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WO2024165764A1 - Plitidepsine destinée à être utilisée dans le traitement d'infections virales à adn non intégrées - Google Patents

Plitidepsine destinée à être utilisée dans le traitement d'infections virales à adn non intégrées Download PDF

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Publication number
WO2024165764A1
WO2024165764A1 PCT/EP2024/053510 EP2024053510W WO2024165764A1 WO 2024165764 A1 WO2024165764 A1 WO 2024165764A1 EP 2024053510 W EP2024053510 W EP 2024053510W WO 2024165764 A1 WO2024165764 A1 WO 2024165764A1
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day
plitidepsin
pharmaceutically acceptable
stereoisomer
acceptable salt
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Inventor
Jose Maria Fernandez Sousa-Faro
Pablo Manuel Aviles Marin
Juan Francisco GARCÍA ARRIAZA
Guillermo ALBERICIO BONILLA
Mariano ESTEBAN RODRÍGUEZ
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Pharmamar SA
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Pharmamar SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/15—Depsipeptides; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the present invention relates to the antiviral treatment of non-integrated DNA viruses and, in particular, to the antiviral treatment of viral infections of the Orthopoxvirus genus, in particular Mpox (formerly known as Monkeypox).
  • DNA viruses are linked to many infectious diseases and contribute significantly to human and animal morbidity and mortality worldwide. DNA viruses can be classified as integrated or non-integrated, according to whether their genome is integrated into the host cell genome. Non-integrated DNA viruses include some of the most important viruses for public health, for example orthopoxviruses. Non-integrated DNA viruses are diverse, but characteristically all complete their replication cycle without integrating their DNA genome into the host cell genome.
  • Orthopoxvirus Viruses of the genus Orthopoxvirus are responsible for important diseases in humans and animals. Seven species of orthopoxviruses have been reported to infect humans and are estimated to have been responsible for approximately 300 - 500 million deaths during the 20 th century (Theves et al. 2014). Since the eradication of the human-specific Variola virus, all human orthopoxvirus infections are zoonoses, a virus transmitted to humans from an animal reservoir. Infection rates with orthopoxviruses are increasing and spreading across the globe, primarily due to a decrease in immunity following the discontinuation of vaccination against the genus.
  • Orthopoxviruses are enveloped brick-shaped viruses containing a double-stranded DNA genome, of approximately 200 kb, that encodes 150-200 genes. Orthopoxvirus infections are characterised by localized or generalized skin lesions, progressing from papules, to vesicles and scabs. Depending on the species and strain of orthopoxvirus involved, other signs and symptoms can include fever, swollen lymph nodes, malaise, and body aches. Mortality rate varies between species and strains of orthopoxvirus. Despite the significant risk to public health, little is known about the primary hosts and reservoirs of zoonotic orthopoxviruses in nature, or their transmission and maintenance cycles. For this reason, the risk of an outbreak is high and the need for new effective treatments is urgent.
  • Variola virus The most virulent, destructive member of the Orthopoxvirus genus is Variola virus, the causative agent of human smallpox. Smallpox was one of the most devastating diseases known to civilization, causing millions of deaths before it was eradicated in 1980. Variola virus is transmitted through aerosols, with the virus entering the body by inhalation of microdroplets shed from the respiratory tract of infected persons. Following an incubation period of 7-19 days, symptoms of fever, headaches, malaise, and muscle aches present. After 2 or 3 days, a characteristic rash appears on the face, hands and forearms spreads all over the body, developing into ulcerating lesions in the nose and mouth that release virus.
  • Mpox is less contagious than smallpox and causes less severe illness, typically lasting 2 to 4 weeks.
  • Clinical symptoms of Mpox present after 5 - 17 days, and include fever, headaches, a rash that develops into to blisters and, distinguishing swollen lymph nodes.
  • Young children and individuals infected with the Central African (Congo basin) clade of the virus are at greater risk of more severe disease.
  • Complications including secondary infections, bronchopneumonia, sepsis, infection of the cornea and encephalitis have been observed.
  • Major disease sequelae include disfiguring scars and permanent corneal lesions.
  • Mortality rates are 3 - 6% (WHO, Mpox fact sheet).
  • Vaccines and antiviral treatments against orthopoxviruses are known, but are approved for only limited members of the Orthopoxvirus genus. For this additional reason, there is a need for new treatments for viral infections from the Orthopoxvirus genus.
  • the Imvanex vaccine has been approved by the European Medicines Agency (EMA) for administration to adults, to protect against smallpox and Mpox.
  • EMA European Medicines Agency
  • FDA Food and Drug Administration
  • Tecovirimat ST-246 is an orthopoxvirus-specific small molecule antiviral drug, that inhibits the exit of viruses from infected cells through interacting with the F13 protein (F13L gene) found in orthopoxvirus envelopes. Tecovirimat was approved to treat smallpox, cowpox, and Mpox under “exceptional circumstances” within the European Union (EU) in 2022 (EMA, 2022). Cidofovir is a nucleoside analogue that inhibits viral DNA polymerase and reduces replication of DNA viruses.
  • Brincidofovir a pro-drug comprising cidofovir conjugated to a lipid molecule, was approved by the FDA in 2021 under the agency’s Animal Rule for treatment of smallpox disease but is not approved for use in the EU.
  • Brincidofovir acts as an orthopoxvirus nucleotide analogue DNA polymerase inhibitor.
  • plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof for use in the treatment of a viral infection, wherein the virus is a non-integrated DNA virus.
  • plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof for use in the treatment of a viral infection, wherein the virus is a non-integrated DNA virus, excluding the Vaccinia virus.
  • plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof for use in the treatment of a viral infection, wherein the virus is selected from the Orthopoxvirus genus.
  • plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof for use in the treatment of a viral infection, wherein the virus is selected from the Orthopoxvirus genus, excluding the Vaccinia virus.
  • plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof for use in the treatment of a viral infection, wherein the virus is Mpox.
  • the present invention is directed to a pharmaceutical composition comprising plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, for use according to the present invention.
  • a method of treating a viral infection, wherein the virus is a non-integrated DNA virus, to a patient in need thereof comprises administering to a patient in need thereof a therapeutically effective amount of plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof.
  • plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof for use in the manufacture of a medicament for the treatment of a viral infection, wherein the virus is a non-integrated DNA virus.
  • Y is selected from CO and -COCH(CH 3 )CO-; each n and p is independently selected from 0 and 1 , and q is selected from 0, 1 and 2; each R 1 , R 3 , R 5 , R 9 , R 11 , and R 15 is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, and substituted or unsubstituted C 2 -C 6 alkynyl; R 2 is selected from hydrogen, COR a , COOR a , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, and substituted or unsubstituted C 2 -C 6 alkynyl; each R 4 , R 5 , R 10 , R 12 , and R 16 is independently selected from hydrogen and substituted or unsubstituted C 1
  • the compound is Plitidepsin (PLD) or dehydrotamandarin A, or pharmaceutically acceptable salts or stereoisomers thereof.
  • the present invention is also directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as defined herein, and a pharmaceutically acceptable carrier, for use according to the present invention.
  • a method of treating a viral infection, wherein the virus is a non-integrated DNA virus, to a patient in need thereof wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound as defined herein; and wherein the virus is not the Vaccinia virus.
  • a compound as defined herein for use in the manufacture of a medicament for the treatment of a viral infection, wherein the virus is a non- integrated DNA virus, wherein the virus is not the Vaccinia virus.
  • a method of reducing viral load in a cell comprising contacting plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof, to said cell and thereby reducing viral load in said cell, wherein the virus is a non-integrated DNA virus.
  • a process for reducing the infection efficiency of a virus in a cell comprising contacting plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof, to said cell and thereby reducing the infection efficiency of a virus in said cell, wherein the virus is a non-integrated DNA virus.
  • a process for reducing viral propagation in a cell comprising contacting plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof, to said cell and thereby reducing viral propagation in said cell, wherein the virus is a non-integrated DNA virus.
  • a process for reducing viral replication in a cell comprising contacting plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof, to said cell and thereby reducing viral replication in said cell, wherein the virus is a non-integrated DNA virus.
  • the virus is selected from the Orthopoxvirus genus.
  • the virus is selected from Abatino macaquepox, Akhmeta virus, Buffalopox, Camelpox, Cowpox, Camelpox, Ectromelia, Horsepox, Mpox, Rabbitpox, Raccoonpox, Skunkpox, Taterapox, llasin Gishu disease virus, Variola, Vaccinia-like Brazilian isolates and Volepox.
  • the virus is Mpox.
  • the virus is Variola (also known as smallpox virus).
  • R 3 and R 4 may be independently selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl; preferably wherein R 3 is isopropyl and R 4 is hydrogen.
