WO2017060524A1 - (e)-n-(2-aminophényl)-3-(1-((4-(1-méthyl-1h-pyrazol-4-yl)phényl)sulfonyl)-1h-pyrrol-3-yl)acrylamide pour le traitement d'infections virales latentes - Google Patents

(e)-n-(2-aminophényl)-3-(1-((4-(1-méthyl-1h-pyrazol-4-yl)phényl)sulfonyl)-1h-pyrrol-3-yl)acrylamide pour le traitement d'infections virales latentes Download PDF

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WO2017060524A1
WO2017060524A1 PCT/EP2016/074197 EP2016074197W WO2017060524A1 WO 2017060524 A1 WO2017060524 A1 WO 2017060524A1 EP 2016074197 W EP2016074197 W EP 2016074197W WO 2017060524 A1 WO2017060524 A1 WO 2017060524A1
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hiv
virus
cells
methyl
treatment
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PCT/EP2016/074197
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Hella KOHLHOF
Manfred GRÖPPEL
Daniel Vitt
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4Sc Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • HHV, EBV, HCMV and HBV have the ability to enter a latent (dormant) state.
  • the viral genetic information is integrated into cells of the host, and the infection persists although proliferation and production of virus particles ceases.
  • viral proliferation can be reactivated, resulting in the production of viral progeny without a new infection of the host.
  • the latent virus can stay within the host throughout the host's lifetime.
  • Episomal latency is generated via the introduction of stabilized genetic episomes of viral nucleic acids present into the cytoplasm or nucleus of the host cell.
  • Herpesviridae such as Chicken-pox virus and Herpes simplex viruses (HSV-1 , HSV-2) are capable of establishing latent infection via episomal latency in the cytoplasm of the host's cells, e.g. neurons or immune system cells, e.g. B-cells in the case of Epstcin-Barr Virus (EBV).
  • EBV Epstcin-Barr Virus
  • Viral genetic episomes may be prone to degradation via cellular enzymes, thus potentially removing the virus from the cell.
  • proviral latency viral genome is directly integrated into the DNA of the host cell. Upon division of the host cell, the virus gene is thus replicated along with the cells genome.
  • the expression of specific viral genes during latency serves to maintain latency, e.g. to prevent episomes from being digested by cellular ribozymes or prevent cells from being identified and Inactivated (e.g. killed) by the immune system.
  • Viral gene products can also inhibit apoptosis to maintain infected cells viable over prolonged periods of time, or induce ceil growth and division to allow more copies of the infected cell to be produced.
  • HIV proviral latency for example leads to extreme longevity of Infected CD4+ T cells. Infected Patients live without symptoms for years before an outbreak occurs.
  • a latent viral infection no viruses are produced and pathological symptoms are not observed.
  • External activators i.e. sunlight, stress
  • the introduction of viral genetic material causes the cell to enter a malignant state resulting in cancer.
  • HPV human papilloma virus
  • Present therapeutic concepts do not provide adequate treatment options to cure patients suffering from latent viral infections.
  • therapies for v iral infections aim to inhibit virus proliferation (e.g. by inhibiting the viruses capability of intruding the cell ), and allow the host ' s immune system to dispense of acutely infected cells.
  • the immune system does not recognize infected cells as such and consequently does not eliminate them.
  • present therapies can help to maintain the status quo by limiting the extent of newly infected cells, they do not remove the infection as such.
  • HAART highly active antiretro viral therapy
  • HAART highly active antiretro viral therapy
  • HAART decreases the patient's total burden of HIV
  • the depots of latently infected cells remain intact.
  • Patients on Highly Active Anti-Retroviral Therapy maintain a persistent lowlevel viremia requiring lifelong adherence to antiretroviral therapies. This viremia may arise from latently infected reservoirs such as resting memory CD4+ T-celis.
  • presently available antiretroviral regimens have several downsides, including side-effects, development of resistances, and high cost of treatment, all of which become more relevant, the longer such treatment continues.
  • VPA may not function as an effective HDAC inhibitor in vivo at the concentrations achieved in patients under standard regimen.
  • ex vivo modelling studies had suggested that the doses employed would have induced proviral expression, in addition, VPA may not have induced sufficiently robust proviral expression to result in the death or clearance of reactivated cells, and/or host antiviral immune responses in these patients might have been insufficient to allow clearance of infection following induction.
  • the present invention relates to the medical application of (E)-N-(2-aminophenyl)-3-(l -((4 ⁇ ( 1 -methyl- lH-pyrazol-4-yl)phenyl)sulfonyl)-l H-p)Trol-3-yl)acrylamide or a salt, prodrug or solvate thereof in the treatment of latent viral infections.
  • This treatment can include the use of further therapeutic agents, e.g. antiviral agents.
  • 4SC-202 is used synonymously to (E)-N-(2-aminophenyl )-3-( 1 - ((4-( 1 -methyl- 1 H-pyrazol-4-yl)phcnyl )sulfonyl)- 1 H-pyrrol-3 -yl )acryiamide. It has the following chemical structure:
  • the aim of the present invention is to activate cells with latent viral infection, thus making them detectable by the subject's immune system.
  • the immune system may then inactivate these infected cells, and/or cells might be inactivated by apoptotis and/or lysis.
  • the treatment with 4SC-202 according to the present invention surprisingly has several advantages:
  • 4SC-202 is a combined and selective inhibitor of LSD 1 and HDAC1 , HDAC2, and HDAC3 (see herein below), which has not been described for any other HDAC inhibitor.
