Compounds for use in inflammatory conditions

Abstract

The present invention relates to the use of compounds in the treatment of inflammation, preferably inflammation associated with activation of Toll-like receptors. The invention also relates to the use of compounds to treat pathogen-induced inflammation.

1 . A compound of general formula I
                       wherein X is selected from O and NH;   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 -C 6  alkyl;   each R 7  and R 13  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; each R 6  and R 14  is independently selected from hydrogen and substituted or unsubstituted C 1 -C 6  alkyl; or 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 heterocyclic group;   R 17  is selected from hydrogen, COR a , COOR a , CONHR b , COSR c , (C=NR b )OR a , (C=NR b )NHR b , (C=NR b )SR c , (C=S)OR a , (C=S)NHR b , (C=S)SR c , SO 2 R c , SO 3 R c , substituted or unsubstituted C 1 -C 12  alkyl, substituted or unsubstituted C 2 -C 12  alkenyl, substituted or unsubstituted C 2 -C 12  alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, with the proviso that when n, p, and q are 0 then R 17  is not hydrogen; and   each R a , R b , and R c  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 12  alkyl, substituted or unsubstituted C 2 -C 12  alkenyl, substituted or unsubstituted C 2 -C 12  alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group;   or a pharmaceutically acceptable salt or stereoisomer thereof, for use in the treatment of inflammation.   
     
     
         2 . A compound of general formula I
                       wherein X is selected from O and NH;   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 -C 6  alkyl;   each R 7  and R 13  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; each R 6  and R 14  is independently selected from hydrogen and substituted or unsubstituted C 1 -C 6  alkyl; or 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 heterocyclic group;   R 17  is selected from hydrogen, COR a , COOR a , CONHR b , COSR c , (C=NR b )OR a , (C=NR b )NHR b , (C=NR b )SR c , (C=S)OR a , (C=S)NHR b , (C=S)SR c , SO 2 R c , SO 3 R c , substituted or unsubstituted C 1 -C 12  alkyl, substituted or unsubstituted C 2 -C 12  alkenyl, substituted or unsubstituted C 2 -C 12  alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, with the proviso that when n, p, and q are 0 then R 17  is not hydrogen; and   each R a , R b , and R c  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 12  alkyl, substituted or unsubstituted C 2 -C 12  alkenyl, substituted or unsubstituted C 2 -C 12  alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group;   or a pharmaceutically acceptable salt or stereoisomer thereof, for use in the treatment of inflammation associated with activation of Toll-like receptors.   
     
     
         3 . A compound of general formula I
                       wherein X is selected from O and NH;   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 -C 6  alkyl;   each R 7  and R 13  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; each R 6  and R 14  is independently selected from hydrogen and substituted or unsubstituted C 1 -C 6  alkyl; or 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 heterocyclic group;   R 17  is selected from hydrogen, COR a , COOR a , CONHR b , COSR c , (C=NR b )OR a , (C=NR b )NHR b , (C=NR b )SR c , (C=S)OR a , (C=S)NHR b , (C=S)SR c , SO 2 R c , SO 3 R c , substituted or unsubstituted C 1 -C 12  alkyl, substituted or unsubstituted C 2 -C 12  alkenyl, substituted or unsubstituted C 2 -C 12  alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, with the proviso that when n, p, and q are 0 then R 17  is not hydrogen; and   each R a , R b , and R c  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 12  alkyl, substituted or unsubstituted C 2 -C 12  alkenyl, substituted or unsubstituted C 2 -C 12  alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group;   or a pharmaceutically acceptable salt or stereoisomer thereof, for use in the treatment of a disorder selected from pneumonia, acute respiratory distress (ARDS), immunopathology, preferably hypercytokinemia (cytokine storm syndrome), sepsis and graft-versus-host disease.   
     
     
         4 . A compound of general formula I
                       wherein X is selected from O and NH;   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 -C 6  alkyl;   each R 7  and R 13  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; each R 6  and R 14  is independently selected from hydrogen and substituted or unsubstituted C 1 -C 6  alkyl; or 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 heterocyclic group;   R 17  is selected from hydrogen, COR a , COOR a , CONHR b , COSR c , (C=NR b )OR a , (C=NR b )NHR b , (C=NR b )SR c , (C=S)OR a , (C=S)NHR b , (C=S)SR c , SO 2 R c , SO 3 R c , substituted or unsubstituted C 1 -C 12  alkyl, substituted or unsubstituted C 2 -C 12  alkenyl, substituted or unsubstituted C 2 -C 12  alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, with the proviso that when n, p, and q are 0 then R 17  is not hydrogen; and   each R a , R b , and R c  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 12  alkyl, substituted or unsubstituted C 2 -C 12  alkenyl, substituted or unsubstituted C 2 -C 12  alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group;   or a pharmaceutically acceptable salt or stereoisomer thereof, for use in the treatment of pathogen-induced inflammation.   
     
