Compounds for preventing or treating a viral infection

Abstract

The invention which is the subject of the present application relates to a compound of structure I: A-B-C for use in the prophylaxis and/or treatment of a viral infection, and in particular for preventing and/or inhibiting viral replication, in which A is a quinoline or a quinoline-type group, B is a single amino acid or a peptide or polypeptide having a given amino acid sequence, C is an O-phenoxy group and the symbol “-” indicates that the entities A, B and C are chemically bonded within the compound I. According to a particular embodiment, said compound is a protease inhibitor, in particular a caspase inhibitor, and more particularly the inhibitor Q-VD-OPh (N-(2(quinolyl)valyl-aspartyl-(2,6-difluorophenoxy)methyl ketone), optionally in an O-methylated form. The invention relates also to a novel antiviral composition, and to a novel combination (or kit) comprising (i) said compound of structure I and (ii) at least one other antiviral agent, in particular at least one transcriptase inhibitor and/or at least one viral protease inhibitor.

1 . Compound of structure I: A-B-C, in which:
 A is a quinoline or quinoline-type group,   B is a single amino acid or a peptide or polypeptide having a given amino acid sequence,   C is an O-phenoxy group, and   the symbol “-” indicates that the entities A, B and C are chemically bonded within the compound I,   
       for use in the prophylaxis and/or treatment of a viral infection. 
     
     
         2 . Compound according to  claim 1 , in which the structure I is: 
       
         
           
           
               
               
           
         
       
       in which:
 B is a single amino acid or a peptide or polypeptide having a given amino acid sequence, 
 R1 and R2 are selected from a hydrogen, an alkyl, an alkoxy, a fluoro, a chloro, a carboxy, a carbonyl, an arylcarbonyl and an amino, and 
 R3 and R4 are selected from a hydrogen, an alkyl, an alkoxy, a fluoro, a chloro, a carboxy, a carbonyl, an arylcarbonyl and an amino. 
 
     
     
         3 . Compound according to  claim 1 , in which B is a peptide or polypeptide, in particular a peptide having a di-, tri- or tetra-peptide sequence. 
     
     
         4 . Compound according to  claim 1 , in which the single amino acid is an aspartic acid (D) or said peptide or polypeptide comprises at least one aspartic acid. 
     
     
         5 . Compound according to  claim 1 , in which said peptide or polypeptide comprises an aspartic acid (D) and a valine (V). 
     
     
         6 . Compound according to  claim 1 , in which the amino acid sequence of said peptide is the sequence Valine-Aspartic acid (VD) or the sequence Valine-Alanine-Aspartic acid (VAD). 
     
     
         7 . Compound according to  claim 1 , in which the single amino acid or at least one of the amino acids of said peptide or polypeptide is O-methylated. 
     
     
         8 . Compound according to  claim 1 , in which said compound is O-methylated on the single aspartic acid or on at least one of the aspartic acids of said peptide or polypeptide. 
     
     
         9 . Compound according to  claim 1 , in which the single amino acid or the amino acid sequence of said peptide or polypeptide is not O-methylated. 
     
     
         10 . Compound according to  claim 2 , in which R1 and/or R2 is a hydrogen. 
     
     
         11 . Compound according to  claim 2 , in which R3 and/or R4 is a fluoro. 
     
     
         12 . Compound according to  claim 1 , in which the compound of structure I is a protease inhibitor, in particular a caspase inhibitor. 
     
     
         13 . Compound according to  claim 1 , for use in inhibiting:
 at least one caspase selected from the inflammatory caspases (group I), in particular caspase-1, -4, -5, -11, -12, -13 and -14, more particularly caspase-1 and -12; and/or   at least one caspase selected from the initiator caspases (group II), in particular caspase-2, -8, -9 and -10, more particularly caspase-8 and -10; and/or   at least one caspase selected from the effector caspases (group III), in particular caspase-3, -6 and -7, more particularly caspase-3.   
     
     
         14 . Compound according to  claim 1 , in which said compound of structure I is the compound Q-VD-OPh, of structure N-(2(quinoly)valyl-O-methyl-aspartyl-(2,6-difluorophenoxy)methyl ketone or N-(2(quinolyl)valyl-aspartyl-(2,6-difluorophenoxy)methyl ketone. 
     
     
         15 . Compound according to  claim 1 , in which said viral infection is caused by a DNA virus or an RNA virus. 
     
     
         16 . Compound according to  claim 15 , in which said virus is a virus selected from the following families:
 the flaviviridae, in particular the genus flavivirus, for example the dengue viruses and the yellow fever virus;   the orthomyxoviruses, represented by the influenza viruses;   the paramyxoviridae, in particular the genus morbillivirus, especially the measles virus, and the genus pneumovirus, for example human respiratory syncytial virus and metapneumovirus;   the reoviridae, in particular the genus rotavirus;   the picornaviridae, in particular the genus enterovirus, represented by the polioviruses and the viruses responsible for viral meningitis, the genus aphthovirus, especially the aphthous fever virus, and the genus rhinovirus;   the filoviridae, in particular the Ebola virus;   the arenaviridae, in particular the Lassa virus;   the rhabdoviridae, in particular the genus rhabdovirus, including the rabies viruses, and the genus vesiculovirus, which includes the vesicular stomatitis virus;   the togaviridae, in particular the genus Rubivirus, including the rubella virus;   the poxviridae, in particular the vaccinia and variola viruses;   the herpesviridae, in particular the Herpes, varicella and Zona viruses;   the hepatitis A, B, C, D and E viruses;   the coronaviridae, in particular the genus coronavirus, for example the SARS virus;   the retroviruses, in particular the genus lentivirus and the genus oncovirus, for example the HTLV-1 virus.   
     
