Methods of treating respiratory tract infections using chestnut spermine analogs

Abstract

Disclosed herein are methods of treating or preventing a disease caused by respiratory syncytial virus (RSV) infection in a human subject, the method comprising administering to the human subject a compound of Formula (I) or a pharmaceutical composition comprising a compound of Formula (I). In certain embodiments, the compound is Sigosivir.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 358,341, filed on July 5, 2022, which is hereby incorporated by reference in its entirety, including any figures, tables, nucleic acid sequences, amino acid sequences, or drawings. Background of the Invention

[0004] Human respiratory syncytial virus (RSV), also known as human orthopneumovirus, is a human pathogen that causes respiratory tract infections. RSV infections are usually mild in healthy adults, often similar to the common cold, and usually do not require treatment or hospitalization. However, RSV infections are more problematic in children. RSV is the leading cause of lower respiratory tract infections and hospital visits in infancy and childhood. In fact, in the United States, RSV may be the most common cause of bronchiolitis and pneumonia in children under one year old. In the United States, an estimated 60% of infants are infected with the virus during their first viral season, and nearly 100% of children are infected with RSV during the first two years of their lives. Of those children infected with RSV, 2%-3% will require hospitalization for bronchiolitis or pneumonia. This serious complication caused by RSV infection is also common in elderly patients. More specifically, in the United States, more than 50,000 children under the age of 5 and more than 150,000 elderly people are hospitalized each year for RSV infection, and more than 14,000 people die each year from RSV infection.

[0005] Like many other infections, RSV infection induces a protective immune response. However, protective immunity to RSV is known to wane rapidly, allowing an individual to be infected multiple times in a relatively short period of time. In fact, infants can be infected with RSV more than once over a period of several years, or even within a single RSV season. Young adults can be infected again every 5 to 7 years.

[0006] There are no treatments that reduce the severity of RSV infection or shorten recovery time. Instead, treatment of RSV infection is limited to supportive care, including the administration of supplemental oxygen and fluids until the virus dies out on its own. Palivizumab, a monoclonal antibody that targets the RSV surface protein, has been used with some success as a preventive medication in high-risk individuals, such as premature infants or infants with heart or lung disease. However, this preventive measure is not particularly effective and is expensive, making its use cost-prohibitive in many parts of the world.

[0007] Conventional antiviral drugs are often associated with reduced activity when initial administration is delayed relative to viral exposure and / or symptom onset. RSV therapies that do not directly target the virus but modulate the immune response to infection, either in treatment or prevention, have the potential to provide therapeutic benefit that is less dependent on the timing of viral exposure or symptom onset.

[0008] Therefore, there remains an urgent medical need to develop effective methods for treating and / or preventing RSV infection. SUMMARY OF THE INVENTION

[0010] The present application relates to methods of treating or preventing disease caused by respiratory syncytial virus (RSV) infection in human subjects.

[0011] In one aspect, the method includes administering at least one initial (loading) dose of a compound of formula (I), formula (II) and / or formula (III) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula (I), formula (II) and / or formula (III) or a pharmaceutically acceptable salt thereof to a human subject infected with RSV, followed by administering multiple subsequent doses of a compound of formula (I), formula (II) and / or formula (III) or a pharmaceutical composition comprising a compound of formula (I), formula (II) and / or formula (III) or a pharmaceutically acceptable salt thereof to treat RSV infection in a human subject. In certain embodiments, the method further includes detecting the presence of RSV infection before or simultaneously administering multiple doses of a compound of formula (I), formula (II) and / or formula (III). In specific embodiments, the human subject has symptoms of RSV infection at the time of administration.

[0012] On the other hand, the method includes administering at least one initial (loading) dose of a compound of formula (I), formula (II) and / or formula (III) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula (I), formula (II) and / or formula (III) or a pharmaceutically acceptable salt thereof to a human subject at risk of RSV infection, followed by administering multiple subsequent doses of a compound of formula (I), formula (II) and / or formula (III) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula (I), (II) and / or (III) or a pharmaceutically acceptable salt thereof to prevent RSV infection in a human subject. In a specific embodiment, the human subject has no symptoms of RSV infection at the time of administration and / or has been diagnosed as RSV negative. Any suitable method for diagnosing or detecting RSV infection can be used, and such methods are well known in the art, including nucleic acid assays. In other specific embodiments, the human subject is a premature child. In another embodiment, the premature child is less than one year old.

[0013] In certain embodiments, the compound of formula (I), formula (II) and / or formula (III) is administered orally, parenterally (e.g., intravenously, intramuscularly, intraperitoneally, subcutaneously, etc.) to a patient who is not infected, asymptomatically infected, or symptomatically infected. In certain embodiments, parenteral administration is intravenous administration or intramuscular administration. In certain embodiments, the compound of formula (I), formula (II) and / or formula (III) can be administered parenterally to a patient with symptomatic infection, such as a hospitalized patient.

[0014] When administered parenterally, the dosage of the compound of formula (I), formula (II) and / or formula (III) may be optionally reduced compared to oral administration, for example, by 50%, 25%, 10%, 5% or 1% of the oral dosage by parenteral administration. In certain embodiments, the dosage of the compound of formula (I), (II) and / or (III) received by a human subject is based on the subject's body weight and is between about 1 mg / kg / day and about 50 mg / kg / day. In certain embodiments, the dosage is at least about 1 mg / kg / day, 2 mg / kg / day, 3 mg / kg / day, 4 mg / kg / day, 5 mg / kg / day, 6 mg / kg / day, 7 mg / kg / day, 8 mg / kg / day, 9 mg / kg / day, 10 mg / kg / day, 11 mg / kg / day, 12 mg / kg / day, 13 mg / kg / day, 14 mg / kg / day, 15 mg / kg / day, 16 mg / kg / day, 17 mg / kg / day, 18 mg / kg / day, 19 mg / kg / day, 20 mg / kg / day, 21 mg / kg / day, 22 mg / kg / day, 23 mg / kg / day, 24 mg / kg / day, 25 mg / kg / day or 50 mg / kg / day.In other embodiments, the dosage is less than about 50 mg / kg / day, 49 mg / kg / day, 48 mg / kg / day, 47 mg / kg / day, 46 mg / kg / day, 45 mg / kg / day, 44 mg / kg / day, 43 mg / kg / day, 42 mg / kg / day, 41 mg / kg / day, 40 mg / kg / day, 39 mg / kg / day, 38 mg / kg / day, 37 mg / kg / day, 36 mg / kg / day, 35 mg / kg / day, 34 mg / kg / day, 33 mg / kg / day, 32 mg / kg / day, 31 mg / kg / day, 30 mg / kg / day, 29 mg / kg / day, 28 mg / kg / day, 27 mg / kg / day / kg / day, 26 mg / kg / day, 25 mg / kg / day, 24 mg / kg / day, 23 mg / kg / day, 22 mg / kg / day, 21 mg / kg / day, 20 mg / kg / day, 19 mg / kg / day, 18 mg / kg / day, 17 mg / kg / day, 16 mg / kg / day, 15 mg / kg / day, 14 mg / kg / day, 13 mg / kg / day, 12 mg / kg / day, 11 mg / kg / day, 10 mg / kg / day, 9 mg / kg / day, 8 mg / kg / day, 7 mg / kg / day, 6 mg / kg / day, 5 mg / kg / day, 4 mg / kg / day, 3 mg / kg / day, 2 mg / kg / day or 1 mg / kg / day. In further embodiments, the compound of Formula (I), Formula (II) and / or Formula (III) is administered at a dosage of about 1 mg / kg / day to 50 mg / kg / day, about 1.5 mg / kg / day to 40 mg / kg / day, about 2 mg / kg / day to 30 mg / kg / day, about 2.5 mg / kg / day to 20 mg / kg / day, about 3 mg / kg / day to 15 mg / kg / day, about 4 mg / kg / day to 12 mg / kg / day, about 5 mg / kg / day to 10 mg / kg / day, about 6 mg / kg / day to 9 mg / kg / day, or about 7 mg / kg / day to 8 mg / kg / day.

[0015] For treatment methods and prevention methods, in certain embodiments, at least one initial (loading) dose comprises about 40 mg to 600 mg of a compound of formula (I), formula (II) and / or formula (III) or a pharmaceutically acceptable salt thereof. In additional embodiments, each of a plurality of subsequent doses comprises about 25 mg to about 400 mg of a compound of formula (I), formula (II) and / or formula (III) or a pharmaceutically acceptable salt thereof.

[0016] In certain embodiments, subsequent doses are administered at intervals of about 6 hours to about 12 hours. In other embodiments, subsequent doses are administered about every 6 hours, about every 8 hours, about every 12 hours, or about every 24 hours. In further embodiments, subsequent doses are administered once, twice, three times, four times, or five times per day.

[0017] In certain embodiments, the total amount of the compound of formula (I), formula (II) and / or formula (III) does not exceed 600 mg / day. In other embodiments, the total amount of the compound of formula (I), formula (II) and / or formula (III) administered in a single dose is 400 mg or less.

[0018] In additional embodiments, subsequent doses are administered for about 1 day to 10 days, about 1 day to 15 days, about 1 day to 20 days, about 1 day to 25 days, about 30 days, about 4 weeks, about 6 weeks, about 8 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 1 year. In other embodiments, subsequent doses are administered for about 5 days to 20 days, 5 days to 30 days, 10 days to 40 days, or 10 days to 50 days.

