WO2011008230A2

WO2011008230A2 - Rapamycin derivatives and ethers of n-propanolamines and uses related to infection

Info

Publication number: WO2011008230A2
Application number: PCT/US2010/001279
Authority: WO
Inventors: Natalie Mcdonald; Thomas Hodge
Original assignee: Zirus Inc
Current assignee: Zirus Inc
Priority date: 2009-04-29
Filing date: 2010-04-29
Publication date: 2011-01-20
Anticipated expiration: 2011-10-29
Also published as: WO2011008230A3

Abstract

The present invention relates to the use of rapamycin derivatives and ethers of N- propanolamines for decreasing infection by a pathogen. More particularly, the invention relates to the use of O-alkylated rapamycin derivatives, as well as bepridil, for decreasing viral infection.

Description

RAPAMYCIN DERIVATIVES, ETHERS OF N-PROPANOLAMINES AND

USES RELATED TO INFECTION

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Application No. 61/214,841, filed on April

29, 2009, U.S. Application No. 61/215,084, filed on May 01, 2009, and U.S. Application No. 61/271,362, filed on July 20, 2009, all three of which are hereby incorporated in their entireties by this reference. FIELD OF THE INVENTION

The present invention relates to the use of rapamycin derivatives and ethers of n- propanolamines for decreasing infection by a pathogen. More particularly, the invention relates to the use of everolimus (an O-alkylated rapamycin derivative) for decreasing infection in a subject by a virus. The invention also relates to the use of bepridil for decreasing infection in a subject by a virus.

BACKGROUND

Infectious diseases affect the health of people and animals around the world, causing serious illness and death. Black Plague devastated the human population in Europe during the middle ages. Pandemic flu killed millions of people in the 20^th century and is a threat to reemerge.

Some of the most feared, widespread, and devastating human diseases are caused by viruses that interfere with normal cellular processes. These include influenza, poliomyelitis, smallpox, Ebola, yellow fever, measles and AIDS, to name a few. Viruses are also responsible for many cases of human disease including encephalitis, meningitis, pneumonia, hepatitis and cervical cancer, warts and the common cold. Furthermore, viruses causing respiratory infections, and diarrhea in young children lead to millions of deaths each year in less-developed countries. Also, a number of newly emerging human diseases such as SARS are caused by viruses. In addition, the threat of a bioterrorist designed pathogen is ever present.

While vaccines have been effective to prevent certain viral infections, relatively few vaccines are available or wholly effective, have inherent risks and tend to be specific for particular conditions. Vaccines are of limited value against rapidly mutating viruses and cannot anticipate emerging viruses or new bioterrorist designed viruses. Currently there is no good answer to these threats.

Traditional treatments for viral infection include pharmaceuticals aimed at specific virus derived proteins. However, the vast majority of viruses lack an effective drug. Those drugs that exist have several limitations and drawbacks that including limited effectiveness, toxicity, and high rates of viral mutations which render antiviral pharmaceuticals ineffective. Thus, an urgent need exists for alternative treatments for viruses and other infectious diseases. DETAILED DECRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the Examples included therein.

Before the present compounds, compositions and/or methods are disclosed and described, it is to be understood that this invention is not limited to specific nucleic acids, specific polypeptides, or to particular methods, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. The term "or" refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, "comprises" means "includes." Thus, "comprising A or B," means "including A, B, or A and B," without excluding additional elements.

Ranges may be expressed herein as from "about" one particular value, and/or to

"about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, the phrase "optionally obtained prior to treatment" means obtained before treatment, after treatment, or not at all.

As used throughout, by "subject" is meant an individual. Preferably, the subject is a mammal such as a primate, and, more preferably, a human. Non-human primates include marmosets, monkeys, chimpanzees, gorillas, orangutans, and gibbons, to name a few. The term "subject" includes domesticated animals, such as cats, dogs, etc., livestock (for example, cattle, horses, pigs, sheep, goats, etc.), laboratory animals (for example, ferret, chinchilla, mouse, rabbit, rat, gerbil, guinea pig, etc.) and avian species (for example, chickens, turkeys, ducks, pheasants, pigeons, doves, parrots, cockatoos, geese, etc.). The subjects of the present invention can also include, but are not limited to fish (for example, zebrafish, goldfish, tilapia, salmon and trout), amphibians and reptiles.

Methods of Decreasing Infection

The present invention provides a method of decreasing infection in a subject by a pathogen comprising administering to the subject an effective amount of a compound having the structure of formula I, a compound having the structure of formula IV, a compound having the structure of formula V, a compound having the structure of formula VI, or a compound having the structure of formula VII, as set forth below. Pharmaceutically acceptable salts of all of the compounds set forth herein are also provided.

"Pharmaceutically acceptable salts" are those salts derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium) and ammonium salts. Preferred salts include hydrochlorides, hydrobromides, sulfates, mesylates, maleates, and fumarates. Throughout this application, references to a compound according to the invention include the compounds as well as its pharmaceutically acceptable salts.

Some of the compounds set forth herein, for example, everolimus, are typically also mTOR inhibitors. mTOR is also known as K506 binding protein 12-rapamycin associated protein 1 (FRAPl). Additional information for this protein can be found under Entrez Gene No. 2475 at http://www.ncbi.nlm.nih.gov/gene/2475. FRAPl is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. Therefore, the compounds set forth herein can inhibit infection by decreasing the activity of mTOR and/or interaction of mTOR with other cellular or pathogenic proteins.

Some of the compounds set forth herein, for example, bepridil, are calmodulin inhibitors. Calmodulin is also known as CALMl or CALM2. Additional information for these proteins can be found under Entrez Gene No. 801 at

http://www.ncbi.nlm.nih.gov/gene/801, and under Entrez Gene No. 805 at

http://www.ncbi.nlm.nih.gov/gene/805. Calmodulin is a calcium binding protein that is involved in cell growth and the cell cycle as well as in signal transduction and the synthesis and release of neurotransmitters. Therefore, the compounds set forth herein can inhibit viral infection by decreasing the activity of a calmodulin and/or interaction of a calmodulin with other cellular or pathogenic proteins.

An infection can be a viral infection, bacterial infection, fungal infection or a parasitic infection, to name a few. All strains and types of pathogenic infection are contemplated herein. A decrease or inhibition of infection can occur in a cell, in vitro, ex vivo or in vivo. As utilized throughout, the term "infection" encompasses all phases of pathogenic life cycles including, but not limited to, attachment to cellular receptors, entry, internalization, disassembly, replication, genomic integration of pathogenic sequences, transcription of viral RNA, translation of viral RNA, transcription of host cell mRNA, translation of host cell mRNA, proteolytic cleavage of pathogenic proteins or cellular proteins, assembly of particles, endocytosis, cell lysis, budding, and egress of the pathogen from the cells.

Therefore, a decrease in infection can be a decrease in attachment to cellular receptors, a decrease in entry, a decrease in internalization, a decrease in disassembly, a decrease in replication, a decrease in genomic integration of pathogenic sequences, a decrease in translation of mRNA, a decrease in proteolytic cleavage of pathogenic proteins or cellular proteins, a decrease in assembly of particles, a decrease in endocytosis, a decrease in cell lysis, a decrease in budding, or a decrease in egress of the pathogen from the cells. This decrease does not have to be complete as this can range from a slight decrease to complete ablation of the infection. A decrease in infection can be at least about 10%, 20%, 30%, 40%, 50%, 60, 70%, 80%, 90%, 95%, 100% or any other percentage decrease in between these percentages as compared to the level of infection in a cell that has not been contacted with a compound set forth herein. Examples of viral infections include but are not limited to, infections caused by RNA viruses (including negative stranded RNA viruses, positive stranded RNA viruses, double stranded RNA viruses and retroviruses) and DNA viruses. All strains, types, subtypes of DNA and RNA viruses are contemplated herein.

Examples of RNA viruses include, but are not limited to picornaviruses, which include aphthoviruses (for example, foot and mouth disease virus O, A, C, Asia 1, SATl, SAT2 and SAT3), cardioviruses (for example, encephalomycarditis virus and Theiller's murine encephalomyelitis virus), enteroviruses (for example polioviruses 1 , 2 and 3, human enteroviruses A-D, bovine enteroviruses 1 and 2, human coxsackieviruses A1-A22 and A24, human coxsackieviruses B1-B5, human echoviruses 1-7, 9, 11-12, 24, 27, 29-33, human enteroviruses 68-71, porcine enteroviruses 8-10 and simian enteroviruses 1-18), erboviruses (for example, equine rhinitis virus), hepatovirus (for example human hepatitis A virus and simian hepatitis A virus), kobuviruses (for example, bovine kobuvirus and Aichi virus), parechoviruses (for example, human parechovirus 1 and human parechovirus 2), rhinovirus (for example, rhinovirus A, rhinovirus B, HRV₁₆, HRVi₆ (VR-11757), HRV_M (VR-284), or HRVi_A (VR-1559), human rhinovirus 1-100 and bovine rhinoviruses 1-3) and teschoviruses (for example, porcine teschovirus).

Additional examples of RNA viruses include caliciviruses, which include noroviruses (for example, Norwalk virus), sapoviruses (for example, Sapporo virus), lagoviruses (for example, rabbit hemorrhagic disease virus and European brown hare syndrome) and vesiviruses (for example vesicular exanthema of swine virus and feline calicivirus).

Other RNA viruses include astroviruses, which include mamastorvi ruses and avastroviruses. Togaviruses are also RNA viruses. Togaviruses include alphaviruses (for example, Chikungunya virus, Sindbis virus, Semliki Forest virus, Western equine

encephalitis, Getah virus, Everglades virus, Venezuelan equine encephalitis virus and Aura virus) and rubella viruses. Additional examples of RNA viruses include the the flaviviruses (for example, tick-borne encephalitis virus, Tyuleniy virus, Aroa virus, Dengue virus (types 1 to 4), Kedougou virus, Japanese encephalitis virus (JEV), West Nile virus (WNV), Kokobera virus, Ntaya virus, Spondweni virus, Yellow fever virus, Entebbe bat virus, Modoc virus, Rio Bravo virus, Cell fusing agent virus, pestivirus, GB virus A, GBV-A like viruses, GB virus C, Hepatitis G virus, hepacivirus (hepatitis C virus (HCV)) all six genotypes), bovine viral diarrhea virus (BVDV) types 1 and 2, and GB virus B).

Other examples of RNA viruses are the coronaviruses, which include, human respiratory coronaviruses such as SARS-CoV, HCoV-229E, HCoV-NL63 and HCoV-OC43. Coronaviruses also include bat SARS-like CoV, turkey coronavirus, chicken coronavirus, feline coronavirus and canine coronavirus. Additional RNA viruses include arteriviruses (for example, equine arterivirus, porcine reproductive and respiratory syndrome virus, lactate dehyrogenase elevating virus of mice and simian hemorraghic fever virus). Other RNA viruses include the rhabdoviruses, which include lyssaviruses (for example, rabies, Lagos bat virus, Mokola virus, Duvenhage virus and European bat lyssavirus), vesiculoviruses (for example, VSV-Indiana, VSV-New Jersey, VSV-Alagoas, Piry virus, Cocal virus, Maraba virus, Isfahan virus and Chandipura virus), and ephemeroviruses (for example, bovine ephemeral fever virus, Adelaide River virus and Berrimah virus). Additional examples of RNA viruses include the filoviruses. These include the Marburg and Ebola viruses (for example, EBOV-Z, EBOV-S, EBOV-IC and EBOV-R.

The paramyxoviruses are also RNA viruses. Examples of these viruses are the rubulaviruses (for example, mumps, parainfluenza virus 5, human parainfluenza virus type 2, Mapuera virus and porcine rubulavirus), avulaviruses (for example, Newcastle disease virus), respoviruses (for example, Sendai virus, human parainfluenza virus type 1 and type 3, bovine parainfluenza virus type 3), henipaviruses (for example, Hendra virus and Nipah virus), morbilloviruses (for example, measles, Cetacean morvilliirus, Canine distemper virus, Peste- des-petits-ruminants virus, Phocine distemper virus and Rinderpest virus), pneumoviruses (for example, human respiratory syncytial virus A2, Bl and S2, bovine respiratory syncytial virus and pneumonia virus of mice), metapneumoviruses (for example, human

metapneumovirus and avian metapneumovirus). Additional paramyxoviruses include Fer-de- Lance virus, Tupaia paramyxovirus, Menangle virus, Tioman virus, Beilong virus, J virus, Mossman virus, Salem virus and Nariva virus. Additional RNA viruses include the orthomyxoviruses.