  • R 3 and R 4 may be methyl (this compound is also designated as a compound of general formula II).
  • R 11 may be selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl; preferably wherein R 11 may be methyl or isobutyl; more preferably wherein R 11 is isobutyl.
  • R 1 , R 5 , R 9 , and R 15 may be independently selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl; preferably wherein R 1 is selected from sec-butyl and isopropyl, R 5 is isobutyl, R 9 is p-methoxybenzyl, and R 15 is selected from methyl and benzyl, or wherein R 1 is selected from sec-butyl and isopropyl, R 5 is isobutyl, R 9 is p- methoxybenzyl, and q is 0; more preferably wherein R 1 is sec-butyl, R 5 is isobutyl, R 9 is p-methoxybenzyl, and q is 0.
  • R 8 , R 10 , R 12 , and R 16 may be independently selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl; preferably wherein R 8 , R 10 and R 12 are methyl, and R 16 is hydrogen, or wherein R 8 , R 10 and R 12 are methyl, and q is 0; more preferably wherein R 8 , R 10 and R 12 are methyl, and q is 0.
  • R 6 and R 14 may be independently selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl; preferably wherein R 6 is selected from hydrogen and methyl, and R 14 is hydrogen.
  • R 7 and R 13 may be independently selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl; preferably wherein R 7 is methyl and R 13 is selected from hydrogen, methyl, isopropyl, isobutyl, and 3-amino-3-oxopropyl.
  • R 6 and R 7 and/or R 13 and R 14 together with the corresponding N atom and C atom to which they are attached may form a substituted or unsubstituted pyrrolidine group.
  • R 2 may be selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, and COR a , and wherein R a is a substituted or unsubstituted C 1 -C 6 alkyl; preferably wherein R 2 is hydrogen.
  • X may be NH.
  • X may be O.
  • Y may be CO.
  • Y may be -COCH(CH 3 )CO-.
  • n may be 1 .
  • p may be 1 .
  • q may be 0.
  • n, p and q may be 1, 1 and 0 respectively.
  • the compound has the following structure: or pharmaceutically acceptable salts or stereoisomers thereof.
  • the viral infection may be a mild infection; and/or moderate infection; and/or severe infection.
  • the use may include use in the treatment of a patient with signs and symptoms of the viral infection for up to 4 weeks; and/or from 4 weeks to 12 weeks; and/or for more than 12 weeks.
  • the use may include use in the prophylaxis, reduction or treatment of persistent, viral symptoms.
  • the use may reduce the infectivity of infected patients; including wherein the patient is asymptomatic or not very symptomatic yet has a high viral load.
  • the use may reduce the occurrence of supercontagators (asymptomatic or not very symptomatic patients with high viral loads (e.g. cycle threshold (Ct)-value ⁇ 25)).
  • the present invention achieves a rapid and significant reduction in the viral burden. Reducing the viral burden may reduce the infectiveness of patients. This is particularly beneficial with patients who are asymptomatic or not very symptomatic yet have a high viral loads (e.g. Ct-value ⁇ 25). Such patients may be supercontagators or superspreaders.
  • Administration of compounds according to the present invention upon detection of infection can reduce the viral burden and therefore reduce the infectiveness of the patient.
  • the treatment may result in a reduction of viral load. This may be expressed as a replication cycle threshold (Ct) value greater than 30 (Ct> 30), on day 6 after the administration.
  • the treatment may reduce viral load from baseline. This may be expressed as a reduction in the percentage of patients requiring hospitalisation following administration. This may be expressed as a reduction in the percentage of patients requiring invasive mechanical ventilation and I or admission to the intensive care unit (ICU) following administration. This may be expressed as a reduction of patients who develop sequelae related to persistent disease. This may be expressed as an increase in the percentage of patients with normalization of analytical parameters chosen as poor prognosis criteria (including, for example, lymphopenia, lactate dehydrogenase or D- dimer).
  • This may be expressed as an increase in the percentage of patients with normalization of clinical criteria (disappearance of symptoms), including, for example: headache, fever, muscle aches, skin lesions, swollen glands, fatigue, dyspnea (shortness of breath), arthromyalgia or diarrhoea.
  • the compound may be administered in combination with a corticosteroid, preferably dexamethasone.
  • a corticosteroid preferably dexamethasone.
  • the compound and corticosteroid may be administered concurrently, separately or sequentially.
  • the compound may be administered according to a regimen of a once daily dose for 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day; preferably 2-5 days, 3-5 days, or 3, 4 or 5 days; most preferably 3 days or 5 days; most preferably 3 days.
  • the compound may be administered at a dose of 5 mg a day or less, 4.5 mg a day or less, 4 mg a day or less, 3.5 mg a day or less, 3 mg a day or less, 2.5 mg a day or less or 2 mg a day or less; 0.5 mg/day, 1 mg/day, 1.5 mg/day, 2 mg/day, 2.5 mg/day, 3 mg/day, 3.5 mg/day, 4 mg/day, 4.5 mg/day, or 5 mg/day; preferably 1 mg/day, 1.5 mg/day, 2 mg/day or 2.5 mg/day; preferably 1.5-2.5 mg/day; further preferably 1.5 mg/day, 2 mg/day or 2.5 mg/day.
  • the compound may be administered at a total dose of 1-50 mg, 1-40 mg, 1-30 mg, 1-20 mg, 1-15 mg, 3-15 mg, 3-12 mg, 4-12 mg, 4-10 mg, or 4.5-10 mg; 4 mg, 4.5 mg, 5 mg,
  • the total dose may be split over 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 days, preferably 3 days or 5 days; most preferably 3 days.
  • the compound may be administered at a once daily dose for 3 days at a dose of 1.5-2.5 mg/day.
  • the dose may be 1.5 mg/day.
  • the dose may be 2.5 mg/day.
  • the compound may be PLD administered as a 1.5-hour infusion, once a day for 3 consecutive days.
  • 1.5 mg of PLD may be administered as a 1.5-hour infusion, once a day for 3 consecutive days.
  • 2 mg of PLD may be administered as a 1.5-hour infusion, once a day for 3 consecutive days.
  • 2.5 mg of PLD may be administered as a 1.5-hour infusion, once a day for 3 consecutive days.
  • 1 mg of PLD may be administered as a 1.5- hour infusion, once a day for 5 consecutive days.
  • 2 mg of PLD may be administered as a 1.5-hour infusion, once a day for 5 consecutive days.
  • the regimen may be a single dose (1 day).
  • the compound may be administered as a single dose of 1-10 mg, 4-10 mg, 4.5-10 mg; 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg; preferably 4.5 mg, 5 mg, 6 mg, 7.5 mg, 8 mg, 9 mg or 10 mg; more preferably 5-9 mg, 6.5-8.5 mg, 7-8 mg or 7.5 mg.
  • the compound may be PLD administered as a single dose 1.5-hour infusion.
  • the single dose regimen may be utilised with all therapies set out in the present invention.
  • Combined use with corticosteroids may be used in embodiments with the single dose regimen.
  • the multi- day regimen may be utilised with all therapies set out in the present invention.
  • the corticosteroid may be administered daily on the same day(s) as administering a compound according to the present invention.
  • the corticosteroid may be administered on one or more subsequent days.
  • the corticosteroid may be administered on 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more subsequent days.
  • the corticosteroid may be administered at a higher dose when administered on the same day(s) as a compound according to the present invention and at a lower dose on subsequent days.
  • the corticosteroid may be dexamethasone.
  • the compound according to the present invention may be administered at a dose according to the present invention on days 1-3 of the dosage regimen.
  • the corticosteroid may be administered intravenously (IV) on days 1-3 of the dosage regimen.
  • the corticosteroid may thereafter be administered by oral administration or IV from day 4 and up to day 10 (as per physician judgement according to patient clinical condition and evolution).
  • the corticosteroid may be dexamethasone.
  • the dose may be 6.6 mg/day IV on days 1 to 3 (for example 8 mg dexamethasone phosphate), followed by dexamethasone 6 mg/day (for example 7.2 mg dexamethasone phosphate or 6 mg dexamethasone base) oral administration or IV from day 4 and up to day 10.
  • dexamethasone is dexamethasone phosphate and is administered at a dose of 8 mg/day IV on days 1 to 3, followed by dexamethasone 7.2 mg/day oral administration or IV from day 4 and up to day 10.
  • the compound according to the present invention may be administered as an infusion, preferably a 1-hour infusion, a 1.5-hour infusion, a 2-hour infusion, a 3-hour infusion or longer; particularly preferably a 1.5-hour infusion.
