sign in sign up
<<
Home , Bamipine, Chlorothen, Deptropine, Didesmethylcitalopram, Etymemazine, Fenethazine

US 20100081713A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0081713 A1 Sharma et al. (43) Pub. Date: Apr. 1, 2010

(54) COMPOSITIONS AND METHODS FOR (22) Filed: Mar. 18, 2009 TREATINGVIRAL INFECTIONS Related U.S. Application Data (75) Inventors: Geeta Sharma, Singapore (SG); (60) Provisional application No. 61/069,917, filed on Mar. Ralf Altmeyer, Singapore (SG); 19, 2008. Vishal Pendharker, Singapore (SG); Yu Chen, Singapore (SG); Publication Classification Michael Foley, Chestnut Hill, MA (51) Int. Cl. (US) A63L/35 (2006.01) A6II 3L/25 (2006.01) Correspondence Address: A63L/35 (2006.01) Gearhart Law LLC A6II 3/13 (2006.01) 4 Femdale Avenue A6IP3L/2 (2006.01) Chatham, NJ 07928 (US) (52) U.S. Cl...... 514/459; 514/529; 514/647: 514/662 (73) Assignee: CombinatoRx, (Singapore) Pte. (57) ABSTRACT Ltd. The present invention provides compositions, methods, and kits for treating or preventing a viral infection (e.g., an infec (21) Appl. No.: 12/406,716 tion caused by an influenza virus). Patent Application Publication Apr. 1, 2010 Sheet 1 of 2 US 2010/0081713 A1

------80 r -0. Vehicle 0.5% HPMC g - - -30mg/kg/day - £ 60 “A Sertraline-100mg/kg/day/kg/day i -v. Oseltamivir-30mg/kg/day ...i -0. Oseltamivir-100mg/kg/day -0. (Sertraline 30mg/kg+ . . 40 0.1 mg/Kg)

Figure 1 Patent Application Publication Apr. 1, 2010 Sheet 2 of 2 US 2010/0081713 A1

100 468OOO

2 O

Wehicle Sentraline 10 mg/kg Sentraline 30mg/kg Setraline 100mg/kg

Figure 2 US 2010/008 1713 A1 Apr. 1, 2010

COMPOSITIONS AND METHODS FOR TREATINGVIRAL INFECTIONS TABLE 1-continued CROSS-REFERENCE TO RELATED Desloratidine + (e.g., HCI) Dipyridamole + APPLICATIONS Dipyridamole + Ibudilast + Prednisolone 0001. This application claims the benefit of U.S. Provi Nortriptyline (e.g., HCl) + Prednisolone sional Application No. 61/069,917, filed Mar. 19, 2008, (e.g., HCl) + Prednisolone which is hereby incorporated by reference. Paroxetine (e.g., HCl) + Dipyridamole Sertraline + Prednisolone BACKGROUND OF THE INVENTION 0002 The invention relates to treating viral infections 0005. In another aspect, the invention features a method Such as influenza. Diseases caused by viruses are major health for treating or preventing a viral infection in a patient. The problems worldwide, and include many potentially fatal or method includes administering to the Subject an amount of an disabilitating illnesses. Influenza virus, for example, affects SSRI sufficient to treat or prevent the viral infection in the 5-15% of the population during epidemics and causes upper patient. In certain embodiments, the patient has not been respiratory tract infections. Hospitalization and deaths can diagnosed with or does not suffer from depression, major occur, especially in high-risk groups (elderly, chronically ill depressive disorder, obsessive-compulsive disorder, panic and immuno-compromised). Between three and five million disorder, posttraumatic stress disorder, social anxiety disor cases of severe influenza and between 250,000 and 500,000 der, generalized anxiety disorder, or premenstrual dysphoric deaths are recorded every year around the world. Accord disorder. The SSRI may be selected from the group consisting ingly, there exists a need for reducing influenza and other viral of , , clovoxamine, cyanodothiepin, infections. , , , , fluvoxam ine, , , , , milnacip SUMMARY OF THE INVENTION ran, paroxetine, Sertraline, , Viqualine, and Zimel dine; or analog thereof. 0003) We have identified agents and combinations of 0006. In another aspect, the invention features a method agents which reduce inflammatory response in cells infected for treating or preventing a viral infection in a patient. The with an influenza virus, and further, have shown that agents method includes administering to the patient a combination and combinations of agents can reduce mortality rates of mice of agents selected from the group consisting of: infected with an influenza virus. On this basis, the present 0007 (a) a (e.g., , invention provides compositions, methods, and kits useful in nortriptyline, or an analog thereof) and a (e.g., treating viral infections such as influenza. prednisolone, budesonide, or an analog thereof); 0004. Accordingly, in a first aspect, the invention features 0008 (b) an SSRI (e.g., sertraline, paroxetine, orananalog a composition comprising a combination of agents listed in thereof) and a corticosteroid (e.g., prednisolone, or an analog Table 1 (e.g., further in combination with an antiviral agent) thereof); or a combination of an SSRI with an antiviral agent. The SSRI 0009 (c) a (e.g., amoxapine, may be cericlamine, citalopram, clovoxamine, cyanodothi nortriptyline, or an analog thereof) and a tetra-substituted epin, dapoxetine, escitalopram, femoxetine, fluoxetine, flu pyrimidopyrimidine (e.g., dipyridamole, or an analog Voxamine, ifoxetine, indalpine, indeloxazine, litoxetine, mil thereof); nacipran, paroxetine, Sertraline, tametraline, Vicqualine, and 0010 (d) a corticosteroid (e.g., budesonide, or an analog Zimeldine; or analog thereof. In certain embodiments, the thereof); and a tetra-substituted pyrimidopyrimidine (e.g., SSRI is sertraline or an analog thereof. The antiviral agent dipyridamole, or an analog thereof); may be a Group A antiviral agent (e.g., oseltamivir, Zan 0011 (e) an SSRI (e.g., paroxetine, or an analog thereof) amivir, , and rimantadine). The agents may be and a tetraSubstituted pyrimidopyrimidine (e.g., dipy present in an amount Sufficient to treat a viral infection (e.g., ridamole, or an analog thereof); an influenza infection caused by any of the types, Subtypes, or 0012 (f) tetrasubstituted pyrimidopyrimidine (e.g., dipy strains described herein). The composition may be formu ridamole, or an analog thereof) and ibudilast, or analog lated for administration by any route known in the art such as thereof; oral, parenteral (e.g., intravenously or intramuscularly), rec 0013 (g) an (e.g., epinastine, or an analog tal, determatological, cutaneous, nasal, vaginal, inhalant, skin thereof) and a corticosteroid (e.g., prednisolone, or an analog (patch), ocular, intrathecal, and intracranial. In certain thereof); embodiments the composition includes, consists of, or con 0014 (h) a corticosteroid (e.g., prednisolone, or an analog sists essentially of (a) a pair of agents shown in Table 1, or thereof) and bufexamac, or analog thereof; pharmaceutically acceptable salts thereof, and (b) a pharma 0015 (i) an antihistamine (e.g., desloratidine, oran analog ceutically acceptable carrier. thereof) and a non-steroidal immunophilin-dependent immu nosuppressant (NSIDI) (e.g., a cyclosporine); TABLE 1. 0016 () a tricyclic antidepressant (e.g., nortriptyline, or Amoxapine + Dipyridamole an analog thereof) and an antihistamine (e.g., desloratidine, Amoxapine + Prednisolone or an analog thereof); and Budesonide + Nortriptyline (e.g., HCI) Bufexamac + Prednisolone 0017 (k) an antihistamine (e.g., desloratidine, or an ana CME-Amoxapine + Prednisolone log thereof) and an SSRI (e.g., fluoxetine, or an analog Desloratidine + Cyclosporine thereof); Desloratidine + Fluoxetine where the two are administered simultaneously or within 14 days of each other in amounts that together are US 2010/008 1713 A1 Apr. 1, 2010

sufficient to treat or prevent said viral infection in said patient. oid, a tetrasubstituted pyrimidopyrmidine, and an antihista The SSRI may be selected, for example, from the group mine to a patient for treating or preventing a viral infection. consisting of cericlamine, citalopram, clovoxamine, cyan 0030. Another kit includes (a) a corticosteroid; and (b) odothiepin, dapoxetine, escitalopram, femoxetine, fluoxet instructions for administering (a) with at least one of a tricy ine, , ifoxetine, indalpine, indeloxazine, litoxet clic antidepressant, a tetraSubstituted pyrimidopyrmidine, an ine, , paroxetine, Sertraline, tametraline, antihistamine, an SSRI, and bufeXamac or an analog thereof Vicqualine, and Zimeldine, or analog thereof. The tricyclic to a patient for treating or preventing a viral infection. antidepressant may be selected from the group consisting of 0031. Another kit includes (a) a tetrasubstituted pyrimi , amoxapine, 8-hydroxyamoxapine, 7-hy dopyrmidine; and (b) instructions for administering (a) with droxyamoxapine, , loxapine Succinate, loxapine at least one of a corticosteroid, a tricyclic antidepressant, an hydrochloride, 8-hydroxyloxapine, , clomi SSRI, and ibudilast or an analog thereof to a patient for pramine, , , , , treating or preventing a viral infection. nortriptyline, and ; or an analog thereof. 0032. Another kit includes (a) an antihistamine; and (b) 0018. In certain embodiments, the combination of agents instructions for administering (a) with at least one of a corti is selected from the combinations of Table 1, oracombination costeroid, an NSIDI, a tricyclicantidepressant, and an SSRI to including one or more analogs of the agents of Table 1. An a patient for treating or preventing a viral infection. agent may be administered by any route known in the art Such 0033. Another kit includes (a) ibudilast or an analog as oral, parenteral (e.g., intravenously or intramuscularly), thereof, and (b) instructions for administering (a) with a tet rectal, determatological, cutaneous, nasal, Vaginal, inhalant, rasubstituted pyrimidopyrmidine to a patient for treating or skin (patch), ocular, intrathecal, and intracranial. In any of the preventing a viral infection. above methods, the two agents may be administered within 0034. Another kit includes (a) bufexamac, or an analog 10, 7, 5, 4, 3, or 2 days, or within 24, 12, 6, 3, 2, or 1 hour). thereof, and (b) instructions for administering (a) with a cor 0019. In either of the above methods, the method may ticosteroid to a patient for treating or preventing a viral infec further include administration of additional antiviral therapy tion. (e.g., a Group A antiviral agent). The additional antiviral 0035. Yet another kit includes (a) an NSIDI, or an analog therapy may be administered by any of routes described thereof, and (b) instructions for administering (a) with an herein and may be administered within 14 days (e.g., within antihistamine to a patient for treating or preventing a viral 10, 7, 5, 4, 3, 2, 1 days or within 12, 6, 3, 2, or 1 hours) of one infection. or both of agents. 0036 Another kit includes (a) a combination of agents 0020. In either of the above methods, if the SSRI is sertra selected from Table 1; and (b) instructions for administering line, it may be administered in doses of at least 1, 2, 5, 10, 20, (a) with a Group A antiviral agent to a patient for treating or 30, 40, 50, 60, 75, 100, 150, or 200 mg/kg/day. preventing a viral infection. 0021. The invention also features kits. One kit includes (a) 0037 Another kit includes (a) a Group A antiviral agent; an SSRI; and (b) instructions for administering the SSRI to a and (b) instructions for administering(a) with an SSRI or with patient for treating or preventing a viral infection. a combination of agents selected from Table 1 to a patient for 0022. Another kit includes (a) a tricyclic antidepressant; treating or preventing a viral infection. (b) a corticosteroid; and (c) instructions for administering (a) 0038 Another kit includes (a) an SSRI; (b) a Group A and (b) to a patient for treating or preventing a viral infection. antiviral agent; and (c) instructions for administering (a) and 0023. Another kit includes (a) an SSRI; (b) a corticoster (b) to a patient for treating or preventing a viral infection. oid; and (c) instructions for administering (a) and (b) to a 0039. Another kit includes (a) an SSRI; and (b) instruc patient for treating or preventing a viral infection. tions from administering (a) to a patient with a Group A 0024 Yet another kit includes (a) a tricyclic antidepres antiviral for treating or preventing a viral infection. sant, a corticosteroid, an SSRI, or ibudliast, or an analog 0040. The above kits may include a composition including thereof; (b) a tetrasubstitutied pyrimidopyrimide; and (c) a combination of agents listed in Table 1, oran analog of Such instructions for administering (a) and (b) to a patient for an agent. treating or preventing a viral infection. 0041. In any of the above embodiments, the viral infection 0025. Another kit includes (a) an antihistamine; (b) a cor may be caused by a virus of a family selected from the group ticosteroid, an NSIDI, a tricyclic antidepressant, or an SSRI; consisting of orthomyxoviridae, adenoviridae, paramyxoviri and (c) instructions for administering (a) and (b) to a patient dae, and coronaviridae (e.g., an influenza virus or any virus for treating or preventing a viral infection. described herein). 0026. Another kit includes (a) bufexamac, or an analog 0042. To “treat’ is meant to administer one or more agents thereof; (b) a corticosteroid; and (c) instructions for admin to measurably slow or stop the replication of a virus in vitro or istering (a) and (b) to a patient for treating or preventing a in Vivo, to measurably decrease the load of a virus (e.g., any viral infection. virus described herein including an influenza virus) in a cell in 0027. In the above kits containing two agents, the agents vitro or in vivo, or to reduce at least one symptom (e.g., may be present in a single composition or in separate com inflammation) associated with having a viral infection in a positions. patient. Desirably, the slowing in replication, the decrease in 0028. Another kit includes (a) a tricyclic antidepressant; viral load, or reduction in the symptom is at least 20%, 30%, and (b) instructions for administering (a) with at least one of 50%, 70%, 80%, 90%. 95%, or 99%, as determined using a a corticosteroid, a tetrasubstituted pyrimidopyrmidine, and Suitable assay (e.g., a inflammation assay described herein) as an antihistamine to a patient for treating or preventing a viral compared to in the absence of the agent. infection. 0043. To “prevent a disease is meant to reduce to fre 0029. Another kit includes (a) an SSRI; and (b) instruc quency of appearance of the disease in a population of tions for administering (a) with at least one of a corticoster patients, the likelihood of an individual patient developing the US 2010/008 1713 A1 Apr 1, 2010 disease, or to reduce the symptoms or severity of a disease upon its appearance by administering one or more agents to a TABLE 2-continued patient prior to diagnosis of the disease or manifestation of A 91883A disease symptoms. A98881 0044. By “an effective amount' is meant the amount of a A-837.093 agent, alone or in combination with another therapeutic regi Abacavir men, required to treat a patient with a viral infection (e.g., AC2 Acemannan caused by any virus described herein including an influenza Acetylcysteine-Zambon virus) in a clinically relevant manner. A Sufficient amount of ACH 126445 an agent used to practice the present invention for therapeutic ACH 126447 Aciclovir (e.g., extended release, treatment of conditions caused by a virus varies depending controlled release, topical patch) upon the manner of administration, the age, body weight, and Aciclovir-PMPA general health of the patient. Ultimately, the prescribers will ACPHIP decide the appropriate amount and dosage regimen. Addition Actinohivin AD 439 ally, an effective amount may be an amount of an agent in a ADS 19 combination of the invention that is safe and efficacious in the Adamantylamide dipeptide treatment of a patient having a viral infection over each agent Adefovir (e.g., dipivoxil) alone as determined and approved by a regulatory authority ADSJ1 Afovirsen (such as the U.S. Food and Administration). AG 1284 0045. By “more effective' is meant that a treatment exhib AG 1350 its greater efficacy, or is less toxic, safer, more convenient, or AG 1478 less expensive than another treatment with which it is being AG 1859 compared. Efficacy may be measured by a skilled practitioner AG SSS AG 6840 using any standard method that is appropriate for a given AG 6863 indication. AG-021541 0046 By a “low dosage” is meant at least 5% less (e.g., at AGT-1 AHAO08 least 10%, 20%, 50%, 80%, 90%, or even 95%) than the Aidfarel lowest standard recommended dosage of a particular agent L 721 formulated for a given route of administration for treatment of amifovir any human disease or condition. For example, a low dosage of buferon an agent that treats a viral infection and that is formulated for bumin/interferon-alpha administration by intravenous injection will differ from a low desleukin dosage of the same agent formulated for oral administration. ovudine 0047. By a “high dosage' is meant at least 5% (e.g., at least pha HGA pha-1 PDX 10%, 20%, 50%, 100%, 200%, 300%, 500%, 1,000%, pha-antitrypsin 2,000%, 5,000%, or 10,000%) more than the highest standard vircept Sudotox recommended dosage of a particular agent for treatment of vocidib any human disease or condition. 0048. By a “Group A Antiviral' is meant any of the com AM285 pounds listed in Table 2. AM365 Amantadine TABLE 2 AMD O70 AMD 3329 (+)-Calanolide A AMD 3465 (+)-Dihydrocalanolide A AMD 8664 145U87 Amdoxovir 2'-C-methyl-7-deaza-adenosine Amidinomycin 2'-C-Methylcytidine Aminopeptidase 2-Nor-cyclic GMP Amitivir 3,4-Dicaffeoylquinic acid Ampligen 3-Hydroxymethyl dicamphanoyl Amprenavir khellactone AMZOO26 3-Hydroxyphthaloyl-beta ANA 971 lactoglobulin ANA 975 3-Nitrosobenzamide Ancriviroc 4-Azidothymidine Andrographis 4-Methyl dicamphanoyl Anti-CCR5 monoclonal antibody khellactone Anti-CCR5/CXCR4 sheep monoclonal antibody Anti-CD3 monoclonal antibody A 160621 CD4IgG conjugate A 315675 Anti-CD4 monoclonal antibody A 315677 Anti-CD7 monoclonal antibody A SO21 Anti-CD8 monoclonal antibody A 74259 Anti-CMV monoclonal antibody A 74704 Anti-hepatitis B ribozyme A 77003 Anti-HIV catalytic antibody A 80735 Anti-HIV immunotoxin (IVAX) A 80987 Anti-HIV-1 human monoclonal US 2010/008 1713 A1 Apr. 1, 2010

