WO2011089166A1 - Inhibiteurs du protéasome à base de semicarbazone pour traiter une infection par le vih et une infection par une hépatite - Google Patents

Inhibiteurs du protéasome à base de semicarbazone pour traiter une infection par le vih et une infection par une hépatite Download PDF

Info

Publication number
WO2011089166A1
WO2011089166A1 PCT/EP2011/050711 EP2011050711W WO2011089166A1 WO 2011089166 A1 WO2011089166 A1 WO 2011089166A1 EP 2011050711 W EP2011050711 W EP 2011050711W WO 2011089166 A1 WO2011089166 A1 WO 2011089166A1
Authority
WO
WIPO (PCT)
Prior art keywords
patients
hcv
hiv
infection
treatment
Prior art date
Application number
PCT/EP2011/050711
Other languages
English (en)
Inventor
Ulrich Schubert
Original Assignee
Virologik Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/EP2010/060796 external-priority patent/WO2011009961A1/fr
Application filed by Virologik Gmbh filed Critical Virologik Gmbh
Publication of WO2011089166A1 publication Critical patent/WO2011089166A1/fr

Links

Classifications

    • 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
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the invention relates to semicarbazone proteasome inhibitors for treating retroviral infections, e.g. Human Immunodeficiency virus (HIV) infections and/or viral hepatitis infections, in particular for treating Hepatitis C Virus (HCV) infections.
  • HIV Human Immunodeficiency virus
  • HCV Hepatitis C Virus
  • the present invention further concerns pharmaceutical compositions and kits of pharmaceutical compositions which may be used for treating HIV infections and or viral hepatitis infections, in particular for treating HCV infections as well as methods and uses of said proteasome inhibitors and pharmaceutical compositions comprising the same.
  • Pegylated interferon (PEG-IFN) alpha-2a or alpha-2b in combination with nucleoside analogon ribavirin when being administered for 24 or 48 weeks currently is the standard therapy for patients suffering from chronic HCV infections.
  • the aim of the standard therapy is to achieve elimination of the HC virus, meaning that no HCV- R A is detectable after treatment.
  • the guanosine analogon ribavirin in combination with interferons has been authorized for therapy of chronic HCV infections since 1999. However, the mode of action of this medicament is only partially understood. A complete elimination of HCV after administration of ribavirin without IFN is not to be expected.
  • IFN interleukin-12
  • ribavirin The standard therapy of IFN and ribavirin is frequently associated with side effects which can be partially attributed to the specific substance respectively.
  • the most frequently observed side effects of an IFN therapy are flu- like symptoms such as fever, headache, muscle pain, joint pain as well as fatigue, loss of appetite and loss of weight.
  • mood swings including depression have been described.
  • a frequent side effect observed with ribavirin treatment is anemia, which necessitates continuous control of blood parameters during therapy.
  • patients undergoing treatment for viral hepatitis, and particularly for HCV infections can be categorized as “responder”, “non-responder” and “patients showing a relapse/therapy refractory patients”.
  • a response is typically understood to refer to a sustained decrease of the virus load below the detection limit for at least 6 months after standard therapy has ceased ("sustained virological response", SVR).
  • SVR sustained virological response
  • a relapse typically refers to a complete virological response up until the 24th week of treatment at the latest. However, after the standard therapy has ceased, a renewed increase of virus load may be observed (therapy refractory).
  • Non-responders are patients for which typically no decrease of virus load by a factor of at least 2 log steps is observed during 24 weeks or for which up to week 24, HCV-RNA are still detectable during standard therapy (therapy resistant). For example, more than 50% of patients infected with HCV of Genotype 1 do not react towards standard therapy (“non-responder”) or suffer from a setback after therapy has ended (“relapser”). Treatment options, especially for non-responders and relapsed patients, are sparse (Kronenberger, B., Zeuzem, S., Annals of
  • HIV-1 and type 2 are the etiological agents that are responsible for the acquired immune deficiency syndrome (AIDS) and related disorders (Barre-Sinoussi, et al, Science, 220:868-871 (1983); Gallo, et al, Science, 224:500-503 (1984); Levy, et al, Science. 225:840-842 (1984); Popovic, et al, Science. 224:497-500 (1984); Sarngadharan, et al, Science. 224:506-508 (1984); Siegal, et al, Nl Engl. J. Med..
  • HIV is transmitted through direct contact of a mucous membrane or the bloodstream with a bodily fluid containing HIV, such as blood, semen, vaginal fluid, preseminal fluid, and breast milk.
  • a bodily fluid containing HIV such as blood, semen, vaginal fluid, preseminal fluid, and breast milk.
  • This transmission can involve anal, vaginal or oral sex, blood transfusion, contaminated hypodermic needles, exchange between mother and baby during pregnancy, childbirth, breastfeeding or other exposure to one of the above bodily fluids.
  • AIDS occurs after an asymptomatic period following infection with HIV-1 or HIV-2. Main characteristics of the syndrome are the progressive degeneration of the immune system and the central nervous system. The infection with HIV itself, does not necessarily cause death. However, infected individuals will eventually suffer from severe immunosuppression, so that various other diseases , such as opportunistic infections, e.g viral infections (e.g. HCV, HSV, CMV, EBV, HHV6), bacterial and fungal infections, or malignancies, especially Kaposi's sarcoma, occur. HIV-infected individuals eventually succumb to these secondary conditions. In as far as a treatment is available, such secondary conditions may of course be treated.
  • opportunistic infections e.g viral infections (e.g. HCV, HSV, CMV, EBV, HHV6)
  • malignancies especially Kaposi's sarcoma
  • AIDS is now a pandemic. In 2007, it was estimated that 33.2 million people lived with the disease worldwide, and that AIDS killed an estimated 2.1 million people, including 330,000 children. Over three-quarters of these deaths occurred in sub- Saharan Africa. Although treatments for AIDS and HIV can slow the course of the disease, there is currently no known cure or vaccine leading to the elimination of the virus.
  • Antiretro viral treatment reduces both the mortality and the morbidity of HIV infection, but these drugs are expensive and routine access to antiretroviral medication is not available in all countries.
  • the family of retroviruses which also includes the human immune deficiency viruses (HIV) belongs to the large group of eukaryotic retrotransposable elements (for a review, see Doolittle, R F; et al. (1990) Curr. Top. Microbiol. Immunol. 157: 1-18.). Said elements are distinguished by the ability to transcribe RNA genomes into DNA intermediates by using the enzyme reverse transcriptase.
  • HAV human immune deficiency viruses
  • Retroviruses are divided into five subfamilies: (i) spumaviruses; (ii) mammalian type C oncoviruses; (iii) BLV (bovine leukemia virus)/HTLV (human T-cell leukeumia virus) leukemia viruses; (iv) a heterogeneous group of RSV (Rous sarcoma virus), type A, B and D viruses; and (v) lentiviruses (for a review, see Doolittle et al, 1990). Lentiviruses replicate predominantly in lymphocytes and fully differentiated macrophages and usually cause long-lasting and/or incurable diseases. Retroviruses contain at least three characteristic genes: gag (groupspecific antigen), polys, and the like.
  • the lentivirus subfamily includes, in addition to HIV, SIV (simian immunodeficiency virus), EIAV (equine infectious anemia virus), BIV (bovine immunodeficiency virus), FIV (feline immunodeficiency virus) and Visna virus. HIV in turn is divided into the two subtypes HIV-1 and HIV-2 (for a review, see Doolittle et al, 1990).
  • the HIV replication cycle starts with the virus binding to various cell receptors among which the glycoprotein CD4 acts as the primary receptor and various cellspecific chemokine receptors act as co-receptors, after binding to CD4.
  • the viral RNA genome is transcribed by means of reverse transcriptase (RT), RNase H and polymerase into double-stranded DNA which, in association with the preintegration complex, is then transported into the nucleus and incorporated as provirus genome into chromosomal DNA by means of viral integrase.
  • RT reverse transcriptase
  • Gag/Gag-Pol polyproteins and envelope proteins are transported to the cell membrane where virions are being assembled.
  • HIV structural proteins are translated in the form-of three polyproteins: Gag and Gag-Pol for the inner core proteins and viral enzymes and Env for proteins of the viral envelope proteins.
  • Gag and Gag-Pol for the inner core proteins
  • viral enzymes and Env for proteins of the viral envelope proteins.
  • Env proteins of the viral envelope proteins.
  • complete proteolytic processing of the Gag polyprotein Pr55 results in the formation of the matrix (MA), capsid (CA) and nucleocapsid (NC) and of the C-terminal p6Gag- protein.
  • HIV-1 virions are detached from the plasma membrane as mature
  • virus budding noninfectious virus particles
  • proteolytic processing of Gag and Gag-Pol polyproteins commences with the activation of PR.
  • the proteolytic maturation of the virions is accompanied by morphological changes.
  • a characteristic feature is the condensation of the inner core, resulting in the formation of a conical core cylinder typical for the mature virus (for a review, see Swanstrom and Wills, 1997).
  • the system is utilized for proteolysis of de novo synthesized virus receptor CD4.
  • This pathway is mediated by the HIV-1 -specific protein Vpu which directs CD4 from the membrane of the endoplasmic reticulum (ER) to the site of proteosomal degradation in the cytoplasm (Schubert et al, 1998, J. Virol, 72:2280).
  • monoubiquitinated forms of Gag have been described for HIV-1 and Mo-MuLV Gag proteins (Ott et al, 1998, J. Virol, 72:2962).
  • New therapeutic approaches intend to prevent the spread of infectious viruses, the development of immunodeficiencies, such as AIDS, HIV- dementia, or other retrovirus-related diseases or conditions, etc.
  • the present invention also provides new therapies for both, retroviral infections, e.g. infection by HIV and hepatitis virus infections, particularly HCV infections.
  • Hepatitis C virus is a small (55-65 nm in size), enveloped, positive-sense single- stranded RNA virus of the family Flaviviridae. Hepatitis C virus is the cause of hepatitis C in humans.
  • the hepatitis C virus particle consists of a core of genetic material (RNA), surrounded by an icosahedral protective shell of protein, and further encased in a lipid (fatty) envelope of cellular origin.
  • Hepatitis C virus has a positive sense single-stranded RNA genome.
  • the genome consists of a single open reading frame that is 9600 nucleotide bases long. This single open reading frame is translated to produce a single protein product, which is then further processed to produce smaller active proteins.
  • the UTR At the 5' and 3' ends of the R A are the UTR, that are not translated into proteins but are important to translation and replication of the viral RNA.
  • the 5' UTR has a ribosome binding site (IRES - Internal ribosome entry site) that starts the translation of a very long protein containing about 3,000 amino acids.
  • IRES Internal ribosome entry site
  • Structural proteins made by the hepatitis C virus include Core El and E2; nonstructural proteins include p7, NS2, NS3, NS4, NS4A, NS4B, NS5A, and NS5B.
  • the virus replicates mainly in the hepatocytes of the liver.
  • the virus may also replicate in peripheral blood
  • HCV mononuclear cells, potentially accounting for the high levels of immunological disorders found in chronically-infected HCV patients.
  • HCV has a wide variety of genotypes and mutates rapidly due to a high error rate on the part of the virus' RNA- dependent RNA polymerase. The mutation rate produces so many variants of the virus it is considered a quasispecies rather than a conventional virus species. Entry into host cells occur through complex interactions between virions and cell-surface molecules, e.g. CD81, Claudin-1, Occludin-1, Scavenger Receptor Bl . Inside the hepatocyte, HCV takes over portions of the intracellular machinery to replicate. The HCV genome is translated to produce a single protein of around 3011 amino acids.
  • the polyprotein is then proteolytically processed by viral and cellular proteases to produce three structural (virion-associated) and seven nonstructural (NS) proteins.
  • a frameshift may occur in the Core region to produce an Alternate Reading Frame Protein (ARFP).
  • HCV encodes two proteases, the NS2 cysteine autoprotease and the NS3-4A serine protease.
  • the NS proteins then recruit the viral genome into an RNA replication complex, which is associated with rearranged cytoplasmic membranes.
  • RNA replication takes places via the viral RNA-dependent RNA polymerase NS5B, which produces a negative-strand RNA intermediate.
  • the negative strand RNA then serves as a template for the production of new positive- strand viral genomes. Nascent genomes can then be translated, further replicated, or packaged within new virus particles. New virus particles are thought to bud into the secretory pathway and are released at the cell surface.
  • compositions, uses, kits, and methods of treatment which allow treatment of retroviral, particularly HIV infections and/or viral hepatitis infections, in particular of Hepatitis C Virus (HC V) infections.
  • retroviral particularly HIV infections and/or viral hepatitis infections, in particular of Hepatitis C Virus (HC V) infections.
  • HC V Hepatitis C Virus
  • the invention relates to a semicarbazone proteasome inhibitor for use in the treatment of hepatitis virus-infected individuals and/or retrovirally, e.g. HIV-infected individuals.
  • the semicarbazone proteasome inhibitor is used for treatment of hepatitis virus infected individuals are infected with Hepatitis C Virus (HCV).
  • HCV Hepatitis C Virus
  • the semicarbazone proteasome inhibitor for use in the treatment of hepatitis virus-infected individuals and/or retrovirally, e.g.
  • HIV-infected individuals is selected from [l-[l- ⁇ l-[(2,4-Dioxo-imidazolidin-l- ylimino)-methyl] -2-phenyl-ethylcarbamoyl ⁇ -2-( 1 H-indo 1-3 -yl)-ethylcarbamoyl] -2- (lH-indol)], pharmaceutically acceptable salts thereof, or structural and/or functional analogues thereof.
  • the invention pertains to the use of semicarbazone proteasome inhibitors such as [l-[l- ⁇ l-[(2,4-Dioxo-imidazolidin-l-ylimino)- methyl] -2-phenyl-ethylcarbamoyl ⁇ -2-( 1 H-indo 1-3 -yl)-ethylcarbamoyl] -2-( 1 H- indol)], pharmaceutically acceptable salts thereof, or structural and/or functional analogues thereof as the sole pharmaceutical agent in the therapy for hepatitis virus infections, such as infections by HCV, or in the treatment and/or prevention of HIV infections, within a given defined treatment period.
  • semicarbazone proteasome inhibitors such as [l-[l- ⁇ l-[(2,4-Dioxo-imidazolidin-l-ylimino)- methyl] -2-phenyl-ethylcarbamoyl ⁇ -2-( 1 H-in
  • Such a defined treatment period may last for about 1 to 48 weeks or longer, e.g. for about 1 week to 12 months, 1 week to 1 week to 9 months, 1 week to 8 months, 1 week to 7 months, 1 week to 6 months, 1 week to 5 months, or for about 2 to 4 weeks, 2 to 6 weeks, 1 to 2 months, 1 to 3 months, 1 to 4 months, etc..
  • the duration of the treatment period depends on the medical practitioner's decision.
  • the semicarbazone proteasome inhibitor in the treatment of HCV is intended for use in treating HCV-infected individuals selected from the following groups of patients: (i) patients not refractory to interferon and/or ribavirin;
  • cardiovascular or a cerebrovascular disease cardiovascular or a cerebrovascular disease.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a semicarbazone proteasome inhibitor for use in the treatment of retrovirally, particularly HIV infected patients, and/or hepatitis virus infected individuals, e.g. HCV infected individuals, wherein said semicarbazone proteasome inhibitor is selected from [l-[l- ⁇ l-[(2,4-Dioxo-imidazolidin-l-ylimino)-methyl]-2- phenyl-ethylcarbamoyl ⁇ -2-(lH-indol-3-yl)-ethylcarbamoyl]-2-(lH-indol)], pharmaceutically acceptable salts or structural and/or functional analogues.
  • the present invention also relates to a kit comprising the semicarbazone proteasome inhibitor as defined herein or a pharmaceutical composition comprising the same for use in the treatment of retrovirally, e.g. HIV-infected and/or hepatitis- virus-infected individuals, particularly HCV-infected, individuals.
  • retrovirally e.g. HIV-infected and/or hepatitis- virus-infected individuals, particularly HCV-infected, individuals.
  • Yet other embodiments of the invention relate to the uses in methods of treating human or animal individuals infected with retrovirus, e.g. HIV and/or hepatitis viruses, e.g. HCV, with at least one semicarbazone proteasome inhibitor, and optionally concomitantly with or subsequently or previously to said treatment herewith, with a pharmaceutical composition comprising at least one retrovirus, e.g. HIV and/or hepatitis viruses, e.g. HCV, with at least one semicarbazone proteasome inhibitor, and optionally concomitantly with or subsequently or previously to said treatment herewith, with a pharmaceutical composition comprising at least one
  • pharmaceutically active agent in use againt retroviral infection e.g. HIV infection
  • at least one pharmaceutically active agent in use against hepatitis virus infection e.g. HCV infection
  • the methods of treatment in accordance with the invention are practiced on human or animal individuals which are in need of such treatment. These may be individuals suffering from HIV infections [or infections with other retroviruses] and/or a hepatitis viral infections. Specifically, said hepatitis virus infection is a HCV infection.
  • the viral hepatitis infection is preferably a Hepatitis C Virus (HCV) infection.
  • HCV Hepatitis C Virus
  • HBV Hepatitis B Virus
  • viral hepatitis refers to hepatitis induced by viral infections. Such viral infections may be infections with one or more viruses that may infect hepatic cells, such as, for example, without limitation, Hepatitis Virus A, B, C, D, E and G.
  • the hepatitis may be induced by an infection with a virus which may infect and potentially damage the liver as part of a more generalized infection, such as, for example, without limitation, certain Retro-, Herpes, Adeno-, Entero-,
  • the hepatitis may be induced by infection with one or more viruses chosen from the group of: Herpes Simplex Virus, HIV, Cytomegalovirus, Epstein- Barr virus, yellow fever virus, mumps virus, rubella virus.
  • viruses chosen from the group of: Herpes Simplex Virus, HIV, Cytomegalovirus, Epstein- Barr virus, yellow fever virus, mumps virus, rubella virus.
  • the treatment of a viral hepatitis caused by HCV infection is preferred in the context of the present invention.
  • pharmaceutically active agent in use against viral hepatitis infections refers to a pharmaceutically active compound for which the art recognizes that it can be used for treatment of viral hepatitis infections, for example for the treatment of HCV infections.
  • pharmaceutically active agents as they are authorized by regulatory agencies such as the FDA or the European
  • EMA Medicines Agency
  • the term for the purposes of the present invention may not refer to proteasome inhibitors. Recognition in the art of a pharmaceutically active compound as useful for hepatitis treatment may have occurred at the time the instant invention was made, but nothing herein shall be construed as limiting the instant invention to such compounds.
  • Pharmaceutically active compounds, which are characterized as useful for the therapy of viral hepatitis at a later date, are well within the scope of the instant invention, and are expressly included.
  • the terms "retroviral” or “retrovirus” relate to enveloped viruses belonging to the family Retroviridae.
  • This family comprises RNA viruses having a positive-mRNA- stranded RNA genome which is reverse transcribed and replicated in a host cell via the enzyme reverse transcriptase (RT) to produce DNA from its RNA genome.
  • the DNA is incorporated as a so-called "provirus” into the host's genome by the viral integrase enzyme.
  • the Retroviridae family comprises such important members as HIV, HTLV, Xenotropic murine leukemia virus-related virus (XMRV), FIV, SIV etc.
  • an important aspect relates to the treatment of human immunodeficiency virus, i.e. HIV, which encompasses at least two types of HIV, e.g. HIV-1 and HIV-2.
  • HIV-1 is the dominant type in the Western World, and certain examples provided herein use viruses of this type, the scope of the instant invention shall not be understood as limited to HIV-1, and preferably includes not just types of HI viruses presently known, but also further types which may arise or be characterized and/or typified in the future.
  • pharmaceutically active agent in use against retroviral infections refers to a pharmaceutically active compound for which the art recognizes that it can be used for treatment of retroviral infections, preferably for the treatment of HIV infections.
  • the term relates to pharmaceutically active agents as they are authorized by regulatory agencies such as the FDA or the EMA for treating retroviral infections, in particular HIV infections.
  • the term for the purposes of the present invention may not refer to proteasome inhibitors. Recognition in the art of a pharmaceutically active compound as useful for the treatment of retrovirus infection may have occurred at the time the instant invention was made, but nothing herein shall be construed as limiting the instant invention to such compounds.
  • Pharmaceutically active compounds, which are characterized as useful for the therapy of retroviral infections at a later date are well within the scope of the instant invention, and are expressly included.
  • retroviral disease refers to diseases or conditions caused by an infection with a retrovirus.
  • HIV-related disease refers to diseases and conditions including those which are commonly attributed to, or are causally related to, infection with a Human Immunodeficiency Virus, and specifically may include, without limitation, Acquired Immuno-Deficiency Syndrome (AIDS), and all diseases and conditions commonly referred to thereunder, and/or the condition of infection with a Human Immunodeficiency Virus, including in the absence of any overt symptoms of disease or discomfort directly or indirectly linked thereto, and furthermore including before the presence of the virus may be detected with certain diagnostics test as customary for this indication.
  • AIDS Acquired Immuno-Deficiency Syndrome
  • HIV-related disease will preferably not refer to diseases and conditions ultimately brought about by HIV infection through the associated Immunodficiency, but which, by their nature, cannot be alleviated or cured by removing or eradicating the virus alone, e.g. certain malignancies which often occur in HIV-posistive or AIDS patients, e.g. Karposi Sarcoma.
  • standard therapy for HIV infection shall mean a therapy of an HIV infection following the recommendations summarized in "Guidelines for the Use of Antiretro viral Agents in HIV- 1 -Infected Adults and Adolescents" (Panel on
  • administering or "administration of, a compound or agent, e.g. an anti-retroviral compound or a proteasome inhibitor, as used herein, shall be interpreted as equivalent to "administering a pharmaceutical composition comprising” or
  • proteasome inhibitor refers to a compound which is capable of inhibiting, reversibly or irreversibly, the proteasome-mediated degradation of ubiquitin- modified peptides and proteins.
