursor of a desig­ Chem. 1996, 39, 10. Free amines can also be derivatized as nated compound that, following administration to a subject, amides, sulfonamides or phosphonamides. These prodrug yields the compound in vivo via a chemical or physiological moieties may incorporate groups including ether, amine, and process such as solvolysis, enzymatic cleavage, or enzymatic carboxylic acid functionalities. biotransformation, or under physiological conditions ( e.g., 25 The present invention also relates to a method ofproviding where a prodrug upon being brought to physiological pH is a pharmaceutically active metabolite of a compound of a formula described herein, and uses ofsuch a metabolite in the converted to the compound hydroxy-SB-3CT). A "pharma­ methods of the invention. A "pharmaceutically active ceutically acceptable prodrug" is a prodrug that is non-toxic, metabolite" refers to a pharmacologically active product of biologically tolerable, and otherwise biologically suitable for 30 metabolism inthe body ofa compound ofa formula described administration to the subject. Illustrative procedures for the herein. A prodrug or an active metabolite ofa compound may selection and preparation of suitable prodrug derivatives are be determined using routine techniques known or available in described, for example, in Design of Prodrugs, H. Bund­ the art. See, e.g., Bertolini, et al., J. Med. Chem. 1997, 40, gaard, Ed.; Elsevier, 1985. 2011-2016; Shan, et al.,J. Pharm. Sci. 1997, 86 (7), 765-767; Examples of prodrugs include compounds of formula A Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. 35 wherein the solubilizing group is an amino acid residue, or a Drug Res. 1984, 13, 224-331; Bundgaard, Design of Pro­ polypeptide chain of two or more (e.g., two, three or four) drugs (Elsevier Press, 1985); and Larsen, Design and Appli­ amino acid residues, covalently joined through an amide or cation ofProdrugs, Drug Design and Development (Krogs­ ester bond to a free amino or hydroxy, such as the hydroxy gaard-Larsen, et al., eds., Harwood Academic Publishers, group ofhydroxy-SB-3CT. Examples ofamino acid residues 1991). include the twenty naturally occurring amino acids, com­ 4° Compounds and Methods ofthe Invention monly designated by three letter symbols, as well as 4-hy­ A compound of a formula described herein, or a pharma­ droxyproline, hydroxylysine, demosine, isodemosine, 3-me­ ceutically acceptable salt thereof, can be administered to a thylhistidine, norvalin, beta-alanine, gamma-aminobutyric mammal (e.g., human) alone or in conjunction with a second acid, citrulline homocysteine, homoserine, omithine, agent, such as a neurological agent, or a pharmaceutically methionine sulfone, taurine, and protected versions thereof. 45 acceptable salt thereof. Accordingly, the compound can be administered in conjunction with a thrombolytic agent, such Additional types of a prodrug may be produced, for as tPA to treat a disorder, disease, or condition as described instance, by derivatizing (chemically converting) the herein. hydroxyl group to an amide or alkyl ester or an amino group The term "neurological agent" refers to a compound, to an amide or secondary amine (e.g., thereby providing a 50 including chemical and biological compounds ( e.g., peptides, 'solubilizing group'). Examples of amides include those oligonucleotides and antibodies), that has an effect on the derived from ammonia, primary C 1_6alkyl amines and sec­ nervous system, e.g., compounds capable of treating, inhib­ ondary di(C1_6 alkyl) amines. Secondary amines include 5- or iting or preventing disorders affecting the nervous system or 6-membered heterocycloalkyl or heteroaryl ring moieties. compounds capable ofeliciting a neurological and/or an oph­ Examples of amides include those that are derived from 55 thalmological disorder or symptoms thereof. ammonia, C 1_ 3 alkyl primary amines, and di(C1_2 alkyl) Specific examples of the compounds of Formula A and amines. Examples ofesters ofthe invention include C 1_7 alkyl, Formula I include:

lla 9a US 8,937,151 B2 19 20 -continued llb 9b

llc 9c

lld 9d

lle

9e

14

13 US 8,937,151 B2 21 22 the preparation of which are described in the examples sec­ tion below. Other compounds of Formula A and Formula I that can be readily prepared using the techniques described herein as well as those well known to those of skill in the art include:

30 where R is an amino acid or a peptide, such as a linear or branched chain of two to five amino acids. For techniques well known in the art, see for example, March, Advanced Organic Chemistry, Reactions, Mechanisms and Structure, rd Ed., 1977 and Carey & Sundberg, Advanced Organic nd 35 Chemistry, Part B: Reactions, 2 Ed., 1983. Protecting Groups Compounds of the invention include compounds of For­ mula A and Formula I, as well as such compounds that also include suitable protecting groups. The term "protecting 40 group" refers to any group that, when bound to a hydroxyl, nitrogen, or other heteroatom prevents undesired reactions 0 o'QI~ from occurring at this group and that can be removed by conventional chemical or enzymatic steps to reestablish the o # s:"pregnancy, hypertension, cancer, given unit dosage form. The amount of active compound in hepatitis, allergic airway disease, autoimmune diabetes, such therapeutically useful compositions is such that an effec­ intractable pruritus, neuroinflammation, or a combination tive dosage level can be obtained. thereof. The tablets, troches, pills, capsules, and the like may also The invention further includes a pharmaceutical composi­ 55 contain one or more of the following: binders such as gum tion for treating a disease, disorder, or medical condition tragacanth, acacia, corn starch or gelatin; excipients such as mediated by MMP activity, comprising: (a) an effective dicalcium phosphate; a disintegrating agent such as corn amount of at least one compound of a formula described starch, potato starch, alginic acid and the like; and a lubricant herein, or a pharmaceutically acceptable salt, a pharmaceuti­ such as magnesium stearate. A sweetening agent such as cally acceptable prodrug, or an pharmaceutically active 60 sucrose, fructose, lactose or aspartame; or a flavoring agent metabolite thereof, or any combination thereof, and a phar­ such as peppermint, oil of wintergreen, or cherry flavoring, maceutically acceptable excipient. The invention also may be added. When the unit dosage form is a capsule, it may includes a method of inhibiting fatty acid amide hydrolase contain, in addition to materials of the above type, a liquid activity comprising contacting the fatty acid amide hydro lase carrier, such as a vegetable oil or a polyethylene glycol. with an effective amount of a compound of any one of the 65 Various other materials may be present as coatings or to formulas described herein. The contacting can be in vivo or in otherwise modify the physical form of the solid unit dosage vitro. form. For instance, tablets, pills, or capsules may be coated US 8,937,151 B2 29 30 with gelatin, wax, shellac or sugar and the like. A syrup or bent pads, used to impregnate bandages and other dressings, elixir may contain the active compound, sucrose or fructose or sprayed onto the affected area using a pump-type or aerosol as a sweetening agent, methyl and propyl parabens as preser­ sprayer. vatives, a dye and flavoring such as cherry or orange flavor. Thickeners such as synthetic polymers, fatty acids, fatty Any material used in preparing any unit dosage form should 5 acid salts and esters, fatty alcohols, modified celluloses, or be pharmaceutically acceptable and substantially non-toxic modified mineral materials can also be employed with liquid in the amounts employed. In addition, the active compound carriers to form spreadable pastes, gels, ointments, soaps, and may be incorporated into sustained-release preparations and the like, for application directly to the skin of the user. devices. Examples of dermatological compositions for delivering 10 active agents to the skin are known to the art; for example, see The active compound may be administered intravenously Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. or intraperitoneally by infusion or injection. Solutions of the 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157), and Wortz­ active compound or its salts can be prepared in water or man (U.S. Pat. No. 4,820,508). Such dermatological compo­ saline, optionally mixed with a nontoxic surfactant. Disper­ sitions can be used in combinations with the compounds sions can be prepared in glycerol, liquid polyethylene gly­ 15 described herein. cols, triacetin, or mixtures thereof, or in a pharmaceutically Useful dosages ofthe compounds described herein can be acceptable oil. Under ordinary conditions ofstorage and use, determined by comparing their in vitro activity, and in vivo preparations may contain a preservative to prevent the growth activity in animal models. Methods for the extrapolation of of microorganisms. effective dosages in mice, and other animals, to humans are Pharmaceutical dosage forms suitable for injection or infu­ 20 known to the art; for example, see U.S. Pat. No. 4,938,949 sion can include sterile aqueous solutions, dispersions, or (Barch et al.). The amount ofa compound, or an active salt or sterile powders comprising the active ingredient adapted for derivative thereof, required for use in treatment will vary not the extemporaneous preparation ofsterile injectable or infus­ only with the particular compound or salt selected but also ible solutions or dispersions, optionally encapsulated in lipo­ with the route of administration, the nature of the condition somes. The ultimate dosage form should be sterile, fluid and 25 being treated, and the age and condition of the patient, and stable under the conditions of manufacture and storage. The will be ultimately at the discretion of an attendant physician liquid carrier or vehicle can be a solvent or liquid dispersion or clinician. The compound can be conveniently administered in a unit medium comprising, for example, water, ethanol, a polyol 2 dosage form, for example, containing 5 to 1000 mg/m , con­ (for example, glycerol, propylene glycol, liquid polyethylene 2 glycols, and the like), vegetable oils, nontoxic glyceryl esters, 30 veniently 10 to 750 mg/m , most conveniently, 50 to 500 mg/m2 ofactive ingredient per unit dosage form. The desired and suitable mixtures thereof. The proper fluidity can be dose may conveniently be presented in a single dose or as maintained, for example, by the formation of liposomes, by divided doses administered at appropriate intervals, for the maintenance of the required particle size in the case of example, as two, three, four or more sub-doses per day. The dispersions, orby the use ofsurfactants. The prevention ofthe 35 sub-dose itself may be further divided, e.g., into a number of action of microorganisms can be brought about by various discrete loosely spaced administrations. antibacterial and antifungal agents, for example, parabens, In one embodiment, the invention provides therapeutic chlorobutanol, phenol, sorbic acid, thiomersal, and the like. methods of treating cancer in a manimal, which involve In many cases, it will be preferable to include isotonic agents, administering to a mammal having cancer an effective for example, sugars, buffers, or sodium chloride. Prolonged 40 amount of a compound or composition described herein. A absorption of the injectable compositions can be brought mammal includes a primate, human, rodent, canine, feline, about by agents delaying absorption, for example, aluminum bovine, ovine, equine, swine, caprine, bovine and the like. monostearate and/or gelatin. Cancer refers to any various type ofmalignant neoplasm, for Sterile injectable solutions can be prepared by incorporat­ example, breast cancer, colon cancer, lung cancer, prostate ing the active compound in the required amount in the appro­ 45 cancer, melanoma and leukemia, and in general is character­ priate solvent with various of the other ingredients enumer­ izedby an undesirable cellular proliferation, e.g., unregulated ated above, as required, followed by filter sterilization. In the growth, lack of differentiation, local tissue invasion, and case ofsterile powders for the preparation ofsterile injectable metastasis. solutions, methods ofpreparation can include vacuum drying The ability of a compound ofthe invention to treat cancer and freeze drying techniques, which yield a powder of the 50 may be determined by using assays well known to the art. For active ingredient plus any additional desired ingredient example, the design of treatment protocols, toxicity evalua­ present in the previously sterile-filtered solutions. tion, data analysis, quantification of tumor cell kill, and the For topical administration, compounds may be applied in biological significance of the use of transplantable tumor pure form, e.g., when they are liquids. However, it will gen­ screens are known. erally be desirable to administer the active agent to the skin as 55 Combination Therapy a composition or formulation, for example, in combination In the following description, component "(b )" is to be with a dermatologically acceptable carrier, which may be a understood to represent one or more agents as described solid or a liquid. herein (e.g., a compound ofFormula A or Formula I). Thus, if Useful solid carriers include finely divided solids such as components (a) and (b) are to be treated the same or indepen­ talc, clay, microcrystalline cellulose, silica, alumina, and the 60 dently, each agent of component (b) may also be treated the like. Useful liquid carriers include water, dimethyl sulfoxide same or independently. Components (a) and (b) may be for­ (DMSO), alcohols, glycols, or water-alcohol/glycol blends, mulated together, in a single dosage unit (that is, combined in which a compound can be dissolved or dispersed at effec­ together, e.g., in one lotion, cream, gel, ointment, or formu­ tive levels, optionally with the aid of non-toxic surfactants. lation for injection) as a combination product. When compo­ Adjuvants such as fragrances and additional antimicrobial 65 nent (a) and (b) are not formulated together in a single dosage agents can be added to optimize the properties for a given use. unit, the component (a) may be administered at the same time The resultant liquid compositions can be applied from absor­ as component (b), or in any order. For example component (a) US 8,937,151 B2 31 32 may be administered first, followed by administration of pertensive agent, benzoporphyrin phtosensitiser, immuno­ component (b), or they may be administered in the reverse suppressive antimetabolite, anti-convulsant, barbiturate, order. Ifcomponent (b) contains more than one agent, e.g., a benzodiazipine, GABA inhibitors, hydantoin, anti-psychotic, thrombolytic agent and NSAID, these agents may be admin­ neurolaptic, antidysknetic, adrenergic agent, tricyclic antide­ istered together or separately in any order. When not admin­ 5 pressant, anti-hypoglycemic, glucose solution, plypeptide istered at the same time, the administration of component (a) hormone, antibiotic, thrombolytic agent, blood thinner, anti- and (b) occurs less than about ten hours apart, or about one arrhythmic agent, corticosteroid, seizure disorder agent, anti­ hour apart in some embodiments. cholinesterase, dopamine blocker, antiparkinsonian agent, As is appreciated by a medical practitioner skilled in the muscle relaxant, anxiolytic muscle relaxant, CNS stimulant, art, the dosage of the combination therapy of the invention 10 antiemetic, beta adrenergic blocking agents, ergot derivative, may vary depending upon various factors such as the phar­ isometheptene, antiserotonin agent, analgesic, selective sero­ macodynamic characteristics of the particular agent and its tonin reuptake inhibitors (SSRis), monoamine oxidase mode of administration, the age, health and weight of the inhibitor, aids adjunct agents, anti infective agent, systemic recipient, the nature and extent of the symptoms, the kind of aids adjunct anti infective, aids chemotherapeutic agent, concurrent treatment, the frequency of treatment, and the 15 nucleoside reverse transcriptase, a protease inhibitor, or a effect desired, as described above. The proper dosage of thrombolytic agent such as tPA. components (a) and (b) will be readily ascertainable by a Specifically, the MMP inhibitor can optionally be co-ad­ medical practitioner skilled in the art. By way of general ministered with at least one ofthe following: guidance, typically a daily dosage may be about 100 milli­ A beta adrenergic blocking agent, carbonic anhydrase grams to about 1.5 grams of each component. Ifcomponent 20 inhibitor, cholinesterase inhibitor, cholinergic (miotic ), (b) represents more than one compound, then typically a daily docosanoid, prostaglandin, tricyclic antidepressant, psycho­ dosage may be about 100 milligrams to about 1.5 grams of therapeutic agent, antianxiety agent, analgesic, anti-seizure each agent of component (b). By way of general guidance, agent, tricyclic antidepressants having analgesic effect in when the compounds of component (a) and component (b) neuropathic pain, linolenic acid, coenzyme, vitamin, immu­ are administered in combination, the dosage amount of each 25 nosuppressive antimetabolite, antiviral, copolymer, barbitu­ component may be reduced by about 50-80% relative to the rate, benzodiazepine, GABA inhibitor, hydantoin, tranquil­ usual dosage ofthe component when it is administered alone izer, anti-psychotic, norephedrine, peptide, antibacterial, as a single agent for the treatment of a disorder, and related tissue plasminogen activator (TPA), blood thinner/anticoagu­ symptoms, in view of synergistic effect of the combination. lant, cardiostimulant, carbonic anhydrase inhibitor, keto­ Pharmaceutical kits useful for the treatment of disorders 30 derivative of carbamazepine, acetylcholinesterase, antipsy­ described herein, and related symptoms, which include a chotic, alkaloid, GABA-B receptor agonist, benzodiazepine, therapeutically effective amount ofa pharmaceutical compo­ antiparkinsonian, antidepressant, CNS stimulant, receptor sition that includes a compound of component (a) and one or antagonist, beta adrenergic blocking agent, ergot derivatives more compounds of component (b ), in one or more sterile (anti migraine), anticonvulsant, serotonin (5-HT) receptor containers, are also within the ambit of the invention. Steril­ 35 agonist, antimanic, SSRI, MAOI, aids adjunct anti infective ization ofthe container may be carried out using conventional agent, antiviral, and protease inhibitor. sterilization methodology well known to those skilled in the Additionally, the MMP inhibitor can optionally be co­ art. Component (a) and component (b) may be in the same administered with at least one of the following: sterile container or in separate sterile containers. The sterile Timolol or Maleate; Betaxolol HCl; Carteolol HCl; containers of materials may include separate containers, or 40 Metipranolol; Timolol Hemihydrate; Brimonidine Tartarate; one or more multi-part containers, as desired. Component (a) Brinzolamide; Dorzolamide; Acetazolamide; Echothiophate and component (b), may be separate, or physically combined Iodide; Pilocarpine HCl; Unoprostone Isopropyl ester; into a single dosage form or unit as described above. Such kits Latanoprost; Acamprosate, a drug with additional neuropro­ may further include, if desired, one or more of various con­ tective properties; Amitriptyline; Perphenazine; Chlordiaz­ ventional pharmaceutical kit components, such as for 45 epoxide; Trimipramine Maleate; Chlodiazepoxide HCl; example, one or more pharmaceutically acceptable carriers, Alprazolam; Hydroxyzine dihydrochloride; Meprobamate; additional vials for mixing the components, etc., as will be Doxipin HCl; Hydroxyzine Pamoate; Aspirin; Acetami­ readily apparent to those skilled in the art. Instructions, either nophen; Ibuprofen; Carbamazipine; Flupirtine, a drug with as inserts or as labels, indicating quantities ofthe components neuroprotective properties using additional pathways to to be administered, guidelines for administration, and/or 50 MMP antagonists; Lamotrigine; Phenyloin Sodium; Pentaxi­ guidelines for mixing the components, may also be included fylline; Thioctic Acid; Levocamitine; Biotin; Nicotinic acid; in the kit. Taurine; Verteporfin; Azathioprine; Interferon Beta 1 ~' a gly­ The MMP inhibitor can optionally be co-administered with coprotein containing 166 amino acids; Interferon Beta la, a a neuroprotectant drug, used, for example, in the treatment of glycoprotein containing 166 amino acids; Cyclophospha­ Alzheimer's disease or other neurologic or ophthalmologic 55 mide; Methotrexate; Neurmexane, an NMDAR antagonist disorders (e.g., glaucoma), including, but not limited to, with improved properties compared to memantine; Glati­ memantine or a derivative thereof. ramer, an L-GlutamicAcid Polymer with L-alanine, L-lycine, The MMP inhibitor can optionally be co-administered with and L-tyrocine; Mephobarbitol; Pentobarbitol; Lorazipam; at least one of the following: Clonazepam; Chlorazeptate Dipotassium salt; Fosphenyloin An anti glaucoma agent, beta adrenergic blocking agent, 60 Sodium; Olanzapine; Heloperidol; Trifluoperizine; carbonic anhydrase inhibitor, miotic agent, sympathomi­ Fluphenazine; Phenylpropanol amine; Pseudoephedrine metic agent, acetylcholine blocking agent, antihistamine, HCl; Imipramine; Glucagon; Glucagon-related peptide-I, a anti-viral agent, quinolone, anti-inflanimatory agent, non­ 37 amino acid peptide; Glucagon-related peptide-2, a peptide steroidal anti-inflammatory agent, steroidal anti-inflamma­ that contains 33 amino acids; Penicilin G, N, 0, or V; Ampi­ tory agent, antidepressant ( e.g., serotonin reuptake inhibitors, 65 cillin; Chloramphenicol; Phorbol; Heparin, D-glucosamine SSRis), psychotherapeutic agent, anti-anxiety agent, analge­ with L-iduronic or D-glucuronic acids; Warfarin; Epineph­ sic, antiseizure agent, anti-convulsant, gabapentine, anti-hy­ rine; Amiodarone; Lidocaine; Nitroglycerin, isosorbide dini­ US 8,937,151 B2 33 34 trate, amyl, butyl, isobutyl or various other nitrates that have Carpal tunnel syndrome (CTS); Causalgia; Central pain syn­ been shown to be neuroprotective; Atenolol; Dexamethasone; drome; Central pontine myelinolysis; Cephalic disorder; Prednisolone; Acetazolamide; Phenyloin; Tiagabin HCI; Cerebral aneurysm; Cerebral arteriosclerosis; Cerebral atro­ Gabapentin; Oxacarbazepine; Tacrine; Donepezil; Rivastig­ phy; Cerebral gigantism; Cerebral palsy; Charcot-Marie- mine; Heloperidol; Phenothiazine; Reserpine; Tetrabena­ 5 Tooth disease; Chemotherapy-induced neuropathy and neu­ zene; Bromocryptine; Tiapride; Baclofen; Diazepam; Trihex­ ropathic pain; Chiari malformation; Chorea; Chronic yphenidyl HCI; Amitrityline; Amphetamines; inflammatory demyelinating polyneuropathy (CIDP); Methylphenidate; Amitriptylinec; Clomipramine; Dolas­ Chronic pain; Chronic regional pain syndrome; Coffin Lowry etron; Granisetron; Huperzine, an herb used for dementia; syndrome; Coma, including Persistent Vegetative State; Con­ Metoclopramide; Prochlorperazine; Dexamethasone; 10 genital facial diplegia; Corticobasal degeneration; Cranial Timolol Hydrogen maleate salt; Propanolol; Isometheptine; artent1s; Craniosynostosis; Creutzfeldt-Jakob disease; Atenolol; Metoprolol; Nadolol; Ergotamine; Dihydroargota­ Cumulative trauma disorders; Cushing's syndrome; Cytome­ mine; Naratriptan; Sumatriptan; Rizatriptan; Zolmitriptan; galic inclusion body disease (CIBD); Cytomegalovirus Infec­ Imipramine HCI; Dopamine; Clozapine; Valproic Acid; Ami­ tion; Dancing eyes-dancing feet syndrome; Dandy-Walker triptylinec; Imipramine HCI; Imipramine Pamoate; Clomi­ 15 syndrome; Dawson disease; De Morsier's syndrome; pramine; Amphetamine; Methylphenidate; Phenyloin; Phe­ Dejerine-Klumpke palsy; Dementia; Dermatomyositis; Dia­ nobarbital; Amitryptyline; Imipramine Pamoate; betic neuropathy; Diffuse sclerosis; Dysautonomia; Dys­ Nortrityline; Trazodone; Nefazodone; Sertraline; Fluoxetine; graphia; Dyslexia; Dystonias; Early infantile epileptic Paroxetine; Phenalzine; Tranylcypromine; Erythropoietin, a encephalopathy; Empty sella syndrome; Encephalitis; glycoprotein; Immunoglobulins (gamma globulins); Tetrahy­ 20 Encephaloceles; Encephalotrigeminal angiomatosis; Epi­ drocannabinols;Alitretinoin; Lamivudin; Stavudin; Zalcitab­ lepsy; Erb's palsy; Essential tremor; Fabry's disease; Fahr's ine; Abacavir; Ritonavir; Indinavir; and Nelfinavir; the syndrome; Fainting; Familial spastic paralysis; Febrile sei­ chemical names of which are well known in the art and are zures; Fisher syndrome; Friedreich's ataxia; Pronto-Tempo­ also described in U.S. Publication No. 2009/0209615 (Lip­ ral Dementia and other "Tauopathies"; Gaucher's disease; tion et al.), which is incorporated herein by reference. Any 25 Gerstmann's syndrome; Giant cell arteritis; Giant cell inclu­ one or more of the above compounds can be used in a phar­ sion disease; Globoid cell Leukodystrophy; Guillain-Barre maceutically acceptable salt form, solvate form ( e.g., a mono­ syndrome; HTLV-1 associated myelopathy; Hallervorden­ or di-hydrate), or any combination thereof. Spatz disease; Head injury; Headache; Hemifacial Spasm; Diseases, Disorders, and Conditions Hereditary Spastic Paraplegia; Heredopathia atactica poly­ The term "neurological disorder" refers to any disorder of 30 neuritiformis; Herpes zoster oticus; Herpes zoster; Hirayama the nervous system and/or visual system. "Neurological dis­ syndrome; HIV-Associated Dementia and Neuropathy (see orders" include disorders that involve the central nervous also Neurological manifestations of AIDS); Holoprosen­ system (brain, brainstem and cerebellum), the peripheral ner­ cephaly; Huntington's disease and other polyglutamine vous system (including cranial nerves), and the autonomic repeat diseases; Hydranencephaly; Hydrocephalus; Hyper­ nervous system (parts ofwhich are located in both central and 35 cortisolism; Hypoxia; Immune-Mediated encephalomyelitis; peripheral nervous system). Neurodegenerative disorder also Inclusion body myositis; Incontinentia pigmenti; Infantile; refers to a type ofneurological disease marked by the loss of phytanic acid storage disease; Infantile Refsum disease; nerve cells, including, but not limited to, Alzheimer's disease, Infantile spasms; Inflarnniatory myopathy; Intracranial cyst; Parkinson's disease, amyotrophic lateral sclerosis, tauopa­ Intracranial hypertension; Joubert syndrome; Keams-Sayre thies (including fronto-temporal dementia), and Hunting­ 40 syndrome; Kennedy disease; Kinsboume syndrome; Klippel ton's disease. Feil syndrome; Krabbe disease; Kugelberg-Welander dis­ Major groups ofneurological disorders include, but are not ease; Kuru; Lafora disease; Lambert-Eaton myasthenic syn­ limited to, headache, stupor and coma, dementia, seizure, drome; Landau-Kleffner syndrome; Lateral medullary (Wal­ sleep disorders, trauma, infections, neoplasms, neurooph­ lenberg) syndrome; Learning disabilities; Leigh's disease; thalmology, movement disorders, demyelinating diseases, 45 Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; Leu­ spinal cord disorders, and disorders of peripheral nerves, kodystrophy; Lewy body dementia; Lissencephaly; Locked­ muscle and neuromuscular junctions. Addiction and mental In syndrome; Lou Gehrig's disease (aka Motor Neuron Dis­ illness, include, but are not limited to, bipolar disorder and ease or Amyotrophic Lateral Sclerosis); Lumbar disc disease; schizophrenia, are also included in the definition of neuro­ Lyme disease-Neurological Sequelae; Machado-Joseph dis­ logical disorder. The following is a list ofseveral neurological 50 ease; Macrencephaly; Megalencephaly; Melkersson­ disorders, symptoms, signs and syndromes: Acquired Epilep­ Rosenthal syndrome; Menieres disease; Meningitis; Menkes tiform Aphasia; Acute Disseminated Encephalomyelitis; disease; Metachromatic leukodystrophy; Microcephaly; Adrenoleukodystrophy; Agenesis of the corpus callosum; Migraine; Miller Fisher syndrome; Mini-Strokes; Mitochon­ Agnosia; Aicardi syndrome; Alexander disease; Alpers' dis­ drial Myopathies; Mobius syndrome; Monomelic amyotro­ ease; Alternating hemiplegia; Alzheimer's disease; Amyo­ 55 phy; Motor Neurone Disease; Moyamoya disease; Muco­ trophic lateral sclerosis; Anencephaly; Angelman syndrome; polysaccharidoses; Multi-Infarct Dementia; Multifocal Angiomatosis; Anoxia; Aphasia; Apraxia; Arachnoid Cysts; motor neuropathy; Multiple sclerosis and other demyelinat­ Arachnoiditis; Amold-Chiari malformation; Arteriovenous ing disorders; Multiple system atrophy with postural malformation; Asperger syndrome; Ataxia Telangiectasia; hypotension; Muscular dystrophy; Myasthenia gravis; Attention Deficit Hyperactivity Disorder; Autism; Auto­ 60 Myelinoclastic diffuse sclerosis; Myoclonic encephalopathy nomic Dysfunction; Back Pain; Batten disease; Behcet's dis­ of infants; Myoclonus; Myopathy; Myotonia congenital; ease; Bell's palsy; Benign Essential Blepharospasm; Benign Narcolepsy; Neurofibromatosis; Neuroleptic malignant syn­ Focal; Amyotrophy; Benign Intracranial Hypertension; drome; Neurological manifestations of AIDS; Neurological Binswanger's disease; Blepharospasm; Bloch Sulzberger sequelae oflupus; Neuromyotonia; Neuronal ceroid lipofus­ syndrome; Brachia! plexus injury; Brain abscess; Brain 65 cinosis; Neuronal migration disorders; Niemann-Pick dis­ injury; Brain tumors (including Glioblastoma multiforme); ease; O'Sullivan-McLeod syndrome; Occipital Neuralgia; Spinal tumor; Brown-Sequard syndrome; Canavan disease; Occult Spinal Dysraphism Sequence; Ohtahara syndrome; US 8,937,151 B2 35 36 Olivopontocerebellar Atrophy; Opsoclonus Myoclonus; features, with atypical features, with postpartum onset, in Optic neuritis; Orthostatic Hypotension; Overuse syndrome; partial remission, in full remission), dysthymic disorder, Paresthesia; Parkinson's disease; Paramyotonia Congenita; adjustment disorder with depressed mood, adjustment disor­ Paraneoplastic diseases; Paroxysmal attacks; Parry Romberg der with mixed anxiety and depressed mood, premenstrual syndrome; Pelizaeus-Merzbacher disease; Periodic Paraly­ 5 dysphoric disorder, minor depressive disorder, recurrent brief ses; Peripheral Neuropathy; Painful Neuropathy and Neuro­ depressive disorder, postpsychotic depressive disorder of pathic Pain; Persistent Vegetative State; Pervasive develop­ schizophrenia, a major depressive disorder associated with mental disorders; Photic sneeze reflex; PhytanicAcid Storage Parkinson's disease, and a major depressive disorder associ­ disease; Pick's disease; Pinched Nerve; Pituitary Tumors; ated with dementia. Polymyositis; Porencephaly; Post-Polio syndrome; Posther­ 10 The term "anxiety disorders" refers to an excessive or petic Neuralgia (PHN); Postinfectious Encephalomyelitis; inappropriate aroused state characterized by feelings of Postural Hypotension; Prader-Willi syndrome; Primary Lat­ apprehension, uncertainty, or fear. Anxiety disorders have eral Sclerosis; Prion diseases; Progressive; Hemifacial Atro­ been classified according to the severity and duration oftheir phy; Progressive multifocal leukoencephalopathy; Progres­ symptoms and specific behavioral characteristics. Categories sive Sclerosing Poliodystrophy; Progressive Supranuclear 15 include: Generalized anxiety disorder (GAD), which is long­ Palsy; Pseudotumor cerebri; Ramsay-Hunt syndrome (Type I lasting and low-grade; Panic disorder, which has more dra­ and Type II); Rasmussen's Encephalitis; Reflex Sympathetic matic symptoms; Phobias; Obsessive-compulsive disorder Dystrophy syndrome; Refsum disease; Repetitive Motion (OCD); Post-traumatic stress disorder (PTSD); and Separa­ Disorders; Repetitive Stress Injuries; Restless Legs syn­ tion anxiety disorder. drome; Retrovirus-Associated Myelopathy; Rett syndrome; 20 The neurological disorder can be pain associated depres­ Reye's syndrome; Saint Vitus Dance; Sandhoff disease; sion (PAD). The term "pain associated depression" refers to a Schilder's disease; Schizencephaly; Septa-Optic Dysplasia; depressive disorder characterized by the co-morbidity ofpain Shaken Baby syndrome; Shingles; Shy-Drager syndrome; and atypical depression. Specifically, the pain can be chronic Sjogren's syndrome; Sleep Apnea; Soto's syndrome; Spas­ pain, neuropathic pain, or a combination thereof. Specifically, ticity; Spina bifida; Spinal cord injury; Spinal cord tumors; 25 the pain associated depression can include atypical depres­ Spinal Muscular Atrophy; Stiff-Person syndrome; Stroke; sion and chronic pain wherein the chronic pain precedes the Sturge-Weber syndrome; Subacute Sclerosing Panencephali­ atypical depression. Alternatively, the pain associated depres­ tis; Subarachnoid Hemorrhage; Subcortical Arteriosclerotic sion can include atypical depression and chronic pain Encephalopathy; Sydenham Chorea; Syncope; Syringomy­ wherein the atypical depression precedes the chronic pain. elia; Tardive dyskinesia; Tay-Sachs disease; Temporal arteri­ 30 The pain associated depression can include atypical depres­ tis; Tethered Spinal Cord syndrome; Thomsen disease; Tho­ sion and neuropathic pain. racic Outlet syndrome; Tic Douloureux; Todd's Paralysis; "Chronic pain" refers to pain that continues or recurs over Tourette syndrome; Transient ischemic attack; Transmissible a prolonged period oftime (i.e., >3 mos.), caused by various Spongiform Encephalopathies; Transverse myelitis; Trau­ diseases or abnormal conditions, such as rheumatoid arthritis. matic Brain injury; Tremor; Trigeminal Neuralgia; Tropical 35 Chronic pain may be less intense than acute pain. The person Spastic Paraparesis; Tuberous Sclerosis; Vascular Dementia with chronic pain does not usually display increased pulse (Multi-Infarct Dementia); Vasculitis including Temporal and rapid perspiration because the automatic reactions to pain Arteritis; Von Rippel-Lindau Disease (VHL); Wallenberg's carmot be sustained for long periods of time. Others with syndrome; Werdnig-Hoffman disease; West syndrome; chronic pain may withdraw from the environment and con­ Whiplash; Williams syndrome; Wilson's disease; and Zell­ 40 centrate solely on their affliction, totally ignoring their family, weger syndrome. their friends, and external stimuli. See, Mosby 's Medical, The term "ophthalmologic disease" or "ophthalmologic Nursing &Allied Health Dictionary, 5th Edition (1998). disorder" refers to a disease or disorder involving the anatomy Chronic pain can be selected from the group oflower back and/or function ofthe visual system, including but not limited pain, atypical chest pain, headache, pelvic pain, myofascial to, glaucoma, retinal artery occlusion, ischemic optic neur­ 45 face pain, abdominal pain, and neck pain or chronic pain is apathy and wet or dry macular degeneration. caused by a disease or condition selected from the group of A neurological disorder can be an affective disorder ( e.g., arthritis, temporal mandibular joint dysfunction syndrome, depression or anxiety). The term "affective disorder" or traumatic spinal cord injury, multiple sclerosis, irritable "mood disorder" refers to a variety of conditions character­ bowel syndrome, chronic fatigue syndrome, premenstrual ized by a disturbance in mood as the main feature. Ifmild and 50 syndrome, multiple chemical sensitivity, closed head injury, occasional, the feelings may be normal. Ifmore severe, they fibromyalgia, rheumatoid arthritis, diabetes, cancer, HIV, may be a sign of a major depressive disorder or dysthymic interstitial cystitis, migraine headache, tension headache, reaction or be symptomatic of bipolar disorder. Other mood post-herpetic neuralgia, peripheral nerve injury, causalgia, disorders may be caused by a general medical condition. See, post-stroke syndrome, phantom limb syndrome, and chronic Mosby 's Medical, Nursing &Allied Health Dictionary, 5th 55 pelvic pain. Edition (1998). "Atypical depression" refers to a depressed affect, with the The term "depression" refers to an abnormal mood distur­ ability to feel better temporarily in response to positive life bance characterized by feelings of sadness, despair, and dis­ effect (mood reactivity), plus two or more neurovegetative couragement. Depression refers to an abnormal emotional symptoms selected from the group ofhypersomnia, increased state characterized by exaggerated feelings of sadness, me!­ 60 appetite or weight gain, leaden paralysis, and a long standing ancholy, dejection, worthlessness, emptiness, and hopeless­ pattern of extreme sensitivity to perceived interpersonal ness, that are inappropriate and out of proportion to reality. rejection; wherein the neurovegetative symptoms are present See, Mosby's Medical, Nursing &Allied Health Dictionary, for more than about two weeks. It is appreciated that those of 5th Edition (1998). Depression can be at least one of a major skill in the art recognize that the neurovegatative symptoms depressive disorder (single episode, recurrent, mild, moder­ 65 can be reversed compared to those found in other depressive ate, severe without psychotic features, severe with psychotic disorders (e.g., melancholic depression); hence the term features, chronic, with catatonic features, with melancholic "atypical." US 8,937,151 B2 37 38 The term "mammal" refers to a class ofvertebrate animals the physiological dependence) but also drug abuse (in which of more than 15,000 species, including humans, distin­ the pathological craving for drugs seems unrelated to physical guished by self-regulating body temperature, hair, and in the dependence). Examples include, but are not limited to, alco­ females, milk-producing mammae. Specifically, mammal hol, opiates, synthetic analgesics with morphine-like effects, can refer to a human. More specifically, mammal can refer to 5 barbiturates, hypnotics, sedatives, some antianxiety agents, a human adult, e.g., 18 years or older. More specifically, cocaine, psychostimulants, marijuana, nicotine and psy­ mammal can refer to an elderly human adult, e.g., 60 years or chotomimetic drugs. older. The term "drug withdrawal" refers to the termination of The term "acute neurological disorder" refers to a neuro­ drug taking. Drug withdrawal also refers to the clinical syn­ logical disorder, as defined above, wherein the disorder has a 10 drome ofpsychological, and, sometimes physical factors that rapid onset which is followed by a short but severe course, result from the sustained use of a particular drug when the including, but not limited to, Febrile Seizures, Guillain-Barre drug is abruptly withdrawn. Symptoms are variable but may syndrome, stroke, and intracerebral hemorrhaging (ICH). include anxiety, nervousness, irritability, sweating, nausea, The term "chronic neurological disorder" refers to a neu­ vomiting, rapid heart rate, rapid breathing, and seizures. rological disorder, as defined above, wherein the disorder 15 The term "drug addiction" or dependence is defined as lasts for a long period oftime (e.g., more than about 2 weeks; having one or more ofthe ofthe following signs: a tolerance specifically, the chronic neurological disorder can continue or for the drug (needing increased amounts to achieve the same recur for more than about 4 weeks, more than about 8 weeks, effect), withdrawal symptoms, taking the drug in larger or more than about 12 weeks) or is marked by frequent recur­ amounts than was intended or over a longer period of time rence, including, but not limited to, narcolepsy, chronic 20 than was intended, having a persistent desire to decrease or inflammatory demyelinating polyneuropathy, Cerebral palsy the inability to decrease the amount of the drug consumed, (CP), epilepsy, multiple sclerosis, dyslexia, Alzheimer's dis­ spending a great deal oftime attempting to acquire the drug, ease and Parkinson's Disease. or continuing to use the drug even though the person knows The term "trauma" refers to any injury or shock to the body, there are reoccurring physical or psychological problems as from violence or an accident. The term trauma also refers 25 being caused by the drug. to any emotional wound or shock, many ofwhich may create In one embodiment, when treating drug withdrawal, substantial, lasting damage to the psychological development dependence and/or tolerance, the MMP inhibitor is adminis­ of a person, often leading to neurosis. tered with an NMDAR antagonist (e.g., memantine). The term "ischemic conditions" refers to any condition The term "tardive dyskinesia" refers to a serious, irrevers­ which results in a decrease in the blood supply to a bodily 30 ible neurological disorder that can appear at any age. Tardive organ, tissue, or part caused by constriction or obstruction of Dyskinesia, e.g., Tourette's syndrome, can be a side effect of the blood vessels, often resulting in a reduction ofoxygen to long-term use ofantipsychotic/neuroleptic drugs. Symptoms the organ, tissue, or part. can be hardly noticeable or profound. Symptoms involve The term "hypoxic conditions" refers to conditions in uncontrollable movement ofvarious body parts, including the which the amount/concentration ofoxygen in the air, blood or 35 body trunk, legs, arms, fingers, mouth, lips, or tongue. tissue is low (subnormal). The term "movement disorder" refers to a group ofneuro­ The term "painful neuropathy" or "neuropathy" refers to logical disorders that involve the motor and movement sys­ chronic pain that results from damage to or pathological tems, including, but are not limited to, Ataxia, Parkinson's changes of the peripheral or central nervous system. Periph­ disease, Blepharospasm, Angelman Syndrome, Ataxia eral neuropathic pain is also referred to as painful neuropathy, 40 Telangiectasia, Dysphonia, Dystonic disorders, Gait disor­ nerve pain, sensory peripheral neuropathy, or peripheral neu­ ders, Torticollis, Writer's Cramp, Progressive Supranuclear ritis. With neuropathy, the pain is not a symptom ofinjury, but Palsy, Huntington's Chorea, Wilson's Disease, Myoclonus, rather the pain is itself the disease process. Neuropathy is not Spasticity, Tardive dyskinesia, Tics and Tourette syndrome associated with the healing process. Rather than communi­ and Tremors. cating that there is an injury somewhere, the nerves them­ 45 The term "cerebral infections that disrupt the blood-brain selves malfunction and become the cause of pain. barrier" refers to infections of the brain or cerebrum that "Neuropathic pain" refers to pain associated with inflam­ result in an alteration in the effectiveness of the blood-brain mation or degeneration of the peripheral nerves, cranial barrier, either increasing or decreasing its ability to prevent, nerves, spinal nerves, or a combination thereof. The pain is for example, substances and/or organisms from passing out of typically sharp, stinging, or stabbing. The underlying disor­ 50 the bloodstream and into the CNS. der can result in the destruction ofperipheral nerve tissue and The term "the blood-brain barrier" refers to a semi-perme­ can be accompanied by changes in the skin color, tempera­ able cell layer of endothelial cells (interior walls) within ture, and edema. See, Mosby 's Medical, Nursing &Allied capillaries of the central nervous system (CNS). The blood­ Health Dictionary, 5th Edition (1998); and Stedman's Medi­ brain barrier prevents large molecules, immune cells, many cal Dictionary, 25th Edition (1990). 55 potentially damaging substances, and foreign organisms The term "diabetic neuropathy" refers to a peripheral nerve (e.g., viruses), from passing out of the bloodstream and into disorder/nerve damage caused by diabetes, including periph­ the CNS (Brain and Spinal Cord). A dysfunction in the Blood­ eral, autonomic, and cranial nerve disorders/damage associ­ Brain Barrier may underlie in part the disease process in MS ated with diabetes. Diabetic neuropathy refers to a common (multiple sclerosis). complication of diabetes mellitus in which nerves are dam­ 60 The term "meningitis" refers to inflammation of the aged as a result of hyperglycemia (high blood sugar levels). meninges ofthe brain and the spinal cord, most often caused The term "drug dependence" refers to habituation to, abuse by a bacterial or viral infection and characterized by fever, of, and/or addiction to a chemical substance. Largely because vomiting, intense headache, and stiff neck. ofpsychological craving, the life ofthe drug-dependent per­ The term "meningoencephalitis" refers to inflammation of son revolves around the need for the specific effect ofone or 65 both the brain and meninges. more chemical agents on mood or state ofconsciousness. The The term "stroke" refers to a sudden loss ofbrain function term thus includes not only the addiction (which emphasizes caused by a blockage or rupture ofa blood vessel to the brain US 8,937,151 B2 39 40 (resulting in the lack ofoxygen to the brain), characterized by degenerate (usually the "upper" (in the cerebrocortex) and loss of muscular control, diminution or loss of sensation or "lower" (in the spinal cord) motor neurons, although some consciousness, dizziness, slurred speech, or other symptoms variants kuown as primary lateral sclerosis, apparently rep­ that vary with the extent and severity of the damage to the resenting a separate disease, affect only the upper motor brain, also called cerebral accident, or cerebrovascular acci­ 5 neurons). The loss ofthese motor neurons causes the muscles dent. The term "cerebral ischemia" ( or "stroke") also refers to under their control to weaken and waste away, leading to a deficiency in blood supply to the brain, often resulting in a paralysis. ALS manifests itself in different ways, depending lack of oxygen to the brain. on which muscles weaken first. Symptoms may include trip­ The term "hypoglycemia" refers to an abnormally low ping and falling, loss of motor control in hands and arms, level of glucose in the blood. 10 difficulty speaking, swallowing and/or breathing, persistent The term "cardiac arrest" refers to a sudden cessation of fatigue, and twitching and cramping, sometimes quite heartbeat and cardiac function, resulting in a temporary or severely. Upper motor neuron variants (e.g., primary lateral permanent loss ofeffective circulation. sclerosis) are also included. The term "spinal cord trauma" refers to damage to the The term "glaucoma" refers to any of a group of eye dis­ spinal cord that results from direct injury to the spinal cord 15 eases characterized by abnormally high intraocular fluid pres­ itselfor indirectly by damage to the bones and soft tissues and sure, damaged optic disk, hardening ofthe eyeball, and partial vessels surrounding the spinal cord. It is also called Spinal to complete loss ofvision. The retinal ganglion cells are lost cord compression; Spinal cord injury; or Compression of in glaucoma. Some variants of glaucoma have normal spinal cord. intraocular pressure (kuown also as low tension glaucoma). The term "head trauma" refers to a head injury ofthe scalp, 20 The term "retinal ischemia" refers to a decrease in the skull, orbrain. These injuries can range from a minor bump on blood supply to the retina. the skull to a devastating brain injury. Head trauma can be The term "ischemic optic neuropathy" refers to a condition classified as either closed or penetrating. In a closed head that usually presents with sudden onset of unilaterally injury, the head sustains a blunt force by striking against an reduced vision. The condition is the result ofdecreased blood object. A concussion is a type of closed head injury that 25 flow to the optic nerve (ischemia). There are two basic types: involves the brain. In a penetrating head injury, an object arteritic and non-arteritic ischemic optic neuropathy. Non­ breaks through the skull and enters the brain. arteritic ischemic optic neuropathy is generally the result of The term "perinatal hypoxia" refers to a lack of oxygen cardiovascular disease. Those patients at greatest risk have a during the perinatal period ( defined as the period of time history ofhigh blood pressure, elevated cholesterol, smoking, occurring shortly before and after birth, variously defined as 30 diabetes, or combinations of these. Arteritic ischemic optic beginning with completion of the twentieth to twenty eighth neuropathy is a condition caused by the inflammation of week of gestation and ending 7 to 28 days after birth). vessels supplying blood to the optic nerve, kuown as temporal The term "hypoglycemic neuronal damage" refers to neu­ arteritis. This condition usually presents with sudden and ronal damage, for example, nerve damage, as a result of a severe vision loss in one eye, pain in the jaw with chewing, hypoglycemic condition (an abnormally low level ofglucose 35 tenderness in the temple area, loss ofappetite, and a general­ in the blood). ized feeling offatigue or illness. The term "epilepsy" refers to any of various neurological The term "macular degeneration" refers to the physical disorders characterized by sudden recurring attacks ofmotor, disturbance ofthe center ofthe retina called the macula. The sensory, or psychic malfunction with or without loss of con­ macula is the part of the retina which is capable of our most sciousness or convulsive seizures. 40 acute and detailed vision. Macular degeneration is the leading The term "Alzheimer's disease" refers to a disease marked cause oflegal blindness in people over age 55 (legal blindness by the loss of cognitive ability, generally over a period of 10 means that a person can see 20/200 or less with eyeglasses.) to 15 years, and associated with the development ofabnormal Even with a loss of central vision, however, color vision and tissues and protein deposits in the cerebral cortex (kuown as peripheral vision may remain clear. Vision loss usually occurs plaques and tangles). 45 gradually and typically affects both eyes at different rates. The term "Huntington's disease" refers to a disease that is As used herein a "demyelinating disorder" refers to a medi­ hereditary in nature and develops in adulthood and ends in cal condition where the myelin sheath is damaged. The dementia. More specifically, Huntington's disease (HD) myelin sheath surrounds nerves and is responsible for the results from genetically programmed degeneration of brain transmission ofimpulses to the brain. Damage to the myelin cells, called neurons, in certain areas ofthe brain caused by a 50 sheath may result in muscle weakuess, poor coordination and polyglutamine repeat in the DNA sequence of the gene possible paralysis. Examples of demyelinating disorders encoding the protein huntingtin. This degeneration causes include Multiple Sclerosis (MS), optic neuritis, transverse uncontrolled movements, loss of intellectual faculties, and neuritis andGuillain-Barre Syndrome (GBS). In one embodi­ emotional disturbance. ment, when treating a demyelinating disorder, an MMP The term "Parkinsonism" refers to a disorder similar to 55 inhibitor is administered with an NMDAR antagonist (e.g., Parkinson's disease, but which is caused by the effects of a memantine) orwith ~-interferon isoforms, copaxone or Ante­ medication, a different neurodegenerative disorder or another gren (natalizumab ). Recently, it has been noted that underly­ illness. The term "parkinsonism" also refers to any condition ing neuronal damage can occur in demyelinating conditions that causes any combination ofthe types ofmovement abnor­ such as MS, and therefore useful drugs may also protect the malities seen in Parkinson's disease by damaging or destroy­ 60 neurons instead or in addition to the myelin. ing dopamine neurons in a certain area of the brain. The term "multiple sclerosis" refers to a chronic disease of The term "amyotrophic lateral sclerosis" (ALS), also the central nervous system, which predominantly affects called Lou Gehrig's disease and Motor Neuron Disease, young adults. Viral and autoimmune etiologies are postu­ refers to a progressive, fatal neurological disease. The disor­ lated. Genetic and environmental factors are kuown to con­ der belongs to a class of disorders kuown as motor neuron 65 tribute to MS, but a specific cause for this disease is not yet diseases. ALS occurs when specific nerve cells in the brain identified. Pathologically, MS is characterized by the pres­ and spinal cord that control voluntary movement gradually ence of areas of demyelination and T-cell predominant US 8,937,151 B2 41 42 perivascular inflammation in the brain white matter. Some includes sweating, shaking, headache, drug craving, nausea, axons may be spared from these pathological processes. The vomiting, abdominal cramping, diarrhea, inability to sleep, disease begins most commonly with acute or subacute onset confusion, agitation, depression, anxiety, and other behav­ of neurologic abnormalities. Initial and subsequent symp­ ioral changes. toms may dramatically vary in their expression and severity 5 The term "emesis" refers to the act of vomiting. over the course of the disease, that usually lasts for many The term "brain edema" refers to an excessive accumula­ years. Early symptoms may include numbness and/or pares­ tion of fluid in, on, around and/or in relation to the brain. thesia, mono- or paraparesis, double vision, optic neuritis, The term "AIDS induced dementia" or "HIV-associated ataxia, and bladder control problems. Subsequent symptoms dementia" refers to dementia ( deterioration of intellectual also include more prominent upper motor neuron signs, i.e., 10 faculties, such as memory, concentration, and judgment, increased spasticity, increasing para- or quadriparesis. Ver­ resulting from an organic disease or a disorder of the brain) tigo, incoordination and other cerebellar problems, depres­ induced byAIDS (Acquired Immunodeficiency Syndrome­ sion, emotional !ability, abnormalities in gait, dysarthria, an epidemic disease caused by an infection by human immu­ fatigue and pain are also commonly seen. nodeficiency virus (HIV-1, HIV-2), a retrovirus that causes The term "sequelae of hyperhomocystinemia" refers to a 15 immune system failure and debilitation and is often accom­ condition following as a consequence hyperhomocystinemia, panied by infections such as tuberculosis). meaning elevated levels ofhomocysteine. The term "HIV-related neuropathy" refers to a neuropathy The term "convulsion" refers to a violent involuntary con­ in a mammal infected with HIV were the neuropathy is traction or series ofcontractions of the muscles. caused by infections such as CMV or other viruses of the The term "pain" refers to an unpleasant sensation associ­ 20 herpes family. Neuropathy is the name given to a group of ated with actual or potential tissue damage, and mediated by disorders whose symptoms may range from a tingling sensa­ specific nerve fibers to the brain where its conscious appre­ tion or numbness in the toes and fingers to paralysis. Neur­ ciation may be modified by various factors. See, Mosby's opathy might more accurately be called "neuropathies" Medical, Nursing &Allied Health Dictionary, 5th Ed. (1998); because there are several types and can be painful. th and Stedman 's Medical Dictionary, 25 Ed. (1990). 25 The term "ocular damage" refers to any damage to the eyes The term "anxiety" refers to a state ofapprehension, uncer­ or in relation to the eyes. tainty, and/or fear resulting from the anticipation ofa realistic The term "retinopathy" refers to any pathological disorder or fantasized threatening event or situation, often impairing ofthe retina. physical and psychological functioning. The term "cognitive disorder" refers to any cognitive dys­ The term "schizophrenia" refers to any ofa group of psy­ 30 function, for example, disturbance ofmemory (e.g., amnesia) chotic disorders usually characterized by withdrawal from or learning. reality, illogical patterns of thinking, delusions, and halluci­ The term "neuronal injury associated with HIV infection" nations, and accompanied in varying degrees by other emo­ refers to damage/injury ofnerve cells caused either directly or tional, behavioral, or intellectual disturbances. Schizophrenia indirectly by infection with HIV. is associated with dopamine imbalances in the brain and 35 The term "dysfunction in cognition, movement and sensa­ defects of the frontal lobe and is caused by genetic, other tion" refers to abnormal or impaired functioning in cognition biological, and/or psychosocial factors. (mental process ofknowing, including aspects such as aware­ The term "muscle spasm" refers to an often painful invol­ ness, perception, reasoning, and judgment), movement or untary muscular contraction sensation. The term "migraine headache" refers to a severe, debilitat­ 40 Any ofthe above diseases, disorders, or conditions can be ing headache often associated with photophobia and blurred treated by administering a compound or composition that VIS!On. includes a compound described herein to treat the disease, The term "urinary incontinence" refers to the inability to disorder, or condition by inhibiting matrix a metalloprotein­ control the flow of urine and involuntary urination. ase. The term "nicotine withdrawal" refers to the withdrawal 45 The following Examples illustrate the above invention and from nicotine, an addictive drug found in tobacco, which is should not be construed as to narrow its scope. One skilled in characterized by symptoms that include headache, anxiety, the art will readily recognize that the Examples suggest many nausea and a craving for more tobacco. Nicotine creates a other ways in which the invention could be practiced. It chemical dependency, so that the body develops a need for a should be understood that numerous variations and modifi­ certain level of nicotine at all times. Unless that level is 50 cations may be made while remaining within the scope ofthe maintained, the body will begin to go through withdrawal. invention. For tobacco users trying to quit, symptoms of withdrawal from nicotine are unpleasant and stressful, but temporary. EXAMPLES Most withdrawal symptoms peak 48 hours after one quits and are completely gone in six months. 55 Example 1 The term "opiate tolerance" can be explained, at least in part, as a homeostatic response that reduces the sensitivity of Preparation of MMP Inhibitors and Prodrugs the system to compensate for continued exposure to high levels of, for example, morphine or heroin. When the drug is The p-aminophenoxybenzene scaffold was assembled by stopped, the system is no longer as sensitive to the soothing 60 the methodology developed by Ikejiri et al. (J. Biol. Chem. effects ofthe enkephalin neurons and the pain ofwithdrawal 2005, 280, 33992-34002). This methodology includes the is produced. coupling of l-fluoro-4-nitrobenzene (1) and 4-( allylthio )phe­ The term "opiate withdrawal" refers to an acute state nol (2) under basic condition, followed by reduction of the caused by cessation or dramatic reduction of use of opiate nitro group to amine over elemental zinc in acetic acid. The drugs that has been heavy and prolonged (several weeks or 65 resulting amine 3 was treated with di-tert-butyl di carbonate to longer). Opiates include heroin, morphine, codeine, Oxycon­ give the Boe protected compound 4. The Boe group was tin, Dilaudid, methadone, and others. The reaction frequently chosen as the amine protecting group because the sulfonyl­ US 8,937,151 B2 43 44 methylthiirane is relatively stable under acidic condition that -continued is used for the removal ofBoe at the end ofthe synthesis (see 4NHC1 transformation of 5 to 6). The rest of the transformations, in 1,4­ o'QI~ dioxane including oxidation to sulfone, epoxide formation using 82% m-chloroperbenzoic acid, and thiirane conversion using thio­ 5 BocHN # S~ urea, were performed by the methodology developed by the #t s 0 0 Mobashery group earlier (Org. Lett. 2005, 7, 4463-4465; J. Org. Chem. 2004, 69, 3572-3573). Removal ofthe Boe group in compound 5 was carried out in the presence of 4 N HCl in 1,4-dioxane at room temperature for 24 hours to yield com­ 10 I~ pound 6 as the HCl salt in 82%. HCl•H2N V # S~ o'°' #t s 0 0 Scheme 1. Synthesis ofCompound 6. 15