TABLE 2-continued TABLE 2-continued antibody 2F5 BIRMECA 10-142 Anti-HIV-1 human monoclonal BIVN4O1 antibody 2G12 BL 1743 Anti-HIV-1 human monoclonal BLX 833 (e.g., controlled antibody 4E10 release) Antineoplaston AS21 (e.g., oral) BMS10836 Anti-RSV antibody (Intracel, BMS 181167-O2 Corp.) BMS 181184 Antisense oligonucleotide PB2 BMS 1821.93 AUG BMS 1863.18 Aop-RANTES BMS 187071 Aphidicolin BMS 488043 AplaViroc BMS 806 Apricitabine BMY 27709 AQ 148 Boceprevir (SCH 5.03034) AR 132 Brecanavir AR.177 Brefeld in A ARB 952.14 Brequinar ARB 9726S Brivudine ARB 97268 BRL 47923DP Arbidol BSL 4 ARQ 323 BST SOO1 Artemether BTA 188 Artemisinin BTA 798 Artesunate C 1605 AS 101 C2507 AT 61 C31G Atazanavir Calcium spirulan Atewirdine Canventol Atorvastatin Capravirine AV 1101 Carbendazim AV 2921 Carbocyclic deazaadenosine AV 2923 Carbopol polymer gel AV 2925 Carbovir AV 2927 CC 3052 Avarol CD4 fusion toxin AVI406S CD4 IgG AVR 118 CD4-ricin chain A AXD 455 Celgosivir AZidodideoxyguanosine CellCept AZodicarbonamide Cellulose sulfate Bafilomycin A1 Cepharanthine Ceplene Bavituximab CF 1743 BAY 414109 CFY 196 BAY 43969S CGA 137053 BAY SO4798 CGP 35269 BAY Z 430S CGP 4.9689 CGP 53437 BB 2116 CGP 53820 BCH 10652 CGP 57813 BCH371 CGP 61.783 BCH 527 CGP 64222 BCTP CGP 70726 BCX 140 CGP 75136 BCX 1591 CGP 751.76 BCX1827 CGP 75355 BCX 1898 Chloroquine (e.g., phosphate) BCX 1923 CI1012 BEA CI1013 BEA OOS Cidofovir Bellenamine Ciluprevir (BILN 2061) Benanomicin A Civacir Benzalkonium (e.g., ) Civamide Benzalkonium CL 190O38 chloridefoctoxynol 9 (e.g., CL 387626 vaginal gel) Clevudine Beta-D-FDOC CMV 423 Beta-L-ddC CMXOO1 Beta-L-FoldC CNBA-Na. Bevirimat CNJ IO2 BG 777 Cobra venom peptide BGP 15 Colloidal silver BILA 2185 BS Conocurvone BILN 303 SE Cosalane BILR 355 Costatolide US 2010/008 1713 A1 Apr. 1, 2010

TABLE 2-continued TABLE 2-continued

CP 1018161. Elvucitabine CP 38 EM 1421 CP51 EM2487 CPFDD Emivirine CpG 10101 Emtricitabine CRL 1072 Emtricitabineftenofovir Crofelemer disoproxil fumarate CS 8958 EMZ 702 CS 92 Enfuwirtide CT 2576 Entecavir CTC96 Eosinophil-derived neutralizing Curcumin agent Curdlan sulfate Episiastatin B Cyanovirin-N ET007 Cyclosporine Etanercept CYT 99007 Ether lipid analogue Cytarabine Etoviram Cytomegalovirus immune Etravirine globulin F 105 DAB486interleukin-2 F 36 DABO 1220 F50003 Dacopafant Famciclovir DAP 30 Fas-ligand inhibitor DAP 32 Fasudi Dapivirine Fattiviracin A1 Darunavir FEAU D-aspartic-beta-hydroxamate Feglymycin DB340 Felvizumab DDCDP-DG FG345 DDGA Fiacitabine Deazaadenosine Fialuridine DeaZaneplanocin A FLG DEB O2S Floxuridine DEBIO-O2S Flutimide Delavirdine Fluvastatin (e.g., sodium) Delimitide Fomivirsen Denileukin diftitox Fosalvudine tidoxil Deoxyfluoroguanosine Fosamprenavir DES 6 Foscarnet Sodium Dexelvucitabine Fozivudine Dextran sulfate FP 21.399 Dextrin 2-sulfate DG 3S FPMPA Didanosine FPMPDAP Dideoxyadenosine FR 191512 Dideoxyguanosine FR 198248 Dideoxythymidine Galactan Sulfate Didox Ganciclovir Dihydroartemisinin GAP 31 Dihydrocostatolide GCA 186 Dinitrochlorobenzene GCPK DL110 GE 20372A DMP 323 GE 20372B DMP 850 GEM 122 DMP 851 GEM132 DmTr-ODN12 GEM 144 Docosanol GEM 92 DP107 GEM 93 DPC 082 Gemcitabine (e.g., DPC 083 hydrochloride) DPC 681 Ginseng DPC 684 Glamolec DPC 961 Glutathionarsenoxide DPC 963 Glycovir Droximavir Glycyrrhizin DUP 925 GMDP DYE GO 6976 E913 GO 7716 EB-Foscarnet GO 7775 Edodekin alfa Gossypol Edoxudine GPG-NH2 E-EPSEU GPI 1485 EGS 21 GPS O193 EHC 18 GR 137615 EHT 899 GR92938X US 2010/008 1713 A1 Apr. 1, 2010 6

TABLE 2-continued TABLE 2-continued GS 2838 release, intranasal, Omniferon) GS 2992 interferon alpha-2b (e.g., GS3333 controlled release or tranadermal) GS 3435 interferon alpha-2b gene therapy GS4O71 interferon alpha-n3 GS 438 interferon beta-1a GS 7340 interferon beta-1b GS 900S interferon gamma-1b GS 91.32 Lnterferon omega GS 916O interferol-tal GS 930 interleukin 10 (e.g., human GW 275175 recombinant) GW 595OX interleukin-1 receptor type I HB 19 interleukin-13 HBY 946 interleukin-15 HCVO86 interleukin-16 HCV 371 interleukin-2 agonist HCVAB 68 interleukin-4 HCV-796 PR HCVSM pilimumab HE 2000 satoribine HE317 SIS 13312 Hepatitis B immune globulin SIS 14803 Hepatitis C immune globulin so doA Hepex C TIOO2 HEPT TIO11 Heptazyme TMN-191 HGS-HIA27 BP 485 HI 236 CA 304 HI 240 E2147 HI 244 M1596 HI 28O M2763 HI346 TKOO3 HI443 TK109 HI445 TK303 K12 Histamine dihydrochloride (e.g., K37 injection, oral) K42 HIV DNA vaccine (Antigen Kamizol Express, Inc.) kethoxal HIV immune globulin Kiimicin HIV immune plasma Kistamicin HL 9 KKKI 538 HOE BAY 793 KMO43 HRG 214 KNI 102 HSO58 KNI 241 HuMax-HepC KNI 272 Hydroxycarbamide KNI 413 Hydroxychloroquine KNI 684 Hypericin Kootikuppala 152 KP 1461

CN 17261 KPE OOOO1113 DN 6.556 KPEO2OO3OO2 doxuridine KRH 1120 M28 L 6895O2 miquimod L 693549 mmStat L 696229 mmuDyn L 696474 mmunocal L 696661 mreg 1 L 697639 incadronic acid L 697661 NCB 94.71 L 708906 indinavir L 731988 nfliximab L 7328O1 influenza matrix protein Zn2+ L 734OOS finger peptide L 735882 ngenol Triacetate L 738372 nophyllum B L 7386.84 nosine pranohex L 738872 interferon L 739594 interferon Alfa-2a. L 748496 interferon alfa-2b (e.g., L 754394 inhalation) L 75.6423 interferon alfacon-1 L 87.08.10 interferon alpha (e.g., Sustained LHSAara AMP US 2010/008 1713 A1 Apr. 1, 2010

TABLE 2-continued TABLE 2-continued

Lactoferrin MDL 74968 Lamivudine MDX 240 Lamivudine? abacavir ME 3.738 Lamivudine? zidovudine ME 609 Lamivudine? zidovudine? abacavir MEDI488 Lasinavir Medusa Interferon LB 71116 MEN 10690 LB 71148 MEN 10979 LB 71262 MERNSO7SA LB 71350 Merimepodib (VX-497) LB 8038O Met-enkephalin LB 84451 Methisazone L-chicoric acid Mevastatin Lecithinized Superoxide MGN 3 dismutase Michellamine B Leflunomide Miglustat Lentinan Milk thistle Leukocyte interleukin injection Mitoquinone (CEL-SCI Corp.) MIV 150 Leukotriene B4-LTB4 MIV 210 Levcycloserine Mivotilate Levofloxacin MKOS18 Lexithromycin Licorice root MM1 Liposomal ODG-PFA-OMe MMS 1 Succinate MOL O275 Lobucavir Monoclonal antibody 1F7 Lodenosine Monoclonal antibody 2F5 Lopinavir Monoclonal antibody 3F12 Lovastatin Monoclonal antibody 447-52D Loviride Monoclonal antibody 50-61A Luftronil Monoclonal antibody B4 LY 180299 Monoclonal antibody HNK20 LY214624 Monoclonal antibody NMO1 LY 253963 Mopyridone LY 28961.2 Moroxydine LY 296.242 Motavizumab LY 296416 Motexafin gadolinium LY 309391 Mozenavir LY30984O MPC 531 LY311912 MRK1 LY314163 MS 1060 LY314177 MS 1126 LY316683 MS 8209 LY 326.188 MS 888 LY 326594 MSC 127 LY 32662O MSH 143 LY 338387 MTCH 24 LY 343814 MTP-PE LY3S4400 Murabutide LY355455 MVO26048 LY 366094 MX 1313 LY3664OS Mycophenolate mofetil LY 368.177 Mycophenolic Acid LY 73497 Nawuridine Lysozyme NBOO1 M4O4O1 Nelfinavir (e.g., meSylate) B-arginine conjugate Madu Neotripterifordin Mannan sulfate Nevirapine MAP 30 NIM 811 Maraviroc Nitazoxanide Maribavir (e.g., ProStrakan) Masoprocol Nitrodeazauridine MB-Foscarnet MC2O7044 NM 49 MC2O7685 NM 55 MC 867 N-nonyl-DNJ CDS71 NNY-RANTES MDI-P Nonakine MDL 101028 NOV 205 MDL 20610 MDL 273.93 MDL 73669 NPC 15437 MDL 74428 NSC 158393 MDL 74.695 NSC 20625 US 2010/008 1713 A1 Apr. 1, 2010

TABLE 2-continued TABLE 2-continued

NSC 28.7474 Plerixafor NSC 4493 PM 104 NSC 615985 PM 19 NSC 620055 PM 523 NSC 6241.51 PM921.31 NSC 62.4321 PM 94116 NSC 627708 PMEDAP NSC 651O16 PMS 601 NSC 667952 PMTG NSC 708199 PMTI NV O1 PN355 NV-08 PNU 103657 Octoxynol 9 PNU 142721 OCXO191 podophyllotoxin OH1 Poly ICLC OKU 40 Polyadenylic polyuridylic acid OKU 41 Polysaccharide K Oltipraz PP 29 Omaciclovir PPB 2. Opaviraline PPL 100 OPTTL3 Pradefovir Oragen Pradimicin A ORI902O Prasterone Oseltamivir PRO 140 Oxetanocin PRO 2000 Oxothiazolidine carboxylate PRO 367 P 56 PRO S42 PA 344, PA 344B Probucol (Vyrex Corp.) Palinavir Propagermanium PaliwiZumab Prostratin PAMBAEEG Pseudohypericin Papuamide A PSI SOO4 BS 119 PSI-6130 C 12SO PTPR PTX111 Pyriferone Q 8045 QM 96521 QM96639 QR 435 Quinobene Quinoxapeptin A Quinoxapeptin B QYL 438 QYL 609 QYL 685 QYL 769 R 1518 90497 R 1626 egaldesleukin R 170591 eginterferon alfa-2a. R 18893 eginterferon alfa-2b R 61837 EGinterferon alfacon-1 R71762 EGylated interferon R 803 egylated thymalfasin R 821SO eldesine R 82913 R 851 Penciclovir R87366 Pentosan polysulfate R91767 Pentoxifylline R944 Peptide T R95288 Peramivir R-1626 PETT 4 R7128 PF-03491390 Raluridine PG 3.01029 Ramatroban PG 36 Ranpirinase Phellodendrine B 2121 Phosphatidyllamivudine BC CD4 Phosphatidylzalcitabine D 30O28 Phosphatidylzidovudine D 42024 Phosphazid D 42138 Phosphinic cyclocreatine D 42217 Pinosylvin D 42227 Pirodavir D 621.98 PL 2500 D 65071 Pleconaril D6Y664 US 2010/008 1713 A1 Apr. 1, 2010

TABLE 2-continued TABLE 2-continued Regavirumab SKF 108922 Residuimod SKI 1695 Resobene SO 324 Respiratory syncytial virus Sodium laurilsulfate immune globulin Solutein Retrogen Sorivudine (e.g., topical) REV 123 SP 10 RFI 641 P 1093V. Ribavirin parfosic acid Rilpivirine PC3 Rimantadine PD 756 Ritonavir pecifEx-Hep B RKS 1443 PI 119 RO O334649 PL 2992 RO 247429 PL 7013 RO 2SO236 PV 30 RO 316840 R 10204 RO 53335 R 10208 Robustaflavone R 11335 Rolipram RosiglitaZone R3773 RP 70034 R3775 RP 71955 R. 3784 RPI312 R3785 RPI 856 R. 41476 RPR 103611 RL 172 RPR 106868 RPR111423 T 135647 RS 654 achyflin RS 980 stallimycin RSV 604 Stampidine Rubitecan Statolon Rupintrivir Stavudine S 1360 Stepronin S 2720 Suksdorfin S 9a Sulfated maltoheptaose SA 1042 Superoxide dismutase SA8443 Suramin (e.g., sodium) Saquinavir (e.g., mesylate) Sy 801 Sargramostim T 1100 SB 180922 T 118 SB 2057OO T 22 SB 206343 T30695 SB 73 T 611 SC 49.483 T 705 SC 55099 SCH350634 Tacrine SCH6 TAK 220 Schisandra TAK 652 SCVO7 TAK779 SCY635 Talviraline SD 894 TAP 29 S-DABO Taribavirin SDF1 TASP SDZ, 282870 Teceleukin SDZ, 28.3053 Tecogalan (e.g., Sodium) SDZ, 2834.71 TEI 2306 SDZ 891.04 Telaprevir (VX-950) SDZ PRIOS3 Telbivudine SEO63 Telinavir Semapimod Temacrazine Sevirumab Tenidap SF 950 Tenofovir SF 953 Tenofovir disoproxil fumarate Siamycin 1 TGG II 23A Siamycin 2 SICAM-1 TH 9411 Sifuwirtide Thalidomide SIGA246 Thiophosphonoformic acid Silipide Thiovir Simvastatin Thymalfasin (e.g., Zadaxin) Simvastatin hydroxy acid, Thymoctonian ammonium salt Thymosin fraction 5 Sizofiran Thymotrinan SJ 3366 Thymus extract SKO34 tICAM-1 US 2010/008 1713 A1 Apr. 1, 2010 10

