WO2021094563A1 - Treatment and prevention of dengue disease - Google Patents

Treatment and prevention of dengue disease Download PDF

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Publication number
WO2021094563A1
WO2021094563A1 PCT/EP2020/082102 EP2020082102W WO2021094563A1 WO 2021094563 A1 WO2021094563 A1 WO 2021094563A1 EP 2020082102 W EP2020082102 W EP 2020082102W WO 2021094563 A1 WO2021094563 A1 WO 2021094563A1
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WIPO (PCT)
Prior art keywords
compound
dengue
logio copies
logio
medicament
Prior art date
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Ceased
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PCT/EP2020/082102
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English (en)
French (fr)
Inventor
Olivia Gabriella M GOETHALS
Bart Rudolf Romanie Kesteleyn
Bart Henri Theresia STOOPS
Jean-François BONFANTI
Tim Hugo Maria Jonckers
Marnix Van Loock
Suzanne Kaptein
Johan Neyts
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Katholieke Universiteit Leuven
Janssen Pharmaceuticals Inc
Original Assignee
Katholieke Universiteit Leuven
Janssen Pharmaceuticals Inc
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Publication date
Application filed by Katholieke Universiteit Leuven, Janssen Pharmaceuticals Inc filed Critical Katholieke Universiteit Leuven
Priority to KR1020227020173A priority Critical patent/KR20220101679A/ko
Priority to CN202080093897.0A priority patent/CN114980884A/zh
Priority to IL292970A priority patent/IL292970A/en
Priority to BR112022009199A priority patent/BR112022009199A2/pt
Priority to AU2020382911A priority patent/AU2020382911A1/en
Priority to UAA202202003A priority patent/UA129409C2/uk
Priority to MX2022005879A priority patent/MX2022005879A/es
Priority to EP20803432.2A priority patent/EP4058019A1/en
Priority to JP2022528008A priority patent/JP2023502053A/ja
Priority to US17/777,019 priority patent/US20220409583A1/en
Priority to CA3161338A priority patent/CA3161338A1/en
Priority to PH1/2022/551160A priority patent/PH12022551160A1/en
Publication of WO2021094563A1 publication Critical patent/WO2021094563A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • 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

  • the present invention relates to the use of substituted indole derivatives and substituted indoline derivatives in the manufacture of a medicament for the treatment or the prevention of dengue disease in an individual at risk of being infected by Dengue virus.
  • the invention further provides a method for the treatment or the prevention of dengue disease in an individual at risk of being infected by Dengue virus.
  • Dengue is caused by any of the 4 antigenically distinct DENV serotypes (DENV-1 , -2, -3, and -4), which belong to the genus Flavivirus in the family of the Flaviviridae.
  • the DENVs are human pathogens which are transmitted through the bite of an infected female mosquito of the genus Aedes, mainly of the species Aedes aegypti and to a lesser extent Aedes albopictus (Carrington et a!., 2014).
  • Dengue is endemic in more than 125 countries, and has also again become endemic in the United States (US) territories of Puerto Rico, American Samoa, and the Virgin Islands (CDC, 2019).
  • dengue cases The actual numbers of dengue cases are underreported. It is estimated that there are 390 million DENV infections globally per year, of which 96 million manifests clinically (with any severity of the disease) (Bhatt et al., 2013). On average, each year about 500,000 dengue cases require hospitalization due to severe and life-threatening disease and up to 25,000 patients die due to dengue.
  • the chimeric yellow fever - DENV tetravalent dengue vaccine (CYD-TDV; Dengvaxia ® ) is a tetravalent live attenuated vaccine developed by Sanofi Pasteur.
  • CYD-TDV Dengvaxia ®
  • the vaccine had been approved for use in 18 countries including Brazil, Mexico, El Salvador, Costa Rica, and the Philippines.
  • the vaccine was also approved in the US for the prevention of dengue disease caused by all DENV serotypes (DENV-1, DENV-2, DENV-3, and DENV- 4) in people, 9 to 16 years of age, who have laboratory-confirmed previous dengue infection and who live in endemic areas.
  • WO 2017/167951 and WO 2016/180696 disclose compounds for the prevention and treatment of dengue viral infections.