[0019] In various embodiments, the human subject can be an adult or a child. In a specific embodiment, the human subject is a child, such as 10 years old or less, 9 years old or less, 8 years old or less, 7 years old or less, 6 years old or less, 5 years old or less, 4 years old or less, 3 years old or less, 2 years old or less or 1 year old or less. In other specific embodiments, the human subject is a premature 1 year old or less child. In a further specific embodiment, the human subject is an adult of advanced age, such as 55 years old or more, 56 years old or more, 57 years old or more, 58 years old or more, 59 years old or more, 60 years old or more, 61 years old or more, 62 years old or more, 63 years old or more, 64 years old or more, 65 years old or more, 66 years old or more, 67 years old or more, 68 years old or more, 69 years old or more, 70 years old or more, 75 years old or more or 80 years old or more of adults.

[0020] The compound of formula (I) is represented by the following structure:

[0021]

[0022] or a pharmaceutically acceptable salt thereof;

[0023] Where R 1 , R 2 and R 3 are independently H, (C1-C 14 ) acyl, (C1-C 14 )alkenoyl, (C3-C8)cycloalkylacyl, (C1-C 14) haloalkyl acyl (C1-C8) alkoxy acyl or (C6-C 10 )aroyl.

[0024] In certain embodiments, the compound of formula (I) is specifically a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0025]

[0026] In a preferred embodiment, the compound of formula (I) is a prodrug of castanospermum australe, a natural product derived from the seeds of Castanospermum australe. Once administered, the compound of formula (I) is rapidly converted to castanospermum australe. The compound of formula (I) (e.g., celgosivir) is absorbed faster and more effectively than castanospermum australe. The compound of formula (I) is also more easily absorbed into cells. Therefore, the compound of formula (I) may have a higher 50% effective concentration (EC50) value and in vivo efficacy against RSV than castanospermum australe.

[0027] In certain embodiments, at least one initial dose comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, or at least 30 doses. In other embodiments, at least one initial dose comprises one, at most two, at most three, at most four, at most five, at most six, at most seven, at most eight, at most nine, at most ten, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, at most 25, at most 26, at most 27, at most 28, at most 29 or at most 30 doses. In some embodiments, two or more initial doses are administered at intervals of about 6 hours to about 12 hours. In other embodiments, two or more initial doses are administered once every 6 hours, about every 8 hours, about every 12 hours or about every 24 hours. In further embodiments, two or more initial doses are administered once, twice, three times, four times or five times a day.

[0028] In certain embodiments, the subsequent dose is administered within one day of administering at least one initial dose. In further embodiments, the subsequent dose is administered about 20 hours, about 15 hours, about 12 hours, about 8 hours, or about 6 hours after the last initial dose is administered.

[0029] In certain embodiments, at least one initial dose is the same as a subsequent dose, while in other embodiments, at least one initial dose is different from a subsequent dose. In a specific embodiment, at least one initial dose is higher than a subsequent dose. In a further embodiment, at least one initial dose is the same dose throughout the method. In other embodiments, at least one initial dose changes the amount of administration throughout the method. In a further embodiment, multiple subsequent doses are the same dose throughout the method. In other embodiments, multiple subsequent doses change the amount of administration throughout the method.

[0030] In certain embodiments, the initial dose for adult subjects can be about 40 mg to about 600 mg. In other embodiments, the initial dose for adult subjects can be about 75 mg-600 mg, 100 mg-600 mg, 150 mg-600 mg, about 200 mg-500 mg, or about 250 mg-400 mg. In further embodiments, the initial dose for adult subjects can be about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg. In a further embodiment, the initial dose for adult subjects is about 550 mg to about 600 mg. In another embodiment, the initial dose for adult subjects is about 500 mg to about 550 mg. In yet another embodiment, the initial dose in adult subjects is about 450 mg to about 500 mg. In a further embodiment, the initial dose for adult subjects is about 400 mg to about 450 mg. In another embodiment, the initial dose for adult subjects is about 350 mg to about 400 mg. In a further embodiment, the initial dose for adult subjects is about 300 mg to about 350 mg. In yet another embodiment, the initial dose for adult subjects is about 250 mg to about 300 mg. In a further embodiment, the initial dose for adult subjects is about 200 mg to about 250 mg. In another embodiment, the initial dose for adult subjects is about 150 mg to about 200 mg. In another embodiment, the initial dose for adult subjects is about 100 mg to about 150 mg. In a further embodiment, the initial dose for adult subjects is about 50 mg to about 100 mg.

[0031] Subsequent doses for adult subjects can be between about 40 mg and about 400 mg. In one embodiment, the subsequent dose for adult subjects is between about 250 mg and about 300 mg. In another embodiment, the subsequent dose for adult subjects is between about 200 mg and about 250 mg. In yet another embodiment, the subsequent dose for adult subjects is between about 150 mg and about 200 mg. In a further embodiment, the subsequent dose for adult subjects is between about 100 mg and about 200 mg. In other embodiments, the subsequent dose for adult subjects is between about 40 mg and about 80 mg. In a further embodiment, the subsequent dose for adult subjects is between about 80 mg and about 100 mg. In an additional embodiment, the subsequent dose for adult subjects is between about 125 mg and about 175 mg. In yet another embodiment, the subsequent dose for adult subjects is about 150 mg.

[0032] For pediatric subjects, the initial dose can be from about 15 mg to about 450 mg. In one embodiment, the initial dose for pediatric subjects is from about 15 mg to about 25 mg. In another embodiment, the initial dose for pediatric subjects is from about 25 mg to about 50 mg. In yet another embodiment, the initial dose for pediatric subjects is from about 50 mg to about 75 mg. In another embodiment, the initial dose for pediatric subjects is from about 75 mg to about 100 mg. In a further embodiment, the initial dose for pediatric subjects is from about 100 mg to about 150 mg. In another embodiment, the initial dose for pediatric subjects is from about 150 mg to about 200 mg. In yet another embodiment, the initial dose for pediatric subjects is from about 200 mg to about 250 mg. In a further embodiment, the initial dose for pediatric subjects is from about 250 mg to about 300 mg. In another embodiment, the initial dose for pediatric subjects is from about 300 mg to about 350 mg. In yet another embodiment, the initial dose for pediatric subjects is from about 350 mg to about 400 mg. In each case, the dose can be administered in a single dose or divided doses.

[0033] Subsequent doses for child subjects may be from about 15 mg to about 200 mg. In one embodiment, the subsequent dose for child subjects is from about 15 mg to about 25 mg. In another embodiment, the subsequent dose for child subjects is from about 25 mg to about 50 mg. In yet another embodiment, the subsequent dose for child subjects is from about 50 mg to about 75 mg. In yet another embodiment, the subsequent dose for child subjects is from about 75 mg to about 100 mg. In a further embodiment, the subsequent dose for child subjects is from about 100 mg to about 125 mg. In another embodiment, the subsequent dose for child subjects is from about 125 mg to about 150 mg. In yet another embodiment, the subsequent dose for child subjects is from about 150 mg to about 200 mg. In each case, the dosage may be administered in a single dose or divided doses.

[0034] In certain specific embodiments, the pediatric subject is less than one month old. In specific embodiments, a pediatric subject <1 month old receives an initial dose of about 15 mg to about 450 mg or about 15 mg to about 250 mg in a single or divided dose. In other embodiments, a child <1 month old receives subsequent doses of about 15 mg to about 250 mg or about 15 mg to about 250 mg in a single or divided dose.

[0035] The compounds or pharmaceutical compositions of the present invention can be administered intravenously, orally, rectally or sublingually. In one embodiment, the route of administration is intravenous injection. In another embodiment, the route of administration is oral. In another embodiment, the route of administration is rectal administration. In yet another embodiment, the route of administration is sublingual.

[0036] The compound or pharmaceutical composition of the present invention can be administered in a single dose or divided dose. In some embodiments, at least one initial dose can be a single, divided dose, or a combination thereof. In some embodiments, a subsequent dose can be a single, divided dose, or a combination thereof. In one embodiment, for subsequent doses, a human subject is administered a divided dose of about 25 mg to about 400 mg of a compound of formula (I), formula (II), and / or formula (III) or a pharmaceutical composition comprising a compound of formula (I), formula (II), and / or formula (III) for about 5 days to about 30 days. In another embodiment, a subsequent dose is administered to a human subject for about 5 days to about 40 days with a single dose of about 25 mg to about 400 mg. In yet another embodiment, a subsequent dose is administered to a human subject for about 5 days to about 60 days with a single dose of about 25 mg to about 400 mg. In a further embodiment, a subsequent dose is administered to a human subject for about 5 days to about 60 days with a single dose of about 25 mg to about 400 mg. In other forms, subsequent doses are administered for no more than about 10 days; in other forms, no more than about 20 days; in further forms, no more than about 50 days; in other forms, no more than about 100 days; and in other forms, no more than about one year.

[0037] The present invention also relates to a method for preventing a disease caused by RSV infection by achieving a steady-state Cmin serum or plasma concentration of about 0.05 micrograms / mL to about 2.0 micrograms / mL castanospermine in an adult or child subject. In one embodiment, the steady-state Cmin serum or plasma concentration achieved in an adult or child subject is about 0.08 micrograms / mL to about 0.5 micrograms / mL castanospermine. In another embodiment, the steady-state Cmin serum or plasma concentration achieved in an adult or child subject is about 0.05 micrograms / mL to about 0.08 micrograms / mL castanospermine. In yet another embodiment, the steady-state Cmin serum or plasma concentration achieved in an adult or child subject is about 0.08 micrograms / mL to about 0.11 micrograms / mL castanospermine. In a further embodiment, the steady-state Cmin serum or plasma concentration achieved in an adult or child subject is about 0.11 micrograms / mL to about 0.3 micrograms / mL castanospermine. In another embodiment, the steady-state serum or plasma concentration of Cmin achieved in an adult or pediatric subject is between about 0.3 micrograms / mL and about 0.75 micrograms / mL castanospermine. In a further embodiment, the steady-state serum or plasma concentration of Cmin achieved in an adult or pediatric subject is between about 0.75 micrograms / mL and about 1.0 micrograms / mL castanospermine. In yet another embodiment, the steady-state serum or plasma concentration of Cmin achieved in an adult or pediatric subject is between about 1.0 micrograms / mL and about 2.0 micrograms / mL castanospermine. In another embodiment, the steady-state serum or plasma concentration of Cmin achieved in an adult or pediatric subject is between about 1.0 micrograms / mL and about 1.5 micrograms / mL castanospermine. In a further embodiment, the steady-state serum or plasma concentration of Cmin achieved in an adult or pediatric subject is between about 1.5 micrograms / mL and about 2.0 micrograms / mL castanospermine. In yet another embodiment, the steady-state Cmin serum or plasma concentration achieved in an adult or pediatric subject is between about 1.25 micrograms / mL and about 1.75 micrograms / mL castanospermine.