  • the regimen may be 1.5 mg of PLD administered as a 1.5-hour infusion, once a day for 3 consecutive days; or 2 mg of PLD administered as a 1.5-hour infusion, once a day for 3 consecutive days; or 2.5 mg of PLD administered as a 1.5-hour infusion, once a day for 3 consecutive days; or 1 mg of PLD administered as a 1.5-hour infusion, once a day for 5 consecutive days; or 2 mg of PLD administered as a 1 ,5-hour infusion, once a day for 5 consecutive days.
  • the regimen may be 7.5 mg of PLD administered as a 1.5-hour infusion, as a single dose on day 1.
  • the compound according to the present invention may be administered using a loading dose and a maintenance dose.
  • the regimen according to the present invention may be: a loading dose of 2.5 mg for day 1 , and followed by a maintenance dose of 2 mg/day for subsequent days; a loading dose of 2.5 mg for day 1, and followed by a maintenance dose of 1.5 mg/day for subsequent days; a loading dose of 2.5 mg for day 1 , and followed by a maintenance dose of 1 mg/day for subsequent days; a loading dose of 2.5 mg for day 1, and followed by a maintenance dose of 0.5 mg/day for subsequent days; a loading dose of 2 mg for day 1, and followed by a maintenance dose of 1.5 mg/day for subsequent days; a loading dose of 2 mg for day 1 , and followed by a maintenance dose of 1 mg/day for subsequent days; a loading dose of 2 mg for day 1, and followed by a maintenance dose of 0.5 mg/day for subsequent days; a loading dose of 1.5 mg for day 1 , and followed by a maintenance dose of 1 mg/day for subsequent days; a loading dose of 1.5 mg for day 1 , and followed by a maintenance dose of 1 mg/day for subsequent
  • the compound according to the present invention may be administered in combination with a corticosteroid.
  • the corticosteroid may be administered on the same day(s) as administration of the compound.
  • the corticosteroid may also be administered on one or more subsequent days.
  • the corticosteroid is administered with the compound on days 1-3 and the corticosteroid is further administered on one or more of days 4-10.
  • the corticosteroid may be administered intravenously on days when the compound is administered but administered by oral administration or IV on subsequent days.
  • the corticosteroid may be dexamethasone.
  • Dexamethasone may be administered at a dose of 6.6 mg/day IV on days when the compound is administered.
  • Dexamethasone may be administered at a dose of 6 mg/day oral administration or IV on subsequent days, preferably one or more of days 4, 5, 6, 7, 8, 9 and 10.
  • the dexamethasone dose as defined herein refers to the base weight.
  • the dose can therefore be adjusted if used in salt form.
  • the dexamethasone may be dexamethasone phosphate such that 8 mg/day is equivalent to 6.6 mg of dexamethasone base, and 7.2 mg/day is equivalent to 6 mg of dexamethasone base.
  • the compound according to the present invention may be administered to the patient.
  • IV intravenous
  • PO oral administration
  • the compound according to the present invention may be administered 2.0 mg/day intravenous (IV) combined with dexamethasone 6.6 mg/day IV on days 1 to 3, followed by dexamethasone 6 mg/day oral administration (PO)/IV from day 4 and up to day 10 (as per physician judgement according to patient clinical condition and evolution).
  • IV intravenous
  • PO oral administration
  • the compound according to the present invention may be administered to the patient.
  • IV intravenous
  • PO oral administration
  • the corticosteroid may be administered 20 to 30 minutes prior to starting treatment with the compound as defined herein.
  • the patient may additionally receive the following medications, preferably 20 to 30 minutes prior to starting treatment with the compound according to the present invention:
  • patients may receive ondansetron (or equivalent) 4 mg twice a day PO.
  • patients When administered as a single dose, patients may receive the following prophylactic medications 20-30 minutes prior to PLD infusion:
  • Ondansetron 4 mg orally may be given every 12 hours for 3 days after PLD administration to relieve drug-induced nausea and vomiting. If PLD is administered in the morning the patient may receive the first dose of ondansetron in the afternoon.
  • the present invention is also directed to the use of a compound according to the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the treatment of a viral infection, wherein the virus is selected from a non-integrated DNA virus, preferably from the Orthopoxvirus genus, wherein the virus is not the Vaccinia virus.
  • the present invention is also directed to a method of treating viral infection, wherein the virus is selected from a non-integrated DNA virus, preferably from the Orthopoxvirus genus, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or stereoisomer thereof; and wherein the virus is not the Vaccinia virus.
  • the present invention is also directed to a kit comprising the compound as defined herein, together with instructions for treating a viral infection, wherein the virus is selected from a non-integrated DNA virus, preferably from the Orthopoxvirus genus; and wherein the virus is not the Vaccinia virus.
  • the present invention is also directed to a corticosteroid for use in the treatment of a viral infection, wherein the virus is selected from a non-integrated DNA virus, preferably from the Orthopoxvirus genus, wherein the corticosteroid is administered in combination with a compound as defined herein; and wherein the virus is not the Vaccinia virus.
  • the present invention is also directed to a compound as defined herein and a corticosteroid for use in the treatment of viral infection, wherein the virus is selected from a non-integrated DNA virus, preferably from the Orthopoxvirus genus; wherein the use is according to the present invention; and wherein the virus is not the Vaccinia virus.
  • the present invention is also directed to a method of treatment of a viral infection, wherein the virus is selected from a non-integrated DNA virus, preferably from the Orthopoxvirus genus, the method comprising administering a combination therapy of compound as described herein or a pharmaceutically acceptable salt thereof and a corticosteroid to a patient in need thereof, thereby treating the infection; wherein said method is as defined herein.
  • the present invention is also directed to the use of a compound as defined herein or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the treatment of a viral infection, wherein the virus is selected from a non-integrated DNA virus, preferably from the Orthopoxvirus genus; wherein said treatment includes administration of a corticosteroid; and wherein the virus is not the Vaccinia virus.
  • the present invention is also directed to the use of a corticosteroid in the manufacture of a medicament for the treatment of a viral infection, wherein the virus is selected from a non-integrated DNA virus, preferably from the Orthopoxvirus genus; wherein said treatment includes administration of a compound as defined herein or a pharmaceutically acceptable salt or stereoisomer thereof; and wherein the virus is not the Vaccinia virus.
  • the present invention is also directed to the use of a compound as defined herein or a pharmaceutically acceptable salt or stereoisomer thereof and a corticosteroid in the manufacture of a medicament for the treatment of a viral infection, wherein the virus is selected from a non-integrated DNA virus, preferably from the Orthopoxvirus genus; and wherein the virus is not the Vaccinia virus.
  • the present invention is also directed to a pharmaceutical package comprising a compound as defined herein and a corticosteroid, optionally further comprising instructions as defined herein.
  • FIG. 1 Determination of cytoprotective and cytotoxic activity of Plitidepsin and derivatives on MPXV infection.
  • A, C Percentage of MPXV infection.
  • BSC-40 cells were infected with MPXV at a multiplicity of infection (MOI) of 0,01 plaque-forming units (PFU)/cell and then treated for 48 hours after infection with the indicated concentrations of Plitidepsin, compound PM02348 (dehydrotamandarin A), and Tecovirimat as a control effective drug.
  • IC50 inhibitory concentration (50%), for each compound is included. Two different replicas are included in panels A and C.
  • B, D Percentage of cell viability detected in BSC-40 cells treated during 48 hours with the indicated concentrations of Plitidepsin, compound PM02348 (dehydrotamandarin A), and Tecovirimat as a control drug.
  • CC50 cytotoxic concentration (50%), for each compound is included. Two different replicas are included in panels B and D.
  • Plitidepsin reduced MPXV viral RNA in infected cells.
  • MPXV viral RNA detected in BSC-40 cells treated during 48 hours after MPXV infection with the indicated concentrations of Plitidepsin, compound PM02348 (dehydrotamandarin A) and Tecovirimat were analyzed by RT-qPCR using primers and probes for the MPXV G2R gene.
  • MPXV RNA after each treatment were represented as arbitrary units, relative to uninfected control cells.
  • Plitidepsin reduced infectious MPXV viral titers in infected cells.
  • MPXV infectious virus titers detected in BSC-40 cells treated during 48 hours after MPXV infection with the indicated concentrations of Plitidepsin, compound PM02348 (dehydrotamandarin A) and Tecovirimat were analyzed by plaque formation assay. Viral titers after each treatment were represented as PFU/ml.
  • Plitidepsin reduced MPXV protein expression in infected cells.
  • Cell lysates of BSC-40 cells treated during 48 hours after MPXV infection with the indicated concentrations of Plitidepsin, compound PM02348 (dehydrotamandarin A) and Tecovirimat were subjected to Western blotting.
  • Vaccinia virus (VACV) E3 protein levels were quantified relative to a-Tubulin loading control and represented as a normalization to MPXV viral infection control.