  • dengue disease also called dengue
  • the present invention relates to the use of substituted indole derivatives and substituted indoline derivatives in the manufacture of a medicament for the treatment of dengue disease in an individual infected with Dengue virus or the prevention of dengue disease in an individual at risk of being infected by Dengue virus.
  • the invention further provides a method for the treatment of dengue disease in an individual infected with Dengue virus or the prevention of dengue disease in an individual at risk of being infected by Dengue virus.
  • the present invention provides for the use of substituted indole derivatives and/or substituted indoline derivatives in the manufacture of a medicament for the prevention of dengue in an individual at risk of being infected by Dengue virus.
  • the medicament is preferably administered intermittently at a time interval of at least 6 hours, preferably at least 12 hours, preferably at least 20 hours, more preferably at least 24 hours, more preferably at least 36 hours, more preferably at least 48 hours, more preferably at least 72 hours, .
  • the substituted indole derivatives and/or substituted indoline derivatives are as described herein.
  • the invention further provides for the use of substituted indole derivatives and/or substituted indoline derivatives in the manufacture of a medicament for the treatment of dengue disease in an individual infected by Dengue virus.
  • the present invention provides a method for the prevention of dengue in an individual at risk of being infected by Dengue virus.
  • Said method comprises administering to the individual at risk a medicament comprising substituted indole derivatives and/or substituted indoline derivatives wherein the medicament is administered intermittently at a time interval of at least 6 hours, preferably at least 12 hours, preferably at least 20 hours, more preferably at least 24 hours, more preferably at least 36 hours, more preferably at least 48 hours, more preferably at least 72 hours.
  • the substituted indole derivatives and/or substituted indoline derivatives are as described below.
  • the invention further provides a method for the treatment of dengue in an individual infected by Dengue virus.
  • the present invention provides for the use of compounds for the prevention, also called prophylactic treatment or pre-exposure prophylaxis, of dengue disease.
  • prophylaxis The concept behind prophylaxis is that the compound would be present and displays a sufficient level of systemic exposure prior to viral infection and/or prior to the time point that the viremia reaches its peak (peak viral load).
  • the invention leads to a considerable inhibition of dengue viral replication, thereby minimizing and even eliminating the risk of contracting dengue. This is beneficial for multiple populations including but not limited to populations living in endemic regions and travelers to dengue endemic regions such as aid workers, tourists, business and military travelers, and those visiting friends and family.
  • Figure 1 Schematic representation of the in vivo viremia AG 129 mouse experiment where compound (a) is tested for efficacy against a high viral input or inoculum of DENV-2/Rega of 10 6 plaque forming unit (PFU).
  • PFU plaque forming unit
  • the arrows at the bottom of the figure indicate administration of compound (a)/vehicle.
  • the mice were infected intraperitoneal (i.p.) with 10 6 PFU DENV-2/Rega.
  • Figure 2 Mean logio Viral Load (copies/mL) in serum of DENV-2/Rega infected mice (10 6 PFU) treated b.i.d. with compound (a) at 0.1 , 0.3, 1 , 3, 10, and 30 mg/kg/dose twice daily (b.i.d.), per os (p.o.) in comparison with vehicle and 2’-C-Methylcytidine (2’CMC) b.i.d. treated mice at 3 days post infection (p.i.).
  • Dotted line Lower limit of quantification (LLOQ) (3.8 logio copies/mL).
  • Figure 3 Schematic representation of the in vivo viremia mouse experiment where compound (a) (q.d.) is tested for efficacy against a high viral input or inoculum of DENV- 2/Rega (10 6 PFU).
  • the arrows at the bottom of the figure show the q.d. administrations of compound (a)/vehicle p.o.
  • the mice were infected i.p. with 10 6 PFU DENV-2/Rega.
  • Figure 4 Mean logio Viral Load (copies/mL) in serum of DENV-2/Rega infected mice (10 6 PFU) treated q.d. with compound (a) at 0.3, 3 and 30 mg/kg/dose q.d. p.o. in comparison with vehicle, q.d. and 2’CMC, b.i.d. treated mice at 3 days p.i. Standard deviations are shown as error bars in the figure.