TABLE 2-continued TABLE 2-continued

Tifuwirtide VP 50406 Tilarginine VRT 21493 Tipranavir WRX 496 Tiviciclovir VX 10166 Tivirapine VX 10217 VX 10493 TT 9 VX 11106 TL3024 WF 10 TMC 126 WHIO5 TNF-alpha inhibitor WHIO7 TNK 6123 WIN 49569 TNX355 WIN 496.11 Todoxin WM 5 TOFA WR 151327 Tomeglovir XK216 Transforming growth factor XK234 alpha XN 482 TraT XP 951 Trecovirsen XQ 9302 Tremacamra XR 83S Trichosanthin XTL 2125 Triciribine XTL 6865 Triconal XU 348 Trifluridine XU 430 Trimidox Y-ART-3 Trodusquemine YHI1 Tromantadine YKFH312 Trovirdine Z 100 Tucaresol Z 15 Tunicamycin Zalcitabine Tuvirumab Zanamivir U103017 Zidovudine (e.g., phosphate U 75875 didanosine dimer) U 78036 Zidovudine triphosphate mimics U 80493 ZXO610 U81749 ZXO62O ZXO791 U 96988 ZXO792 U 98.43 ZXO793 UA926 ZXO851 Obenimex ZY II UC 10 UC 16 UC 38 0049. The term “pharmaceutically acceptable salt' repre UC 42 UC 68 sents those salts which are, within the scope of sound medical UC 70 judgment, Suitable for use in contact with the tissues of UC 781 UC 81 humans and lower animals without undue toxicity, irritation, UC 82 allergic response and the like, and are commensurate with a UIC 94.003 reasonable benefit/risk ratio. Pharmaceutically acceptable Ukrain salts are well known in the art. The salts can be prepared in UL36ANTI UMD 828 situ during the final isolation and purification of the agents of Ursodeoxycholic acid the invention, or separately by reacting the free base function UT 231B with a suitable organic acid. Representative acid addition Valaciclovir Valganciclovir salts include acetate, adipate, alginate, ascorbate, aspartate, Valomaciclovir benzenesulfonate, benzoate, bisulfate, borate, butyrate, cam Valopicitabine (NM 283) phorate, campherSulfonate, citrate, cyclopentanepropionate, Valopicitabine (NM-283) digluconate, dodecylsulfate, ethanesulfonate, fumarate, glu Valtorcitabine coheptonate, glycerophosphate, hemisulfate, heptonate, hex Varicella Zoster immune globulin VB 19038 anoate, hydrobromide, hydrochloride, hydroiodide, 2-hy Vesnarinone droxy-ethanesulfonate, isethionate, lactobionate, lactate, WF 1634 laurate, lauryl Sulfate, malate, maleate, malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, VGX410 Vicriviroc nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persul Vidarabine fate, 3-phenylpropionate, phosphate, picrate, pivalate, propi Vincristine (e.g., Sulfate) onate, Stearate. Succinate, Sulfate, tartrate, thiocyanate, tolu VIR 101 Viraprexin enesulfonate, undecanoate, Valerate salts, and the like. Virodene Representative alkali or alkaline earth metal salts include Virostat Sodium, lithium, potassium, calcium, magnesium, and the Viscum album extract like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, US 2010/008 1713 A1 Apr. 1, 2010 tetramethylammonium, tetraethylammonium, methylamine, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluo dimethylamine, trimethylamine, triethylamine, ethylamine, ralkyl, amino, aminoalkyl, disubstituted amino, quaternary and the like. amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. 0050 Compounds useful in the invention include those C. alkynyls include, without limitation, ethynyl, 1-propy described herein in any of their pharmaceutically acceptable nyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl. forms, including isomers such as diastereomers and enanti 0056 By “C. heterocyclyl is meant a stable 5- to omers, salts, Solvates, and polymorphs thereof, as well as racemic mixtures. Compounds useful in the invention may 7-membered monocyclic or 7- to 14-membered bicyclic het also be isotopically labeled compounds. Useful isotopes erocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic), and which consists of 2 to 6 carbon include hydrogen, carbon, , oxygen, phosphorous, atoms and 1, 2, 3, or 4 heteroatoms independently selected fluorine, and chlorine, (e.g., H, H, C, C, N, O, '70, from N, O, and S and including any bicyclic group in which 'P 'P, S, F, and Cl). Isotopically-labeled compounds any of the above-defined heterocyclic rings is fused to a can be prepared by Synthesizing a compound using a readily ring. The heterocyclyl group may be substituted or available isotopically-labeled reagent in place of a non-iso unsubstituted. Exemplary Substituents include alkoxy, ary topically-labeled reagent. loxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoro 0051. In the generic descriptions of compounds of this alkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, invention, the number of atoms of a particular type in a quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl Substituent group is generally given as a range, e.g., an alkyl groups. The nitrogen and Sulfur heteroatoms may optionally group containing from 1 to 4 carbon atoms or C alkyl. be oxidized. The heterocyclic ring may be covalently attached Reference to such a range is intended to include specific via any heteroatom or carbon atom which results in a stable references to groups having each of the integer number of structure, e.g., an imidazolinyl ring may be linked at either of atoms within the specified range. For example, an alkyl group the ring-carbon atom positions or at the nitrogen atom. A from 1 to 4 carbon atoms includes each of C, C, C, and C. nitrogen atom in the heterocycle may optionally be quater A C-2 heteroalkyl, for example, includes from 1 to 12 car nized. Preferably when the total number of S and O atoms in bon atoms in addition to one or more heteroatoms. Other the heterocycle exceeds 1, then these heteroatoms are not numbers of atoms and other types of atoms may be indicated adjacent to one another. Heterocycles include, without limi in a similar manner. tation, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1.5.2-dithiazi 0052. As used herein, the terms “alkyl and the prefix nyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, “alk- are inclusive of both straight chain and branched chain 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, groups and of cyclic groups, i.e., cycloalkyl. Cyclic groups benzimidazolyl, benzofuranyl, benzothiofuranyl, ben can be monocyclic or polycyclic and preferably have from 3 Zothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, to 12 ring carbon atoms, inclusive. Exemplary cyclic groups benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimi include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl daZalonyl, carbazolyl, 4aH-carbazolyl b-carbolinyl, chroma groups. nyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1.5. 0053. By "C alkyl is meant a branched or unbranched 2-dithiazinyl, dihydrofuroI2,3-btetrahydrofuran, furanyl, hydrocarbon group having from 1 to 4 carbon atoms. A Ca furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-in alkyl group may be substituted or unsubstituted. Exemplary dazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzo Substituents include alkoxy, aryloxy, Sulfhydryl, alkylthio. furanyl, isochromanyl, isolindazolyl, isoindolinyl, isoindolyl, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naph aminoalkyl, disubstituted amino, quaternary amino, thyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1.2.3-Oxa hydroxyalkyl, carboxyalkyl, and carboxyl groups. Calkyls diazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadia include, without limitation, methyl, ethyl, n-propyl, isopro Zolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, pyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, butyl, tert-butyl, and cyclobutyl. phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, 0054 By “C. alkenyl is meant a branched or piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperido unbranched hydrocarbon group containing one or more nyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, double bonds and having from 2 to 4 carbon atoms. A Ca pyrazolinyl, pyrazolyl pyridazinyl, pyridooxazole, pyri alkenyl may optionally include monocyclic or polycyclic doimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, rings, in which each ring desirably has from three to six pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, members. The C- alkenyl group may be substituted or 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tet unsubstituted. Exemplary Substituents include alkoxy, ary rahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinoli loxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoro nyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadia alkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, Zolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimi groups. Calkenyls include, without limitation, vinyl, allyl, dazolyl, thiophenyl, triazinyl, 1.2.3-triazolyl, 1,2,4-triazolyl, 2-cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred 5 to 3-butenyl, 2-methyl-1-propenyl, and 2-methyl-2-propenyl. 10 membered heterocycles include, but are not limited to, 0055. By "C. alkynyl' is meant a branched or pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, unbranched hydrocarbon group containing one or more triple pyrrolyl pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetra bonds and having from 2 to 4 carbon atoms. A C alkynyl Zolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimida may optionally include monocyclic, bicyclic, or tricyclic Zolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotria rings, in which each ring desirably has five or six members. Zolyl, benzisoxazolyl, OXindolylbenzoxazolinyl, quinolinyl, The C- alkynyl group may be substituted or unsubstituted. and isoquinolinyl. Preferred 5 to 6 membered heterocycles Exemplary Substituents include alkoxy, aryloxy, Sulfhydryl, include, without limitation, pyridinyl, pyrimidinyl, triazinyl, US 2010/008 1713 A1 Apr. 1, 2010

furanyl, thienyl, thiazolyl pyrrolyl, piperazinyl, piperidinyl, 0070. By “quaternary amino” is meant a chemical sub pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl. stituent of the formula—(R) N(R')(R") (R")", wherein R, 0057 By “Caryl' is meant an aromatic group having a R", R", and R" are each independently an alkyl, alkenyl, ring system comprised of carbon atoms with conjugated at alkynyl, or aryl group. R may be an alkyl group linking the electrons (e.g., phenyl). The aryl group has from 6 to 12 quaternary amino nitrogen atom, as a Substituent, to another carbon atoms. Aryl groups may optionally include monocy moiety. The nitrogen atom, N, is covalently attached to four clic, bicyclic, or tricyclic rings, in which each ring desirably carbon atoms of alkyl, heteroalkyl, heteroaryl, and/or aryl has five or six members. The aryl group may be substituted or groups, resulting in a positive charge at the nitrogen atom. unsubstituted. Exemplary substituents include alkyl, 0071. Other features and advantages of the invention will hydroxy, alkoxy, aryloxy, Sulfhydryl, alkylthio, arylthio. be apparent from the following Detailed Description, the halide, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, drawings, and the claims. amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups. BRIEF DESCRIPTION OF THE DRAWINGS 0058. By “C, alkaryl is meant an alkyl substituted by an aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophen 0072 FIG. 1 is a graph showing survival data for sertraline ethyl) having from 7 to 14 carbon atoms. and oseltamivir in the lethal infection of influenza A/PR/8/34 0059 By “Coalkheterocyclyl is meant an alkyl substi induced in C57/BL6 mice. tuted heterocyclic group having from 3 to 10 carbon atoms in 0073 FIG. 2 is a graph showing dose dependant increase addition to one or more heteroatoms (e.g., 3-furanylmethyl, in Survival rate of Sertraline-treated groups as compared to 2-furanylmethyl, 3-tettrahydrofuranylmethyl, or 2-tetrahy vehicle-treated groups. drofuranylmethyl). DETAILED DESCRIPTION 0060. By “C, heteroalkyl is meant a branched or unbranched alkyl, alkenyl, or alkynyl group having from 1 to 0074. We have identified agents and combinations of 7 carbon atoms in addition to 1, 2, 3, or 4 heteroatoms inde agents that reduce the inflammatory response observed upon pendently selected from the group consisting of N, O, S, and influenza infection in vitro and in vivo, and thus may be useful P. Heteroalkyls include, without limitation, tertiary amines, in treating or preventing viral infections, for example, those secondary amines, ethers, thioethers, amides, thioamides, caused by an influenza virus. On this basis, the invention , thiocarbamates, hydrazones, imines, phosphodi provides compositions, methods, and kits for treating a viral esters, phosphoramidates, sulfonamides, and disulfides. A infection. The agents and combinations of agents described heteroalkyl may optionally include monocyclic, bicyclic, or herein can reduce cytokine and chemokine expression and tricyclic rings, in which each ring desirably has three to six thus prevent or reduce symptoms associated with viral infec members. The heteroalkyl group may be substituted or tions (e.g., influenza). unsubstituted. Exemplary Substituents include alkoxy, ary 0075. In particular, we have shown that the exemplary loxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoro SSRI, sertraline, can be used to reduce the mortality associ alkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, ated with an influenza viral infection. On this basis, the inven quaternary amino, hydroxyalkyl, hydroxyalkyl, carboxy tion features methods for treating or preventing viral infec alkyl, and carboxyl groups. Examples of C, heteroalkyls tions, such as influenza, using an SSRI either alone or in include, without limitation, methoxymethyl and ethoxyethyl. combination with another agent (e.g., a corticosteroid, or an 0061. By “halide' or “halogen' is meant bromine, chlo antiviral agent). The invention also features compositions rine, iodine, or fluorine. including an SSRI and an antiviral agent, and kits including 0062 By “fluoroalkyl is meant an alkyl group that is an SSRI (e.g., sertraline). substituted with a fluorine atom. 0076 We have also identified the combinations of agents 0063. By “perfluoroalkyl is meant an alkyl group consist shown in Table 1 as being capable of reducing cytokine and ing of only carbon and fluorine atoms. chemokine expression in cells infected with an influenza 0064. By “carboxyalkyl is meanta chemical moiety with virus. Because inflammation in the lung has been identified as the formula—(R)—COOH, wherein R is selected from C, playing an important role in mortality associated with influ alkyl, C2-7 alkenyl, C2-7 alkynyl, C-heterocyclyl, C-2 aryl, enza infection, one strategy to reduce the mortality rates C- alkaryl, Coalkheterocyclyl, or C, heteroalkyl. associated with Such infections is to reduce lung inflamma 0065. By “hydroxyalkyl is meant a chemical moiety with tion. In particular, these combinations of agents are observed the formula —(R) -OH, wherein R is selected from C, to reduce expression of one or more of TNF-alpha, IFN-beta, alkyl, C2-7 alkenyl, C2-7 alkynyl, C-heterocyclyl, C-2 aryl, IP-10, IL-6, IL-8, monocyte chemotactic protein-1 (MCP-1) C- alkaryl, Coalkheterocyclyl, or C, heteroalkyl. and, in addition, can reduce influenza HSN matrix gene 0066 By “alkoxy” is meant a chemical substituent of the expression. formula —OR, wherein R is selected from C, alkyl, C-7 alkenyl, C-7 alkynyl, C. heterocyclyl, C-2 aryl, C7 Viruses alkaryl, Coalkheterocyclyl, or C-7 heteroalkyl. 0077. The invention relates to the treatment of viral dis 0067 By “aryloxy' is meant a chemical substituent of the ease, which can be caused by viruses from the families orth formula —OR, wherein R is a C-2 aryl group. omyxoviridae, adenoviridae, paramyxoviridae, and coro 0068. By “alkylthio’ is meant a chemical substituent of naviridae. Virus of the orthomyxoviridae family include the the formula—SR, wherein R is selected from C, alkyl, C.- influenza A virus, influenza B virus, influenza C virus, the alkenyl, C2-7 alkynyl, C2-a heterocyclyl, C-2 aryl, C7-14 infectious salmon anemia virus (isavirus), Thogoto Virus, and alkaryl, Coalkheterocyclyl, or C-7 heteroalkyl. Dhori Virus. Members of the adenoviridae family include 0069. By “arylthio’ is meant a chemical substituent of the human adenovirus A, B, C, D, E, and F. bovine adenovirus A, formula—SR, wherein R is a Caryl group. B, and C. canine adenovirus; equine adenovirus A and B; US 2010/008 1713 A1 Apr. 1, 2010

murine adenovirus A. ovine adenovirus A and B; porcine tion are discussed in greater detail below. It will be under adenovirus A, B, and C.; and tree shrew adenovirus. Members stood that analogs of any these compound can be used in the of the paramyxoviridae family include bovine parainfluenza methods, compositions, and kits of the present invention. virus 3 (BPIV-3), human parainfluenza virus 1 (HPIV-1), Additional information regarding these compounds can be human parainfluenza virus 3 (HPIV-3); sendai virus (murine found in U.S. Pat. Nos. 6,897,206 and 7.253,155 and U.S. Pat. parainfluenza virus 1); simian parainfluenza virus 10 (SPIV Application Publication Nos. 2004/0220153, 2004/0224876, 10), bovine respiratory syncytial virus (BRSV), human res 2005/0192261, 2005/01 19160, 2005/0187200, 2006/ piratory syncytial virus (HRSV), pneumonia virus of mice 0286.177, and 2005/0112199, each of which is incorporated (PVM), canine distemper virus (CDV), dolphin distemper by reference. virus (DMV), measles virus (MeV), Peste des petits rumi nants virus (PPRV), phocine (seal) distemper virus (PDV), Selective Inhibitors porpoise distemper virus, rinderpest virus (RPV), avian paramyxovirus 2 (APMV-2), avian paramyxovirus 3 I0084. The methods, compositions, and kits of the inven (APMV-3), avian paramyxovirus 4 (APMV-4), avian tion can includean SSRI or an analog thereof. Suitable SSRIs paramyxovirus 5 (APMV-5), avian paramyxovirus 6 include cericlamine (e.g., cericlamine hydrochloride); citalo (APMV-6), avian paramyxovirus 7 (APMV-7), avian pram (e.g., citalopram hydrobromide); clovoxamine; cyan paramyxovirus 8 (APMV-8), avian paramyxovirus 9 odothiepin; dapoxetine; escitalopram (escitalopram oxalate); (APMV-9), human parainfluenza virus 2 (HPIV-2), human femoxetine (e.g., femoxetine hydrochloride); fluoxetine (e.g., parainfluenza virus 4a (HPIV-4a), human parainfluenza virus fluoxetine hydrochloride); fluvoxamine (e.g., fluvoxamine 4b (HPIV-4-b), mumps virus, newcastle disease virus (avian maleate); ifoxetine; indalpine (e.g., indalpine hydrochloride); paramyxovirus 1) (NDV: APMV-1), porcine rubulavirus, indeloxazine (e.g., indeloxazine hydrochloride); litoxetine; simian parainfluenza virus 5 (SV-5), and simian parainflu milnacipran (e.g., minlacipran hydrochloride); paroxetine enza virus 41 (SV-41). Members of the coronaviridae family (e.g., paroxetine hydrochloride hemihydrate; paroxetine include infectious bronchitis virus, bovine coronavirus, maleate; paroxetine mesylate); Sertraline (e.g., Sertraline canine coronviarus, feline coronavirus, human coronavirus, hydrochloride); tametraline hydrochloride; vidualine; and and SARS-coronavirus. Zimeldine (e.g., Zimeldine hydrochloride). 0078 Influenza Types, Subtypes, and Strains 0085 Sertraline 0079. In certain embodiments, the virus is an influenza I0086) Sertraline has the following structure: virus. Influenza viruses are RNA viruses of the family Orth omyxoviridae. Three types of influenza viruses (types A, B, and C) have been identified. Subtypes of type A are based on NHCH variations in the hemagglutinin (HA) polypeptide and the neuraminidase (N) polypeptide. Fifteen (H1, H2,H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, and H15) differ ent HA subtypes have been identified, and nine (N1, N2, N3. N4, N5, N6, N7, N8, and N9)N subtypes have been identified. Strains including these Subtypes can occur in various combi nations (e.g., H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, H10N7). One serotype of infleunza B has been identified, and influenza type C is generally less C virulent that types A or B. 0080 Influenza Symptoms C 0081 Influenza is characterized by fever, headache, tired ness, cough, Sore throat, runny or stuffy nose, body aches, and I0087 Structural analogs of sertraline are those having the diarrhea and Vomiting. Complications which can develop formula: from an influenza infection include bacterial pneumonia, dehydration, and worsening of chronic medical conditions, Such as congestive heart failure, asthma or diabetes. Sinus NRR problems and ear infections can also develop. 0082 Mortality due to influenza infection is often associ 21 ated with lung inflammation, which can be severe. Influenza virus can induce cytokines including interleukin-6, interleu w N kin-8, interleukin-10, and tumor necrosis factor-alpha in the serum and nasopharyngeal fluid (Laurent et. al., J MedVirol 64:262-268, 2001; Hayden et. al., J. Clin Investig 101:643 21 649, 1998). Mortality associated with influenza infection is often due to the ability of the influenza A virus to infect the Sás-X entire lung and induce high levels of macrophage-derived X Y chemokines and cytokines, which results in infiltration of inflammatory cells and severe haemorrhage (Kobasa et. al., Nature 431:703-707, 2004). wherein R is selected from the group consisting of hydrogen and Calkyl, R is Calkyl, XandYare each selected from Compounds the group consisting of hydrogen, fluoro, chloro, bromo, tri 0083) Certain compounds that may be employed as agents fluoromethyl, Calkoxy, and cyano; and W is selected from in the methods, compositions, and kits of the present inven the group consisting of hydrogen, fluoro, chloro, bromo, tri US 2010/008 1713 A1 Apr. 1, 2010 fluoromethyl and C alkoxy. Preferred Sertraline analogs are in the cis-isomeric configuration. The term “cis-isomeric' -continued refers to the relative orientation of the NRR and phenyl moieties on the cyclohexene ring (i.e. they are both oriented Name on the same side of the ring). Because both the 1- and 4-car bons are asymmetrically Substituted, each cis-compound has Sertraline B-Ring two optically active enantiomeric forms denoted (with refer Para-Phenoxy ence to the 1-carbon) as the cis-(1R) and cis-(1S) enanti omers. Sertraline analogs are also described in U.S. Pat. No. 4,536,518. Other related compounds include (S,S) N-des methylsertraline, rac-cis-N-, (1S,4S)- desmethyl sertraline, 1-des (methylamine)-1-oxo-2-(R.S)- hydroxy sertraline, (1R,4R)-desmethyl sertraline, sertraline Sulfonamide, Sertraline (reverse) methanesulfonamide, 1R4R sertraline enantiomer, N,N-dimethyl sertraline, nitro Sertraline, Sertraline aniline, Sertraline iodide, Sertraline Sul fonamide NH sertraline sulfonamide ethanol, sertraline nitrile, sertraline-CME, dimethyl sertraline reverse sulfona mide, sertraline reverse sulfonamide (CH linker), sertraline B-ring ortho methoxy, Sertraline A-ring methyl ester, Sertra line A-ring ethanol, sertraline N,N-dimethylsulfonamide, Sertraline A ring carboxylic acid, Sertraline B-ring para-phe Sertraline B-Ring 1. noxy, sertraline B-ring para-trifluoromethane, N,N-dimethyl Ortho-Methoxy sertraline B-Ring para-trifluoromethane, and UK-416244. Structures of these analogs are shown below.