These viruses include influenza viruses and strains (e.g., influenza A, influenza A strain A/Victoria/3/75, influenza A strain A/Puerto Rico/8/34, influenza A HlNl (including but not limited to A/WS/33, A/NWS/33 and A/California/04/2009 strains) influenza B, influenza B strain Lee, and influenza C viruses) H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3 and H10N7), as well as avian influenza (for example, strains H5N1, H5N1 Duck/MN/ 1525/81, H5N2, H7N1 , H7N7 and H9N2) thogotoviruses and isaviruses.

Orthobunyaviruses (for example, Akabane virus, California encephalitis, Cache Valley virus, Snowshoe hare virus,) nairoviruses (for example, Nairobi sheep virus, Crimean-Congo hemorrhagic fever virus Group and Hughes virus), phleboviruses (for example, Candiru, Punta Toro, Rift Valley Fever, Sandfly Fever, Naples, Toscana, Sicilian and Chagres), and hantaviruses (for example, Hantaan, Dobrava, Seoul, Puumala, Sin Nombre, Bayou, Black Creek Canal, Andes and Thottapalayam) are also RNA viruses. Arenaviruses such as lymphocytic choriomeningitis virus, Lujo virus, Lassa fever virus, Argentine hemorrhagic fever virus, Bolivian hemorrhagic fever virus, Venezuelan hemorrhagic fever virus, SABV and WWAV are also RNA viruses. Borna disease virus is also an RNA virus. Hepatitis D (Delta) virus and hepatitis E are also RNA viruses.

Additional RNA viruses include reoviruses, rotaviruses, birnaviruses, chrysoviruses, cystoviruses, hypoviruses partitiviruses and totoviruses. Orbiviruses such as African horse sickness virus, Blue tongue virus, Changuinola virus, Chenuda virus, Chobar Gorge Corriparta virus, epizootic hemorraghic disease virus, equine encephalosis virus, Eubenangee virus, Ieri virus, Great Island virus, Lebombo virus, Orungo virus, Palyam virus, Peruvian Horse Sickness virus, St. Croix River virus, Umatilla virus, Wad Medani virus, Wallal virus, Warrego virus and Wongorr virus are also RNA viruses.

Retroviruses include alpharetro viruses (for example, Rous sarcoma virus and avian leukemia virus), betaretroviruses (for example, mouse mammary tumor virus, Mason-Pfizer monkey virus and Jaagsiekte sheep retrovirus), gammaretroviruses (for example, murine leukemia virus and feline leukemia virus, deltraretroviruses (for example, human T cell leukemia viruses (HTLV-I , HTL V-2), bovine leukemia virus, STLV-I and STLV-2), epsilonretriviruses (for example, Walleye dermal sarcoma virus and Walleye epidermal hyperplasia virus 1), reticuloendotheliosis virus (for example, chicken syncytial virus, Antiviruses (for example, human immunodeficiency virus (HIV) type 1 , human

immunodeficiency virus (HIV) type 2, human immunodeficiency virus (HIV) type 3, simian immunodeficiency virus, equine infectious anemia virus, feline immunodeficiency virus, caprine arthritis encephalitis virus and Visna maedi virus) and spumaviruses (for example, human foamy virus and feline syncytia-forming virus).

Examples of DNA viruses include polyomaviruses (for example, simian virus 40, simian agent 12, BK virus, JC virus, Merkel Cell polyoma virus, bovine polyoma virus and lymphotrophic papovavirus), papillomaviruses (for example, human papillomavirus, bovine papillomavirus, adenoviruses (for example, adenoviruses A-F, canine adenovirus type I, canined adeovirus type 2), circoviruses (for example, porcine circovirus and beak and feather disease virus (BFDV)), parvoviruses (for example, canine parvovirus), erythroviruses (for example, adeno-associated virus types 1-8), betaparvoviruses, amdoviruses, densoviruses, iteraviruses, brevidensoviruses, pefudensoviruses, herpes viruses 1 ,2, 3, 4, 5, 6, 7 and 8 (for example, herpes simplex virus 1, herpes simplex virus 2, varicella- zoster virus, Epstein-Barr virus, cytomegalovirus, Kaposi's sarcoma associated herpes virus, human herpes virus-6 variant A, human herpes virus-6 variant B and cercophithecine herpes virus 1 (B virus)), poxviruses (for example, smallpox (variola), cowpox, monkeypox, vaccinia, Uasin Gishu, camelpox, psuedocowpox, pigeonpox, horsepox, fowlpox, turkeypox and swinepox), and hepadnaviruses (for example, hepatitis B and hepatitis B-like viruses). Chimeric viruses comprising portions of more than one viral genome are also contemplated herein.

For animals, in addition to the animal viruses listed above, viruses include, but are not limited to, the animal counterpart to any above listed human virus. The provided compounds can also decrease infection by newly discovered or emerging viruses. Such viruses are continuously updated on http://en.wikipedia.org/wiki/Virus and www.virology.net.

Examples of bacterial infections include, but are not limited to infections caused by the following bacteria: Listeria (sp.), Franscicella tularensis, Mycobacterium tuberculosis, Rickettsia (all types), Ehrlichia, Chlamydia. Further examples of bacteria that can be targeted by the present methods include M. tuberculosis, M. bovis, M. bovis strain BCG, BCG substrains, M. avium, M. intracellular, M. africanum, M. kansasii, M. marinum, M. ulcerans, M. avium subspecies paratuberculosis, Nocardia asteroides, other Nocardia species, Legionella pneumophila, other Legionella species, Salmonella typhi, other

Salmonella species, Shigella species, Yersinia pestis, Pasteurella haemolytica, Pasteurella multocida, other Pasteurella species, Actinobacillus pleuropneumoniae, Listeria

monocytogenes, Listeria ivanovii, Brucella abortus, other Brucella species, Cowdria ruminantium, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydia psittaci, Coxiella burnetii, other Rickettsial species, Ehrlichia species, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus agalactiae, Bacillus anthracis,

Escherichia coli, Vibrio cholerae, Kingella kingae, Campylobacter species, Neiserria meningitidis, Neiserria gonorrhea, Pseudomonas aeruginosa, other Pseudomonas species, Haemophilus influenzae, Haemophilus ducreyi, other Hemophilus species, Clostridium tetani, other Clostridium species, Yersinia enterolitica, and other Yersinia species.

Examples of parasitic infections include, but are not limited to infections caused by the following parasites: Cryptosporidium, Plasmodium (all species), American trypanosomes (7! cruzϊ), African trypanosomes, Acanthamoeba, Entaoeba histolytica, Angiostrongylus, Anisakis, Ascaris, Babesia, Balantidium, Baylisascaris, lice, ticks, mites, fleas, Capillaria, Clonorchis, Chilomastix mesnili, Cyclspora, Diphyllobothrium, Dipylidium caninum, Fasciola, Giardia, Gnathostoma, Hetetophyes, Hymenolepsis, Isospora, Loa loa,

Microsporidia, Naegleήa, Toxocara, Onchocerca, Opistorchis, Paragonimus,

Baylisascaris, Strongyloides, Taenia, Trichomonas and Trichuris.

Furthermore, examples of protozoan and fungal species contemplated within the present methods include, but are not limited to, Plasmodium falciparum, other Plasmodium species, Toxoplasma gondii, Pneumocystis carinii, Trypanosoma cruzi, other trypanosomal species, Leishmania donovani, other Leishmania species, Theileria annulata, other Theileria species, Eimeria tenella, other Eimeria species, Histoplasma capsulatum, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioides immitis, Paracoccidioides brasiliensis, Penicillium marneffei, and Candida species. The provided compounds can also decrease infection by newly discovered or emerging bacteria, parasites or fungi, including multidrug resistant strains of same.

Methods of Decreasing Infection with Rapamycin and Rapamycin Derivatives

The present invention provides a method of decreasing infection in a subject by a pathogen comprising administering to the subject an effective amount of a compound having the structure of formula I, a compound having the structure of formula IV, or a compound having the structure of formula V, as set forth below.

More specifically, the present invention provides a method of decreasing infection by a respiratory virus in a subject said method comprising administering to the subject an effective amount of a compound having the structure of formula I

wherein:

Ri is alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, benzyl, alkoxybenzyl or chlorobenzyl, R₂ is selected from formula II or formula III:

Formula II

Formula III

wherein:

R₃ is selected from H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl and alkylsilyl;

R₄ is H, methyl or together with R₃ forms C_2-6 alkylene;

R₅ is R₆O-CH₂--, wherein R₆ is selected from H, alkyl , alkenyl, alkynyl, aryl, alkylcarbonyl, ary lcarbonyl, heteroarylcarbony 1 , hydroxyalky 1 carbony 1 ,

aminoalkylcarbonyl, formyl, thioalkyl, arylalkyl, hydroxyarylalkyl, hydroxyaryl,

hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl,

dihydroxyalkylarylalkyl,alkoxyalkyl, alkylcarbonyloxyalkyl, anlinoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonalnidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl and carbalkoxyalkyl; R₇CO-, wherein R₇ is selected from H, alkyl, hydroxy, alkoxy, aryloxy, amino, alkylamino, a residue of an amino acid, or N,N-disubstituted-amino wherein the substituents (a) are selected from alkyl, aryl or arylalkyl or (b) form a heterocyclic structure; R₈NCH-, wherein R₈ is alkyl, aryl, amino, alkylamino, arylamino, hydroxy, alkoxy or arylsulfonylamino;— O-CH-O-; or substituted

dioxymethylyne; Y is selected from O (H, OH), and (H, OR₉) wherein R₉ is selected from Ci-₄alkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl or aryl; wherein "alk" or "alkyl" refers to a Ci- 1₀ aliphatic substituent optionally interrupted by an oxy linkage, and "ar" or "aryl" refers to a monocyclic, optionally heterocyclic, optionally substituted, C₄. i₄ aromatic substituent.

Any "alk" moiety or "alkyl" mentioned above may be branched, linear or cyclic; preferably it is a C _I-6 aliphatic substituent optionally interrupted by an oxy linkage. More preferably uninterrupted by oxy. Examples of "ar" moiety or "aryl" mentioned above and optionally substituted may include e.g. phenyl, benzyl, tolyl, pyridyl and the like.

When Ri is chlorobenzyl or alkoxybenzyl, the substituent is preferably in ortho.

When R₇CO- is N,N-disubstituted-carbamoyl, it may be e.g. N-methyl-N -(2-pyridin- 2-yl-ethyl)-carbamoyl, (4-methyl-piperazin-l-yl)-carbonyl or (morpholin-4yl)carbonyl.

When R₅ is substituted dioxymethylyne, it may be e.g. O,O-(alkylene)-dioxy- methylyne, i.e. wherein the 2 oxygens are linked by an alkylene group.

As used throughout, the term "aliphatic" refers to saturated and unsaturated straight chained, branched chain, cyclic, or polycyclic hydrocarbons that may be optionally substituted at one or more positions. Illustrative examples of aliphatic groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. The term "alkyl" refers to straight or branch chain saturated hydrocarbon substituent, for example, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, secbutyl and tert butyl. "Alkenyl" refers to a straight or branched chain hydrocarbon with at least one carbon-carbon double bond. "Alkynl" refers to a straight or branched chain hydrocarbon with at least one carbon carbon triple bound.

The term "aryl" refers to monocyclic or polycyclic groups having at least one aromatic ring structure that optionally include one or more heteroatorns and preferably include three to fourteen carbon aloms. Aryl substituents may optionally be substituted at one or more positions. Illustrative examples of aryl groups include but are not limited to: furanyl, imidazolyl, indanyl, indenyl, indolyl, isooxazolyl, isoquinolinyl, naphthyl, oxazolyl, oxadiazolyl, phenyl, pyrazinyl, pyridyl, pyrimidinyl, pyrazoly, quinolyl, quinoxalyl, tetrazolyl, thiazolyl, thienyl, and the like.

The terms "alkylaryl' or "arylalkyl" refer to an aryl group with an aliphatic substituent bonded to the compound through the aliphatic group. An illustrative example of an alkylaryl or arylalkyl group is benzyl, a phenyl with a methyl group that is bonded to the compound through the methyl group (-CH₂Ph where Ph is phenyl).

The term "acyl" refers to -C(=O)R where R is an alphatic group, preferably a Ci-C₆ moiety. The term "alkoxy" refers to -OR wherein O is oxygen and R is an aliphatic group. The term "aminoalkyl" refers to -RNH₂ where R is an aliphatic moiety. The terms

"halogen," "halo," or "halide" refer to fluorine, chlorine, bromine and iodine. The term "haloalkyl" refers to -RX where R is an aliphatic moiety and X is one or more halogens. The term "hydroxyalkyl" refers to -ROH where R is an aliphatic moiety. The term '"oxo" refers to a carbonyl oxygen (=O).