  • LLOQ Lower limit of quantification
  • Figure 5 Schematic representation of the in vivo viremia mouse experiment where compound (a) b.i.d. is tested for efficacy against a low viral input or inoculum of DENV- 2/Rega (10 2 PFU). Arrows pointing up: b.i.d. administration of compound (a)/vehicle. Arrows pointing down: collection of blood samples to measure viral RNA load. At day 0, 1 hour after the first administration of compound (a), the mice were infected i.p. with 10 2 PFU DENV-2/Rega.
  • Figure 6 Median logio viral load (copies/mL) in serum of DENV-2/Rega infected mice (10 2 PFU) over 11 days; treated with compound (a) at 0.1, 1 , and 10 mg/kg/dose b.i.d. in comparison with vehicle-treated mice.
  • the arrows below the x-axis indicate b.i.d. administration of compound (a).
  • Lowest limit of quantification (LLOQ) 3.8 logio copies/mL. All negative values were imputed to a value of 2.6 logio copies/mL, which corresponds with a Ct-value of 40.
  • Figure 7 Schematic representation of the in vivo viremia mouse experiment where compound (a) q.d. is tested for efficacy against a low viral input or inoculum of DENV- 2/Rega (10 2 PFU). Arrows pointing up: q.d. administration of compound (a) /vehicle. Arrows pointing down: collection of blood samples to measure viral RNA load. At day 0, 1 hour after the first administration of compound (a), the mice were infected i.p. with 10 2 PFU DENV-2/Rega.
  • Figure 8 Median logio viral load (copies/mL) in serum of DENV-2/Rega infected mice (10 2 PFU) over 11 days; treated with compound (a) at 0.1 , 0.6, and 30 mg/kg/dose q.d. in comparison with vehicle-treated mice.
  • the arrows below the x-axis indicate q.d. administration of compound (a).
  • Lowest limit of quantification (LLOQ) 3.8 logio copies/mL. All negative values were imputed to a value of 2.6 logio copies/mL, which corresponds with a Ct-value of 40.
  • Figure 9 Median logio viral load (copies/mL) in serum of DENV-2/Rega infected mice (10 2 PFU) over 11 days; treated with compound (a) at 0.1 , 0.3, and 1 mg/kg/dose q.d. in comparison with vehicle-treated mice.
  • the arrows below the x-axis indicate q.d. administration of compound (a).
  • Lowest limit of quantification (LLOQ) 3.8 logio copies/mL. All negative values were imputed to a value of 2.6 logio copies/mL, which corresponds with a Ct-value of 40.
  • Figure 10 Median logio viral load (copies/mL) in serum of DENV-2/Rega infected mice (10 2 PFU) over 11 days; treated with compound (a) at 1 , 3, and 10 mg/kg/dose q.d. in comparison with vehicle-treated mice.
  • the arrows below the x-axis indicate q.d. administration of compound (a).
  • Lowest limit of quantification (LLOQ) 3.8 logio copies/mL. All negative values were imputed to a value of 2.6 logio copies/mL, which corresponds with a Ct-value of 40.
  • Figure 11 Schematic representation of the in vivo Non-Human Primate (NHP) experiment where rhesus macaques were infected with a viral inoculum of 10 2 TCID 50 DENV-2/16681.
  • the horizontal arrow indicates q.d. administration of compound (a)/vehicle from day -1 until and including Day 10.
  • Dark grey arrows pointing down collection of blood samples to measure viral RNA load.
  • Figure 12 A and B Logio viral RNA (GCE/mL) in serum of DENV-2/16681 infected rhesus monkeys (infected with 10 2 TCID50 DENV-2/16681); treated for 12 days with compound (a) at 0.01 ; 0.024; 0.09; 0.18; 0.93 and 3 mg/kg/dose q.d. in comparison with vehicle-treated rhesus monkeys (0 mg/kg/dose q.d.). Oral dosing of compound (a) was started 1 day before infection with DENV-2 and continued with daily dosing until 10 days post inoculation. The grey dashed line represents the lowest limit of quantification (LLOQ) of the assay (1286 RNA genome copy equivalents (GCE/mL). All negative values were imputed to a value of 42 GCE/mL, which corresponds with a Ct-value of 35.