     
         17 . Compound according to  claim 15 , in which said virus is a human retrovirus, in particular a human lentivirus. 
     
     
         18 . Compound according to  claim 17 , in which said human retrovirus is a human immunodeficiency virus (HIV), in particular HIV-1 or HIV-2. 
     
     
         19 . Compound according to  claim 17 , in which said human retrovirus is HIV-1. 
     
     
         20 . Compound according to  claim 15 , in which said virus is a simian retrovirus, in particular a simian lentivirus. 
     
     
         21 . Compound according to  claim 20 , in which said simian retrovirus is a simian immunodeficiency virus (SIV). 
     
     
         22 . Compound according to  claim 1 , in which said viral infection is selected from the group constituted by viral encephalitis, viral meningitis, aphthous fever, influenza, yellow fever, respiratory virus infections, infantile diarrhoea, heamorrhagic fevers, poliomyelitis, rabies, measles, rubella, varicella, smallpox, herpes zoster, genital herpes, hepatitises A, B, C, D and E, SARS, leukaemia and paralysis due to HTLV-1, and infections caused by an HIV virus, in particular acquired immunodeficiency syndrome (AIDS). 
     
     
         23 . Compound according to  claim 15  for use in preventing and/or inhibiting viral replication in an animal or human infected by said virus. 
     
     
         24 . Compound according to  claim 15  for use in preventing and/or inhibiting viral protein synthesis in an animal or human infected by said virus. 
     
     
         25 . Compound according to  claim 1 , in which said viral infection correlates with an increase in cell death in an animal, in particular with an increase in the death of the T cells, and more particularly with an increase in the death of the CD4+ T cells, in a human infected by said virus. 
     
     
         26 . Compound according to  claim 15  for use in, further, preventing and/or inhibiting an increase in cell death in an animal infected by said virus. 
     
     
         27 . Compound according to  claim 26  for use in preventing and/or inhibiting an increase in the death of the T lymphocytes, in particular an increase in the death of the CD4 +  T lymphocytes. 
     
     
         28 . Compound according to  claim 23 , in which said animal is a non-human mammal, in particular an ape or a cat. 
     
     
         29 . Composition comprising as active ingredient the compound according to  claim 1  and further comprising one or more carrier(s), diluent(s) or adjuvant(s) or a combination thereof, for use in the prophylaxis and/or treatment of a viral infection. 
     
     
         30 . Composition according to  claim 29 , characterized in that it is formulated for administration by the enteral, parenteral (intravenous, intramuscular or subcutaneous), transcutaneous, cutaneous, oral, mucosal, in particular transmucous-buccal, nasal, ophthalmological, otological, vaginal or rectal route, or alternatively by the intragastric, intracardiac, intraperitoneal, intrapulmonary or intratracheal routes. 
     
     
         31 . Compound according to  claim 1 , characterized in that it is administered to an animal or human before said animal or human is exposed to said virus and/or during exposure to the virus and/or after exposure to the virus, in particular within 48 hours of said animal or human being exposed to said virus. 
     
     
         32 . Compound according to  claim 1 , characterized in that said compound or composition is administered several times in succession. 
     
     
         33 . Antiviral composition comprising or consisting of:
 (i) at least one compound of structure I as defined in  claim 1 ; and   (ii) at least one other antiviral agent, in particular at least one other antiretroviral agent.   
     
     
         34 . Antiviral composition according to  claim 33 , further comprising one or more carrier(s), diluent(s) or adjuvant(s) or a combination thereof. 
     
     
         35 . A combination comprising or consisting of:
 (i) at least one compound of structure I as defined in  claim 1 ; and   (ii) at least one other antiviral agent, in particular at least one other antiretroviral agent, in which compounds (i) and (ii) are separate from one another.   
     
     
         36 . Combination according to  claim 35 , in which compounds (i) and (ii) are present in two distinct compositions. 
     
     
         37 . Combination according to  claim 35 , in which compounds (i) and (ii) are formulated for simultaneous administration in terms of time. 
     
     
         38 . Combination according to  claim 35 , in which said compound(s) (i) is(are) formulated for sequential administration preceding and/or following administration of said compound(s) (ii). 
     
     
         39 . Combination according to  claim 36 , in which the composition comprising compound (i) and/or the composition comprising compound (ii) further comprises one or more carrier(s), diluent(s) or adjuvant(s) or a combination thereof. 
     