Compounds having the structure of formula I can be made according to the methods set forth in US Patent No. 5,985,890, which is hereby incorporated in its entirety by this reference.

Also provided is a method of decreasing infection by a respiratory virus in a subject said method comprising administering to the subject an effective amount of a compound having the structure of formula IV

wherein

X is (H,0H) or O;

Y is (H,0H) or O;

Ri and R₂ are independently selected from H, alkyl, thioalkyl, arylalkyl,

hydroxyalkyl, dihydroxyalkyl hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl,

alkoxyalkyl, acyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, acylaminoalkyl, arylsulfonamidoalkyl, allyldihydroxyalkylallyl, dioxolanylallyl,

carbalkoxyalkyl and (R₃)₃Si where each R₃ is independently selected from H, methyl, ethyl, isopropyl, t-butyl and phenyl; wherein "alk-" or "alkyl" refers to C i _-6 alkyl branched or linear preferably Ci _{- 3} alkyl in which the carbon chain may be optionally interrupted by an ether (— 0~) linkage; and

R₄ is methyl, or R₄ and Ri together form C_{2- 5} alkylene; provided that Ri and R₂ are not both H; and provided that where Ri is (R₃)₃Si or carbalkoxyalkyl, X and Y are not both O.

For example, and not to be limiting, compounds having the structure of formula IV include the following: 40-O-Benzyl-rapamycin, 40-O-(4'-Hydroxymethyl)benzyl-rapamycin, 40-O-[4'-(l,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin, 40-O-[3'-(2,2- Dimethyl-l,3-dioxolan-4(S)-yl)-prop-2'-en-l'-yl]raparnycin, (2¹E, 4'S)-40-O-(4',5'- Dihydroxypent-2'-en- 1 '-yl)rapamycin, 40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin, 40-O-(2-Hydroxy)ethyl-rapamycin, 40-O-(3-Hydroxy)propyl-rapamycin, 40-O-(6- Hydroxy)hexyl-rapamycin, 40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin, 40-O-[(3S)-2,2- Dimethyldioxolan-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-Dihydroxyprop-l-yl]-rapamycin, 40-O-(2-Acetoxy)ethyl-rapamycin, 40-O-(2-Nicotinoyloxy)ethyl-rapamycin, 40-O-[2-(N- Morpholino)acetoxy]ethyl-rapamycin, 40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin, 40-O- [2-(N-Methyl-N'-piperazinyl)acetoxy]ethyl-rapamycin, 39-O-Desmethyl-39,40-O,O- ethylene-rapamycin, (26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl rapamycin, 40-O-(2-Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin, 40-O-(2- Nicotinamidoethyl)-rapamycin, 40-O-(2-(N-Methyl-imidazo-2'-ylcarbethoxamido)ethyl)- rapamycin, 40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin, 40-O-(2-

Tolylsulfonamidoethyl)-rapamycin, 40-O-[2-(4',5'-Dicarboethoxy- 1 ',2',3'-triazol- 1 '-yl)ethyl]- rapamycin.

Compounds having the structure of formula IV can be made according to the methods set forth in US Patent No. 5,665,772. U.S. Patent No. 5,665,772 is hereby incorporated by reference in its entirety. Everolimus can also be obtained from Sigma Chemical Company (St. Louis, MO).

A preferred compound of formula IV is everolimus, set forth below as formula V. Everolimus is also known as Zortress®, Certican® and Afinitor®. This compound is also referred to as 40-O-(2-hydroxyethyl)rapamycin. It is noted that due to a renumbering of the structure for everolimus, C-40 of formula IV set forth above has been renumbered as C-42 in the literature. Therefore, everolimus is also known as 42-O-(2-hydroxyethyl)rapamycin which is the same compound as 40-O-(2-hydroxyethyl)rapamycin. Everolimus is also known as dihydroxy- 12- [(2R)- 1 -[( 1 S',3/?,4/?)-4-(2-hydroxyethoxy)-3-methoxycyclohexy l]propan-2- yl]- 19,30-dimethoxy- 15, 17,21 ,23,29,35-hexamethyl- 11 ,36-dioxa-4- azatricyclo[30.3.1.0⁴'⁹]hexatriaconta- 16,24,26,28-tetraene-2,3, 10, 14,20-pentone.

The present invention further provides a method of decreasing infection by a respiratory virus in a subject said method comprising administering to the subject an effective amount of everolimus having the structure of compound V

Respiratory viruses can include, but are not limited to, picornaviruses,

orthomyxoviruses, paramyxoviruses, coronaviruses and adenoviruses. More specifically, and not to be limiting, the respiratory virus can be an influenza virus, a parainfluenza virus, an adenovirus, a rhino virus (for example, rhinovirus A, rhinovirus B, HRV ι_6; HRVi₆ (VR-

11757), HRV₁₄ (VR-284), or HRV, _A (VR- 1559)) or a respiratory syncytial virus (RSV) (for example RSV strain A2). As mentioned above, all strains of viruses are contemplated herein. For example, and not to be limiting, influenza viruses include influenza A, influenza A strain A/Victoria/3/75, influenza A strain A/Puerto Rico/8/34, influenza B, influenza B strain Lee, and influenza C viruses. Also included are animal counterparts of the pathogens set forth herein. These include animal influenza viruses such as avian influenza (for example, strains H5N1, H5N1 A/Duck/MN/ 1525/81, H5N2, H7N1, H7N7 and H9N2) and swine influenza (for example, swine influenza A, strains HlNl (including but not limited to A/WS/33, A/NWS/33, and A/California/04/2009 strains), H1N2 and H3N2). Also provided is a method of decreasing infection by a gastrointestinal virus in a subject said method comprising administering to the subject an effective amount of a compound having the structure of formula I

wherein:

Formula II

Formula III

wherein:

R₄ is H, methyl or together with R₃ forms C_2-6 alkylene;

R₅ is R₆O-CH₂--, wherein R₆ is selected from H, alkyl, alkenyl, alkynyl, aryl, alky lcarbony 1, arylcarbonyl, heteroarylcarbony 1 , hydroxyalky 1 carbony 1 ,

hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl,

dihydroxyalkylarylalkyl,alkoxyalkyl, alkylcarbonyloxyalkyl, anlinoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonalnidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl and carbalkoxyalkyl; R₇CO-, wherein R₇ is selected from H, alkyl, hydroxy, alkoxy, aryloxy, amino, alkylamino, a residue of an amino acid, or N,N-disubstituted-amino wherein the substituents (a) are selected from alkyl, aryl or arylalkyl or (b) form a heterocyclic structure; R₈NCH-, wherein R₈ is alkyl, aryl, amino, alkylamino, arylamino, hydroxy, alkoxy or arylsulfonylamino; --O-CH-O-; or substituted

dioxymethylyne;

Y is selected from O (H, OH), and (H, OR₉) wherein R₉ is selected from

Ci_-4alkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl,

aminoalkylcarbonyl, formyl or aryl; wherein "alk" or "alkyl" refers to a Ci- 10 aliphatic substituent optionally interrupted by an oxy linkage, and "ar" or "aryl" refers to a monocyclic, optionally heterocyclic, optionally substituted, C_{4 -} I₄ aromatic substituent.

Any "alk" moiety or "alkyl" mentioned above may be branched, linear or cyclic; preferably it is a C i_-6 aliphatic substituent optionally interrupted by an oxy linkage. More preferably uninterrupted by oxy. Examples of "ar" moiety or "aryl" mentioned above and optionally substituted may include e.g. phenyl, benzyl, tolyl, pyridyl and the like.

Further provided is a method of decreasing infection by a gastrointestinal virus in a subject said method comprising administering to the subject an effective amount of a compound having the structure of formula IV

wherein

X is (H,OH) or O;

Y is (H,OH) or O;

Ri and R₂ are independently selected from H, alkyl, thioalkyl, arylalkyl,

hydroxyalkyl, dihydroxyalkyl hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl,

carbalkoxyalkyl and (R₃)₃Si where each R₃ is independently selected from H, methyl, ethyl, isopropyl, t-butyl and phenyl; wherein "alk-" or "alkyl" refers to C i _-6 alkyl branched or linear preferably Ci .₃ alkyl in which the carbon chain may be optionally interrupted by an ether (-- 0—) linkage; and

R₄ is methyl, or R₄ and Ri together form C_2- 5 alkylene; provided that Ri and R₂ are not both H; and provided that where Ri is (R₃)₃Si or carbalkoxyalkyl, X and Y are not both O.

Further provided is a method of decreasing infection by a gastrointestinal virus in a subject said method comprising administering to the subject an effective amount of everolimus and has the structure of compound V

Gastrointestinal viruses include, but are not limited to, picornaviruses, adenoviruses, filoviruses, flaviviruses, calciviruses and reoviruses. More specifically, and not to be limiting, the gastrointestinal virus can be a reovirus, a Norwalk virus, an Ebola virus, a Marburg virus, a rotavirus, an enterovirus, an adenovirus, a West Nile virus, a Dengue fever virus or a yellow fever virus.

The present invention also provides a method of decreasing infection by a virus in a subject said method comprising administering to the subject an effective amount of a compound set forth herein, wherein the virus is a pox virus, BVDV, a herpes virus, HIV, an RSV virus, an influenza virus, a hepatitis C virus, a hepatitis B virus, Epstein Barr Virus, Human Papilloma Virus, CMV, West Nile virus, a rhinovirus, an adenovirus, measles virus, Marburg virus, Ebola virus, Rift Valley Fever Virus, LCM, Junin virus, Machupo virus, Guanarito virus, Lassa Fever virus, Hantavirus, SARS virus, Nipah virus, Caliciviruses, Hepatitis A, LaCrosse, California encephalitis, VEE, EEE₅WEE, Japanese Encephalitis Virus, Kyasanur Forest Virus, Yellow Fever, Rabies, Chikungunya virus or a Dengue fever virus. For example, the compound can be a compound of structure I as defined above, a compound of structure IV as defined above, or a compound of structure V as defined above.

Other rapamycin derivatives such as, tacrolimus, pimecrolimus, zotarolimus, temsirolimus, deforolimus, CCI-779, AP23841, ABT-578 and SDZ-RAD and

pharmaceutically acceptable salts thereof can also be used to decrease infection in the methods set forth herein. Therefore, the present invention also provides a method of decreasing infection by a respiratory virus in a subject said method comprising administering to the subject an effective amount of a compound selected from the group consisting of: tacrolimus, sirolimus, pimecrolimus, zotarolimus, temsirolimus, deforolimus, CCI-779, AP23841 , ABT-578 and SDZ-RAD. Also provided is a method of decreasing infection by a gastrointestinal virus in a subject said method comprising administering to the subject an effective amount of a compound selected from the group consisting of: tacrolimus, sirolimus, pimecrolimus, zotarolimus, temsirolimus, deforolimus, CCI-779, AP23841, ABT-578 and SDZ-RAD. Further provided is a method of decreasing infection by a virus in a subject said method comprising administering to the subject an effective amount of a compound selected from the group consisting of tacrolimus, sirolimus, pimecrolimus, zotarolimus, temsirolimus, deforolimus, CCI-779, AP23841, ABT-578 and SDZ-RAD, wherein the virus is a pox virus, BVDV, a herpes virus, HIV, an RSV virus, an influenza virus, a hepatitis C virus, a hepatitis B virus, Epstein Barr Virus, Human Papilloma Virus, CMV, West Nile virus, a rhinovirus, an adenovirus, measles virus, Marburg virus, Ebola virus, Rift Valley Fever Virus, LCM, Junin virus, Machupo virus, Guanarito virus, Lassa Fever virus, Hantavirus, SARS virus, Nipah virus, Caliciviruses, Hepatitis A, LaCrosse, California encephalitis, VEE, EEE₅WEE, Japanese Encephalitis Virus, Kyasanur Forest Virus, Yellow Fever, Rabies, Chikungunya virus or a Dengue fever virus.

A compound can be single compound or a mixture, cocktail or combination of two or more compounds, for example, two or more compounds having a structure selected from the group consisting of formula I, IV, or V, as defined above. It is understood that any compound set forth herein and derivatives of same can be utilized in the methods set forth herein.

The compounds set forth herein can be used alone or in combination with other therapeutic agents such as antiviral compounds, antibacterial agents, antifungal agents, antiparasitic agents, anti-inflammatory agents, anti-cancer agents, etc. All of the compounds described herein can be contacted with a cell in vitro, ex vivo or in vivo.