  • LSD I and HDAC synergistically act in multiple repressor complexes.
  • LSD1 promotes HIV silencing and LSD1 inhibition potentiates HDAC inhibition for the transcriptional reactivation of pro viral HIV DNA.
  • a combined inhibition of LSD1 and HDACs 1 , 2, and 3 could thus further- increase activation of transcription of viral RNA in latent cells.
  • 4SC-202 exhibits all features enabling the depletion of latent HIV.
  • HIV infected cells normally evade apoptosis by mechanisms like overexpression of anti- apoptotic genes or inactivation of pro-apoptotic proteins (Badley et al., Cell Death and Disease, 2013).
  • 4SC-202 is able to induce the expression of pro-apoptotic genes in cell lines and in the blood cells of patients treated with 4SC-202 in a clinical trial. Enhancing pro- apoptotic signals in infected cells may inactivate these cells and supports the immune system to kill HIV infected cells.
  • 4SC-202 is not mutagenic as determined by AMES test.
  • the mutagenic potential of 4SC-202 in concentrations up to 5000 jig/plate was tested in the so called AMES test, a well-known and standardized test.
  • 4SC-202 is non-mutagenic in the Salmonella typhimurium and Escherichia coli reverse mutation assay up to the highest concentration (not shown herein).
  • Certain other HDAC inliibitors are mutagenic to a certain extent (see e.g.
  • 4SC-202 provides a broad therapeutic window for the treatment of HIV infection.
  • 4SC-202 is well tolerated (see poster presented at 2014 ASCO Annual Meeting, Abstract Number: 8559, see http://www.4sc.de/sites/default/Tiles/documents/4SC-202___TOPAS-ASCO-Poster- 2014.pdf), which was also shown in tests with human peripheral mono nucleated cells (PBMC).
  • PBMC peripheral mono nucleated cells
  • the estimated inhibitory concentration to inhibit 50% of cells is higher than 100 ⁇ (see herein below).
  • Exposure of 4SC-202 in patients can be up to 8 ⁇ in a human subject's plasma (see herein below).
  • Certain other HDAC inhibitors are less well tolerated and exhibit significant toxicity. E.g. according to Tlicr Adv Hematol 2014, Vol. 5(6) 197-210, cumulative toxicity is still a main concern for treatment with panobinostat.
  • FIGURES show the results of a Human Apoptosis Array (R&D ARY009) for RKO cells using 10 ⁇ 4SC-202 and using 350 Lig protein per array.
  • the left column relates to the 4SC-202-treated samples
  • the right column is DM SO control.
  • the Y-axis is adjusted OD.
  • the upper horizontal line relates to the positive control, while the lower horizontal line relates to the negative control.
  • Figure 2 shows the results of a Human Apoptosis Array (R&D ARY009) for RKO cells using 10 ⁇ 4SC-202 and using 350 ⁇ ig protein per array. Only the most relevant proteins are shown.
  • the left column relates to the 4SC-202-trea.ted samples, the right column is DMSO control.
  • the Y-axis is adjusted OD.
  • the upper horizontal line relates to the positive control, while the lower horizontal line relates to the negative control.
  • Figure 3 shows a comparison of the PK behavior of 2 x 200 mg daily administered 4SC-202 vs SAHA administered 1 x 400 mg daily.
  • the Y-axis is the mean plasma concentration ( ⁇ . ⁇ ).
  • the X-axis is time [h j.
  • the upper curve shows rising levels for the 4SC-202 PK of patients with high exposure, while the lower curve shows SAHA PK.
  • Figure 4 shows the effect of 4SC-202 on latent/induced HIV-1 production in Ul cells, as evidenced by p24 expression in Ul cells latently infected with HIV. HIV p24 release (indicative of reactivation of virus from latent state) was tested by ELISA, expression was determined after 72h incubation.
  • the Y-axis is in percent of cell or virus control, respectively, the X-axis is concentration [ ⁇ ].
  • the black diamond data points are in relation to virus control, i.e. % increase of viral p24 expression), while the white boxed data points are in relation to cell control, i.e. to determine cellular survival.
  • Figure 5 shows the effect of 4SC-202 on latent/induced HIV-1 production in Ul cells, as evidenced by RT (reverse transcriptase) expression in Ul cells latently infected with HIV.
  • HIV RT release (indicative of reactivation of virus from latent state) was tested by ELISA, expression was determined after 72h incubation.
  • the Y-axis is in percent of cell or virus control, respectively, the X-axis is concentration [ ⁇ ].
  • the black diamond data points are in relation to virus control, i.e. % increase of viral RT expression), while the white boxed data points are in relation to cell control, i.e. to detemiine cellular survival.
  • Figure 6 shows the results of latent HIV reactivation in primary CD4+ T cells, Experiment 1 ( 18 hour incubation and activation). Results for samples from two different patients are shown (left and right panel, respectively). Y-axis is x-fold reactivation, compared to DMSO negative control. For each panel, the columns from left to right relate to incubation with DMSO as negative control (-), 20nM PMA plus 1 ⁇ ionomycin as positive control (+), and 5 ⁇ 4SC- 202 (202), respectively.
  • Figure 7 shows the results of latent HIV reactivation in primary CD4+ T cells, Experiment 2 (24 and 48 hour incubation and activation). Results for samples from two different patients are shown (left and right panel, respectively).