HO~ Syntheses of amino acid conjugates of benzamine ( 6) and phenol (7) as prodrugs ofgelatinase inhibitors are outlined in Scheme 2. Compound 7, prepared according to the literature ~s~ (Chem. Biol. & Drug Des. 2009, 73, 189-202), was acylated 2 20 with Boe-protected N-hydroxysuccinimide esters of amino 1) Cs2CO3 acids (Gly, L-Lys, L-Glu, L-Arg, and L-Arg-L-Arg) in the 2) Zn/AcOH, 69% presence of 4-(dimethylamino )pyridine (DMAP) to give the ester 8. The Boe group in compound 8, in turn, was readily removed by treatment with 4 N HCl in 1,4-dioxane to result in 25 (Boc)2O, the ester prodrug 9. The acid treatment for removal ofthe Boe I~ Et3N group in the presence ofthiirane works well, as described in Vo'Q 82% Scheme 1 for the synthesis of compound 6. H2N # S~ When the compound 6 was subjected to the same acylation conditions, the desired amide bond was not formed, instead, 3 30 it gave only recovery of the two starting materials. Boe­ m- protected amino acid was activated to mixed anhydride by f)o'QI~ CPBA thiourea treatment ofisobutyl chloroformate in the presence ofN-me­ thylmorpholine, which was allowed to react with compound BocHN # S~ - 58% from4 6 to give the desired amide linkage. The removal ofBoe group 4 in compound 10 was carried out by acid treatment resulting in the amide prodrug 11. Scheme 2. Preparation ofProdrugs 9 and 11.