  • Proteasome inhibitors encompass semicarbazone proteasome inhibitors that are used according to the invention as detailed below. In specific embodiments of the invention other non-semicarbazone proteasome inhibitors may be used in addition to the semicarbazone inhibitor.
  • semiconductorarbazone proteasome inhibitor refers particularly to [ 1 -[ 1 - ⁇ 1 -[(2,4-Dioxo-imidazolidin- 1 -ylimino)-methyl]-2-phenyl- ethylcarbamoyl ⁇ -2-(lH-indol-3-yl)-ethylcarbamoyl]-2-(lH-indol)], also referred to as S-2209, pharmaceutically acceptable salts, as well as structural and/or functional analogs thereof.
  • Zl is (CH 2 ) t R 2 ;
  • Z 2 is (CH 2 ) t -R 3 ;
  • Z 3 is (CH 2 ) t -R 4 ;
  • Z 4 is H, or methyl;
  • R 2 , R 3 , R 4 are independently from each other H, Phenyl, Benzyl, 3-Benzothienyl, 2- Thienyl, 2-Thiazolyl, 4-Pyridyl, 3-Pyridyl, 2-Pyridyl, 2-Quinolyl, 2-Indolyl, 3- Indolyl, Ethylbenzene, 2-Naphtyl, 1-Naphtyl, p-Aminobenzyl, p-Azidobenzyl, p- Bromobenzyl, p-Hydroxyphenyl, p-tButyl-benzyl, p-Carboxybenzyl, p-Chloro- benzyl, p-Cyanobenzyl, 3,4-Dichlorobenzyl, p-Fluorobenzyl, p-Iodobenzyl, p- Nitrobenzyl, Pentafluorobenzyl,
  • R 2 , R 3 , R 4 are independently of each other H, benzyl,or indolyl optionally substituted by halogen.
  • “Inhibition of proteasome activity” as the term is used herein, shall mean the reduction of proteasome activity inside or outside a cell by at least 20%>, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 98% or at least 99% compared to the situation where no compound or a compound which is known to not affect proteasome activity is administered.
  • the proteasome that is inhibited by a proteasome inhibitor referred to herein thus has a residual activity of not more than about 80%, more particularly not more than about 75%, yet more particularly not more than about 70%, yet more particularly not more than about 65%, yet more particularly not more than about 60%, yet more particularly not more than about 55%, yet more particularly not more than about 50%, yet more particularly not more than about 45%, yet more particularly not more than about 40%, yet more particularly not more than about 35%, yet more particularly not more than about 30%, yet more particularly not more than about 20%, yet more particularly not more than about 5 to 15%, and particularly not more than about 10% residual activity.
  • the inventive proteasome inhibitors may inhibit the activity of the proteasome in a relevant cell, for example a cell in vitro that is a model for the cell type desired to be impacted by the proteasome inhibitory activity in vivo, by only a limited amount, e.g. by not more than about 20%, not more than about 25%, not more than about 30%, not more than about 35%, not more than about 40%, not more than about 45%, not more than about 50%, not more than about 55%, not more than about 60%, not more than about 70%, or not more than about 75%.
  • the proteasome inhibitor inhibits one or more of the catalytic activities of the 26-S proteasome, and more preferably one or more of the postglutamyl-peptide-hydrolyzing (caspase-like, Bl-subunit), trypsin- like (B2 subunit), and/or chymotrypsin-like (B5 subunit) catalytic activities. Yet more specifically, the proteasome inhibitor inhibits all three, yet more specifically not more than two, and most particularly only one of these 26-S proteasome catalytic activities. In another specific embodiment, the proteasome inhibitor inhibits at least two of these 26-S proteasome catalytic activities.
  • the proteasome inhibitor may inhibit at least one activity of the proteasome, but may actually activate another of the 26-S proteasome catalytic activities. In yet another specific embodiment, the proteasome inhibitor does not activate any of the 26-S proteasome catalytic activities.
  • the inhibitory activity is observed at nanomolar concentrations in cell culture in vitro, e.g. at concentrations ranging between 1 nM and 1 ⁇ , or 10 nM to 1 ⁇ , or 100 nM to 1 ⁇ , or 1 nM to 100 nM, or 1 nM to 10 nM, or 10 nM to 100 nM, or 1 nM to 10 ⁇ , or 10 nM to 10 ⁇ , or lOO nM to 10 ⁇ , or 1 ⁇ to 10 ⁇ .
  • the inhibitory activity on the proteasome of a candidate proteasome inhibitor may be assessed by, for example, the assay described in Adams, J., et al, Cancer Research 1999, 59:2615, or the commercially available Proteasome GloTM Assay (Promega Corp. Madison WI, USA). These assays may be used to determine an IC 50 for the candidate proteasome inhibitor respective the one or more proteasome catalytic activities; any other suitable assay may then be used to determine an IC 50 for the candidate proteasome inhibitor respective another relevant activity in question; and these IC 50 values may hence be compared to obtain a measure of the specificity of the inhibitory activity of the candidate proteasome inhibitor. Further methods of testing the inhibitory activity of S-2209 and the like are disclosed in Baumann et al., Brit. J. Haematology 144: 875-886, 2009.
  • proteasome inhibitors include, without limitation: naturally-occurring proteasome inhibitors e.g. epoxomicine, eponemicin, aclacinomycin A (also known as aclarubicin), lactacystin and its modified variants, e.g. clasto-lactacystin ⁇ -lactone);
  • naturally-occurring proteasome inhibitors e.g. epoxomicine, eponemicin, aclacinomycin A (also known as aclarubicin), lactacystin and its modified variants, e.g. clasto-lactacystin ⁇ -lactone
  • proteasome inhibitors e.g. modified peptide aldehydes, such as N-carbobenzoxy-L-leucinyl-L-leucinyl-l-leucinal, sometimes referred to as MG132 or zLLL, its boronic acid derivative MG232, N-carbobenzoxy-Leu-Leu-Nva-H, sometimes referred to as
  • N-acetyl-L-leuzinyl-L-leuzinyl-L-norleuzinal sometimes referred to as LLnL
  • N-carbobenzoxy-Ile-Glu(Obut)-Ala-Leu-H sometimes referred to as PSI
  • synthetic peptides that carry at their C-terminal end an ⁇ , ⁇ - epoxyketone group vinyl- sulphone group,e.g.
  • benzyloxycarbonyl(CbZ)-Leu-Leu-boroLeu-pinacol-ester and chemically modified derivatives of naturally occurring proteasome inhibitors, such as the ⁇ -lacton derivative PS-519 (1R-[1S, 4R, 5S]]-l-(l-hydroxy-2-methylpropyl)- 4-propyl-6-oxa-2-azabicyclo[3.2.0]heptanes-3,7-dione, (molecular formula: C12H19NO4), a derivative of lactacystine;
  • dipeptidyl-boronic acid derivatives such as PS-341 (N-(2,3- pyrazine)carbonyl-L-Phenylalanine-L-leucine-boronic acid, molecular formula: C19H25BN4O4).
  • suitable proteasome inhibitors that may be used in addition to the semicarbazone proteasome inhibitor thus include PS-341, also commonly known as Bortezomib, and the active ingredient in the pharmaceutical preparation sold under the trade name Velcade ® , in use for the treatment of multiple myeloma; "PS-273” (Morpholin-CONH-(CH-napthyl)-CONH-(CH-isobutyl)- B(OH) 2 and its enantiomer "PS-293", “PS-296” (8-quinolyl-sulfonyl-CONH-(CH- napthyl)-CONH(-CH-isobutyl)-B(OH) 2 ); "PS-303” (NH 2 (CH-Napthyl)-CONH-(CH- isobutyl)-B(OH) 2 );”PS-321 " (morpholino-CONH-(CH-napthyl)-CONH-(CH- phen
  • proteasome inhibitors include (Groll, M., et al, J. Pept. Sci. 2009, 15:58): the aldehydes calpain inhibitor I, Mal- -Ala-Val-Arg-al and fellutamide B (Hines J., et al, Chem. Biol.2008, 15:501), syringolin A (Groll M, et al, J. Am. Chem. Soc.
  • glidobactin A members of the new class of Syrbactins
  • the vinyl sulfone peptide Ac-Pro-Arg-Leu-Asn-vs the analogue of epoxomocin carfilzomib, also known as PR-171 (Demo, SD., Cancer Res. 2007, 67:6383); the TMC-95 family of cyclic tripeptides from Apiospora todayi
  • proteasome inhibitors include (Huang, L., Chen, CH, Current Medicinal Chemistry, 2009, 16:931): CEP1612, a dipeptide aldehyde proteasome inhibitor that is highly selective for the chymotrypsin-like proteolytic activity of the proteasome; ZLVS (ZLLL-vs) and YLVS (YLLL-vs), further examples of vinyl sulfones (herein, -vs is used as shorthand for a vinyl sulfone group); MG-262, a boronate analog of MG132, which exhibits a 100-fold increase in anti-proteasome activity compared to its parent compound; Tyropeptin A, a tripeptide aldehyde natural product isolated from Kitasatospora sp.
  • MK993-dF2 preferentially inhibiting the chymotrypsin-like proteasome activity by binding to the ⁇ 5 subunit of the proteasome
  • Peptide epoxyketones isolated from various microbials, are small peptides with a ketone epoxide functional group; for example, epoxomycin was derived from Streptomyces hygroscopicus (Hanada, M., et al, J. Antibiot.
  • TMC-86 and TMC-89 were isolated from Streptomyces sp. [Koguchi, Y., et al, J. Antibiot. (Tokyo) 2000, 53:63; Koguchi, Y, et al, J. Antibiot.
  • Carfilzomib an epoxyketone peptide structurally related to epoxomicin, is in Phase 2 clinical trials for patients with relapsed solid tumors including non- small cell lung cancer, small cell lung cancer, ovarian cancer, and renal cancer (Kuhn, DJ, et al, Blood 2007, 110:3281); it is also in a phase 2 single-agent trial for patients with multiple myeloma and in a phase 1 study for lymphoma patients; some peptide epoxyketone derivatives, such as dihydroeponemycin analogs, were shown to preferentially target the immunoproteasome (Ho, Y.K., et al, Chem. Biol. 2007,
  • PR39 is a naturally occurring antibacterial peptide containing 39 amino acid residues isolated from pig intestine, and was shown to inhibit the proteasome; unlike small tripeptide proteasome inhibitors that bind to the proteolytic active site located at ⁇ 5 subunit, PR39 binds to the nonproteolytic ⁇ 7 subunit of the 20S proteasome.
  • PR11 first 11 residues of PR39 sequence: RRRPRPPYLPR
  • PR11 and PR39 exhibit similar activity to that of PR39
  • Inhibition of the proteasome by PR11 and PR39 results in accumulation of ⁇ , a factor that regulates the NF-KB-dependent gene expression pathways
  • natural products derived from plant sources such as celastrol, isolated from the traditional herbal medicine "Thunder-god vine", and withaferin A, isolated from Indian winter cherry, which were shown to inhibit the proteasome at low micro molar concentrations (Celastrol is a triterpene and withaferin A is structurally related to steroids);
  • Gliotoxin a fungal metabolite structurally related to the epipolythiodioxo- piperazines; green tea polyphenolic catechins such as (-)- epigallocatechin- 3-gallate ⁇ (-)-EGCG ⁇ and its analogs have been widely studied for their possible benefits in cancer prevention; EGCG was reported to potently inhibit the chy
  • GLA glycyrrhetinic acid
  • proteasome inhibitors may include: NEOSH-101, also known as OSH-101, a tetrapeptide aldehyde in clinical trials for androgenetic alopecia; CEP- Structure of (1 ), PR-047
  • a P2 threonine boronic acid derivative under development for, e.g., multiple myeloma; IPSIOOl, IPSI007, as well as MLN2238 and its prodrug MLN9708, under development for indications in oncology by Millennium Pharmaceuticals/Takeda; ONX 0912 (formerly PR-047 (1) by Proteolix, Inc.; Peese, K., Drug Discovery
  • AVR-147 a development candidate by Advanced Viral Research, Corp., in oncology
  • BU-32 pyrazy 1-2,5 -bis- CONH(CHPhe)CONH(CHisobutyl)-B(OH) 2 , NSC D750499-S
  • 4E12 a non-peptidyl small molecule proteasome inhibitor identified by Telik, Inc., and intended for development in oncology
  • Compound 13 and Compound 20 Purandare, AS, et al, Am. Assoc. Cancer Res. Annual Meeting 2007, 98 th : April 15, Abs.
  • proteasome inhibitors having high activity (low nM IC 50 values) as well as high specificity (>100 fold selective against chymotrypsin, trypsin, elastase and Factors Xa, Xia and Vila).
  • suitable proteasome inhibitors may include: ALLnL, ALLnM; LLnV; DFLB (dansyl-Phe-Leu-boronate); Ada-(Ahx) 3 -(Leu) 3 -vs; YU101 (Ac-hFLFL-ex), MLN519.
  • Proteasome inhibitors may thus include di-, tri,- tetra-, penta-, hexa-, hepta-, octa-, nona-peptide aldehydes or peptide aldehydes having ten or more amino acids such as 15, 20, 30, 40 or more amino acids.
  • Such di-, tri,- tetra-, penta-, hexa-, hepta-, octa-, nona-peptide aldehydes or peptide aldehydes having ten or more amino acids may carry at their C-terminus and a,B- epoxyketone functionality, a vinyl- sulphone functionality, a glyoxal functionality, a boronic acid functionality, pinacol ester functionality or other functionalities.
  • Such di-, tri,- tetra-, penta-, hexa-, hepta-, octa-, nona-peptide aldehydes or peptide aldehydes having ten or more amino acids may comprise natural or non-natural amino acids.
  • Such di-, tri,- tetra-, penta-, hexa-, hepta-, octa-, nona-peptide aldehydes or peptide aldehydes having ten or more amino acids may also be chemically modified by hydrogenation, dehydrogenation, hydroxylation, dehydroxylation, acylation, deacylation, alkylation, dealkylation, pegylation, hesylation, glycosylation and the like.
  • Such di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-peptide aldehydes or peptide aldehydes having ten or more amino acids and which optionally may carry ⁇ , ⁇ - epoxyketone functionality, a vinyl- sulphone functionality, a glyoxal functionality, a boronic acid functionality, pinacol ester functionality or other functionalities at their C-terminus may also may comprise natural or non-natural amino acids.
  • Such di-, tri,- tetra-, penta-, hexa-, hepta-, octa-, nona-peptide aldehydes or peptide aldehydes having ten or more amino acids and which optionally may carry ⁇ , ⁇ - epoxyketone functionality, a vinyl- sulphone functionality, a glyoxal functionality, a boronic acid functionality, pinacol ester functionality or other functionalities at their C-terminus may also be further chemically modified by hydrogenation,
  • Such di-, tri,- tetra-, penta-, hexa-, hepta-, octa-, nona-peptide aldehydes or peptide aldehydes having ten or more amino acids and which optionally may carry ⁇ , ⁇ - epoxyketone functionality, a vinyl- sulphone functionality, a glyoxal functionality, a boronic acid functionality, pinacol ester functionality or other functionalities at their C-terminus may also be further chemically modified by hydrogenation,
  • dehydrogenation hydroxylation, dehydroxylation, acylation, deacylation, halogenations, alkylation, dealkylation, pegylation, hesylation, glycosylation and the like may comprise natural or non-natural amino acids.
  • proteasome inhibitors act on one or more of the postglutamyl-peptide- hydro lyzing (caspase-like, Bl -subunit), trypsin- like (B2 subunit), and/or
  • proteasome inhibitors may not only inhibit the proteasome as described above, but also further cellular proteases.
  • a subgroup of proteasome inhibitors which can be particularly suitable for the pharmaceutical compositions, the kits, the uses and the methods as described herein, comprises so called specific proteasome inhibitors.
  • Specific proteasome inhibitor or “specific inhibition” of an activity of the proteasome by an inhibitor, herein shall mean that the inhibitor reduces the said activity by 50% at a concentration (termed IC50 or IC 50 ) that is lower by at least a factor of 1/2, 1/3, 1/5, 1/10, 1/20, 1/50, 10 "2 , 5 x 10 "3 , 2 x 10 "3 , 10 "3 , or less, than the IC 50 of that same inhibitor for the inhibition of another, or many other, or, specifically, any other relevant activity in question, e.g. a proteolytic activity not associated with the proteasome.
  • a specific proteasome inhibitor may be at least twice as potent with respect to the inhibition of any one, or more, of the 26S proteasome catalytic activities than with respect to the inhibition of non-proteasomal cellular proteases or microorganism derived proteases, e.g., a lysosomal protease or an HIV protease, or at least three times as potent, or at least five times as potent, etc.
  • Such specific proteasome inhibitors include, without limitation, the proteasome inhibitors PS-519, PS-341 (Bortezomib) and PS-273. These proteasome inhibitors are potent, specific for the proteasome and substantially do not block other cellular proteases.
  • proteasome inhibitors PS-341 and PS-519 have moreover been tested pre-clinically in animal models and in humans for clinical studies (cancer patients).
  • Pharmaceutically active agents in use against viral hepatitis infections may be broadly classified in two categories.
  • Pharmaceutically active agents in use against viral hepatitis infections of the first category support or assist the body's natural response in dealing with viral infections.
  • Pharmaceutically active agents of the second category will interfere with the function of a viral target, such as a virus- specific protease or polymerase.
  • such pharmaceutically active agents of the first category which will be administered in addition to semicarbazone proteasome inhibitors and preferably in addition to S-2209 include, without intent to limitation, cytokines, such as interferons and their derivatives, and interleukins, preferably IL-1, IL-2, IL-6, IL-8, IL-12, IL- 15, IL-18, IL-21, and IL-2, inhibitors of viral enzymes, e.g. protease inhibitors e.g.
  • telaprevir telaprevir
  • boceprevir ITNM-191, SCH 900518, TMC435, BI201335 and MK-7009
  • nucleoside analoga nucleotide analoga and non-nucleoside analogous inhibitors of viral enzymes which may, for example, inhibit a viral polymerase and/or a viral protease, steroids, thymosin alpha 1, vaccines including vaccines allowing for passive and active vaccination, therapeutic and prophylactic vaccination,
  • glycyrrhizin immunomodulators, e.g. Thymosin, ME3738, SCV-07, Alinia, Oglufavide, IPH-1101, CYT 107, or EGS-21, and/or immunosuppressants and/or inhibitors of assisted protein folding, e.g. ciclosporin and derivatives thereof, e.g. SCY-635, DEBIO-025, NIM811, Silibinin, Nitazoxanide, A-831, KPE02001003, TCM700C, PYN-17, BIT225, JTK-652, BMS-791325, amantadine or rimantadine and derivatives thereof, and azathoprine.
  • immunomodulators e.g. Thymosin, ME3738, SCV-07, Alinia, Oglufavide, IPH-1101, CYT 107, or EGS-21
  • immunosuppressants and/or inhibitors of assisted protein folding e.g. cicl
  • Pharmaceutically active agents which support or assist the body's natural response in dealing with viral infections will specifically, and in some embodiments exclusively, be used for viral hepatitis infections.
  • Such agents may comprise interferons, interleukins, steroids, immunomodulators, immunosuppressants and inhibitors of assisted protein folding.
  • interferons are one option for pharmaceutically active agents which support or assist the body's natural response in dealing with viral infections.
  • interferon refers to the various forms of interferons including their derivatives.
  • interferon alpha- 1, alpha-2, beta, gamma, delta, lambda and omega as well as the glycosylated, pegylated and hesylated forms thereof, and other forms wherein the interferon is fused or otherwise conjugated to another moiety conveying desirable properties to the overall molecule, e.g.
  • albinterferon a fusion polypeptide of interferon with albumin, PEG-IFN alpha-2a, alpha-2b or lambda, Locteron, Omega IFN, Medusa IFN, DA-3021, EMZ702, Infradure, IL-29, Amarillo, Soluferon and Belerofon (see e.g. Thompson, A., et al, J. Hepatology , 50: 184 (2009)).
  • Albinterferon is a genetic fusion polypeptide of albumin and interferon alpha-2b with a longer half life than pegylated interferons.
  • ACHIEVE- 1 and ACHIEVE-2 were designed to demonstrate non- inferiority of the albinterferon alpha-2b regimes compared with PEG-interferon alpha-2a. Both studies achieved the primary objective.
  • Locteron is a controlled-release interferon alpha-2b which is injected every 2 weeks. In a short term study controlled release interferon alpha-2b showed less flu-like symptoms than PEG-interferon alpha-2b injected every week indicating that the controlled-release formulation may have a better tolerability.
  • PEG-interferon lambda is a pegylated type III interferon that binds to a unique receptor with more limited distribution than the type I interferon receptor.
  • PEG-interferon lambda is currently investigated in combination with ribavirin.
  • interferon varieties under development for hepatitis treatment include Omega IFN, Medusa IFN, DA-3021, EMZ702, Infradure, IL-29, Amarillo, and Belerofon. Also envisaged is Soluferon.
  • PEG-interferon-alpha pegylated interferon alpha
  • This may be PEG-interferon-alpha 2a or 2b.
  • Pharmaceutically active agents of the second category which interfere with the function of a viral target may be agents that inhibit viral enzymes such as, for example, a virus-specific protease or polymerase or virus envelope protein. In case of HCV infections this may be inhibitors of e.g. the HCV NS3/4A protease and/or the HCV NS5B polymerase.
  • Nucleoside analoga, nucleotide analoga and non-nucleoside analogous inhibitors of viral enzymes include lamivudine, cidovir, ribavarin, viramidine, didanosine, vidarabine, cytarabine, emtricitabine, zalcitabine, abacavir, stavudine, zidovudine, idoxuridine, trifhiridine, valopiticabine, R1626, R7128, IDX184, HCV-796, Filibuvir (PF 00868554), VCH-916, ANA598, BI 207127, VCH-222 PSI- 6130, ANA773, MK-3281, ABT-072, ABT-333, R1728, VCH-759, GS9190, BMS-650032, BE- 868554.
  • the nucleoside analogon ribavirin is particularly preferred.
  • the structure identification of the NS3/4A protease and the HCV NS5B polymerase and the development of a (sub) genomic replicon system have enabled the development and testing of HCV specific compounds.
  • Further attractive targets within the HCV genome for antiviral therapy are the envelope proteins which are involved in HCV entry and NS5A which is involved in replication and in interferon alpha resistance.
  • the clinical development of NS3/4A protease inhibitors is currently most advanced.
  • the NS3/4A protease has key functions in the hepatitis C virus replication cycle.
  • NS3/NS4A cleaves at four downstream sites in the polyprotein to generate the N- termini of the NS4A, NS4B, NS5A, and NS5B proteins.
  • the NS3/4A serine protease has also been shown to cleave and inactivate the host proteins Trif and Cardif. Both proteins have important roles in the interferon response mediated by TLR3 and RIG-I, respectively.
  • NS3 is not only a protease but also an integral part of the viral RNA replication complex, functions as a RNA helicase and a nucleotide triphosphatase (NTPase). Due to the multiple functions, NS3 is an attractive target for anti-HCV therapy.
  • protease inhibitors were investigated in clinical trials. Monotherapy with protease inhibitors ciluprevir, telaprevir and boceprevir was shown to be effective in lowering the viral load. Clinical evaluation of telaprevir and boceprevir is most advanced. Both protease inhibitors showed a rapid occurrence of drug resistant HCV strains within 2 weeks of therapy indicating that protease monotherapy is not sufficient for treatment of patients with chronic hepatitis C.
  • telaprevir The peptidomimetic inhibitor of the NS3/4A serine protease telaprevir showed a 3 log 10 IU/mL decline of HCV RNA during the first 2 days of monotherapy in patients infected with HCV genotype 1 and previous non response to interferon based antiviral treatment.
  • telaprevir is one of the first STAT-C compound for which sustained virologic response rates have been reported for the combination therapy with PEG-interferon alpha-2a and ribavirin.
  • triple therapy was given for 12 weeks.
  • the sustained virologic response rates in PROVE 1 and PROVE2 were 67% and 69% in patients treated with PEG- interferon alpha-2a/ribavirin/ telaprevir for 12 weeks followed by PEG- interferon/ribavirin for 36 or 12 weeks, respectively.
  • the sustained virologic response rates in these telaprevir arms were significantly higher compared with the sustained virologic response rates in the standard of care control arms (41% and 46% in PROVE 1 and PROVE2 respectively).
  • the PROVE-studies confirm that protease inhibitors are able to increase sustained virologic response rates in patients with HCV genotype 1 infection. Furthermore, the PROVE2 study indicates that by addition of telaprevir to standard therapy higher sustained virologic response rates can be achieved with shorter treatment duration.