  • Y-axis is x-fold reactivation, normalized to DMSO negative control.
  • the symbols relate to incubation with 5 ⁇ 4SC-202 (circles), 5 ⁇ SAHA as comparison (squares), and CD3/CD28 stimulation as positive control (crosses); (DMSO as a negative control and normalization basis not shown), respectively.
  • Figure 8 shows the results of latent HIV reactivation in primary CD4+ T cells.
  • Experiment 3 24 hour incubation and activation, dose titration of 4SC-202).
  • Y-axis is x-fold reactivation, normalized to DMSO negative control.
  • the columns from left to right relate to incubation with DMSO as a negative control (-), CD3/CD28 stimulation as positive control (+), 4SC-202 In 1 , 2 and 5 ⁇ , respectively (1 , 2 and 5), 5 ⁇ SAHA as comparison (S).
  • the present invention correspondingly also encompasses a method of treatment of a latent viral infection in a subject, particularly a subject in need of such treatment, said method comprising administering to said subject of (E)-N-(2-aminophenyl)-3-( 1 -((4-( 1 -methyl- 1 H- pyrazol-4-yl)phenyl)sulfonyl)-l H-pyrrol-3-yl)acrylamide or a salt, prodrug or solvate thereof, particularly a therapeutically effective amount thereof.
  • said method of treatment encompasses in particular embodiments all embodiments of the present invention as mentioned herein and in particular those directly related to the above item 1.
  • the present invention correspondingly also encompasses the use of (E)-N-(2-aminophenyl)-3- ( 1 -((4-( 1 -methyl- 1 i l-pvrazol-4-yl)phenyl)sulfonyl)- 1 H-pyrrol-3-yl)acrylamide or a salt, prodrug or solvate thereof for use in the manufacture of a medicament for use in the treatment, of a latent viral infection in a subject.
  • said use encompasses in particular embodiments all embodiments of the present invention as mentioned herein and in particular those directly related to the above item 1.
  • viruses capable o forming latent infections arc in the context of the present invention herpesviridae, in particular simplexvirus.
  • variccllovirus and cytomegalovirus more particularly HCMV, human herpesvirus 3 (HHV-3, also known as varicella zoster virus (VZV)), human herpes virus 1 (HHV- 1 , also known as Herpes-simplex- irus 1), human herpes virus 2 (HHV-2, also known as Herpes-simplex- Virus 2), Human immunodeficiency virus 1 (HIV- 1 ), Hu an immunodeficiency virus 2 (HIV-2 ), hepatitis B virus (HBV), and Eppstein-Barr virus (EBV).
  • HIV- 1 HIV-2 and HBV, even more particularly HIV- 1 and HIV-2.
  • said treatment comprises the administration of at least one antiviral agent.
  • said at least one antiviral agent administered to said subject before 4SC-202 is administered and said at least one antiviral agent is administered during treatment with 4SC-202 are the same, whereas in other embodiments they are different antiviral agents or combinations thereof.
  • the antiviral agents might be changed during the course of the treatment, before the treatment with 4SC-202 and/or during treatment with 4SC-202. In this way, the treatment can be adapted to the specific needs of the subject, if necessary.
  • "Administered during treatment with 4SC-202” includes the administration of 4SC-202 and the at least one antiviral agent in a fixed combination, or simultaneously, sequential or chronologically staggered. This includes in certain embodiments that during certain intervals of the treatment, administration of 4SC-202 or the at least one antiviral agent is paused, while the administration of the other agent is continued.
  • administering may prevent the infection of new cells by the virus.
  • HAART highly active anti- rctroviral therapy
  • said subject has an HIV infection.
  • the following definitions are meant to further define certain terms used in the context of the present invention. If a particular term used herein is not specifically defined, the term should not be considered to be indefinite. Rather, such terms are to be construed in accordance with their meaning as regularly understood by the skilled artisan in the field of art to which the invention is directed, particularly in the field of organic chemistry, pharmaceutical sciences and medicine.
  • antiviral agent refers to a therapeutic agent that has an influence on the viral cycle, including the viruses entry into or fusion with the subject's host cell, reverse transcription of viral RNA, integration of viral DNA (e.g. reverse transcribed from viral RNA) into the subject's DNA, or by modulating the activity of any viral protein resulting in a change of viral activity.
  • Latent viral infection refers to a state of viral infection, wherein the viral genetic information is integrated into cells of the subject. Typically, no proliferation and production of virus particles takes place in this stage. This includes episomal latency and proviral latency, particularly proviral latency. In proviral latency, viral genome is directly integrated into the DNA of the host cell
  • infected cells In latent stage, infected cells cannot be identified and killed by the immune system. Potentially, apoptosis of infected cells is suppressed. HIV proviral latency for example leads to extreme longevity of infected CD4+ T cells. Typically, during latent stage, the infected cells produce no viruses and pathological symptoms are not observed. However, some infected cells in the patient may be in latent stage, while other cells are not.
  • the term "latent viral infection” as used herein includes a state wherein a part of the infected cells in a subject are in a latent state, while the rest of the infected cells in said subject are in an active state, producing the virus.
  • said subject can in a first step be treated with an antiviral therapy, e.g. a HAART therapy in the case of HIV, in order to prevent infection of further cells and reduce the subject's viral load. This can then be followed by the treatment with 4SC- 202 as detailed herein.
  • said subject such as a subject in need of treatment of said latent viral infection
  • a patient which typically is a mammal, particularly a human.