AA

Roc~\0-:~ 0 ~ ~ ,--~~1------~1 o~~ 0~ ,,u~ 0 HCl ,? DMAP Roc~, Jl I s;"-

8 . 9

AA, a~ Gly, b ~ Lys, c ~ Glu d ~ Arg, e ~ Arg-Arg 0~I #s X 0 f("

10 11

.i;... O'I US 8,937,151 B2 47 48 When compounds 6 and 7 were treated with J?-nitropheny~ -continued carbonate 12 in the presence of DAMP, the desJred prodrug 13 and 14 were accessed.

Scheme 3. Preparation of Prodrugs 13 and 14. 16

1. Fe/Nl¼Cl, H2O, reflux 2. Boc2O, Et3N, 17 63% 6,X~NH2 7,X~OH 15 1.KOH,MeOH, MOMO:OOC o reflux 2. epichlorohydrin, BocHN # # S)lNMe2 68% DMAP 18 ------­ 20 MOMO:n:YO'QS m-CPBA 89% BocHN ~

19 25 MOMo:Vo'Qs thiourea 83% 30 BocHN //~ 0 0 13,X~O 14,X~NH 20

TABLE 1

Various S ecific Prodru s. 0 '0 ('Yo'0 I ~s X O # s:'<]x-N }J It~ - It~ S H O 0 O 0

X Compound No Compound No

Gly 9a lla Lys 9b llb Glu 9c llc Arg 9d lld Arg-Arg 9e lle dioxolone* 13 14 dioxolone* = OY03i}-o 0

-continued Scheme 4. Synthesis of Compound 22. HCl, MeOH reflux, 95%

15 21 US 8,937,151 B2 49 50 -continued 136.0, 150.0, 153.0, 163.6; HRMS-FAB (m/z): [Mt, calcd for C H NO S , 421.1018. found, 421.1009. HO'YYO~ 20 23 5 2 4-[ 4-( (Thiiran-2-yl)methylsulfonyl)phenoxy ]ben­ H2N~ 5 zamine.HCl salt ~S~//~ s 0 0 22 The thiirane (4.0 g, 9.5 mmol) was dissolved in a 1:1 mixture of CH2 Cl2 and ethyl acetate ( 40 mL) and HCl (10 mL, 4 N in dioxane) was added. The reaction mixture was 10 stirred for 24 hand concentrated under reduced pressure. The Experimental Procedures resulting crude compound was triturated with diethyl ether and the product was obtained by filtration (2.8 g, 82%). 1H

t-Butyl [4-( 4-allylthiophenoxy)phenyl]carbamate ( 4) NMR (500 MHz, D2 O) Ii 2.03 (d, 1=4.8 Hz, lH), 2.42 (d, 1=6.4 Hz, lH), 2.94 (m, 1=6.4, 6.4 Hz, lH), 3.42 (dd, 1=14.4, Compound 3 (10.3 g, 40.0 mmol), which was prepared by 15 6.4 Hz, lH), 3.61 (dd, 1=14.4, 6.4 Hz, lH), 7.11 (d, 1=8.0 Hz, a literature method (J. Biol. Chem. 2005, 280, 33992-34002), 2H), 7.16 (d, 1=8.0 Hz, 2H), 7.35 (d, 1=8.0 Hz, 2H), 7.80 (d, 13 was dissolved in a mixture ofMeOH and triethylamine (7:1, 1=8.0 Hz, 2H); C NMR (126 MHz, D2 O) ll 23.5, 26.0, 61 .4, 80 mL) and di-t-butyldicarbonate (17.5 g, 80 mmol) was 118.6, 121.9, 125.2, 126.8, 130.8, 131.1, 155.2, 162.5; added. The resulting solution was stirred for 2 hat 60° C. and HRMS-FAB (m/z): [M+H]+, calcd for C15H16NO3 S2 , concentrated under reduced pressure. The crude material was 20 322.0572. found, 322.0569. purified by colunm chromatography on silica gel to give the 1 Syntheses of Ester Prodrugs (9) title compound (11.7 g, 82%). HNMR (600 MHz, CDC1 3 ) Ii 1.53 (s, 9H), 3.48 (d, 1=6.7 Hz, 2H), 4.96-5.09 (m, 2H), 5.86 Synthesis of the lysine prodrug (9b) is provided here as a (m, 1=16.7, 10.3 Hz, lH), 6.47 (br. s, lH), 6.89 (d, 1=8.8 Hz, 25 13 representative example. 2H), 6.96 (d, 1=8.8 Hz, 2H), 7.24-7.39 (m, 4H); C NMR To a solution of7 (0.20 g, 0.62 mmol) (prepared according (151 MHz, CDC1 3 ) Ii 28.5, 38.9, 80.7, 117.7, 118.6, 120.3, to the method of Stella and Nti-Addae; Adv. Drug Deliv. Rev. 120.5, 128.9, 133.3, 134.0, 134.5, 152.2, 153.1, 157.4; 2007, 59, 677-94) in CH2 Cl2 (5 mL) was added NwNE-di­ HRMS-FAB (m/z): [Mt, calcd for C20H23NO3 S, 357.1399. Boc-L-lysine hydroxysuccinimide ester (0.41 g, 0.93 mmol) found, 357.1402. 30 at room temperature. 4-Dimethylamino-pyridine (76 mg, 0.62 mmol) was added and the reaction mixture was stirred t-Butyl [4-( 4-(thiiran-2-yl)methylsulfonylphenoxy) for 3 h at room temperature. After concentrating under phenyl]carbamate (5) reduced pressure, the crude product was purified by colunm chromatography on silica gel to give the desired product (Sb, To a solution of compound 4 (10.0 g, 28.0 mmol) in 35 0.30 g, 74%). The ester (0.30 g, 0.46 mmol) was dissolved in