  • the results of the PROVE2- trial provide evidence that ribavirin has additive antiviral activity to telaprevir and PEG-interferon alpha-2a.
  • Boceprevir another NS3/4A serine protease inhibitor, binds reversibly to the NS3 protease active site and has potent activity in the Replicon system alone and in combination with interferon alpha-2b. Recently, the final results of the HCV
  • ITNM-191 SCH 900518, TMC435, BI201335 and MK-7009 are novel NS3/4A protease inhibitors currently in clinical trials.
  • ITMN-191 is a potent HCV NS3/4A protease inhibitor that achieves high liver concentrations following oral
  • ITNM-191 in combination with PEG-interferon alpha-2a/ribavirin showed a stronger decline of HCV RNA compared with PEG-interferon alpha- 2a/ribavirin standard of care after two weeks of treatment (4.7-5.7 loglO IU/mL vs 2.0 loglO IU/mL). After 2 weeks, 13-57% of patients in the triple therapy arm while no patient in the standard of care arm showed undetectable HCV RNA.
  • SCH-900518 with and without ritonavir boostering showed robust reductions in HCV RNA levels in both treatment-experienced and naive HCV genotype 1 -infected patients (4.01 loglO IU/mL and 4.5 loglO IU/mL vs 0.09-0.19 loglO IU/mL after 8 days in patients treated with SCH 900518 400 mg twice/day plus PEG-interferon alpha-2a/ribavirin plus ritonavir 100 mg/d and SCH 900518 800 mg thrice/day plus PEG-interferon alpha-2a/ribavirin, respectively, vs. patients receiving PEG- interferon alpha-2a/ribavirin alone).
  • TMC435 administered for 4 weeks in combination with PEG-interferon-alpha2a/ribavirin was well tolerated and demonstrated potent antiviral activity in HCV genotype 1 infected treatment- experienced patients (4.3-5.3 loglO IU/mL in the TMC435 arms vs 1.5 loglO IU/mL in the control arms).
  • BI 201335 was investigated as monotherapy for 14 days and in combination with PEG-interferon alpha-2a/ribavirin for 28 days in experienced patients and showed a median HCV R A decline of 3-4.2 loglO IU/mL in monotherapy and 4.8-5.3 loglO IU/ml in combination therapy.
  • MK-7009 is a noncovalent competitive inhibitor of HCV NS3/4A protease.
  • MK-7009 was administered for 28 days in combination with pegylated interferon-alpha/ribavirin.
  • the rapid virologic rate was higher in patients treated with triple therapy than in patients treated with standard of care (68.8-82.4% vs
  • nucleoside and non-nucleoside polymerase inhibitors Two classes of NS5B polymerase inhibitors, nucleoside and non-nucleoside polymerase inhibitors, have been developed. Nucleoside analogue polymerase inhibitors are converted into triphosphates by cellular kinases and incorporated into the elongating RNA strand as chain terminators. Generally, they show similar efficacy against all HCV genotypes. The mechanisms of action of non-nucleoside polymerase inhibitors are different from that of nucleoside polymerase inhibitors. Therefore, cross resistance between these two classes is unlikely to occur.
  • Several structurally distinct non-nucleoside inhibitors of the HCV RNA-dependent RNA- polymerase NS5B have been reported to date, including benzimidazole,
  • Valopicitabine was the first nucleoside analogue polymerase inhibitor tested in patients with chronic hepatitis C. Valopicitabine showed antiviral activity in monotherapy (mean HCV-RNA decline 0.15-1.21 loglO IU/mL after 14 days in patients infected with HCV genotype 1 and prior non response to interferon based antiviral treatment) and in combination therapy with interferon alpha (mean HCV- RNA decline 3.75-4.41 loglO IU/mL after 36 weeks in treatment na ' ive patients infected with HCV genotype 1).
  • the nucleoside analogue R1479 (4'-azidocytidine) is a potent inhibitor of NS5Bdependent RNA synthesis and hepatitis C virus replication in cell culture.
  • Rl 626 is a prodrug of Rl 479.
  • Rl 626 was investigated in treatment na ' ive patients with HCV genotype 1 infection in combination with PEG- interferon alpha-2a and ribavirin.
  • R1626 a prodrug of a cytidine analog, is a nucleoside inhibitor currently in phase 2 development. When used in combination with PEG-IFN and RBV for 4 weeks, the mean maximal viral load reduction from baseline was 5.2 loglO IU/mL.
  • R7128 is another nucleoside analogue NS5B polymerase inhibitor.
  • Non responders treated with R7128 1,500 mg twice daily showed a mean viral decline of 2.7 loglO IU/mL after 14 days of therapy.
  • R7128 is currently evaluated in combination with PEG- interferon alpha-2a and ribavirin in treatment naive patients with chronic
  • IDX184 is a liver-targeted nucleotide prodrug designed to enhance formation of its active triphosphate in the liver while minimizing systemic exposure of the parent drug and its nucleoside metabolite.
  • Oral administration of IDX184 to HCV-infected chimpanzees resulted in potent antiviral activity (mean HCV-RNA decline after 4 days 1.4 to 3.8 log 10 copies/mL). The antiviral activity was achieved with low systemic levels of the parent drug and its nucleoside metabolite.
  • HCV-796 is a non-nucleoside polymerase inhibitor that has demonstrated potent antiviral activity in vitro and in patients with chronic hepatitis C. Monotherapy showed a maximum antiviral effect after 4 days of treatment with a mean HCV RNA reduction of 1.4 loglO IU/ mL. The combination of HCV-796 and PEG-interferon alpha-2b produced a mean viral reduction of 3.3-3.5 loglO IU/mL after 14 days of treatment compared to 1.6 loglO IU/mL with PEG-interferon alpha-2b alone.
  • Filibuvir (PF 00868554) showed in monotherapy of patients with chronic HCV genotype 1 infection a dose-dependent inhibition of viral replication, with maximum reductions in HCV RNA ranging from 0.97 to 2.13 loglO IU/mL.
  • triple therapy with PEG-interferon alpha-2a and ribavirin was associated with a rapid viro logic response rate of 60-75% while no patient in the placebo arm achieved a rapid viro logic response.
  • VCH-916 showed a maximum HCV-RNA decline ranging between 0.2 and 2.5 loglO IU/mL within 14 days of treatment.
  • ANA598 showed a decline of HCVRNA after 3 days of monotherapy ranging between 0.4 and 3.4 loglO IU/mL.43 ANA598 was combined in vitro with interferon alpha, the HCV NS3/4 protease inhibitor telaprevir, the NS5B nucleoside polymerase inhibitor PSI- 6130, and the TLR7 agonist ANA773, respectively.
  • BI 207127 monotherapy showed an HCV-RNA decline after 5 days ranging between 0.6 and 3.1 loglO IU/ mL in patients with chronic hepatitis C genotype 1 infection. Similar to ANA598, no increase in HCV RNA levels was observed during short term BI 207127
  • MK-3281, ABT-072 and ABT-333 are additional nonnucleoside polymerase inhibitors in development. Further polymerase inhibitors under development for hepatitis treatment include
  • Chronic hepatitis C is characterized by a high turnover of infected cells and continuous de novo infection of target cells. Due to the vital role of de novo infection in maintenance of HCV infection, blocking of de novo infection is a potential target for antiviral therapy.
  • a target to block de novo infection is the HCV envelope protein E2.
  • a fully humanized monoclonal antibody to a linear epitope of HCV E2 glycoprotein MBL-HCV1 that neutralizes pseudoviruses from multiple HCV genotypes was developed. The antibody was shown to completely neutralize infectious HCV particles in cell culture. Three chimpanzees received a single dose of the Anti-E2 antibody intravenously before challenge with HCV la strain H77.
  • HCV RNA was detected in the serum of 250 mg/kg dosed chimpanzees through week 20 while the 0 mg/kg and 50 mg/kg dosed chimpanzees both became infected by day 14.
  • inhibitors of viral targets in the context of the present invention.
  • an inhibitor of an HCV protease together with inhibitors of HCV polymerase and/or an HCV envelope protein.
  • these agents may be additionally combined with e.g. active agents which support or assist the body's natural response in dealing with viral infections such as interferons, interleukins, steroids, immunomodulators, immunosuppressants and inhibitors of assisted protein folding.
  • the nucleoside polymerase inhibitor R7128 and the protease inhibitor ITNM-191 showed substantial antiviral activity in patients with chronic hepatitis C.
  • the INFORM- 1 trial is the first trial to investigate the combination of a nucleoside polymerase inhibitor and a protease inhibitor in patients with chronic hepatitis C. Both compounds have different resistance profiles and thus are good candidates for combination therapy. After 14 days of combination therapy (with yet lower doses for both compounds), a decline of HCV-RNA ranging between 2.9 and 5.0 to loglO IU/mL was observed. One patient had undetectable HCV-RNA. No viral rebound was observed.
  • cyclophilins are ubiquitous proteins in human cells that are involved in protein folding. Moreover, cyclophilins participate in HCV replication. It was shown that cyclophilin B binds to the HCV NS5B polymerase and stimulates its RNA-binding activity. Cyclophilin inhibitors show strong antiviral activity in vitro and in vivo. The cyclophilin inhibitor DEBIO-025 showed dual antiviral activity against HCV and HIV in a phase 1 trial with HCV/HIV co-infected patients.
  • DEBIO-025 was investigated in combination with PEG-interferon alpha-2a and ribavirin in HCV genotype 1 null responders to previous PEG-interferon/ribavirin combination therapy.
  • Triple combination therapy showed a HCV RNA decline after 29 days of 0.88-2.38 loglO IU/mL in the different dosing arms while no antiviral activity was observed in patients receiving DEBIO-025 monotherapy.
  • NIM811 is another oral non- immunosuppressive cyclophilin inhibitor which has in vitro activity against HCV.
  • NIM811 in combination with PEG- interferon alpha-2a showed a mean HCV RNA decline of 2.78 loglO IU/mL after 14 days compared with a 0.58 loglO decline of HCVRNA in the PEG-interferon alpha- 2a monotherapy arm.
  • SCY-635 is also a non-immunosuppressive analog of cyclosporine A that exhibits potent suppression of HCV RNA replication in vitro. SCY 635 binds to human cyclophilin A at nanomolar concentrations. Different doses of SCY-635 were investigated in patients infected with HCV genotype 1 and viral load above 100,000 IU/mL. Consistent decreases in plasma HCV RNA were observed in the highest dose group (mean nadir values were 2.20 log 10 IU/mL).
  • Oral silibinin is widely used for treatment of hepatitis C, but its efficacy is unclear. Intravenous silibinin was investigated in non-responders to prior interferon-based antiviral therapy and showed a significant decline in HCV RNA between 0.55 to 3.02 log 10 IU/mL after 7 days and a further decrease after additional 7 days in
  • intravenous silibinin was investigated as rescue treatment for patients with chronic hepatitis C who were still HCV-RNA positive after 24 weeks of treatment with PEG-interferon alpha-2a/ribavirin. After 24 weeks of treatment with standard of care the patients received additionally 20 mg/kg/d silibinin intravenously for 15 days. Thereafter PEG-interferon/ribavirin was continued. After 15 days of intravenous silibinin therapy HCV-RNA decreased in all patients and 7 out of 9 patients achieved undetectable HCV RNA plasma levels. After the end of silibinin administration patients were followed for at least 12 weeks. In one patient HCV-RNA increased to 100 IU/mL, and a second course of intravenous silibinin for 15 days was given. HCV-RNA became negative again and remained negative so far.
  • Nitazoxanide is a thiazolide anti- infective with activity against a number of protozoa, bacteria, and viruses. It is FDA approved for treatment of Cryptosporidium and giardia. Nitazoxanide inhibits replication of hepatitis C virus, hepatitis B virus, and rotavirus in vitro. Based on its broad antiviral activity, the mechanism of action is likely through cellular processes rather than specific anti- viral targets. Rossignol et al.
  • nitazoxanide in combination with PEG-interferon alpha-2a with or without ribavirin among treatment-naive hepatitis C patients infected with genotype 4 significantly improved viral response rates compared to the standard of care (PEG-interferon alpha-2a plus ribavirin).
  • the sustained virologic response rates were 79% and 64% in patients treated with PEG-interferon alpha- 2a/ribavirin/nitazoxanide and PEG-interferon alpha-2a/nitazoxanide, respectively, versus 45% in patients treated with PEG-interferon alpha-2a/ribavirin.
  • a patient which does not respond to viral hepatitis treatment, and in particular to HCV treatment may be designated as a ,, ⁇ -responder" or “therapy resistant” patient.
  • a response is understood to refer to a decrease of the virus load below the detection limit for at least 6 months after standard therapy has ceased ("sustained virological response", SVR).
  • SVR sustained virological response
  • the therapy usually is a combination of pegylated interferon alpha and ribavirin.
  • Non-responders are patients for which no decrease of virus load by a factor of least 2 log steps is observed during 24 weeks or for which up to week 24, HCV-RNA is still detectable during therapy.
  • the terms "therapy” and "treatment” can be used interchangeably.
  • a relapse refers to a complete virological response up until the 24th week of treatment at the latest. However, after the standard therapy has ceased, a renewed increase of virus load is observed (therapy refractory). Such patients are designated as “relapser” or “therapy refractory” patients.
  • the terms “therapy” and “treatment” can be used interchangeably.
  • a patient that is "resistant or refractory to therapy with at least one pharmaceutically active agent in use against viral hepatitis infection” is a patient that has undergone therapy with at least one pharmaceutically active agent in use against viral hepatitis infection, and preferably has undergone Standard of Care (SOC) therapy for his condition, but was either found resistant to such therapy, or who relapsed after such therapy.
  • SOC Standard of Care
  • the at least one pharmaceutically active agent in use against viral hepatitis infection to be used in the inventive methods, kits etc. for the treatment of such a patient may be the same as the one or several pharmaceutically active agents in use against viral hepatitis infection which he was found resistant or refractory to, or it, or they, may be different.
  • first different pharmaceutically active agent in use against viral hepatitis or a “second different pharmaceutically active agent in use against viral hepatitis”
  • these agents are meant to differ from each other and from the proteasome inhibitor, not from the agent that a patient has shown to be resistant or refractory to.
  • this term preferably relates to patients suffering from a hepatitis viral infection which are selected according to inclusion and exclusion criteria in accordance with the guidelines of the International Conference of Harmonization (ICH) as they are practiced e.g. by the Food and Drug Administration (FDA) or the European Medicines Agency (EMEA) for clinical trials being concerned with hepatitis viral infections.
  • Patients may thus be of Caucasian origin, of average weight, male or female and may be 20 to 60 years of age.
  • Common viral hepatitis infection treatment schedules include:
  • Hepatitis A dietary and lifestyle adjustments (no alcohol, reduced lipid intake) until the infection is cleared; these adjustments are usually considered to have a significant negative impact on quality of life by affected patients;
  • Acute Hepatitis B symptomatic treatment (bed rest, reduction of intake of agents causing hepatic stress), until symptoms abate; in severe cases, recovery is assisted by lamivudine treatment (typically 2 mg/kg body weight, twice daily);
  • Active chronic Hepatitis B administration of interferon-cc (typically 5-6 Mio. Units 3 times per week), Peg-Interferon alpha-2a (typically 180 ⁇ g once per week) Peg-Interferon alpha-2b (typically 50-100 ⁇ g once per week), lamivudin (typically 100 mg daily), entecavir (typically 0,5 mg to 1 mg once daily), telbivudin (typically 600 mg once daily), or adefovir (typically 10 mg to 30 mg once daily), for at least several months and up to several years; combination therapies do apparently not improve primary outcome, but are employed if and when resistance emerges;
  • Hepatitis C The standard of care (SOC) for patients with chronic hepatitis C is pegylated interferon alpha in combination with ribavirin (herein also referred to as "standard therapy" in the context of Hepatitis C treatment). Two pegylated interferons, alpha-2a (40 kD) and -2b (12 kD), are approved. The aim of antiviral therapy is the sustained elimination of the hepatitis C virus.
  • the HCV genotype is the most important predictive factor for treatment response of patients with chronic hepatitis C and has become an important decision criterion for treatment duration and ribavirin dosage.
  • the SOC treatment duration is 48 weeks and 24 weeks for patients infected with HCV genotype 1 and 2/3, respectively.
  • the SOC ribavirin dosage is 1,000- 1,200 mg and 800 mg for patients infected with HCV genotype 1 and 2/3, respectively.
  • the initial virologic response of patients with chronic hepatitis C shows large individual variation and can be classified into rapid virologic response (HCV undetectable after 4 weeks of therapy), complete early virologic response (HCV undetectable after 12 weeks of therapy), partial early virologic response (> 2 loglO decline of HCV RNA after 12 weeks of treatment but still HCV RNA positive), slow virologic response (> 2 log 10 decline of HCV RNA after 12 weeks of treatment but still HCV RNA positive followed by undetectable HCV RNA by week 24) and non-response (detectable HCV RNA 24 weeks after start of antiviral treatment).
  • HCV genotype 1 Patients infected with HCV genotype 1 who start with a low baseline viral load ( ⁇ 600.000 IU/mL) and who achieve a rapid virologic response were shown to have favorable sustained virologic response rates after 24 weeks of antiviral treatment indicating that a shorter treatment duration can be considered in this group of patients.
  • the possibility of shorter treatment duration was also investigated in patients with HCV genotype 2/3 infection. Smaller trials showed that a shorter treatment duration of 12-14 weeks is equally effective as the standard treatment duration in patients infected with HCV genotype 2/3 who achieve a rapid virologic response after 4 weeks of therapy.
  • Patients infected with HCV genotype 1 and slow virologic response have a high risk to relapse after 48 weeks of treatment with PEG-interferon and ribavirin.
  • An approach to reduce the relapse rates is treatment extension to 72 weeks.
  • patients infected with HCV genotype 1 were randomized for treatment with PEG-interferon alpha-2a/ribavirin 800 mg for 48 weeks and 72 weeks, respectively.
  • the overall sustained viro logic response rate was not superior in patients infected with genotype 1 treated for 72 weeks with PEG-interferon alpha-2a/ribavirin 800 mg compared with patients treated for 48 weeks.
  • the SUCCESS study was the first prospective study to compare 48 weeks of treatment with 72 weeks of treatment in slow responders.
  • slow responders were randomized at week 36 of treatment to receive PEG-interferon alpha-2b (1.5 ⁇ g/kg/week) plus weight-based dosed ribavirin (800-1400 mg/day) for a total of 48 or 72 weeks.
  • PEG-interferon alpha-2b 1.5 ⁇ g/kg/week
  • weight-based dosed ribavirin 800-1400 mg/day
  • sustained viro logic rates were not different between the two groups (43% and 48% in the 48 and the 72 week treatment arms, respectively). Patients, however, who showed 80/80/80 compliance had sustained viro logic response rates of 44% and 57% in the 48 weeks and 72 weeks treatment arms, respectively. Overall, these studies indicate that extended treatment duration can be considered in slow responders, however, adherence to treatment is crucially important.
  • Hepatitis D as HDV virions are incapable of replication absent
  • Hepatitis E symptomatic therapy until symptoms abate
  • Hepatitis G GB virus C (GBV-C), formerly known as Hepatitis G virus (HGV), is a virus in the Flaviviridae family which has not yet been assigned to a genus.
  • Hepatitis G virus and GB virus C (GBV-C) are RNA viruses that were independently identified in 1995, and were subsequently found to be two isolates of the same virus.
  • GBV-C was initially thought to be associated with chronic hepatitis, extensive investigation failed to identify any association between this virus and any clinical illness. So far, no therapy has been approved;
  • Infectious mononucleosis also known as EBV infectious mononucleosis, Pfeiffer's disease or Filatov's disease, and colloquially as kissing disease, mono (in North America) and glandular fever (in other English-speaking countries) is an infectious, very widespread viral disease caused by the Epstein-Barr virus (EBV); hepatitis occurs as a rare ( ⁇ 5%) complication of EBV infectious mononucleosis.
  • Infectious mononucleosis is generally self-limiting and only symptomatic and/or supportive treatments are used
  • acetaminophen/paracetamol or non-steroidal anti- inflammatory drugs may be used to reduce fever and pain; Prednisone is commonly used as an antiinflammatory to reduce symptoms of pharyngeal pain, odynophagia, or enlarged tonsils). There is little evidence to support the use of aciclovir, although it may reduce initial viral shedding. However, the antiviral drug valacyclovir has recently been shown to lower or eliminate the presence of the Epstein-Barr virus in patients afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms;
  • Cytomegalovirus is a herpes viral genus of the Herpesviruses group; in humans it is commonly known as HCMV or Human Herpesvirus 5 (HHV-5). Most healthy people who are infected by HCMV after birth have no symptoms. Some of them develop an infectious mononucleosis/glandular fever- like syndrome, with prolonged fever, and a mild hepatitis. A sore throat is common. After infection, the virus remains latent in the body for the rest of the person's life. Overt disease rarely occurs unless immunity is suppressed either by drugs, infection or old-age.
  • Cytomegalovirus Immune Globulin Intravenous (Human) (CMV- IGIV), is an immunoglobulin G (IgG) containing a standardized amount of antibody to Cytomegalovirus (CMV). It may be used for the prophylaxis of cytomegalovirus disease associated with transplantation of kidney, lung, liver, pancreas, and heart.
  • Ganciclovir treatment is used for patients with depressed immunity who have either sight-related or life-threatening illnesses.
  • Valganciclovir may be applied effectively by orally administration, yet its therapeutic efficacy is frequently compromised by the emergence of drug-resistant virus isolates.
  • Foscarnet or cidofovir are only given to patients with CMV resistant to ganciclovir, as, e.g., foscarnet often causes
  • Yellow fever virus is a 40 to 50 nm enveloped R A virus with positive sense of the Flaviviridae family. The virus is transmitted by the bite of mosquitos.
  • a safe and efficient vaccine exists, yet official estimations of the WHO still amount to 200,000 cases of disease and 30,000 deaths a year. The disease presents itself in most cases with fever, nausea and pain and it disappears after several days. In some patients, a toxic phase follows, in which liver damage with jaundice (giving the name of the disease) can occur and lead to death.
  • a symptomatic treatment includes rehydration and pain relief with drugs like paracetamol; • Hepatitis as a complication of mumps virus and rubella virus infection: Rare incidences of acute or fulminant hepatitis have been reported in conjunction with mumps virus and rubella virus (Matsunaga, T., et al, Journal of the Japan Pediatric Society 2003, 107: 1645; Masao, A., et al, Journal of
  • retroviral therapy The main focus of retroviral therapy currently relates to the treatment of HIV- infected individuals.