[0038] In another aspect of the present invention, the viral load reduction of human subjects receiving the treatment method is at least 50% higher than that of people who do not use the compound or the group that uses a placebo. In one embodiment, the virological logarithm of human subjects receiving the treatment method is reduced by at least 50% higher than that of people who do not use the compound or the group that uses a placebo. In another embodiment, the virological logarithm of human subjects receiving the treatment method is reduced by about 60% to about 70% higher than that of people who do not use the compound or the group that uses a placebo. In another embodiment, the virological logarithm of human subjects receiving the treatment method is reduced by about 70% to about 80% higher than that of people who do not use the compound or the group that uses a placebo. In another embodiment, the virological logarithm of human subjects receiving the treatment method is reduced by at least 80% to about 90% higher than that of people who do not use the compound or the group that uses a placebo. DETAILED DESCRIPTION OF THE INVENTION

[0040] A description of exemplary embodiments of the invention follows.

[0041] definition

[0042] All definitions of substituents listed below further apply to the use of that term in combination with another substituent. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0043] "Alkyl" used alone or as part of a larger moiety as "aralkyl" or "aryloxyalkyl" refers to a saturated aliphatic branched or straight chain monovalent hydrocarbon radical, typically C1-C 16 , preferably C1-C 12 For example, "(C1-C6) alkyl" refers to a group having 1 to 6 carbon atoms arranged in a straight or branched chain. "(C1-C6) alkyl" includes methyl, ethyl, propyl, butyl, tert-butyl, pentyl and hexyl.

[0044] "Alkylene" refers to a saturated aliphatic straight chain divalent hydrocarbon group. Thus, "(C1-C6) alkylene" refers to a divalent saturated aliphatic group having 1 to 6 linearly arranged carbon atoms. "(C1-C6) alkylene" includes methylene, ethylene, propylene, butylene, pentylene and hexylene.

[0045] "Cycloalkyl" refers to a saturated aliphatic cyclic hydrocarbon ring. Thus, "C3-C8 cycloalkyl" refers to a (3- to 8-membered) saturated aliphatic cyclic hydrocarbon ring. C3-C8 cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Preferably, the cycloalkyl is a C3-C6 cycloalkyl.

[0046] The term "alkoxy" refers to -O-alkyl; "arylalkoxy" refers to alkoxy substituted with aryl on any carbon; "hydroxyalkyl" refers to alkyl substituted with hydroxy; "arylalkyl" refers to alkyl substituted with aryl; "alkoxyalkyl" refers to alkyl substituted with alkoxy; "cycloalkylalkyl" refers to alkyl substituted with cycloalkyl; "alkylcarbonyl" refers to -C(O)-A * , where A * Alkyl; "alkoxycarbonyl" refers to -C(O)-OA * , where A * is alkyl; and wherein alkyl is as defined above. Alkoxy is preferably O(C1-C6)alkyl and includes methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy.

[0047] "Cycloalkoxy" refers to a cycloalkyl-O- group, wherein cycloalkyl is as defined above. Exemplary (C3-C7)cycloalkoxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy.

[0048] "Halogen" and "halo" are used interchangeably herein and each refers to fluorine, chlorine, bromine, or iodine.

[0049] The terms "haloalkyl", "halocycloalkyl" and "haloalkoxy" refer to alkyl, cycloalkyl or alkoxy groups (as appropriate) substituted with one or more halogen atoms. The term "halogen" or "halo" refers to F, Cl, Br or I.

[0050] "Acyl" refers to R"-C(O)-, where R" is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, alkylaryl, or substituted alkylaryl, and is represented in the general formula of specific embodiments as "Ac".

[0051] "Alkylene" is composed of -[CH2] z - represents, wherein z is a positive integer, preferably 1 to 8, more preferably 1 to 4.

[0052] "Alkenylene" is an alkylene group in which at least one pair of adjacent methylene groups is replaced by -CH=CH-.

[0053] The term "(C6-C8)" used alone or as part of a larger moiety such as "aralkyl", "aralkyloxy", "aryloxy" or "aryloxyalkyl" 10 ) aryl" refers to a carbocyclic aromatic ring. The term "carbocyclic aromatic group" can be used interchangeably with the terms "aryl", "aryl ring", "carbocyclic aromatic ring", "aryl" and "carbocyclic aromatic group". Aryl groups typically have 6-10 ring atoms. "Substituted aryl" is substituted on any one or more substitutable ring atoms. The term "C6-C 16 "Aryl" refers to a monocyclic, bicyclic or tricyclic carbon ring system containing 6 to 16 carbon atoms, and includes phenyl (Ph), naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, etc. (C6-C 10 )Aryl(C1-C6)Alkyl(C6-C 10 The (C1-C6)alkyl portion of the )aryl(C1-C6)alkyl is attached to the remainder of the molecule.

[0054] The term "alkenyl", used alone or as part of a larger moiety such as "alkenoyl" or "haloalkylacyl", refers to a straight or branched hydrocarbon group having the specified number of carbon atoms and including at least one double bond. Alkenyl groups typically have 2 to 6 carbon atoms. (C6-C 10)Aryl (C2-C6)Alkenyl (C6-C 10 The (C2-C6)alkenyl portion of the )aryl(C2-C6)alkenyl is attached to the remainder of the molecule.

[0055] "Alkenyl" refers to the acyl group R"-C(O)-, where R" is alkenyl or substituted alkenyl (eg, CH3-CH=CH-C(O)-).

[0056] "Pharmaceutically acceptable carrier" refers to a non-therapeutic component of sufficient purity and quality for the formulation of the compositions of the present invention, which generally does not produce adverse reactions when properly administered, and which is used as a solvent for the drug substance (e.g., compound of formula (I)).

[0057] As used herein, "intraperitoneal injection" refers to the injection of a substance into the peritoneum (body cavity).

[0058] As used herein, "three times daily dosing" or "three times daily" means administering the composition three times every 24 hours.

[0059] As used herein, "four daily dosing" (QDS) or "four times a day" refers to administration of the composition four times every 24 hours.

[0060] As used herein, "BDI" means twice daily. In addition, as used herein, "QD" means once daily.

[0061] As used herein, "Cmin" refers to the minimum concentration of a drug achieved after administration of the drug and before administration of a second or additional dose. In addition, as used herein, "Cmax" refers to the maximum concentration. Likewise, as used herein, "Tmax" refers to the time of maximum concentration. In addition, "AUC" as used herein is the area under the concentration-time curve. In addition, as used herein, "50% effective concentration" (EC50) refers to the concentration of an antiviral drug that produces 50% of the maximum possible antiviral effect.

[0062] As used herein, the term "about" refers to a number that differs from a given number by less than 10%. In other embodiments, the term "about" means that the number differs from a given number by less than 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%.

[0063] As used herein, "viral load" refers to the amount of virus in the bloodstream of a human subject.

[0064] As used herein, "initial dose" refers to a dose administered to an asymptomatic human subject. In addition, "loading dose" and "initial dose" have the same meaning and can be used interchangeably herein.

[0065] As used herein, "asymptomatic" refers to a human subject who may or may not have been exposed to RSV, but who does not exhibit symptoms associated with RSV infection.

[0066] As used herein, "preventing" or "prevention" refers to partially, substantially or completely achieving one or more of the following results: avoiding a disease, condition or syndrome caused by RSV infection; avoiding clinical symptoms or indicators associated with a disease, condition or syndrome caused by RSV infection; reducing the severity of a disease, condition or syndrome caused by RSV infection; or avoiding RSV infection.

[0067] Dosage regimen

[0068] The present invention relates to a method for preventing or treating a disease caused by RSV infection in a human subject, the method comprising administering to the human subject at least one initial (loading) dose of a compound of formula (I), formula (II) and / or formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), formula (II) and / or formula (III) or a pharmaceutically acceptable salt thereof, followed by administering multiple subsequent doses of a compound of formula (I), formula (II) and / or formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), formula (II) and / or formula (III) or a pharmaceutically acceptable salt thereof.

[0069] In certain embodiments, the method is used to prevent the disease caused by RSV infection. In such embodiments, the human subject may not have RSV infection symptoms when applying and / or has been diagnosed as RSV negative when applying. Any suitable method for diagnosing or detecting RSV infection can be used, and such methods are well known in the art, including nucleic acid determination. In specific embodiments, the human subject is a premature child. In additional embodiments, the premature child is less than one year old.

[0070] In other embodiments, the method is used to treat RSV infection. In such embodiments, at the time of administration, the human subject may be asymptomatic for RSV infection and / or at the time of administration, the human subject may have been determined to be currently infected with RSV. In a specific embodiment, the method also includes detecting the presence of RSV infection before or simultaneously administering a dose of a compound of formula (I), formula (II) and / or formula (III).