  • the treatment according to the present invention involves administering of an effective amount of 4SC-202 to said subject.
  • the treatment according to the present invention causes the virus to leave its latent stage. This typically causes said vims to enter the lytic part of its viral life cycle.
  • the subject's immune system can identifiy and attack infected cells wherein the virus has left the latent stage. The cells might also go into apoptosis upon activation of integrated viral DNA transcription by the treatment with 4SC-202.
  • the term "further therapeutic agents” refers to pharmaceutical agents. These may be e.g. nucleotide-based, peptide- or protein-based, or other chemical compounds. Such therapeutic agents may aid in killing cells infected upon reactivation of the virus from the latent state.
  • HAA T Highly active anti-retroviral therapy
  • HIV HIV
  • HAART typically compounds from two or more of the following classes are administered:
  • NRTI Nucleoside reverse transcriptase inhibitors
  • NtRTI nucleotide reverse transcriptase inhibitors
  • Integrase inhibitors also known as intcgrase nuclear strand transfer inhibitors or INSTI. These inhibit the viral enzyme integrasc. which is responsible for integration of viral DNA into the DNA of the infected host cell. Examples are raltegravir, elvitegravir and dolutegravir.
  • Protease inhibitors These block the viral protease enzyme necessary to produce mature virions upon budding from the host membrane. Examples are Lopinavir, Indinavir, Nelfinavir, Amprenavir. Ritonavir, Darunavir and atazanavir.
  • HAART for example two NRTIs are combined with a PI, NNRTI or INSTI.
  • Dutrebis® lamivudine + raltegravir The following listing gives further examples of therapeutic agents or combinations thereof which may be used in in particular embodiments of the present invention (where available, brand names and or INNs are given): Multi-Class Combination Drugs
  • trip la® efavirenz + tenofovir DF + emtricitabine
  • Complera® (Eviplera, rilpivirine + tenofovir DF + emtricitabine)
  • Stribild® (elvitegravir + cobicistat + tenofovir DF + emtricitabine)
  • Triumeq® (doiutegravir + abacavir + lamivudine)
  • Emtriva® (emtricitabine)
  • Epzicom® also known as Kivexa® (abacavir + lamivudine)
  • Retrovir® (zidovudine)
  • Trizivir® (abacavir + zidovudine + lamivudine)
  • Viread® tenofovir disoproxil fumarate
  • Tybost® cobicistat on-Nucleosidc Reverse Transcriptase inhibitors (NNRTIs)
  • Sustiva® also known as Stoerin® (efavirenz)
  • Viramune® or Viramunc® XR (nevirapine)
  • KaletraS also known as Aluvia® ( 1 o p in a vi r/ri to na vi r )
  • Lexiva® also known as Telzir® (fosamprenavir)
  • Prezcobix® also known as Rezoista® (darunavir + cobicistat)
  • HAART therapy may be applied according to national or international guidelines, such as of the International AIDS Society-USA, the US government's Department of Health and Human Services guidelines, the European AIDS Clinical Society guidelines, or the World Health
  • the initial HAAR combinations for adults and adolescents recommended by the US DHHS presently are: Tenofovir, emtricitabine and raltegravir; Tenofovir, emtricitabine and dolutegravir abacavir, lamivudine and dolutegravir; tenofovir, emtricitabine, elvitegravir and cobicistat; tenofovir, emtricitabine, ritonavir, and darunavir.
  • the WHO preferred initial HAART combination for adults and adolescents presently is tenofovir, and efavirenz, combined with lamivudine or emtricitabine.
  • treatment of HIV in the context of the present invention is directed towards infected dendritic cells and/or CD4 ⁇ -T-cclls. more particularly CD4 -T-cells.
  • Detection of virus infection is well-known to the skilled person and standardized and/or commercial tests are available.
  • a combination immunoassay is used that detects HIV- 1 and HIV-2 antibodies and HIV- 1 p24 antigen. All specimens reactive on this initial assay undergo supplemental testing with an immunoassay that differentiates HIV- 1 from HIV-2 antibodies. Specimens that are reactive on the initial immunoassay and non reactive or indeterminate on the antibody differentiation assay proceed to HIV- 1 nucleic acid testing for resolution. The results of this algorithm may be used to identify persons likely to benefit from treatment, to reassure persons who are uninfected.
  • Positive results from the recommended algorithm indicate the need for HIV medical care and an initial evaluation that includes additional laboratory tests (such as HIV- 1 viral load, CD4+ T-lymphocyte determination, and an antiretroviral resistance assay) to confirm the presence of HIV-1 infection, to stage HIV disease, and to assist in the selection of an initial antiretroviral drug regimen (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 -infected adults and adolescents. 2013. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed May 27,
  • references to 4SC-202 also relate to pharmaceutically acceptable salts, solvates or prodrugs thereof, as well as to salts or solvates of said prodrugs and solvates of said salts.
  • the term "prodrug" specifies a compound derived from 4SC-202. wherein at least one of the following groups are derivatized as specified in the following: A carboxylic acid group is derivati/ed into an ester, a hydroxy! group is derivatized into an ester, a carboxylic acid is derivatized into an amide, an amine is derivatized into an amide, a hydroxy! group is derivatized into a phosphate ester.
  • the prodrug is intended to be cleaved and release 4SC-202 in the subject to which it is administered.
  • the salts are in particular embodiments pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts are such salts which are usually considered by the skilled person to be suitable for medical applications, e.g. because they are not harmful to subjects which may be treated with said salts, or which give rise to side effects which are tolerable within the respective treatment.