  • Other currently known retrovirus infections in humans are rare, e.g. infections with HTLV-I causing blood cancer.
  • the infection with HTLV-I is believed to occur from mother to child.
  • HTLV-I infected individuals are frequented treated with anti-cancer drugs, but the treatment with the nucleoside analogue reverse transcriptase inhibitor azidothymide and cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and prednisone/prednisolone has also been attempted (Taylor GP, Matsuoka M (September 2005), Oncogene 24 (39): 6047-57).
  • HAART antiretro viral therapy
  • Standard goals of HAART include improvement in the patient's quality of life, reduction in complications, and reduction of HIV viremia below the limit of detection, but it does not cure the patient of HIV nor does it prevent the return, once treatment is stopped, of high blood levels of HIV, often HAART resistant.
  • HAART achieves far less than optimal results, due to medication intolerance/side effects, prior ineffective antiretroviral therapy and infection with a drug-resistant strain of HIV.
  • Non-adherence and non-persistence with therapy are the major reasons why some people do not benefit from HAART.
  • the reasons for non-adherence and non- persistence are varied and include poor access to medical care, inadequate social supports, psychiatric disease and drug abuse.
  • HAART regimens can also be complex and thus hard to follow, with large numbers of pills taken frequently.
  • a huge number of anti-retrovirus compounds has been authorized in various countries or is clinically investigated. These compounds may be broadly classified by the phase of the retrovirus life-cycle that is inhibited:
  • Nucleoside and nucleotide reverse transcriptase inhibitors inhibit reverse transcription by being incorporated into the newly synthesized viral DNA and preventing its further elongation.
  • Non-nucleoside reverse transcriptase inhibitors inhibit reverse transcriptase directly by binding to the enzyme and interfering with its function.
  • Protease inhibitors target viral assembly by inhibiting the activity of protease, an enzyme used by HIV to cleave nascent proteins for final assembly of new virions.
  • Integrase inhibitors inhibit the enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. There are several integrase inhibitors currently under clinical trial, and raltegravir became the first to receive FDA approval in October 2007.
  • Entry inhibitors interfere with binding, fusion and entry of HIV- 1 to the host cell by blocking one of several targets.
  • Maraviroc and enfuvirtide are the two currently available agents in this class.
  • Maturation inhibitors inhibit the last step in gag processing in which the viral capsid polyprotein is cleaved, thereby blocking the conversion of the polyprotein into the mature capsid protein (p24). Because these viral particles have a defective core, the virions released consist mainly of non- infectious particles. There are no drugs in this class currently available, though two are under investigation, bevirimat and Vivecon.
  • 'virostatics' combine immunomodulating and antiviral properties to inhibit a specific antiviral target while also limiting the hyper-elevated state of immune system activation driving disease progression.
  • Some natural antivirals such as extracts from certain species of mushrooms like Shiitake and Oyster mushrooms, may contain multiple pharmacologically active compounds, which inhibit the virus at various different stages in its life cycle.
  • researchers have also isolated a protease inhibitor from the Shiitake mushroom.
  • Anti-retroviral compounds to be combined with (a) proteasome inhibitor(s) according to the invention include, but are not limited to, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhbitors, inhibitors of HIV TAT, budding/maturation inhibitors, entry inhibitors, including fusion inhibitors, inhibitors of the CD4 receptor, inhibitors of the CCR5 co-receptor and inhibitors of the CXCR4 coreceptor.
  • Reverse transcriptase inhibitors include, but are not limited to BCH-189, AzdU, carbovir, ddA, d4C, d4T (stavudine), 3TC (lamivudine), DP-AZT, FLT
  • Retroviral protease inhibitors include, but not limited to, ritonavir, lopinavir, saquinavir, Saquinavir Transdrug, amprenavir (VX-478), fosamprenavir, nelfmavir (AG 1343), tipranavir, indinavir, atazanavir, TMC-126, Darunavir (TMC-114), mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC- 681, DPC-684, GW640385X, SC-52151, BMS 186,318, SC-55389a, BILA 1096 BS, DMP-323, KNI-227, HEPT compounds, PA-457, KPC-2, AG-1859, GS224338, R- 944, VX-385, GW640385, P-1946, CTP-518, Doxovir-M, DG17, DG
  • HIV integrase inhibitors include, but are not limited to, S-1360, zintevir (AR-177), L-870812, L-870810, L-c-2507 and S(RSC)-1838 ), TG-10, INH001, S-247303, S- 265744, S-349572, Raltegravir, Elvitegravir, HIV Integrase Inhibitors by
  • AMBRILIA e.g. AMBRILIA Compound 1, AMBRILIA Compound 2, AMBRILIA Compound 3
  • HIV Integrase Inhibitors by AVEXA HIV Integrase Inhibitors by BIOALLIANCE (e.g. derivatives of styrylquino lines), HIV Integrase Inhibitors by CRITICAL OUTCOME, HIV Integrase Inhibitors by VIROCHEM, and the like
  • TAT inhibitors include, for example, RO-24-7429 and the like.
  • HIV budding/maturation inhibitors include, but are not limited to, PA-457 and the like.
  • HIV entry/fusion inhibitors include, but are not limited to, AMD-070 (AMD 11070), BlockAide/CR, BMS 806 (BMS-378806), Enfurvirtide (T-20, R698, Fuzeon), KRH1636, ONO-4128 (GW-873140, AK-602, E-913), PRO-140 , PRO-542, Schering C (SCH-C), SCH-D (SCH-417690), T-1249 (R724), TAK-220, TNX-355 and UK 427,857, PRO 2000, AMD-3100, Peptide T, FP21399 and the like.
  • CCR5 antagonists include, but are not limited to: TAK-779, Vicriviroc (SCH- 417690), Aplaviroc (GW871340), Maraviroc, INCB9471, PF-232798, and
  • anti-retroviral compounds to be administered in combination with at least one proteasome inhibitor according to the present invention may include AL-721, polymannoacetate, HPA-23, trisodium phosphono formate, foscarnet, eflonithine, Reticulose, UA001, cylobut-G, cyclobut-A, ara-M, BW882C87, BW256U87, L- 693,989, FIAC, HOE-602, ganciclor, rCD4/CD4-IgG, CD4-PE40, butyl-DNJ, oxamyristic acid, and dextran sulfate.
  • a patient which does not respond to retroviral treatment, and in particular to HIV treatment may be designated as a ,, ⁇ -responder" or “therapy resistant” patient. Resistances may not only be determined in clinical trials but also in cell culture tests in vitro. For example, the antiviral activity of a drug in cell culture systems may be determined using the inhibition of replication as a read-out parameter. The concentration of a compound under investigation to inhibit virus replication by 50 percent (EC 50 for cell-based assays; IC 50 for biochemical or subcellular assays) should be determined. A large number of tools to determine this value are known to the person skilled in the art. A well-characterized wild-type HIV laboratory strain should serve as a reference standard.
  • cytotoxicity and therapeutic indices protein binding assays to human serum proteins
  • genotypic and phenotypic assays using, for example, nucleic acid sequencing methodology to determine mutations that have evolved in viruses under investigation
  • standard virus assays such as p24, viral RNA, RT assay, MTT cytotoxic assay and reporter gene expression assays. See, for example, Walter, H.,
  • Anti-retro viral compounds that are currently used in the treatment of HIV are, e.g., the multi-class combination products comprising efavirenz, emtricitabine and tenovir disoproxil fumarate; Nucleoside Reverse Transcriptase Inhibitors (NRTIs) such as lamivudine, zidovudine, emtricitabine, lamivudine, abacavir, zalcitabine,
  • NRTIs Nucleoside Reverse Transcriptase Inhibitors
  • NRTIs Nonnucleoside Reverse Transcriptase Inhibitors
  • Other drugs that are currently tested include monoclonal antibodies and fragments thereof, etc. Any of these pharmaceutical agents may be used in combination with the semicarbazone proteasome inhibitors described above.
  • a preferred combination comprises methods, kits, compositions, uses etc., as described above which involve S-2209 or pharmaceutically acceptable salts or analogues thereof. Additionally, PS- 341 or related molecules as proteasome inhibitor(s) and darunavir or related active agents as a further anti-retroviral compound may be used.
  • HIV resistances are mainly due to its high rate of replication (often of a magnitude of 10 9 to 10 10 virions per person per day) and error-prone polymerase. Therefore, HIV can easily develop mutations that alter susceptibility to anti-retroviral compounds. As a result, the emergence of resistance to one or more anti-retroviral compound is one reason for therapeutic failure in the treatment of HIV. In addition, the emergence of resistance to one anti-retroviral compound sometimes confers a reduction in or a loss of susceptibility to other or all anti-retroviral compounds of the same class (U.S. Dept. of Health and Human Services, FDA, CDER, 2007, in "Guidance for Industry - Role of HIV resistance testing in antiretro viral drug development).
  • the present invention provides a new strategy to fight against retroviral, e.g. HIV-infections.
  • retroviral e.g. HIV-infections.
  • the therapy presented herein is particularly well-suited to fight against the development of resistances, or may be used in patients that have already developed resistances to one or more of the above described anti-retroviral compound.
  • the treatments may be initiated in patients which received therapy for retroviral infections and in particular for HIV infections such as HAART and which have been classified as non responders or refractory, or in patients which have recently received the diagnosis of a retrovirus infection, i.e. before the treatment with any
  • the treatment may prevent or delay the onset of disease/symptoms associated with the retroviral infection, e.g. AIDS.
  • the patient has never received therapy or prophylaxis for a retrovirus infection, more particularly an HIV infection.
  • the patient has previously received therapy or prophylaxis for a retroviral infection, or more particularly an HIV infection.
  • the patient has not responded to treatment for a retroviral disease, or more particularly an HIV infection.
  • the patient can be a patient that received therapy but continued to suffer from viral infection or one or more symptoms thereof.
  • the patient can be a patient that received therapy but failed to achieve a sustained viro logic response.
  • the patient has received therapy for a virally induced disease, or more particularly a disease induced by a HIV infection, but has failed to show, for example, a 2 log 10 (2 orders of magnitude, 100-fold) decline in viral R A levels after 12 weeks of therapy.
  • the patient is a patient that discontinued therapy for a retroviral disease, or more particularly conditions induced by HIV infection, because of one or more adverse events associated with the therapy.
  • the patient is a patient where current therapy is not indicated.
  • kits, methods and compositions provided herein may reduce or eliminate the need for exposing patients to the agents of current therapy, either by reducing the dose needed or reducing the required time of exposure to these agents, or by facilitating the replacement of certain agents of current therapy.
  • a retroviral disease or more particularly an HIV-related disease.
  • methods of treating or preventing a retroviral disease more particularly an HIV-related disease.
  • methods of treating a retroviral infection, or AIDS induced by an HIV infection in patients where a neuropsychiatric event, such as depression, or risk of such indicates a different treatment of the current HIV therapy.
  • the patient has received treatment for a retroviral disease, or more particularly AIDS or related conditions induced by HIV infection, and discontinued that therapy prior to administration of a method provided herein.
  • the patient has received therapy and continues to receive that therapy along with administration of a method provided herein.
  • the proteasome inhibitors described herein may be used in the treatment or prevention of HIV infections, particularly in patients that have developed resistances to conventional therapy such as HAART.
  • the protease inhibitor may be used before or after or simultaneously with at least one, or alternatively before, following or simultaneously with more than one conventionally used compounds that are administered to patients infected with or suspected of being infected, with retroviruses, e.g. HIV.
  • the present invention thus relates to the use of at least one semicarbazone proteasome inhibitor alone or together with at least one different pharmaceutically active agent in use against retroviral infections in the manufacture of a medicament for treating patients which do not respond or are refractory to treatment with a pharmaceutically active agent in use against retroviral infections (e.g. HIV infections) alone.
  • retroviral infections e.g. HIV infections
  • Yet another embodiment of the present invention relates to the use of at least one semicarbazone proteasome inhibitor alone or together with at least one first and at least one second pharmaceutically active agent in use against retroviral infections in the manufacture of a medicament for treating patients which do not respond or are refractory to treatment with a pharmaceutically active agent in use against retroviral infections alone.
  • specific semicarbazone proteasome inhibitors such as S-2209 or pharmaceutically acceptable salts or analogs together with structurally different proteasome inhibitors such as PS-519, PS-341
  • this may be selected from the above mentioned anti-retroviral compounds used in the treatment of retroviral, e.g. HIV-infection.
  • compositions, kits, uses and methods in particular where they relate to a combination of a proteasome inhibitor, and another anti-retroviral compound it is possible to reduce the virus load or to even completely remove the virus.
  • At least one first pharmaceutical composition comprising at least one semicarbazone proteasome inhibitor, and optionally
  • At least one further pharmaceutical composition comprising at least one pharmaceutically active agent in use against retroviral infection and/or viral hepatitis infections
  • the pharmaceutically active agent in use against viral hepatitis infections may specifically be an interferon preparation chosen from the list of: albinterferon, PEG-IFN alpha-2a, alpha-2b or lambda, Locteron, Omega IFN, Medusa IFN, DA- 3021, EMZ702, Iniradure, IL-29, Amarillo, Soluferon and Belerofon.
  • the interferon may also be replaced by, or assisted by, additional administration of, for example, an interleukin, preferably IL-1, IL-2, IL-6, IL-8, IL-12, IL-15, IL-18, IL-21, and IL-2, a steroid, or an immunomodulator, e.g. Thymosin, ME3738, SCV-07, Alinia,
  • an interleukin preferably IL-1, IL-2, IL-6, IL-8, IL-12, IL-15, IL-18, IL-21, and IL-2
  • an immunomodulator e.g. Thymosin, ME3738, SCV-07, Alinia
  • the pharmaceutically active agent in use against viral hepatitis infections may be one that, for example, stimulates or assists the body's own functions, and specifically the body's natural defenses, more specifically against viruses.
  • the pharmaceutically active agent in use against viral hepatitis infections is one that, stimulates or assists the body's own functions, and specifically the body's natural defenses, it ma ybe advantageous to provide an additional pharmaceutically active agent in use against viral hepatitis infections, and specifically one which interferes with the function of a viral target.
  • Such additional pharmaceutically active agent may be one of, or any combination of the elements of the following list: telaprevir, boceprevir, ITNM-191, SCH 900518, TMC435, BI201335,MK-7009, lamivudine, cidovir, ribavarin, viramidine, didanosine, vidarabine, cytarabine, emtricitabine, zalcitabine, abacavir, stavudine, zidovudine, idoxuridine, trifhiridine, valopiticabine, R1626, R7128, IDX184, HCV-796, Filibuvir (PF 00868554), VCH-916, ANA598, BI 207127,VCH-222 PSI- 6130, ANA773, MK-3281, ABT-072, ABT-333, R1728, VCH-759, GS9190, BMS-650032, BE- 868554, thymosin al
  • SCY-635 DEBIO-025, NIM811, Silibinin, Nitazoxanide, A-831, KPE02001003, TCM700C, PYN-17, BIT225, JTK-652, BMS-791325, amantadine, rimantadine and derivatives thereof, and azathoprine.
  • the inventive pharmaceutical composition preferably comprises at least one semicarbazone proteasome inhibitor and optionally at least one further active agent against HIV and/or viral hepatitis infections, particularly at least two, three or even at least 4 active agents in use against HIV infections or viral hepatitis infections.
  • the semicarbazone proteasome inhibitor is preferably S-2209 or an analog thereof.
  • compositions and kits may be used for treating patients suffering from retroviral, particularly HIV infections and/or viral hepatitis, in particular due to an infection with HCV.
  • kits in accordance with the present invention contain the pharmaceutical compositions in separate form, e.g. as different solutions, tablets etc. This may allow for a timely ordered, i.e. subsequent administration of the separate pharmaceutical compositions which can be important when treating patients suffering e.g from HCV infections and/or HIV infections.
  • the kits in accordance with the present invention may comprise instructions in paper or electronic form advising the user to first administer the semicarbazone proteasome inhibitor or a pharmaceutical composition comprising the same and to administer the additional active agent or a pharmaceutical composition comprising the same concommitantly, subsequently or before.
  • the instructions may further instruct the user to wait a specified time period between administering one active agent or pharmaceutical composition and administering one or more additional active agent(s) or pharmaceutical composition(s).
  • the instructions may for example advise to wait for about 2 to 4 days, about 4 to 6 days, about 1 week, about 1 to 2 weeks, about 2 to 3 weeks, about 3 to 4 weeks, or more than 4 weeks after treatment with the semicarbazone proteasome inhibitor has ended and before commencing treatment with at least one different pharmaceutical composition.
  • the instructions may additionally advise that treatment with the semicarbazone proteasome inhibitor may on a three to four daily basis such as e.g. on day 1, 4, 8 and 11, or on day 1, 4, 7, 10 or on day 1, 5, 9 and 13 and the like.
  • kits for treatment with one or more pharmaceutical composition(s) in addition to the semicarbarzone proteasome inhibitor may follow the dosage regimen developed for these compositions.
  • an additional use of interferon such as PEG-interferon-alpha and/or a nucleoside analogon such as ribavirin may be undertaken on a one to two weekly basis for 32 to 60 weeks such as 48 weeks in case of infections with HCV genotype 1 and on a one to two weekly basis for 12 to 36 weeks such as 24 weeks in case of infections with HCV genotype 2/3.
  • the pharmaceutical compositions may be formulated for oral, subcutaneous, transdermal, rectal, peritoneal or intravenous administration and may contain suitable pharmaceutically acceptable excipients.
  • the present invention relates to the use of at least one semicarbazone proteasome inhibitor and at least one pharmaceutically active agent in use against HIV infection and/or viral hepatitis infections, particularly HCV infections, in the manufacture of a medicament for treating human or animal individuals, wherein:
  • a medicament with said at least one semicarbazone proteasome inhibitor is first administered to an individual infected with HIV and/or a hepatitis virus such as HCV;
  • a medicament with said at least one pharmaceutically active agent in use against hepatitis virus infection or at least one pharmaceutically active agent in use against retroviral infection is administered subsequent to treatment with the medicament with said at least one semicarbazone proteasome inhibitor.
  • the present invention relates to the use of least one semicarbazone proteasome inhibitor and at least one pharmaceutically active agent in use against HIV infections and/or viral hepatitis infections, particularly HCV infections, in the manufacture of a medicament for treating human or animal individuals, wherein:
  • a medicament with said at least one semicarbazone proteasome inhibitor is administered to an individual infected with HIV and/or a hepatitis virus such as HCV;
  • the patient can be any patient infected with, or at risk for infection with, a virus inducing hepatitis, specifically HCV, or the patient may be infected with, or at risk of an infection with a retrovirus, specifically with HIV.
  • An infection can be determined according to any technique deemed suitable by the practitioner of skill in the art. The risk of an infection may be given, when sufficient contact with a source might have occurred or has occurred, e.g. with a body fluid suspected of containing the above infectious agent(s), or a source known to contain the above infectious agent(s).
  • the patient has never received therapy or prophylaxis for a retrovirus infection or a virally induced hepatitis, or more particularly an HIV infection and/or HCV infection.
  • the patient has previously received therapy or prophylaxis for an HIV infection and/or a virally induced hepatitis, or more particularly an HCV infection.
  • the patient has never received therapy or prophylaxis for a retrovirus infection or a virally induced hepatitis, or more particularly an HIV infection and/or HCV infection.
  • the patient has previously received therapy or prophylaxis for an HIV infection and/or a virally induced hepatitis, or more particularly an HCV infection.
  • the patient has not responded to treatment for an HIV infection and/or a virally induced hepatitis, or more particularly an HCV infection.
  • the patient can be a patient that received therapy but continued to suffer from viral infection or one or more symptoms thereof.
  • the patient can be a patient who received therapy but failed to achieve a sustained viro logic response.
  • the patient has received therapy for an HIV infection and/or a virally induced hepatitis, or more particularly a hepatitis induced by HCV infection, but has failed to show, for example, a 2 log 10 (2 orders of magnitude, 100 fold) decline in viral RNA levels after 12 weeks of therapy.
  • the patient is a patient who discontinued therapy for a virally induced hepatitis, or more particularly an HIV infection and/or a hepatitis induced by HCV infection, because of one or more adverse events associated with the therapy.
  • the patient is a patient where current therapy is not indicated.
  • Interferon (IFN)-alpha plus ribavirin is associated with a high rate of depression.
  • Depressive symptoms have been linked to a worse outcome in a number of medical disorders.
  • Life-threatening or fatal neuropsychiatric events including suicide, suicidal and homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive behavior have occurred in patients with and without a previous psychiatric disorder during HCV therapy.
  • Interferon-induced depression is a limitation for the treatment of chronic hepatitis C, especially for patients with psychiatric disorders.
  • Psychiatric side effects are common with interferon therapy and responsible for about 10% to 20% of discontinuations of current therapy for HCV infection.
  • semicarbazone proteasome inhibitors according to the present invention, or a pharmaceutical compositions or kits comprising the same, preferably of S-2209, for preventing side effects associated with conventional HCV treatments and/or HIV treatments is contemplated herein.