Examples of antiviral compounds include, but are not limited to, amantadine, rimantadine, ribavirin, zanamavir (Relenza®) and oseltamavir (Tamiflu®) for the treatment of flu and its associated symptoms. Antiviral compounds useful in the treatment of HIV include Combivir® (lamivudine-zidovudine), maraviroc, Crixivan® (indinavir), Emtriva® (emtricitabine), Epivir® (lamivudine), Fortovase® (saquinavir-sg), Hivid® (zalcitabine), Invirase® (saquinavir-hg), Kaletra® (lopinavir-ritonavir), LexivaTM (fosamprenavir), Norvir® (ritonavir), Retrovir® (zidovudine), Sustiva® (efavirenz), Videx EC® (didanosine), Videx® (didanosine), Viracept® (nelfinavir), Viramune® (nevirapine), Zerit® (stavudine), Ziagen® (abacavir), Fuzeon® (enfuvirtide), Rescriptor® (delavirdine), Reyataz®

(atazanavir), Trizivir® (abacavir-lamivudine-zidovudine), Viread® (tenofovir disoproxil fumarate), Truvada® (tenofovir-emtricitabine), Atripla® (tenofovir-emtricitabine-efavirenz) and Agenerase® (amprenavir). Other antiviral compounds useful in the treatment of Ebola and other filoviruses include ribavirin and cyanovirin-N (CV-N). For the treatment of herpes virus, Zovirax®(acyclovir) is available. Antibacterial agents include, but are not limited to, antibiotics (for example, penicillin and ampicillin), sulfa Drugs and folic acid Analogs, Beta- Lactams, aminoglycosides, tetracyclines, macrolides, lincosamides, streptogramins, fluoroquinolones, rifampin, mupirocin, cycloserine, aminocyclitol and oxazolidinones.

Antifungal agents include, but are not limited to, amphotericin, nystatin, terbinafine, itraconazole, fluconazole, ketoconazole, and griselfulvin.

Antiparasitic agents include, but are not limited to, anthelmintics, antinematodal agents, antiplatyhelmintic agents, antiprotozoal agents, amebicides, antimalarials, antitrichomonal agents, aoccidiostats and trypanocidal agents.

The present invention also provides a method of decreasing an unspecified viral infection in a subject comprising: a) diagnosing a subject with an unspecified viral infection; and; b) administering to the subject an effective amount of a compound having the structure of formula I

wherein:

Ri is alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, benzyl, alkoxybenzyl or chlorobenzyl, R₂ is selected from formula II or formula III: Formula II

Formula III

wherein:

R₄ is H, methyl or together with R₃ forms C_2-6 alkylene;

R₅ is R₆O-CH₂-, wherein R₆ is selected from H, alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkyl carbonyl,

hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl,

dioxymethylyne;

Y is selected from O (H, OH), and (H, OR₉) wherein R₉ is selected from

C]_-4alkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl or aryl; wherein "alk" or "alkyl" refers to a Ci_{- 10} aliphatic substituent optionally interrupted by an oxy linkage, and "ar" or "aryl" refers to a monocyclic, optionally heterocyclic, optionally substituted, C_{4 -} 14 aromatic substituent;

and wherein the compound inhibits infection by two or more viruses. The two or more viruses can be selected from the group consisting of a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus, an adenovirus, a flavivirus, a filovirus, a calicivirus and a reovirus.

Further provided is a method of decreasing an unspecified viral infection in a subject comprising: a) diagnosing a subject with an unspecified viral infection; and; b) administering to the subject an effective amount of a compound having the structure of formula IV

wherein

X is (H₃OH) or O;

Y is (H,0H) or O; Ri and R₂ are independently selected from H, alkyl, thioalkyl, arylalkyl,

hydroxyalkyl, dihydroxyalkyl hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl,

carbalkoxyalkyl and (R₃)₃Si where each R₃ is independently selected from H, methyl, ethyl, isopropyl, t-butyl and phenyl; wherein "alk-" or "alkyl" refers to C i_-6 alkyl branched or linear preferably Q .₃ alkyl in which the carbon chain may be optionally interrupted by an ether (-- 0—) linkage; and

R₄ is methyl, or R₄ and Ri together form C_{2- 5} alkylene; provided that Ri and R₂ are not both H; and provided that where Ri is (R₃)₃Si or carbalkoxyalkyl, X and Y are not both O; and wherein the compound inhibits infection by two or more viruses. The two or more viruses can be selected from the group consisting of a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus, an adenovirus, a flavivirus, a filovirus, a calicivirus and a reovirus.

Also provided is a method of decreasing an unspecified viral infection in a subject comprising: a) diagnosing a subject with an unspecified viral infection; and; b) administering to the subject an effective amount of everolimus having the structure of compound V

wherein the compound inhibits infection by two or more viruses. The two or more viruses can be selected from the group consisting of a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus, an adenovirus, a flavivirus, a filovirus, a calicivirus and a reovirus.

Further provided is a method of decreasing an unspecified respiratory or

gastrointestinal infection in a subject comprising: a) diagnosing a subject with an unspecified respiratory or gastrointestinal infection; and b) administering to the subject an effective amount of a compound having the structure of formula I

wherein:

Formula II

Formula III

wherein: R₃ is selected from H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, ally!, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl and alkylsilyl;

R₄ is H, methyl or together with R₃ forms C_2-6 alkylene;

R₅ is RnO-CH₂-, wherein R₆ is selected from H, alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalky 1 carbony 1 ,

hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl,

dihydroxyalkylarylalkyl,alkoxyalkyl, alkylcarbonyloxyalkyl, anlinoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonalnidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl and carbalkoxyalkyl; R₇CO-, wherein R₇ is selected from H, alkyl, hydroxy, alkoxy, aryloxy, amino, alkylamino, a residue of an amino acid, or N,N-disubstituted-amino wherein the substituents (a) are selected from alkyl, aryl or arylalkyl or (b) form a heterocyclic structure; RsNCH-, wherein R₈ is alkyl, aryl, amino, alkylamino, arylamino, hydroxy, alkoxy or arylsulfonylamino;— O-CH-O-; or substituted

dioxymethylyne;

Y is selected from O (H, OH), and (H, OR₉) wherein R₉ is selected from

alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl or aryl; wherein "alk" or "alkyl" refers to a Ci_{- 10} aliphatic substituent optionally interrupted by an oxy linkage, and "ar" or "aryl" refers to a monocyclic, optionally heterocyclic, optionally substituted, C_{4 -} I₄ aromatic substituent;

and wherein the compound inhibits infection by two or more gastrointestinal viruses selected from the group consisting of a flavivirus, a filovirus, an adenovirus, a calcivirus and a reovirus or the compound inhibits infection by two or more respiratory viruses selected from the group consisting of a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus, and an adenovirus.

Any "alk" moiety or "alkyl" mentioned above may be branched, linear or cyclic;

preferably it is a C _I-6 aliphatic substituent optionally interrupted by an oxy linkage. More preferably uninterrupted by oxy. Examples of "ar" moiety or "aryl" mentioned above and optionally substituted may include e.g. phenyl, benzyl, tolyl, pyridyl and the like.

Also provided is a method of decreasing an unspecified respiratory or gastrointestinal infection in a subject comprising: a) diagnosing a subject with an unspecified respiratory or gastrointestinal infection; and; b) administering to the subject an effective amount of a compound having the structure of formula IV

wherein

X is (H,0H) or O;

Y is (H,0H) or O;

Ri and R₂ are independently selected from H, alkyl, thioalkyl, arylalkyl,

hydroxyalkyl, dihydroxyalkyl hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl,

carbalkoxyalkyl and (R₃^Si where each R₃ is independently selected from H, methyl, ethyl, isopropyl, t-butyl and phenyl; wherein "alk-" or "alkyl" refers to C i _-6 alkyl branched or linear preferably Ci .₃ alkyl in which the carbon chain may be optionally interrupted by an ether (-- 0—) linkage; and

R₄ is methyl, or R₄ and Ri together form C_{2- 5} alkylene; provided that Ri and R₂ are not both H; and provided that where Ri is (R₃)₃Si or carbalkoxyalkyl, X and Y are not both O; and wherein the compound inhibits infection by two or more gastrointestinal viruses selected from the group consisting of a flavivirus, a filovirus, an adenovirus, a calcivirus and a reovirus or the compound inhibits infection by two or more respiratory viruses selected from the group consisting of a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus, and an adenovirus.

Also provided is a method of decreasing an unspecified respiratory or gastrointestinal infection in a subject comprising: a) diagnosing a subject with an unspecified respiratory or gastrointestinal infection; and; b) administering to the subject an effective amount of everolimus having the structure of compound V

wherein the compound inhibits infection by two or more gastrointestinal viruses selected from the group consisting of a flavivirus, a filovirus, an adenovirus, a calcivirus and a reovirus or the compound inhibits infection by two or more respiratory viruses selected from the group consisting of a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus, and an adenovirus.

As set forth above, the methods and compounds set forth herein can be utilized to inhibit infection by two or more respiratory viruses. Therefore, the methods and compounds set forth herein can be utilized to inhibit infection by two or more, three or more, four or more, or five or more respiratory viruses. These can be selected from the group consisting of: a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus and an adenovirus. Since picornaviruses, orthomyxoviruses, paramyxoviruses, coronaviruses and adenoviruses are families of viruses, two or more, three or more, four or more, or five or more respiratory viruses can be from the same or from different families. For example, and not to be limiting, a compound set forth herein can inhibit infection by two or more orthomyxoviruses; two or more picornaviruses; an orthomyxovirus, an adenovirus, and a picornavirus; an

orthomyxovirus, a paramyxovirus and an adenovirus; an orthomyxovirus, two picornaviruses and a paramyxovirus; three orthomyxoviruses, a picornavirus and an adenovirus, etc. More particularly, the composition can inhibit infection by two or more, three or more or four or more respiratory viruses selected from the group consisting of an influenza virus, a parainfluenza virus, an adenovirus, a rhinovirus and an RSV virus.

As set forth above, the methods and compounds provided herein can be utilized to inhibit infection by two or more gastrointestinal viruses. Therefore, the methods and compounds provided herein can be utilized to inhibit infection by two or more, three or more, four or more, or five or more gastrointestinal viruses. These viruses can be selected from the group consisting of: a fϊlovirus, a picornavirus, an adenovirus, a calcivirus, a flavivirus or a reovirus. Since filoviruses, picornaviruses, calciviruses, flaviviruses and reoviruses are families of viruses, the composition can inhibit infection by two or more, three or more, four or more, or five or more gastrointestinal viruses from the same or from different families. More particularly, the composition can inhibit infection by two or more, three or more, four or more, or five or more gastrointestinal viruses selected from the group consisting of a reovirus, a Norwalk virus, an Ebola virus, an adenovirus, a Marburg virus, a Dengue fever virus, a West Nile virus, a yellow fever virus, a rotavirus and an enterovirus.

The present invention also provides a method of decreasing infection in a subject comprising administering to the subject an effective amount of a compound set forth herein that inhibits co-infection by HIV and one or more viruses, bacteria, parasites or fungi. For example, decreasing co-infection of HIV and any of the viruses set forth herein, including for example any families, genus, species, or group of viruses. As a further example, co-infection of HIV and a respiratory virus is provided herein. Respiratory viruses include picornaviruses, orthomyxoviruses, paramyxoviruses, coronaviruses, and adenoviruses. More specifically, the respiratory virus can be any strain of influenza, rhinovirus, adenovirus, parainfluenza virus or RSV. Also provided is decreasing co-infection of HIV and a gastrointestinal virus.

Gastrointestinal viruses include picornaviruses, filoviruses, flaviviruses, adenoviruses, calciviruses and reoviruses. More specifically, and not to be limiting, the gastrointestinal virus can be any strain of reovirus, a Norwalk virus, an Ebola virus, an adenovirus, a Marburg virus, a rotavirus, an enterovirus, a Dengue fever virus, a yellow fever virus, or a West Nile virus. Further provided is a method of decreasing co-infection of HIV with a pox virus, LCM, Junin virus, Machupo virus, Guanarito virus, Lassa Fever virus, hantavirus, Rift Valley Fever virus Ebola virus, Marburg virus or Dengue Fever virus. More particularly, decreasing co-infection of HIV and a hepatitis virus, such as Hepatitis A, Hepatitis B or Hepatitis C is provided.