[0071] For treatment methods and prevention methods, in certain embodiments, at least one initial (loading) dose comprises about 40 mg to 600 mg of a compound of formula (I), formula (II) and / or formula (III) or a pharmaceutically acceptable salt thereof. In additional embodiments, each of a plurality of subsequent doses comprises about 25 mg to about 400 mg of a compound of formula (I), formula (II) and / or formula (III) or a pharmaceutically acceptable salt thereof.

[0072] In certain embodiments, the total amount of the compound of formula (I), formula (II) and / or formula (III) does not exceed 600 mg / day. In other embodiments, the total amount of the compound of formula (I), formula (II) and / or formula (III) administered in a single dose is 400 mg or less.

[0073] In further embodiments, the subsequent dose is applied at intervals of about 6 hours to about 12 hours. In other embodiments, the subsequent dose is applied once every 6 hours, about every 8 hours, about every 12 hours or about every 24 hours. In further embodiments, the subsequent dose is applied once, twice, three times, four times or five times a day. In additional embodiments, the subsequent dose is applied about 1 day-10 days, about 1 day-15 days, about 1 day-20 days, about 1 day-25 days, about 30 days, about 4 weeks, about 6 weeks, about 8 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months or about 1 year. In other embodiments, the subsequent dose is applied about 5 days-20 days, 5 days-30 days, 10 days-40 days or 10 days-50 days.

[0074] In various embodiments, the human subject can be an adult or a child. As used herein, "child" refers to a human subject aged 1 day to <18 years old. The term "adult" refers to a human subject 18 years old or older. In specific embodiments, the human subject is a child, such as 10 years old or younger, 9 years old or younger, 8 years old or younger, 7 years old or younger, 6 years old or younger, 5 years old or younger, 4 years old or younger, 3 years old or younger, 2 years old or younger, or 1 year old or younger. In other specific embodiments, the human subject is a premature 1 year old or younger child. In further specific embodiments, the human subject is an adult of advanced age, such as an adult of 55 years or more, 56 years or more, 57 years or more, 58 years or more, 59 years or more, 60 years or more, 61 years or more, 62 years or more, 63 years or more, 64 years or more, 65 years or more, 66 years or more, 67 years or more, 68 years or more, 69 years or more, 70 years or more, 75 years or more, or 80 years or more. In addition, a plurality of human subjects may include an adult or a child. In some embodiments, a plurality of human subjects may include only an adult. In another embodiment, a plurality of human subjects may include only a child. In yet another embodiment, a plurality of human subjects may include an adult and a child.

[0075] In one embodiment, the compound of the present invention is a compound of formula (I):

[0076]

[0077] or a pharmaceutically acceptable salt thereof;

[0078] Where R 1 , R 2 and R 3 are independently H, (C1-C 14 ) acyl, (C1-C 14 )alkenoyl, (C3-C8)cycloalkylacyl, (C1-C 14 ) haloalkyl acyl (C1-C8) alkoxy acyl or (C6-C 10 )aroyl.

[0079] In another embodiment, R 1 and R 2 is H and R 3 Yes (C1-C 14 In another embodiment, R 1 is CH3-CH2CH2-C(O)-. In yet another embodiment, R 2 is CH3-CH2CH2-C(O)-. In a further embodiment, R 3is CH3-CH2CH2-C(O)-. In another embodiment, R 1 , R 2 , and R 3 At least one but no more than two of them are hydrogen.

[0080] In yet another embodiment, the compound of the present invention is a compound of formula (II):

[0081]

[0082] or a pharmaceutically acceptable salt thereof.

[0083] The compound of formula (II) or a pharmaceutical composition comprising the compound of formula (II) can be used in any of the embodiments of formula (I) provided herein.

[0084] In a further embodiment, the compound of the present invention is a compound of formula (III):

[0085]

[0086] or a pharmaceutically acceptable salt thereof;

[0087] Where R 1 , R 2 and R 3 are independently H, (C1-C 14 ) acyl, (C1-C 14 )alkenoyl, (C3-C8)cycloalkylacyl, (C1-C 14 ) haloalkyl acyl (C1-C8) alkoxy acyl or (C6-C 10 )aroyl.

[0088] The compound of formula (III) or a pharmaceutical composition comprising the compound of formula (III) can be used in any of the embodiments of formula (I) provided herein.

[0089] The compounds of the present invention that can be used to implement the methods described herein can have one or more chiral centers and therefore exist in a variety of stereoisomeric forms. All stereoisomers and mixtures thereof are included within the scope of the present invention. Racemic compounds can be separated using preparative HPLC and a column with a chiral stationary phase, or can be split using methods known to those skilled in the art to produce single enantiomers. In addition, chiral intermediate compounds can be split and used to prepare chiral compounds of the present invention.

[0090] The compounds described herein may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included within the scope of the present invention.

[0091] The compounds of the invention can be administered as free bases or pharmaceutically acceptable salts. For example, acid salts of compounds of the invention containing amines or other basic groups can be obtained by reacting the compounds with suitable organic or inorganic acids to give pharmaceutically acceptable anionic salt forms. Examples of anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estotate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, methylsulfate, mucate, naphthylate, nitrate, pamoate, pantothenate, phosphate / hydrogenphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, tosylate and triiodide salts. In one embodiment, the compound of formula (I) is a hydrochloride salt. In another embodiment, the compound of formula (II) is a hydrochloride salt.

[0092] The present invention also relates to the method of the present invention using a pharmaceutical composition comprising a compound of formula (I), formula (II) or formula (III). The disclosed compounds of formula (I) and formula (II) can be combined with an acceptable pharmaceutical carrier or diluent as part of a pharmaceutical composition for preventing or treating a disease caused by RSV infection, and administered to a subject according to any dosing regimen described herein. The preparation of the compound to be administered will vary according to the selected route of administration (e.g., solution, emulsion, capsule). Suitable pharmaceutical carriers may contain inert ingredients that do not interact with the compound. Standard pharmaceutical preparation techniques, such as those described in "Remington's Pharmacy" (Mack Publishing Company, Easton, PA), may be used. Pharmaceutical carriers suitable for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg / ml benzyl alcohol), phosphate buffered saline, Hank's solution, lactated Ringer's solution, etc. Methods of encapsulating compositions (eg, in a coating of hard gelatin or cyclodextrin) are known in the art (Baker, et al., "Controlled Release of Biological Active Agents", John Wiley and Sons, 1986).

[0093] In one embodiment, a pharmaceutical composition comprises a pharmaceutically acceptable carrier or diluent and a compound of Formula (I), Formula (II) and / or Formula (III).

[0094] In a preferred embodiment, the compound is a prodrug of castanospermine, a natural product derived from the seeds of the Castanopsis castanoides. In another embodiment, the compound of formula (I), formula (II) or formula (III) is converted to castanospermine after administration to a human subject. In yet another embodiment, a steady-state Cmin serum or plasma concentration of about 0.05 micrograms / mL to about 2.0 micrograms / mL castanospermine is achieved in an adult or child human subject. The compound of formula (I), formula (II) or formula (III) (e.g., celgosivir) is more rapidly and effectively absorbed by cells than castanospermine. Therefore, the claimed compound may have a higher EC against RSV than castanospermine. 50 values ​​and in vivo efficacy.

[0095] The human subject can be administered the compounds of the invention over a period of about 1 day to about 1 year. In one embodiment, subsequent doses are administered for about 5 days to about 180 days. In a further embodiment, subsequent doses are administered for about 30 days to about 120 days. In another embodiment, subsequent doses are administered for about 60 days to about 90 days. In yet another embodiment, subsequent doses are administered for about 90 days to about 120 days. In another embodiment, subsequent doses are administered for about 120 days to about six months.

[0096] In certain embodiments, the at least one initial dose includes at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 27, at least 28, at least 29, or at least 30 doses. In other embodiments, at least one initial dose comprises one, at most two, at most three, at most four, at most five, at most six, at most seven, at most eight, at most nine, at most ten, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, at most 25, at most 27, at most 28, at most 29 or at most 30 doses. In some embodiments, two or more initial doses are administered at intervals of about 6 to about 12 hours. In other embodiments, two or more initial doses are administered once every 6 hours, about every 8 hours, about every 12 hours, or about every 24 hours. In further embodiments, two or more initial doses are administered once, twice, three times, four times, or five times a day.

[0097] In certain embodiments, the subsequent dose is administered within one day of administering at least one initial dose. In further embodiments, the subsequent dose is administered about 20 hours, about 15 hours, about 12 hours, about 8 hours, or about 6 hours after the last initial dose is administered.

[0098] In certain embodiments, at least one initial dose is the same as a subsequent dose, while in other embodiments, at least one initial dose is different from a subsequent dose. In a specific embodiment, at least one initial dose is higher than a subsequent dose. In a further embodiment, at least one initial dose is the same dose throughout the method. In other embodiments, at least one initial dose changes the amount of administration throughout the method. In a further embodiment, multiple subsequent doses are the same dose throughout the method. In other embodiments, multiple subsequent doses change the amount of administration throughout the method.

[0099] In certain embodiments, for adult subjects, the initial dose can be about 40 mg to about 600 mg. In other embodiments, the initial dose of adult subjects can be about 75 mg-600 mg, 100 mg-600 mg, 150 mg-600 mg, about 200 mg-500 mg or about 250 mg-400 mg. In further embodiments, the initial dose of adult subjects can be about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg or about 600 mg. In a further embodiment, the initial dose for adult subjects is about 550 mg to about 600 mg. In another embodiment, the initial dose for adult subjects is about 500 mg to about 550 mg. In yet another embodiment, the initial dose for adult subjects is about 450 mg to about 500 mg. In a further embodiment, the initial dose for adult subjects is about 400 mg to about 450 mg. In another embodiment, the initial dose for adult subjects is about 350 mg to about 400 mg. In a further embodiment, the initial dose for adult subjects is about 300 mg to about 350 mg. In yet another embodiment, the initial dose for adult subjects is about 250 mg to about 300 mg. In a further embodiment, the initial dose for adult subjects is about 200 mg to about 250 mg. In another embodiment, the initial dose for adult subjects is about 150 mg to about 200 mg. In another embodiment, the initial dose for adult subjects is about 100 mg to about 150 mg. In a further embodiment, the initial dose for adult subjects is about 50 mg to about 100 mg.