CH2 Cl2 (100 mL) was added a solution ofm-chloroperoxy­ CH2 Cl2 and ethyl acetate (1: 1, 4 mL) and HCl (2 mL, 4 N in benzoic acid (31.2 g, 140 mmol, 77%) in an ice-water bath. dioxane) was added. The reaction mixture was stirred for 24 After 48 h, the suspension was filtered and the filtrate was h and concentrated under reduced pressure. The resulting diluted with EtOAc and washed with 10% aqueous sodium crude compound was triturated with diethyl ether and the thiosulfate, followed by washes with saturated sodium bicar­ 40 product (9b) was obtained by filtration (0.18 g, 75%). bonate and brine. The organic layer was dried over MgSO4 and was concentrated. The product was purified by silica gel Syntheses ofAmide Prodrugs (11) chromatography to yield the oxirane (7.4 g, 81 % ) with recov­ ery of some of the allylsulfone derivative (2.1 g, 19%). 1H Synthesis of the lysine prodrug (11 b) is provided as a

NMR (600 MHz, CDC1 3 ) Ii 1.50 (s, 9H), 2.45 (dd, 1=5.0, 1.2 45 representative example. Hz, lH), 2.79 (dd, 1=4.4, 2.6 Hz, lH), 3.24-3.34 (m, 3H), 6.85 i-Butylchloroformate (83 µL, 0.53 mmol) was added to a (s, lH), 6.99 (d, 1=8.8 Hz, 2H), 7.02 (d, 2H), 7.42 (d, 1=8.2 mixture of NwNE-di-Boc-L-lysine dicyclohexylamine salt Hz, 2H), 7.84 (d, 1=8.8 Hz, 2H); 13C NMR (151 MHz, (0.28 g, 0.64 mmol) and N-methylmorpholine (140 µL, 1.3

CDC13 ) Ii 28.4, 46.0, 46.0, 59.7, 117.2, 120.5, 121.3, 130.6, mmol) in THF (4 mL) at-15° C.After stirring for0.5 hat the 132.2, 136.0, 149.8, 153.0, 163.4; HRMS-FAB (m/z): [Mt, 50 same temperature, the suspension of 6 (0.19 g, 0.53 mmol) calcd for C20H23NO6 S, 405.1246. found, 405.1230. andN-methylmorpholine (58 µL, 0.53 mmol) in THF (2 mL) Thiourea (2.4 g, 31.5 mmol) was added to a solution of was added to the reaction mixture. Stirring was continued for oxirane (6.0 g, 14.8 mmol), obtained above, in a 1:1 mixture 1 h, while temperature was gradually increased to room tem­ ofmethanol and CH2 Cl2 (50 mL). The reaction mixture was perature. The reaction mixture was diluted with CH2 Cl2 / stirred at room temperature for 24 h. The solvent was removed 55 water and layers were separated. The aqueous layer was under reduced pressure. The residue was partitioned between extracted and the combined organic layers were dried

CH2 Cl2 and water, the organic layer was washed with brine (MgSO4 ) and evaporated. The crude material was purified by and water, dried (MgSO4 ) and the suspension was filtered. colunm chromatography on silica gel to afford the desired Evaporation of solvent gave the crude product, which was product (!Ob, 0.21 g, 64%). Amide (0.20 g, 0.30 mmol) was purified by colunm chromatography on silica gel to give 60 dissolved in CH2 Cl2 and ethyl acetate (1: 1, 3 mL) and HCl (2 1 thiirane5 (4.4 g, 72%). HNMR(600MHz, CDC13 ) ll 1.53 (s, mL, 4 N in dioxane) was added. The reaction mixture was 9H), 2.16 (dd, 1=5.1, 1.6 Hz, lH), 2.54 (dd, 1=6.2, 1.2 Hz, stirred for 24 hand concentrated under reduced pressure. The lH), 3.06 (dq, 1=7.6, 5.7 Hz, lH), 3.17 (dd, 1=14.1, 7.9 Hz, resulting crude compound was triturated with diethyl ether lH), 3.53 (dd, 1=14.1, 5.6 Hz, lH), 6.61 (br. s, lH), 7.06 (d, and the product (11 b) was obtained by filtration (0.11 g, 1=8.8 Hz, 2H), 7.03 (d, 1=8.8 Hz, 2H), 7.44 (d, 1=8.5 Hz, 2H), 65 71%). 13 1 7.84 (d, 1=8.8 Hz, 2H); C NMR (151 MHz, CDC13 ) ll 24.5, Spectral data ofGly ester prodrug compound Sa. H NMR

26.3, 28.5, 62.8, 81.0, 117.4, 120.6, 121.4, 130.9, 131.8, (500 MHz, CDC1 3 ) ll 1.48 (s, 9H), 2.17 (dd, 1=5.0, 1.8 Hz, US 8,937,151 B2 51 52 lH), 2.55 (dd, 1=6.2, 1.8 Hz, lH), 3.04-3.10 (m, lH), 3.20 163.6, 171.2; HRMS-ESI (m/z): [M+Ht, calcd for (dd, 1=14.4, 7.8 Hz, lH), 3.52 (dd, 1=14.2, 5.6 Hz, lH), 4.19 c36H5IN4O11 S2, 779.2990. found, 779.3001. (d, 1=5.8 Hz, 2H), 7.11 (d, 1=9.0 Hz, 2H), 7.12 (d, 1=8.8 Hz, Compound 9d. 13 1 2H), 7.18 (d, 1=9.0Hz, 2H), 7.88 (d, 1=9.0Hz, 2H); CNMR H NMR (500 MHz, 10% CDC13 in CD3OD) ll 1.78-2.26 (126 MHz, CDC13) Ii 24.4, 26.2, 28.5, 42.7, 62.7, 80.5, 117.9, 5 (m, 4H), 2.14 (dd, 1=5.1, 1.3 Hz, lH), 2.52 (dd, 1=6.2, 0.8 Hz, 121.5, 123.3, 131.0, 132.4, 147.3, 152.6, 162.8, 169.3; lH), 3.04 (quin, 1=6.2 Hz, lH), 3.27 (m, 2H), 3.43 (dd, HRMS-ESI (m/z): [M+H]+, calcd for C22H26N2O6S2, 1=14.4, 7.0 Hz, lH), 3.52 (dd, 1=14.8, 6.6 Hz, lH), 4.39 (t, 480.1145. found, 480.1145. 1=6.5 Hz, lH), 7.17 (d, 1=9.0Hz, lH), 7.21 (d, 1=9.0Hz, lH), Compound 9a. 1 7.30 (d, 1=9.0 Hz, 2H), 7.92 (d, 1=8.8 Hz, 2H); HRMS-ESI H NMR (500 MHz, D O) ll 2.17 (dd, 1=5.2, 1.2 Hz, lH), 10 2 (m/z): [M+Ht, calcd for C H N O S , 479.1417. found, 2.56 (d, 1=6.2 Hz, lH), 3.09 (quin, 1=6.2 Hz, lH), 3.57 (dd, 21 27 4 5 2 479.1423. 1=14.6, 7.2 Hz, lH), 3.74 (dd, 1=14.6, 6.4 Hz, lH), 4.25 (s, Spectral Data ofArg-Arg Ester Prodrug Compound Se. 2H), 7.21-7.35 (m, 6H), 7.93 (d, 1=8.8 Hz, 2H); HRMS-ESI 1 H NMR (500 MHz, CDC13) ll 1.39-1.53 (m, 45H), 1.54­ (m/z): [M+H]+, calcd for C17H18NO5S2, 380.0621. found, 380.0597. 15 2.11 (m, SH), 2.16 (dd, 1=5.2, 1.4 Hz, lH), 2.54 (d, 1=5.2 Hz, Spectral Data of Lys Ester Prodrug Compound Sb. lH), 3.06 (m, lH), 3.19 (dd, 1=14.2, 7.8 Hz, lH), 3.47 (dd, 1 1=12.8, 7.0 Hz, 2H), 3.52 (dd, 1=14.4, 5.6 Hz, lH), 3.74-3.95 H NMR (500 MHz, CDC13) ll 1.45 (s, 9H), 1.47 (s, 9H), 1.52 (m, 2H), 1.56 (m, 4H), 1.85 (m, lH), 1.99 (m, lH), 2.17 (m, 2H), 4.32 (dd, 1=14.8, 6.4 Hz, lH), 4.77 (m, lH), 5.92 (d, (dd, 1=5.2, 1.8 Hz, lH), 2.55 (dd, 1=6.2, 1.8 Hz, lH), 3.07 (m, 1=7.8 Hz, lH), 7.07-7.12 (m, 4H), 7.16 (d, 1=9.0 Hz, 2H), lH), 3.17 (m, 2H), 3.19 (dd, 1=14.2, 7.8 Hz, lH), 3.53 (dd, 20 7.33 (d, 1=7.6 Hz, lH), 7.87 (d, 1=8.8 Hz, 2H), 8.38 (t, 1=4.9 1=14.2, 5.6 Hz, lH), 4.49 (m, lH), 4.61 (m, lH), 5.23 (d, Hz, lH), 9.30 (br. s, 2H), 11.50 (s, lH); 13C NMR (126 MHz, 1=7.4 Hz, lH), 7.10 (d, 1=9.0Hz, lH), 7.11 (d, 1=8.8 Hz, 2H), CDC13) Ii 24.4, 24.9, 25.6, 26.2, 28.2, 28.2, 28.5, 28.6, 29.3, 13 7.17 (d, 1=9.0 Hz, lH); C NMR (126 MHz, CDC13) ll 22.7, 40.4, 44.1, 52.5, 54.3, 62.8, 79.5, 80.2, 83.4, 83.5, 84.2, 117.9, 24.4, 26.3, 28.5, 28.6, 29.9, 32.1, 40.1, 53.8, 62.8, 79.5, 80.3, 121.5, 121.5, 123.4, 130.8, 131.0, 132.3, 147.5, 152.5, 153.4, 81.3, 117.9, 121.6, 123.4, 131.0, 132.4, 147.6, 152.6, 162.9, 25 155.0, 156.4, 160.8, 160.9, 162.9, 163.7, 170.6, 172.7; 171.8; HRMS-ESI (m/z): [M+H]+, calcd for C H N O S , 31 43 2 9 2 HRMS-ESI (m/z): [M+H]+, calcd for C52H79N8O16S2, 651.2404. found, 651.2414. 1135.5050. found, 1135.5039. Compound 9b. Compound 9e. 1H NMR (500 MHz, 10% CDC1 in CD OD) ll 1.62-1.84 1 3 3 H NMR (500 MHz, 10% CDC13 in CD3OD) ll 1.71-2.23 1=5.0, 30 (m, 4H), 2.05-2.26 (m, 2H), 2.14 (dd, 1.4 Hz, lH), 2.52 (m, SH), 2.16 (dd, 1=5.0, 1.2 Hz, lH), 2.54 (dd, 1=6.2, 0.8 Hz, (dd, 1=6.3, 1.1 Hz, lH), 3.01 (t, 1=7.6 Hz, 2H), 3.06 (m, lH), lH), 3.03-3.10 (m, lH), 3.23-3.32 (m, 4H), 3.47 (dd, 1=14.4, 3.46 (dd, 1=14.6, 7.0 Hz, lH), 3.54 (t, 1=6.6 Hz, lH), 4.40 (t, 7.0 Hz, lH), 3.54 (dd, 1=14.2, 6.4 Hz, lH), 4.16 (t, 1=6.4 Hz, 1=6.5 Hz, lH), 7.19 (d, 1=9.0Hz, 2H), 7.23 (d, 1=9.0Hz, 2H), lH), 4.72 (dd, 1=9.1, 4.5 Hz, lH), 7.15-7.23 (m, 4H), 7.25 (d, 7.32 (d, 1=9.2 Hz, 2H), 7.94 (d, 1=9.0 Hz, 2H); HRMS-ESI 1=9.0 Hz, 2H), 7.94 (d, 1=8.8 Hz, 2H); HRMS-ESI (m/z): (m/z): [M+H]+, calcd for C21 H27N2O5S2, 451.1356. found, 35 541.1298. [M+H]+, calcd for C27H39N8O652 , 635.2428. found, Spectral Data ofG!u Ester Prodrug Compound Sc. 635.2449. 1HNMR (500MHz, CDC1 ) ll 1.45 (s, 18H), 2.09 (m, lH), Spectral Data of Gly Amide Prodrug Compound 10a. 3 1 2.15 (dd, 1=5.2, 1.8 Hz, lH), 2.29 (m, lH), 2.43 (q, 1=7.4 Hz, H NMR (500 MHz, CDC13) Ii 1.37 (s, 9H), 2.05 (dd, 2H), 2.52 (dd, 1=6.2, 1.8 Hz, lH), 3.05 (m, lH), 3.18 (dd, 40 1=5.2, 1.8 Hz, lH), 2.44 ( dd, 1=6.2, 1.8 Hz, lH), 2.94 (m, lH), 1=14.4, 7.8 Hz, lH), 3.51 (dd, 1=14.4, 5.8 Hz, lH), 4.52 (m, 3.14 (dd, 1=14.4, 7.6 Hz, lH), 3.41 (dd, 1=14.4, 6.0 Hz, lH), lH), 5.26 (d, 1=8.2 Hz, lH), 7.08 (d, 1=9.0 Hz, 2H), 7.09 (d, 3.80 (d, 1=5.2 Hz, 2H), 3.82 (s, lH), 6.96 (d, 1=15.2 Hz, 2H), 1=9.0Hz, 2H), 7.17 (d, 1=9.2 Hz, 2H), 7.86 (d, 1=9.0Hz, 2H); 6.98 (d, 1=15.4 Hz, 2H), 7.52 (d, 1=8.8 Hz, 2H), 7.75 (d, 1=9.0 13 13 C NMR (126 MHz, CDC13) ll 24.4, 26.2, 27.3, 28.2, 28.4, Hz, 2H); C NMR (126 MHz, CDC13) Ii 24.0, 25.9, 28.2, 31.7, 53.5, 62.7, 80.4, 81.1, 117.9, 121.4, 123.3, 130.9, 132.3, 45 44.2, 62.5, 80.4, 117.4, 121.0, 121.8, 130.7, 131.4, 150.7, 147.5, 152.5, 155.6, 162.8, 171.3, 172.1; HRMS-ESI (m/z): 163.3, 168.3, 172.9; HRMS-ESI (m/z): [M+Nat, calcd for