Methods of Decreasing Toxicity with Rapamycin and Rapamycin Derivatives

The present invention also provides a method of decreasing the toxicity of a toxin in a cell comprising administering to the cell an effective amount of a compound having the structure of formula I

wherein:

Formula II

Formula III

wherein:

R₃ is selected from H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxy alkyl and alkylsilyl;

R₄ is H, methyl or together with R₃ forms C_2-6 alkylene;

hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl,

dioxymethylyne;

Y is selected from O (H, OH), and (H, OR₉) wherein R₉ is selected from

Ci_-4alkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl or aryl; wherein "alk" or "alkyl" refers to a Ci_{- 10} aliphatic substituent optionally interrupted by an oxy linkage, and "ar" or "aryl" refers to a monocyclic, optionally heterocyclic, optionally substituted, C_{4 - 14} aromatic substituent.

Any "alk" moiety or "alkyl" mentioned above may be branched, linear or cyclic; preferably it is a C ι_-6 aliphatic substituent optionally interrupted by an oxy linkage. More preferably uninterrupted by oxy. Examples of "ar" moiety or "aryl" mentioned above and optionally substituted may include e.g. phenyl, benzyl, tolyl, pyridyl and the like.

When R₅ is substituted dioxymethylyne, it may be e.g. O,O-(alkylene)-dioxy- methylyne, i.e. wherein the 2 oxygens are linked by an alkylene group. It is understood that cellular toxicity is also known as intoxication. Therefore, decreasing the toxicity of a toxin also means decreasing intoxication in or of a cell.

Further provided is a method of decreasing the toxicity of a toxin in a cell comprising administering to the cell an effective amount of a compound having the structure of formula IV

wherein

X is (H,0H) or O;

Y is (H,0H) or O;

Ri and R₂ are independently selected from H, alkyl, thioalkyl, arylalkyl,

hydroxyalkyl, dihydroxyalkyl hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl,

carbalkoxyalkyl and (Rs)₃Si where each R₃ is independently selected from H, methyl, ethyl, isopropyl, t-butyl and phenyl; wherein "alk-" or "alkyl" refers to C i _-6 alkyl branched or linear preferably Q .₃ alkyl in which the carbon chain may be optionally interrupted by an ether (— 0—) linkage; and

Further provided is a method of decreasing the toxicity of a toxin in a cell comprising administering to the cell an effective amount of everolimus having the structure of compound V

The cell can be in vitro, ex vivo or in vivo (for example in a subject). Toxins can include, but are not limited to, a bacterial toxin, a neurotoxin, such as a botulinum

neurotoxin, a mycotoxin, ricin, a Clostridium perfringens toxin, a Clostridium difficile toxin, a saxitoxin, a tetrodotoxin, abrin, a conotoxin, a Staphlococcat 'toxin, an E. coli toxin, a streptococcal toxin, a shigatoxin, a T-2 toxin, an anthrax toxin, chimeric forms of the toxins listed herein, and the like. The decrease in toxicity can be at least about 10%, 20%, 30%, 40%, 50%, 60, 70%, 80%, 90%, 95%, 100% or any other percentage decrease in between these percentages as compared to the level of toxicity in a cell not contacted with a compound that decreases the toxicity of a toxin. Toxicity can be measured, for example, via a cell viability assay, apopotosis assay, LDH release assay or cytotoxicity assay (See, for example, Kehl-Fie and St. Geme "Identification and characterization of an RTX toxin in the emerging pathogen Kingella kingae " J. Bacteriol. 189(2):430-6 (2006) and Kirby "Anthrax Lethal Toxin Induces Human Endothelial cell Apoptosis," Infection and Immunity 72: 430- 439 (2004), both of which are incorporated herein in their entireties by this reference).

Methods of Decreasing Infection Using Ethers of N-Propanolamines

The present invention further provides a method of decreasing infection in a subject by a pathogen comprising administering to the subject an effective amount of a compound having the structure of formula VI or a compound having the structure of formula VII.

More specifically, the present invention provides a method of decreasing infection by a respiratory virus in a subject said method comprising administering to the subject an effective amount of a compound having the structure of formula VI

wherein A is a tertiary aliphatic, cycloaliphatic or heterocyclic amino group, R is a straight or branched chain alkyl group or an aralkyl group, Ar is an aromatic group and Ar¹ is an aromatic or heterocyclic group, and pharmacologically acceptable salts thereof. When Ar and Ar¹ are both aromatic groups they may be like or unlike. Ar and Ar' may both be monocyclic aromatic groups and Ar¹ may be a heteromonocyclic group which may contain a nuclear nitrogen atom with or without an additional nuclear hetero atom.

The present invention also provides a method of decreasing infection by a respiratory virus in a subject said method comprising administering to the subject an effective amount of a compound having the structure of formula VI:

wherein A is morpholino, pyrrolidino, piperidyl, or di-alkyl amino, R is a straight or branched chain alkyl, or benzyl, Ar is aryl and Ar¹ is aryl or pyridyl, and pharmacologically acceptable salts thereof.

In the methods desribed herein, the compound can be a compound having the structure of formula VI wherein A is pyrrolidino, R is isobutyl and Ar and Ar¹ are both phenyl, and the hydrochloride thereof; a compound having the structure of formula VI wherein A is pyrrolidino, R is isobutyl, Ar is phenyl and Ar' is 2-pyridyl and the acid fumarate thereof; a compound having the structure of formula VI wherein A is diethylamino, R is an isobutyl and Ar and Ar¹ are both phenyl and the acid fumarate thereof; a compound having formula VI wherein A is morpholino, R is isobutyl and Ar and Ar¹ are both phenyl and the acid fumarate thereof; or a compound having the structure of formula VI wherein A is piperidyl, R is benzyl and Ar and Ar¹ are both phenyl and the hydrochloride thereof.

A preferred compound of formula VI is bepridil, set forth below as formula VII.

Bepridil is a calcium channel blocker also known as Vascor®. This compound is also known as N-benzyl-N-(3-isobutoxy-2-pyrrolidin-l-yl-propyl)aniline or l-(3-isobutoxy-2- (phenylbenzyl)-amino)-propyl-pyrrolidino-hydrochloride.

Therefore, the present invention also provides a method of decreasing infection by a respiratory virus in a subject said method comprising administering to the subject an effective amount of a compound, wherein the compound is bepridil and has the structure of formula VII, and pharmacologically acceptable salts thereof

Compounds having the structure of formula VI or formula VII can be made according to the methods set forth in U.S. Patent No. 3,962,238 or U.S. Patent Reissue No. 30,577, both of which are hereby incorporated in their entirety by this reference. Bepridil can also be obtained from Sigma Chemical Co. (St. Louis, MO).

Respiratory viruses can include, but are not limited to, picornaviruses,

orthomyxoviruses, paramyxoviruses, coronaviruses and adenoviruses. More specifically, and not to be limiting, the respiratory virus can be an influenza virus, a parainfluenza virus, an adenovirus, a rhinovirus (for example, rhinovirus A, rhinovirus B, HRVi₆, HRVi₆ (VR- 11757), HRV₁₄ (VR-284), or HRV_1A (VR-1559)) or a respiratory syncytial virus (RSV) (for example RSV strain A2). As mentioned above, all strains of viruses are contemplated herein. For example, and not to be limiting, influenza viruses include influenza A, influenza A strain A/Victoria/3/75, influenza A strain A/Puerto Rico/8/34, influenza B, influenza B strain Lee, and influenza C viruses. Also included are animal counterparts of the pathogens set forth herein. These include animal influenza viruses such as avian influenza (for example, strains H5N1 , H5N1 Duck/MN/1525/81 , H5N2, H7N1, H7N7 and H9N2) and swine influenza (for example, swine influenza A, strains HlNl (including but not limited to A/WS/33, A/NWS/33, and A/California/04/2009 strains), H1N2 and H3N2).

Also provided is a method of method of decreasing infection by a gastrointestinal virus in a subject said method comprising administering to the subject an effective amount of a compound having the structure of formula VI

wherein A is a tertiary aliphatic, cycloaliphatic or heterocyclic amino group, R is a straight or branched chain alkyl group or an aralkyl group, Ar is an aromatic group and Ar' is an aromatic or heterocyclic group, and pharmacologically acceptable salts thereof. When Ar and Ar' are both aromatic groups they may be like or unlike. Ar and Ar' may both be monocyclic aromatic groups and Ar¹ may be a heteromonocyclic group which may contain a nuclear nitrogen atom with or without an additional nuclear hetero atom.

The present invention also provides a method of decreasing infection by a

gastrointestinal virus in a subject said method comprising administering to the subject an effective amount of a compound having the structure of formula VI

The present invention further provides a method of decreasing infection by a gastrointestinal virus in a subject said method comprising administering to the subject an effective amount of a compound, wherein the compound is bepridil and has the structure of formula VII, and pharmacologically acceptable salts thereof

Gastrointestinal viruses include, but are not limited to, picornaviruses, adenoviruses, fϊloviruses, flaviviruses, calciviruses and reoviruses. More specifically, and not to be limiting, the gastrointestinal virus can be a reovirus, a Norwalk virus, an Ebola virus, a Marburg virus, a rotavirus, an enterovirus, an adenovirus, a West Nile virus, a Dengue fever virus or a yellow fever virus.

The present invention also provides a method of decreasing infection by a virus in a subject said method comprising administering to the subject an effective amount of a compound set forth herein, wherein the virus is a pox virus, BVDV, a herpes virus, HIV, an RSV virus, an influenza virus, a hepatitis C virus, a hepatitis B virus, Epstein Barr Virus, Human Papilloma Virus, CMV, West Nile virus, a rhinovirus, an adenovirus, measles virus, Marburg virus, Ebola virus, Rift Valley Fever Virus, LCM, Junin virus, Machupo virus, Guanarito virus, Lassa Fever virus, Hantavirus, SARS virus, Nipah virus, Caliciviruses, Hepatitis A, LaCrosse, California encephalitis, VEE, EEE₅WEE, Japanese Encephalitis Virus, Kyasanur Forest Virus, Yellow Fever, Rabies, Chikungunya virus or a Dengue fever virus. For example, the compound can be a compound of structure VI as defined above or a compound of structure VII as defined above.

A compound can be single compound or a mixture, cocktail or combination of two or more compounds, for example, two or more compounds having a structure selected from the group consisting of formula I, IV, V, VI, and VII as defined above. It is understood that any compound set forth herein and derivatives of same can be utilized in the methods set forth herein.

Antifungal agents include, but are not limited to, amphotericin, nystatin, terbinafϊne, itraconazole, fluconazole, ketoconazole, and griselfulvin.

Antiparasitic agents include, but are not limited to, anthelmintics, antinematodal agents, antiplatyhelmintic agents, antiprotozoal agents, amebicides, antimalarials,

antitrichomonal agents, aoccidiostats and trypanocidal agents.

The present invention also provides a method of decreasing an unspecified viral infection in a subject comprising: a) diagnosing a subject with an unspecified viral infection; and b) administering to the subject an effective amount of a compound having the structure of formula VI

wherein A is a tertiary aliphatic, cycloaliphatic or heterocyclic amino group, R is a straight or branched chain alkyl group or an aralkyl group, Ar is an aromatic group and Ar¹ is an aromatic or heterocyclic group, and pharmacologically acceptable salts thereof. When Ar and Ar¹ are both aromatic groups they may be like or unlike. Ar and Ar¹ may both be monocyclic aromatic groups and Ar¹ may be a heteromonocyclic group which may contain a nuclear nitrogen atom with or without an additional nuclear hetero atom; and wherein the compound inhibits infection by two or more viruses. The two or more viruses can be selected from the group consisting of a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus, an adenovirus, a flavivirus, a filovirus, a calicivirus and a reovirus.

Further provided is a method of decreasing an unspecified viral infection in a subject comprising: a) diagnosing a subject with an unspecified viral infection; and b) administering to the subject an effective amount of a compound having the structure of formula VI

wherein A is morpholino, pyrrolidino, piperidyl, or di-alkyl amino, R is a straight or branched chain alkyl, or benzyl, Ar is aryl and Ar¹ is aryl or pyridyl, and pharmacologically acceptable salts thereof, and wherein the compound inhibits infection by two or more viruses. The two or more viruses can be selected from the group consisting of a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus, an adenovirus, a flavivirus, a filovirus, a calicivirus and a reovirus.