[0100] Subsequent doses for adult subjects can be between about 40 mg and about 400 mg. In one embodiment, the subsequent dose for adult subjects is between about 250 mg and about 300 mg. In another embodiment, the subsequent dose for adult subjects is between about 200 mg and about 250 mg. In yet another embodiment, the subsequent dose for adult subjects is between about 150 mg and about 200 mg. In a further embodiment, the subsequent dose for adult subjects is between about 100 mg and about 200 mg. In other embodiments, the subsequent dose for adult subjects is between about 40 mg and about 80 mg. In a further embodiment, the subsequent dose for adult subjects is between about 80 mg and about 100 mg. In an additional embodiment, the subsequent dose for adult subjects is between about 125 mg and about 175 mg. In yet another embodiment, the subsequent dose for adult subjects is about 150 mg.

[0101] For pediatric subjects, the initial dose for pediatric subjects can be about 15 mg to about 450 mg. In one embodiment, the initial dose for pediatric subjects is about 15 mg to about 25 mg. In another embodiment, the initial dose for pediatric subjects is about 25 mg to about 50 mg. In another embodiment, the initial dose for pediatric subjects is about 50 mg to about 75 mg. In another embodiment, the initial dose for pediatric subjects is about 75 mg to about 100 mg. In a further embodiment, the initial dose for pediatric subjects is about 100 mg to about 150 mg. In another embodiment, the initial dose for pediatric subjects is about 150 mg to about 200 mg. In another embodiment, the initial dose for pediatric subjects is about 200 mg to about 250 mg. In a further embodiment, the initial dose for pediatric subjects is about 250 mg to about 300 mg. In another embodiment, the initial dose for pediatric subjects is about 300 mg to about 350 mg. In another embodiment, the initial dose for pediatric subjects is about 350 mg to about 400 mg. In each case, the dose can be administered in a single dose or divided doses.

[0102] Subsequent doses for child subjects may be between about 25 mg and about 200 mg. In one embodiment, the subsequent dose for child subjects is between about 25 mg and about 50 mg. In another embodiment, the subsequent dose for child subjects is between about 50 mg and about 75 mg. In yet another embodiment, the subsequent dose for child subjects is between about 75 mg and about 100 mg. In a further embodiment, the subsequent dose for child subjects is between about 100 mg and about 125 mg. In another embodiment, the subsequent dose for child subjects is between about 125 mg and about 150 mg. In yet another embodiment, the subsequent dose for child subjects is between about 150 mg and about 200 mg.

[0103] In certain specific embodiments, the pediatric subject is less than one month old. In specific embodiments, the pediatric subject <1 month old receives an initial dose of about 15 mg to about 450 mg or about 15 mg to about 250 mg as a single dose or divided doses. In other embodiments, the child <1 month old receives subsequent doses of about 15 mg to about 250 mg or about 15 mg to about 250 mg as a single dose or divided doses.

[0104] In certain embodiments of the present invention, the initial dose and / or subsequent dose are administered three times a day, wherein each dose is about 167 mg to about 200 mg. In other embodiments, the initial dose and / or subsequent dose are administered four times a day, wherein each dose is about 125 mg to about 150 mg. In one embodiment, the initial dose and / or subsequent dose are administered in two divided doses, wherein the total daily dose is about 225 mg to about 600 mg. In another embodiment, the initial dose and / or subsequent dose are administered in two divided doses, wherein the total daily dose is about 75 mg to about 600 mg. In other embodiments, the initial dose and / or subsequent dose are administered in two divided doses, wherein each dose is about 250 mg to about 300 mg. In yet another embodiment, the initial dose and / or subsequent dose are administered in one dose per day, wherein the total daily dose is about 40 mg to about 400 mg. In a further embodiment, the initial dose and / or subsequent dose are administered in one dose per day, wherein each dose is about 225 mg to about 400 mg.

[0105] In another embodiment, the initial dose and / or subsequent dose is about 225mg, about 240mg, about 260mg, about 280mg, about 320mg, about 340mg, about 360mg, about 380mg or about 400mg, and is applied once a day to a human subject. In other embodiments, the initial dose and / or subsequent dose is about 110mg, about 225mg, about 260mg, about 280mg or about 300mg, and is applied twice a day to a human subject. In a further embodiment, the initial dose and / or subsequent dose is about 75mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg or about 200mg, and is applied three times a day to a human subject. In yet another embodiment, the initial dose and / or subsequent doses are about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, and are administered four times a day to human subjects.

[0106] In one embodiment of the invention, the human subject is administered an initial dose and / or subsequent doses once a day, wherein each dose is about 3.8 mg / kg to about 6.7 mg / kg. In other embodiments, the human subject is administered an initial dose and / or subsequent doses twice a day, wherein each dose is about 4.2 mg / kg to about 5 mg / kg. In further embodiments, the human subject is administered an initial dose and / or subsequent doses three times a day, wherein each dose is about 2.8 mg / kg to about 3.33 mg / kg. In other embodiments, the human subject is administered an initial dose and / or subsequent doses four times a day, wherein each dose is about 2.1 mg / kg to about 2.5 mg / kg.

[0107] In one embodiment of the invention, a human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 100 mg is administered every 6 hours for about 5 days to about 30 days. In another embodiment, a human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 100 mg is administered every 6 hours for about 30 days to about 90 days. In yet another embodiment, a human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 100 mg is administered every 6 hours for about 90 days to about six months. In a further embodiment, a human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 100 mg is administered every 8 hours for about 5 days to about 30 days. In certain embodiments, a human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 100 mg is administered every 8 hours for about 30 days to about 90 days. In another embodiment, a human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 100 mg is administered every 8 hours for about 90 days to about six months. In yet another embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 100 mg is administered every 12 hours for about 5 days to about 30 days. In another embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 100 mg is administered every 12 hours for about 30 days to about 90 days. In another embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 100 mg is administered every 12 hours for about 90 days to about six months. In yet another embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 150 mg is administered every 6 hours for about 5 days to about 30 days. In another embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 150 mg is administered every 6 hours for about 30 days to about 90 days. In yet another embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 150 mg is administered every 6 hours for about 90 days to about six months. In another embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 150 mg is administered every 8 hours for about 5 days to about 30 days. In certain embodiments, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 150 mg is administered every 8 hours for about 30 days to about 90 days. In another embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 150 mg is administered every 8 hours for about 90 days to about six months. In one embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 150 mg is administered every 12 hours for about 5 days to about 30 days. In a further embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 150 mg is administered every 12 hours for about 30 days to about 90 days.In yet another embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 150 mg is administered every 12 hours for about 90 days to about six months. In another embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 200 mg is administered every 6 hours for about 5 days to about 30 days. In one embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 200 mg is administered every 6 hours for about 30 days to about 90 days. In another embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 200 mg is administered every 6 hours for about 90 days to about six months. In a further embodiment, wherein the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 200 mg is administered every 8 hours for about 5 days to about 30 days. In yet another embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 200 mg is administered every 8 hours for about 30 days to about 90 days. In one embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 200 mg is administered every 8 hours for about 90 days to about six months. In another embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 200 mg is administered every 12 hours for about 5 days to about 30 days. In a further embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 200 mg is administered every 12 hours for about 30 days to about 90 days. In another embodiment, the human subject is administered an initial dose of about 150 mg, and a subsequent dose of about 200 mg is administered every 12 hours for about 90 days to about six months. In certain embodiments, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 100 mg is administered every 6 hours for about 5 days to about 30 days. In yet another embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 100 mg is administered every 6 hours for about 30 days to about 90 days. In another embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 100 mg is administered every 6 hours for about 90 days to about six months. In one embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 100 mg is administered every 8 hours for about 5 days to about 30 days. In a further embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 100 mg is administered every 8 hours for about 30 days to about 90 days. In yet another embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 100 mg is administered every 8 hours for about 90 days to about six months.In another embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 100 mg is administered every 12 hours for about 5 days to about 30 days. In one embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 100 mg is administered every 12 hours for about 30 days to about 90 days. In another embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 100 mg is administered every 12 hours for about 90 days to about six months. In a further embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 150 mg is administered every 6 hours for about 5 days to about 30 days. In another embodiment of the present invention, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 150 mg is administered every 6 hours for about 30 days to about 90 days. In yet another embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 150 mg is administered every 6 hours for about 90 days to about six months. In another embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 150 mg is administered every 8 hours for about 5 days to about 30 days. In one embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 150 mg is administered every 8 hours for about 30 days to about 90 days. In another embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 150 mg is administered every 8 hours for about 90 days to about six months. In another embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 150 mg is administered every 12 hours for about 5 days to about 30 days. In another embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 150 mg is administered every 12 hours for about 30 days to about 90 days. In embodiments of the present invention, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 150 mg is administered every 12 hours for about 90 days to about six months. In a further embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 200 mg is administered every 6 hours for about 5 days to about 30 days. In yet another embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 200 mg is administered every 6 hours for about 30 days to about 90 days. In another embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 200 mg is administered every 6 hours for about 90 days to about six months. In an embodiment of the present invention, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 200 mg is administered every 8 hours for about 5 days to about 30 days.In a further embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 200 mg is administered every 8 hours for about 30 days to about 90 days. In yet another embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 200 mg is administered every 8 hours for about 90 days to about six months. In another embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 200 mg is administered every 12 hours for about 5 days to about 30 days. In an embodiment of the present invention, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 200 mg is administered every 12 hours for about 30 days to about 90 days. In one embodiment, the human subject is administered an initial dose of about 200 mg, and a subsequent dose of about 200 mg is administered every 12 hours for about 90 days to about six months. In another embodiment, the human subject is administered a single dose or divided dose of about 25 mg to about 400 mg of the compound or pharmaceutical composition for about 5 days to about 1 year. In yet another embodiment, the human subject is administered divided doses of about 25 mg to about 400 mg of the compound or pharmaceutical composition for about 5 days to about 1 year.