  • kits, methods and compositions provided herein may reduce or eliminate the need for exposing patients to the agents of current therapy, either by reducing the dose needed or reducing the required time of exposure to these agents, or by facilitating the replacement of certain agents of current therapy.
  • a virally induced hepatitis or more particularly a hepatitis induced by HCV and/or HIV infection
  • a neuropsychiatric event such as depression, or risk of such indicates dose reduction, or reduction of time of exposure to, current HCV or HIV therapy.
  • Treatment with at least one semicarbazone proteasome inhibitor may include concentrations of the semicarbazone proteasome inhibitors used within the range of about 1 nM to about 50 ⁇ , preferably about 10 nM to about 10 ⁇ in the pharmaceutical composition.
  • the semicarbazone proteasome inhibitors may be used at doses of about 0.25 to about 5, of about 0.4 to about 2.5, or of about 0.7 to about 1.5 mg/m 2 , or at doses of about 2.5 to about 50, of about 4 to about 25, or of about 7 to about 15 mg/m 2 , or at doses of about 25 to about 500, of about 40 to about 250, or of about 70 to about 150 mg/m 2 body surface.
  • the treatment with a different pharmaceutical agent may follow the treatment with the semicarbazone proteasome inhibitor either rather directly (e.g. the following day) or after a break (i.e. a therapy free period) of one to several days or weeks, such as 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, more than 6 weeks etc. Starting with the therapy after a break of about 1, 2, 3, 4, 5, or 6 weeks may be
  • proteasome specific inhibitors such as S-2209 or analogs thereof are applied during treatment of a viral Hepatitis C infection and if this treatment is followed by standard therapy with pegylated interferons and ribavirine
  • treatment with pegylated interferons and ribavirine may be undertaken on a twice a week, once a week, or two weekly basis for 48 weeks in case of infections with HCV genotype 1 and on a twice a week, once a week, or two weekly basis for 24 weeks in case of infections with HCV genotype 2/3.
  • a combination of at least one semicarbazone proteasome inhibitor together with at least one other pharmaceutically active agent which is known to be effective in treating HIV and/or viral hepatitis may also be administered simultaneously.
  • the present invention thus relates to the use of at least one semicarbazone proteasome inhibitor together with at least one pharmaceutically active agent in use against HIV infections and/or viral hepatitis infections in the manufacture of a medicament for treating patients infected with retroviruses, e.g. HIV and/or hepatitis viruses, e.g. HCV.
  • retroviruses e.g. HIV and/or hepatitis viruses, e.g. HCV.
  • proteasome inhibitors such as PS-519, PS-341 (Bortezomib) and PS-273 in addition to the semicarbazone proteasome inhibitor.
  • a different pharmaceutical agent for hepatitis virus infected patients, e.g. HCV-infected patients, this may be preferably selected from interferons including their derivatives such as pegylated interferon alpha as first different pharmaceutically active agent or from nucleoside analoga such as ribavirin as second different pharmaceutically active agent.
  • interferons including their derivatives such as pegylated interferon alpha as first different pharmaceutically active agent and from nucleoside analoga such as ribavirin as second different pharmaceutically active agent.
  • nucleoside analoga such as ribavirin
  • compositions, kits, uses and methods in particular where they relate to a combination of a semicarbazone proteasome inhibitor, optionally together with an interferon and a nucleoside analog, it is possible to reduce the virus load in chronic HCV patients referred to in the claims (over several orders of magnitude) or to even completely remove the virus.
  • the present invention does not include semicarbazone proteasome inhibitors such as S-2209, pharmaceutically acceptable salts thereof or structural or functional analogs thereof, uses thereof, pharmaceutical compositions comprising these pharmaceutically active agents, uses of such pharmaceutical compositions, methods involving such pharmaceutically active agents, methods involving such pharmaceutical compositions, methods involving such uses, kits involving such pharmaceutically active agents, kits involving such pharmaceutical compositions, etc. as far as such pharmaceutically active agents, such pharmaceutical compositions, such uses, such methods, such kits etc. have been disclosed in
  • such semicarbazone proteasome inhibitors such as S-2209, the pharmaceutically acceptable salts, structural or functional analogs thereof, uses thereof, pharmaceutical compositions, uses of such pharmaceutical compositions, methods, kits etc. as mentioned herein are excluded where the emicarbazone proteasome inhibitors such as S-2209, the pharmaceutically acceptable salts, structural or functional analogs thereof, uses thereof, pharmaceutical compositions, uses of such pharmaceutical compositions, methods, kits etc. as disclosed in European patent application EP 10151135.0, US patent application US61/296,363 or international patent application PCT/EP/2010/060796 involve a combination of semicarbazone proteasome inhibitors such as S-2209, the
  • pharmaceutically active agent in use against viral hepatitis infections may include pharmaceutically active agents which support or assist the body's natural response in dealing with viral infections and/or pharmaceutically active agents which interfere with a viral target.
  • pharmaceutically active agents which support or assist the body's natural response in of dealing with viral infections include the interferons, pegylated versions thereof etc.
  • the present invention is directed to the afore-mentioned semicarbazone proteasome inhibitors such as S-2209, the pharmaceutically acceptable salts, structural or functional analogs thereof as mentioned herein, the uses thereof as mentioned herein, the pharmaceutical compositions as mentioned herein, the uses of such pharmaceutical compositions as mentioned herein, the methods as mentioned herein, the kits as mentioned herein, etc. but excluding the semicarbazone proteasome inhibitors such as S-2209, the pharmaceutically acceptable salts, structural or functional analgos thereof as mentioned herein, the uses thereof as mentioned herein, the pharmaceutical compositions as mentioned herein, the uses of such pharmaceutical compositions as mentioned herein, the methods as mentioned herein, the kits as mentioned herein, as far as these
  • semicarbazone proteasome inhibitors such as S-2209, the pharmaceutically acceptable salts, structural or functional analogs thereof, the uses thereof, the pharmaceutical compositions, the uses of such pharmaceutical compositions, the methods, the kits etc. involve a combination of semicarbazone proteasome inhibitors such as S-2209, the pharmaceutically acceptable salts, structural or functional analogs thereof and pharmaceutically active agents in use against viral hepatitis infections as mentioned herein. More preferably the semicarbazone proteasome inhibitors such as S-2209, the pharmaceutically acceptable salts, structural or functional analogs thereof as mentioned herein, the uses thereof as mentioned herein, the pharmaceutical compositions as mentioned herein, the uses of such
  • compositions as mentioned herein, the uses of such pharmaceutical compositions as mentioned herein, the methods as mentioned herein, the kits as mentioned herein, are excluded as far as these semicarbazone proteasome inhibitors such as S-2209, the pharmaceutically acceptable salts, structural or functional analogs thereof, the uses thereof, the pharmaceutical compositions, the uses of such pharmaceutical compositions, the methods, the kits etc. involve a combination of semicarbazone proteasome inhibitors such as S-2209, the pharmaceutically acceptable salts, structural or functional analgos thereof with such pharmaceutically active agents in use against viral hepatitis infections for treating a human or animal individual or patient who does not respond or is refractory to treatment with at least one pharmaceutically acceptable agent in use against viral hepatitis infection. Even more preferably such a human or animal individual or patient is affected by a HCV infection and does not respond or is refractory to treatment with at least one pharmaceutically acceptable agent in use against viral hepatitis infection.
  • Pharmaceutical Compositions and Methods of Administration are excluded as far as these semi
  • the semicarbazone proteasome inhibitors can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Such compounds can be used in some embodiments to enhance delivery of the drug to the liver.
  • the methods provided herein encompass administering pharmaceutical compositions containing at least one semicarbazone proteasome inhibitor as described herein, with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, and/or with at least one pharmaceutically active agent in use against HIV infections and/or viral hepatitis infection, e.g. HCV infections.
  • the at least one pharmaceutically active agent in use against HIV infections and/or viral hepatitis infections can be formulated or packaged with the semicarbazone proteasome inhibitor.
  • the at least one pharmaceutically active agent in use against HIV infections and/or viral hepatitis infections, such as HCV infections will only be formulated with the semicarbazone proteasome inhibitor when, according to the judgment of those of skill in the art, such co- formulation should not interfere with the activity of either agent or the method of administration.
  • the semicarbazone proteasome inhibitor and the at least one pharmaceutically active agent are formulated separately. They can be packaged together, or packaged separately, for the convenience of the practitioner of skill in the art.
  • compositions for oral administration of tablets, pills, hard gelatin capsules, powders or granules.
  • the active product is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.
  • compositions for oral administration of solutions which are pharmaceutically acceptable, suspensions, emulsions, syrups and elixirs containing inert diluents, such as water or liquid paraffin.
  • solutions which are pharmaceutically acceptable, suspensions, emulsions, syrups and elixirs containing inert diluents, such as water or liquid paraffin.
  • inert diluents such as water or liquid paraffin.
  • These compositions can also comprise substances other than diluents, for example wetting, sweetening or flavoring products.
  • compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active principle, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
  • the compositions can also be aerosols.
  • the compositions can be stable sterile solutions or solid compositions dissolved at the time of use in apyrogenic sterile water, in saline or any other pharmaceutically acceptable vehicle.
  • the active principle is finely divided and combined with a water-soluble solid diluent or vehicle, for example dextran, mannitol or lactose.
  • compositions provided herein is a pharmaceutical composition or a single unit dosage form.
  • Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a proteasome inhibitor, or other prophylactic or therapeutic agent), and a typically one or more pharmaceutically acceptable carriers or excipients.
  • prophylactic or therapeutic agents e.g., a proteasome inhibitor, or other prophylactic or therapeutic agent
  • typically one or more pharmaceutically acceptable carriers or excipients e.g., the term "pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • Typical pharmaceutical compositions and dosage forms comprise one or more excipients.
  • Suitable excipients are well-known to those skilled in the art of pharmacy, and non limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for
  • Lactose free compositions can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopia (USP) SP(XXI)/NF (XVI).
  • lactose free compositions comprise an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • Exemplary lactose free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate.
  • anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
  • water e.g., 5%
  • water is widely accepted in the pharmaceutical arts as a means of simulating long term storage in order to determine characteristics such as shelf life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379 80.
  • water and heat accelerate the decomposition of some compounds.
  • the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
  • Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in certain embodiments, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
  • the formulation should suit the mode of administration.
  • the pharmaceutical compositions or single unit dosage forms are sterile and in suitable form for administration to a patient, for example, an animal patient, such as a mammalian patient, for example, a human patient.
  • a pharmaceutical composition is formulated to be compatible with its intended route of administration.
  • routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intra-tumoral, intra-synovial and rectal administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings.
  • a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings.
  • suppositories ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non aqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
  • suspensions e.g., aqueous or non aqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions
  • solutions elixirs
  • sterile solids
  • compositions, shape, and type of dosage forms provided herein will typically vary depending on their use.
  • a dosage form used in the initial treatment of viral infection may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the maintenance treatment of the same infection.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder.
  • compositions which may be provided according to the invention, such pharmaceutical composition may be provided in a container. Where there is mention of more than one pharmaceutical composition, these compositions may be provided in one container, or they may be provided in separate containers, e.g. one container for each pharmaceutical composition provided. Embodiments wherein different pharmaceutical compositions are provided in separate containers constitute preferred embodiments of the instant invention. However, nothing herein shall be interpreted as indicating that separate containers may not be packaged together to make up but a single product, including for manufacturing and/or sales purposes.
  • compositions are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile
  • composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • Typical dosage forms comprise a proteasome inhibitor, or a pharmaceutically acceptable salt, solvate or hydrate thereof lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose in the morning or as divided doses throughout the day taken with food.
  • Particular dosage forms can have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 400, 500, 600, 750, 800 1000, 1250 or 1500 mg of the active compound.
  • compositions that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton Pa.
  • the oral dosage forms are solid and prepared under anhydrous conditions with anhydrous ingredients, as described in detail in the sections above.
  • anhydrous ingredients as described in detail in the sections above.
  • the scope of the compositions provided herein extends beyond anhydrous, solid oral dosage forms. As such, further forms are described herein.
  • excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free flowing form such as powder or granules, optionally mixed with an excipient.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl
  • fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof.
  • a specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103.TM. and Starch 1500 LM.
  • Disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of
  • disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms.
  • the amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar agar, alginic acid, calcium carbonate,
  • microcrystalline cellulose croscarmnellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R.
  • Active ingredients such as the compounds provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719;
  • Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example,
  • hydropropylmethyl cellulose other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.
  • single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled release.
  • controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non controlled counterparts.
  • the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
  • the drug may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
  • a pump may be used (see, Sefton, CRC Crit. Ref. Biomed. Eng. 1987, 14:201; Buchwald et al, Surgery 1980, 88:507; Saudek et al, N. Engl. J. Med. 1989, 321 :574).
  • polymeric materials can be used.
  • a controlled release system can be placed in a patient at an appropriate site determined by a practitioner of skill, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical
  • polyvinylchloride vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.
  • the active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step.
  • the percentage of active ingredient in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the patient.
  • parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art.
  • Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polyprop
  • Transdermal, topical, and mucosal dosage forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16.sup.th, 18th and 20.sup.th eds., Mack Publishing, Easton Pa. (1980, 1990 & 2000); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985).
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16.sup.th, 18th and 20.sup.th eds., Mack Publishing, Easton Pa. (1980, 1990 & 2000).
  • kits for treating or preventing HIV associated clinical symptoms and/or a viral hepatitis e.g. hepatitis caused by an HCV infection
  • a viral hepatitis e.g. hepatitis caused by an HCV infection
  • administering to a patient in need thereof, inter alia an effective amount of a semicarbazone proteasome inhibitor, or a pharmaceutically acceptable salt thereof.
  • the amount of the compound or composition which will be effective in the prevention or treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered.
  • exemplary doses of a composition include milligram or microgram amounts of the active compound per kilogram of patient or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram).
  • the dosage administered to a patient is 0.140 mg/kg to 35 mg/kg of the patient's body weight, based on weight of the active compound. In certain embodiments, the dosage administered to a patient is between 0.20 mg/kg and 20.0 mg/kg, or between 0.30 mg/kg and 15.0 mg/kg of the patient's body weight.
  • an estimate of the surface area of the patient's body may be used to scale the dose, as the surface area is sometimes a more accurate predictor of certain properties related to drug distribution and clearance (see, for example, Pinkel, D., Cancer Res. 1958, 18:853).
  • the proteasome inhibitors may be used at doses of about 0.25 to about 5, of about 0.4 to about 2.5, or of about 0.7 to about 1.5 mg/m 2 , or at doses of about 2.5 to about 50, of about 4 to about 25, or of about 7 to about 15 mg/m 2 0, or at doses of about 25 to about 500, of about 40 to about 250, or of about 70 to about 150 mg/m 2 body surface.
  • the recommended daily dose range of a composition provided herein for the conditions described herein lie within the range of from about 0.1 mg to about 5000 mg per day, given as a single once-a-day dose or as divided doses throughout a day. In one embodiment, the daily dose is administered twice daily in equally divided doses.
  • amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the composition provided herein are also encompassed by the above described dosage amounts and dose frequency schedules.
  • the dosage administered to the patient may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular patient is experiencing.
  • the dosage of the composition or a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a patient is a unit dose of 0.1 mg to 1500 mg, 0.1 mg to 1000 mg, 0.1 mg to 500 mg, 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg..
  • treatment or prevention can be initiated with one or more loading doses of a compound or composition provided herein followed by one or more maintenance doses.
  • the loading dose can be, for instance, about 40 to 4000 mg per day, 60 to about 2000 mg per day, or about 100 to about 1000 mg per day for one day to five weeks.
  • the loading dose can be followed by one or more maintenance doses.
  • each maintenance does is, independently, about from about 10 mg to about 2000 mg per day, between about 25 mg and about 1500 mg per day, or between about 25 and about 800 mg per day.
  • Maintenance doses can be administered daily and can be administered as single doses, or as divided doses.
  • loading doses can be administered to achieve steady-state blood or serum concentrations of about 1200 to about 8000 ng/mL or higher, or about 2000 to about 4000 ng/mL for one to five days.
  • maintenance doses can be administered to achieve a steady-state concentration in blood or serum of the patient of from about 300 to about 4000 ng/mL, from about 400 to about 1600 ng/mL, or from about 600 to about 1200 ng/mL.
  • administration of the same composition may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • unit dosages comprising a compound, or a pharmaceutically acceptable salt thereof, in a form suitable for administration. Such forms are described in detail above.
  • the unit dosage comprises 1 to 5000 mg, 5 to 2500 mg or 10 to 1000 mg active ingredient.
  • the unit dosages comprise about 1, 5, 10, 25, 50, 100, 125, 250, 400, 500, 600, 800, 1000, 1500, 2000, 2500, 3000, 4000, or 5000 mg active ingredient.
  • Such unit dosages can be prepared according to techniques familiar to those of skill in the art.
  • the dosages of the at least one different pharmaceutically active agent in use against HIV infections and/or viral hepatitis (e.g. HCV) infections are to be used in the combination therapies provided herein.
  • dosages lower than those which have been or are currently being used to prevent or treat HIV infection and/or a viral hepatitis are used in the combination therapies provided herein.
  • the recommended dosages of at least one pharmaceutically active agent in use against viral hepatitis (e.g. HCV) infections can be obtained from the knowledge of those of skill.
  • recommended dosages are described in, for example, Hardman et al, eds., 1996, Goodman &
  • the therapies are administered no more than 24 hours apart or no more than 48 hours apart. In certain embodiments, two or more therapies are administered within the same patient visit. In other embodiments, the semicarbazone proteasome inhibitor and the at least one pharmaceutically active agent in use against HIV infections and/or viral hepatitis (e.g. HCV) infections are administered concurrently.
  • HIV infections and/or viral hepatitis e.g. HCV
  • administration of the same agent may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • a semicarbazone proteasome inhibitor and at least one pharmaceutically active agent in use against HIV infections and/or viral hepatitis infections are administered to a patient, for example, a mammal, such as a human, in a sequence and within a time interval such that the semicarbazone proteasome inhibitor can act together with the other agent(s) to provide an increased benefit than if they were administered otherwise.
  • the at least one pharmaceutically active agent can be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect.
  • the proteasome inhibitor and the at least one first and/or second different pharmaceutically active agent exert their effect at times which overlap.