OMe Name Structure

(1R4S) Sertraline 1. Hydrochloride HN 1R4R Sertraline Enantiomer

oHC

C

C

(1S,4R) Sertraline 1. Sertraline Hydrochloride HN Sulfonamide N 1

oHC

C C . US 2010/008 1713 A1 Apr. 1, 2010

-continued -continued

Name Structure Name Structure

Nitro Sertraline N (1R4R)-Desmethyl NH2 NH Sertraline ON O O

O C C C C Sertraline A-Ring NHMe Sertraline Aniline N NH Methyl Ester MeOC HN

C C C

Sertraline Reverse 1. Sulfonamide O HN rac-cis-N-Desmethyl NH2 HCI (CH2 linker) NA Sertraline, S n Hydrochloride A NN O H

C C

C C

UK-416244 N 1 Dimethyl Sertraline N 1 N Reverse Sulfonamide N O H HNOS Y 1. N W O O

C

SMe C US 2010/008 1713 A1 Apr. 1, 2010 16

-continued -continued

Name Structure Name Structure

Sertraline N,N- Sertraline Iodide Dimethylsulfonamide HN1 N H O2 S N Y In

Cl C

C C

Sertraline OH NHMe 1-Des(methylamine)- O A-Ring Ethanol 1-oxo-2-(R.S)- hydroxy Sertraline wOH

C C

C C Sertraine Nitrile YNH Sertraine-CME 1. OH NC O O

C

C O C C

Sertraline NHCH, HCI Hydrochloride (1S,4S)-Desmethyl Cla Sertraline, H Hydrochloride HN

C

C C C US 2010/008 1713 A1 Apr. 1, 2010

-continued -continued

Name Structure Name Structure Sertraline NHMe Sulfonamide Ethanol O2 N,N-Dimethyl HO S Sertraline N1 n1n N1 B-Ring Para H Trifluoromethane

C

C Sertraline B-Ring N CF Para-Trifluoromethane NH

Sertraline Sulfonamide NH2

CF

. N,N-Dimethyl N 1 Sertraline (Reverse) Sertraline N Methanesulfonamide

C

C

I0088 Particularly useful are the following compounds, in either the (1S)-enantiomeric or (1S)(1R) racemic forms, and their pharmaceutically acceptable salts: cis-N-methyl-4-(3,4- Sertraline A-Ring N Carboxylic Acid NH dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; cis N-methyl-4-(4-bromophenyl)-1,2,3,4-tetrahydro-1-naphtha HOOC lenamine; cis-N-methyl-4-(4-chlorophenyl)-1,2,3,4- tetrahydro-1-naphthalenamine; cis-N-methyl-4-(3- trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-1- naphthalenamine; cis-N-methyl-4-(3-trifluoromethyl-4- chlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; cis-N. N-dimethyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-1- naphthalenamine: cis-N,N-dimethyl-4-(3-trifluoromethyl phenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; and cis-N- C methyl-4-(4-chlorophenyl)-7-chloro-1,2,3,4-tetrahydro-1- C naphthalenamine. Of interest also is the (1R)-enantiomer of cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- naphthalenamine. US 2010/008 1713 A1 Apr. 1, 2010

0089 Cericlamine as well as pharmaceutically acceptable salts thereof, wherein 0090 Cericlamine has the following structure: each of R and R is independently selected from the group consisting of bromo, chloro, fluoro, trifluoromethyl, cyano C and R CO , wherein R is C alkyl. 0096 Exemplary citalopram structural analogs (which are CH3 thus SSRI structural analogs according to the invention) are C N 1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-5-bro YCH, mophthalane: 1-(4-chlorophenyl)-1-(3-dimethylaminopro Me pyl)-5-chlorophthalane: 1-(4-bromophenyl)-1-(3-dimethy CHOH laminopropyl)-5-chlorophthalane: 1-(4'-fluorophenyl)-1-(3- dimethylaminopropyl)-5-chlorophthalane; 1-(4'- 0091 Structural analogs of cericlamine are those having chlorophenyl)-1-(3-dimethylaminopropyl)-5- the formula: trifluoromethyl-phthalane; 1-(4-bromophenyl)-1-(3- dimethylaminopropyl)-5-trifluoromethyl-phthalane: 1-(4'- fluorophenyl)-1-(3-dimethylaminopropyl)-5- C trifluoromethyl-phthalane; 1-(4'-fluorophenyl)-1-(3- dimethylaminopropyl)-5-fluorophthalane; 1-(4'- C chlorophenyl)-1-(3-dimethylaminopropyl)-5- fluorophthalane; 1-(4-chlorophenyl)-1-(3- R dimethylaminopropyl)-5-phthalancarbonitrile; 1-(4'- CHOH fluorophenyl)-1-(3-dimethylaminopropyl)-5- phthalancarbonitrile; 1-(4-cyanophenyl)-1-(3- as well as pharmaceutically acceptable salts thereof, wherein dimethylaminopropyl)-5-phthalancarbonitrile; 1-(4'- R is a C-C alkyl and R is H or C. alkyl, R is H. C. cyanophenyl)-1-(3-dimethylaminopropyl)-5- alkyl, Calkenyl, phenylalkyl or cycloalkylalkyl with 3 to 6 chlorophthalane; 1-(4-cyanophenyl)-1-(3- cyclic carbon atoms, alkanoyl phenylalkanoyl or cycloalky dimethylaminopropyl)-5-trifluoromethylphthalane: 1-(4'- lcarbonyl having 3 to 6 cyclic carbon atoms, or R and R fluorophenyl)-1-(3-dimethylaminopropyl)-5- form, together with the nitrogen atom to which they are linked, a heterocycle saturated with 5 to 7 chain links which phthalancarbonitrile; 1-(4-chlorophenyl)-1-(3- can have, as the second heteroatom not directly connected to dimethylaminopropyl)-5-ionylphthalane; 1-(4- the nitrogen atom, an oxygen, a Sulphur or a nitrogen, the (chlorophenyl)-1-(3-dimethylaminopropyl)-5- latter nitrogen heteroatom possibly carrying a C- alkyl. propionylphthalane; and pharmaceutically acceptable salts of 0092 Exemplary cericlamine structural analogs are 2-me thyl-2-amino-3-(3,4-dichlorophenyl)-propanol, 2-pentyl-2- any thereof. Additional analogs are described in U.S. Pat. No. amino-3-(3,4-dichlorophenyl)-propanol, 2-methyl-2-methy 4,136,193. lamino-3-(3,4-dichlorophenyl)-propanol, 2-methyl-2- 0097. Clovoxamine dimethylamino-3-(3,4-dichlorophenyl)-propanol, and 0.098 Clovoxamine has the following structure: pharmaceutically acceptable salts of any thereof. 0093 Citalopram 0094) Citalopram has the following structure: NC rs, O " OCH or C F 0099 Structural analogs of clovoxamine are those having 0095 Structural analogs of citalopram are those having the formula: the formula: R O O

O (CH2)3.N(CH3)2 M Hal C V (CH2)4-R R US 2010/008 1713 A1 Apr. 1, 2010

as well as pharmaceutically acceptable salts thereof, wherein 0107 Structural analogs of fluoxetine are those com Hal is a chloro, bromo, or fluoro group and R is a cyano, pounds having the formula: methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxy ethoxy, or cyanomethyl group. 0100 Exemplary clovoxamine structural analogs are 4'-chloro-5-ethoxyvalerophenone O-(2-aminoethyl)oxime; 4'-chloro-5-(2-methoxyethoxy)Valerophenone O-(2-amino RO N ethyl)oxime; 4'-chloro-6-methoxycaprophenone O-(2-ami noethyl)oxime; 4'-chloro-6-ethoxycaprophenone O-(2-ami noethyl)oxime; 4'-bromo-5-(2-methoxyethoxy) Valerophenone O-(2-aminoethyl)oxime; 4'-bromo-5- methoxyvalerophenone O-(2-aminoethyl)oxime; 4'-chloro 6-cyanocaprophenone O-(2-aminoethyl)oxime; 4'-chloro-5- cyanovalerophenone O-(2-aminoethyl)oxime; 4'-bromo-5- cyanovalerophenone O-(2-aminoethyl)oxime; and as well as pharmaceutically acceptable salts thereof, wherein pharmaceutically acceptable salts of any thereof. each R is independently hydrogen or methyl; R is naphthyl or 0101 Femoxetine 0102) Femoxetine has the following structure:

HC-N wherein each of R and R is, independently, bromo, chloro, fluoro, trifluoromethyl, C. alkyl, C. alkoxy or C. alk enyl; and each of n and m is, independently, 0, 1 or 2. When R is naphthyl, it can be either C.-naphthyl or 3-naphthyl. 0.108 Exemplary fluoxetine structural analogs are 3-(p- isopropoxyphenoxy)-3-phenylpropylamine methane sulfonate, N,N-dimethyl 3-(3',4'-dimethoxyphenoxy)-3-phe nylpropylamine p-hydroxybenzoate, N,N-dimethyl 3-(o- naphthoxy)-3-phenylpropylamine , N,N-dimethyl OCH 3-(B-naphthoxy)-3-phenyl-1-methylpropylamine iodide, 3-(2-methyl-4,5'-dichlorophenoxy)-3-phenylpropylamine 0103 Structural analogs of femoxetine are those having nitrate, 3-(p-t-butylphenoxy)-3-phenylpropylamine glut the formula: arate, N-methyl 3-(2-chloro-p-tolyloxy)-3-phenyl-1-meth ylpropylamine lactate, 3-(2',4'-dichlorophenoxy)-3-phenyl 2-methylpropylamine citrate, N,N-dimethyl 3-(m- anisyloxy)-3-phenyl-1-methylpropylamine maleate, N-methyl 3-(p-tolyloxy)-3-phenylpropylamine sulfate, N.N- dimethyl 3-(2',4'-difluorophenoxy)-3-phenylpropylamine 2,4-dinitrobenzoate, 3-(o-ethylphenoxy)-3-phenylpropy lamine dihydrogen phosphate, N-methyl 3-(2-chloro-4-iso CHOR propylphenoxy)-3-phenyl-2-methylpropylamine maleate, N,N-dimethyl 3-(2-alkyl-4-fluorophenoxy)-3-phenyl-pro wherein R represents a C alkyl or C. alkynyl group, or a pylamine Succinate, N,N-dimethyl 3-(o-isopropoxyphe phenyl group optionally Substituted by C. alkyl, C. alky noxy)-3-phenyl-propylamine phenylacetate, N,N-dimethyl lthio, C alkoxy, bromo, chloro, fluoro, nitro, acylamino, methylsulfonyl, methylenedioxy, or tetrahydronaphthyl, R 3-(o-bromophenoxy)-3-phenyl-propylamine B-phenylpropi represents a C alkyl or C. alkynyl group, and R repre onate, N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine sents hydrogen, C alkyl, Calkoxy, trifluoroalkyl, propiolate, and N-methyl 3-(3-n-propylphenoxy)-3-phenyl hydroxy, bromo, chloro, fluoro, methylthio, or aralkyloxy. propylamine decanoate. Additional flouxetine analogs are 0104 Exemplary femoxetine structural analogs are dis described in U.S. Pat. No. 4,314,081. closed in Examples 7-67 of U.S. Pat. No. 3,912,743, hereby 0109 Fluvoxamine incorporated by reference. 0110 Fluvoxamine has the following structure: 0105. Fluoxetine 0106 Fluoxetine has the following structure: NH2

O YCH, O V FC re-( )-(/ / /OCH US 2010/008 1713 A1 Apr. 1, 2010 20

0111 Structural analogs of fluvoxamine are those having 0116 Indeloxazine the formula: 0117 Indeloxezine has the following structure: ()

N O ()

re-() {(CH)-R 0118 Structural analogs of indeloxazine are those having the formula: as well as pharmaceutically acceptable salts thereof, wherein

R is cyano, cyanomethyl, methoxymethyl, or ethoxymethyl. Analogs of fluvoxamine are also described in U.S. Pat. No. 4,085,225. 0112 Indalpine 0113 Indalpine has the following structure:

and pharmaceutically acceptable salts thereof, wherein R and Rs each represents hydrogen, C alkyl, or phenyl; R. represents hydrogen, C alkyl, C., cycloalkyl, phenyl, or N NH benzyl, one of the dotted lines means a single bond and the other means a double bond, or the tautomeric mixtures thereof. 0114 Structural analogs of indalpine are those having the 0119 Exemplary indeloxazine structural analogs are 2-(7- formula: indenyloxymethyl)-4-isopropylmorpholine, 4-butyl-2-(7-in denyloxymethyl)morpholine: 2-(7-indenyloxymethyl)-4- methylmorpholine; 4-ethyl-2-(7-indenyloxymethyl) A-(CH)n morpholine, 2-(7-indenyloxymethyl)-morpholine: 2-(7- indenyloxymethyl)-4-propylmorpholine, 4-cyclohexyl-2-(7- f N indenyloxymethyl)morpholine; 4-benzyl-2-(7- RS-2 \ indenyloxymethyl)-morpholine: 2-(7-indenyloxymethyl)-4- N. NH phenylmorpholine; 2-(4-indenyloxymethyl)morpholine; 2-(3-methyl-7-indenyloxymethyl)-morpholine: 4-isopropyl 2-(3-methyl-7-indenyloxymethyl)morpholine: 4-isopropyl or pharmaceutically acceptable salts thereof, wherein R is a 2-(3-methyl-4-indenyloxymethyl)morpholine: 4-isopropyl hydrogen atom, a C-C alkyl group, or an aralkyl group of 2-(3-methyl-5-indenyloxymethyl)morpholine: 4-isopropyl which the alkyl has 1 or 2 carbon atoms, R is hydrogen, Ca 2-(1-methyl-3-phenyl-6-indenyloxymethyl)morpholine; alkyl, C. alkoxy or C. alkylthio, chloro, bromo, fluoro, 245-indenyloxymethyl)-4-isopropyl-morpholine, 2-(6-inde trifluoromethyl, nitro, hydroxy, oramino, the latter optionally nyloxymethyl)-4-isopropylmorpholine; and 4-isopropyl-2- Substituted by one or two C alkyl groups, an acyl group or (3-phenyl-6-indenyloxymethyl)morpholine; as well as phar a Calkylsulfonyl group; A represents —CO or —CH2— maceutically acceptable salts of any thereof. Additional group; and n is 0, 1 or 2. Indeloxazine analogs are described in U.S. Pat. No. 4,109, 0115 Exemplary indalpine structural analogs are O88 indolyl-3 (piperidyl-4 methyl) ketone; (methoxy-5-indolyl 0120 Milnacipran 3) (piperidyl-4 methyl) ketone; (chloro-5-indolyl-3) (pip 0121 Milnacipran has the following structure: eridyl-4 methyl) ketone; (indolyl-3)-1 (piperidyl-4)-3 pro panone, indolyl-3 piperidyl-4, ketone; (methyl-1 indolyl-3) (piperidyl-4 methyl) ketone, (benzyl-1 indolyl-3) (pip eridyl-4 methyl) ketone; (methoxy-5 indolyl-3)-2 ethyl-pi peridine, (methyl-1 indolyl-3)-2 ethyl-4-piperidine; (in dolyl-3)-2 ethyl-4 piperidine; (indolyl-3 methyl)-4 piperidine, (chloro-5 indolyl-3)-2 ethyl-4 piperidine; (in NH2 dolyl-b 3)-3 propyl-4 piperidine; (benzyl-1 indolyl-3)-2 N-Et ethyl-4 piperidine; and pharmaceutically acceptable salts of Et any thereof. Additional indalpine derivatives are described in U.S. Pat. No. 4,064.255. US 2010/008 1713 A1 Apr. 1, 2010 21

0122 Structural analogs of milnacipran are those having 0.126 Structural analogs of paroxetine are those having the formula: the formula:

O N s O 2 R4 t O N-R2 Ye, | R R \ / as well as pharmaceutically acceptable salts thereof, wherein each R, independently, represents hydrogen, bromo, chloro, fluoro, Calkyl, Calkoxy, hydroxy, nitro or amino; each and pharmaceutically acceptable salts thereof, wherein R of R and R2, independently, represents hydrogen, Calkyl, represents hydrogen or a C alkyl group, and the fluorine Caryl or C. alkylaryl, optionally substituted, prefer atom may be in any of the available positions. ably in paraposition, by bromo, chloro, or fluoro, or RandR 0127. Zimeldine together form a heterocycle having 5 or 6 members with the I0128 Zimeldine has the following structure: adjacent nitrogen atoms; R and R represent hydrogen or a Calkyl group or R and R form with the adjacent nitrogen atom a heterocycle having 5 or 6 members, optionally con Br taining an additional heteroatom selected from nitrogen, Sul phur, and oxygen. 0123 Exemplary milnacipran structural analogs are 2n-1N 1-phenyl 1-aminocarbonyl 2-dimethylaminomethyl cyclo : 1-phenyl 1-dimethylaminocarbonyl 2-dimethy laminomethylcyclopropane; 1-phenyl 1-ethylaminocarbonyl N21 2-dimethylaminomethyl : 1-phenyl 1-diethy laminocarbonyl 2-aminomethyl cyclopropane: 1-phenyl N 2-dimethylaminomethyl N-(4-chlorophenyl)cyclopropane carboxamide: 1-phenyl 2-dimethylaminomethyl N-(4-chlo Structural analogs of Zimeldine are those compounds having robenzyl)cyclopropane carboxamide: 1-phenyl 2-dimethy the formula: laminomethyl N-(2-phenylethyl)cyclopropane carboxamide; (3,4-dichloro-1-phenyl) 2-dimethylaminomethyl N,N-dim ethylcyclopropane carboxamide: 1-phenyl 1-pyrrolidinocar bonyl 2-morpholinomethyl cyclopropane: 1-p-chlorophenyl 1-aminocarbonyl 2-aminomethyl cyclopropane: 1-or thochlorophenyl 1-aminocarbonyl 2-dimethylaminomethyl cyclopropane: 1-p-hydroxyphenyl 1-aminocarbonyl 2-dim ethylaminomethyl cyclopropane, 1-p-nitrophenyl 1-dim CO-l ethylaminocarbonyl 2-dimethylaminomethyl cyclopropane; 1-p-aminophenyl 1-dimethylaminocarbonyl 2-dimethylami nomethyl cyclopropane: 1-p-tolyl 1-methylaminocarbonyl () 2-dimethylaminomethyl cyclopropane: 1-p-methoxyphenyl 1-aminomethylcarbonyl 2-aminomethyl cyclopropane; and and pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salts of any thereof. Additional pyridine nucleus is bound in ortho-, meta- or para-position to milnaciprain analogs are described in U.S. Pat. No. 4,478, the adjacent carbon atom and where R is selected from the 836. group consisting of H. chloro, fluoro, and bromo. 0.124 Paroxetine I0129. Exemplary Zimeldine analogs are (e)- and (Z)-3-(4- 0.125 Paroxetine has the following structure: bromophenyl-3-(2"-pyridyl)-dimethylallylamine: 3-(4-bro mophenyl)-3-(3'-pyridyl)-dimethylallylamine: 3-(4-bro mophenyl)-3-(4"-pyridyl)-dimethylallylamine; and pharmaceutically acceptable salts of any thereof. analogs are also described in U.S. Pat. No. 3,928,369. s 0.130 Structural analogs of any of the above SSRIs are O considered herein to be SSRI analogs and thus may be employed in any of the methods, compositions, and kits of the invention. O Metabolites I0131 Pharmacologically active metabolites of any of the HN F foregoing SSRIs can also be used in the methods, composi tions, and kits of the invention. Exemplary metabolites are , , desmethylser traline, and norfluoxetine. US 2010/008 1713 A1 Apr. 1, 2010 22

Analogs formyl or alkanoyl; R is hydrogen or C. alkyl; Rs and R. are, independently, hydrogen, hydroxyl, C. alkyl, 0132) Functional analogs of SSRIs can also be used in the Calkoxy, C. alkanoyloxy, cyano, nitro, alkylmercapto, methods, compositions, and kits of the invention. Exemplary amino, C alkylamino, dialkylamino, C alkanamido, SSRI functional analogs are provided below. One class of halo, trifluoromethyl or, taken together, methylenedioxy; and SSRI analogs includes SNRIs (selective serotonin norepi nephrine reuptake inhibitors), which include , n is 0, 1, 2, 3 or 4. dulloxetine, and 4-(2-fluorophenyl)-6-methyl-2-piperazi 0.137 nothieno 2,3-dipyrimidine. 0.138. Duloxetine has the following structure: 0.133 Venlafaxine 0134 Venlafaxine hydrochloride (EFFEXORTM) is an -CH3 antidepressant for oral administration. It is designated (R/S)- N 1-2-(dimethylamino)-1-(4-methoxyphenyl)ethylcyclohex H anol hydrochloride or (t)-1-(alpha)-(dimethyl-amino)me thyl-p-methoxybenzylcyclohexanol hydrochloride. Compressed tablets contain Venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg. or 100 mg Venlafaxine. The recommended starting dose for Venlafaxine is 75 mg/day, administered in two or three divided doses, taken with food. Depending on tolerability and the need for further clinical effect, the dose may be increased to 150 mg/day. If desirable, the dose can be further increased up to 0.139 Structural analogs of dulloxetine are those com 225 mg/day. When increasing the dose, increments of up to 75 pounds described by the formula disclosed in U.S. Pat. No. mg/day are typically made at intervals of no less than four 4.956.388, hereby incorporated by reference. days. 0140. Other SSRI analogs are 4-(2-fluorophenyl)-6-me thyl-2-piperazinothieno 2,3-dipyrimidine, 1,2,3,4-tetrahy 0135 Venlafaxine has the following structure: dro-N-methyl-4-phenyl-1-naphthylamine hydrochloride: 1,2,3,4-tetrahydro-N-methyl-4-phenyl-(E)-1-naphthylamine hydrochloride: N,N-dimethyl-1-phenyl-1-phthalanpropy CH3 lamine hydrochloride; gamma-(4-(trifluoromethyl)phe noxy)-benzenepropanamine hydrochloride; BP 554. CP Neil, 53261; 0-desmethylvenlafaxine: WY 45,818: WY 45,881: OH N-(3-fluoropropyl)paroxetine: Lu 19005; and SNRIs described in PCT Publication No. WO 04/004734.

H3CO SSRI Standard Recommended Dosages 0141 Standard recommended dosages for exemplary SSRIs are provided in Table 4, below. Other standard dosages 0.136 Structural analogs of Venlafaxine are those com are provided, e.g., in the Merck Manual of Diagnosis & pounds having the formula: Therapy (17th Ed. MH Beers et al., Merck & Co.) and Phy sicians’ Desk Reference 2003 (57" Ed. Medical Economics Staffet al., Medical Economics Co., 2002). R TABLE 4 N 2 A Compound Standard Dose N R3 Fluoxetine 20-80 mg/day Sertraline 50-200 mg/day Paroxetine 20-50 mg/day R-t 2 Fluvoxamine 50-300 mg/day A Citalopram 10-80 mg qid Escitalopram 10 mg did as well as pharmaceutically acceptable salts thereof, wherein A is a moiety of the formula: 0142. In some embodiments of the invention, it may be desirable to administer SSRIs at doses higher or lower than a standard dosing. For example, Sertraline may be administered at doses 100%, 200%, 500%, or 1000% fold greater than a dose falling with the range of the standard doses. (CH2)n O (CH)n 0143. In certain embodiments, a corticosteroid can be used in the compositions, methods, and kits of the invention. where the dotted line represents optional unsaturation; R is Corticosteroids include prednisolone, budesonide, and any of hydrogen oralkyl, R is Calkyl; R is hydrogen, Calkyl, those described herein. US 2010/008 1713 A1 Apr. 1, 2010

0144) Prednisolone 0151. Other Corticosteroids (0145 Prednisolone has the following structure: 0152. Other corticosteroids that may be used in the com positions, methods, and kits of the invention include 11-al

pha,17-alpha,21-trihydroxypregn-4-ene-320-dione; 11-beta, 16-alpha, 17.21-tetrahydroxypregn-4-ene-320-di one; 11-beta, 16-alpha, 17.21-tetrahydroxypregn-1,4-diene-3, 20-dione; 11-beta, 17-alpha,21-trihydroxy-6-alpha-methyl pregn-4-ene-3,20-dione; 11-dehydrocorticosterone: 11-deoxycortisol; 11-hydroxy-1,4-androstadiene-3,17-di one; 11-ketotestosterone; 14-hydroxyandrost-4-ene-3,6,17 trione; 15,17-dihydroxyprogesterone; 16-methylhydrocorti O sone; 17,21-dihydroxy-16-alpha-methylpregna-1,4,9(11)- triene-3,20-dione; 17-alpha-hydroxypregn-4-ene-320 dione; 17-alpha-hydroxypregnenolone; 17-hydroxy-16-beta 014.6 Analogs of prednisolone are described in U.S. Pat. methyl-5-beta-pregn-9(11)-ene-320-dione; 17-hydroxy-4,6, No. 3,134,718 and have the formula: 8(14)-pregnatriene-320-dione; 17-hydroxypregna-4,9011)- diene-320-dione; 18-hydroxycorticosterone:

18-hydroxycortisone; 18-oxocortisol; 21-acetoxypreg nenolone; 21-deoxyaldosterone; 21-deoxycortisone; 2-deoxyecdysone; 2-methylcortisone; 3-dehydroecdysone; 4-pregnene-17-alpha,20-beta,21-triol-3,11-dione: 6,17.20 trihydroxypregn-4-ene-3-one; 6-alpha-hydroxycortisol; 6-alpha-fluoroprednisolone, 6-alpha-methylprednisolone, 6-alpha-methylprednisolone 21-acetate, 6-alpha-methyl prednisolone 21-hemisuccinate sodium salt, 6-beta-hydroxy cortisol, 6-alpha, 9-alpha-difluoroprednisolone 21-acetate O 17-butyrate, 6-hydroxycorticosterone: 6-hydroxydexam ethasone; 6-hydroxyprednisolone; 9-fluorocortisone; 0147 where R is selected from the group of hydrogen and alclomethasone dipropionate; aldosterone; algestone; alpha lower alkanoyl. derm; amadinone; amcinonide; anagestone; androstenedi 0148 Budesonide one; anecortave acetate; beclomethasone; beclomethasone 0149 Budesonide has the following structure: dipropionate; 17-Valerate; betamethasone Sodium acetate; betamethasone sodium phosphate: betamethasone Valerate; bolasterone; calusterone; chlorma dinone; chloroprednisone; chloroprednisone acetate; choles terol, ; clobetasol, clobetasol propionate; clobeta Sone; clocortolone; clocortolone pivalate; clogestone; cloprednol; corticosterone; cortisol; cortisol acetate; cortisol butyrate; cortisol cypionate; cortisol octanoate; cortisol Sodium phosphate; cortisol Sodium Succinate; cortisol Valer ate; cortisone; cortisone acetate; cortivaZol; cortodoxone; O daturaolone; deflazacort, 21-deoxycortisol, dehydroepi 0150 Structural analogs of budesonide are those com ; delmadinone; deoxycorticosterone; depro pounds having the formula: done; descinolone; desonide; desoximethasone; dexafen;

; dexamethasone 21-acetate; dexamethasone acetate; dexamethasone sodium phosphate; dichlorisone; diflorasone; diflorasone diacetate; diflucortolone; diflupred nate; dihydroelatericina; domoprednate: doxibetasol, ecdys one; ecdysterone; emoXolone; endry Sone; enoXolone; fluaza cort, flucinolone; flucloronide; fludrocortisone; fludrocortisone acetate; flugestone; flumethasone; flumetha sone pivalate; flumoxonide; ; fluocinolone; fluoci nolone acetonide; fluocinonide; fluocortin butyl; 9-fluorocor tisone; fluocortolone; fluorohydroxyandrostenedione; fluorometholone; fluorometholone acetate; fluoxymesterone: fluperolone acetate; fluprednidene; fluprednisolone; fluran where X and Y are independently selected from hydrogen and drenolide; fluticasone; ; formebolone; fluorine, X being selected from hydrogen and fluorine when Y formestane; formocortal: gestonorone; glyderinine; halcino is hydrogen and X being fluorine when Y is fluorine, Z is nide; halobetasol propionate; halometasone; halopredone; selected from hydroxyl and esterified hydroxyl preferably haloprogesterone; hydrocortamate; hydrocortiosone cypi containing a maximum of 12 carbon atoms, if any, in the onate; ; hydrocortisone 21-butyrate; hydro esterifying group, R is selected from Straight and branched cortisone aceponate; hydrocortisone acetate; hydrocortisone hydrocarbon chains having 2-10 and preferably 2-6 carbon buteprate; hydrocortisone butyrate; hydrocortisone cypi atoms. Analogs are described in U.S. Pat. No. 3,929,768. onate; hydrocortisone hemisuccinate; hydrocortisone probu US 2010/008 1713 A1 Apr. 1, 2010 24 tate; hydrocortisone sodium phosphate; hydrocortisone Sodium Succinate; hydrocortisone Valerate; hydroxyprogest -continued erone; inokosterone; isoflupredone; isoflupredone acetate; (II) isoprednidene; loteprednoletabonate; meclorisone; mecorto X X lon; medrogestone; medroxyprogesterone; medrysone; X Y. X megestrol; megestrol acetate; melengestrol; meprednisone; methandrostenolone; methylprednisolone; methylpredniso lone aceponate; methylprednisolone acetate; methylpred X X nisolone hemisuccinate; methylprednisolone sodium Succi X A X n nate; methyltestosterone; metribolone; (analogs N(B) described in U.S. Pat. No. 4,472.393); mometasone furoate: (III) mometasone furoate monohydrate; nisone; nomegestrol; X X norgestomet; norvinisterone; oxymesterone; paramethasone; X paramethasone acetate; ponasterone; prednicarbate; pred nisolamate; prednisolone 21-diethylaminoacetate; predniso X D lone 21-hemisuccinate; prednisolone acetate; prednisolone X farnesylate; prednisolone hemisuccinate; prednisolone-21 (beta-D-glucuronide); prednisolone metasulphobenzoate; X N2 X prednisolone sodium phosphate; prednisolone steaglate; prednisolone tebutate; prednisolone tetrahydrophthalate: prednisone; prednival; prednylidene; pregnenolone; procino X ( N nide; tralonide; ; ; rhapontister V one; rimexolone; roxibolone; rubrosterone; stizophyllin; B ; topterone; ; triamcinolone (IV) acetonide; 21-palmitate; triamcino X X lone benetonide; triamcinolone diacetate; triamcinolone hexacetonide; trimegestone; turkesterone; and wortmannin or derivatives thereof (see, e.g., U.S. Pat. No. 7,081,475). X CIC O X 0153 Steroid Receptor Modulators X X 0154 Steroid receptor modulators (e.g., antagonists and X A X agonists) may be used as a Substitute for or in addition to a n corticosteroid in the compositions, methods, and kits of the N(B) invention. wherein each X is, independently, H, Cl, F, Br, I, CH, CF, 0155 Glucocorticoid receptor modulators that may used OH, OCH, CHCH, or OCHCH;Y is CH, O, NH, S(O) in the compositions, methods, and kits of the invention o, (CH), (CH), CHO, CHNH, CHN, or CHS; Z is C or include compounds described in U.S. Pat. Nos. 6,380.207, S; A is a branched or unbranched, saturated or mono-unsat 6,380,223, 6,448,405, 6,506,766, and 6,570,020, U.S. Pat. urated hydrocarbon chain having between 3 and 6 carbons, Application Publication Nos. 2003/0176478, 2003/0171585, inclusive; each B is, independently, H., Cl, F, Br, I, CX, 2003/0120081, 2003/0073703, 2002/015631, 2002/ CHCH, OCX, or OCXCX; and D is CH, O, NH, S(O) O-2 0147336, 2002/0107235, 2002/0103217, and 2001/0041802, 0157. In preferred embodiments, each X is, indepen and PCT Publication No. WO 00/66522, each of which is dently, H., Cl, or F: Y is (CH), Z is C; A is (CH); and each hereby incorporated by reference. Other steroid receptor B is, independently, H., Cl, or F. modulators may also be used in the methods, compositions, 0158 Exemplary tricyclic are mapro and kits of the invention are described in U.S. Pat. Nos. tiline, amoxapine, 8-hydroxyamoxapine, 7-hydroxyamoxap 6,093,821, 6,121,450, 5,994,544, 5,696,133, 5,696, 127, ine, loxapine, loxapine Succinate, loxapine hydrochloride, 5,693,647, 5,693,646, 5,688,810, 5,688,808, and 5,696,130, 8-hydroxyloxapine, amitriptyline, , doxepin, each of which is hereby incorporated by reference. imipramine, trimipramine, desipramine, nortriptyline, and protriptyline. Tricyclic Antidepressants 0159. Amoxapine 0160 In certain embodiments, amoxapine or an amoxap 0156 Tricyclic antidepressants include compounds hav ine analog can be used in the compositions, methods, and kits ing one of the formulas (I), (II), (III), or (IV): of the invention. Amoxapine has the structure:

(I)