Further provided is a method of decreasing an unspecified viral infection in a subject comprising: a) diagnosing a subject with an unspecified viral infection; and b) administering to the subject an effective amount of a compound having the structure of formula VII, and pharmacologically acceptable salts thereof

Further provided is a method of decreasing an unspecified respiratory or

gastrointestinal infection in a subject comprising: a) diagnosing a subject with an unspecified respiratory or gastrointestinal infection; and b) administering to the subject an effective amount of a compound having the structure of formula VI

wherein A is a tertiary aliphatic, cycloaliphatic or heterocyclic amino group, R is a straight or branched chain alkyl group or an aralkyl group, Ar is an aromatic group and Ar' is an aromatic or heterocyclic group, and pharmacologically acceptable salts thereof. When Ar and Ar¹ are both aromatic groups they may be like or unlike. Ar and Ar¹ may both be monocyclic aromatic groups and Ar¹ may be a heteromonocyclic group which may contain a nuclear nitrogen atom with or without an additional nuclear hetero atom; and wherein the compound inhibits infection by two or more gastrointestinal viruses selected from the group consisting of a flavivirus, a filovirus, an adenovirus, a calcivirus or a reovirus; or the compound inhibits infection by two or more respiratory viruses selected from the group consisting of a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus, and an adenovirus.

Further provided is a method of decreasing an unspecified respiratory or

gastrointestinal infection in a subject comprising: a) diagnosing a subject with an unspecified respiratory or gastrointestinal infection; and b) administering to the subject an effective amount of a compound having the structure of formula VI Ar -

wherein A is morpholino, pyrrolidino, piperidyl, or di-alkyl amino, R is a straight or branched chain alkyl, or benzyl, Ar is aryl and Ar¹ is aryl or pyridyl, and pharmacologically acceptable salts thereof, and wherein the compound inhibits infection by two or more gastrointestinal viruses selected from the group consisting of a flavivirus, a filovirus, an adenovirus, a calcivirus or a reovirus; or the compound inhibits infection by two or more respiratory viruses selected from the group consisting of a picornavirus, an orthomyxovirus, a

paramyxovirus, a coronavirus, and an adenovirus.

Also provided is a method of decreasing an unspecified respiratory or gastrointestinal infection in a subject comprising: a) diagnosing a subject with an unspecified respiratory or gastrointestinal infection; and; b) administering to the subject an effective amount of a compound having the structure of formula VII, and pharmacologically acceptable salts thereof

wherein the compound inhibits infection by two or more gastrointestinal viruses selected from the group consisting of a flavivirus, a filovirus, an adenovirus, a calcivirus or a reovirus; or the compound inhibits infection by two or more respiratory viruses selected from the group consisting of a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus, and an adenovirus.

As set forth above, the methods and compounds provided herein can be used to inhibit infection by two or more respiratory viruses. Therefore, the methods and compounds set forth herein can be used to inhibit infection by two or more, three or more, four or more, or five or more respiratory viruses. These can be selected from the group consisting of: a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus and an adenovirus. Since picornaviruses, orthomyxoviruses, paramyxoviruses, coronaviruses and adenoviruses are families of viruses, two or more, three or more, four or more, or five or more respiratory viruses can be from the same or from different families. For example, and not to be limiting, a compound set forth herein can inhibit infection by two or more orthomyxoviruses; two or more picornaviruses; an orthomyxovirus, an adenovirus, and a picornavirus; an orthomyxovirus, a paramyxovirus and an adenovirus; an orthomyxovirus, two picornaviruses and a paramyxovirus; three orthomyxoviruses, a picornavirus and an adenovirus, etc. More particularly, the composition can inhibit infection by two or more, three or more or four or more respiratory viruses selected from the group consisting of an influenza virus, a parainfluenza virus, an adenovirus, a rhinovirus and an RSV virus.

As set forth above, the methods and compounds provided herein can be used to inhibit infection by two or more gastrointestinal viruses. Therefore, the methods and compounds can be used to inhibit infection by two or more, three or more, four or more, or five or more gastrointestinal viruses. These viruses can be selected from the group consisting of: a filovirus, a picornavirus, an adenovirus, a calcivirus, a flavivirus or a reovirus. Since fϊloviruses, picornaviruses, adenoviruses, calciviruses, flaviviruses and reoviruses are families of viruses, the composition can inhibit infection by two or more, three or more, four or more, or five or more gastrointestinal viruses from the same or from different families. More particularly, the composition can inhibit infection by two or more, three or more, four or more, or five or more gastrointestinal viruses selected from the group consisting of a reovirus, a Norwalk virus, an Ebola virus, an adenovirus, a Marburg virus, a Dengue fever virus, a West Nile virus, a yellow fever virus, a rotavirus and an enterovirus.

Gastrointestinal viruses include picornaviruses, filoviruses, flaviviruses, adenoviruses, calciviruses and reoviruses. More specifically, and not to be limiting, the gastrointestinal virus can be any strain of reovirus, adenovirus, a Norwalk virus, an Ebola virus, an adenovirus, a Marburg virus, a rotavirus, an enterovirus, a Dengue fever virus, a yellow fever virus, or a West Nile virus. Further provided is a method of decreasing co-infection of HIV with a pox virus, LCM, Junin virus, Machupo virus, Guanarito virus, Lassa Fever virus, hantavirus, Rift Valley Fever virus Ebola virus, Marburg virus or Dengue Fever virus. More particularly, decreasing co-infection of HIV and a hepatitis virus, such as Hepatitis A, Hepatitis B or Hepatitis C is provided.

Methods of Decreasing Toxicity Using Ethers of N-Propanolamines

The present invention also provides a method of decreasing the toxicity of a toxin in a cell comprising administering to the cell an effective amount of a compound having the structure of formula VI

Ar -

wherein A is a tertiary aliphatic, cycloaliphatic or heterocyclic amino group, R is a straight or branched chain alkyl group or an aralkyl group, Ar is an aromatic group and Ar¹ is an aromatic or heterocyclic group, and pharmacologically acceptable salts thereof. When Ar and Ar¹ are both aromatic groups they may be like or unlike. Ar and Ar¹ may both be monocyclic aromatic groups and Ar¹ may be a heteromonocyclic group which may contain a nuclear nitrogen atom with or without an additional nuclear hetero atom.

Further provided is a method of decreasing the toxicity of a toxin in a cell comprising administering to the cell an effective amount of a compound having the structure of formula VI

Ar -

wherein A is morpholino, pyrrolidino, piperidyl, or di-alkyl amino, R is a straight or branched chain alkyl, or benzyl, Ar is aryl and Ar¹ is aryl or pyridyl, and pharmacologically acceptable salts thereof. Further provided is a method of decreasing the toxicity of a toxin in a cell comprising administering to the cell an effective amount of a compound having the structure of formula VII, and pharmacologically acceptable salts thereof

neurotoxin, a mycotoxin, ricin, a Clostridium perfringens toxin, a Clostridium difficile toxin, a saxitoxin, a tetrodotoxin, abrin, a conotoxin, a Staph iococca/ toxin, an E. coli toxin, a streptococcal toxin, a shigatoxin, a T-2 toxin, an anthrax toxin, chimeric forms of the toxins listed herein, and the like. The decrease in toxicity can be at least about 10%, 20%, 30%, 40%, 50%, 60, 70%, 80%, 90%, 95%, 100% or any other percentage decrease in between these percentages as compared to the level of toxicity in a cell not contacted with a compound that decreases the toxicity of a toxin. Toxicity can be measured, for example, via a cell viability assay, apopotosis assay, LDH release assay or cytotoxicity assay (See, for example, Kehl-Fie and St. Geme "Identification and characterization of an RTX toxin in the emerging pathogen Kingella kingae " J. Bacteriol. 189(2):430-6 (2006) and Kirby "Anthrax Lethal Toxin Induces Human Endothelial cell Apoptosis," Infection and Immunity 72: 430- 439 (2004), both of which are incorporated herein in their entireties by this reference). Delivery systems

Methods of introduction include, but are not limited to, mucosal, topical, intradermal, intrathecal, intratracheal, via nebulizer, via inhalation, intramuscular, otic delivery (ear), eye delivery (for example, eye drops), intraperitoneal, vaginal, rectal, intravenous, subcutaneous, intranasal, and oral routes. The compounds can be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (for example, oral mucosa, rectal, vaginal and intestinal mucosa, etc.) and can be administered together with other biologically active agents. Administration can be systemic or local. Pharmaceutical compositions can be delivered locally to the area in need of treatment, for example by topical application or local injection. The pharmaceutically acceptable carriers useful herein are conventional. Remington 's Pharmaceutical Sciences, by Martin, Mack Publishing Co., Easton, PA, 15th Edition (1975), describes compositions and formulations suitable for pharmaceutical delivery of the therapeutic agents herein disclosed. In general, the nature of the carrier will depend on the mode of administration being employed. For instance, parenteral formulations usually include injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, sesame oil, glycerol, ethanol, combinations thereof, or the like, as a vehicle. The carrier and composition can be sterile, and the formulation suits the mode of administration. In addition to biologically-neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.

The composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. For solid compositions (for example powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, sodium saccharine, cellulose, magnesium carbonate, or magnesium stearate. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.

Embodiments of the disclosure including medicaments can be prepared with conventional pharmaceutically acceptable carriers, adjuvants and counterions as would be known to those of skill in the art.

The amount of therapeutic agent effective in decreasing or inhibiting infection can depend on the nature of the pathogen and its associated disorder or condition, and can be determined by standard clinical techniques. Therefore, these amounts will vary depending on the type of virus, bacteria, fungus, parasite or other pathogen. For example, the dosage can be anywhere from 0.01 mg/kg to 100 mg/kg. For further example, when administered in pill form, the doseage strength can be 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3.0 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4.0 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5.0 mg, 5.25 mg, 5.5 mg, 5.75 mg, 6.0 mg, 6.25 mg, 6.5 mg, 6.75 mg, 7.0 mg, 7.25 mg, 7.5 mg, 7.75 mg, 8.0 mg, 8.25 mg, 8.5 mg, 8.75 mg, 9.0 mg, 9.25 mg, 9.5 mg, 9.75 mg, 10.0 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, etc. Multiple dosages can also be administered depending on the type of pathogen, and the subject's condition. In addition, in vitro assays can be employed to identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each subject's circumstances. Effective doses can be extrapolated from dose- response curves derived from in vitro or animal model test systems.

The disclosure also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration and in particular for viral infection such as a pox virus, BVDV, a herpes virus, HIV, an RSV virus, an influenza virus, a hepatitis C virus, a hepatitis B virus, Epstein Barr Virus, Human Papilloma Virus, CMV, West Nile virus, a rhinovirus, an adenovirus, measles virus, Marburg virus, Ebola virus, Rift Valley Fever Virus, LCM, Junin virus, Machupo virus, Guanarito virus, Lassa Fever virus, Hantavirus, SARS virus, Nipah virus,

Caliciviruses, Hepatitis A, LaCrosse, California encephalitis, VEE, EEE, WEE, Japanese Encephalitis Virus, Kyasanur Forest Virus, Yellow Fever, Rabies, Chikungunya virus or a Dengue fever virus. Instructions for use of the composition, in particular instructions for administration to treat viral infection in a subject can also be included.

The present invention also provides a method of deriving a compound with activity against a pathogen comprising modifying the compound having the structure of formula V

This method can further comprise determining the antipathogenic activity of the compound. The antipathogenic activity of the derivative compound can be determined in silico, in vitro or in vivo.

The present invention also provides a method of deriving a compound with activity against a pathogen comprising modifying the compound having the structure of formula VII, and pharmacologically acceptable salts thereof

EXAMPLES

EXAMPLE 1: RAPAMYCIN DERIVATIVES AND INFECTION

Duplicate experiments were performed as follows. Prior to compound exposure cells were seeded into 12-well tissue culture plates and allowed to adhere to the vessel surface. Everolimus was serially diluted and lOOul was added to the growth medium in triplicate wells to obtain the indicated final concentration of compound or solvent. Cells were incubated in the presence of the test compound for 24 hours at 37°C under 5% CO₂.

Following the pre-treatment period, cells were examined under a phase-contrast microscope to determine any cytotoxic effects at the treatment dosages. The pre-treatment medium was then aspirated off the cells, and the specified virus, diluted in serum- and compound-free growth medium, was added to the cells. Virus was allowed to adsorb to the cells at 37°C with the exception of Rhinovirus, which was adsorbed at 33⁰C, under 5%CO₂. Following adsorption, the viral inoculum was aspirated off the cells and replaced with growth medium supplemented with 2% FBS, 1% L-glutamine, 1% penicillin/streptomycin and the respective concentration of test compound. Cells were incubated under the same conditions for an additional 72 hours. 200ul samples were harvested from each well and viral RNA or DNA was extracted using the PureLink 96 Viral RNA/DNA extraction kit (Invitrogen) as directed by the manufacturer. Viral nucleic acid was subjected to reverse transcription to generate cDNA, which was subsequently used as the template for quantitative real-time TaqMan PCR to titrate viral replication using a Mastercycler ep realplex² (Eppendorf).