  • treating means reversing, attenuating, alleviating or inhibiting the progress of the disease or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treating as used herein may also include prophylactic treatment.
  • Treat”, “treating”, and “treatment” in the context of a viral infection may refer to one or more of the following: 1) reduction in the number of infected cells; 2) reduction in the number of virions present in the serum, including reduction in viral titre (which can be measured by qPCR); 3) inhibition (i.e. , slowing to some extent, preferably stopping) the rate of viral replication; 4) reduction in the viral RNA and/or DNA and/or protein load; 5) reduction in the viral infectivity titre (the number of virus particles capable of invading a host cell); and 6) relieving or reducing to some extent one or more of the symptoms associated with the viral infection. This may include inflammation associated with viral infection.
  • “Reduction” or “inhibition” in embodiments may mean a reduction or inhibition of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% versus control.
  • the control may be an absence of a compound according to the present invention.
  • the control may be a standard therapy.
  • Patient includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).
  • non-human mammals e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like
  • non-mammals e.g., birds, and the like.
  • the patient may require hospitalisation for management of the infection.
  • Plitidepsin is a cyclic depsipeptide originally isolated from the marine tunicate Aplidium albicans. PLD is also known as Aplidin or Aplidine. Such terms are used interchangeably herein. PLD analogues are those analogues as defined herein as compounds of Formula I, II or III. In a preferred embodiment, the present invention relates to the use of PLD.
  • Orthopoxvirus belongs to the viral subfamily Chordopoxvirinae, and the wider Poxviridae family.
  • twelve species of virus make up the Orthopoxvirus genus, causing infections in a range of mammals; Abatino macapox, Akhmeta virus, Alaskapox, Buffalopox, Cowpox, Camelpox, Ectromelia, Horsepox, Mpox, Rabbitpox, Raccoonpox, Skunkpox, Taterapox, Uasin Gishu disease virus, Variola, Vaccinia-like Brazilian isolates and Volepox.
  • the present invention relates to a treatment against smallpox and Mpox. In another preferred embodiment, the present invention relates to the treatment of Mpox.
  • Alkyl groups may be branched or unbranched, and preferably have from 1 to about 12 carbon atoms. One more preferred class of alkyl groups has from 1 to about 6 carbon atoms. Even more preferred are alkyl groups having 1 , 2, 3 or 4 carbon atoms. Methyl, ethyl, n-propyl, isopropyl and butyl, including n-butyl, tert-butyl, sec-butyl and isobutyl are particularly preferred alkyl groups in the compounds of the present invention. As used herein, the term alkyl, unless otherwise stated, refers to both cyclic and noncyclic groups, although cyclic groups will comprise at least three carbon ring members.
  • alkenyl and alkynyl groups in the compounds of the present invention may be branched or unbranched, have one or more unsaturated linkages and from 2 to about 12 carbon atoms.
  • One more preferred class of alkenyl and alkynyl groups has from 2 to about 6 carbon atoms. Even more preferred are alkenyl and alkynyl groups having 2, 3 or 4 carbon atoms.
  • Suitable aryl groups in the compounds of the present invention include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups.
  • Typical aryl groups contain from 1 to 3 separated or fused rings and from 6 to about 18 carbon ring atoms.
  • Preferably aryl groups contain from 6 to about 10 carbon ring atoms.
  • Specially preferred aryl groups include substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl, substituted or unsubstituted phenanthryl, and substituted or unsubstituted anthryl.
  • Suitable heterocyclic groups include heteroaromatic and h ete roa I i cyclic groups containing from 1 to 3 separated or fused rings and from 5 to about 18 ring atoms.
  • heteroaromatic and heteroalicyclic groups contain from 5 to about 10 ring atoms, most preferably 5, 6 or 7 ring atoms.
  • Suitable heteroaromatic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, e.g., coumarinyl including 8-coumarinyl, quinolyl including 8-quinolyl, isoquinolyl, pyridyl, pyrazinyl, pyrazolyl including pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl, pyrimidinyl, furanyl including furan-2-yl, furan-3-yl, furan-4-yl and furan- 5-yl, pyrrolyl, thienyl, thiazolyl including thiazol-2-yl, thiazol-4-yl and thiazol-5-yl, isothiazolyl, thiadiazolyl including thiadiazol-4-yl and thiadiazol-5-yl, triazolyl, tetrazolyl, isoxazolyl
  • Suitable heteroalicyclic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, e.g., pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidinyl including piperidin-3-yl, piperidin-4-yl and piperidin-5- yl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 , 2,3,6- tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydropyr
  • Suitable halogen substituents in the compounds of the present invention include F, Cl, Br and I.
  • salts refers to any salt which, upon administration to the patient is capable of providing (directly or indirectly) a compound as described herein. It will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts.
  • the preparation of salts can be carried out by methods known in the art. For instance, pharmaceutically acceptable salts of compounds provided herein are synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
  • alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium and ammonium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, /V,/V-dialkylenethanolamine, triethanolamine and basic amino acids salts.
  • the compounds of the invention may be in crystalline form either as free compounds or as solvates (e.g. hydrates, alcoholates, particularly methanolates) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art.
  • the compounds of the invention may present different polymorphic forms, and it is intended that the invention encompasses all such forms.
  • any compound referred to herein is intended to represent such specific compound as well as certain variations or forms.
  • compounds referred to herein may have asymmetric centres and therefore exist in different enantiomeric or diastereomeric forms.
  • any given compound referred to herein is intended to represent any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof.
  • stereoisomerism or geometric isomerism about the double bond is also possible, therefore in some cases the molecule could exist as (E)-isomer or (Z)-isomer (trans and cis isomers).
  • each double bond will have its own stereoisomerism, that could be the same or different than the stereoisomerism of the other double bonds of the molecule.
  • compounds referred to herein may exist as atropisomers. All the stereoisomers including enantiomers, diastereoisomers, geometric isomers and atropisomers of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention.
  • R 1 , R 5 , R 9 , R 11 , and R 15 are independently selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl. More preferred R 1 , R 5 , R 9 , R 11 , and R 15 are independently selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl.
  • R 1 is selected from sec-butyl and isopropyl, being sec-butyl the most preferred.
  • Particularly preferred R 5 is selected from isobutyl and 4-aminobutyl, being isobutyl the most preferred.
  • Particularly preferred R 11 is methyl and isobutyl, being isobutyl the most preferred.
  • Particularly preferred R 9 is selected from p-methoxybenzyl, p-hydroxybenzyl, and cyclohexyl methyl, being p-methoxybenzyl the most preferred.
  • Particularly preferred Ris (if present) is selected from methyl, n-propyl, and benzyl, being methyl and benzyl the most preferred.
  • R 1 , R 5 , R 9 , and Ris are independently selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl. More preferred R 1 , R 5 , R 9 , and Ris are independently selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n- propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl.
  • substituents may be chosen from the foregoing list.
  • Hydrogen, methyl, n-propyl, isopropyl, isobutyl, sec-butyl, 4-aminobutyl, 3-amino-3-oxopropyl, benzyl, p- methoxybenzyl, p-hydroxybenzyl, and cyclohexylmethyl are the most preferred R 1 , R 5 , R 9 , and R 15 groups.
  • particularly preferred R 1 is selected from sec-butyl and isopropyl, being sec-butyl the most preferred.
  • Particularly preferred R 5 is selected from isobutyl and 4-aminobutyl, being isobutyl the most preferred.
  • Particularly preferred R 9 is selected from p-methoxybenzyl, p-hydroxybenzyl, and cyclohexyl methyl, being p- methoxybenzyl the most preferred.
  • Particularly preferred R 15 is selected from methyl, n-propyl, and benzyl, being methyl and benzyl the most preferred.
  • R 8 , R 10 , R 12 , and R 16 are independently selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl. More preferred R 8 , R 10 , R 12 , and R 16 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and butyl, including n-butyl, tert-butyl, isobutyl and sec-butyl, and even more preferred they are independently selected from hydrogen and methyl. Specifically, particularly preferred R 8 , R 10 and R 12 are methyl, and particularly preferred R 16 (if present) is hydrogen.
  • R 3 and R 4 are independently selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl. More preferred R 3 and R 4 are independently selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n- propyl, substituted or unsubstituted isopropyl, and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl.
  • substituents may be chosen from the foregoing list.
  • Hydrogen, methyl, isopropyl, and sec-butyl are the most preferred R 3 and R 4 groups.
  • particularly preferred R 3 is selected from methyl and isopropyl and particularly preferred R 4 is methyl or hydrogen.
  • R 6 and R 7 are independently selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl. More preferred R 7 is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl.
  • R 6 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and butyl, including n-butyl, tert-butyl, isobutyl and sec-butyl. Most preferred R 6 is selected from hydrogen and methyl and most preferred R 7 is methyl.