(N ) NS C US 2010/008 1713 A1 Apr. 1, 2010

0161 Amoxapine analogs include 8-hydroxyamoxapine, where R is hydrogen or a cyano radical; R is hydrogen oran 7-hydroxyamoxapine, loxapine, loxapine Succinate, loxapine alkyl or alkenyl radical having up to 6 carbons, either straight hydrochloride, 8-hydroxyloxapine, clothiapine, , or branched chain, or cycloalkyl having up to 8 carbons or , and dibenz(b.f)(1,4)oxazepine, 2-chloro-1 1-(4- aralkyl groups such as benzyl, Y is hydrogen or halogen, methyl-1-piperazinyl)-, monohydrochloride, N-acetylamox preferably bromine or chlorine; X and X’ are similar or dis apine, N-formyl-7-hydroxyamoxapine, and carboxymethyl similar and are selected from hydrogen, an alkyl group having ester-amoxapine (CME-amoxapine). CME-amoxapine has up to 6 carbon atoms, an alkenyl group having up to 6 carbon atoms, a perfluoroalkyl group having up to 4 carbon atoms, a the structure: phenyl or a Substituted phenyl radical, an acyl group having up to 4 carbon atoms, a perfluoroacyl group having up to 4 carbon atoms, amino, an alkylamino group having up to 4 carbon atoms, a dialkylamino group having up to 8 carbon atoms, an acylamino group having up to 4 carbon atoms, a perfluoroacylamino group having up to 4 carbon atoms, an alkylsulfonylamino group having up to 4 carbonatoms, halo gen (fluorine, chlorine, bromine or iodine), hydroxyl, an alkoxyl group having up to 4 carbon atoms, a perfluoro alkoxyl group having up to 4 carbon atoms, cyano, carboxy, carbamoyl, an alkylcarbamoyl group having up to 5 carbon C atoms, a dialkylcarbamoyl group having up to 9 carbon atoms, a carbalkoxy group having up to 6 carbon atoms, mercapto, an alkylmercapto group having up to 4 carbon atoms, a perfluoroalkylmercapto group having up to 4 carbon atoms, an alkylsulfonyl group having up to 4 carbon atoms, a Analogs of CME-amoxapine are described in U.S. Pat. No. perfluoroalkylsulfonyl group having up to 4 carbon atoms, 5,344,828. Sulfamoyl, an alkylsulfamoyl group having up to 4 carbon Nortriptyline atoms, or a dialkylsulfamoyl group having up to 8 carbon (0162 atoms. More than one of these substituents may be on each 0163. In certain embodiments, nortriptyline or a nortrip benzenoid ring. The compounds may have substituents on the tyline analog can be used in the compositions, methods, and propyl or propylidene chain Such as lower alkyl radicals, kits of the invention. Nortriptyline has the structure: preferably having from 1 to 4 carbon atoms. 0.165 Nortriptyline analogs include 10-hydroxynortrip tyline, 10-oxonortriptyline, desmethylnortriptyline, and . Bufexamac (0166 In certain embodiments, bufexamac or a bufexamac analog can be used in the compositions, methods, and kits of the invention. By "bufexamac analog is meant a compound N having the formula (VI):

0164. Nortriptyline analogs are described in U.S. Pat. No. 3,922,305 and have the structures:

R2 R3

wherein R' is

and

wherein R'' is and R' is H. halo, CF, optionally substituted Calkyl, optionally Substituted Coalkenyl, optionally Sub stituted C- alkynyl, optionally substituted Cls cycloalkyl, optionally Substituted C. alkoxy, or optionally Substituted C, thioalkoxy; each of RandR is, independently, H, C, a alkyl, or CF; and R is optionally substituted C. alkyl or optionally Substituted Cls cycloalkyl. US 2010/008 1713 A1 Apr. 1, 2010 26

Tetra-Substituted Pyrimidopyrimidines embodiment, each Z is the same moiety, each Z is the same moiety, and Z and Z are different moieties. 0167. In certain embodiments, a tetra-substituted pyrimi 0171 Tetra-substituted pyrimidopyrimidines that are use dopyrimidine can be used in the compositions, methods, and ful in the methods, compositions, and kits of this invention kits of the invention. include 2,6-disubstituted 4,8-dibenzylaminopyrimido 5,4-d pyrimidines. Particularly useful tetra-substituted pyrimi 0168 Tetra-substituted pyrimidopyrimidines have the for dopyrimidines include dipyridamole (also known as 2,6-bis mula (V): (diethanolamino)-4,8-dipiperidinopyrimido(5,4-d) pyrimidine); mopidamole; dipyridamole monoacetate; NU3026 (2,6-di-(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxy (V) 4,8-di-piperidinopyrimidopyrimidine); NU3059 (2,6-bis-(2, 3-dimethyoxypropoxy)-4,8-di-piperidinopyrimidopyrimi dine); NU3060 (2,6-bisN,N-di(2-methoxy)ethyl-4,6-di piperidinopyrimidopyrimidine); and NU3076 (2,6-bis (diethanolamino)-4,8-di-4- methoxybenzylaminopyrimidopyrimidine). Other tetra substituted pyrimidopyrimidines are described in U.S. Pat. Nos. 3,031,450 and 4,963,541. The standard recommended Y(R), dosage for dipyridamole is 300-400 mg/day. Ibudilast 0.172. In certain embodiments, ibudilast or an ibudilast 0169 wherein each Z and each Z is, independently, N, O, analog, as defined by formula below, may be used in the compositions, methods, and kits of the invention. 1N-N R3 N-N R X-R

In this formula, R and R are each, independently, selected -O from H. C., alkyl, C-, alkenyl, C-, alkynyl, Cheterocy clyl, Caryl, Cza alkaryl, Coalkheterocyclyl, and C-7 heteroalkyl; R is selected from H. halide, alkoxy, and Ca (0170 When Z or Z is O or alkyl: X is selected from C=O, C=N NH-R, C=C (Rs)—C(O)—R, C=CH=CH-C(O)—R, and C(OH)— R; R is selected from H and acyl: Rs is selected from H. O halide, and C alkyl, R is selected from OH, alkoxy and amido; and R, is selected from H. C., alkyl, C-, alkenyl, -S- s C2-7 alkynyl, C2-sheterocyclyl, Cs-12aryl, C7-14 alkaryl, Cso O alkheterocyclyl, and C-7 heteroalkyl. 0173 Compounds of formula (VI) include, the com pounds described in U.S. Pat. Nos. 3,850,941; 4,097.483: 4,578,392: 4,925,849: 4,994,453; and 5,296.490. Commer cially available compounds of formula (VI) include ibudilast and KC-764. 0.174. The standard recommended dosage for the treat ment of bronchial asthma is typically 10 mg of ibudilast twice daily, while in the case of cerebrovascular disorders, the stan dard recommended dosage is 10 mg of ibudilast three times daily. The structure of ibudilast is shown below:

then p=2, and when Z or Z is C, then p=3. In formula (V), each R, is, independently, X, OH, N-alkyl (wherein the alkyl group has 1 to 20, more preferably 1-5, carbon atoms); a branched or unbranched alkyl group having 1 to 20, more preferably 1-5, carbon atoms; or a heterocycle, preferably as defined in formula (Y), below. Alternatively, when p>1, two R groups from a common Z or Zatom, in combination with each other, may represent—(CY) - in which kis an integer between 4 and 6, inclusive. Each X is, independently, Y. CY, C(CY), CYCY. (CY)-OY, substituted or unsubstituted Ibudilast cycloalkane of the structure C.Y., wherein in 3-7, inclu sive. Each Y is, independently, H. F. Cl, Br, or I. In one US 2010/008 1713 A1 Apr. 1, 2010 27

(0175 KC-764 (CAS94457-09-7) is reported to be a plate difumarate); epinastine; hydrochloride; fex let aggregation inhibitor. The structure of KC-764 is shown ofenadine (e.g., hydrochloride); histapyrrod below: ine; hydroxy Zine (e.g., hydroxy Zine hydrochloride; hydrox yZine pamoate); ; ;

(e.g., levocabastine hydrochloride); mebhy droline; meduitazine; methafurylene; ; met ron; , olapatadine (e.g., hydrochlo ride); ; (e.g., phenindamine tartrate); ; ; p-methyldiphen hydramine; ; ; ; ; ; thiazinamium (e.g., thiazinamium methylsul KC-764 fate); hydrochloride; ; triproli dine; and . KC-764 and other compounds of formula (VI) can be pre 0186 Antihistamine analogs may also be used in the com pared using the synthetic methods described in U.S. Pat. Nos. positions, methods, and kits of the invention. Antihistamine 3,850,941; 4,097483; 4,578,392: 4,925,849: 4,994,453; and analogs include 10-piperazinylpropylphenothiazine: 4-(3-(2- 5,296,490. chlorophenothiazin-10-yl)propyl)-1-piperazineethanol dihy drochloride: 1-(10-(3-(4-methyl-1-piperazinyl)propyl)-10H phenothiazin-2-yl)-(9CI) 1-propanone; 0176). In certain embodiments, an antihistamine oran anti 3-methoxycyproheptadine: 4-(3-(2-Chloro-1 OH-phenothi histamine analog can be used in the compositions, methods, azin-10-yl)propyl)-1-ethanol hydrochloride: and kits of the invention. Antihistamines are compounds that 10, 11-dihydro-5-(3-(4-ethoxycarbonyl-4-phenylpiperidino) block the action of histamine. Classes of antihistamines propylidene)-5H-dibenzo(a,d)cycloheptene; include: aceprometazine; ; alimemazin (e.g., alime 0177 (1) Ethanolamines (e.g., bromodiphenhydramine, mazin hydrochloride); aminopromazine; ; , , , diphenhy ; ; chlorfenethazine; chlormidazole; dramine, , and ); cinprazole; desmethylastemizole; desmethylcyproheptadine; 0.178 (2) (e.g., pheniramine, pyril diethazine (e.g., diethazine hydrochloride); ethopropazine amine, , and ); (e.g., ethopropazine hydrochloride); 2-(p-bromophenyl-(p'- 0179 (3) (e.g., diethazine, ethopropazine, tolyl)methoxy)-N,N-dimethyl-ethylamine hydrochloride; , , , and trimepra N,N-dimethyl-2-(diphenylmethoxy)-ethylamine methylbro Zine); mide: EX-10-542A; ; fuprazole; methyl 10-(3-(4- 0180 (4) Alkylamines (e.g., , bromphe methyl-1-piperazinyl)propyl)phenothiazin-2-yl ketone; niramine, chlorpheniramine, desbrompheniramine, dexchlo ; ; ; methylpromazine; rpheniramine, pyrrobutamine, and triprolidine); N-desmethylpromethazine; nilprazole; northioridazine; per 0181 (5) (e.g., , , chlorcy phenazine (e.g., enanthate); 1043-dimethy clizine, , , hydroxy Zine); laminopropyl)-2-methylthio-: 4-(dibenzo(b.e) 0182 (6) Piperidines (e.g., , , cypro thiepin-6(11H)-ylidene)-1-methyl-piperidine hydrochloride; heptadine, , fexofenadine, , , ; ; (e.g., propiom olopatadine, phenindamine, and terfenadine); azine hydrochloride); rotoxamine; ; SCH 37370; 0183 (7) Atypical antihistamines (e.g., , levo SCH 434; tecastemizole; thiazinamium; ; thior cabastine, methapyrilene, and phenyltoxamine). idazine (e.g., hydrochloride); and 3-(10,11-dihy 0184. In the compositions, methods, and kits of the inven dro-5H-dibenzo(a,d)cyclohepten-5-ylidene)-. tion, both non-sedating and sedating antihistamines may be 0187. Other compounds that are suitable for use in the employed. Non-sedating antihistamines include loratadine invention are AD-0261; AHR-5333; allinastine; arpromidine: and desloratadine. Sedating antihistamines include azata ATI-19000; bermastine; bilastin; Bron-12; carebastine; chlo dine, bromodiphenhydramine; chlorpheniramine; ; rphenamine; clofurenadine; corsym: DF-1 105501; ; dimenhydrinate; : doxy DF-1 1062: DF-111 1301; EL-301; elbanizine; F-7946T: lamine; meclizine; promethazine; pyrilamine; thiethylpera F-9505; HE-90481; HE-90512; hivenyl; HSR-609; icotidine: Zine; and tripelennamine. KAA-276; KY-234; lamiakast, LAS-36509; LAS-36674; 0185. Other antihistamines suitable for use in the compo ; levoprotiline; : NIP-531; sitions, methods, and kits of the invention are acrivastine; noberastine; : PR-881-884A; quisultazine; rocas ahistan; ; astemizole; azelastine (e.g., azelsatine tine; selenotifen; SK&F-94461; SODAS-HC; tagorizine; hydrochloride); ; ; benztropine, biet TAK-427; temelastine; UCB-34742; UCB-35440; VUF-K- anautine; (e.g., brompheniramine male 8707; Wy-49051; and ZCR-2060. ate); carbinoxamine (e.g., carbinoxamine maleate); cetirizine 0188 Still other compounds that are suitable for use in the (e.g., cetirizine hydrochloride); cetoxime; chlorocyclizine; invention are described in U.S. Pat. Nos. 2,595,405, 2,709, ; ; ; cinnariz 169, 2,785,202, 2,899,436, 3,014,911, 3,813,384, 3,956,296, ine; clemastine (e.g., clemastine fumarate); , 4,254,129, 4,254,130, 4,282,833, 4,283,408, 4.362,736, ; ; cyclizine (e.g., cyclizine hydro 4,394,508, 4,285,957, 4,285,958, 4,440,933, 4,510,309, chloride; cyclizine lactate); ; dexchlorphe 4,550,116, 4,659,716, 4,692,456, 4,742,175, 4,833,138, niramine; maleate; diphenylpyraline; 4,908,372, 5,204.249, 5,375,693, 5,578,610, 5,581,011, doxepin; ; ; (e.g., emedastine 5,589.487, 5,663,412, 5,994,549, 6,201,124, and 6,458,958. US 2010/008 1713 A1 Apr. 1, 2010 28

(0189 Epinastine 0.195 Analogs of desloratadine are described in U.S. Pat. 0190. In certain embodiments, epinastine or an analog No. 4,659,716 and have the structure: thereof is used in the compositions, methods, and kits of the H invention. N (0191) Epinastine has the formula:

NS COO X \ Z N where X and Y independently represent H, halo (i.e., fluoro, HN -& N chloro, bromo or iodo), or trifluoromethyl with the proviso that at least one of X and Y is halo or trifluoromethyl. Pre ferred compounds include those where X is F and Y is H or 0.192 Analogs of epinastine, which are described in U.S. where X is C1 and Y is H. Pat. No. 4.313,931, have the following structure. 0196. Related compounds include loratadine, 3-hydroxy desloratadine, des(ethoxycarbonyl)loratadine, and SCH 434. Loratadine functional and/or structural analogs include other R2 f H1-receptor antagonists, such as AHR-1 1325, acrivastine, R-f e X NisY-R, antazoline, astemizole, azatadine, azelastine, bromophe niramine, carebastine, cetirizine, chlorpheniramine, chlorcy N 2 clizine, clemastine, cyproheptadine, descarboethoxylorata N dine, dexchlorpheniramine, dimenhydrinate, diphenylpyraline, diphenhydramine, ebastine, fexofenadine, -R6N -SN hydroxy Zine ketotifen, , levocabastine, methdila / Zine, meduitazine, oxatomide, pheniramine pyrilamine, promethazine, pyrilamine, setastine, tazifylline, temelastine, terfenadine, trimeprazine, tripelennamine, triprolidine, utriz where R. R. R. and Ra, which may be the same or different, ine, and similar compounds (described, e.g., in U.S. Pat. Nos. each represent a hydrogen or halogen atom or an alkyl or 3,956,296, 4,254,129, 4,254,130, 4,283,408, 4,362,736, 4,394,508, 4,285,957, 4,285,958, 4,440,933, 4,510,309, alkoxy group of from 1 to 6 carbon atoms; Rs and R, which 4,550,116, 4,692,456, 4,742,175, 4,908,372, 5,204.249, may be the same or different, each representahydrogenatom, 5,375,693, 5,578,610, 5,581,011, 5,589.487, 5,663,412, an alkyl group of from 1 to 6 carbon atoms, or an alkenyl 5,994,549, 6,201,124, and 6,458,958). group of from 3 to 6 carbonatoms, or Rs and R together with 0.197 Loratadine, cetirizine, and fexofenadine are second the nitrogen atom to which they are attached represent a generation H1-receptor antagonists that lack the sedating pyrrolidino, piperidino, or morpholino group; and X repre effects of many first generation H1-receptor antagonists. Pip sents oxygen, Sulfur, or a methylene group, and non-toxic, eridine H1-receptor antagonists include loratadine, cypro pharmacologically acceptable acid addition salts thereof. heptadine hydrochloride (PERIACTIN), and phenindiamine These analogs can occuras racemates or as pure enantiomers, tartrate (NOLAHIST). piperazine H1-receptor antagonists or as mixtures with various portions of the enantiomers, each include hydrochloride (ATARAX), hydrox in form of the free bases or the acid addition salts. yzine pamoate (VISTARIL), cyclizine hydrochloride (MAREZINE), cyclizine lactate, and meclizine hydrochlo 0193 Desloratadine ride. 0194 In certain embodiments, desloratadine or a deslora 0198 The structure of loratadine is: tadine analog can be used in the compositions, methods, and kits of the invention. The structure of desloratadine is:

C A / C A / US 2010/008 1713 A1 Apr. 1, 2010 29

(0199 Analogs ofloratadine are described in U.S. Pat. No. cyclosporine, tacrolimus, ascomycin, pimecrolimus, as well 4,282,233 and have the structure: as other agents (peptides, peptide fragments, chemically modified peptides, or peptide mimetics) that inhibit the phos phatase activity of calcineurin. NSIDIs also include rapamy cin (sirolimus) and everolimus, which bind to an FK506 binding protein, FKBP-12, and block antigen-induced proliferation of white blood cells and cytokine secretion. 0204 Cyclosporines 0205 The cyclosporines are fungal metabolites that com prise a class of cyclic oligopeptides that act as immunosup pressants. Cyclosporine A is a hydrophobic cyclic polypep tide consisting of eleven amino acids. It binds and forms a complex with the intracellular receptor cyclophilin. The cyclosporine/cyclophilin complex binds to and inhibits cal cineurin, a Ca"-calmodulin-dependent serine-threonine where the dotted line represents an optional double bond and specific protein phosphatase. Calcineurin mediates signal wherein the numbering system used herein is illustrated. In transduction events required for T-cell activation (reviewed in this formula, X is hydrogen or halo and Y is substituted Schreiber et al., Cell 70:365-368, 1991). Cyclosporines and carboxylate or substituted sulfonyl for example Y is COOR their functional and structural analogs Suppress the T cell or SOR, with the proviso that when Y is —COOR, R is C to dependent immune response by inhibiting antigen-triggered C alkyl, Substituted C to C2 alkyl, phenyl, Substituted signal transduction. This inhibition decreases the expression phenyl, C7 to C phenylalkyl, C7 to C phenylalkyl wherein of proinflammatory cytokines, such as IL-2. the phenyl moiety is substituted or R is -2, -3, or -4 piperidyl 0206. Many different cyclosporines (e.g., cyclosporine A, or N-substituted piperidyl wherein the substituents on said B, C, D, E, F, G, H, and I) are produced by fungi. Cyclospo Substituted C to C2 alkyl are selected from amino or Substi rine A is a commercially available under the trade name tuted amino and the Substituents on said Substituted amino are NEORAL from Novartis. Cyclosporine A structural and selected from C to Calkyl, the substituents on said substi functional analogs include cyclosporines having one or more tuted phenyl and on said substituted phenyl moiety of the C7 fluorinated amino acids (described, e.g., in U.S. Pat. No. to C phenylalkyl are selected from C to C alkyl and halo, 5.227.467); cyclosporines having modified amino acids (de and the substituent on said N-substituted piperidyl is C to Ca scribed, e.g., in U.S. Pat. Nos. 5,122,511 and 4.798,823); and alkyl; and with the proviso that whenY is SOR, R is C to C. deuterated cyclosporines, such as ISAtx247 (described in alkyl, phenyl, Substituted phenyl, C, to C phenylalkyl, C7 to U.S. Pat. Application Publication No. 2002/0132763 A1). C phenyl alkyl wherein the phenyl moiety is substituted, Additional cyclosporine analogs are described in U.S. Pat. wherein the substituents on said substituted phenyl and said Nos. 6,136,357, 4,384,996, 5,284.826, and 5,709,797. substituted phenyl moiety of the C7 to C phenylalkyl are Cyclosporine analogs include, but are not limited to, D-Sar selected from C to C alkyl and halo. (C-SMe) Val-DH-Cs (209-825), Allo-Thr-2-Cs, Norvaline (0200. In a preferred embodiment, Y is -COOR and R is 2-Cs, D-Ala(3-acetylamino)-8-Cs. Thr-2-Cs, and D-MeSer C to Calkylor substituted alkyl, phenyl, substituted phenyl, 3-Cs, D-Ser(O CHCH -OH)-8-Cs, and D-Ser-8-Cs, C, to Caralkyl or substituted aralkyl or -2, -3 or -4 piperidyl which are described in Cruz et al. (Antimicrob. Agents or N-substituted piperidyl. When R is substituted alkyl, R is Chemother. 44:143-149, 2000). substituted with amino or with substituted amino. The sub 0207 Tacrolimus stituents on the substituted amino are C to C alkyl. The 0208 Tacrolimus and tacrolimus analogs are described by substituents on the aforementioned substituted phenyl and on Tanaka et al., (J. Am. Chem. Soc., 109:5031, 1987) and in the phenyl moiety of the substituted aralkyl are preferably C U.S. Pat. Nos. 4,894,366, 4,929,611, and 4,956,352. FK506 to C alkyl or halo. related compounds, including FR-900520, FR-900523, and 0201 In a second preferred embodiment of the present FR-900525, are described in U.S. Pat. No. 5.254.562; O-aryl, invention, Y is SOR and R is C to C alkyl, phenyl, substi O-alkyl, O-alkenyl, and O-alkynylmacrollides are described tuted phenyl, C, to Caralkyl or substituted aralkyl, wherein in U.S. Pat. Nos. 5,250,678, 532,248, 5,693,648; amino the substituents on said substituted phenyl and on the phenyl O-aryl macrollides are described in U.S. Pat. No. 5,262,533; moiety of the substituted aralkyl are C to C alkyl or halo. alkylidene macrollides are described in U.S. Pat. No. 5.284, 0202 The aforementioned alkyl groups may be linear, 840; N-heteroaryl, N-alkylheteroaryl, N-alkenylheteroaryl, branched or cyclic or may contain both cyclic and linear or and N-alkynylheteroaryl macrollides are described in U.S. cyclic and branched moieties. Halo may be fluoro, chloro, Pat. No. 5,208,241; aminomacrollides and derivatives thereof bromo or iodo. are described in U.S. Pat. No. 5,208,228; fluoromacrollides are described in U.S. Pat. No. 5,189,042; amino O-alkyl, Nonsteroidal Immunophilin-Dependent Immunosuppressant O-alkenyl, and O-alkynylmacrollides are described in U.S. 0203. In certain embodiments, a non-steroidal immuno Pat. No. 5,162.334; and halomacrollides are described in U.S. philin-dependent immunosuppressant (NSIDI) is used in the Pat. No. 5,143,918. compositions, methods, or kits of the invention. Non-steroi 0209 Tacrolimus is extensively metabolized by the dal agents that decreases proinflammatory cytokine produc mixed-function oxidase system, in particular, by the cyto tion or secretion, binds an immunophilin, or causes a down chrome P-450 system. The primary mechanism of metabo regulation of the proinflammatory reaction can be used in the lism is demethylation and hydroxylation. While various tac invention. Ns|IDIs include calcineurin inhibitors, such as rolimus metabolites are likely to exhibit immunosuppressive US 2010/008 1713 A1 Apr. 1, 2010 30 biological activity, the 13-demethyl metabolite is reported to controlled by the design of linker (L) and the covalent bonds have the same activity as tacrolimus. formed with drug (A) and drug (B) during the synthesis of the 0210 Pimecrolimus conjugate. 0211 Pimecrolimus is the 33-epi-chloro derivative of the 0221 Conjugates can be prepared using techniques famil macrolactam ascomyin. Pimecrolimus structural and func tional analogs are described in U.S. Pat. No. 6,384,073. iar to those skilled in the art. For example, the conjugates can 0212 Rapamycin be prepared using the methods disclosed in G. Hermanson, 0213 Rapamycin structural and functional analogs Bioconjugate Techniques, Academic Press, Inc., 1996. The include mono- and diacylated rapamycin derivatives (U.S. synthesis of conjugates may involve the selective protection Pat. No. 4.316,885); rapamycin water-soluble (U.S. and deprotection of , amines, ketones, sulfhydryls or Pat. No. 4,650,803); carboxylic acid esters (PCT Publication carboxyl functional groups of drug (A), the linker, and/or No. WO92/05179); carbamates (U.S. Pat. No. 5,118,678); drug (B). For example, commonly used protecting groups for amide esters (U.S. Pat. No. 5,118,678); biotin esters (U.S. amines include carbamates, such as tent-butyl, benzyl, 2.2.2- Pat. No. 5,504,091); fluorinated esters (U.S. Pat. No. 5,100, trichloroethyl 2-trimethylsilylethyl, 9-fluorenylmethyl, 883); acetals (U.S. Pat. No. 5,151,413); silyl ethers (U.S. Pat. allyl, and m-nitrophenyl. Other commonly used protecting No. 5,120,842); bicyclic derivatives (U.S. Pat. No. 5,120, groups for amines include amides, such as formamides, 725); rapamycin dimers (U.S. Pat. No. 5,120,727); O-aryl, acetamides, trifluoroacetamides, Sulfonamides, trifluo O-alkyl, O-alkyenyl and O-alkynyl derivatives (U.S. Pat. No. romethanesulfonyl amides, trimethylsilylethanesulfona 5,258,389); and deuterated rapamycin (U.S. Pat. No. 6,503, mides, and tert-butylsulfonyl amides. Examples of com 921). Additional rapamycin analogs are described in U.S. Pat. monly used protecting groups for carboxyls include esters, Nos. 5,202,332 and 5,169,851. such as methyl, ethyl, tert-butyl, 9-fluorenylmethyl 2-(trim 0214 Peptide Moieties ethylsilyl)ethoxy methyl, benzyl, diphenylmethyl, O-ni 0215 Peptides, peptide mimetics, peptide fragments, trobenzyl, ortho-esters, and halo-esters. Examples of com either natural, synthetic or chemically modified, that impair monly used protecting groups for alcohols include ethers, the calcineurin-mediated dephosphorylation and nuclear Such as methyl, methoxymethyl, methoxyethoxymethyl, translocation of NFAT are suitable for use in practicing the methylthiomethyl, benzyloxymethyl, tetrahydropyranyl, invention. Examples of peptides that act as calcineurin inhibi ethoxyethyl, benzyl, 2-napthylmethyl, O-nitrobenzyl, P-ni tors by inhibiting the NFAT activation and the NFAT tran trobenzyl, P-methoxybenzyl, 9-phenylxanthyl, trityl (includ Scription factor are described, e.g., by Aramburu et al., Sci ing methoxy-trityls), and silyl ethers. Examples of commonly ence 285:2129-2133, 1999) and Aramburu et al., Mol. Cell. used protecting groups for sulfhydryls include many of the 1:627-637, 1998). As a class of calcineurin inhibitors, these same protecting groups used for hydroxyls. In addition, Sulf agents are useful in the methods of the invention. hydryls can be protected in a reduced form (e.g., as disulfides) oran oxidized form (e.g., as Sulfonic acids, Sulfonic esters, or Additional Antiviral Agents Sulfonic amides). Protecting groups can be chosen Such that 0216. One or more (e.g., two, three, four, five, or six) selective conditions (e.g., acidic conditions, basic conditions, additional antiviral agents can be used in the compositions, catalysis by a nucleophile, catalysis by a lewis acid, or hydro methods, and kits of the invention. Exemplary agents are genation) are required to remove each, exclusive of other those shown in Table 2. Agents useful in treating viral infec protecting groups in a molecule. The conditions required for tions such as influenza include neuraminidase inhibitors (e.g., the addition of protecting groups to amine, , Sulfhy oseltamivir and Zanamivir) and M2 ion channel inhibitors dryl, and carboxyl functionalities and the conditions required (e.g., amantadine and rimantadine). Other agents which, for for their removal are provided in detail in T. W. Green and P. example, inhibit viral replication, transcription, reverse tran G. M. Wuts, Protective Groups in Organic Synthesis (2" Scription, or viral particticle production may also be used in Ed.), John Wiley & Sons, 1991 and P.J. Kocienski, Protecting the compositions, methods and kits of the invention. Groups, Georg Thieme Verlag, 1994. Additional synthetic details are provided below. Conjugates 0217. If desired, the agents used in any of the combina Linkers tions described herein may be covalently attached to one 0222. The linker component of the invention is, at its sim another to form a conjugate of formula I. plest, a bond between drug (A) and drug (B), but typically (A)-(L)-(B) (I) provides a linear, cyclic, or branched molecular skeleton hav 0218. In formula I, (A) is an agent described herein ing pendant groups covalently linking drug (A) to drug (B). covalently tethered via a linker (L) to (B), to a second agent 0223 Thus, linking of drug (A) to drug (B) is achieved by described herein. covalent means, involving bond formation with one or more 0219 Conjugates of the invention can be administered to a functional groups located on drug (A) and drug (B). subject by any route and for the treatment of viral infection Examples of chemically reactive functional groups which (e.g., those described herein such as influenza). may be employed for this purpose include, without limitation, 0220. The conjugates of the invention can be prodrugs, amino, hydroxyl, Sulfhydryl, carboxyl, carbonyl, carbohy releasing drug (A) and drug (B) upon, for example, cleavage drate groups, vicinal diols, thioethers, 2-aminoalcohols, of the conjugate by intracellular and extracellular enzymes 2-aminothiols, guanidinyl, imidazolyl, and phenolic groups. (e.g., amidases, esterases, and phosphatases). The conjugates 0224. The covalent linking of drug (A) and drug (B) may of the invention can also be designed to largely remain intact be effected using a linker which contains reactive moieties in vivo, resisting cleavage by intracellular and extracellular capable of reaction with Such functional groups present in enzymes. The degradation of the conjugate in Vivo can be drug (A) and drug (B). For example, an amine group of drug US 2010/008 1713 A1 Apr. 1, 2010

(A) may react with a carboxyl group of the linker, or an 0243 (vi) other useful reagents foramide bond formation, activated derivative thereof, resulting in the formation of an for example, as described by M. Bodansky, Principles of amide linking the two. Peptide Synthesis, Springer-Verlag, 1984; 0225. Examples of moieties capable of reaction with sulf 0244 (vii) acylazides, e.g., wherein the azide group is hydryl groups include O.-haloacetyl compounds of the type generated from a preformed hydrazide derivative using XCHCO (where X=Br, Cl, or I), which show particular sodium nitrite, as described by Wetz et al., Anal. Biochem. reactivity for sulfhydryl groups, but which can also be used to 58:347 (1974); and modify imidazolyl, thioether, , and amino groups as 0245 (viii) imidoesters, which form stable amidines on described by Gurd, Methods Enzymol. 11:532 (1967). N-Ma reaction with amino groups, for example, as described by leimide derivatives are also considered selective towards Sulf Hunter and Ludwig, J. Am. Chem. Soc. 84:3491 (1962). hydryl groups, but may additionally be useful in coupling to 0246 Aldehydes and ketones may be reacted with amines amino groups under certain conditions. Reagents such as to form Schiff's bases, which may advantageously be stabi 2-iminothiolane (Traut et al., Biochemistry 12:3266 (1973)), lized through reductive amination. Alkoxylamino moieties which introduce a thiol group through conversion of an amino readily react with ketones and aldehydes to produce stable group, may be considered as Sulfhydryl reagents if linking alkoxamines, for example, as described by Webb et al., in occurs through the formation of disulfide bridges. Bioconjugate Chem. 1:96 (1990). 0226 Examples of reactive moieties capable of reaction 0247 Examples of reactive moieties capable of reaction with amino groups include, for example, alkylating and acy with carboxyl groups include diazo compounds Such as dia lating agents. Representative alkylating agents include: Zoacetate esters and diazoacetamides, which react with high 0227 (i) C-haloacetyl compounds, which show specificity specificity to generate ester groups, for example, as described towards amino groups in the absence of reactive thiol groups by Herriot, Adv. Protein Chem. 3:169 (1947). Carboxyl modi and are of the type XCH-CO (where X=Br, Cl, or I), for fying reagents such as carbodiimides, which react through example, as described by Wong Biochemistry 24:5337 O- formation followed by amide bond formation, (1979); may also be employed. 0228 (ii) N-maleimide derivatives, which may react with 0248. It will be appreciated that functional groups in drug amino groups either through a Michael type reaction or (A) and/or drug (B) may, if desired, be converted to other through acylation by addition to the ring carbonyl group, for functional groups prior to reaction, for example, to confer example, as described by Smyth et al., J. Am. Chem. Soc. additional reactivity or selectivity. Examples of methods use 82:4600 (1960) and Biochem. J. 91:589 (1964); ful for this purpose include conversion of amines to carboxyls 0229 (iii) aryl halides such as reactive nitrohaloaromatic using reagents such as dicarboxylic anhydrides; conversion compounds; of amines to thiols using reagents such as N-acetylhomocys 0230 (iv) alkyl halides, as described, for example, by teine thiolactone, S-acetylmercaptosuccinic anhydride, McKenzie et al., J. Protein Chem. 7:581 (1988); 2-iminothiolane, or thiol-containing Succinimidyl deriva 0231 (v) aldehydes and ketones capable of Schiff's base tives; conversion of thiols to carboxyls using reagents such as formation with amino groups, the adducts formed usually C-haloacetates; conversion of thiols to amines using reagents being stabilized through reduction to give a stable amine; Such as ethylenimine or 2-bromoethylamine; conversion of 0232 (vi) epoxide derivatives such as epichlorohydrin and carboxyls to amines using reagents such as carbodiimides bisoxiranes, which may react with amino, Sulfhydryl, or phe followed by diamines; and conversion of alcohols to thiols nolic hydroxyl groups; using reagents such as tosyl chloride followed by transesteri 0233 (vii) chlorine-containing derivatives of s-triazines, fication with thioacetate and hydrolysis to the thiol with which are very reactive towards nucleophiles such as amino, Sodium acetate. Sufhydryl, and hydroxyl groups; 0249 So-called Zero-length linkers, involving direct cova 0234 (viii) aziridines based on s-triazine compounds lent joining of a reactive chemical group of drug (A) with a detailed above, e.g., as described by Ross, J. Adv. Cancer Res. reactive chemical group of drug (B) without introducing addi 2:1 (1954), which react with nucleophiles such as amino tional linking material may, if desired, be used in accordance groups by ring opening: with the invention. 0235 (ix) squaric acid diethyl esters as described by 0250 More commonly, however, the linker will include Tietze, Chem. Ber: 124:1215 (1991); and two or more reactive moieties, as described above, connected 0236 (x) O-haloalkyl ethers, which are more reactive by a spacer element. The presence of Such a spacer permits alkylating agents than normal alkyl halides because of the bifunctional linkers to react with specific functional groups activation caused by the ether oxygen atom, as described by within drug (A) and drug (B), resulting in a covalent linkage Benneche et al., Eur: J. Med. Chem. 28:463 (1993). between the two. The reactive moieties in a linker may be the 0237 Representative amino-reactive acylating agents same (homobifunctional linker) or different (heterobifunc include: tional linker, or, where several dissimilar reactive moieties are 0238 (i) isocyanates and isothiocyanates, particularly present, heteromultifunctional linker), providing a diversity aromatic derivatives, which form stable urea and thiourea of potential reagents that may bring about covalent attach derivatives respectively; ment between drug (A) and drug (B). 0239 (ii) sulfonyl , which have been described 0251 Spacer elements in the linker typically consist of by Herzig et al., Biopolymers 2:349 (1964); linear or branched chains and may include a Coalkyl, Co 0240 (iii) acid halides; alkenyl, Co alkynyl, C2-a heterocyclyl, C-2 aryl, C7-14 0241 (iv) active esters such as nitrophenylesters or N-hy alkaryl, Coalkheterocyclyl, or Coheteroalkyl. droxysuccinimidyl esters; 0252. In some instances, the linker is described by formula 0242 (V) acid anhydrides such as mixed, symmetrical, or (II): N-carboxyanhydrides; US 2010/008 1713 A1 Apr. 1, 2010 32