  • said pharmaceutically acceptable salts are such salts which are considered as acceptable by the regulatory authorities, such as the US Food and Drag Administration (FDA), the European Medicines Agency (EMA), or the Japanese Ministry of Health, Labor and Welfare Pharmaceuticals and Medical Devices Agency (PMDA).
  • FDA US Food and Drag Administration
  • EMA European Medicines Agency
  • PMDA Japanese Ministry of Health, Labor and Welfare Pharmaceuticals and Medical Devices Agency
  • the present invention in principle also encompasses salts which are as such not pharmaceutically acceptable, e.g. as intermediates in the production of 4SC- 202 or prodrugs thereof, r as intermediates in the production pharmacologically acceptable salts of 4SC-202 or prodrugs thereof.
  • Particular salts according to the present invention are the hydrobromide, methanesulfonate, hemiethane- 1 ,2 -di sulfonate, benzenesulfonate, toluenesulfonate, 2-naphthalenesulfonate and HQ salt, more particularly the toluenesulfonate salt of 4SC-202.
  • Said salts per se are as known to the skilled person. A description thereof, including methods for their production are described in WO 2009/1 12522 Al .
  • a “solvate” is a complex formed in the crystalline state between a compound (or prodrug or salt thereof) and one or more solvent molecules.
  • such solvates are 1 :2, 2: 1 or 1 : 1 , more particularly 1 : 1 stoichiometric complexes.
  • complexes, such solvates are formed with a solvent selected from the group comprising water, methanol, ethanol or propanol, particularly water, methanol or ethanol, more particularly water (the latter is typically also known under the term “hydrate”).
  • the term “room temperature”, “rt” or “r.t.” relates to a temperature of about 25°C, unless specified otherwise.
  • the term “treating' " or “treatment” encompasses complete or partial healing of a disease, alleviation of a disease or stop of progression of a given disease, the amelioration or stabilization of one or more of the following: Disease state, symptom severity, viral load, viral aggressiveness, and patient's overall physical state.
  • Disease state means that all infected cells are killed or otherwise inactivated.
  • Partial healing' means that part of the infected cells are killed or otherwise inactivated, in particular resulting in a lower number of infected cells after treatment. In case of a partial healing, the treatment might in certain embodiments be repeated.
  • treatment with 4SC-202 should initially increase levels of HIV mRNA, as well as viral proteins p24 ⁇ and Reverse Transcriptase.
  • Reactivation of HIV in latent cells can be determined by HIV mRNA measurement via qPCR, before and upon or after treatment with 4SC-202, Additionally, levels of virus antigen p24 and Reverse transciptase can be determined by immunoassay e.g. ELISA. The methods to determine these levels are well- known.
  • Virus load can e.g. be detected in blood or plasma samples of subjects by determination of HIV nucleic acids (RNA) or quantification of proteins and enzymes specific to HIV like p24 or reverse transcriptase (see above paragraph).
  • RNA HIV nucleic acids
  • the number f CD4+ infected cells should be reduced during or after treatment according to the present invention, e.g. by cell lysis, apoptosis and/or detection and inactivation by the subject's immune system.
  • CD4 T lymphocytes are found to be infected showing active viral replication.
  • the infected CD4 cells release virions by budding through the cell membrane or by lysis of the infected cells.
  • the released virus particles then infect uninfected CD4 T lymphocytes.
  • CD4 T lymphocytes also serve as important reservoirs of
  • HIV a small proportion of these cells carry HIV proviras integrated in the host DNA without active virus multiplication. Deteniiination of the number of CD4+ cells according to the WHO Guideline (ISBN 978-92-9022-298-9).
  • PBMCs Peripheral blood mononuclear cells
  • real-time PGR was performed on genomic DNA isolated from 2 x 106 purified CD4+ T cells (Qiagen). Then 1 ⁇ g of DNA was used as a template for real-time PGR in a 7500 Real-Time PGR System (Applied Biosystems). The amplification reaction was performed in triplicate using HIV-specific primers and probe (FAM), RNaseP-specific primers and probe (VIC) (Applied Biosystems), and Taqman Gene Expression Master Mix (Applied Biosystems) in 50 ⁇ total volume.
  • FAM HIV-specific primers and probe
  • VIC RNaseP-specific primers and probe
  • Taqman Gene Expression Master Mix Applied Biosystems
  • the following primers were used for amplification of HIV LTR: 5 '-GGTCTCTCTGGTI AG ACCAG AT-3 ' (5' primer) and 5'- CTG CT A G A G ATTTTC C A C AO G -3 '( 3 ' primer), along with the fluorescent probe 5'- 6FAM-AGTAGTGTGTGCCCGTCTGTT-TAMRA-3'.
  • PGR conditions consisted of a step at 95°C for 10 min followed by 45 cycles of 15 sec at 95°C and 1 min at 60°C.
  • Serially diluted ACH-2 DNA was also subjected to the PCR described above to obtain standard curves. The detection limit of the assay was 2.6 HIV DNA copics/mL,
  • the term “medicament” includes 4SC-202 and other therapeutic agents, which are to be administered to a subject in pure form, as well as compositions comprising the same which are suitable for administration to a subject.