  • Each different pharmaceutically active agent can be administered separately, in any appropriate form and by any suitable route.
  • the semicarbazone proteasome inhibitor is administered before administration of the different pharmaceutically active agent(s).
  • the semicarbazone proteasome inhibitor and the at least one pharmaceutically active agent in use against HIV infections and/or viral hepatitis (e.g. HCV) infections are cyclically administered to a patient.
  • Cycling therapy involves the administration of a first agent (e.g. a first prophylactic or therapeutic agents) for a period of time, followed by the administration of at least one second agent for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment.
  • the semicarbazone proteasome inhibitor and the at least one first and/or second different pharmaceutically active agent are administered in a cycle of less than about 6 weeks, about once every four weeks, about once every three weeks, about once every two weeks, about once every 10 days or about once every week.
  • One cycle can comprise the administration of a semicarbazone proteasome inhibitor and the at least one pharmaceutically active agent in use against HIV infections and/or viral hepatitis (e.g. HCV) infections (e.g. by infusion) over about 480 minutes every cycle, about 360 minutes every cycle, about 240 minutes every cycle, about 180 minutes every cycle, about 120 minutes every cycle, about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle.
  • HIV infections and/or viral hepatitis e.g. HCV
  • Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest, or at least 4 weeks of rest.
  • the number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.
  • the at least one pharmaceutically active agent in use against viral hepatitis infections can act additively or synergistically with the semicarbazone proteasome inhibitor.
  • the semicarbazone proteasome inhibitor is administered concurrently with one or more at least one pharmaceutically active agent in use against retroviral, e.g. HIV infections and/or viral hepatitis (e.g. HCV) infections in the same pharmaceutical composition.
  • a semicarbazone proteasome inhibitor is administered concurrently with one or more pharmaceutically active agents in use against retroviral, e.g. HIV infections and/or viral hepatitis (e.g. HCV) infections in separate pharmaceutical compositions.
  • a semicarbazone proteasome inhibitor is administered prior to administration of one or more pharmaceutically active agents in use against retroviral, e.g. HIV infections and/or viral hepatitis infections. Also contemplated are administration of a semicarbazone proteasome inhibitor and at least one pharmaceutically active agent in use against retroviral, e.g. HIV infections and/or viral hepatitis (e.g. HCV) infections by the same or different routes of administration, e.g., oral and parenteral. In certain embodiments, when the semicarbazone proteasome inhibitor is administered concurrently with a at least one
  • the pharmaceutically active agent in use against retroviral e.g. HIV infections and/or viral hepatitis (e.g. HCV) infections that potentially produces adverse side effects including, but not limited to, toxicity
  • the one or more different pharmaceutically active agents in use against retroviral, e.g. HIV infections and/or viral hepatitis (e.g. HCV) infections can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited.
  • kits for use in methods of treatment of an HIV infection and/or liver disorder such as virally induced hepatitis, and more specifically HCV infections.
  • the kits can include at least one semicarbazone proteasome inhibitor, optionally at least one pharmaceutically active agent in use against retroviral, e.g. HIV infections and/or viral hepatitis (e.g. HCV) infections, and instructions providing information to a health care provider regarding usage for treating the disorder. Instructions may be provided in printed form or in the form of an electronic medium such as a floppy disc, CD, or DVD, or in the form of a website address where such instructions may be obtained.
  • pharmaceutically active agent in use against retroviral e.g. HIV infections and/or viral hepatitis (e.g. HCV) infections
  • a therapeutically or prophylactically effective plasma level of the active ingredients(s) can be maintained in the patient for at least 1 day.
  • a composition can be included as a sterile aqueous
  • the kit may comprise instructions to administer at least one proteasome inhibitor and at least one anti-retro viral compound or the pharmaceutical compositions comprising the same, to a human or animal in need of treatment for an HIV-related disease, and/or a viral hepatitis infection, wherein the dose of at least one of the compounds administered is lower than otherwise recommended doses of that compound for such human or animal when said compound is used either in a monotherapy or in standard therapy for HIV infections, or in standard of care therapy for viral hepatitis infections, for anti-retroviral compounds, whichever is the lower, or when it is used without anti-retroviral compound(s) for proteasome inhibitors.
  • said dose is lower by at least a factor of 1/4, by at least a factor of 1/3, or by at least a factor 1/2 than the otherwise recommended doses suggested in the treatment of proliferative diseases as defined in WO 2007/017284 (page 30, lines 1 to 24).
  • the said dose is optionally lower by at least a factor of 1/4, by at least a factor of 1/3, or by at least a factor 1/2 than the otherwise recommended doses suggested in, for example "Guidelines for the Use of
  • suitable packaging includes a solid matrix or material customarily used in a system and capable of holding within fixed limits the at least one semicarbazone proteasome inhibitor and the optional at least one pharmaceutically active agent in use against retroviral, e.g. HIV infections and/or viral hepatitis (e.g. HCV) infections suitable for administration to a patient.
  • materials include glass and plastic (e.g., polyethylene,
  • polypropylene, and polycarbonate bottles vials, paper, plastic, and plastic-foil laminated envelopes and the like. If e-beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents.
  • the Huh-7 Luc-ubi-neo/ET replicon system an in vitro model of HCV replication.
  • the subgenomic HCV replicon system has widely been used for testing of anti-HCV compounds.
  • the Luc-ubi-neo/ET replicon cells represent a stable selected Huh-7 cell line harbouring a subgenomic HCV Conl isolate (EMBL data accession number AJ238799), supporting the autonomous HCV RNA replication in cell culture (Lohmann et al. Science 285: 110-113 (1999)). It contains the HCV 5' nontranslated region directing translation of a fusion protein that is composed of the firefly luciferase (luc), ubiquitin (ubi), and the selectable marker neomycin
  • Example 1.1 Antiviral effect vs. toxicity for the proteasome inhibitor S-2209
  • Huh-7 Luc-ubi-neo/ET cells were seeded in 24-well plates at a density of 4 x 10 4 cells per well and after overnight incubation at 37°C, cells were treated with escalating S-2209 concentrations.
  • 12h pulse treatment cell culture medium was replaced by 1ml of fresh medium 12 hours post treatment. After incubation for an additional 60h, antiviral and cytotoxic effects were determined.
  • structured treatment 24 hours after the initial treatment a repeated treatment for additional 48 hours was performed.
  • Fig. 1 Means and standard deviations of a representative experiment are shown in Fig. 1.
  • S-2209 concentration necessary to inhibit the HCV-replicon-associated luciferase activity by 50% was about 1.3 ⁇ for the structured treatment, and about 7.4 ⁇ for the 12h pulse treatment. (See Fig. 1)
  • the colorimetric WST-1 assay (Roche) is based on the enzymatic cleavage of the tetrazolium salt WST-1 to formazan by cellular mitochondrial dehydrogenases present in viable cells, and is therefore used as a read-out system for cell viability and/or toxicity.
  • Cell culture medium of cells treated in duplicate for each individual drug- combination, was replaced by 0.33 ml cell culture medium supplemented with 10%) WST-1 reagent, incubated for 1 to 3 hours at 37°C and optical density at 450 nm and 650 nm, last-mentioned for the determination of background, was measured in a microplate reader (Synergy 2, BioTek). Means and standard deviations of a representative experiment are shown in Fig. 2.
  • Huh-7 Luc-ubi-neo/ET cells were seeded in 24-well plates at a density of 4 x 10 4 cells per well and, after overnight incubation at 37°C, cells were treated with a nontoxic concentration of S-2209 (1.85 ⁇ ) or fresh medium. Twenty four hours later cell culture medium was removed and cells were cultured for additional 24h with 1ml fresh medium or medium either supplemented with 0.75 U/ml IFN-a (Roferon A, Roche), 0.25 U/ml IFN- ⁇ (Roche) or 100 U/ml IL-6 (Roche). Finally, HCV replicon activity was determined by luciferase activity measurement. Means and standard deviations of a representative experiment are shown in Fig. 3.
  • Huh-7 Luc-ubi-neo/ET replicon cells were seeded onto glass cover slips in 24-well plates at a density of 6xl0 4 cells per well.
  • cells were treated 24 h after seeding with a non-toxic concentration of S-2209 (1.85 ⁇ ) or fresh medium. After 24 hours cell culture medium was replaced by fresh medium or medium supplemented with 100 U/ml IL- 6 (Roche) and incubated for additional 3 hours at 37°C.
  • Huh-7 Luc-ubi-neo/ET cells were seeded in 24-well plates at a density of 4 x 10 4 cells per well and after overnight incubation at 37°C cells were treated with a nontoxic concentration of Stattic (5 ⁇ ) (Merck) or fresh medium. One hour later cell culture medium was removed and cells were cultured for additional 24h with escalating concentrations of S-2209 or IFN-a (Roferon A, Roche). Subsequently the antiviral effect was determined by measurement of the luciferase activity.
  • Huh-7 Luc-ubi-neo/ET cells were seeded in 24-well plates at a density of 4 x 10 4 cells per well and after overnight incubation at 37°C cells were treated with a non-toxic concentration of Stattic (5 ⁇ ) (Merck) or fresh medium. Two hours later cell culture medium was removed and cells were cultured for additional 24 hours with fresh medium or medium supplemented with 1.85 ⁇ S- 2209. Twenty four hours later cell culture medium was removed and cells were cultured for additional 24h with 1ml fresh medium or medium supplemented with 0.75 U/ml IFN-a.
  • STAT proteins are latent cytoplasmic transcription factors that are phosphorylated by Janus kinases in response to cytokines after binding to their corresponding cell surface receptors. Phosphorylated STAT proteins translocate to the nucleus, where they transiently turn on specific sets of cytokine-inducible genes. IFN- ⁇ / ⁇ and IFN-y activate STAT1 proteins after receptor-binding and induce an antiviral (including anti-HCV) status in target cells. In contrast to interferons, IL-6 activates predominantly STAT3.
  • S-2209 slightly induces STAT3 phosphorylation in Huh7 replicon cells, whereas STAT1 was unaffected in cells treated with S-2209 or with the combination of S- 2209 and IFN-a. However, more important is the observation, that S-2209 in combination with IL-6 or IFN-a cooperatively induce STAT3- phosphorylation.
  • Stattic a selective inhibitor of STAT3 activation (Schust et al, Chem. & Biol.
  • Pathogen-free human buffy coat preparations were obtained from a blood bank (lymphocyte concentrate from 500 ml whole blood, Institut fur Trans fusionstechnik Suhl mannnutzige GmbH, Suhl, Germany), were transferred into sterile 50 ml tubes and diluted 1 : 1 with PBS. The diluted preparation was overlaid in another sterile 50 ml tube on 15 ml Ficoll-Histopaque (Sigma- Aldrich, Cat. H8889) and centrifuged at 2.200 rpm (Heraeus Multifuge 3SR) for 20 min without brakes. The white interphase layer formed by peripheral blood mononuclear cells (PBMC) was transferred in a fresh tube and washed twice with ice cold PBS. Subsequently, the cell count was determined by Trypan Blue staining and the cells were adjusted to 5 x 10 6 per ml and cultured in supplemented RPMI 1640.
  • PBMC peripheral blood mononuclear cells
  • cells were pre-stimulated with 10 ⁇ g/ml PHA-P (Sigma- Aldrich,Cat. No. L1668-5mg) and 100 U/ml IL-2 (Proleukin, Roche) and the culture was allowed to grow for at least 72 h.
  • PHA-P Sigma- Aldrich,Cat. No. L1668-5mg
  • IL-2 Proleukin, Roche
  • Tonsil tissue was removed during routine tonsillectomy from HIV, HBV, HCV- negative patients. Tonsils were washed carefully with PBS and capsula, brown necrotic and bloody regions were removed.
  • HLAC Human Lymphoid Aggregate Culture
  • tonsil tissue was mechanically dispersed by cutting tissue in 2- to 3-mm blocks and passing them through 70- ⁇ cell strainers with the plunger of a 2-ml syringe. The cell strainer was washed with PBS and cells were spun down for 5 min at 500 rcf at room temperature.
  • HIV virus stock preparation by transfection of 293T cells
  • Virus stocks were generated by transient transfection of 293T cells using
  • Lipofectamine 2000TM according to manufacturer's protocols.
  • 0.5 x 10 5 293T cells were seeded in 15 ml DMEM in T75 flasks. At a confluence of 50-75% the cells were used for transfection.
  • 48 h post transfection supernatants were collected and centrifuged at 1200 rpm for 5 min (Heraeus Multifuge 3SR). After centrifugation, the supernatant was passed through a 45 ⁇ sterile filter. 1 ml supernatant was overlaid on 200 ⁇ 2% sucrose in a eppendorf tube and centrifuged at 14000 rpm (Eppendorf Centrifuge, model 5417R) for 90 min at 4°C.
  • virus pellet was re-suspended in 50 ⁇ RPMI 1640 and pellets were collected to a final volume of 750 ⁇ virus stock.
  • the HIV-1 p24 antigen concentration of virus stocks was determined by p24 antigen enzyme-linked immunosorbent assay
  • Apoptosis is a tightly regulated process, characterized by DNA fragmentation, shrinkage of cytoplasm, and reassembly of membranes.
  • phosphatidylserine PS
  • PS is located on the cytoplasmic surface of the cell membrane.
  • Annexin V a human anticoagulant conjugated to a fluorophore, binds to PS and can therefore identify apoptotic cells.
  • Propidium iodide is impermeant to live and apoptotic cells, but stains dead cells with red fluorescence by binding tightly to nucleic acids made accessible to membrane impermeant agents only by cell death. Staining a population of cells with Annexin V and PI leads to different fluorescent cell populations, of which apoptotic cells show a green fluorescence, dead cells show a green and red fluorescence, whereas live cells appear unstained. Cells were stained following the protocols described in Immunol Cell Biol 1998, 76:1.
  • the p24 antigen ELISA is a standard method for detection of released HIV viral particles in the supernatant of tissue cell culture or blood samples of patients.
  • the assay was performed using a commercially available assay kit following
  • the area under the curve is calculated for a plot of 32 P-radioactivity in supernatant samples vs. time as an indicator for total viral replication.
  • the average area under the curve obtained from untreated infected samples is defined as 100%, and the results for samples having been treated with test substances are expressed relative to this value.
  • Example 2.2 Inhibition of HIV replication in human lymphoid aggregate cultures
  • HLAC were infected with HIV-1NL4/3 (1 ng p24 per well).
  • Example 2.2.1 Inhibitory potency and cytotoxicity of a proteasome inhibitor (S- 2209)
  • IC 50 concentration yielding 50% inhibition
  • CC 50 concentration yielding 50% cytotoxicity
  • HLAC medium RPMI 1640 containing 15% fetal bovine serum, 2 mM L-glutamine, 100 U/ml PenStrep, 2,5 ⁇ g/ml fungizone, 1 mM sodium pyruvate, 1% non-essential amino acids, 50 ⁇ g/ml gentamycin
  • S-2209 concentrations ranging from 0 nM (mock treated) to 100 ⁇
  • HLAC infected with HIV-1NL4/3 immediately post-infection for S-2209 IC 50
  • uninfected HLAC for cytotoxicity assessment
  • the medium containing S-2209 was exchanged for fresh HLAC medium, and the cultures incubated for another 12 days (up to day 15 post infection) under HLAC medium, exchanging the HLAC medium for fresh HLAC medium every 72 h.
  • Culture supernatants were removed on days 1 , 3, 6, 9, 12 and 15, and HIV-1 replication in infected cultures assessed by RT assay. The amounts of radioactivity measured in these samples were summed up to yield a number roughly corresponding to an aggregate viral production.
  • the co-treated uninfected cultures were subjected to Annexin/PI staining for assessment of cytotoxicity on the day of peak HIV-1 replication in the infected culture treated with the same inhibitor concentration.
  • the average value obtained for mock treated cells was set to 100% replication and 100% viable cells, respectively. All other results were expressed relative to these values.
  • Polynomial regression (4-parameter, GraphPad Prism, GraphPad Software, La Jolla, CA, USA) on the resulting data points yielded an IC 50 (EC 50 ) for inhibiting HIV-1 replication by S-2209 of approximately 375 nM (see Fig. 10), and a CC 50 of approximately 5500 nM (see Fig. 1 l)under the conditions of the experiment as described. It was therefore established, that the inhibition of HIV- 1 replication was not due to S- 2209 rendering the cells non-viable.
  • Example 2.2.2 Comparison of the time course of inhibition of a proteasome inhibitor (S-2209), an agent inhibiting a viral target (protease inhibitor darunavir)
  • the time course of the inhibitory efficacy of a concentration of S-2209 giving near 100% inhibition of peak replication in Example 2.1 was compared to the comparable activity of an agent inhibiting a viral target, which is used routinely in the therapy of HIV infection (darunavir, DRV).
  • HLAC infected with HIV-l N L4/3 were treated with HLAC medium containing 750 nM S-2209 or 15 nM DRV (EC/IC 50 for DRV: 8 nM under the conditions of this experiment, data not shown) for 24 h, the HLAC medium containing the respective agent exchanged for fresh HLAC medium containing the respective agent, and the incubation continued for another 48 h. Subsequently, the medium containing S-2209 or DRV was exchanged for fresh HLAC medium, and the cultures incubated for another 18 days (up to day 21 post infection) under HLAC medium, exchanging the HLAC medium for fresh HLAC medium every 72 h.
  • HLAC were treated with the following regimens (see also Fig. 12):
  • Mock infected cells served as negative (background) controls.
  • Two sets of experiments were performed. In the first, concentrations of 15 nM DRV and 500 nM S-2209 were used for the cells treated with the either DRV or S-2209, and 15 nM DRV and 100 nM S-2209 were used on cells sequentially treated with both substances; supernatant samples were harvested and stored at -80°C for subsequent analysis by RT -Assay or p24-ELISA with every medium exchange. The results of this set of experiments are shown in Fig. 13.
  • a concentration of DRV was used that had previously been found to inhibit viral replication under the conditions of this experiment by about 50% (EC 50 /IC 50 ) compared to untreated controls, up to about the point in time when viral loads start to decrease in untreated cells due to a lack of uninfected cells available for new productive infection, namely 7.5 nM DRV.
  • Post infection cells were hence treated with 7.5 nM DRV on days 1 to 3, 100 nM S-2209 on days 4 to 12, or a combination of both treatments, and supernatant samples were collected for 32 P analysis on days 1, 3, 6, 9, 12 and 15. The amounts of radioactivity measured in these samples were summed up to yield a number roughly
  • Cells of macrophage lineage represent a key target of human immunodeficiency virus (HIV) in addition to CD4-lymphocytes.
  • HIV human immunodeficiency virus
  • the absolute number of infected macrophages in the body is relatively low compared to CD4-lymphocytes.
  • protease inhibitors acting at post-integrational stages of virus replication, are the only drugs able to interfere with virus production and release from macrophages with established and persistent HIV infection (chronically- infected cells). Since this effect is achieved at concentrations and doses higher than those effective in de-novo infected CD4-lymphocytes, it is possible that lack of adherence to therapy, and/or suboptimal dosage leading to insufficient concentrations of protease inhibitors may cause a resumption of virus replication from chronically- infected macrophages, ultimately resulting in therapeutic failure. For all these reasons, therapeutic strategies aimed to achieve the greatest and longest control of HIV replication should inhibit HIV not only in CD4-lymphocytes, but also in macrophages. (Aquaro, S., et al, Antiviral Research 2002, 55:209-225).
  • Macrophage medium DMEM containing 10% human serum, 5 mM glutamine, 5 mM PenStrep, 1 mM sodium pyruvate
  • DMEM fetal calf serum
  • PenStrep 1 mM sodium pyruvate
  • HIV-1-NL4/3-IRES-GFP is a modified pBR-322 vector (Promega GmbH,
  • Macrophages were re-seeded in 24-well plates at a density of 5 x 10 4 cells per well.
  • Cells were infected with 20 ng HIV-1-NL4/3-IRES-GFP (M-tropic) in a final volume of 250 ⁇ per well.
  • M-tropic HIV-1-NL4/3-IRES-GFP
  • S-2209 treatment was performed during infection and on day one post infection.
  • Days three and 10 post infection cells were analyzed by fluorescence microscopy.
  • HIV infection may be eradicated from human macrophages by treatment with proteasome inhibitors
  • HIV infection can effectively be suppressed in monocyte derived macrophages by treatment with a proteasome inhibitor, and preferably by treatment with S-2209, thereby reducing or eliminating the potential of infected macrophages to act as a viral reservoir.
  • Example 2.4 Inhibition of replication of an omni-resistant HIV isolate.
  • NRTIs Nucleoside analog reverse transcriptase inhibitors
  • NRTIs Non-nucleoside reverse transcriptase inhibitors
  • NVP - Nevirapine >72. Inhibition of replication of omni-resistant strain HIVJ LRI
  • HLAC medium was supplemented with S-2209 to attain concentrations of 250 nM, 500 nM, 750 nM or 1 ⁇ , or with darunavir (DRV) to a concentration of 15 nM, saquinavir (SQV) to a concentration of 20 nM, nevirapine (NVP) to a concentration of 200 nM, or lamivudine (3TC) to a concentration of 300 nM.
  • DDV darunavir
  • SQV saquinavir
  • NDP nevirapine
  • 3TC lamivudine
  • HLAC were treated with medium comprising S-2209 on the day of infection and again 24 h later, finally exchanging the medium comprising S-2209 for plain medium on day 3 (i.e. treatment with S-2209 lasted from the day of infection until the medium change on day 3), while DRV, SQV, NVP, 3TC treatment was performed over the whole course of the experiment until termination.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Oncology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des inhibiteurs du protéasome à base de semicarbazone, des compositions pharmaceutiques les comprenant, des utilisations desdits inhibiteurs du protéasome à base de semicarbazone et desdites compositions pharmaceutiques les comprenant dans le traitement d'infections par un virus de l'hépatite, en particulier dans le traitement d'infections par le VHC et/ou d'infections par le VIH.
PCT/EP2011/050711 2010-01-19 2011-01-19 Inhibiteurs du protéasome à base de semicarbazone pour traiter une infection par le vih et une infection par une hépatite WO2011089166A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US29636310P 2010-01-19 2010-01-19
EP10151135 2010-01-19
EP10151135.0 2010-01-19
US61/296,363 2010-01-19
US12/843,650 2010-07-26
EPPCT/EP2010/060796 2010-07-26
PCT/EP2010/060796 WO2011009961A1 (fr) 2009-07-24 2010-07-26 Association d'inhibiteurs du protéasome et de médicaments anti-hépatite dans le traitement de l'hépatite
US12/843,650 US20110020272A1 (en) 2009-07-24 2010-07-26 Combination therapy for treating hepatitis viral infection