[M+H]+, calcd for C29H38NO9S2, 608.1982. found, C22 H26N2O6S2Na, 501.1124. found, 501.1112. 608.1981. Compound 1 la. Compound 9c. 1H NMR (500 MHz, 10% CDC1 in CD OD) ll 2.14 (dd, 1 3 3 H NMR (500 MHz, 10% CDC13 in CD3OD) ll 2.14 (dd, 50 1=5.2, 1.6 Hz, lH), 2.51 (dd, 1=6.3, 1.5 Hz, lH), 3.04 (m, 1=5.1, 1.3 Hz, lH), 2.37 (m, 2H), 2.52 (dd, 1=6.2, 1.0 Hz, lH), 1=7.0, 5.2 Hz, lH), 3.42 (dd, 1=14.4, 7.0 Hz, lH), 3.53 (dd, 2.68 (td, 1=7.1, 1.6 Hz, 2H), 3.05 (quin, 1=6.2 Hz, lH), 3.44 1=14.4, 6.4 Hz, lH), 4.14 (s, 2H), 7.17 (d, 1=9.0, 2.0, 1.8 Hz, (dd, 1=14.4, 7.0 Hz, lH), 3.54 (dd, 1=14.4, 6.4 Hz, lH), 4.43 lH), 7.20 (d, 1=9.2 Hz, 2H), 7.29 (d, 1=9.2 Hz, 2H), 7.92 (d, (t, 1=6.8 Hz, lH), 7.19 (d, 1=8.8 Hz, 2H), 7.22 (d, 1=9.2 Hz, 1=9.2 Hz, lH); HRMS-ESI (m/z): [M+H]+, calcd for

2H), 7.32 (d, 1=9.0 Hz, 2H), 7.93 (d, 1=9.0 Hz, 2H); HRMS­ 55 C17H19N2O4S2, 379.0781. found, 379.0805. ESI (m/z): [M+H]+, calcd for C H NO S , 452.0832. Spectral Data of Lys Amide Prodrug Compound 1Ob. 20 22 7 2 1 found, 452.0769. H NMR (500 MHz, CDC13) ll 1.41 (s, 9H), 1.43 (s, 9H), Spectral Data ofArg Ester Prodrug Compound 8d. 2.02 (s, 3H), 2.13 (dd, 1=5.0, 1.6 Hz, lH), 2.50 (dd, 1=6.2, 1.6 1 H NMR (500 MHz, CDC13) ll 1.46 (s, 9H), 1.50 (s, 9H), Hz, lH), 3.02 (m, lH), 3.09 (m, 2H), 3.16 (dd, 1=14.4, 7.8 Hz, 1.77 (m, lH), 1.94 (m, lH), 2.13 (dd, 1=5.0, 1.6 Hz, lH), 2.51 60 lH), 3.50 (dd, 1=14.4, 5.8 Hz, lH), 4.28 (m, lH), 4.75 (m, (dd, 1=6.2, 1.6 Hz, lH), 3.03 (m, lH), 3.17 (dd, 1=14.2, 7.8 lH), 5.53 (d, 1=7.4 Hz, lH), 6.93 (d, 1=8.4 Hz, 2H), 7.00 (d, Hz, lH), 3.49 (dd, 1=14.2, 5.6 Hz, lH), 3.84 (m, lH), 3.96 (m, 1=8.6 Hz, 2H), 7.55 (d, 1=8.8 Hz, 2H), 7.82 (d, 1=9.0Hz, 2H); 13 lH), 4.50 (m, lH), 5.83 (d, 1=8.2 Hz, lH), 7.07 (d, 1=9.0 Hz, C NMR (126 MHz, CDC13) Ii 24.4, 26.2, 28.5, 28.6, 29.8, 2H), 7.08 (d, 1=8.8 Hz, 2H), 7.14 (d, 1=9.0 Hz, lH), 7.85 (d, 31.9, 39.8, 55.3, 62.7, 79.3, 80.5, 117.4, 121.1, 121.7, 130.8, 13 1=9.0 Hz, 2H); C NMR (126 MHz, CDC13) Ii 24.3, 26.2, 65 131.8, 135.6, 150.5, 156.4, 156.6, 163.3, 171.2; HRMS-ESI 28.1, 28.3, 28.5, 44.1, 53.5, 60.5, 62.7, 84.1, 117.8, 121.4, (m/z): [M+Na]+, calcd for C31 H43 N3O8S2Na, 672.2384. 123.4, 130.9, 132.3, 147.7, 152.4, 155.0, 155.6, 160.6, 162.8, found, 672.2393. US 8,937,151 B2 53 54 Compound 11 b. lH), 3.17 (m, lH), 3.22-3.28 (m, 4H), 3.42 (dd, 1=14.6, 7.0 1 H NMR (500 MHz, 10% CDC13 in CD3 OD) Ii 1.59-1.86 Hz, lH), 3.50 (dd, 1=14.0, 7.0Hz, lH), 4.10 (t, 1=6.3 Hz, lH), (m, 4H), 2.06-2.25 (m, 2H), 2.14 (dd, 1=5.2, 1.4 Hz, lH), 2.52 4.52 (dd, 1=8.7, 5.1 Hz, lH), 7.10 (t, 1=8.9 Hz, 4H), 7.66 (d, (dd, 1=6.4, 1.4 Hz, lH), 3.00 (t, 1=7.6 Hz, 2H), 3.05 (m, lH), 1=9.0 Hz, 2H), 7.89 (d, 1=9.0 Hz, 2H); HRMS-ESI (m/z): 3.45 (dd, 1=14.4, 6.8 Hz, lH), 3.53 (dd, 1=14.6, 6.6 Hz, lH), 5 [M+H]+, calcd for C27H40N9 O5 S2 , 634.2588. found, 4.39 (t, 1=6.5 Hz, lH), 7.18 (d, 1=8.8 Hz, 2H), 7.22 (d, 1=9.2 634.2585. Hz, 2H), 7.32 (d, 1=9.0 Hz, 2H), 7.93 (d, 1=9.0 Hz, 2H);

HRMS-ESI (m/z): [M+Ht, calcd for C21H23N3 O4 S2 , Syntheses of Dioxolone Prodrugs 450.1516. found, 450.1485. Spectral Data of Glu Amide Prodrug Compound 10c. 10 A solution of compound 7 (0.10 g, 0.31 mmol) and 5-me­ 1 H NMR (500 MHz, CDC1 3 ) ll 1.47 (s, 9H), 1.49 (s, 9H), thyl-2-oxo-1,3-dioxol-4-en-4-yl)methyl p-nitrophenyl car­ 2.00 (m, lH), 2.17 (dd, 1=5.2, 1.8 Hz, lH), 2.41 (m, lH), 2.56 bonate (0.10 g, 0.34 mmol) in CH2 Cl2 (2 mL) was stirred at (m, 2H), 3.07 (m, lH), 3.18 (dd, 1=14.3, 7.9 Hz, lH), 3.54 (dd, room temperature for 2 h. The reaction mixture was concen­ 1=14.1, 5.5 Hz, lH), 4.27 (m, lH), 7.07 (d, 1=8.6 Hz, 2H), trated and after colunm chromatography on silica gel, the 7.08 (d, 1=9.0 Hz, 2H), 7.61 (d, 1=9.0 Hz, lH), 7.86 (d, 1=9.0 15 desired product 13 was obtained(0.11 g, 71 %). 1HNMR(500 13 Hz, lH); C NMR (126 MHz, CDC1 ) Ii 24.5, 26.3, 28.2, 3 MHz, CDC13 ) Ii 2.15 (dd, 1=5.2, 1.8 Hz, lH), 2.21 (s, 6H), 28.5, 37.1, 51.5, 62.8, 82.3, 117.6, 121.3, 121.9, 130.9, 131.9, 2.52 (dd, 1=6.2, 1.4 Hz, lH), 3.04 (m, 1=7.0, 6.0Hz, lH), 3.20 135.2, 151.0, 163.3, 169.3, 171.7; HRMS-ESI (m/z): (dd, 1=14.3, 7.7 Hz, lH), 3.49 (dd, 1=14.3, 5.9 Hz, lH), 5.01 [M+Na]+, calcd for C29H38N 2 O8 S2 Na, 629.1962. found, (s, 2H), 7.11 (d, 1=9.2 Hz, 2H), 7.10 (d, 1=9.0 Hz, 2H), 7.24 13 629.1969. 20 (d, 1=9.2 Hz, 2H), 7.87 (d, 1=9.0 Hz, 2H); C NMR (126 Compound l lc. MHz, CDC1 ) ll 9.6, 24.3, 26.2, 57.9, 62.7, 77.4, 118.0, 121.5, 1 3 H NMR (500 MHz, 10% CDC1 3 in CD3 OD) Ii 2.32 (m, 122.8, 130.9, 132.5, 132.6, 141.3, 147.7, 151.9, 152.8, 153.4, lH), 2.42 (m, lH), 2.51 (dd, 1=6.2, 1.4 Hz, lH), 2.68 ( dt, 162.6; HRMS-ESI (m/z): [M+Ht, calcd for C21 H19O9 S2 , 1=7.2, 6.8, 2.0 Hz, 2H), 3.04 (m, lH), 3.44 (dd, 1=14.4, 7.0 479.0465. found, 479.0472. Hz, lH), 3.53 (dd, 1=14.4, 6.4 Hz, lH), 4.43 (t, 1=6.8 Hz, lH), 25 The synthesis ofcarbamate 14 was carried out in an analo­ 4.87 (s, l0H), 7.19 (d, 1=9.2 Hz, 2H), 7.22 (d, 1=9.2 Hz, 2H), gous manner to carbonate 13 using 6 in the presence of 7.32 (d, 1=9.2 Hz, 2H); HRMS-ESI (m/z): [M+Ht, calcd for 1 4-(dimethylamino)pyridine. H NMR (500 MHz, CDC13 ) Ii C20H23N2 O6 S2 , 451.0992. found, 451.1004. 2.17 (dd, 1=5.2, 1.8 Hz, lH), 2.23 (s, 6H), 2.55 (dd, 1=6.0, 1.6 Spectral Data ofArg Amide Prodrug Compound 10d. Hz, lH), 3.07 (m, lH), 3.20 (dd, 1=14.4, 7.8 Hz, lH), 3.52 1 H NMR (500 MHz, CDC1 3 ) ll 1.38 (s, 9H), 1.48 (s, 9H), 30 (dd, 1=14.3, 5.7 Hz, lH), 4.95 (s, 2H), 7.08 (d, 1=9.0 Hz, 2H), 1.53 (s, 9H), 1.59-1.96 (m, 4H), 2.16 (dd, 1=5.2, 1.8 Hz, lH), 7.07 (d, 1=9.2 Hz, 2H), 7.45 (d, 1=8.0 Hz, 2H), 7.86 (d, 1=8.8 2.54 (dd, 1=6.2, 1.6 Hz, lH), 3.06 (m, lH), 3.17 (dd, 1=14.2, 13 Hz, 2H); C NMR (126 MHz, CDC1 3 ) ll 9.7, 24.4, 24.5, 26.3, 8.0Hz, lH), 3.53 (dd, 1=14.2, 5.6 Hz, lH), 3.72 (m, lH), 4.12 54.7, 62.8, 117.0, 117.6, 121.5, 122.0, 130.9, 132.0, 133.8, (s, lH), 4.55 (m, lH), 5.99 (d, 1=8.2 Hz, lH), 7.05 (d, 1=9.0 140.6, 152.4, 163.3; HRMS-ESI (m/z): [M+H]+, calcd for Hz, 2H), 7.07 (d, 1=8.8 Hz, 2H), 7.53 (d, 1=8.6 Hz, 2H), 7.85 35 C21 H20NO8 S2 , 478.0625. found, 478.0625. (d, 1=9.0 Hz, 2H), 9.13 (br. s, lH); 13C NMR (126 MHz,

CDC13 ) ll 24.5, 24.7, 26.3, 28.2, 28.6, 29.3, 44.1, 54.0, 62.8, 4-Fluoro-2-(methoxymethoxy )-1-nitrobenzene (15) 84.6, 117.6, 121.2, 123.4, 130.9, 132.0, 135.1, 151.3, 155.0, 161.3, 163.2, 163.4, 171.l;HRMS-ESI(m/z): [M+Ht,calcd 5-Fluoro-2-nitrophenol (10 g, 63 mmol, 99%) was dis­ for C36H52N5 O10S2 , 778.3150. found, 778.3154. 40 solved in anhydrous DMF (100 mL) in an oven-dried flask. Compound 11 d. The solution was stirred under an atmosphere ofnitrogen and 1 H NMR (500 MHz, 10% CDC13 in CD3 OD) ll 1.71-2.11 cooledinanice-waterbath. Sodium hydride (3.0 g, 75 mmol) (m, 4H), 2.16 (d, 1=5.2 Hz, lH), 2.54 (dd, 1=6.2, 1.2 Hz, lH), was added with stirring, after which chloro methylether (5.3 3.06 (quin, 1=6.2 Hz, lH), 3.29 (m, lH), 3.45 (m, 2H), 3.54 g, 66 mmol) was added dropwise. The resulting mixture was (dd, 1=14.6, 6.4 Hz, lH), 4.14 (m, lH), 7.15 (d, 1=9.0 Hz, 2H), 45 aged at room temperature for 1 h. The reaction was quenched 7.15 (d, 1=9.0 Hz, 2H), 7.77 (d, 1=9.0 Hz, 2H), 7.92 (d, 1=8.8 with MeOH, diluted with ether and washed with water and

Hz, 2H); HRMS-ESI (m/z): [M+H]+, calcd for brine. The ether layer was dried over anhydrous Na2 SO4 and C21H23N5 O4 S2 , 478.1577. found, 478.1580. concentrated in vacuo. Purification ofthe product by silica gel Spectral Data ofArg-Arg Amide Prodrug Compound 10e. chromatography (hexanes/EtOAc=l/7) gave the title com­ 1 1 ) 50 HNMR (500 MHz, CDC13 ll 1.40-1.54 (5xs, 45H), 1.46­ pound in 88% yield. H NMR (500 MHz, CDC1 3 ) ll 3.53 (s, 1.90 (m, SH), 2.16 (dd, 1=5.2, 1.8 Hz, lH), 2.53 (dd, 1=6.2, 3H), 5.30 (d, 1=2.0Hz, 2H), 6.78 (dd, 1=7.3, 9.1 Hz, lH), 7.06 1.4 Hz, lH), 3.05 (m, lH), 3.16 (dd, 1=14.2, 7.8 Hz, lH), 3.39 (dt, 1=2.3, 10.4 Hz, lH), 7.91 (dd, 1=6.0, 9.0 Hz, lH). 13C

(m, lH), 3.53 (dd, 1=14.2, 5.6 Hz, lH), 3.55 (m, 2H), 3.82 (t, NMR (126 MHz, CDC1 3 ) ll 57.0, 95.6, 105.0 (d, 1=26.3 Hz), 1=6.8 Hz, 2H), 4.28 (dd, 1=13.8, 6.4 Hz, lH), 4.59 (q, 1=7.4 108.8 (d, 1=23.0 Hz), 127.8 (d, 1=10.7 Hz), 152.8 (d, 1=11.5 Hz, lH), 6.10 (d, 1=7.4 Hz, lH), 7.03 (d, 1=9.0 Hz, 2H), 7.05 55 Hz), 165.5 (d, 1=255.9 Hz). HRMS (FAB) calcd for

(d, 1=8.8 Hz, 2H), 7.22 (d, 1=6.4 Hz, lH), 7.61 (d, 1=8.4 Hz, C8H8 FNNaO4 (M+Na+) 224.0330. found 224.0328. 2H), 7.84 (d, 1=9.0 Hz, 2H), 8.41 (t, 1=5.6 Hz, lH), 8.84 (s, lH), 9.26 (br. s, lH), 9.35 (br. s, lH), 11.47 (s, lH); 13C NMR S-( 4-(3-(Methoxymethoxy )-4-nitrophenoxy)pheny 1)