  • R 6 and R 7 together with the corresponding N atom and C atom to which they are attached form a substituted or unsubstituted heterocyclic group.
  • preferred heterocyclic group is a heteroalicyclic group containing one, two or three heteroatoms selected from N, O or S atoms, most preferably one N atom, and having from 5 to about 10 ring atoms, most preferably 5, 6 or 7 ring atoms.
  • a pyrrolidine group is the most preferred.
  • R 13 and Ru are independently selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl. More preferred R 13 is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl.
  • R 14 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and butyl, including n-butyl, tert-butyl, isobutyl and sec-butyl.
  • Most preferred R 13 is selected from hydrogen, methyl, isopropyl, isobutyl, and 3-amino-3-oxopropyl and most preferred R 14 is hydrogen.
  • R 13 and R 14 together with the corresponding N atom and C atom to which they are attached form a substituted or unsubstituted heterocyclic group.
  • preferred heterocyclic group is a heteroalicyclic group containing one, two or three heteroatoms selected from N, O or S atoms, most preferably one N atom, and having from 5 to about 10 ring atoms, most preferably 5, 6 or 7 ring atoms.
  • a pyrrolidine group is the most preferred.
  • R 2 is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, and COR a , wherein R a is a substituted or unsubstituted C 1 -C 6 alkyl, and even more preferred R a is methyl, ethyl, n-propyl, isopropyl and butyl, including n-butyl, tert-butyl, sec-butyl and isobutyl. More preferably R 2 is hydrogen.
  • substituents may be chosen from the foregoing list.
  • Hydrogen, COR a , COOR a , and SO 2 RC are the most preferred R 17 groups, and hydrogen, COObenzyl, CObenzo[b]thiophen-2-yl, SO 2 (p-methylphenyl), COCOCH 3 , CO-CH(OH)-CH 3 , and COOC(CH 3 ) 3 are even most preferred.
  • Y is CO. In another embodiment, it is particularly preferred that Y is - COCH(CH 3 )CO-.
  • X is O. In another embodiment, it is particularly preferred that X is NH.
  • n, p and q are 0. In another embodiment, it is particularly preferred that n is 1 and p and q are 0. In another embodiment, it is particularly preferred that n and p are 1 and q is 0. In another embodiment, it is particularly preferred that n, p, and q are 1. In another embodiment, it is particularly preferred that n and p are 1 and q is 2.
  • p and q are 0. In another embodiment, it is particularly preferred that p is 1 and q is 0. In another embodiment, it is particularly preferred that p and q are 1. In another embodiment, it is particularly preferred that p is 1 and q is 2. In additional preferred embodiments, the preferences described above for the different substituents are combined. The present invention is also directed to such combinations of preferred substitutions of formula I, II and III above.
  • R a , R b , and R c present in the compounds of the invention, and unless it is stated explicitly so, it should be understood that they can be each independently different within the given definition, i.e. R a does not represent necessarily the same group simultaneously in a given compound of the invention.
  • a particularly preferred stereochemistry for compounds of general formula I is wherein X, Y, n, p, q, and R 1 -R 17 are as defined above, and when Y is -COCH(CH 3 )CO- it has the following stereochemistry:
  • COCH(CH 3 )CO- it has the following stereochemistry:
  • a particularly preferred stereochemistry for compounds of general formula III is wherein X, Y, p, q, R 1 -R 10 , and R 12 -R 17 are as defined above, and when Y is -
  • Particularly preferred compounds of the invention are the following:
  • the compounds of general formula I, II and III may be prepared following any of the synthetic processes disclosed in Vera et al. Med. Res. Rev. 2002, 22(2), 102-145, WO 2011/020913 (see in particular Examples 1-5), WO 02/02596, WO 01/76616, and WO
  • the preferred compound is PLD or dehydrotamandarin A or pharmaceutically acceptable salts or stereoisomers thereof.
  • the compound may be tamandarin A or tamandarin B or pharmaceutically acceptable salts or stereoisomers thereof. Most preferred is PLD.
  • plitidepsin is (-)-(3S,6R,7S, 10R,11S,15S,17S,20S,25aS)-11- hydroxy-3-(4-methoxybenzyl)-2,6,17-trimethyl-15-(1-methylethyl)-7-[[(2R)-4-methyl-2- [methyl[[(2S)-1-(2-oxopropanoyl)pyrrolidin-2-yl]carbonyl]amino]pentanoyl]amino]-10- [(1S)-1-methylpropyl]-20-(2-methylpropyl)tetradecahydro-15H-pyrrolo[2, 1-f]- [1 , 15,4,7, 10,20]dioxatetrazacyclotricosine-1 ,4,8, 13, 16, 18,21 (17H)-heptone corresponding to the molecular formula C57H87N7O15.
  • Plitidepsin is a cyclic depsipeptide originally isolated from a Mediterranean marine tunicate (Aplidium albicans) and currently manufactured by full chemical synthesis. It is licensed and marketed in Australia under the brand name plitidepsin for the treatment of multiple myeloma.
  • Example 2 treatment of cell lines infected with MPXV with the compounds of the invention reduced the % of infected cells (as shown in Figure 1 A and C) compared with standard (Tecovirimat) treatment for MPXV infections at concentrations below the CC 50 for cell viability ( Figure 1 B and D).
  • the compounds of the invention also reduced the MPXV RNA levels, as determined by RT-qPCR, again compared with the standard treatment, Tecovirimat.
  • the compounds of the invention also reduced the number on infectious MPXV particles, as determined by a plaque assay, again compared with the standard treatment, Tecovirimat.
  • the compounds of the invention also reduced the expression of MPXV proteins, again compared with the standard treatment, Tecovirimat.
  • the present invention provides a compound of the present invention for use in the treatment of a viral infection, where the virus (responsible for the viral infection) is a non- integrated DNA virus; and wherein the virus is not the Vaccinia virus.
  • a method for the treatment of a viral infection where the virus is a non-integrated DNA virus, wherein the method comprises administering to an individual or patient in need thereof a therapeutically effective amount of a compound of the present invention; and wherein the virus is not the Vaccinia virus.
  • a compound of the present invention in the manufacture of a medicament for the treatment of viral infection, wherein the virus is a non-integrated DNA virus; and wherein the virus is not the Vaccinia virus.
  • the infection may also be characterised by excessive or increased production or secretion of one or more pro-inflammatory cytokines, and preferably at least one of IL- 12, IL-10, IL-1 , IL-6, IL-8, CCL-2 and TNF-a and more preferably at least one of IL-1 , IL- 6, IL-8 and TNF-a.
  • pro-inflammatory cytokines preferably at least one of IL- 12, IL-10, IL-1 , IL-6, IL-8, CCL-2 and TNF-a and more preferably at least one of IL-1 , IL- 6, IL-8 and TNF-a.
  • the compound of the invention may be further administered in combination with an (a different) antiviral agent.
  • the anti-viral agent may be administered concurrently, sequentially or separately to administration of a compound of the invention.
  • the compound of the invention may be used as an anti-inflammatory to treat inflammation or hyperinflammation associated or as a consequence of the viral infection.
  • a compound as defined herein for use in the treatment of a disorder caused by a non-integrated DNA virus, preferably selected from the Orthopoxvirus genus (as described herein), wherein the disorder is selected from neuroinflammation, pneumonia and immunopathology, in particular hypercytokinemia (cytokine storm syndrome), and sepsis; wherein the virus is not the Vaccinia virus.
  • a non-integrated DNA virus preferably selected from the Orthopoxvirus genus (as described herein)
  • the disorder is selected from neuroinflammation, pneumonia and immunopathology, in particular hypercytokinemia (cytokine storm syndrome), and sepsis; wherein the virus is not the Vaccinia virus.
  • a compound as defined herein in the manufacture of a medicament for the treatment of a disorder caused by a non-integrated DNA virus, preferably selected from the Orthopoxvirus genus (as described herein), wherein the disorder is selected from neuroinflammation, pneumonia and immunopathology, in particular hypercytokinemia (cytokine storm syndrome), and sepsis; and wherein the virus is not the Vaccinia virus.
  • a non-integrated DNA virus preferably selected from the Orthopoxvirus genus (as described herein)
  • the disorder is selected from neuroinflammation, pneumonia and immunopathology, in particular hypercytokinemia (cytokine storm syndrome), and sepsis; and wherein the virus is not the Vaccinia virus.
  • a method for the treatment of a disorder caused by a non-integrated DNA virus preferably selected from the Orthopoxvirus genus (as described herein), wherein the disorder is selected from neuroinflammation, pneumonia and immunopathology, in particular hypercytokinemia (cytokine storm syndrome) and sepsis, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound as defined herein; and wherein the virus is not the Vaccinia virus.