Publications (1)

Publication Number Publication Date
WO2011089166A1 true WO2011089166A1 (fr) 2011-07-28

Family

ID=44306409

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP2011/050711 WO2011089166A1 (fr) 2010-01-19 2011-01-19 Inhibiteurs du protéasome à base de semicarbazone pour traiter une infection par le vih et une infection par une hépatite
PCT/EP2011/050712 WO2011089167A1 (fr) 2010-01-19 2011-01-19 Inhibiteur du protéasome destiné à traiter le vih

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/EP2011/050712 WO2011089167A1 (fr) 2010-01-19 2011-01-19 Inhibiteur du protéasome destiné à traiter le vih

Country Status (1)

Country Link
WO (2) WO2011089166A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016137844A1 (fr) 2015-02-23 2016-09-01 Mayo Foundation For Medical Education And Research Méthodes et matières pour traiter des infections au virus de l'immunodéficience humaine
CN113845461A (zh) * 2021-10-11 2021-12-28 浙江师范大学行知学院 一种4-(2-金刚烷-1h-吲哚-5-基)氨基脲衍生物及其制备方法和用途
US11938098B2 (en) 2015-04-20 2024-03-26 Mayo Foundation For Medical Education And Research Method for killing HIV-infected cells using Bcl-2 inhibitors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111202723A (zh) * 2020-02-15 2020-05-29 江苏艾立康药业股份有限公司 一种达芦那韦吸入干粉药物组合物及其制备方法