     
         5 . The compound of  claim 4 , wherein the pathogen is selected from a virus and bacteria. 
     
     
         6 . A compound of general formula I
                       wherein X is selected from O and NH;   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 -C 6  alkyl;   each R 7  and R 13  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; each R 6  and R 14  is independently selected from hydrogen and substituted or unsubstituted C 1 -C 6  alkyl; or 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 heterocyclic group;   R 17  is selected from hydrogen, COR a , COOR a , CONHR b , COSR c , (C=NR b )OR a , (C=NR b )NHR b , (C=NR b )SR c , (C=S)OR a , (C=S)NHR b , (C=S)SR c , SO 2 R c , SO 3 R c , substituted or unsubstituted C 1 -C 12  alkyl, substituted or unsubstituted C 2 -C 12  alkenyl, substituted or unsubstituted C 2 -C 12  alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, with the proviso that when n, p, and q are 0 then R 17  is not hydrogen; and   each R a , R b , and R c  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 12  alkyl, substituted or unsubstituted C 2 -C 12  alkenyl, substituted or unsubstituted C 2 -C 12  alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group;   or a pharmaceutically acceptable salt or stereoisomer thereof, for use in the combined treatment of inflammation associated with activation of Toll-like receptors or pathogen-induced inflammation and in the treatment of a viral infection.   
     
     
         7 . A compound of general formula I
                       wherein X is selected from O and NH;   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 -C 6  alkyl;   each R 7  and R 13  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; each R 6  and R 14  is independently selected from hydrogen and substituted or unsubstituted C 1 -C 6  alkyl;   or 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 heterocyclic group;   R 17  is selected from hydrogen, COR a , COOR a , CONHR b , COSR c , (C=NR b )OR a , (C=NR b )NHR b , (C=NR b )SR c , (C=S)OR a , (C=S)NHR b , (C=S)SR c , SO 2 R c , SO 3 R c , substituted or unsubstituted C 1 -C 12  alkyl, substituted or unsubstituted C 2 -C 12  alkenyl, substituted or unsubstituted C 2 -C 12  alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, with the proviso that when n, p, and q are 0 then R 17  is not hydrogen; and   each R a , R b , and R c  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 12  alkyl, substituted or unsubstituted C 2 -C 12  alkenyl, substituted or unsubstituted C 2 -C 12  alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group;   or a pharmaceutically acceptable salt or stereoisomer thereof, for use as an anti-inflammatory and an antiviral.   
     
     
         8 . A compound according to any preceding claim, wherein 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. 
     
     
         9 . A compound according to any preceding claim, of general formula II, wherein R 3  and R 4  are methyl. 
     
     
         10 . A compound according to any preceding claim, wherein R 11  is selected from hydrogen and substituted or unsubstituted C 1 -C 6  alkyl; preferably wherein R 11  is methyl or isobutyl. 
     
     
         11 . A compound according to any preceding claim, of general formula III, wherein R 11  is methyl and n=1. 
     
     
         12 . A compound according to any preceding claim, wherein 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. 
     
     
         13 . A compound according to any preceding claim, wherein 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. 
     
     
         14 . A compound according to any preceding claim, wherein 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. 
     
     
         15 . A compound according to any preceding claim, wherein 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. 
     
     
         16 . A compound according to any of  claims 1 to 13 , wherein 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 form a substituted or unsubstituted pyrrolidine group. 
     
     
         17 . A compound according to any preceding claim, wherein 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. 
     
     
         18 . A compound according to any preceding claim, wherein R 17  is selected from hydrogen, COR a , COOR a , CONHR b , (C=S)NHR b , and SO 2 R c , and wherein each R a , R b , and R c  is independently selected from substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group; preferably wherein R 17  is selected from hydrogen, COObenzyl, CObenzo[b]thiophen-2-yl, SO 2 (p-methylphenyl), COCOCH 3  and COOC(CH 3 ) 3 . 
     