     
         40 . Antiviral composition according to  claim 33  or combination, in which said other antiviral agent is selected from:
 transcriptase inhibitors;   viral protease inhibitors (or antiproteases);   inhibitors of the fusion of the viral envelope with the cell membrane;   receptor or coreceptor inhibitors;   antisense oligonucleotides;   integrase inhibitors; and   molecules that target other steps of viral multiplication.   
     
     
         41 . Antiviral composition or combination according to  claim 33 , in which said other antiviral agent or at least one of said other antiviral agents consist(s) of at least one transcriptase inhibitor and/or at least one viral protease inhibitor. 
     
     
         42 . Antiviral composition or combination according to  claim 40 , characterized in that the transcriptase inhibitor is a reverse transcriptase inhibitor, in particular an HIV virus reverse transcriptase inhibitor. 
     
     
         43 . Antiviral composition or combination according to  claim 40 , characterized in that the reverse transcriptase inhibitor is selected from the group constituted by zidovudine or azidothymidine (AZT), didanosine or ddl, zalcitabine or ddC, stavudine or d4T, lamivudine or 3TC, abacavir or ABC, and emtricitabine or FTC, nevirapine, efavirenz, delavirdine and tenofovir or bis-POC-PMPA. 
     
     
         44 . Antiviral composition or combination according to  claim 40 , characterized in that the reverse transcriptase inhibitor is AZT. 
     
     
         45 . Antiviral composition or combination according to  claim 40 , characterized in that the viral protease inhibitor is an HIV virus protease inhibitor. 
     
     
         46 . Antiviral composition or combination according to  claim 40 , characterized in that the viral protease inhibitor is selected from the group constituted by Indinavir or IDV, Nelfinavir or NLFN, Saquinavir or SQN, Ritonavir or RTN, Amprenavir and Lopinavir. 
     
     
         47 . Antiviral composition or combination according to  claim 40 , characterized in that the viral protease inhibitor is Indinavir. 
     
     
         48 . Antiviral composition or combination according to  claim 33 , in which said compound(s) (i) act(s) in synergy with said compound(s) (ii). 
     
     
         49 . Antiviral composition or combination according to  claim 33 , in which compounds (i) and (ii) are formulated for administration by the enteral, parenteral (intravenous, intramuscular or subcutaneous), transcutaneous, cutaneous, oral, mucosal, in particular buccal, nasal, oesophageal, vaginal or rectal route, or alternatively by the intragastric, intracardiac, intraperitoneal, intrapulmonary or intratracheal routes. 
     
     
         50 . Antiviral composition or combination according to  claim 33  for use as a medicament, in particular as an antiviral agent, and more particularly as an antiretroviral agent. 
     
     
         51 . Antiviral composition or combination according to  claim 33  for use in the prophylaxis and/or treatment of a viral infection, in particular for preventing and/or inhibiting viral replication, in an animal or human. 
     
     
         52 . Antiviral composition or combination according to  claim 50  for use, further, for preventing and/or inhibiting an increase in cell death, in particular an increase in the death of the T lymphocytes, and more particularly an increase in the death of the CD4 +  T lymphocytes, in an animal or human infected by a virus. 
     
     
         53 . Antiviral composition or combination according to  claim 51 , in which said animal is a non-human mammal, in particular an ape or a cat. 
     
     
         54 . Antiviral composition or combination according to  claim 51 , in which said virus is a virus selected from the following families:
 the flaviviridae, in particular the genus flavivirus, for example the dengue viruses and the yellow fever virus;   the orthomyxoviruses, represented by the influenza viruses;   the paramyxoviridae, in particular the genus morbillivirus, especially the measles virus, and the genus pneumovirus, for example human respiratory syncytial virus and metapneumovirus;   the reoviridae, in particular the genus rotavirus;   the picornaviridae, in particular the genus enterovirus, represented by the polioviruses and the viruses responsible for viral meningitis, the genus aphthovirus, especially the aphthous fever virus, and the genus rhinovirus;   the filoviridae, in particular the Ebola virus;   the arenaviridae, in particular the Lassa virus;   the rhabdoviridae, in particular the genus rhabdovirus, including the rabies viruses, and the genus vesiculovirus, which includes the vesicular stomatitis virus;   the togaviridae, in particular the genus Rubivirus, including the rubella virus;   the poxviridae, in particular the vaccinia and variola viruses;   the herpesviridae, in particular the Herpes, varicella and Zona viruses;   the hepatitis A, B, C, D and E viruses;   the coronaviridae, in particular the genus coronavirus, for example the SARS virus;   the retroviruses, in particular the genus lentivirus and the genus oncovirus, for example the HTLV-1 virus.   
     
     
         55 . Antiviral composition or combination according to  claim 51 , in which said viral infection is selected from the group constituted by viral encephalitis, viral meningitis, aphthous fever, influenza, yellow fever, respiratory virus infections, infantile diarrhoea, heamorrhagic fevers, poliomyelitis, rabies, measles, rubella, varicella, smallpox, herpes zoster, genital herpes, hepatitises A, B, C, D and E, SARS, leukaemia and paralysis due to HTLV-1, and infections caused by an HIV virus, in particular acquired immunodeficiency syndrome (AIDS).