[0108] Exemplary embodiments of initial and subsequent doses for adults are shown in Table 1. In certain such embodiments, subsequent doses may be administered from about every 8 hours to about every 96 hours.

[0109] Table 1 : Example of dosing regimen for adults

[0110]

[0111] Exemplary embodiments of combinations of initial and subsequent doses for children are shown in Table 2. In certain such embodiments, subsequent doses may be administered from about every 8 hours to about every 96 hours.

[0112] Table 2 : Example of dosing regimen for children

[0113]

[0114] The compounds or pharmaceutical compositions of the present invention can be administered intravenously, orally, rectally or sublingually. In one embodiment, the route of administration is intravenous injection. In another embodiment, the route of administration is oral. In another embodiment, the route of administration is rectal administration. In yet another embodiment, the route of administration is sublingual.

[0115] The compounds or pharmaceutical compositions of the present invention can be administered in single doses or divided doses. In some embodiments, at least one initial dose can be a single, divided dose, or a combination thereof. In some embodiments, subsequent doses can be single, divided doses, or a combination thereof. In one embodiment, for subsequent doses, human subjects are administered divided doses of about 25 mg to about 400 mg for about 5 days to about 30 days. In another embodiment, human subjects are administered a single dose of about 25 mg to about 400 mg of subsequent doses for about 5 days to about 40 days. In yet another embodiment, human subjects are administered a single dose of about 25 mg to about 400 mg of subsequent doses for about 5 days to about 60 days. In a further embodiment, human subjects are administered a single dose of about 25 mg to about 400 mg of subsequent doses for about 5 days to about 60 days. In other forms, subsequent doses are administered for no more than about 10 days; and in other forms, no more than about 20 days; in another form, no more than about 50 days; other versions are no more than about 100 days; and in other forms, no more than about one year.

[0116] It is known that a steady-state minimum castanospermine concentration of 400 ng / ml in mice is associated with a 50 mg / kg BID dose, and the antiviral effect of celgosivir in vivo appears to be associated with the minimum steady-state concentration of castanospermine (Watanabe et al.). The literature also shows that within the tolerated dose range, the pharmacokinetics of celgosivir are linear with dose (Sorbera et al.). International Publication No. WO 2014 / 143907 discloses the pharmacokinetic parameters of castanospermine used in the CELADEN study. Pharmacokinetic simulations using these pharmacokinetic parameters show that 150 mg administered 4 times a day should produce a steady-state minimum concentration of 1469 ng / ml, 200 mg administered 3 times a day produces a steady-state minimum concentration of castanospermine of 799 ng / ml; and 300 mg twice a day produces a steady-state minimum concentration of castanospermine of 532 ng / ml. Therefore, by linear extrapolation, the minimum protective dose (to reach a steady-state minimum of 400 ng / ml) is approximately 40 mg every 6 h, 75 mg every 8 h, and 225 mg every 12 h. In addition, WO 2014 / 143907 discloses that the CELADEN study protocol produces a steady-state maximum castanospermine concentration of 5100 ng / ml. The adverse event profile in this study showed that at this dose, the incidence of GI reactions was higher, but the severity was not increased. The study also showed that the theoretical maximum daily dose could be as high as a total dose of 600 mg, or a single dose of 400 mg, confirming this effect in the literature. The FDA has published a universal proportionality constant to adjust the mg / kg dose of animals to the mg / kg dose of humans. In general, for mice, the proportionality constant is 12. Therefore, 50 mg / kg BID is equivalent to a 4.2 mg / kg BID dose in humans, which is equivalent to 250 mg for a 60 kg human body. The same dose administered three or four times daily is equivalent to 167 mg and 125 mg and 2.8 mg / kg and 2.1 mg / kg, respectively. In a 60 kg human, the maximum single dose is 6.7 mg / kg and the maximum daily dose is 10 mg / kg.

[0117] The present invention also relates to a method for treating or preventing a disease caused by RSV infection by achieving a steady-state Cmin serum or plasma concentration of castanospermine of about 0.05 micrograms / mL to about 2.0 micrograms / mL in an adult or child subject. In one embodiment, the steady-state Cmin serum or plasma concentration of castanospermine achieved in an adult or child subject is about 0.08 micrograms / mL to about 0.5 micrograms / mL. In another embodiment, the steady-state Cmin serum or plasma concentration of castanospermine achieved in an adult or child subject is about 0.05 micrograms / mL to about 0.08 micrograms / mL. In yet another embodiment, the steady-state Cmin serum or plasma concentration of castanospermine achieved in an adult or child subject is about 0.08 micrograms / mL to about 0.11 micrograms / mL. In a further embodiment, the steady-state Cmin serum or plasma concentration of castanospermine achieved in an adult or child subject is about 0.11 micrograms / mL to about 0.3 micrograms / mL. In another embodiment, the steady-state Cmin serum or plasma concentration of castanospermine achieved in an adult or pediatric subject is about 0.3 micrograms / mL to about 0.75 micrograms / mL. In a further embodiment, the steady-state Cmin serum or plasma concentration of castanospermine achieved in an adult or pediatric subject is about 0.75 micrograms / mL to about 1.0 micrograms / mL. In yet another embodiment, the steady-state Cmin serum or plasma concentration of castanospermine achieved in an adult or pediatric subject is about 1.0 micrograms / mL to about 2.0 micrograms / mL. In another embodiment, the steady-state Cmin serum or plasma concentration of castanospermine achieved in an adult or pediatric subject is about 1.0 micrograms / mL to about 1.5 micrograms / mL. In a further embodiment, the steady-state Cmin serum or plasma concentration of castanospermine achieved in an adult or pediatric subject is about 1.5 micrograms / mL to about 2.0 micrograms / mL. In yet another embodiment, the steady-state Cmin serum or plasma concentration of castanospermine achieved in an adult or pediatric subject is about 1.25 micrograms / mL to about 1.75 micrograms / mL.

[0118] In one embodiment, the minimum steady-state concentration of castanospermine achieved during the administration of the initial dose and / or subsequent doses to a human subject exceeds 0.4 micrograms / mL. In a further embodiment, the minimum steady-state concentration of castanospermine achieved during the administration of the initial dose and / or subsequent doses to a human subject exceeds 0.5 micrograms / mL. In yet another embodiment, the minimum steady-state concentration of castanospermine achieved during the administration of the initial dose and / or subsequent doses to a human subject exceeds 0.6 micrograms / mL. In another embodiment, the minimum steady-state concentration of castanospermine achieved during the administration of the initial dose and / or subsequent doses to a human subject exceeds 0.7 micrograms / mL. And in other embodiments, the minimum steady-state concentration of castanospermine achieved during the administration of the initial dose and / or subsequent doses to a human subject exceeds 0.8 micrograms / mL. In other embodiments, the minimum steady-state concentration of castanospermine achieved during the administration of the initial dose and / or subsequent doses to a human subject exceeds 0.9 micrograms / mL. In yet another embodiment, the minimum steady-state concentration of castanospermine reached during the administration of the initial dose and / or subsequent doses to a human subject exceeds 1.0 micrograms / mL. In some embodiments, the minimum steady-state concentration of castanospermine reached during the administration of the initial dose and / or subsequent doses to a human subject exceeds 1.1 micrograms / mL. In another embodiment, the minimum steady-state concentration of castanospermine reached during the administration of the initial dose and / or subsequent doses to a human subject exceeds 1.2 micrograms / mL. In yet another embodiment, the minimum steady-state concentration of castanospermine reached during the administration of the initial dose and / or subsequent doses to a human subject exceeds 1.3 micrograms / mL. In other embodiments, the minimum steady-state concentration of castanospermine reached during the administration of the initial dose and / or subsequent doses to a human subject exceeds 1.4 micrograms / mL. And in other embodiments, the minimum steady-state concentration of castanospermine reached during the administration of the initial dose and / or subsequent doses to a human subject exceeds 2.0 micrograms / mL.

[0119] In one embodiment, the average steady-state Cmin serum or plasma concentration of castanospermine achieved in a plurality of human subjects is about 0.08 micrograms / mL to about 0.5 micrograms / mL. In another embodiment, the average steady-state Cmin serum or plasma concentration of castanospermine achieved in a plurality of human subjects is about 0.05 micrograms / mL to about 0.08 micrograms / mL. In yet another embodiment, the average steady-state Cmin serum or plasma concentration of castanospermine achieved in a plurality of human subjects is about 0.08 micrograms / mL to about 0.11 micrograms / mL. In a further embodiment, the average steady-state Cmin serum or plasma concentration of castanospermine achieved in a plurality of human subjects is about 0.11 micrograms / mL to about 0.4 micrograms / mL. In another embodiment, the average steady-state Cmin serum or plasma concentration of castanospermine achieved in a plurality of human subjects is about 0.4 micrograms / mL to about 0.75 micrograms / mL. In a further embodiment, the average steady-state Cmin serum or plasma concentration of castanospermine achieved in a plurality of human subjects is about 0.75 micrograms / mL to about 1.0 micrograms / mL. In yet another embodiment, the average steady-state Cmin serum or plasma concentration of castanospermine achieved in a plurality of human subjects is about 1.0 micrograms / mL to about 2.0 micrograms / mL. In another embodiment, the average steady-state Cmin serum or plasma concentration of castanospermine achieved in a plurality of human subjects is about 1.0 micrograms / mL to about 1.5 micrograms / mL. In a further embodiment, the average steady-state Cmin serum or plasma concentration of castanospermine achieved in a plurality of human subjects is about 1.5 micrograms / mL to about 2.0 micrograms / mL. In yet another embodiment, the average steady-state Cmin serum or plasma concentration of castanospermine achieved in a plurality of human subjects is about 1.25 micrograms / mL to about 1.75 micrograms / mL.