  • 4SC-202 can be administered to animals, particularly to mammals, and in particular to humans as therapeutics per se, as mixtures with other therapeutic agents, and particularly in the form of pharmaceutical preparations or compositions which allow enteral (e.g. oral) or parenteral administration and which comprise as active constituent a therapeutically effective amount of 4SC-202, or a salt, solvate or prodrug thereof, in addition to e.g. one or more components selected from the group comprising customary adjuvants, pharmaceutically innocuous excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
  • compositions comprising 4SC-202 may optionally comprise one or more further therapeutically active substances other than 4SC-202.
  • therapeutically active substance which is used synonymously with “therapeutic agents” specifies a substance which upon administration can induce a medical effect in a subject. Said medical effect may include the medical effect described herein for 4SC-202. but may also, in the case of therapeutically active substances which are to be co-administered with 4SC-202, include other medical effects, such as e.g. analgesic, antiinflammatory, antiemetic.
  • pharmaceutically acceptable is well k o to the skilled person and usually means that the respective entity is not harmful to the subject to which the entity or the composition comprising the entity is administered, that said entity is stable and that said entity is chemically compatible (i.e. non-reactive) with other ingredients of the respective pharmaceutical composition.
  • Medicaments and pharmaceutical compositions according to the present invention, comprising 4SC-202 include those suitable for oral, rectal, bronchial, nasal, topical, buccal, sub-lingual, vaginal or parenteral (including transdermal, subcutaneous, intramuscular, intrapulmonary, intravascular, intracranial, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration, or by controlled release (e.g. sustained release, pH-controlled release, delayed, release, repeat action release, prolonged release, extended release) systems.
  • controlled release e.g. sustained release, pH-controlled release, delayed, release, repeat action release, prolonged release, extended release
  • controlled release systems include semipermeable matrices of solid hydrophobic polymers containing 43C-202, which matrices may be in form of shaped articles, e.g. films or microcapsules or colloidal drug carriers, e.g. polymeric nanoparticles, or controlled release solid dosage forms, e.g. core tablets or multi-layer tablets.
  • Pharmaceutically acceptable carriers used in the preparation of a pharmaceutical composition or medicament comprising 4SC-202 can be either solid or liquid.
  • Solid form pharmaceutical compositions comprising 4SC-202 include powders, tablets, pills, capsules, sachets, suppositories, and dispersible granules.
  • a solid carrier may comprise one or more components, which may also act as diluents, flavouring agents, solubili/ers, lubricants, suspending agents, binders, preservatives, tablet di integrating agents, or an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • the tablcting mixture can be granulated, sieved and compressed or direct compressed.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth. methyl cellulose, sodium carbox ymcth ylcel 1 ulose, a low melting wax, cocoa butter, and the like.
  • preparation is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • sachets and lozenges are included. Tablets, powders, capsules, pills, sachets, and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glyceride or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into conveniently sized moulds, allowed to cool, and thereby to solidify.
  • Compositions suitable for vaginal administration may be presented as peccaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid preparations include solutions, suspensions, and emulsions, for example, water or water- propyiene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • 4SC-202 may be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for re- constitution with a suitable vehicle, e.g. sterile, pyrogen- free water, before use.
  • Aqueous solutions suitable for oral administration can be prepared by dissolving the active component in water and adding for example suitable colorants, flavours, stabilizing and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethy!cellulose, or other well- known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethy!cellulose, or other well- known suspending agents.
  • solid form preparations which are intended to be converted, shortly before administration, to liquid form preparations for oral administration.
  • Such liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, f r example colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the medicament is applied topically, e.g. in the form of transdermal therapeutic systems (e.g. patches) or topical formulations (e.g. liposomes, cremes, ointment, lotion, gels, dispersion, suspension, spray, solution, foam, powder).
  • transdermal therapeutic systems e.g. patches
  • topical formulations e.g. liposomes, cremes, ointment, lotion, gels, dispersion, suspension, spray, solution, foam, powder.
  • the medicament may comprise carrier materials or excipients, including but not limited to a lipophilic phase (as for example Vaseline, paraffiiies, triglycerides, waxes, po 1 yal cyl si 1 ox anes ) , oils (olive oil, peanut oil, castor oil, triglyceride oil), emulsifier (as for example lecithin, phosphatidylglyceroles, alky!
  • a lipophilic phase as for example Vaseline, paraffiiies, triglycerides, waxes, po 1 yal cyl si 1 ox anes
  • oils olive oil, peanut oil, castor oil, triglyceride oil
  • emulsifier as for example lecithin, phosphatidylglyceroles, alky!
  • alcohols sodium lauryl sulphate, polysorbates, Cholesterol, sorbitan fatty acid ester, polyoxyethylene fatty acid glycerol and - ester, poloxamers), preservatives (for instance benzalkonium chloride, chlorobutanol, parabene or thiomersal), flavouring agents, buffer substances (for example salts of acetic acid, citric acid, boric acid, phosphoric acid, tartric acid, trometamolc or trolamine), solvents (for instance po 1 ycth y 1 engl y col s , glycerol, ethanol, isopropanol or propylene glycol) or solubilizers, agents for achieving a depot effect, salts for modifying the osmotic pressure, carrier materials for patches (for instance polypropylene, eth y 1 en e- vi n yl acetat e-copol ym er , polyacrylates, silicone
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions may be applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorolluorocarbon (CFC), for example dichlorodifluoromethane, tri ch 1 orofl uorom cth ane, or dichlorotetratluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant such as a chlorolluorocarbon (CFC), for example dichlorodifluoromethane, tri ch 1 orofl uorom cth ane, or dichlorotetratluoroethane, carbon dioxide, or other suitable gas.