     
         19 . A compound according to any preceding claim, wherein X is NH. 
     
     
         20 . A compound according to any of  claims 1 to 18 , wherein X is O. 
     
     
         21 . A compound according to any preceding claim wherein Y is CO. 
     
     
         22 . A compound according to any of  claims 1 to 20 , wherein Y is —COCH(CH 3 )CO—. 
     
     
         23 . A compound according to any one of  claims 1 to 7 , having the following structure:
                                                                                                                                                                                                       or                         or pharmaceutically acceptable salts or stereoisomers thereof.   
     
     
         24 . A compound according to any one of  claims 1 to 7 , wherein the compound is PLD, or pharmaceutically acceptable salts or stereoisomers thereof. 
     
     
         25 . A compound according to any one of  claims 1 to 7 , wherein the compound is didemninB, or pharmaceutically acceptable salts or stereoisomers thereof. 
     
     
         26 . The compound of  claim 2 , wherein the Toll-like receptor is activated by a single stranded RNA virus, wherein preferably the virus is selected from Flaviviridae, Picornaviridae, Togaviridae, Caliciviridae, Retroviridae, Coronaviridae, Orthomyxoviridae, Phlebovirus and Arenaviridae or a dsDNA virus, preferably Herpesviridae. 
     
     
         27 . The compound of any one of  claims 4 to 6 , wherein the pathogen is a virus, preferably a single stranded RNA virus, wherein preferably the virus is selected from Flaviviridae, Picornaviridae, Togaviridae, Caliciviridae, Retroviridae, Coronaviridae, Orthomyxoviridae, Phlebovirus and Arenaviridae or a dsDNA virus, preferably Herpesviridae. 
     
     
         28 . The compound of  claim 5 ,  6  or  7 , wherein the virus is a single stranded RNA virus, wherein preferably the virus is selected from Flaviviridae, Picornaviridae, Togaviridae, Caliciviridae, Retroviridae, Coronaviridae, Orthomyxoviridae, Phlebovirus and Arenaviridae or a dsDNA virus, preferably Herpesviridae. 
     
     
         29 . The compound of any of  claims 26 to 28 , wherein the virus is a Flaviviridae virus; and is optionally selected from Yellow fever virus (YFV), Hepatitis C virus, West Nile Virus (WNV), Dengue virus (DENV), Japanese encephalitis virus (JEV), Tick-borne encephalitis virus (TBEV), Classical swine fever virus and Zika virus (ZIKV). 
     
     
         30 . The compound of any of  claims 26 to 28 , wherein the virus is a Coronavirinae; and is optionally SARS-CoV-2. 
     
     
         31 . The compound of any of  claims 26 to 28 , wherein the virus is a Picornaviridae; and is optionally foot and mouth disease virus, enterovirus A71, Coxsackieviruses, Rhinovirus and Hepatitis A. 
     
     
         32 . The compound of any of  claims 26 to 28 , wherein the virus is a Togaviridae; and is optionally Chikungunya Virus, Sindbis Virus, Semliki Forest Virus, Eastern Equine Encephalitis Virus / Western Equine Encephalitis Virus / Venezuelan Equine Encephalitis Virus and Rubella virus. 
     
     
         33 . The compound of any of  claims 26 to 28 , wherein the virus is a Caliciviridae; and is optionally Lagovirus, Norovirus, Nebovirus, Recovirus, Sapovirus, Valovirus and Vesivirus, and in particular, Norwalk virus. 
     
     
         34 . The compound of any of  claims 26 to 28 , wherein the virus is a Retroviridae; and is optionally HIV. 
     
     
         35 . The compound of any of  claims 26 to 28 , wherein the virus is a Orthomyxoviridae, and is optionally influenza. 
     
     
         36 . The compound of any of  claims 26 to 28 , wherein the virus is a Phlebovirus, and is optionally Sandfly fever virus or Rift Valley fever virus. 
     
     
         37 . The compound of any of  claims 26 to 28 , wherein the virus is a Arenaviridae and is optionally the Pichinde virus. 
     
     
         38 . The compound of any of  claims 26 to 28 , wherein the virus is a Herpesviridae preferably Herpes simplex virus 1 or 2. 
     
     
         39 . The compound of any of  claims 26 to 28 , wherein the virus is a respiratory virus. 
     