[0120] In another aspect of the invention, the viral load of human subjects receiving the treatment method is reduced by at least 50% higher than that of people who do not use the compound or the group that uses a placebo. In one embodiment, the virological logarithm of human subjects receiving the treatment method is reduced by at least 50% higher than that of people who do not use the compound or the group that uses a placebo. In another embodiment, the virological logarithm of human subjects receiving the treatment method is reduced by about 60% to about 70% higher than that of people who do not use the compound or the group that uses a placebo. In another embodiment, the virological logarithm of human subjects receiving the treatment method is reduced by about 70% to about 80% higher than that of people who do not use the compound or the group that uses a placebo. In another embodiment, the virological logarithm of human subjects receiving the treatment method is reduced by at least 80% to about 90% higher than that of people who do not use the compound or the group that uses a placebo. Example

[0121] Example 1: Celgosivir has selective activity against RSV in vitro

[0122] Celgosivir and castanospermine were evaluated in vitro for their efficacy against RSV and human rhinovirus-14. For RSV studies, embryonic African green monkey kidney cells (MA-104) were grown in minimum essential medium (MEM) supplemented with 0.1% NaHCO3 and 10% fetal bovine serum. When performing antiviral assays, serum was reduced to 2% and 50 mg / ml gentamicin was added to the culture medium. RSV strain A2 was used for the studies. For rhinovirus studies, the HeLa Ohio cell line was used instead of MA-104 cells.

[0123] CPE inhibition assays and visual quantification of antiviral activity and cytotoxicity were performed as described by Sidwell and Huffman (1971) with slight modifications. Sidwell, RW and Huffman, JH (1971) Use of disposable micro-tissue culture plates for antiviral and interferon induction studies. Appl. Microbiol. 22, 7979–7801. Celgosivir and castanospermine at concentrations of 0.3 μM, 3 μM, 30 μM and 300 μM and virus at a multiplicity of infection (MOI) = 0.001 were added to near-confluent cell monolayers of 1×10E05 cells / well and incubated at 37°C until cells in control wells showed complete viral CPE observed by light microscopy (6 days). Viral inhibition assays in quadruplicate and cytotoxicity assays in duplicate were performed for all compounds. In the rhinovirus study, pirudavir was used as a positive control compound at a concentration of 0.001 μg / ml to 1 μg / ml. For the RSV study, the positive control compound was ribavirin at a concentration of 0.5 μg / ml to 500 μg / ml. For each compound, two wells were set aside for each test as uninfected, untreated cell controls, and four wells were left alone for each test and represented controls for viral replication. Changes caused by viral cytopathic effects were graded from 1 to 4, with 4 representing the case where the entire (100%) monolayer in the well showed viral cytopathic effects. For all CPE-based assays, the 50% effective concentration (EC50) was calculated by regression analysis using the average of the CPE ratings at each compound concentration. Morphological changes caused by compound cytotoxicity were graded from 0 to 5; grade 5 was defined as 100% cytotoxicity. The 50% cytotoxic dose (IC50) was calculated by regression analysis. The selectivity index (SI) for each compound was calculated (SI = (IC50) / (EC50)).

[0124] Neutral red assays for CPE inhibition and cytotoxicity were performed by a modified method described by Cavenaugh et al. (1990). Cavenaugh, PR, Jr., Moskwa, PS, Donish, WH, Pera, PJ, Richardson, D. and Andrese, AP (1990) A semi-automated neutral red based chemosensitivity assay for drug screening. Invest. New Drugs 8, 347–354. Briefly, the medium was removed from each well of the plate scored for CPE in the visual CPE inhibition assay, 0.2 ml of neutral red (0.034% in PSS) was added to each well of the plate, and the plate was incubated in the dark at 37°C for 2 h. The neutral red solution was removed from the wells and the wells were rinsed twice with PBS (pH 7.4). An equal volume (0.1 ml) of anhydrous ethanol and Citrate buffer (0.1M sodium citrate, 0.1M HCl, pH 4.2) was mixed together and added to each well. The plate was incubated in the dark at room temperature for 30 min to dissolve the dye. The plate was then gently mixed for 1 min on a vortex oscillator adapted for 96-well plates. The absorbance at 540nm and 450nm was read using a microplate reader (Bio-Tek EL 1309; Bio-Tek Instruments). All concentrations were measured in at least three replicates. The absorbance values ​​were expressed as a percentage of the untreated control, and the EC50 and IC50 values ​​were calculated by regression analysis.

[0125] The results of these studies are presented in Tables 3 and 4.

[0126] Table 3. Studies on celgosivir and castanospermine against human rhinovirus-14

[0127]

[0128] Table 4. Studies on Celgosivir and Castanospermine against RSV

[0129]

[0130] Celgosivir and castanospermine were determined to be safe at all tested concentrations because CC 50 Celgosivir and castanospermine were not determined to be effective against human rhinovirus-14 at the concentrations tested. However, celgosivir was effective against RSV infection. Celgosivir produced an EC of 34-37 50 Considering CC 50 At least 300, the SI of celgosivir against RSV 50was at least 8.1, thus demonstrating the potential effectiveness of celgosivir in treating or preventing RSV infection in vivo.

[0131] Example 2: Celgosivir reduces RSV-induced lung inflammation in cotton rats without inhibiting viral replication.

[0132] Animals, dosing, treatment groups, and infection

[0133] On day 0, cotton rats (Sigodon hispidus, 2 males and 3 females, 6-8 weeks old) fed standard rodent chow and water ad libitum were infected intranasally with RSV (A / A2 strain, 10 5 pfu]. Animals received celgosivir daily [25 mg / kg, 50 mg / kg, or 100 mg / kg BID, for a total daily dose of 50 mg / kg, 100 mg / kg, or 200 mg / kg] starting before or one day after infection and were sacrificed on day 5 post infection for histopathology, qPCR, and viral load assessment. Control groups included [i] the positive control Synagis [2.5 mg / kg, im, once daily starting on day 1 post infection], [ii] a vehicle control, in which vehicle was administered twice daily starting one day before RSV infection, [iii] a vehicle control group mock-infected with PBS, treatment started one day before infection, and [iv] an untreated group mock-infected with PBS, which received no treatment. Animals were weighed on days 1 and 5, and plasma was obtained by retro-orbital bleeding on the same day.

[0134] RSV strain A / A2 (RSV A / A2) (ATCC, Manassas, VA) propagated in HEp-2 cells after serial plaque purification was used to reduce defective interfering particles. 8 pfu / mL of the indicated virus stocks. This virus was stored at -80°C and was previously characterized in vivo in the cotton rat model and demonstrated upper and lower respiratory tract replication.

[0135] Endpoint Assay Protocol Overview and Statistics

[0136] Virus titer: Nasal and lung homogenates were centrifuged and diluted in EMEM. Confluent HEp-2 monolayers were infected in duplicate with the diluted homogenates in 24-well plates. After incubation for 1 hour in a 37°C [5% CO2] incubator, the wells were covered with 0.75% methylcellulose. After 4 days of incubation, the medium was removed and the cells were fixed with 0.1% crystal violet stain [1h], then rinsed and air-dried. Plaques were counted for all animals in a group at a given time, and the virus titer was determined as the geometric mean plaque forming units per gram of tissue ± standard deviation.

[0137] Lung Histopathology: Lungs were removed and swollen to standard volume with 10% neutral buffered formalin and then fixed [using the same solution]. After fixation, lungs were embedded in paraffin, sectioned and stained with H&E. Four parameters of lung inflammation were evaluated: peribronchiolitis (inflammatory cell infiltration around the bronchioles), perivasculitis (inflammatory cell infiltration around small blood vessels), interstitial pneumonia (inflammatory cell infiltration and thickening of the alveolar walls), and alveolitis (cells within the alveolar spaces). Slides were blindly scored according to a 0-4 severity scale. Scores were subsequently converted to a standardized scale of 0%-100%.

[0138] statistics: Group means for each parameter were assessed by one-way ANOVA, and individual group means were then compared to the RSV-infected vehicle-treated control group [t-test, corrected for multiple comparisons]. p < 0.05 was considered statistically significant.

[0139] result: The results of these studies can be found in Figure 1 and Figure 2 . Celgosivir reduced inflammation at all doses for three of the four histopathological parameters, with a significant dose effect in two histopathological areas when drug administration began one day before infection. The positive control antiviral drug showed statistically significant reductions in all four histopathological areas. Celgosivir had no effect on viral titers in the nose or lung. Celgosivir showed no significant effect on viral titers in the nose or lung.

[0140] The data demonstrate that celgosivir reduces the extent of RSV-induced lung histopathological changes in a manner that is independent of inhibition of viral replication in the nose or lungs.

[0141] Example 3: Delayed parenteral administration of celgosivir or castanospermine is expected to have a protective effect on RSV-induced histopathological changes.

[0142] Using the method outlined in Example 2, from Figure 1 It is evident from an inspection of the data in the Journal of Clinical Oncology that the timing of celgosivir administration had minimal impact on the degree of anti-inflammatory protection conferred by the drug. This is in contrast to other viral diseases for which celgosivir is effective through an antiviral mechanism, where the timing of administration has a profound impact on the degree of benefit provided.