  • the disorder is immunopathology and in particular, hypercytokinemia.
  • non-integrated DNA virus is meant a virus containing a DNA genome, which completes its life cycle without integrating its genome into the genome of the host cell.
  • life cycle it is meant the fundamental stages of viral attachment, penetration, uncoating, gene expression and replication, assembly, release and/or latency.
  • integrating it is meant the insertion of double-stranded linear viral DNA into the host genome, located in the nucleus.
  • a non-integrating DNA virus may complete none, some or all of its replication cycle within the host’s nucleus.
  • the viral DNA genome may also be closely associated with, but not integrated into, the host genome.
  • Non-integrating DNA viruses may maintain part or all of its DNA genome within the host cell in a latency period, but not integrated into the genome.
  • the viral DNA genome may consist of single stranded or double stranded DNA.
  • the viral DNA genome may also be segmented or linear.
  • the virus is selected from the Orthopoxvirus genus.
  • the virus is selected from Abatino macaquepox, Akhmeta virus, Buffalopox, Camelpox, Cowpox, Camelpox, Ectromelia, Horsepox, Mpox, Rabbitpox, Raccoonpox, Skunkpox, Taterapox, llasin Gishu disease virus, Variola, Vaccinia-like Brazilian isolates and Volepox.
  • the virus is Mpox. In one embodiment the virus is Variola (also known as smallpox virus).
  • compositions having biological/pharmacological activity may be used in pharmaceutical compositions having biological/pharmacological activity for the treatment of the above mentioned conditions.
  • These pharmaceutical compositions comprise a compound of the invention together with a pharmaceutically acceptable carrier.
  • carrier refers to a diluent, adjuvant, excipient or vehicle with which the active ingredient is administered. Suitable pharmaceutical carriers are described in “Remington’s Pharmaceutical Sciences” by E. W. Martin, 1995.
  • Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions, emulsions, etc.) compositions for oral, topical or parenteral administration.
  • Pharmaceutical compositions containing compounds of the invention may be delivered by liposome or nanosphere encapsulation, in sustained release formulations or by other standard delivery means.
  • compositions as described in WO9942125 are in the form of powder for solution for infusion.
  • compositions as described in WO9942125 for example, a lyophilised preparation of a compound of the invention including water-soluble material and secondly a reconstitution solution of mixed solvents.
  • a particular example is a lyophilised preparation of PLD and mannitol and a reconstitution solution of mixed solvents, for example PEG-35 castor oil, ethanol and water for injections.
  • Each vial for example may contain 2 mg of PLD.
  • each mL of reconstituted solution may contain: 0.5 mg of PLD, 158 mg of PEG-35 castor oil, and ethanol 0.15 mL/mL.
  • the specific dosage and treatment regimen for any particular patient may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the particular formulation being used, the mode of application, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, reaction sensitivities, and the severity of the particular disease or condition being treated.
  • the compounds of the present invention may be administered according to a dosing regimen of a daily dose.
  • the compounds of the present invention may be administered according to a dosing regimen of a once daily dose.
  • the compounds of the present invention may be administered according to a dosing regimen of a daily dose for 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day.
  • Preferred regimen is 2-5 days, or 3-5 days, or 3, 4 or 5 days, most preferably 3 days or 5 days.
  • the dose may be a dose of 5 mg a day or less, 4.5 mg a day or less, 4 mg a day or less,
  • Particular doses include 0.5 mg/day, 1 mg/day, 1.5 mg/day, 2 mg/day, 2.5 mg/day, 3 mg/day, 3.5 mg/day, 4 mg/day, 4.5 mg/day, or 5mg/day.
  • Preferred doses are 1 mg/day,
  • the compounds of the present invention may be administered according to a total dose of 1-50 mg, 1-40 mg, 1-30 mg, 1-20 mg, 1-15 mg, 3-15 mg, 3- 12 mg, 4-12 mg, 4-10 mg, or 4.5-10 mg.
  • Total doses may be 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg.
  • Preferred total doses are 4.5 mg, 5 mg, 6 mg, 7.5 mg, 8 mg, 9 mg or 10 mg.
  • the total dose may be split over 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 days, preferably 3 days or 5 days.
  • the compounds of the present invention may be administered according to a dosing regimen of a once daily dose for 5 days, at a dose of 2.5 mg a day or less.
  • the compounds of the present invention may be administered according to a dosing regimen of a once daily dose for 5 days, at a dose of 2mg a day or less.
  • the compounds of the present invention may be administered according to a dosing regimen of a once daily dose for 3 days, at a dose of 1 .5 mg a day or less.
  • the compounds of the present invention may be administered according to a dosing regimen of a once daily dose for 3 days, at a dose of 2 mg a day or less.
  • the compounds of the present invention may be administered according to a dosing regimen of a once daily dose for 3 days, at a dose of 2.5 mg a day or less.
  • the compounds of the present invention may be administered according to a dosing regimen of a once daily dose for 3 days, at a dose of 1.5 mg a day.
  • the compounds of the present invention may be administered according to a dosing regimen of a once daily dose for 3 days, at a dose of 2.0 mg a day.
  • the compounds of the present invention may be administered according to a dosing regimen of a once daily dose for 3 days, at a dose of 2.5 mg a day.
  • the compounds of the present invention may be administered according to a dosing regimen of a once daily dose for 3 days, at a dose of 1 .5 to 2.5 mg a day.
  • An alternative regimen is a single dose on day 1.
  • the single dose may be 1-10 mg, 4-10 mg, 4.5-10 mg; 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg; preferably 4.5 mg, 5 mg, 6 mg, 7.5 mg, 8 mg, 9 mg or 10 mg; more preferably 5-9 mg, 6.5-8.5 mg, 7-8 mg or 7.5 mg.
  • the compounds of the present invention may be administered according to the present invention, wherein the compounds of the present invention are administered with a corticosteroid.
  • the corticosteroid is dexamethasone.
  • the corticosteroid may be administered daily with the compounds of the present invention. Administration may be sequential, concurrent or consecutive.
  • the corticosteroid may be further administered on the days following administration of compounds according to the present invention.
  • the corticosteroid may be administered on days 1-3 and then further administered daily for 3, 4, 5, 6, 7, 8, 9 or 10 or more further days.
  • the corticosteroid may be administered is administered on days 1-3 as an intravenous administration and then on days 6-10 as an oral administration.
  • the dosage of corticosteroid may be higher during the co-administration phase with the compounds of the present invention, and is lowered during the subsequent days.
  • Particular dosing schedules include:
  • patients may receive the following medications 20 to 30 minutes prior to starting the infusion with a compound according to the present invention:
  • patients treated with compounds according to the present invention may receive ondansetron 4 mg twice a day PO.
  • Doses of dexamethasone, ondansetron and ranitidine are herein defined on the basis of the base form.
  • the dose of diphenhydramine hydrochloride is given on the basis of the hydrochloride salt.
  • Doses of compounds of the invention are given on the basis of the base form.
  • the daily doses may be administered as an infusion.
  • the infusion may be a 1 hour infusion, a 1.5 hour infusion, a 2 hour infusion, a 3 hour infusion or longer.
  • the infusion is 1.5 hours.
  • the dose may be administered according to a regimen which uses a loading dose and a maintenance dose.
  • Loading/maintenance doses according to the present invention includes: a loading dose of 2.5 mg for day 1 , and followed by a maintenance dose of 2 mg/day for subsequent days; a loading dose of 2.5 mg for day 1 , and followed by a maintenance dose of 1.5 mg/day for subsequent days; a loading dose of 2.5 mg for day 1 , and followed by a maintenance dose of 1 mg/day for subsequent days; a loading dose of 2.5 mg for day 1 , and followed by a maintenance dose of 0.5 mg/day for subsequent days; a loading dose of 2 mg for day 1 , and followed by a maintenance dose of 1.5 mg/day for subsequent days; a loading dose of 2 mg for day 1 , and followed by a maintenance dose of 1 mg/day for subsequent days; a loading dose of 2 mg for day 1 , and followed by a maintenance dose of 1 mg/day for subsequent days; a loading dose of 2 mg for day 1 , and followed by
  • the daily dose may be reduced in the final day or days of the regimen.
  • the dose may be reduced to 1 mg on days 4 and 5.
  • Particular regimens include:
  • the dose may be reduced to 1 mg/day on days 4 and 5 (total dose 8-10 mg);
  • a single dose regimen includes:
  • PLD administered as a 1.5-hour infusion, once on day 1 at a dose of 1-10 mg, 4- 10 mg, 4.5-10 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6. 5mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg, preferably 4.5 mg, 5 mg, 6 mg, 7.5 mg, 8 mg, 9 mg or 10 mg, more preferably 5-9 mg, 6.5-8.5 mg, 7-8 mg or most preferably 7.5 mg.