     
         40 . A compound according to any one of  claims 1 to 39 , wherein the virus is SARS-CoV-2, for use in the treatment of COVID-19 and/or for use in the treatment of pneumonia or ARDS caused by COVID-19. 
     
     
         41 . A compound according to  claim 30 , wherein the CoV infection is mild infection; and/or wherein the CoV infection is moderate infection; and/or wherein the CoV infection is severe infection. 
     
     
         42 . A compound according to  claim 30 , wherein the CoV infection is acute CoV infection, preferably wherein the CoV infection is acute COVID-19 infection; and/or wherein the CoV infection is ongoing symptomatic CoV infection, preferably wherein the CoV infection is ongoing symptomatic COVID-19 infection; and/or wherein the CoV infection is post-CoV syndrome, CoV persistent or long CoV; preferably wherein the CoV infection is post-COVID-19 syndrome, COVID persistent or long COVID. 
     
     
         43 . A compound according to  claim 42 , wherein the post-CoV syndrome, CoV persistent or long CoV include one or more symptoms arising from the cardiovascular, respiratory, gastrointestinal, neurological, musculoskeletal, metabolic, renal, dermatological, otolaryngological, haematological and autonomic systems; psychiatric problems, generalised pain, fatigue and/or persisting fever. 
     
     
         44 . A compound according to  claim 30 , for use in the treatment of a patient with signs and symptoms of CoV infection (preferably COVID-19) for up to 4 weeks; and/or for use in the treatment of a patient with signs and symptoms of CoV infection (preferably COVID-19) from 4 weeks to 12 weeks; and/or for use in the treatment of a patient with signs and symptoms of CoV infection, preferably COVID-19, for more than 12 weeks. 
     
     
         45 . A compound according to  claim 30 , for use in the prophylaxis, reduction or treatment of COVID persistent, long COVID or post-COVID syndrome; preferably wherein the prophylaxis, reduction or treatment minimises the likelihood that a patient suffers from COVID persistent, long COVID or post-COVID syndrome symptoms; and/or reduces the severity of such symptoms; further preferably wherein the treatment minimising the symptoms of CoV infection. 
     
     
         46 . A compound according to  claim 30 , wherein the treatment reduces the infectivity of CoV patients; including wherein the patient is asymptomatic or not very symptomatic yet has a high viral load. 
     
     
         47 . A compound for use according to any preceding claim, wherein the compound is administered in combination with a corticosteroid, preferably dexamethasone. 
     
     
         48 . A compound for use according to  claim 47 , wherein the compound and corticosteroid are administered concurrently, separately or sequentially. 
     
     
         49 . A compound for use according to any preceding claim, 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. 
     
     
         50 . A compound for use according to any preceding claim wherein the compound is 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; more preferably 1.5-2.5 mg/day; most preferably 1.5 mg/day, 2.0 mg/day or 2.5 mg/day. 
     
     
         51 . A compound for use according to any preceding claim wherein the compound is 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, 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 4.5-7.5 mg/day. 
     
     
         52 . A compound for use according to any preceding claim, wherein the compound is administered by infusion. 
     
     
         53 . A compound for use according to  claim 52 , wherein the infusion is a 1 hour infusion, a 1.5 hour infusion, a 2 hour infusion or a 3 hour infusion; preferably a 1.5 hour infusion. 
     
     
         54 . A compound for use according to any one of  claims 1 to 53 , wherein 1.5 mg of plitidepsin is administered as a 1.5-hour infusion, once a day for 3 consecutive days; or wherein 2 mg of plitidepsin is administered as a 1.5-hour infusion, once a day for 3 consecutive days; wherein 2.5 mg of plitidepsin is administered as a 1.5-hour infusion, once a day for 3 consecutive days; or wherein 1 mg of plitidepsin is administered as a 1.5-hour infusion, once a day for 5 consecutive days; or wherein 2 mg of plitidepsin is administered as a 1.5-hour infusion, once a day for 5 consecutive days. 
     
     
         55 . A compound for use according to any preceding claim, wherein the compound is administered using a loading dose and a maintenance dose. 
     
     
         56 . A compound for use according to  claim 55 , 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 for day 1, and followed by a maintenance dose of 0.5 mg/day for subsequent days; or   a loading dose of 1 mg for day 1, and followed by a maintenance dose of 0.5 mg/day for subsequent days.   
     
     
         57 . A compound for use according to any preceding claim, wherein the compound is administered in combination with a corticosteroid, and wherein the corticosteroid is administered on the same days as administration of the compound according to any one of  claims 1 to 25 . 
     