  • CFC chlorolluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the medicament may be provided in the form of a dry powder, for example a powder mix in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylm ethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylm ethyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form, for example in capsules or cartridges of, e.g., gelatine, or blister packs from which the powder may be administered by means of an inhaler.
  • the active ingredient e.g. 4SC-202
  • the active ingredient will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example
  • compositions adapted to give sustained release of the active ingredient may be employed.
  • the pharmaceutical preparations in certain embodiments arc in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, sachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion arc particular compositions.
  • pharmaceutically inert inorganic or organic excipients can be used.
  • pills tablets, coated tablets and hard gelatine capsules, for example, lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts, etc.
  • Excipients for soft gelatine capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc.
  • Suitable excipients for the production of solutions and syrups are, for example, water, sucrose, invert sugar, glucose, polyols etc.
  • Suitable excipients for the production of injection solutions are, for example, water, alcohols, glycerol, polyols or vegetable oils.
  • the dose can vary within wide limits and is to be suited to the individual conditions in each individual case.
  • the appropriate dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, however, satisfactory results are achieved at dosage rates of about 1 to 100 mg/kg animal body weight particularly 1 to 50 mg/kg.
  • Suitable dosage rates for larger mammals, for example humans are of the order of from about 10 g to 3 g day, conveniently administered once, in divided doses 2 to 4 times a day, or in sustained release form.
  • particular daily doses are 100, 200 or 400 mg, e.g. 50, 100 or 200 mg administered twice daily.
  • Administration of 4SC-202 should typically continue until the number of infected cells is reduced or until no infected cells are detectable in a sample obtainable from the treated subject.
  • Treatment with 4SC-202 may have to be paused in certain intervals, e.g. repeated cycles of administering 4SC-202 for 14 days, followed by 7 days without administration of 4SC-202.
  • the embodiments of the present invention relate to the corresponding methods of treatment or prevention of the medical conditions specified herein, which comprises the administration of an effective amount of 4SC-202, or a prodrug, solvate or salt thereof to a subject in need thereof.
  • the embodiments of the present invention relate to the corresponding use of 4SC-202, or a prodrug, solvate or salt thereof in the treatment or prevention of the medical conditions speci ied herein.
  • the term "therapeutically effective amount” means an amount, which upon administration to a patient in need thereof results in a therapeutic effect on the disease to be treated.
  • Such therapeutic effects may include destroying latently infected cells in the patient's body, which results in lowering the number of latently infected cells in the patient's body, and particularly destroying at least 80%, more particularly at least 90%, even more particularly at least 95%, or yet even more particularly all latently infected cells in the patient's body.
  • Such effects usually do not occur immediately after administration of a compound and may be delayed, e.g. by hours, days, weeks or months after the start of treatment, depending e.g. on the specific patient, type of disease and overall situation under which the therapy is administered.
  • sample includes bodily fluids and/or tissue samples, such as bodily fluid and/or a tissue sample, typically a bodily fluid, obtainable from a subject, e.g. a patient- Said samples from natural sources can be used with or without further processing after being obtained from their source.
  • processing can for instance comprise separation, fractionation, dilution, dispersion, mechanical treatment such as sonifi cation, or grinding, concentration, removal of certain components of said sample, or addition of compounds, such as salts, buffers, detergents, etc.
  • the term “body fluid” specifies a fluid or part of a fluid originating from the body of a patient, typically blood, including peripheral blood, serum, plasma, or interstitial fluid, liquor, aqueous humour and vitreous humour, bile, cerebrospinal fluid, endolymph, perilymph, ejaculate, gastric juice, mucus, peritoneal fluid, pleural fluid, saliva, urine, sweat, tears and vaginal secretion, particularly peripheral blood, serum, or plasma.
  • Said bodily fluid itself may or may not comprise diseased and/or non-diseased cells, depending on what is to be detected in said sample (e.g. if antibodies are to be detected, presence of cells is not necessary.
  • the sample is obtained from the patient by any method and/or means commonly known to the skilled person in the field of medicine, e.g. in certain embodiments blood sample taking by venipuncture.
  • the term “administrapheral blood” specifies blood obtained from the circulation remote from the heart, i.e. the blood in the systemic circulation, as for example blood from acral areas.
  • the term “build whole blood” specifies unmodified blood comprising cells and fluid, as obtained from the donor of said blood, such as a patient.
  • the term compactpatient specifies a subject which is suspected of having or which has a disease, disorder, or medical condition in the form of a latent viral infection as described herein;
  • the patient may have received prior treatment, or the patient may be untreated prior to the application of the treatment according to the present invention.
  • Sample preparation An aliquot of 150 ⁇ ⁇ . of the internal standard solution was transferred to a 96-w r ell protein precipitation plate and an aliquot of 50 uL uman plasma was added. After mixing (5 minutes at 700 rpm), a slight vacuum was applied for the filtration step.
  • 11PI.C-MS MS conditions The quantification of 4SC-202 (free base) was performed by column separation with reverse phase chromatography followed by detection with triple-stage quadnrpole MS/MS in the selected reaction monitoring mode.