  • the single dose regimen may further include the following prophylactic medications 20-30 minutes prior to PLD infusion:
  • Ondansetron 4 mg orally may be given every 12 hours for 3 days after PLD administration to relieve drug-induced nausea and vomiting. If PLD is administered in the morning the patient may receive the first dose of ondansetron in the afternoon.
  • patients may be selected for treatment with compounds of the present invention based on clinical parameters and/or patient characteristics. Suitable parameters may be measurements disclosed in the present application.
  • the present invention is directed to a compound for use according to the present invention, wherein the compound is administered in combination with one or more of the following prophylactic medications: diphenhydramine hydrochloride, ranitidine, dexamethasone, ondansetron.
  • diphenhydramine hydrochloride 25 mg IV or equivalent; Ranitidine 50 mg iv or equivalent; Dexamethasone 8 mg IV; Ondansetron 8 mg IV in slow infusion of 15 minutes or equivalent.
  • Patients may receive said prophylactic medications 20-30 minutes before the infusion of PLD.
  • Dexamethasone 8 mg IV may be dexamethasone phosphate leading to 6.6 mg dexamethasone base.
  • Compound 240 known as DidemninB and shown by the structure below:
  • Compound 241 known as dehydrotamandarin A and shown by the structure below:
  • Compound 242 known as tamandarin A and shown by the structure below:
  • a further compound is Compound 243, known as tamandarin B and shown by the structure below:
  • Cells BSC-40 cells (a continuous line of African green monkey kidney cells derived from BSC- 1 cells; ATCC catalog no. CRL-2761) were grown in Dulbecco’s modified Eagle’s medium (DMEM) (Gibco) supplemented with Penicillin/Streptomycin, HEPES and non- essential amino acids (1X, Sigma-Aldrich) and with 7% heat-inactivated newborn calf serum (NCS) (Gibco-Life Technologies). Cell cultures were kept at 37oC and 5% CO 2 in a humidified incubator.
  • DMEM Dulbecco’s modified Eagle’s medium
  • NCS heat-inactivated newborn calf serum
  • Virus MPXV virus used in this study was isolated from a patient sample obtained from a person infected with MPXV, derived from Hospital General Universitario Gregorio Maranon (Madrid, Spain). The virus was isolated, plaque cloned and amplified at CNB-CSIC in BSC-40 cells. Full-length virus genome sequence confirmed that the virus obtained from the patient isolate correspond to the MPOXMPXV 2022 clade lib, responsible to the 2022 Mpox outbreak.
  • BSC-40 cells Percent viral infection and cytotoxicity after the different drug treatments were measured in BSC-40 cells.
  • 20.000 BSC-40 cells were seeded in DMEM-7% NCS and incubated 24 hours at 37oC, 5% CO 2 .
  • culture medium was replaced by 50 ⁇ l of DMEM (without NCS) and transferred into the BSL-3 facility at the CNB-CSIC.
  • MOI multiplicity of infection
  • DMEM-2%NCS supplemented with the final drug concentration to be tested and, concurrently, with the equivalent DMSO concentration as control.
  • Infected cells were marked by immunofluorescence using a rabbit polyclonal anti- vaccinia virus (VACV) antibody (Ref: PA1-7258; Invitrogen) and Goat anti-Rabbit - 488 (Thermo Fisher; Ref: A11034) as secondary antibody, with a DAPI (Sigma-Merk; Ref: 32670) counterstaining.
  • VACV rabbit polyclonal anti- vaccinia virus
  • DAPI Sigma-Merk; Ref: 32670
  • Percent infection was calculated as: (488 total signal in treatment/ 488 total signal in DMSO correspondent control) *100. DMSO control was then considered as 100% infection rate. Cytotoxicity was quantified using the MTT assay (Thiazolyl Blue Tetrazolium Bromide, Sigma-Aldrich; Ref: M2128), according to the manufacturer's instructions, in non- infected cells with the same treatments than used in viral infection assays. Then, 50% inhibition concentration (IC50) and 50% cytotoxicity concentration (CC50) were determined using GraphPad Prism 8 software. of MPXV mRNA Reverse
  • BSC-40 cell lysates were harvested at 48 hours post-infection in presence of the different drug treatments, and were analyzed to quantify MPXV mRNA expression levels using RT-qPCR.
  • RNA extraction was performed using an in-house TRIzol® (Invitrogen) method, as described elsewhere (Pandit P, Cooper-White J, Punyadeera C. High-yield RNA-extraction method for saliva. Clin Chem. 2013 Jul;59(7):1118-22. doi:10.1373/clinchem.2012.197863).
  • First-strand cDNA synthesis and subsequent real- time PCR were performed using NZYSpeedy One-step RT-qPCR Master Mix (NZYTech), according to the manufacturer’s specifications using ROX as reference dye.
  • MPXV viral mRNA content was determined using previously validated set of primers and probes specific for the MPXV G2R gene (MPXV_WA_fw: CACACCGTCTCTTCCACAGA (SEQ ID NO: 1); MPXV_WA_rv: GATACAGGTTAATTTCCACATCG (SEQ ID NO: 2); MPXV_WA_Probe: 6-FAM- AACCCGTCGTAACCAGCAATACATTT-BHQ-1 (SEQ ID NO: 3).
  • Gene expression was normalized to the expression of the cellular 28S ribosomal RNA gene. Data were acquired with QuantStudio 5 Real-Time PCR System (Applied Biosystems) and analyzed with QuantStudio Design and Analysis Software v1.5.1 (Applied Biosystems). mRNA arbitrary units (A.U.) were quantified relative to negative RNA samples (from uninfected cells) and were performed using the 2-AACt method. All samples were tested in duplicate.
  • BSC-40 cells were harvested at 48 hours post-infection in presence of the different drug treatments and were analysed for the presence of MPXV infectious virus using a plaque assay. Cultured cells and supernatants for each treatment condition were recovered and subjected to three freeze-defreeze cycles. Then, undiluted and serial ten-fold dilutions of treated-cell samples were added in triplicate to BSC-40 cell monolayers seeded in 12- well plates at 5 x 10 5 cells/well. After 1 hour of adsorption the inoculum was removed and plates were incubated at 37oC, 5% CO 2 in DMEM-2% NCS. After 48 hours, cells were fixed for 1 hour with 10% formaldehyde (Sigma-Aldrich).
  • the compounds of the invention also reduced the number on infectious MPXV particles, as determined by a plaque assay, again compared with the standard treatment, Tecovirimat.
  • the compounds of the invention also reduced the expression of MPXV proteins, again compared with the standard treatment, Tecovirimat.
  • Y is selected from CO and -COCH(CH 3 )CO-; each n and p is independently selected from 0 and 1 , and q is selected from 0, 1 and 2; each R 1 , R 3 , R 5 , R 9 , R 11 , and R 15 is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, and substituted or unsubstituted C 2 -C 6 alkynyl; R 2 is selected from hydrogen, COR a , COOR a , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, and substituted or unsubstituted C 2 -C 6 alkynyl; each R 4 , R 8 , R 10 , R 12 , and R 16 is independently selected from hydrogen and substituted or unsubstituted C 1
  • R 3 and R 4 are independently selected from hydrogen and substituted or unsubstituted C 1 - C 6 alkyl; preferably wherein R 3 is isopropyl and R 4 is hydrogen.
  • R 11 is selected from hydrogen and substituted or unsubstituted C 1 - C 6 alkyl; preferably wherein R 11 is methyl or isobutyl; more preferably wherein R 11 is isobutyl.
  • R 1 , R 5 , R 9 , and R 15 are independently selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl; preferably wherein R 1 is selected from sec-butyl and isopropyl, R 5 is isobutyl, R 9 is p- methoxybenzyl, and R 15 is selected from methyl and benzyl, or wherein R 1 is selected from sec-butyl and isopropyl, R 5 is isobutyl, R 9 is p-methoxybenzyl, and q is 0; more preferably wherein R 1 is sec-butyl, R 5 is isobutyl, R 9 is p-methoxybenzyl, and q is 0.
  • R 8 , R 10 , R 12 , and R 16 are independently selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl; preferably wherein R 8 , R 10 and R 12 are methyl, and R 16 is hydrogen, or wherein R 8 , R 10 and R 12 are methyl, and q is 0; more preferably wherein R 8 , R 10 and R 12 are methyl, and q is 0.
  • R 6 and R 14 are independently selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl; preferably wherein R 6 is selected from hydrogen and methyl, and R 14 is hydrogen.
  • R 7 and R 13 are independently selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl; preferably wherein R 7 is methyl and R 13 is selected from hydrogen, methyl, isopropyl, isobutyl, and 3-amino-3-oxopropyl.