(126 MHz, CDC1 3 ) ll 22.8, 24.5, 25.4, 26.1, 26.2, 28.2, 28.2, dimethylcarbamothioate (17) 28.4, 28.4, 28.6, 29.2, 31.8, 34.8, 40.1, 44.1, 53.8, 55.0, 62.8, 60 79.6, 80.6, 83.4, 84.3, 117.5, 121.2, 122.5, 130.9, 131.8, To a round bottom flask was added dimethylcarbamothio­ 135.4, 150.9, 153.4, 154.9, 156.6, 160.8, 163.4, 163.4, 163.5, ate 16 (2.1 g, 11 mmol), compound 15 (2.5 g, 12mmol), DMF

169.6; HRMS-ESI (m/z): [M+H]+, calcd for (50mL) andCs2 CO3 (7.1 g, 22 mmol). The resulting mixture C52H80N9 O15S2 , 1134.5210. found, 1134.5215. was stirred for 24 h, followed by filtration over silica gel. The Compound 11 e. 65 solvent was evaporated and the product was purified by silica 1 H NMR (500 MHz, 10% CDC13 in CD3 OD) ll 1.68-2.05 gel chromatography (hexanes/EtOAc=2/1) to give 17 as a 1 (m, SH), 2.13 (dd, 1=5.1, 1.3 Hz, lH), 2.51 (dd, 1=6.2, 1.0Hz, solid in 88% (3.5 g). H NMR (500 MHz, CDC1 3 ) ll 3.05 (br. US 8,937,151 B2 55 56 s., 3H), 3.12 (br. s., 3H), 3.53 (s, 3H), 5.28 (s, 2H), 6.61 (ddd, layer was separated and the aqueous layer was washed with J=0.8, 2.5, 9.1 Hz, lH), 6.99 (d, J=2.4 Hz, lH), 7.12-7.05 (m, CH2Cl2. The combined organic solution was dried over anhy­ 13 2H), 7.56-7.50 (m, 2H), 7.93-7.88 (m, lH). C NMR (126 drous Na2SO4 , the suspension was filtered and the filtrate was MHz, CDC13) Ii 37.1, 37.2, 57.1, 95.5, 107.1, 110.4, 120.5, concentrated in vacuo. Purification ofthe product by silica gel 125.1, 127.9, 135.7, 137.9, 153.0, 156.1, 162.0, 166.9. 5 chromatography (hexanes/EtOAc=2/1) gave the title com­ pound in 89% yield (0.42 g). 1H NMR (500 MHz, CDC1 ) Ii HRMS (FAB) calcd for C17H19N2O6S (M+H+) 379.0958. 3 found 379.0945. 1.54 (s, 9H), 2.48 (dd, J=2.2, 4.8 Hz, lH), 2.82 (t, J=4.5 Hz, lH), 3.28-3.19 (m, lH), 3.38-3.28 (m, 2H), 3.49 (s, 3H), 5.20 t-Butyl (4-( 4-(( dimethylcarbamoyl)thio )phenoxy)-2­ (s, 2H), 6.73 (dd, J=2.6, 8.8 Hz, lH), 6.91 (d, J=2.6 Hz, lH), (methoxymethoxy)phenyl)carbamate (18) 10 7.03 (s, lH), 7.09-7.04 (m, 2H), 7.89-7.83 (m, 2H), 8.13 (br. 13 s., lH). CNMR (126 MHz, CDC13) ll 28.5, 46.0, 46.1, 56.6, 59.8, 80.9, 95.4, 107.5, 114.2, 117.2, 119.5, 126.3, 130.6, A solution of 17 (2.5 g, 6.6 mmol) in MeOH/H2O (30 132.3, 146.7, 149.4, 152.9, 163.5. HRMS (FAB) calcd for mL/15 mL)was treated withiron(l.9 g, 34 mmol) andNH4 Cl (0.35 g, 6.5 mmol) and the resulting mixture was heated at C22H28NO8S (M+H+) 466.1530. found 466.1543. reflux for 2 h. The crude reaction mixture was filtered through 15 Celite and the filtrate was concentrated in vacuo. The residue t-Butyl (2-(methoxymethoxy)-4-(4-((thiiran-2-ylm­ was dissolved in EtOAc and was washed with water. The ethybsulfonyl)phenoxy )phenyl)-carbamate (21) organic layer was separated and the aqueous layer was washed with EtOAc. The combined organic portions were To a solution of20 (0.40 g, 0.86 mmol) in CH2Cl2 (5 mL) was added a mixture ofthiourea (0.10 g, 1.3 mmol, 99%) in dried over anhydrous Na SO . The solvent was removed 2 4 20 under reduced pressure to provide the amine as a solid (1.9 g, methanol ( 5 mL ). The resulting mixture was stirred for 24 hat 5.5 mmol, 83%). This product was dissolved in MeOH (30 room temperature, after which the solvent was removed under reduced pressure. The residue was partitioned between mL), was treated with TEA (0.6 g, 5.9 mmol) and Boc2O (1.9 g, 8.4 mmol, 97%) and was stirred at room temperature for 24 CH2Cl2 and water. The organic layer was dried over anhy­ h. The solvent was removed under reduced pressure and the drous Na2SO4 and was filtered. Evaporation of solvent and 25 purification by silica gel chromatography (hexanes/ product was purified by silica gel chromatography (hexanes/ 1 EtOAc=3/1) to give the title compound (1.9 g, 76%). 1H EtOAc=4/1) gave 0.34 g of21 (83%). H NMR (500 MHz, CDC1 ) ll 1.53 (s, 9H), 2.14 (dd, J=l.8, 5.0 Hz, lH), 2.52 (dd, NMR (500 MHz, CDC13) ll 1.54 (s, 9H), 3.02 (br. s., 3H), 3.08 3 (br. s., 3H), 3.48 (s, 3H), 5.18 (s, 2H), 6.71 (dd, J=2.6, 8.8 Hz, J=l.5, 5.9 Hz, lH), 3.04 (dq, J=5.6, 7.8 Hz, lH), 3.15 (dd, lH), 6.90 (d, J=2.6 Hz, lH), 6.97-6.92 (m, 2H), 7.00 (br. s., J=8.0, 14.2 Hz, lH), 3.47 (s, 3H), 3.51 (dd, J=5.6, 14.4 Hz, 13 lH), 7.42-7.36 (m, 2H), 8.05 (br. s., lH). C NMR (126 30 lH), 5.19 (s, 2H), 6.72 (dd, J=2.6, 8.8 Hz, lH), 6.91 (d, J=2.6 Hz, lH), 7.08-7.01 (m, 3H), 7.85-7.80 (m, 2H), 8.16-8.08 (m, MHz, CDC13) Ii 28.4, 36.9, 56.5, 80.5, 95.3, 107.2, 113.6, 13 117.7, 119.3, 121.6, 125.3, 137.4, 146.5, 150.6, 152.9, 159.4, lH). C NMR (126 MHz, CDC13) Ii 24.4, 26.2, 28.5, 56.6, 62.7, 80.8, 95.3, 107.3, 114.1, 117.3, 119.4, 126.2, 130.8, 167.4. HRMS (FAB) calcd for C22H29N2O6S (M+H+) 449.1741. found 449.1735. 131.6, 146.6, 149.3, 152.8, 163.5. HRMS (FAB) calcd for C22H2sNO S (M+H+) 482.1302. found 482.1301. 35 7 2 t-Butyl (2-(methoxymethoxy)-4-(4-((oxiran-2-ylm­ ethy l)thio )phenoxy)pheny 1)-carbamate ( 19) 2-Amino-5-( 4-((thiiran-2-ylmethyl)sulfonyl)phe­ noxy)phenol (22) To a solution of compound 18 (0.65 g, 1.5 mmol) in anhy­ drous MeOH (10 mL) was added potassium hydroxide (0.42 To a solution of compound 21 (0.10 mg, 0.21 mmol) in g, 7.5 mmol). The mixture was refluxed for 4 hand then 40 methanol (5 mL) was added a few drops of cone. HCI. After cooled to room temperature. Epichlorohydrin (0.21 g, 2.3 the mixture was stirred at reflux for 1 h, the solvent was mmol) was added dropwise and the mixture was stirred at evaporated in vacuo. The crude product was taken up into room temperature for 15 min, after which the solvent was water and EtOAc. Layers were separated and the aqueous removed under reduced pressure. The concentrate was layer was washed with EtOAc. The combined organic layers diluted with water and extracted with EtOAc. The combined 45 were dried over anhydrous Na2SO4 , the suspension was fil­ tered and the filtrate was concentrated in vacuo. Purification organic extracts were dried over anhydrous Na2SO4 , the sus­ by silica gel chromatography (hexanes/EtOAc=l/1) gave 22 pension was filtered, followed by concentration ofthe filtrate 1 in vacuo. Purification by silica gel chromatography (hexanes/ in 95% yield (66 mg). H NMR (500 MHz, CDC13) Ii 2.14 EtOAc=4/1) gave 19 in 68% yield (0.43 g) 1H NMR (500 (dd, J=l.3, 4.9 Hz, lH), 2.18 (d, J=l.0Hz, lH), 2.56-2.49 (m, lH), 3.08-3.00 (m, lH), 3.17 (dd, J=7.8, 14.4 Hz, lH), 3.51 MHz, CDC13) ll 1.53 (s, 9H), 8.03 (br. s., lH), 2.47 (dd, J=2.6, 50 (dd, J=5.6, 14.2 Hz, 2H), 6.54-6.46 (m, 2H), 6.80-6.73 (m, 5.0 Hz, lH), 2.77 (t, J=4.4 Hz, lH), 2.85 (dd, J=6.1, 13.9 Hz, 13 lH), 3.12-3.05 (m, lH), 3.18-3.12 (m, lH), 5.18 (s, 2H), 3.48 lH), 7.07-6.97 (m, 2H), 7.80 (m, 2H). C NMR (126 MHz, (s, 3H), 6.66 (dd, J=2.6, 8.8 Hz, lH), 6.92-6.85 (m, 3H), 6.98 CDC13) ll 24.4, 26.3, 62.8, 108.5, 113.1, 117.2, 117.9, 130.7, 13 131.1, 131.9, 145.9, 147.3, 164.1. HRMS (FAB) calcd for (br. s., lH), 7.44-7.37 (m, 2H). C NMR (126 MHz, CDC13) ll 28.5, 38.2, 47 .6, 51.3, 56.5, 80.6, 95.4, 106.8, 113.1, 118.4, 55 C15 H16NO4 S2 (M+H+) 338.0515. found 338.0507. 119.4, 125.1, 128.0, 131.8, 133.8, 146.6, 151.2, 152.9, 157.9. Example 2 HRMS (FAB) calcd for C22H28NO4 S (M+H+) 434.1632. found 434.1637. Experimental Inhibition Data t-Butyl (2-(methoxymethoxy)-4-(4-((oxiran-2-ylm­ ethy 1)sulfony l)phenoxy)pheny 1)-carbamate (20) 60 Fluorescence Enzymatic Activity Assays. The enzymatic activity ofMMP-2, MMP-9, and MMP-7 was monitored with the fluorescence quenched substrate Compound 19 (0.44 g, 1.0 mmol) was dissolved in CH2Cl2 (10 ml) and cooled in an ice-water bath. It was treated with MOCAcPLGLA2pr(Dnp )-AR-NH2. Fluorescence was mea­ m-CPBA (0.48 g, 2.1 mmol, 77%) and the resulting white sured with a Photon Technology International (PTI) spectrof­ suspension was stirred at room temperature for 10 min. The 65 luorometer interfaced to a Pentium computer, equipped with mixture was filtered and the filtrate was washed with satu­ the RatioMaster™ and FeliX™ hardware and software rated Na2S2O3, followed by saturated NaHCO3. The organic respectively. The cuvette compartment was thermostated a~ US 8,937,151 B2 57 58 25° C. Substrate hydrolysis was monitored at emission and squares fitted to Equation 1 (Muller-Steffner et al., J. Biol. excitation wavelengths of328 and 393 nm and excitation and Chem. 1992, 267, 9606-9611. ): emission band passes of 1 and 3 nm, respectively. Fluores­ F~v/+I(v -v,)(1-exp(-kt))!k+F (1) cence measurements were taken every 4 seconds. Less than O 0

10% hydrolysis of the fluorogenic substrate was monitored, 5 where v O represents the initial rate, v,, the steady state rate, k, as described by Knight. Knight, C. G. Methods Enzymol. the apparent first order rate constant characterizing the for­

, 1995, 248, 18-34. Stromelysin 1 enzymatic activity was mation ofthe steady-state enzyme-inhibitor complex and F 0 monitored using the synthetic fluorogenic substrate the initial fluorescence, using the program SCIENTIST (Mi­

MOCAcRPKPVE-Nva-WRK(Dnp)-NH2 (Peptides Interna­ croMath Scientific Software, Salt Lake City, Utah). The tional, Louisville, Ky.) at excitation and emission wave­ 10 obtained k values, v0 and vs were further analyzed according lengths of325 and 393 nm and excitation and emission band to Equations 2 and 3 for a one-step association mechanism: passes of 1 and 3 nm, respectively. The following buffers were used in experiments with (2) enzymes: BufferC(50mMHEPES atpH7.5, 150mMNaCl,

(v 0 -vJ!v,~[JJ/(K;(l+[SJ/Km)) (3) 5 mM CaC1 2 , 0.02% Brij-35); buffer R (50 mM HEPES at pH 15

7 .5, 150 mM NaCl, 5 mM CaC1 2 , 0.01 % Brij-35, and 1% v/v Intercept and slope values, obtained by linear regression of

Me2 SO) and buffer D (50 mM Tris at pH 7 .5, 150 mM NaCl, the k versus inhibitor concentration plot (Equation 2), yielded , 5 mM CaC1 2 and 0.02% Brij-35). the association and dissociation rate constants k 0 n and k 0ffi

Enzymes and Protein Inhibitors. respectively, and the inhibition constant K, (k0 Jk 0 n). Alter­ s Human pro-MMP-2, pro-MMP-9, TIMP-1 and TIMP-2 20 natively, K, was determined from the slope ofthe (v O -vs)/v vs were expressed in HeLa S3 cells infected with the appropriate [I] plot according to Equation 3. recombinant vaccinia viruses and were purified to homoge­ The dissociation rate constants were determined indepen­ neity, as previously described. See Fridman et al., J. Biol. dently from the enzyme activity recovered after dilution of a Chem. 1992, 267, 15398-15405 andFridmanetal.,Biochem. pre-formed enzyme-inhibitor complex. To this end, typically J. 1993, 289, 411-416. Pro-MMP-2, pro-MMP-9, TIMP-1 25 200 nM ofenzyme was incubated with 1 µM of inhibitor for and TIMP-2 concentrations were determined using the a sufficient time to reach equilibrium (>45 min) at 25.0° C. extinction coefficients of 122,800, 114,360, 26,500 and The complex was diluted into 2 mL of buffer R containing 39,600 M-1 cm-1, respectively. To obtain active MMP-2, fluorogenic substrate (5-7 µM final concentration) to a final pro-MMP-2 (7.3 µM) was incubated at 37° C. for 1 h with 1 enzyme concentration of 1 nM. Recovery ofenzyme activity mM p-aminophenyl-mercuric acetate (APMA) (dissolved in 30 was monitored for -30 min. The fluorescence versus time 200 mM Tris) in buffer C. The enzyme solution was dialyzed trace was fitted, using the program SCIENTIST, to Equation against buffer D at 4 ° C. to remove APMA. Active MMP-9 4: was obtained by incubating pro-MMP-9 (1 µM) with heat­ activated recombinant human stromelysin 1 ( 68 nM) (MMP­ (4)

3, generously provided by Dr. Paul Cannon, Center for Bone 35 where v 0 represents the initial rate (very small), vs the rate and Joint Research, Palo Alto, Calif.) at 37° C., for 2.5 h in observed when the E.I complex is completely dissociated and bufferC. k 0ffi the first order rate constant when the E.I dissociation. The resulting solution was subjected to gelatin-agarose Analysis for linear competitive inhibition was performed chromatography to remove stromelysin 1. MMP-9 was eluted in the following manner. Initial rates were obtained by adding with buffer D containing 10% DMSO and dialyzed against 40 enzyme (0.5-2 nM) to a mixture offluorogenic substrate (5-7 the same buffer without DMSO to remove the organic sol­ µM) and varying concentrations ofinhibitor in buffer R, con­ vent. Pro-MMP-2 and pro-MMP-9 activation reactions were taining 5-15% DMSO (final volume 1 mL) in semi-micro monitored using the fluorescence quenched substrate quartz cuvettes, and monitoring the increase in fluorescence

MOCAcPLGLA2pr(Dnp )-AR-NH2 (Peptides International, with time for 5-10 minutes. The fluorescence versus time Louisville, Ky.; PLGLAAAR), as will be described below. 45 traces were fitted by linear regression analysis using FeliX™. The MMP-2 and MMP-9 concentrations were determined by The initial rates were fitted to Equation 5 (Segel, I. H. in: titration with TIMP-1. Enzyme Kinetics, Wiley Inc., New York, 1975, pp. 104): Kinetic Analyses. Progress curves were obtained by adding enzyme (0.5-2 (5) nM) to a mixture offluorogenic substrate (5-7 µM) and vary­ 50 where v and V max, represent the initial and maximal veloci­ ing concentrations of inhibitor in buffer R containing 5-15% ties, S and I, the substrate and inhibitor concentrations, DMSO (final volume 2 ml), in acrylic cuvettes with stirring respectively, Km the Michaelis-Menten constant for the sub­ and monitoring the increase in fluorescence with time for strate-enzyme reaction and K, the inhibition constant, using 15-30 minutes. The progress curves were nonlinear least the program SCIENTIST.