[0143] Parenterally administered castanospermine has antiviral activity, and parenterally administered celgosivir is rapidly converted to castanospermine, meaning that the actual therapeutic scaffold in vivo is castanospermine. Therefore, it is predicted that parenterally administered celgosivir or castanospermine will protect treated subjects from RSV-induced lung inflammation and decline in lung function in animals or humans following viral exposure and onset of disease symptoms.

[0144] The teachings of all patents, published applications, and references cited herein are incorporated by reference in their entirety.

[0145] While the invention has been particularly shown and described with reference to exemplary embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the following claims.

Claims

1. A method for treating a disease caused by respiratory syncytial virus (RSV) infection in a human subject, comprising: a) determining that the human subject is infected with RSV; b) administering to the human subject at least one initial dose of about 15 mg to about 600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising about 15 mg to about 600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and c) administering to the human subject a plurality of subsequent doses of about 15 mg to about 400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising about 15 mg to about 400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, Wherein no more than 600 mg of the compound of formula (I) is administered per day, wherein the subsequent doses are administered once, twice, three times or four times daily, and Wherein formula (I) has the following structure, Where R 1 , R 2 and R 3 are independently H, (C1-C 14 ) acyl, (C1-C 14 )alkenoyl, (C3-C8)cycloalkylacyl, (C1-C 14 ) haloalkyl acyl (C1-C8) alkoxy acyl or (C6-C 10 )aroyl.

2. The method according to claim 1, wherein the compound of formula (I) is a compound of formula (II):

3. The method according to any one of claims 1-2, wherein the human subject is an adult.

4. The method of claim 3, wherein the human subject is at least 60 years old.

5. The method of any one of claims 1-2, wherein the human subject is a child.

6. The method of claim 4, wherein the human subject is a premature infant.

7. The method of any one of claims 5-6, wherein the human subject is less than one year old when the at least one initial dose is administered.

8. The method of any one of claims 1-7, wherein the human subject is hospitalized.

9. The method of any one of claims 1-7, wherein the patient is ambulatory but symptomatic and administration of treatment is delayed for at least 48 h.

10. The method of any one of claims 1-9, wherein the compound of formula (I) is converted to castanospermine upon administration to the human subject, and wherein a steady-state Cmin serum or plasma concentration of castanospermine of about 0.4 μg / mL to about 2.0 μg / mL is achieved in the human subject following administration of an initial dose and subsequent doses.

11. The method of claim 10, wherein after administration of the initial dose and subsequent doses, a steady-state Cmin serum or plasma concentration of castanospermine of about 1.0 microgram / mL to about 2.0 microgram / mL is achieved in the human subject.

12. The method of claim 10, wherein after administration of the initial dose and subsequent doses, a steady-state Cmin serum or plasma concentration of castanospermine of about 1.0 micrograms / mL to about 1.5 micrograms / mL is achieved in the human subject.

13. The method of claim 10, wherein after administration of the initial dose and subsequent doses, a steady-state Cmin serum or plasma concentration of castanospermine of about 1.5 micrograms / mL to about 2.0 micrograms / mL is achieved in the human subject.

14. The method of claim 10, wherein after administration of the initial dose and subsequent doses, a steady-state Cmin serum or plasma concentration of castanospermine of about 1.25 micrograms / mL to about 1.75 micrograms / mL is achieved in the human subject.

15. The method of any one of claims 1-14, wherein the compound or the pharmaceutical composition is administered orally or sublingually.

16. The method of any one of claims 1-15, wherein the human subject is administered an initial dose of about 150 mg and subsequent doses of about 100 mg are administered every 6, 8, or 12 hours for about 5 to about 30 days.

17. The method of any one of claims 1-15, wherein the human subject is administered an initial dose of about 150 mg and subsequent doses of about 150 mg are administered every 6 hours for about 5 to about 30 days.

18. The method of any one of claims 1-15, wherein the human subject is administered an initial dose of about 150 mg and subsequent doses of about 150 mg are administered every 8 hours for about 5 to about 30 days.

19. The method of any one of claims 1-15, wherein the human subject is administered an initial dose of about 150 mg and subsequent doses of about 150 mg are administered every 12 hours for about 5 to about 30 days.

20. The method of any one of claims 1-15, wherein the human subject is administered an initial dose of about 150 mg and subsequent doses of about 200 mg are administered every 6, 8, or 12 hours for about 5 to about 30 days.

21. The method of any one of claims 1-15, wherein the human subject is administered an initial dose of about 200 mg and subsequent doses of about 100 mg are administered every 6, 8, or 12 hours for about 5 to about 30 days.

22. The method of any one of claims 1-15, wherein the human subject is administered an initial dose of about 200 mg and subsequent doses of about 150 mg every 6, 8, or 12 hours for about 5 to about 30 days.

23. The method of any one of claims 1-15, wherein the human subject is administered an initial dose of about 200 mg and subsequent doses of about 200 mg are administered every 6 hours, 8 hours, or 12 hours for about 5 days to about 30 days.

24. The method of any one of claims 1-15, wherein the human subject is administered a single or divided dose of about 25 mg to about 300 mg of the compound or the pharmaceutical composition for about 5 days to about 30 days.

25. The method of any one of claims 1-24, wherein the human subject is administered celgosivir or castanospermine to reduce lung inflammation or improve lung function.

26. The method of any one of claims 1-13 or 25, wherein the human subject is administered celgosivir or castanospermine intravenously or intramuscularly.

27. The method of claim 26, wherein the human subject receives a total daily dose of at least 4 mg / kg / day but not more than 12 mg / kg / day, administered in divided doses of at least two but no more than four times daily.

28. A method for preventing disease caused by respiratory syncytial virus (RSV) infection in a human subject, comprising: a) administering to the human subject at least one initial dose of about 15 mg to about 600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising about 15 mg to about 600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and b) administering to the human subject a plurality of subsequent doses of about 15 mg to about 400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising about 15 mg to about 400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, Wherein no more than 600 mg of the compound of formula (I) is administered per day, wherein the human subject is asymptomatic upon administration of the at least one initial dose, wherein the subsequent doses are administered once, twice, three times or four times daily, and Wherein formula (I) has the following structure, Where R 1 , R 2 and R 3 are independently H, (C1-C 14 ) acyl, (C1-C 14 )alkenoyl, (C3-C8)cycloalkylacyl, (C1-C 14 ) haloalkyl acyl (C1-C8) alkoxy acyl or (C6-C 10 )aroyl.

29. The method according to claim 28, wherein the compound of formula (I) is a compound of formula (II): And wherein the human subject is a child less than one year old.

30. The method of any one of claims 28-29, wherein the compound of formula (I) is converted to castanospermine upon administration to the human subject, and wherein a steady-state Cmin serum or plasma concentration of castanospermine of about 0.4 micrograms / mL to about 2.0 micrograms / mL is achieved in the human subject following administration of an initial dose and subsequent doses.

31. The method of claim 30, wherein a steady-state Cmin serum or plasma concentration of castanospermine of about 1.0 microgram / mL to about 2.0 microgram / mL is achieved in the human subject following administration of the initial dose and subsequent doses.

32. The method of claim 30, wherein after administration of the initial dose and subsequent doses, a steady-state Cmin serum or plasma concentration of castanospermine of about 1.0 micrograms / mL to about 1.5 micrograms / mL is achieved in the human subject.

33. The method of claim 30, wherein after administration of the initial dose and subsequent doses, a steady-state Cmin serum or plasma concentration of castanospermine of about 1.5 micrograms / mL to about 2.0 micrograms / mL is achieved in the human subject.

34. The method of claim 30, wherein after administration of the initial dose and subsequent doses, a steady-state Cmin serum or plasma concentration of castanospermine of about 1.25 micrograms / mL to about 1.75 micrograms / mL is achieved in the human subject.

35. The method of any one of claims 28-34, wherein the compound or the pharmaceutical composition is administered orally or sublingually.

36. The method of any one of claims 28-35, wherein the human subject is administered an initial dose of about 150 mg and subsequent doses of about 100 mg are administered every 6, 8, or 12 hours for about 5 to about 30 days.

37. The method of any one of claims 28-35, wherein the human subject is administered an initial dose of about 150 mg and subsequent doses of about 150 mg are administered every 6 hours for about 5 to about 30 days.

38. The method of any one of claims 28-35, wherein the human subject is administered an initial dose of about 150 mg and subsequent doses of about 150 mg are administered every 8 hours for about 5 to about 30 days.

39. The method of any one of claims 28-35, wherein the human subject is administered an initial dose of about 150 mg and subsequent doses of about 150 mg are administered every 12 hours for about 5 to about 30 days.

40. The method of any one of claims 28-35, wherein the human subject is administered an initial dose of about 150 mg and subsequent doses of about 200 mg are administered every 6, 8, or 12 hours for about 5 to about 30 days.

41. The method of any one of claims 28-35, wherein the human subject is administered an initial dose of about 200 mg and subsequent doses of about 100 mg are administered every 6, 8, or 12 hours for about 5 to about 30 days.

42. The method of any one of claims 28-35, wherein the human subject is administered an initial dose of about 200 mg and subsequent doses of about 150 mg every 6, 8, or 12 hours for about 5 to about 30 days.

43. The method of any one of claims 28-35, wherein the human subject is administered an initial dose of about 200 mg and subsequent doses of about 200 mg are administered every 6 hours, 8 hours, or 12 hours for about 5 days to about 30 days.

44. The method of any one of claims 28-35, wherein the human subject is administered a single or divided dose of about 25 mg to about 300 mg of the compound or the pharmaceutical composition for about 5 days to about 30 days.

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