  • R 2 is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, and COR a , and wherein R a is a substituted or unsubstituted C 1 - C 6 alkyl; preferably wherein R 2 is hydrogen.
  • the virus is selected from the Orthopoxvirus genus, excluding the Vaccinia virus.
  • the virus is selected from Abatino macaquepox, Akhmeta virus, Buffalopox, Camelpox, Cowpox, Camelpox, Ectromelia, disease virus, Horsepox,, MPOX, Rabbitpox, Raccoonpox, Skunkpox, Taterapox, llasin Gishu disease virus , Variola, Vaccinia-like Brazilian isolates and Volepox.
  • a compound for use according to any preceding clause wherein the compound is administered according to a regimen of a daily dose for 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day; preferably 2-5 days, 3-5 days, or 3, 4 or 5 days; most preferably 3 days or 5 days; most preferably 3 days.
  • a compound for use according to any preceding clause wherein 1.5 mg of PLD is administered as a 1.5-hour infusion, once a day for 3 consecutive days; or wherein 2 mg of PLD is administered as a 1.5-hour infusion, once a day for 3 consecutive days; wherein 2.5 mg of PLD is administered as a 1.5-hour infusion, once a day for 3 consecutive days; or wherein 1 mg of PLD is administered as a 1.5-hour infusion, once a day for 5 consecutive days; or wherein 2 mg of PLD is administered as a 1.5-hour infusion, once a day for 5 consecutive days.
  • a compound for use according to clause 31 wherein the dosage regimen is: a loading dose of 2.5 mg for day 1 , and followed by a maintenance dose of 2 mg/day for subsequent days; a loading dose of 2.5 mg for day 1 , and followed by a maintenance dose of 1.5 mg/day for subsequent days; a loading dose of 2.5 mg for day 1 , and followed by a maintenance dose of 1 mg/day for subsequent days; a loading dose of 2.5 mg for day 1 , and followed by a maintenance dose of 0.5 mg/day for subsequent days; a loading dose of 2 mg for day 1 , and followed by a maintenance dose of 1.5 mg/day for subsequent days; a loading dose of 2 mg for day 1 , and followed by a maintenance dose of 1 mg/day for subsequent days; a loading dose of 2 mg for day 1 , and followed by a maintenance dose of 0.5 mg/day for subsequent days; a loading dose of 1 .5 mg for day 1 , and followed by a maintenance dose of 1 mg/day for subsequent days; a loading dose of 1.5 mg
  • a compound for use according to clause 33, wherein the corticosteroid may also be administered on one or more subsequent days; preferably wherein the corticosteroid is administered with the compound on days 1-3 and the corticosteroid is further administered on one or more of days 4-10.
  • a compound for use according to any preceding clause wherein PLD is administered 1.5 mg/day IV combined with dexamethasone 6.6 mg/day IV on days 1 to 3, followed by dexamethasone 6 mg/day oral administration (PO)/IV from day 4 and up to day 10 (as per physician judgement according to patient clinical condition and evolution); or wherein PLD is administered 2.0 mg/day intravenous (IV) combined with dexamethasone 6.6 mg/day IV on days 1 to 3, followed by dexamethasone 6 mg/day oral administration (PO)/IV from day 4 and up to day 10 (as per physician judgement according to patient clinical condition and evolution); or wherein PLD is administered 2.5 mg/day intravenous (IV) combined with dexamethasone 6.6 mg/day IV on days 1 to 3, followed by dexamethasone 6 mg/day oral administration (PO)/IV from day 4 and up to day 10 (as per physician judgement according to patient clinical condition and evolution).
  • dexamethasone is dexamethasone phosphate and is administered at a dose of 8 mg if administered on days when a compound of the invention is administered (equating to a dose of 6.6 mg base) and is administered at a dose of 7.2 mg if administered thereafter (equating to a dose of 6 mg base).
  • a pharmaceutical composition comprising a compound as defined in any preceding clause, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment of a non-integrated DNA viral infection, wherein the virus is not the Vaccinia virus, and wherein preferably the virus is selected from the from the Orthopoxvirus genus.
  • a method of treating viral infection wherein the virus is a non-integrated DNA virus, wherein the virus is not the Vaccinia virus, and wherein preferably the virus is selected from the from the Orthopoxvirus genus, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of a compound as defined in any of clauses 1 to 47, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • kits comprising the compound as defined in any of clauses 1 to 48, together with instructions for treating viral infection, wherein the virus is a non-integrated DNA virus, wherein the virus is not the Vaccinia virus, and wherein preferably the virus is selected from the from the Orthopoxvirus genus.
  • a corticosteroid for use in the treatment of a viral infection wherein the virus is a non-integrated DNA virus, wherein the virus is not the Vaccinia virus, and wherein preferably the virus is selected from the from the Orthopoxvirus genus, wherein the corticosteroid is administered in combination with a compound according to any one of clauses 1 to 48.
  • a method of treatment of a viral infection wherein the virus is a non-integrated DNA virus, wherein the virus is not the Vaccinia virus, and wherein preferably the virus is selected from the from the Orthopoxvirus genus, the method comprising administering a combination therapy of compound according to any one of clauses 1 to 17 or a pharmaceutically acceptable salt thereof and a corticosteroid to a patient in need thereof, thereby treating the infection; wherein said method is as defined in any one of clauses 1 to 48.
  • a corticosteroid in the manufacture of a medicament for the treatment of a viral infection, wherein the virus is a non-integrated DNA virus, wherein the virus is not the Vaccinia virus, and wherein preferably the virus is selected from the from the Orthopoxvirus genus; wherein said treatment includes administration of a compound as defined in any of clauses 1 to 48 or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a compound as defined in any of clauses 1 to 48 or a pharmaceutically acceptable salt or stereoisomer thereof and a corticosteroid in the manufacture of a medicament for the treatment of a viral infection, wherein the virus is a non-integrated DNA virus, wherein the virus is not the Vaccinia virus, and wherein preferably the virus is selected from the from the Orthopoxvirus genus.
  • a pharmaceutical package comprising a compound as defined in any of clauses 1 to 18 and a corticosteroid, optionally further comprising instructions according to any one of clauses 1 to 48.

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Abstract

La présente invention concerne le traitement antiviral de virus à ADN non intégrés et, en particulier, le traitement antiviral contre les infections virales du genre Orthopoxvirus, en particulier Mpox.
PCT/EP2024/053510 2023-02-10 2024-02-12 Plitidepsine destinée à être utilisée dans le traitement d'infections virales à adn non intégrées Ceased WO2024165764A1 (fr)

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Citations (8)

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WO1999042125A1 (fr) 1998-02-18 1999-08-26 Pharma Mar, S.A. Formulation pharmaceutique d'un compose de didemnine
WO2001076616A1 (fr) 2000-04-07 2001-10-18 The Trustees Of The University Of Pennsylvania Analogues de tamandarine et de didemnine et methodes de fabrication et d'utilisation correspondantes
WO2002002596A2 (fr) 2000-06-30 2002-01-10 Pharma Mar, S.A. Procedes de synthese pour l'aplidine et de nouveaux derives antitumoraux, leur procede de production et d'utilisation
WO2004084812A2 (fr) 2003-03-21 2004-10-07 Joullie Madeleine M Analogues de « tamandarin », fragments associes et leurs methodes d'elaboration et d'utilisation
WO2011020913A2 (fr) 2009-08-21 2011-02-24 Pharma Mar, S.A. Composés antiviraux cyclodepsipeptides
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WO1999042125A1 (fr) 1998-02-18 1999-08-26 Pharma Mar, S.A. Formulation pharmaceutique d'un compose de didemnine
WO2001076616A1 (fr) 2000-04-07 2001-10-18 The Trustees Of The University Of Pennsylvania Analogues de tamandarine et de didemnine et methodes de fabrication et d'utilisation correspondantes
WO2002002596A2 (fr) 2000-06-30 2002-01-10 Pharma Mar, S.A. Procedes de synthese pour l'aplidine et de nouveaux derives antitumoraux, leur procede de production et d'utilisation
WO2004084812A2 (fr) 2003-03-21 2004-10-07 Joullie Madeleine M Analogues de « tamandarin », fragments associes et leurs methodes d'elaboration et d'utilisation
WO2011020913A2 (fr) 2009-08-21 2011-02-24 Pharma Mar, S.A. Composés antiviraux cyclodepsipeptides
WO2017023694A1 (fr) * 2015-08-03 2017-02-09 Pop Test Oncology Llc Compositions pharmaceutiques et méthodes
WO2018067520A2 (fr) * 2016-10-04 2018-04-12 Pop Test Oncology Llc Procédés et agents thérapeutiques
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