Citations (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536809A (en) 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US5059595A (en) 1989-03-22 1991-10-22 Bioresearch, S.P.A. Pharmaceutical compositions containing 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutically acceptable salts in controlled-release form active in the therapy of organic mental disturbances
US5073543A (en) 1988-07-21 1991-12-17 G. D. Searle & Co. Controlled release formulations of trophic factors in ganglioside-lipsome vehicle
US5120548A (en) 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US5354556A (en) 1984-10-30 1994-10-11 Elan Corporation, Plc Controlled release powder and process for its preparation
US5591767A (en) 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
US5639476A (en) 1992-01-27 1997-06-17 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5639480A (en) 1989-07-07 1997-06-17 Sandoz Ltd. Sustained release formulations of water soluble peptides
US5674533A (en) 1994-07-07 1997-10-07 Recordati, S.A., Chemical And Pharmaceutical Company Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension
US5733566A (en) 1990-05-15 1998-03-31 Alkermes Controlled Therapeutics Inc. Ii Controlled release of antiparasitic agents in animals
US5739108A (en) 1984-10-04 1998-04-14 Monsanto Company Prolonged release of biologically active polypeptides
US5891474A (en) 1997-01-29 1999-04-06 Poli Industria Chimica, S.P.A. Time-specific controlled release dosage formulations and method of preparing same
US5922356A (en) 1996-10-09 1999-07-13 Sumitomo Pharmaceuticals Company, Limited Sustained release formulation
US5972891A (en) 1992-12-07 1999-10-26 Takeda Chemical Industries, Ltd. Sustained-release preparation
US5980945A (en) 1996-01-16 1999-11-09 Societe De Conseils De Recherches Et D'applications Scientifique S.A. Sustained release drug formulations
US5993855A (en) 1995-09-18 1999-11-30 Shiseido Company, Ltd. Delayed drug-releasing microspheres
US6045830A (en) 1995-09-04 2000-04-04 Takeda Chemical Industries, Ltd. Method of production of sustained-release preparation
WO2000033654A1 (fr) 1998-12-04 2000-06-15 University Of Maryland Biotechnology Institute Utilisation d'inhibiteurs de protease pour moduler les chemins cellulaires, immunite et therapies associees
EP1015113A1 (fr) 1997-05-02 2000-07-05 Project S.A.S. Di Menichelli Massimo Dispositif de dosage progressif a butoir pour le bouchon a vis de flacons de liquide comportant une seringue servant a aspirer des doses de liquide
US6087324A (en) 1993-06-24 2000-07-11 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6113943A (en) 1996-10-31 2000-09-05 Takeda Chemical Industries, Ltd. Sustained-release preparation capable of releasing a physiologically active substance
US6197350B1 (en) 1996-12-20 2001-03-06 Takeda Chemical Industries, Ltd. Method of producing a sustained-release preparation
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US6264970B1 (en) 1996-06-26 2001-07-24 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6267981B1 (en) 1995-06-27 2001-07-31 Takeda Chemical Industries, Ltd. Method of producing sustained-release preparation
US6419961B1 (en) 1996-08-29 2002-07-16 Takeda Chemical Industries, Ltd. Sustained release microcapsules of a bioactive substance and a biodegradable polymer
US6589548B1 (en) 1998-05-16 2003-07-08 Mogam Biotechnology Research Institute Controlled drug delivery system using the conjugation of drug to biodegradable polyester
US6613358B2 (en) 1998-03-18 2003-09-02 Theodore W. Randolph Sustained-release composition including amorphous polymer
EP1752467A1 (fr) * 2005-08-10 2007-02-14 4Sc Ag Inhibiteurs de la proliferation de cellules cancereuses, de cellules t, et de keratinocytes

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2425632A1 (fr) * 2000-10-12 2002-04-18 Viromics Gmbh Moyens pour le traitement d'infections a des virus
WO2003002126A1 (fr) * 2001-06-28 2003-01-09 University Of Pretoria Agent antiretroviral en combinaison avec du polyphenol de the pour le traitement d'infections virales
WO2006017346A1 (fr) * 2004-07-13 2006-02-16 GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH A ND HUMAN SERVICES OFFICE OF TECHNOLOGY TRANSFER Traitement d'infections virales au moyen d'inhibiteurs de proteasome

Patent Citations (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536809A (en) 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US5739108A (en) 1984-10-04 1998-04-14 Monsanto Company Prolonged release of biologically active polypeptides
US5354556A (en) 1984-10-30 1994-10-11 Elan Corporation, Plc Controlled release powder and process for its preparation
US5073543A (en) 1988-07-21 1991-12-17 G. D. Searle & Co. Controlled release formulations of trophic factors in ganglioside-lipsome vehicle
US5059595A (en) 1989-03-22 1991-10-22 Bioresearch, S.P.A. Pharmaceutical compositions containing 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutically acceptable salts in controlled-release form active in the therapy of organic mental disturbances
US5639480A (en) 1989-07-07 1997-06-17 Sandoz Ltd. Sustained release formulations of water soluble peptides
US5120548A (en) 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US5733566A (en) 1990-05-15 1998-03-31 Alkermes Controlled Therapeutics Inc. Ii Controlled release of antiparasitic agents in animals
US5639476A (en) 1992-01-27 1997-06-17 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5972891A (en) 1992-12-07 1999-10-26 Takeda Chemical Industries, Ltd. Sustained-release preparation
US5591767A (en) 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
US6087324A (en) 1993-06-24 2000-07-11 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6376461B1 (en) 1993-06-24 2002-04-23 Takeda Chemical Industries, Ltd. Sustained-release preparation
US5674533A (en) 1994-07-07 1997-10-07 Recordati, S.A., Chemical And Pharmaceutical Company Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension
US6267981B1 (en) 1995-06-27 2001-07-31 Takeda Chemical Industries, Ltd. Method of producing sustained-release preparation
US6045830A (en) 1995-09-04 2000-04-04 Takeda Chemical Industries, Ltd. Method of production of sustained-release preparation
US5993855A (en) 1995-09-18 1999-11-30 Shiseido Company, Ltd. Delayed drug-releasing microspheres
US5980945A (en) 1996-01-16 1999-11-09 Societe De Conseils De Recherches Et D'applications Scientifique S.A. Sustained release drug formulations
US6264970B1 (en) 1996-06-26 2001-07-24 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6419961B1 (en) 1996-08-29 2002-07-16 Takeda Chemical Industries, Ltd. Sustained release microcapsules of a bioactive substance and a biodegradable polymer
US5922356A (en) 1996-10-09 1999-07-13 Sumitomo Pharmaceuticals Company, Limited Sustained release formulation
US6699500B2 (en) 1996-10-31 2004-03-02 Takeda Chemical Industries, Ltd. Sustained-release preparation capable of releasing a physiologically active substance
US6113943A (en) 1996-10-31 2000-09-05 Takeda Chemical Industries, Ltd. Sustained-release preparation capable of releasing a physiologically active substance
US6197350B1 (en) 1996-12-20 2001-03-06 Takeda Chemical Industries, Ltd. Method of producing a sustained-release preparation
US5891474A (en) 1997-01-29 1999-04-06 Poli Industria Chimica, S.P.A. Time-specific controlled release dosage formulations and method of preparing same
EP1015113A1 (fr) 1997-05-02 2000-07-05 Project S.A.S. Di Menichelli Massimo Dispositif de dosage progressif a butoir pour le bouchon a vis de flacons de liquide comportant une seringue servant a aspirer des doses de liquide
US6613358B2 (en) 1998-03-18 2003-09-02 Theodore W. Randolph Sustained-release composition including amorphous polymer
US6589548B1 (en) 1998-05-16 2003-07-08 Mogam Biotechnology Research Institute Controlled drug delivery system using the conjugation of drug to biodegradable polyester
WO2000033654A1 (fr) 1998-12-04 2000-06-15 University Of Maryland Biotechnology Institute Utilisation d'inhibiteurs de protease pour moduler les chemins cellulaires, immunite et therapies associees
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
EP1752467A1 (fr) * 2005-08-10 2007-02-14 4Sc Ag Inhibiteurs de la proliferation de cellules cancereuses, de cellules t, et de keratinocytes
WO2007017284A2 (fr) 2005-08-10 2007-02-15 4Sc Ag Inhibiteurs de pproliferation de cellules cancereuses, de lymphocytes t et de keratinocytes

Non-Patent Citations (69)

* Cited by examiner, † Cited by third party
Title
"Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics", 1996, MC-GRAW-HILL
"Introduction to Pharmaceutical Dosage Forms", 1985, LEA & FEBIGER
"Panel on Antiretroviral Guidelines for Adults and Adolescents", 10 January 2011, THE U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, article "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents", pages: 1 - 166
"Physician's Desk Reference (PDR)", 2003, MEDICAL ECONOMICS CO., INC.
"Remington's Pharmaceutical Sciences", 1980, MACK PUBLISHING
"Remington's Pharmaceutical Sciences", 2000, MACK PUBLISHING
ADAMS, J. ET AL., CANCER RESEARCH, vol. 59, 1999, pages 2615
ANDRE ET AL., PROC. NATL. ACAD. SCI. USA, vol. 95, 1998, pages 1312
AQUARO, S. ET AL., ANTIVIRAL RESEARCH, vol. 55, 2002, pages 209 - 225
AYGIN, JK ET AL., BREAST CANCER RES., vol. 11, 2009, pages R74
BARRE-SINOUSSI ET AL., SCIENCE, vol. 220, 1983, pages 868 - 871
BAUMANN ET AL., BRIT. J. HAEMATOLOGY, vol. 144, 2009, pages 875 - 886
BUCHWALD ET AL., SURGERY, vol. 88, 1980, pages 507
CLAVEL, F., AIDS, vol. 1, pages 135 - 140
DEMO, SD., CANCER RES., vol. 67, 2007, pages 6383
DOOLITTLE, R F ET AL., CURR. TOP. MICROBIOL. IMMUNOL., vol. 157, 1990, pages 1 - 18
GALLO ET AL., SCIENCE, vol. 224, 1984, pages 500 - 503
GOODSON, MEDICAL APPLICATIONS OF CONTROLLED RELEASE, vol. 2, 1984, pages 115 - 138
GROLL M ET AL., J. AM. CHEM. SOC., vol. 122, 2000, pages 1237
GROLL M ET AL., NATURE, vol. 386, 1997, pages 463
GROLL, M. ET AL., J. PEPT. SCI., vol. 15, 2009, pages 58
H. DANCYGIER: "Klinische Hepatologie", 2003, SPRINGER-VERLAG, pages: 489
HANADA, M. ET AL., J. ANTIBIOT., vol. 45, 1992, pages 1746
HINES J. ET AL., CHEM. BIOL., vol. 15, 2008, pages 501
HO, Y.K. ET AL., CHEM. BIOL., vol. 14, 2007, pages 419
HUANG, L.; CHEN, CH, CURRENT MEDICINAL CHEMISTRY, vol. 16, 2009, pages 931
IMMUNOL CELL BIOL, vol. 76, 1998, pages 1
KOGUCHI, Y ET AL., J. ANTIBIOT., vol. 53, 2000, pages 967
KOGUCHI, Y. ET AL., J. ANTIBIOT., vol. 53, 2000, pages 63
KOGUCHI, Y., J. ANTIBIOT., vol. 53, 2000, pages 105
KOHNO, J., ORG. CHEM., vol. 65, 2000, pages 990
KRONENBERGER, B.; ZEUZEM, S., ANNALS OF HEPATOLOGY, vol. 8, 2009, pages 103
KUHN, DJ ET AL., BLOOD, vol. 110, 2007, pages 3281
LANGER, SCIENCE, vol. 249, 1990, pages 1527
LEBAN J. ET AL., BIOORG. MED. CHEM., vol. 16, 2008, pages 4579
LESINSKI ET AL., CANCER IMMUNOL IMMUNOTHER, vol. 58, 2009, pages 2031
LEVY ET AL., SCIENCE, vol. 225, 1984, pages 840 - 842
LOHMANN ET AL., J.VIROL., vol. 77, 2003, pages 3007 - 3019
LOHMANN ET AL., SCIENCE, vol. 285, 1999, pages 110 - 113
LOWE J ET AL., SCIENCE, vol. 268, 1995, pages 533
MASAO, A. ET AL., JOURNAL OF GASTROENTEROLOGY, vol. 30, 1995, pages 539
MATSUNAGA, T. ET AL., JOURNAL OF THE JAPAN PEDIATRIC SOCIETY, vol. 107, 2003, pages 1645
MOMOSE, I. ET AL., BIOORG. MED. CHEM. LETT., vol. 15, 2005, pages 1867
MOMOSE, I. ET AL., J. ANTIBIOTICS, vol. 54, 2001, pages 997
MOORE ET AL., J.VIROL., vol. 65, 1991, pages 852 - 860
MOORE ET AL., SCIENCE, vol. 250, 1990, pages 1139 - 1142
MUCHAMUEL, T. ET AL., NATURE MEDICINE, vol. 15, 2009, pages 7
OTT ET AL., J. VIROL., vol. 72, 1998, pages 2962
PALELLA FJ JR ET AL., N. ENGL. J. MED, vol. 338, no. 13, 1998, pages 853 - 860
PEESE, K., DRUG DISCOVERY TODAY, vol. 14, 2009, pages 905
PINKEL, D., CANCER RES., vol. 18, 1958, pages 853
POPOVIC ET AL., SCIENCE, vol. 224, 1984, pages 497 - 500
PURANDARE, AS ET AL., AM. ASSOC. CANCER RES. ANNUAL MEETING, 15 April 2007 (2007-04-15)
SARNGADHARAN ET AL., SCIENCE, vol. 224, 1984, pages 506 - 508
SAUDEK ET AL., N. ENGL. J. MED., vol. 321, 1989, pages 574
SCHINDLER, M. ET AL., J. VIROL., vol. 77, 2003, pages 10548 - 10556
SCHINDLER, M., J. VIROL., vol. 79, 2005, pages 5489 - 5498
SCHMIDTKE ET AL., J. BIOL. CHEM., vol. 274, 1999, pages 35734
SCHUBERT ET AL., J. VIROL., vol. 72, 1998, pages 2280
SCHUST ET AL., CHEM. & BIOL., vol. 13, 2006, pages 1235 - 1242
SEFTON, CRC CRIT. REF. BIOMED. ENG., vol. 14, 1987, pages 201
SIEGAL ET AL., N1 ENGL. J. MED., vol. 305, 1981, pages 1439 - 1444
SWANSTROM, R; WILLS, J ET AL.: "Retroviruses", 1997, COLD SPRING HARBOR PRESS, pages: 263 - 334
TAYLOR GP; MATSUOKA M, ONCOGENE, vol. 24, no. 39, September 2005 (2005-09-01), pages 6047 - 57
THOMPSON, A. ET AL., J. HEPATOLOGY, vol. 50, 2009, pages 184
VIGNERON, N., SCIENCE, vol. 304, 2004, pages 587
VROLIJK ET AL., J.VIROL. METHODS, vol. 110, 2003, pages 201 - 209
WALTER, H., J CLIN VIROL, vol. 13, 1999, pages 71 - 80
WILLEY RL ET AL., J VIROL, vol. 62, 1988, pages 139 - 147

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016137844A1 (fr) 2015-02-23 2016-09-01 Mayo Foundation For Medical Education And Research Méthodes et matières pour traiter des infections au virus de l'immunodéficience humaine
EP3261439A4 (fr) * 2015-02-23 2019-01-09 Mayo Foundation For Medical Education And Research Méthodes et matières pour traiter des infections au virus de l'immunodéficience humaine
US10786519B2 (en) 2015-02-23 2020-09-29 Mayo Foundation For Medical Education And Research Methods and materials for treating human immunodeficiency virus infections
US11376268B2 (en) 2015-02-23 2022-07-05 Mayo Foundation For Medical Education And Research Methods and materials for treating human immunodeficiency virus infections
US11938098B2 (en) 2015-04-20 2024-03-26 Mayo Foundation For Medical Education And Research Method for killing HIV-infected cells using Bcl-2 inhibitors
CN113845461A (zh) * 2021-10-11 2021-12-28 浙江师范大学行知学院 一种4-(2-金刚烷-1h-吲哚-5-基)氨基脲衍生物及其制备方法和用途

Also Published As

Publication number Publication date
WO2011089167A1 (fr) 2011-07-28

Similar Documents

Publication Publication Date Title
US20110020272A1 (en) Combination therapy for treating hepatitis viral infection
US9060971B2 (en) Combination pharmaceutical agents as inhibitors of HCV replication
KR101755058B1 (ko) 특정 ｈｃｖ ｎｓ５ａ 억제제 및 ｈｃｖ ｎｓ３ 프로테아제 억제제의 조합물
US7635690B2 (en) HIV-1 mutations selected for by β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine
KR20140002611A (ko) Ｃ형 간염 바이러스 억제제의 조합
PT1326632E (pt) Tratamento para o tratamento de infecções por vírus da hepatite
US20100173837A1 (en) Dosing forms and regimens comprising 3-[(r)-2-(n,n-dimethylamino)ethylthio-sar]-4-(gammahydroxymethylleucine)cyclosporine
Xu et al. Drug repurposing approach to combating coronavirus: Potential drugs and drug targets
MX2011002896A (es) Combinaciones sinergicas de un inhibidor macrociclico del virus de la hepatitis c y un nucleosido.
MX2007003853A (es) Composiciones antivirales en combinacion que comprenden castanospermina y metodos de uso.
US8912141B2 (en) Treatment of hepatitis C virus
WO2021209563A1 (fr) Composés destinés à être utilisés dans le traitement d'infections virales par un coronavirus associé au syndrome respiratoire
MX2011003121A (es) Regimen terapeutico que comprende polietilenglicol-interferon, ribavirina y vx-950 para el tratamiento de la hepatitis.
WO2011089166A1 (fr) Inhibiteurs du protéasome à base de semicarbazone pour traiter une infection par le vih et une infection par une hépatite
US9833492B2 (en) Combinations of a caspase inhibitor and an antiviral agent
US20230158103A1 (en) Pld for use in combination in the treatment of coronavirus
US7115584B2 (en) HIV-1 mutations selected for by β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine
EP1143976B1 (fr) MUTATIONS DE VIH-1 SELECTIONNEES A L'AIDE DE $g(b)-2',3'-DIDEHYDRO-2',3'-DIDEOXY-5-FLUOROCYTIDINE
US20190046552A1 (en) Compositions and methods for the treatment of hcv infection
Dharmaraj et al. Treatment of Covid-19: A review
Dharmaraj et al. World Journal of Biology Pharmacy and Health Sciences
EP1731155A2 (fr) Beta-D-2', 3' -Didehydro-2', 3' -Dideoxy-5-Fluorcydine pour l´ utilisation dans le traitement d´une infection par le HIV
JP2015509980A (ja) Ｈｃｖ−ｈｉｖ同時感染患者集団のｈｃｖ感染症を治療するための併用療法
MXPA05012352A (en) Compositions for down-regulation of ccr5 expression and methods of use therefor

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11717972

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11717972

Country of ref document: EP

Kind code of ref document: A1