  • LLOQ lowest limit of quantification
  • Figure 13 Schematic representation of in vivo Non-Human Primate (NHP) experiment where rhesus macaques were infected at day 0, with 0.5 mL of DENV-1/45AZ5 (titer of 1.2x10 5 PFU/mL).
  • the horizontal arrow indicates q.d. administration of compound (a)/vehicle from day -3 until and including Day 10.
  • Figure 14 Logio viral RNA (GCE/mL) in serum of DENV-1/45AZ5 infected rhesus monkeys (10 47 PFU), treated for 14 days with compound (a) at 6 mg/kg/dose q.d. (Y) in comparison with vehicle-treated rhesus monkeys (0 mg/kg/dose q.d.)
  • Oral dosing of compound (a) (6 mg/kg) was started 3 days before infection with DENV-1 and continued with daily dosing until 10 days post infection.
  • the assay limit of quantification (LOO) is 100 genomic copies/reaction.
  • Figure 15 In vivo efficacy of compound (b) on viremia and disease development in a prophylactic setting.
  • X Schematic outline of viremia and survival studies.
  • Y Inhibitory effect of compound (b) on viremia on day 3 p.i.
  • Z virus-induced disease in mice treated twice- daily with 30 mg/kg, 10 mg/kg, 3 mg/kg or 1 mg/kg of compound (b), as compared to vehicle- treated mice (black dots).
  • Figure 17 In vivo efficacy of compound (b) on kinetics of DENV replication in a Post- Exposure Prophylaxis (PEP) and therapeutic setting.
  • Z Inhibitory effect of compound (b) on viremia at various time points p.i. in mice treated twice-daily with 30 mg/kg for 6 consecutive days.
  • the present invention provides for the prevention, also called prophylactic treatment, of dengue disease.
  • prophylactic and prophylaxis refer to Post- Exposure Prophylaxis (PEP), and Pre-Exposure Prophylaxis (PrEP).
  • PEP also known as post-exposure prevention, refers to treatment initiated after exposure to the Dengue virus and preferably before reaching peak viral load.
  • PrEP refers to treatment initiated before exposure to the Dengue virus.
  • the invention further relates to the treatment of dengue disease. Treatment is used herein to refer to treatment initiated after exposure to the Dengue virus and preferably after reaching peak viral load and/or symptoms manifestations.
  • the present invention provides for the use of a compound of formula I or formula II in the manufacture of a medicament for the prevention of dengue infection or disease in an individual at risk of being infected by Dengue virus, wherein the medicament is administered intermittently at a time interval of at least 6 hours, preferably at least 12 hours, preferably at least 20 hours, preferably at least 24 hours and wherein compound of formula I corresponds to a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof; said compound is selected from the group wherein:
  • Ri is H
  • R 2 is F
  • R 3 is H or CH 3
  • Ri is H, CH 3 or F, R 2 is OCH 3 and R 3 is H,
  • Ri is H
  • R 2 is OCH 3 and R 3 is CH 3 ,
  • Ri is CH 3 , R 2 is F and R 3 is H, Ri is CF 3 or OCF 3 , R 2 is H and R 3 is H,
  • Ri is OCF 3
  • R 2 is OCH 3 and R 3 is H
  • Ri is OCF 3
  • R 2 is H and R 3 is CH 3
  • compound of formula II corresponds to a stereoisomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein
  • Ri is chloro, R 2 is hydrogen, R 3 is trifluoromethyl, and R 4 is hydrogen; or
  • Ri is chloro, R 2 is hydrogen, R 3 is trifluoromethoxy, and R 4 is hydrogen; or
  • Ri is chloro, R 2 is hydrogen, R 3 is trifluoromethyl, and R 4 is methoxy; or Ri is chloro, R 2 is methoxy, R 3 is trifluoromethyl, and R 4 is hydrogen; or
  • Ri is chloro, R 2 is methoxy, R 3 is trifluoromethyl, and R 4 is methoxy; or
  • Ri is chloro, R 2 is methoxy, R 3 is trifluoromethoxy, and R 4 is hydrogen; or
  • Ri is chloro, R 2 is fluoro, R 3 is trifluoromethyl, and R 4 is hydrogen; or Ri is chloro, R 2 is fluoro, R 3 is trifluoromethoxy, and R 4 is hydrogen; or
  • Ri is chloro, R 2 is fluoro, R 3 is trifluoromethyl, and R 4 is methoxy; or
  • Ri is chloro
  • R 2 is hydrogen
  • R 3 is trifluoromethoxy
  • R 4 is methoxy