  • Liquid chromatography Analytical pump; Mobile phase - Phase A: water containing 0.1 % acetic acid; Phase B: methanol containing 0.1 % acetic acid; Column: YMC Pro C4, 2.1 x 50 mm, 5 ⁇ (YMC Co. Ltd., Kyoto, Japan); Injection volume: 2 ⁇ L (10 ⁇ , in a 2 LI L sample loop); Column temperature 40°C
  • Mass spectrometry Ion source: H ES1; Polarity Positive; Voltage [V] 2500; Sheath gas [au] 60; Sweep gas [an] 0.0; Auxiliary gas [au] 5; Vaporizer [°C] 350; Capillary temperature [°C] 350; Collision gas pressure [mTorr] 1 .0.
  • Seed 250.000 cells per vial, ⁇ ⁇ ⁇ . per vial, 20 pL substance dilutions in DMSO and medium / control per (see below) per vial
  • 4SC-202 provides a broad therapeutic window for the treatment of HIV infection. 4SC-202 is well tolerated, as shown in tests with human peripheral mononucleated cells (PBMC). The estimated inhibitory concentration to inhibit 50%» of cells is higher than 100 ⁇ . 3) Human Apoptosis Array
  • 35 apoptosis relevant Proteins are measured qualitatively.
  • Day 1 seed 4Mio RKO-celis in each well of a 6- well plate (in 2700 ⁇ 1 Medium); Incubate over night at 37°C
  • Catalase Enzym catalyses hydrogen peroxide into water and 0 2
  • HSP27 chapcrone activity thermotolerance, inhibition of apoptosis, regulation of cell development, and cell differentiation
  • pro-apoptotic genes like BAD, BIM, HRK, and NOXA were up-regulated by at least 1 .5-fold, while anti-apoptotic genes like MCL-1 and Bi ' L l were repressed by at least 1.5-fold.
  • U l cell line Promonocytic cell line
  • HIV latently infected HIV p24 protein or HIV reverse transcriptase (RT) release (indicative of reactivation of virus from latent state) was tested by ELISA, expression was determined after 72h incubation.
  • Figure 4 shows that 4SC-202 induces HIV release (p24) by more than 6-fold at concentrations well tolerated in human.
  • Figure 5 shows that 4SC-202 induces HIV release (RT) by more than 60-fold at concentrations well tolerated in human trials.
  • HDACl to 1 1 were assessed by using an aeetylated AMC-labelcd fluorogcnie peptide substrate.
  • the protocol involved a two-step reaction: first, the substrate with the aeetylated lysine side chain is incubated with a sample containing HDAC activity, to produce the deacetylated products, which are then digested in the second step by the addition of developer to produce the fluorescent signal proportional to the amount of deacetylated substrates.
  • the fluorescence was measured by an Envision (excitation, 355 nm; emission, 460 nm). IC50 values and curve fits were obtained using Prism (GraphPad Software).
  • Assay Buffer 50mM Tris-HCl, pH8.0, 137 mM NaCL 2.7 mM KC1, 1 mM MgC12. 1 mg ml BSA and DMSO are added before use.
  • Substrates ⁇ Substrate for HDACl , 2, 3, 6, 10, 1 1 : Fluoroge ie peptide from p53 residues 379-382 (RHKK(Ac)AMC) * Substrate for HDAC 4, 5, 7, 9: Fluorogenie HDAC Class2a Substrate (Triiluoroacetyl Lysine, Ac-LGK(TFA)-AMC) * Substrate for HDAC 8: Fluorogenie peptide from p53 residues 379-382 (RHK(Ac)K(Ac)AMC) Reaction Procedure :
  • HDAC 1 1 is 1.43E-05 molar, i.e. significantly weaker.
  • Assay format Enzyme coupling fluorescence assay Buffer conditions for LSD1 : 50 mM Tris-HCl, pH 7.5 and 1 % DMSO. Substrate: Histone H3 peptide ( 1 -21 ) 4mc2, 10 DM Reaction Procedure: Demcthylation Step:
  • 4SC-202 IC50 on LSD1 (also known as KDM1A) is 2.00E-06 molar.
  • CD4+ T cells were isolated from samples taken from successfully treated (HA ART) HIV-infected patients. 2-5 million CD4+ T cells were incubated at 37°C.with 4SC-202, comparators, or controls (substances were dissolved in DM SO ) (2 to 4 replicates per experiment).
  • RNA and DNA were extracted using Qiagen All Prep 96 DNA RNA kit according to manufacturer's instructions. Then qPCR of cell associated HIV gag RNA was conducted (triplicate technical replicates), by which the absolute number of HIV gag RNA copies/reactions was determined using HIV gag gBlock standard according to manufacturer's instructions. HIV gag RNA data was normalized to RNaseP (single copy reference gene) using co-extracted genomic DNA.
  • CD3/CD28 coupled beads for the activation of T cells positive control
  • CD3/CD2S coupled beads for the activation of T cells (positive control),

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Abstract

La présente invention concerne l'utilisation médicale de (E)-N-(2-aminophényl)-3-(1-((4-(1-méthyl-1H-pyrazol-4-yl)phényl)sulfonyl)-1 H-pyrrol-3-yl)acrylamide ou son sel, promédicament ou solvate dans le traitement d'infections virales latentes, telles que les infections virales latentes par le VIH.
PCT/EP2016/074197 2015-10-09 2016-10-10 (e)-n-(2-aminophényl)-3-(1-((4-(1-méthyl-1h-pyrazol-4-yl)phényl)sulfonyl)-1h-pyrrol-3-yl)acrylamide pour le traitement d'infections virales latentes WO2017060524A1 (fr)

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