     
         58 . A compound for use according to  claim 57 , 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. 
     
     
         59 . A compound for use according to  claim 58 , wherein the corticosteroid is administered intravenously on days when the compound is administered but is administered by oral administration or IV on subsequent days. 
     
     
         60 . A compound for use according to any one of  claims 57 to 59 , wherein the corticosteroid is dexamethasone; preferably wherein dexamethasone is administered at a dose of 6.6 mg/day IV on days when the compound according to the present invention is administered. 
     
     
         61 . A compound for use according to  claim 60 , wherein dexamethasone is 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. 
     
     
         62 . A compound for use according to any preceding claim, wherein PLD is administered 1.5 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); 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).   
     
     
         63 . A compound for use according to any one of  claims 57 to 62 , wherein the corticosteroid is administered 20 to 30 minutes prior to starting treatment with the compound according to any one of  claims 1 to 25 . 
     
     
         64 . A compound for use according to any preceding claim, wherein the patient additionally receives the following medications, preferably 20 to 30 minutes prior to starting treatment with the compound according to any one of  claims 1 to 25 :
 Ondansetron 8 mg IV (or equivalent);   Diphenhydramine hydrochloride 25 mg IV (or equivalent); and   Ranitidine 50 mg IV (or equivalent).   
     
     
         65 . A compound for use according to any preceding claim, wherein on Days 4 and 5, patients receive ondansetron (or equivalent) 4 mg twice a day PO. 
     
     
         66 . A compound for use according to any one of  claims 1 to 53 , wherein the compound is administered as a single dose (on day 1). 
     
     
         67 . A compound for use according to  claim 66 , wherein the single dose is 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 most preferably 7.5 mg. 
     
     
         68 . A compound for use according to any one of  claims 66 to 67 , wherein the compound is administered as a 1.5-hour infusion. 
     
     
         69 . A compound for use according to any one of  claims 66 to 68 , wherein a corticosteroid is administered according to the regimen according to any one of  claims 57 to 63 . 
     
     
         70 . A compound for use according to any one of  claims 66 to 69 , wherein the following prophylactic medications are administered 20-30 minutes prior to administration with a compound of the present invention:
 Ondansetron 8 mg IV (or equivalent), particularly in slow infusion of 15 minutes;   Diphenhydramine hydrochloride 25 mg IV (or equivalent);   Ranitidine 50 mg IV (or equivalent).   
     
     
         71 . A compound for use according to any one of  claims 66 to 70 , wherein ondansetron 4 mg orally is given every 12 hours for 3 days after administration of a compound of the present invention. 
     
     
         72 . A compound for use according to any preceding claim, wherein 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). 
     
     
         73 . A pharmaceutical composition comprising a compound as defined in any preceding claim, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment of inflammation. 
     
     
         74 . A pharmaceutical composition comprising a compound as defined in any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment of inflammation associated with activation of Toll-like receptors. 
     
     
         75 . A pharmaceutical composition comprising a compound as defined in any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment of a disorder selected from pneumonia, acute respiratory distress (ARDS) and immunopathology, in particular hypercytokinemia (cytokine storm syndrome), sepsis and graft-versus-host disease. 
     
     
         76 . A pharmaceutical composition comprising a compound as defined in any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment of pathogen-induced inflammation. 
     
     
         77 . A pharmaceutical composition comprising a compound as defined in any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, for use in the combined treatment of inflammation associated with activation of Toll-like receptors or pathogen-induced inflammation and in the treatment of a viral infection. 
     
     
         78 . A pharmaceutical composition comprising a compound as defined in any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, for use as an anti-inflammatory and an antiviral. 
     
     
         79 . Use of a compound as defined in to any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the treatment of inflammation. 
     
     
         80 . Use of a compound as defined in to any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the treatment of inflammation associated with activation of Toll-like receptors. 
     
     
         81 . Use of a compound as defined in to any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the treatment of a disorder selected from pneumonia, acute respiratory distress (ARDS) and immunopathology, in particular hypercytokinemia (cytokine storm syndrome), sepsis and, graft-versus-host disease. 
     
     
         82 . Use of a compound as defined in to any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the treatment of pathogen-induced inflammation. 
     
     
         83 . Use of a compound as defined in to any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the combined treatment of inflammation associated with activation of Toll-like receptors or pathogen-induced inflammation and in the treatment of a viral infection. 
     