Toxicity of the compounds set forth herein was assessed using the CytoTox-Glo assay (see Niles, A. et al. (2007) Anal. Biochem. 366, 197-206 or the Cell-Titer-Glo assay from Promega); however the toxicity of the compounds set forth herein can be assessed via any of the toxicity measurement methods known to one of skill in the art.

Everolimus inhibited infection by pox virus and Dengue fever virus. The decrease in pox virus infection was at least 50% at 4.5 uM, 450 nM and 45 nM concentrations of everolimus, as compared to control. The decrease in Dengue fever virus infection was at least 50% at 4.5 uM and 45OnM concentrations of everolimus as compared to control. A decrease in Dengue fever virus infection of at least 40% was observed with a 4.5 nM concentration of everolimus.

Everolimus also inhibited influenza (IC₅₀ < 0.1 uM; SI = 205) and RSV (IC₅₀ < 0.1 uM; SI = 150) infection. Infection by influenza strains HlNl A/NWS/33, H5N1

A/Duck/MN/ 1525/81, and HlNl A/Puerto Rico/8/34 was also inhibited by everolimus. As utilized herein, IC₅₀ is a quantitative measure which indicates the concentration of a test compound needed to inhibit viral infection by 50%, and SI (selectivity index) = CC₅o/IC₅o. In in vivo studies, influenza infected mice that were contacted with everolimus did not lose weight as rapidly or to the same extent as influenza infected mice that were contacted with vehicle control or ribavirin.

EXAMPLE 2: BEPRIDIL AND INFECTION

Duplicate experiments were performed as follows. Prior to compound exposure cells were seeded into 12-well tissue culture plates and allowed to adhere to the vessel surface.

Bepridil was serially diluted and lOOul was added to the growth medium in triplicate wells to obtain the indicated final concentration of compound or solvent. Cells were incubated in the presence of the test compound for 24 hours at 37°C under 5% CO₂.

Following the pre-treatment period, cells were examined under a phase-contrast microscope to determine any cytotoxic effects at the treatment dosages. The pre-treatment medium was then aspirated off the cells, and the specified virus, diluted in serum- and compound-free growth medium, was added to the cells. Virus was allowed to adsorb to the cells at 37°C with the exception of Rhinovirus, which was adsorbed at 33⁰C, under 5% CO₂. Following adsorption, the viral inoculum was aspirated off the cells and replaced with growth medium supplemented with 2% FBS, 1% L-glutamine, 1% penicillin/streptomycin and the respective concentration of test compound. Cells were incubated under the same conditions for an additional 72 hours. 200ul samples were harvested from each well and viral RNA or DNA was extracted using the PureLink 96 Viral RNA/DNA extraction kit (Invitrogen) as directed by the manufacturer. Viral nucleic acid was subjected to reverse transcription to generate cDNA, which was subsequently used as the template for quantitative real-time TaqMan PCR to titrate viral replication using a Mastercycler ep realplex² (Eppendorf).

Bepridil inhibited infection by Dengue fever virus. Bepridil also inhibited infection by influenza virus (IC50 = 0.13uM, SI = 162), RSV (IC50 < 0.1 uM, SI = 283) and BVDV (IC50 = 1.5uM, SI = 41).

Claims

What is claimed is:

1. A method of decreasing infection by a respiratory virus in a subject said method

comprising administering to the subject an effective amount of a compound having the structure of formula I

wherein:

Formula II

Formula III

wherein: R₃ is selected from H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl and alkylsilyl;

R₄ is H, methyl or together with R₃ forms C_2-6 alkylene;

R₅ is R₆O-CH₂--, wherein R₆ is selected from H, alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkyl carbonyl,

hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl,

dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, anlinoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonalnidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl and carbalkoxyalkyl; R₇CO-, wherein R₇ is selected from H, alkyl, hydroxy, alkoxy, aryloxy, amino, alkylamino, a residue of an amino acid, or N,N-disubstituted-amino wherein the substituents (a) are selected from alkyl, aryl or arylalkyl or (b) form a heterocyclic structure; R₈NCH-, wherein R₈ is alkyl, aryl, amino, alkylamino, arylamino, hydroxy, alkoxy or arylsulfonylamino;— O-CH-O-; or substituted

dioxymethylyne;

Y is selected from O (H, OH), and (H, OR₉) wherein R₉ is selected from

aminoalkyl carbonyl, formyl or aryl;

and wherein "alk" or "alkyl" refers to a Ci- 10 aliphatic substituent optionally interrupted by an oxy linkage, and "ar" or "aryl" refers to a monocyclic, optionally heterocyclic, optionally substituted, C_{4 -} u aromatic substituent.

2. A method of decreasing infection by a respiratory virus in a subject said method

comprising administering to the subject an effective amount of a compound having the structure of formula IV

wherein

X is (H,OH) or O;

Y is (H,OH) or O;

Ri and R₂ are independently selected from H, alkyl, thioalkyl, arylalkyl,

hydroxyalkyl, dihydroxyalkyl hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl,

carbalkoxyalkyl and (R₃)₃Si where each R₃ is independently selected from H, methyl, ethyl, isopropyl. t-butyl and phenyl; wherein "alk-" or "alkyl" refers to C i _-6 alkyl branched or linear preferably Ci .₃ alkyl in which the carbon chain may be optionally interrupted by an ether (-- 0—) linkage; and

3. The method of claim 2, wherein the compound is everolimus and has the structure of compound V

4. The method of claim 1, 2 or 3, wherein the subject is human.

5. The method of claim 1, 2 or 3, wherein the compound decreases the activity of mTOR.

6. The method of claim 1, 2 or 3, wherein the virus is an influenza virus, rhinovirus or RSV.

7. A method of decreasing infection by a gastrointestinal virus in a subject said method comprising administering to the subject an effective amount of a compound having the structure of formula I

wherein:

Formula II

Formula III

wherein:

R₄ is H, methyl or together with R₃ forms C_2-6 alkylene;

hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl,

dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, anlinoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonalnidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl and carbalkoxyalkyl; R₇CO-, wherein R₇ is selected from H, alkyl, hydroxy, alkoxy, aryloxy, amino, alkylamino, a residue of an amino acid, or N,N-disubstituted-amino wherein the substituents (a) are selected from alkyl, aryl or arylalkyl or (b) form a heterocyclic structure; R₈NCH-, wherein R₈ is alkyl, aryl, amino, alkylamino, arylamino, hydroxy, alkoxy or arylsulfonylamino; --O-CH-O-; or substituted

dioxymethylyne;

Y is selected from O (H, OH), and (H, OR9) wherein R9 is selected from

Ci_-4alkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkyl carbonyl, formyl or aryl;

and wherein "alk" or "alkyl" refers to a Ci_{- 10} aliphatic substituent optionally interrupted by an oxy linkage, and "ar" or "aryl" refers to a monocyclic, optionally heterocyclic, optionally substituted, C_{4 - I4} aromatic substituent.

8. A method of decreasing infection by a gastrointestinal virus in a subject said method comprising administering to the subject an effective amount of a compound having the structure of formula IV

wherein

X is (H,OH) or O;

Y is (H,OH) or O;

Ri and R₂ are independently selected from H, alkyl, thioalkyl, arylalkyl,

hydroxyalkyl, dihydroxyalkyl hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl,

alkoxyalkyl, acyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, acylaminoalkyl, arylsulfonamidoalkyl, allyldihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl and (Ra)₃Si where each R₃ is independently selected from H, methyl, ethyl, isopropyl. t-butyl and phenyl; wherein "alk-" or "alkyl" refers to C | _-6 alkyl branched or linear preferably Ci _{- 3} alkyl in which the carbon chain may be optionally interrupted by an ether (— 0—) linkage; and

R₄ is methyl, or R₄ and R| together form C_{2- 5} alkylene; provided that Ri and R₂ are not both H; and provided that where Ri is (R₃)₃Si or carbalkoxyalkyl, X and Y are not both O.

9. The method of claim 8, wherein the compound is everolimus and has the structure of compound V

10. The method of claim 7, 8 or 9, wherein the subject is human.

11. The method of claim 7, 8 or 9, wherein the compound decreases the activity of

mTOR.

12. The method of claim 7, 8 or 9, wherein the gastrointestinal virus is Dengue fever virus.

13. A method of decreasing infection by a pox virus in a subject said method comprising administering to the subject an effective amount of a compound having the structure of formula I

wherein:

Formula II

Formula III

wherein:

R₄ is H, methyl or together with R₃ forms C_2-6 alkylene;

R₅ is R_OO-CH₂--, wherein R₆ is selected from H, alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl,

hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl,

dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, anlinoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylarninoalkyl, arylsulfonalnidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl and carbalkoxyalkyl; R₇CO-, wherein R₇ is selected from H, alkyl, hydroxy, alkoxy, aryloxy, amino, alkylamino, a residue of an amino acid, or N,N-disubstituted-amino wherein the substituents (a) are selected from alkyl, aryl or arylalkyl or (b) form a heterocyclic structure; R₈NCH-, wherein R₈ is alkyl, aryl, amino, alkylamino, arylamino, hydroxy, alkoxy or arylsulfonylamino;— O-CH-O-; or substituted

dioxymethylyne;

Y is selected from O (H, OH), and (H, OR₉) wherein R9 is selected from

aminoalkyl carbonyl, formyl or aryl;

and wherein "alk" or "alkyl" refers to a Ci_{- )0} aliphatic substituent optionally interrupted by an oxy linkage, and "ar" or "aryl" refers to a monocyclic, optionally heterocyclic, optionally substituted, C_{4 -} u aromatic substituent.

14. A method of decreasing infection by a pox virus in a subject said method comprising administering to the subject an effective amount of a compound having the structure of formula IV

wherein

X is (H₅OH) or O;

Y is (H,OH) or O;

Ri and R₂ are independently selected from H, alkyl, thioalkyl, arylalkyl,

hydroxyalkyl, dihydroxyalkyl hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl,

carbalkoxyalkyl and (R₃)₃Si where each R₃ is independently selected from H, methyl, ethyl, isopropyl. t-butyl and phenyl; wherein "alk-" or "alkyl" refers to C i _-6 alkyl branched or linear preferably Ci .₃ alkyl in which the carbon chain may be optionally interrupted by an ether (— 0—) linkage; and

15. The method of claim 14, wherein the compound is everolimus and has the structure of compound V

16. The method of claim 13, 14 or 15, wherein the subject is human.

17. The method of claim 13, 14 or 15, wherein the compound decreases the activity of mTOR.

18. A method of decreasing an unspecified viral infection in a subject comprising:

a) diagnosing a subject with an unspecified viral infection; and; b) administering to the subject an effective amount of a compound having the structure of formula I

wherein:

Formula II

Formula III

wherein:

R₃ is selected from H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxy alkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alky lcarbonyloxy alkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl,

dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl and alkylsilyl;

R₄ is H, methyl or together with R₃ forms C_2-6 alkylene;

hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl,

dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, anlinoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonalnidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl and carbalkoxyalkyl; R₇CO--, wherein R₇ is selected from H, alkyl, hydroxy, alkoxy, aryloxy, amino, alkylamino, a residue of an amino acid, or N,N-disubstituted-amino wherein the substituents (a) are selected from alkyl, aryl or arylalkyl or (b) form a heterocyclic structure; R₈NCH-, wherein R₈ is alkyl, aryl, amino, alkylamino, arylamino, hydroxy, alkoxy or arylsulfonylamino;— O-CH-O-; or substituted

dioxymethylyne;

Y is selected from O (H, OH), and (H, OR₉) wherein R₉ is selected from

C|.4alkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkyl carbonyl, formyl or aryl;

wherein "alk" or "alkyl" refers to a Ci_{- 10} aliphatic substituent optionally interrupted by an oxy linkage, and "ar" or "aryl" refers to a monocyclic, optionally heterocyclic, optionally substituted, C_{4 - I4} aromatic substituent;

and wherein the compound inhibits infection by two or more viruses.