TABLE2

Inhibition Data of Certain Specific Compounds.

Half-life Half-life Water in hwnan plasma in human blood Cmpd. MMP-2 MMP-9 Solubility at 37° C. (min) at 37° C. (min)

1 : : lla k00 1.9 ± 0.6 k00 0.21 ± 0.04 >l0mg/mL 32.4 ± 2.7 27.1 ± 2.5 2 k 0ff 8.2 ± 0.9 k 0ff 6.5 ± 0.6 3K;: 0.44 ± 0.05 K;: 3.1 ± 0.3

: : llb k 00 3.4 ± 0.1 k00 0.27 ± 0.04 >l0mg/mL 25.1 ± 5.2 15.3 ± 1.9

k 0ff 2.1 ± 0.9 k 0ff 4.2 ± 0.7 K;: 0.062 ± 0.025 K;: 1.6 ± 0.3 US 8,937,151 B2 59 60 TABLE 2-continued

Inhibition Data ofCertain Specific Compounds.

Half-life Half-life Water in human plasma in human blood Cmpd. MMP-2 MMP-9 Solubility at 37° C. (min) at 37° C. (min)

: : llc k00 2.5 ± 0.1 k 00 2.3 ± 0.1 >10 mg/mL 32.8 ± 3.6 27.9 ± 3.8

k 0ff 1.8 ± 1.6 k 0ff 12.0 ± 0.7 K;: 0.069 ± 0.064 K;:5.4±0.3

: : lld k00 7.6 ± 2.9 k 00 0.031 ± 0.006 >10 mg/mL 29.5 ± 0.7 25.4 ± 0.1

k 0.tf- 1.5 ± 0.1 k 0.tf- 6.0 ± 0.3 K;: 0.52 ± 0.20 K;: 19.6 ± 1.0

: : lle k00 1.5 ± 0.1 k 00 0.044 ± 0.004 >10 mg/mL 11.8 ± 0.5 5.9 ± 0.6

k 0.tf- 6.1 ± 2.1 k 0.tf- 8.3 ± 2.3 K;: 0.42 ± 0.15 K;: 18.7 ± 5.6 14 K;: 2.4 ± 0.6 37% inhibition *1.01 (±0.02) 1.6 ± 0.4 at 80 µM µg/mL llc,_n: X 103 M-1 s-1 2lc,,_ff X 10--4 S-l 3Ki:inµM *in 100% water; solubility calculated using E ofMIK-G6 (p-N-acetyl SB-3CT)

TABLE3 incorporated herein by reference in its entirety. Compound 1ld was evaluated for its mutagenic potential by measuring Kinetic Parameters for Inhibition ofMMPs by Compounds 1 ld, 6, and 22. its ability to induce reverse mutations at selected loci ofAmes 25 kon: koff II mixed strains and strain TA98 in the presence and absence Compound MMP x103 M-1 s-1 x10-• s-1 ofrat liver S9 metabolic activation at six concentrations up to 1 mg/mL (equivalent to 300 µM). Compound lid was nega­ lld MMP-2 7.6 ± 2.9 1.5 ± 0.1 0.52 ± 0.20 MMP-9 0.031 ± 0.006 6.0 ± 0.3 19.6 ± 1.0 tive (non-mutagenic) in this Ames mutagenicity assay with MMP-1 43% inhibition and without metabolic activation. atlmM 30 MMP-3 40.5 ± 1.2 MMP-7 160 ± 14 Example 3 MMP-14 0.42 ± 0.01 12.0 ± 0.1 28.9 ± 2.3 MMP-2 8.9 ± 0.2 2.1 ± 1.3 0.024 ± 0.G15 MMP-9 0.61 ± 0.01 5.3 ± 0.7 0.87 ± 0.11 MMP-1 No inhibition 35 Pharmaceutical Dosage Forms at20 µM MMP-3 3% inhibition at20 µM The following formulations illustrate representative phar­ MMP-7 No inhibition maceutical dosage forms that may be used for the therapeutic at200 µM or prophylactic administration of a compound of a formula MMP-14 8.0 ± 0.4 8.0 ± 0.3 0.1 ± 0.006 40 described herein, a compound specifically disclosed herein, 22 MMP-2 1.7 ± 0.1 1.4 ± 0.7 0.078 ± 0.043 MMP-9 1.07 ± 0.12 5.3 ± 1.0 0.49 ± 0.11 or a pharmaceutically acceptable salt or solvate thereof (here­ MMP-1 11 % inhibition inafter referred to as 'Compound X'): at300 µM MMP-3 54% inhibition at300 µM 45 MMP-7 116 ± 13 (i) Tablet 1 mg/tablet MMP-14 2.69 ± 0.27 7.02 ± 1.61 0.26 ± 0.07 'Compound X' 100.0 Lactose 77.5 TABLE4 Povidone 15.0 50 Croscarmellose sodium 12.0 Half-lives in Liver Microsomes. Microcrystalline cellulose 92.5 Magnesiwn stearate 3.0 Half-life in min

Compound Mouse Rat Human 300.0 55 lld >60 59.3 ± 4.5 >60 6 27.3 ± 2.1 23.4 ± 0.7 >60

As can be observed from the data above, the compounds (ii) Tablet 2 mg/tablet 60 described herein have significantly improved solubilities over 'Compound X' 20.0 SB-3CT and convert to the active compound 6 in human Microcrystalline cellulose 410.0 blood and plasma within 30 minutes. The methods used to Starch 50.0 obtain the data of Table 2 are known in the art and are Sodium starch glycolate 15.0 described, for example, by Brown et al., J. Amer. Chem. Soc. Magnesiwn stearate 5.0 2000, 122(28), 6799-6800, and the references cited therein. 65 500.0 Additional useful assays and techniques are described in U.S. Patent Publication No. 2009/0209615 (Lipton et al.), which is US 8,937,151 B2 61 62 What is claimed is: (iii) Capsule mg/capsule 1. A compound of Formula A:

'Compound X' 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 (A) Pregelatinized starch 120.0 Magnesiwn stearate 3.0

600.0

10

(iv) Injection 1 (1 mg/mL) mg/mL wherein X is 0, NH or -S-NH-, and R 1 is: 'Compound X' (free acid form) 1.0 Di basic sodium phosphate 12.0 15 Mono basic sodium phosphate 0.7 Sodium chloride 4.5 LON Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL 20 0

(v) Injection 2 (10 mg/mL) mg/mL Y-(C,-Co)•">',,~,

'Compound X' (free acid form) 10.0 25 Mono basic sodium phosphate 0.3 Di basic sodium phosphate 1.1 Polyethylene glycol 400 200.0 O.lN Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL 30

(vi) Aerosol mg/can

'Compound X' 20 35 Oleic acid 10 Trichloromonofluoromethane 5,000 3 orR ; Dichlorodifluoromethane 10,000 Dichlorotetrafluoroethane 5,000 wherein

Lis 0, NH, ---OCH2 0-, or -C(=0)0-CH20-; 40 each Y is independently -NH , ---C0 H, -P(=0) These formulations may be prepared by conventional pro­ 2 2 (0H)2 , ---OP(=0)(0H)2 , Het, or a guanidine moi­ cedures well known in the pharmaceutical art. It will be ety; appreciated that the above pharmaceutical compositions may Het is a 5 or 6 memberedheterocyclic ring comprising 1, be varied according to well-known pharmaceutical tech­ 2, or 3 heteroatoms selected from 0, N, S, or P, niques to accommodate differing amounts and types ofactive 45 wherein the ring optionally includes one or two sites ingredient 'Compound X'. Aerosol formulation (vi) may be ofunsaturation and the ring is optionally substituted used in conjunction with a standard, metered dose aerosol with 1, 2, or 3 oxo, halo, nitro, or methyl groups; and dispenser. Additionally, the specific ingredients and propor­ R3 is an amino acid or a linear or branched chain oftwo tions are for illustrative purposes. Ingredients may be to five amino acids, linked to X or the carbonyl ofR1 exchanged for suitable equivalents and proportions may be 50 by a nitrogen or sulfur atom; varied, according to the desired properties ofthe dosage form or a salt thereof; wherein the compound has an aqueous of interest. solubility ofat least 5 mg/mL. While specific embodiments have been described above 2. The compound ofclaim 1 wherein each (C 1 -C 6 )alkyl is with reference to the disclosed embodiments and examples, independently -(CH2 )-, -(CH2 ) 2-, -(CH2 ) 3-, 55 such embodiments are only illustrative and do not limit the -(CH2 ) 4-, -(CH2 ) 5-, or -(CH2 ) 6-­ scope of the invention. Changes and modifications can be 3. A compound of Formula I: made in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined (I) in the following claims. 60 All publications, patents, and patent documents are incor­ porated by reference herein, as though individually incorpo­ rated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many 65 variations and modifications may be made while remaining within the spirit and scope of the invention. US 8,937,151 B2 63 64 wherein Xis 0, NRa, or -S-NH-; 0

Ra is Hor (C 1 -C4 )alkyl; 1 R is -(C=O)-L-(CH )cm-l)-CH , -(C=O)­ Y-(c,-c,J,"''~, 2 3 5 (CH2)m-Y; -(C=O)-L-(CH2)m-Y; -(C=O)­ (CHRX)-NHRY; -P(=O)(OH)2; an amino acid; or a linear or branched chain oftwo to five amino acids; O H2N, ~~ Lis 0, NH, ---OCH2O-, or ----C(=O)O-CH2O-; Y-(C1-C6)alkyl'-.. "-T l Rx is Hor -(CH )mY; 10 2 I; ; Y-(C1-C6)alkyl ; RY is Hor -(C=O)----CH(NH2)-(CH2)mY; NH2 0 mis 1-6; each Y is independently -NH , -CO H, -P(=O) 2 2 Y-(C,-Co)•">'~ij~ (OH) , ---OP(=O)(OH) , Het, or a guanidine moi­ 2 2 15 ety; Het is a 5 or 6 membered heterocyclic ring comprising 1, (C1-C6)alkyl-Y; 2, or 3 heteroatoms selected from 0, N, S, or P, wherein the ring optionally includes one or two sites of unsaturation and the ring is optionally substituted 20 with 1, 2, or 3 oxo, halo, nitro, or methyl groups; 2 each R is independently hydroxy, (C 1 -C 6 )alkyl, (C 1 ­ C6 )alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, 3 aryl, heteroaryl, carboxy, cyano, nitro, halo, trifluo­ orR ; 2 2 2 2 romethyl, trifluoromethoxy, SR , SO2N(R ) 2, NR R , 25 wherein or COOR2; wherein each R2 is independently H, (C ­ 1 Lis 0, NH, ---OCH2O-, or -C(=O)O-CH2O-; C6 )alkyl, (C1-C6)alkanoyl, (CcC10)aroyl, aryl, aryl R3 is an amino acid or a linear or branched chain oftwo (C -C )alkyl, heteroaryl, heteroaryl(C -C )alkyl, or 1 6 1 6 to five amino acids, linked to X by a carbonyl or sulfur optionally a nitrogen protecting group when residue; covalently bonded to a nitrogen atom; and 30 or a salt thereof. each n is independently 0, 1, 2, 3, or 4; 5. The compound ofclaim 3 wherein each (C 1 -C 6 )alkyl is or a salt thereof; and independently -(CH2)-, -(CH2)2-, -(CH2)3-, wherein the compound has an aqueous solubility of at -(CH2)4-, -(CH2)5 -, or -(CH2)6-. 1 least 5 mM. 35 6. The compound ofclaim 1 wherein R -X-is meta or 4. The compound ofclaim 3 wherein X is O or NH, n is 0, para with respect to the phenoxy moiety. andR1 is: 7. The compound ofclaim 3 wherein the compound is: US 8,937,151 B2 65 66 -continued o o'QI ~ o~)lxD' ##\~. ro O 0 0

HO O I ~ \ // ou HO/P'-x D # s~ j'~ S; 0 0 0 o'QI~

X # S~ #~ S; 0 0

wherein X is O or NH; octahydroindole-2-carboxylic acid; statine; 1,2,3,4,­ or a salt thereof. tetrahydroisoquinoline-3-carboxylic acid; penicil­ 8. The compound of claim 3 wherein the compound is a lamine; omithine; citrulline; a-methyl-alanine; para­ compound of Formula II or Formula III: 40 benzoy1-pheny !alanine; pheny!glycine; propargylglycine; sarcosine; and tert-butylglycine; or R3 is a combination of any two to five amino acids in a (II) linear or branched configuration; and R4 is a residue of a sulfur-containing amino acid linked 45 to Formula III by its sulfur atom shown as part of Formula III; or a salt thereof. or 9. A pharmaceutical composition comprising a compound (III) 50 of claim 3 and a pharmaceutically acceptable diluent or car­ ner. 10. The pharmaceutical composition ofclaim 9 formulated for intravenous, subcutaneous, intracardiac, intramuscular, intraperatoneal, or topical administration. 55 11. The compound of claim 3 wherein the compound is a gelatinase inhibitor that has a water solubility that is at least 5000-fold greater than SB-3CT. wherein 12. The compound: XOorNH; 60 R3 is an amino acid moiety selected from Ala, Cys, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gin, Arg, Ser, Thr, Val, Tip, or Tyr, optionally protected on any nitrogen, sulfur, or carboxylic acid with a protect­ ing group, or a non-natural amino acid selected from 65 phosphoserine; phosphothreonine; phosphotyrosine; hydroxyproline; y-carboxyglutamate; hippuric acid; US 8,937,151 B2 67 68 -continued

o'QI~

N # S~ H #~ S; 0 0

30 where R is an amino acid or a linear or branched chain of o (Yo~ two to five amino acids. 13. The compound: OA/ ~~ ;/~ S· 0 0 ' (lld) 35 (Yo~

Arg-NA/ ~S~ 40 H #~ S; or 0 0 (22)

45

14. The compound ofclaim 3 wherein the compound inhib­ 50 its MMP-2 and has a K, of less than 3 µM. 15. The compound ofclaim 3 wherein the compound inhib­ its MMP-9 and has a K, of less than 20 µM. 16. The compound ofclaim 3 wherein R 1-X-is meta or para with respect to the oxygen of the phenoxy moiety of 55 Formula I. * * * * *