     
         84 . Use of a compound or a pharmaceutically acceptable salt as defined in to any of  claims 1 to 72 , or stereoisomer thereof, in the manufacture of a medicament as an anti-inflammatory and an antiviral. 
     
     
         85 . A method of treating inflammation, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of a compound as defined in any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         86 . A method of treating inflammation associated with activation of Toll-like receptors, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of a compound as defined in any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         87 . A method of treating a disorder selected from pneumonia, acute respiratory distress (ARDS), and immunopathology, in particular hypercytokinemia (cytokine storm syndrome), sepsis and graft-versus-host disease, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of a compound as defined in any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         88 . A method of treating pathogen-induced inflammation, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of a compound as defined in any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         89 . A method of combined treatment of inflammation associated with activation of Toll-like receptors or pathogen-induced inflammation and in the treatment of a viral infection, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of a compound as defined in any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         90 . A method of anti-inflammatory and antiviral treatment, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of a compound as defined in any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         91 . A kit comprising the compound as defined in any of  claims 1 to 72 , together with instructions for treating inflammation; for treating inflammation associated with activation of Toll-like receptors; for treating a disorder selected from pneumonia, acute respiratory distress (ARDS) and immunopathology, in particular hypercytokinemia (cytokine storm syndrome), sepsis and graft-versus-host disease; for treating pathogen-induced inflammation; for the combined treatment of inflammation associated with activation of Toll-like receptors or pathogen-induced inflammation and in the treatment of a viral infection; or for use as an anti-inflammatory and an antiviral. 
     
     
         92 . A method of decreasing the expression and/or secretion of one or more pro-inflammatory cytokine in a subject or in a sample obtained from a subject or in a cell culture, the method comprising administering a compound as defined in any of  claims 1 to 72 . 
     
     
         93 . A method of increasing macrophage activation and/or recruitment in a subject or in a sample obtained from a subject or in a cell culture, the method comprising administering a compound as defined in any of  claims 1 to 72 . 
     
     
         94 . A method of prophylaxis, reduction or treatment of inflammatory aspects of CoV persistent, long CoV or post-CoV syndrome, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of a compound as defined in any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof; preferably wherein the CoV is SARS-CoV-2; optionally wherein the treatment minimises the likelihood that a patient suffers from COVID persistent, long COVID or post-COVID syndrome symptoms; and/or reduces the severity of such symptoms. 
     
     
         95 . A method of reducing the infectivity and inflammation of CoV patients, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of a compound as defined in any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof; preferably wherein the CoV is SARS-CoV-2; optionally wherein the patient is asymptomatic or not very symptomatic yet has a high viral load. 
     
     
         96 . A method of minimising the inflammatory symptoms of CoV infection, wherein the method comprises administering to an individual in need thereof, a therapeutically effective amount of a compound as defined in any of  claims 1 to 72 , or a pharmaceutically acceptable salt or stereoisomer thereof; preferably wherein the CoV is SARS-CoV-2. 
     
     
         97 . A corticosteroid for use in the treatment of inflammation, wherein the corticosteroid is administered in combination with a compound according to any one of  claims 1 to 72 . 
     
     
         98 . A compound according to any one of  claims 1 to 25  and a corticosteroid for use in the treatment of inflammation; wherein the use is according to any one of  claims 1 to 72 . 
     
     
         99 . A method of treatment of inflammation, the method comprising administering a combination therapy of compound according to any one of  claims 1 to 25  or a pharmaceutically acceptable salt thereof and a corticosteroid to a patient in need thereof, thereby treating the inflammation; wherein said method is as defined in any one of  claims 1 to 72 . 
     
     
         100 . Use of a compound as defined in any of  claims 1 to 72  or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the treatment of inflammation; wherein said treatment includes administration of a corticosteroid. 
     
     
         101 . Use of a corticosteroid in the manufacture of a medicament for the treatment of inflammation; wherein said treatment includes administration of a compound as defined in any of  claims 1 to 72  or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         102 . Use of a compound as defined in any of  claims 1 to 72  or a pharmaceutically acceptable salt or stereoisomer thereof and a corticosteroid in the manufacture of a medicament for the treatment of inflammation. 
     
     
         103 . A pharmaceutical package comprising a compound as defined in any of  claims 1 to 25  and a corticosteroid, optionally further comprising instructions according to any one of  claims 1 to 72 .