19. A method of decreasing an unspecified viral infection in a subject comprising: a) diagnosing a subject with an unspecified viral infection; and; b) administering to the subject an effective amount of a compound having the structure of formula IV

wherein

X is (H,0H) or O;

Y is (H,0H) or O;

Ri and R₂ are independently selected from H, alkyl, thioalkyl, arylalkyl, hydroxyalkyl, dihydroxyalkyl hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, acyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, acylaminoalkyl, arylsulfonamidoalkyl, allyldihydroxyalkylallyl, dioxolanylallyl,

carbalkoxyalkyl and (R₃)₃Si where each R₃ is independently selected from H, methyl, ethyl, isopropyl. t-butyl and phenyl; wherein "alk-" or "alkyl" refers to C ι _-6 alkyl branched or linear preferably Ci .₃ alkyl in which the carbon chain may be optionally interrupted by an ether (-- 0—) linkage; and

R₄ is methyl, or R₄ and Ri together form C_2- 5 alkylene; provided that Ri and R₂ are not both H; and provided that where Ri is (R₃)₃Si or carbalkoxyalkyl, X and Y are not both O;

and wherein the compound inhibits infection by two or more viruses.

20. A method of decreasing an unspecified viral infection in a subject comprising:

a) diagnosing a subject with an unspecified viral infection; and;

b) administering to the subject an effective amount of a compound having the structure of formula V

wherein the compound inhibits infection by two or more viruses.

21. A method of decreasing an unspecified respiratory or gastrointestinal infection in a subject comprising:

a) diagnosing a subject with an unspecified respiratory or gastrointestinal infection; and; b) administering to the subject an effective amount of a compound having the structure of formula I

wherein:

Formula II

Formula III

wherein:

R₄ is H, methyl or together with R₃ forms C_2-6 alkylene;

R₅ is R₆O-CH₂-, wherein R^ is selected from H, alkyl , alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl,

hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl,

dioxymethylyne;

Y is selected from O (H, OH), and (H, OR₉) wherein R₉ is selected from

wherein "alk" or "alkyl" refers to a Ci- 10 aliphatic substituent optionally interrupted by an oxy linkage, and "ar" or "aryl" refers to a monocyclic, optionally heterocyclic, optionally substituted, C_{4 - I4} aromatic substituent;

and wherein the compound inhibits infection by two or more gastrointestinal viruses selected from the group consisting of a flavivirus, a filovirus, an adenovirus, a calcivirus and a reovirus; or the compound inhibits infection by two or more respiratory viruses selected from the group consisting of a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus, and an adenovirus.

22. A method of decreasing an unspecified respiratory or gastrointestinal infection in a subject comprising:

a) diagnosing a subject with an unspecified respiratory or gastrointestinal infection; and;

b) administering to the subject an effective amount of a compound having the structure of formula IV

wherein

X is (H₅OH) or O;

Y is (H,0H) or O;

Ri and R₂ are independently selected from H, alkyl, thioalkyl, arylalkyl,

hydroxyalkyl, dihydroxyalkyl hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl,

carbalkoxyalkyl and (R₃)₃Si where each R₃ is independently selected from H, methyl, ethyl, isopropyl, t-butyl and phenyl; wherein "alk-" or "alkyl" refers to C i _-6 alkyl branched or linear preferably Ci .₃ alkyl in which the carbon chain may be optionally interrupted by an ether (— 0—) linkage; and

R₄ is methyl, or R₄ and Ri together form C_{2- 5} alkylene; provided that Ri and R₂ are not both H; and provided that where Ri is (R₃)₃Si or carbalkoxyalkyl, X and Y are not both O;

and wherein the compound inhibits infection by two or more gastrointestinal viruses selected from the group consisting of a flavivirus, a filovirus, an adenovirus, a calcivirus and a reovirus; or the compound inhibits infection by two or more respiratory viruses selected from the group consisting of a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus and an adenovirus.

23. A method of decreasing an unspecified respiratory or gastrointestinal infection in a subject comprising:

wherein the compound inhibits infection by two or more gastrointestinal viruses selected from the group consisting of a flavivirus, a filovirus, an adenovirus, a calcivirus and a reovirus; or the compound inhibits infection by two or more respiratory viruses selected from the group consisting of a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus, and an adenovirus.

24. A method of decreasing the toxicity of a toxin in a cell comprising administering to the cell an effective amount of a compound having the structure of formula I

wherein:

Ri is alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, benzyl, alkoxy benzyl or chlorobenzyl, R₂ is selected from formula II or formula III:

Formula II

Formula III

wherein:

R₃ is selected from H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl and alkylsilyl; R₄ is H, methyl or together with R₃ forms C_2-6 alkylene;

R5 is R₆O-CH₂--, wherein R₆ is selected from H, alky 1, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, heteroary lcarbony 1 , hydroxyalkylcarbonyl ,

aminoalkylcarbonyl, foimyl, thioalkyl, arylalkyl, hydroxyarylalkyl, hydroxyaryl,

hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl,

dioxymethylyne;

Y is selected from O (H, OH), and (H, OR₉) wherein R₉ is selected from

aminoalkyl carbonyl, formyl or aryl;

and wherein "alk" or "alkyl" refers to a Ci_{- 10} aliphatic substituent optionally interrupted by an oxy linkage, and "ar" or "aryl" refers to a monocyclic, optionally heterocyclic, optionally substituted, C_{4 -} I₄ aromatic substituent.

25. A method of decreasing the toxicity of a toxin in a cell comprising administering to t the cell an effective amount of a compound having the structure of formula IV

wherein

X is (H₃OH) or O;

Y is (H,0H) or O;

Ri and R₂ are independently selected from H, alkyl, thioalkyl, arylalkyl,

hydroxyalkyl, dihydroxyalkyl hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl,

26. A method of decreasing the toxicity of a toxin in a cell comprising administering to the cell an effective amount of a compound having the structure of formula V

27. A method of deriving a compound with activity against a pathogen comprising modifying the compound having the structure of formula V

28. The method of claim 27, further comprising determining the anti-pathogenic activity of the derivative compound.

29. A kit comprising a pharmaceutical composition comprising a compound having the structure of formula I, formula IV or formula V and instructions for administration to a subject to decrease viral infection.

30. A method of decreasing infection by a respiratory virus in a subject said method comprising administering to the subject an effective amount of a compound having the structure of formula VI

wherein A is morpholino, pyrrolidino, piperidyl, or di-alkyl amino, R is a straight or branched chain alkyl, or benzyl, Ar is aryl and Ar¹ is aryl or pyridyl, and pharmaceutically acceptable salts thereof.

31 . The method of claim 30, wherein A is pyrrolidino, R is isobutyl and Ar and Ar' are both phenyl, and the hydrochloride thereof.

32. The method of claim 30, wherein A is pyrrolidino, R is isobutyl, Ar is phenyl and Ar¹ is 2-pyridyl and the acid fumarate thereof.

33. The method of claim 30, wherein A is diethylamino, R is an isobutyl and Ar and Ar' are both phenyl and the acid fumarate thereof.

34. The method of claim 30, wherein A is morpholino, R is isobutyl and Ar and Ar¹ are both phenyl and the acid fumarate thereof.

35. The method of claim 30, wherein A is piperidyl, R is benzyl and Ar and Ar' are both phenyl and the hydrochloride thereof.

36. The method of claim 30, wherein the compound is bepridil and is a compound having the structure of formula VII, and pharmaceutically acceptable salts thereof

37. The method of any of claims 30-36 wherein the subject is human.

38. The method of any of claims 30-36 wherein the compound decreases the activity of calmodulin.

39. The method of any of claims 30-36, wherein the virus is an influenza virus, RSV, or a rhinovirus.

40. A method of decreasing infection by a gastrointestinal virus in a subject said method comprising administering to the subject an effective amount of a compound having the structure of formula VI

41 . The method of claim 40, wherein A is pyrrolidino, R is isobutyl, Ar and Ar¹ are both phenyl, and the hydroch oride thereof.

42. The method of claim 40, wherein A is pyrrolidino, R is isobutyl, Ar is phenyl and Ar¹ is 2-pyridyl and the acid fumarate thereof.

43. The method of claim 40, wherein A is diethylamino, R is an isobutyl and Ar and Ar' are both phenyl and the acid fumarate thereof.

44. The method of claim 40, wherein A is morpholino, R is isobutyl and Ar and Ar¹ are both phenyl and the acid fumarate thereof.

45. The method of claim 40, wherein A is piperidyl, R is benzyl and Ar and Ar¹ are both phenyl and the hydrochloride thereof.

46. The method of claim 40, wherein the compound is bepridil and is a compound having the structure of formula VII, and pharmaceutically acceptable salts thereof

47. The method of any of claims 40-46 wherein the subject is human.

48. The method of any of claims 40-46 wherein the compound decreases the activity of calmodulin.

49. The method of any of claims 40-46, wherein the virus is a Dengue fever virus.

50. A method of decreasing an unspecified viral infection in a subject comprising:

a. diagnosing a subject with an unspecified viral infection; and;

b. administering to the subject an effective amount of a compound having the structure of formula VI

VI

wherein A is morpholino, pyrrolidino, piperidyl, or di-alkyl amino, R is a straight or branched chain alkyl, or benzyl, Ar is aryl and Ar¹ is aryl or pyridyl, and pharmacologically acceptable salts thereof;

and wherein the compound inhibits infection by two or more viruses.

51. The method of claim 50, wherein A is pyrrolidino, R is isobutyl and Ar and Ar¹ are both phenyl, and the hydrochloride thereof.

52. The method of claim 50, wherein A is pyrrolidino, R is isobutyl, Ar is phenyl and Ar¹ is 2-pyridyl and the acid fumarate thereof.

53. The method of claim 50, wherein A is diethylamino, R is an isobutyl and Ar and Ar¹ are both phenyl and the acid fumarate thereof.

54. The method of claim 50, wherein A is morpholino, R is isobutyl and Ar and Ar¹ are both phenyl and the acid fumarate thereof.

55. The method of claim 50, wherein A is piperidyl, R is benzyl and Ar and Ar¹ are both phenyl and the hydrochloride thereof.

56. The method of claim 50, wherein the compound is bepridil and is a compound having the structure of formula VII, and pharmaceutically acceptable salts thereof

57. A method of decreasing an unspecified respiratory or gastrointestinal infection in a subject comprising:

a. diagnosing a subject with an unspecified repiratory or gastrointestinal infection; and;

VI

and wherein the compound inhibits infection by two or more gastrointestinal viruses selected from the group consisting of a flavivirus, a filovirus, an adenovirus, a calcivirus or a reovirus; or the compound inhibits infection by two or more respiratory viruses selected from the group consisting of a picornavirus, an orthomyxovirus, a paramyxovirus, a coronavirus, and an adenovirus.

58. The method of claim 57, wherein A is pyrrolidino, R is isobutyl ad Ar and Ar¹ are both phenyl, and the hydrochloride thereof.

59. The method of claim 57, wherein A is pyrrolidino, R is isobutyl, Ar is phenyl and Ar¹ is 2-pyridyl and the acid fumarate thereof.

60. The method of claim 57, wherein A is diethylamino, R is an isobutyl and Ar and Ar¹ are both phenyl and the acid fumarate thereof.

61. The method of claim 57, wherein A is morpholino, R is isobutyl and Ar and Ar¹ are both phenyl and the acid fumarate thereof.

62. The method of claim 57, wherein A is piperidyl, R is benzyl and Ar and Ar¹ are both phenyl and the hydrochloride thereof.

63. The method of claim 57, wherein the compound is bepridil and is a compound having the structure of formula VII, and pharmaceutically acceptable salts thereof

64. A method of decreasing the toxicity of a toxin in a cell comprising administering to the cell an effective amount of a compound having the structure of formula VI

65. The method of claim 64, wherein A is pyrrolidino, R is isobutyl ad Ar and Ar¹ are both phenyl, and the hydrochloride thereof.

66. The method of claim 64, wherein A is pyrrolidino, R is isobutyl, Ar is phenyl and Ar¹ is 2-pyridyl and the acid fumarate thereof.

67. The method of claim 64, wherein A is diethylamino, R is an isobutyl and Ar and Ar¹ are both phenyl and the acid fumarate thereof.

68. The method of claim 64, wherein A is morpholino, R is isobutyl and Ar and Ar¹ are both phenyl and the acid fumarate thereof.

69. The method of claim 64, wherein A is piperidyl, R is benzyl and Ar and Ar¹ are both phenyl and the hydrochloride thereof.

70. The method of claim 64, wherein the compound is bepridil having the structure of formula VII, and pharmaceutically acceptable salts thereof

71. A method of deriving a compound with activity against a pathogen comprising

modifying the compound having the structure of formula VII, and pharmaceutically acceptable salts thereof.

72. The method of claim 71, further comprising determining the anti-pathogenic activity of the derivative compound.

73. A kit comprising a pharmaceutical composition comprising compound having the structure of formula VI or the structure of formula VII as defined above, and instructions for administration to a subject to decrease viral infection.