(0253) Informula (II), G' is a bond between drug (A) and in the diseased tissue or organ, (v) formulations that achieve the linker; G is a bond between the linker and drug (B): Z, convenience of dosing, e.g., administering the composition Z, Z, and Zeach, independently, is selected from O, S, and once per week or once every two weeks; and (vi) formulations NR, R is hydrogen, Calkyl, Calkenyl, Calkynyl, that target the action of the agent(s) by using carriers or C2-6 heterocyclyl, C-2 aryl, C7-14 alkaryl, Cao alkhetero chemical derivatives to deliver the combination to a particular cyclyl, or C, heteroalkyl:Y' and Y are each, independently, target cell type. Administration of compound(s) in the form of selected from carbonyl, thiocarbonyl, Sulphonyl, orphospho a controlled release formulation is especially preferred for ryl: o, p, S, t, u, and V are each, independently, 0 or 1; and Rio compounds having a narrow absorption window in the gastro is a Co alkyl, Coalkenyl, Co alkynyl, C. heterocy clyl, C-2 aryl, C7-14 alkaryl, Cao alkheterocyclyl, or Co intestinal tract or a relatively short biological half-life. heteroalkyl, or a chemical bond linking G-(Z)-(Y)-(Z)- 0257 Any of a number of strategies can be pursued in to -(Z)-(Y)-(Z)-G’. order to obtain controlled release in which the rate of release 0254 Examples of homobifunctional linkers useful in the outweighs the rate of metabolism of the compound in ques preparation of conjugates of the invention include, without tion. In one example, controlled release is obtained by appro limitation, diamines and diols selected from ethylenedi priate selection of various formulation parameters and ingre amine, propylenediamine and hexamethylenediamine, ethyl dients, including, e.g., various types of controlled release ene glycol, diethylene glycol, propylene glycol, 1,4- compositions and coatings. Thus, the compound(s) are for diol, 1.6-hexanediol, cyclohexanediol, and polycaprolactone mulated with appropriate excipients into a pharmaceutical diol. composition that, upon administration, releases the com pound(s) in a controlled manner. Examples include single or Formulation of Pharmaceutical Compositions multiple unit tablet or capsule compositions, oil solutions, 0255. The compositions, methods, and kits of the inven Suspensions, emulsions, microcapsules, molecular com tion can include formulation(s) of compound(s) that, upon plexes, microspheres, nanoparticles, patches, and liposomes. administration to a subject, result in a concentration of the compound(s) that treats a viral infection (e.g., an influenza Delivery of Compound(s) infection). The compound(s) may be contained in any appro priate amount in any suitable carrier Substance, and are gen 0258. It is not intended that administration of compounds erally present in an amount of 1-95% by weight of the total be limited to a single formulation and delivery method for all weight of the composition. The composition may be provided compounds of a combination. The combination can be in a dosage form that is Suitable for the oral, parenteral (e.g., administered using separate formulations and/or delivery intravenously or intramuscularly), rectal, determatological, methods for each compound of the combination using, for cutaneous, nasal, vaginal, inhalant, skin (patch), ocular, example, any of the above-described formulations and meth intrathecal, or intracranial administration route. Thus, the ods. In one example, a first agent is delivered orally, and a composition may be in the form of, e.g., tablets, capsules, second agent is delivered intravenously. pills, powders, granulates, Suspensions, emulsions, Solutions, gels including hydrogels, pastes, ointments, creams, plasters, Dosages drenches, osmotic delivery devices, Suppositories, enemas, injectables, implants, sprays, or aerosols. The pharmaceutical 0259. The dosage of a compound or a combination of compositions may be formulated according to conventional compounds depends on several factors, including: the admin pharmaceutical practice (see, e.g., Remington: The Science istration method, the type of viral infection to be treated, the and Practice of Pharmacy, 20th edition, 2000, ed. A. R. severity of the infection, whether dosage is designed to treat Gennaro, Lippincott Williams & Wilkins, Philadelphia, and or prevent a viral infection, and the age, weight, and health of Encyclopedia of Pharmaceutical Technology, eds. J. Swar the patient to be treated. brick and J. C. Boylan, 1988-1999, Marcel Dekker, New 0260 For combinations that include an anti-viral agent in York). addition to a compound(s) identified herein, the recom 0256 Pharmaceutical compositions according to the mended dosage for the anti-viral agent is can be less than or invention or used in the methods of the invention may be equal to the recommended dose as given in the Physicians formulated to release the active compound immediately upon Desk Reference, 60' Edition (2006). In other cases, the dos administration or at any predetermined time or time period age of the compound orantiviral agent may be higher than the after administration. The latter types of compositions are recommended dose. generally known as controlled release formulations, which 0261. As described above, the compound in question may include (i) formulations that create Substantially constant be administered orally in the form of tablets, capsules, elixirs concentrations of the agent(s) of the invention within the or syrups, or rectally in the form of suppositories. Parenteral body over an extended period of time; (ii) formulations that administration of a compound is suitably performed, for after a predetermined lag time create Substantially constant example, in the form of solutions or with the compound concentrations of the agent(s) of the invention within the incorporated into liposomes. In cases where the compound in body over an extended period of time; (iii) formulations that itself is not sufficiently soluble to be dissolved, a solubilizer Sustain the agent(s) action during a predetermined time Such as ethanol can be applied. The correct dosage of a com period by maintaining a relatively constant, effective level of pound can be determined by examining the efficacy of the the agent(s) in the body with concomitant minimization of compound in viral replication assays, as well as its toxicity in undesirable side effects associated with fluctuations in the humans. plasma level of the agent(s) (Sawtooth kinetic pattern); (iv) 0262 An agent is usually given by the same route of formulations that localize action of agent(s), e.g., spatial administration that is known to be effective for delivering it as placement of a controlled release composition adjacent to or a monotherapy. For example, when used in combination US 2010/008 1713 A1 Apr. 1, 2010

therapy an agent is dosed in amounts and frequencies equiva 0264. In other embodiments, agents, either as monothera lent to or less than those that result in its effective monothera pies in combination with other agents can be administered at peutic use. higher dosages than the recommended dosage. 0263. A combination described herein may be adminis Example 1 tered to the patient in a single dose or in multiple doses. Components of the combination may be administered sepa In-Vitro Activity of Combinations in H5N1 Stimu rately or together, and by the same or different routes. In lated Macrophages addition, various components of the combination may be 0265 Monocytes purified from blood mononuclear cell administered at the same or different times. When multiple preparation were differentiated to macrophages (14 days) in doses are administered, the doses may be separated from one 5% autologous serum. Macrophages were then infected with another by, for example, one, two, three, four, or five days; an A/VN/3212/04 (H5N1) virus at a MOI of two. Cells were one or two weeks; or one month. For example, the combina incubated with the combination, one hour prior to the infec tion may be administered once a week for, e.g., 2, 3, 4, 5, 6, 7, tion. During the infection, the drug was washed off for 30 8, 10, 15, 20, or more weeks. Both the frequency of dosing minutes and reintroduced for 3 hours. RT-PCR analysis of and length of treatment may be different for each compound mRNA in virus infected macrophages was carried out for the of the combination. It is to be understood that, for any par following cytokines: TNF-alpha, IFN-beta, IP-10, IL-6, IL-8, ticular Subject, specific dosage regimes should be adjusted H.N. matrix gene (Lee et al., J. Virol. 79:10147-10154, over time according to the individual need and the profes 2005). Cytotoxicity was evaluated visually and by Beta-actin sional judgment of the person administering or Supervising gene expression. Fifteen combinations of agents were tested the administration of the compositions. For example, the at three concentrations each. dosage of the combination, or components thereof, can be 0266. From these experiments, the RT-PCR data was ana increased if the lower dose does not sufficiently treat the viral lyzed and calculated as a percentage inhibition versus a infection. Conversely, the dosage of the combination can be DMSO-treated control. The percent inhibition data is show in decreased if the viral infection is cleared from the patient. Table 3 below.

TABLE 3 Test Combination TNF-ct. IFN-B IP-10 IL-6 IL-8 MCP-1 M gene Amoxapine 0.3 M + ------Prednisolone 0.03 M Amoxapine 3 IM + ------Prednisolone 0.3 M Amoxapine 30 M + ------Prednisolone 3 M Paroxetine HCl 0.17 M + ------Prednisolone 0.0062 IM Paroxetine HCI 1.7 M + ------Prednisolone 0.062 IM Paroxetine HCl 17 M + ------Prednisolone 0.62M Amoxapine 0.2 IM + ------Dipyridamole 0.5 L.M Amoxapine 2 IM + ------Dipyridamole 5 M Amoxapine 20 IM + ------Dipyridamole 50 M Budesonide 0.00012 IM + ------3 -- -- Nortriptyline HCI 0.41 M Budesonide 0.0012 IM + ------Nortriptyline HCl 4.1 M Budesonide 0.012 IM+ ------Nortriptyline HCl 41 IM Dipyridamole 0.0032 M + ------Budesonide 0.0017 Dipyridamole 0.032 M + ------Budesonide 0.017 Dipyridamole 0.32 IM+ ------Budesonide 0.17 Nortriptyline HCl 0.25 M + ------Prednisolone 0.062 IM Nortriptyline HCI 2.5 M + ------Prednisolone 0.0062 IM Nortriptyline HCI 25 M + ------Prednisolone 0.62M Paroxetine HCl 0.4 IM + ------Dipyridamole 0.24 M Paroxetine HCl 4 IM+ ------Dipyridamole 2.4M US 2010/008 1713 A1 Apr. 1, 2010 34

TABLE 3-continued

Test Combination TNF-ct. IFN-B IP-10 IL-6 IL-8 MCP-1 Mgene

Paroxetine HCl 40 IM + ------Dipyridamole 24 M Dipyridamole 0.06 M+ ------budilast 0.025 IM Dipyridamole 0.6 M + ------budilast 0.25 M Dipyridamole 6 M + ------budilast 2.5 L.M Epinastine 0.22 M + ------Prednisolone 0.0062 M Epinastine 2.2 M + ------Prednisolone 0.062 IM Epinastine 22 M + ------Prednisolone 0.62M Bufexamac 0.28 M + ------Prednisolone 0.0016 M Bufexamac 2.8 M + ------Prednisolone 0.016 M Bufexamac 28 M + ------Prednisolone 0.16 M Sertraline 0.38 M+ ------Prednisolone 0.025 IM Sertraline 3.8 M + ------Prednisolone 0.25 M Sertraline 38M + ------Prednisolone 2.5 L.M Desloratidine 0.2 M + ------Cyclosporine 0.004 IM Desloratidine 2 M + ------Cyclosporine 0.04M Desloratidine 20 M + ------Cyclosporine 0.4 M CME-Amoxapine 0.17 M + ------Prednisolone 0.0063 M CME-Amoxapine 1.7 M + ------Prednisolone 0.063 M CME-Amoxapine 17 M + ------Prednisolone 0.63 M Desloratidine 5.3 M + ------Nortriptyline HCl 0.73 M Desloratidine 16 M + ------Nortriptyline HCI 2.2 M Desloratidine 48 M+ ------Nortriptyline HCl 6.6M Desloratidine 5.3 M + ------Fluoxetine 0.15 M Desloratidine 16 M + ------Fluoxetine 0.45 M Desloratidine 48 M+ ------Fluoxetine 1.35 M No inhibition - 0%-20% inhibition + 21%-40% inhibition ++ 41%-60% inhibition +++ 61%-80% inhibition ++++ 81%-100% inhibition +++++

Example 2 0268 Specific pathogen free, male C57/BL6 mice weigh Activity of Sertraline and Combinations Thereof in ing 20-25 g were procured from Biological Resource Centre Influenza Mouse Model (BRC) and housed in groups of 3, in cages with Corncob 0267 We also tested the effectiveness of sertraline and bedding (Harlan-Teklad, U.K.). Experiments were conducted combinations thereof in an influenza mouse model. Mouse in Animal Bio-safety level 3 (ABSL-3) rooms. Cages were adapted influenza A/PR/8/34 was procured from American placed in isolator maintained at -100 pa pressure and Supply Type Culture Collection (ATCC) and propagated in Madin of HEPA filtered air. Mice were provided with commercial Darby Canine Kidney (MDCK) cells. The virus stock was rodent diet (Harlan-Teklad, U.K.) and distilled water ad libi titrated in MDCK cells to give a 10 TCIDso/mL, prior to use tum in mice. The virus stock was diluted in phosphate buffered 0269 Mice were orally administered with respective treat saline (PBS) such that the working concentration was 10' ments starting 4 hours before virus inoculation daily for five TCIDs of virus per 50 uL. days. At the time of virus inoculation mice were anesthetized US 2010/008 1713 A1 Apr. 1, 2010

with (75 mg/kg)+Xylazine (50 mg/kg). 50 uL of 6. The composition of claim 1, wherein said viral infection 10 TCIDso virus suspension was administered intranasally is caused by an influenza virus. to each mouse. Previous experiments have shown that 10 7. A composition comprising: TCIDs/mouse of virus is lethaland produces 100% mortality (a) a combination of agents selected from the combinations in C57/BL6 mice (data not shown). Mice were weighed daily, of Table 1; and and the weights were used for dose adjustment. Sertraline and (b) an additional antiviral therapy. prednisolone were suspended in 0.5% HPMC and adminis 8. The composition of claim 7, wherein said additional tered once daily while oseltamivir was dissolved in distilled antiviral therapy is a Group A antiviral agent. water and administered twice daily. Sertraline, sertraline-- 9. The composition of claim 7, where said additional anti prednisolone combination, oseltamivir, and vehicle were viral agent is oseltamivir, Zanamivir, amantadine, or rimanta orally administered for 5 days starting 4 hr before virus inocu dine. lation. The survival rate of animals was monitored for 10 days 10. The composition of claim 7, wherein (a) and (b) are after infection. present in amounts that together are effective to treat or pre 0270. From these experiments, vehicle treated mice began vent a viral infection. to die on day 7 and their survival rate on day 9 was 0%. The 11. The composition of claim 7, wherein said viral infec survival rate of mice receiving sertraline at a dose of 30 tion is caused by an influenza virus. mg/Kg/day was 22.2% on day 10. In mice treated with ser 12. A method for treating or preventing a viral infection in traline at 100 mg/kg/day, the survival rate was 55.5% on day a patient, said method comprising administering to said Sub 8, 44.4% on day 9, and 22.2% on day 10. Thus, sertraline shows dose dependant increase in survival rate by day 9 by ject an amount of an SSRI sufficient to treat or prevent said which vehicle treated group shows 100% mortality (FIGS. 1 viral infection in said patient. and 2). 13. The method of claim 12, wherein said SSRI is sertra 0271 Mice treated with a combination of sertraline 30 line, or an analog thereof. mg/kg and prednisolone 0.1 mg/Kg showed 30% survival on 14. The method of claim 12, wherein said viral infection is day 10. Oseltamivir was used as a positive control and the an influenza virus infection. survival rates for 30 mg/kg/day and 100 mg/kg/day were 15. The method of claim 12, wherein said method further 33.3% and 100% respectively on day 10. Sertraline alone or comprises administration of an additional antiviral therapy. in combination with prednisolone improves survival rate of 16. The method of claim 15, wherein said additional anti C57/BL6 mice infected with lethal dose of influenza A/8/PR/ viral therapy is a Group A antiviral. 34. 17. A method for treating or preventing a viral infection in a patient, said method comprising administering a pair of Other Embodiments agents selected from the group consisting of (a) a tricyclic 0272 All patents, patent applications including U.S. Pro antidepressant and a corticosteroid, (b) an SSRI and a corti visional Patent Application No. 61/ , filed Mar. 19, costeroid, (c) atricyclic antidepressant and a tetra-substituted 2008, titled “Compositions and Methods for Treatment of pyrimidopyrimidine, (d) corticosteroid and a tetra-substi Viral Diseases.” Attorney Docket No. 50425/004004, and tuted pyrimidopyrimidine, (e) an SSRI and a tetra-substituted publications mentioned in this specification are herein incor pyrimidopyrimidine, (f) a tetra-substituted pyrimidopyrimi porated by reference to the same extent as if eachindependent dine and ibudilast, (g) an antihistamine and a corticosteroid, patent, patent application, or publication was specifically and (h) a corticosteroid and bufeXamac, (i) an antihistamine and a individually indicated to be incorporated by reference. non-steroidal immunophilin-dependent immunosuppressant 0273 Various modifications and variations of the (NSIDI), () a tricyclic antidepressant and an antihistamine, described method and system of the invention will be appar and (k) an antihistamine and an SSRI, wherein said pair of ent to those skilled in the art without departing from the scope agents is administered simultaneously or within 14 days of and spirit of the invention. Although the invention has been described in connection with specific desired embodiments, it each other in amounts that together are sufficient to treat or should be understood that the invention as claimed should not prevent said viral infection in said patient. be unduly limited to such specific embodiments. Indeed, vari 18. The method of claim 17, wherein said viral infection is ous modifications of the described modes for carrying out the an influenza virus infection. invention that are obvious to those skilled in the fields of 19. The method of claim 17, wherein said method further molecular biology, medicine, immunology, , comprises administration of an additional antiviral therapy. Virology, or related fields are intended to be within the scope 20. The method of claim 19, wherein said additional anti of the invention. viral therapy is a Group A antiviral. What is claimed is: 21. A method for treating or preventing a viral infection in 1. A composition comprising: a patient, said method comprising administering to said (a) a selective serotonin (SSRI); and patient a combination of agents of Table 1, wherein each (b) an additional antiviral therapy. agent of said combination is administered simultaneously or 2. The composition of claim 1, wherein said SSRI is ser within 14 days of each other in amounts that together are traline, or an analog thereof. effective to treat or prevent said viral infection in said patient. 3. The composition of claim 1, wherein said additional 22. The method of claim 21, wherein said viral infection is antiviral therapy is a Group A antiviral agent. an influenza virus infection. 4. The composition of claim 1, where said additional anti 23. The method of claim 21, wherein said method further viral agent is oseltamivir, Zanamivir, amantadine, or rimanta comprises administration of an additional antiviral therapy. dine. 24. The method of claim 23, wherein said additional anti 5. The composition of claim 1, wherein (a) and (b) are viral therapy is a Group A antiviral. present in amounts that together are effective to treat or pre vent a viral infection. c c c c c