  • the present invention also provides a compound of formula I for use in the prevention of dengue disease in an individual at risk of being infected by Dengue virus or for the treatment of dengue disease in an individual infected by Dengue virus wherein the compound is comprised in a medicament which is administered intermittently at a time interval of at least 6 hours, preferably at least 12 hours, preferably at least 20 hours, preferably at least 24 hours, preferably at least 36 hours, preferably at least 48 hours, preferably at least 72 hours, and wherein formula I corresponds to a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof; said compound is selected from the group wherein:
  • Ri is H
  • R 2 is F
  • R 3 is H or CH 3
  • Ri is H, CH 3 or F, R 2 is OCH 3 and R 3 is H,
  • Ri is H
  • R 2 is OCH 3 and R 3 is CH 3 ,
  • Ri is CH 3 , R 2 is F and R 3 is H,
  • Ri is CF 3 or OCF 3 , R 2 is H and R 3 is H,
  • Ri is OCF 3
  • R 2 is OCH 3 and R 3 is H
  • Ri is OCF 3
  • R 2 is H
  • R 3 is CH 3 .
  • Included within the scope of the present invention are all stereo-isomeric forms of the compounds of formula I or formula II, including mixtures of one or more thereof.
  • a pharmaceutically acceptable salt, solvate or polymorph thereof is selected from the group:
  • a pharmaceutically acceptable salt, solvate or polymorph thereof is selected from the group:
  • Pharmaceutically acceptable salts of the compounds of formula I and II include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Suitable base salts are formed from bases which form non-toxic salts. The compounds of formula I and II may be used in un-solvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising the compound of formula I and II and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the compounds of formula I according to the present invention may be synthesized according to methods described in the art, as disclosed in WO 2016/180696.
  • the compounds of formula II according to the present invention may be prepared according to methods described in the art, as disclosed in WO2017/167951.
  • the compound of Formula (I) is compound (a) or a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof.
  • Compound (a) may be in a solvated form, for example as a monohydrate.
  • the compound of Formula (I) is the (S)- enantiomer of Compound (a).
  • compound (a) is in anhydrous form.
  • compound (a) is in amorphous form.
  • compound (a) or a pharmaceutically acceptable salt form thereof is in amorphous form or dissolved state.
  • compound (a) is in amorphous form or dissolved state.
  • the compound of Formula (I) is the (S)- enantiomer in amorphous form.
  • the compound of Formula (I) is the (S)- enantiomer in anhydrous form.
  • compound (a) is the (S)- enantiomer in amorphous form.
  • the compound (a) is the (S)- enantiomer in anhydrous form.
  • the compounds may be administered as crystalline or amorphous products. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs. Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient depends largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • polymorph refers to the ability of the compounds of formula I and II to exist in more than one form or crystal structure.
  • the medicament is administered at least once every 6 hours, at least once every 8 hours, at least once every 12 hours, at least once every 20 hours at least once every 24 hours, at least once every 36 hours, at least once every 48 hours, at least once every 72 hours, at least once every week, at least once every two weeks, at least once every three weeks, at least once every month, at least once every 6 weeks, at least once every two months, at least once every three months, at least once every four months, at least once every five months, at least once every sixth months or at least once a year.
  • month and “4 weeks” are used herein as equivalents.
  • the medicament may be administered to an individual at risk of being infected by Dengue virus. Said individual is living in or traveling to a dengue endemic region.
  • the medicament may be also administered to an individual who is already infected by Dengue virus but the peak viral load in blood has not yet been reached.
  • the first administration of the medicament is occurring at least 5 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours, at least one week, at least two weeks, at least three weeks, at least one month, at least two months, at least three months, at least four months prior to infection (so for example prior to entering into an endemic geographical area for travelers or prior to dengue season for individuals living in endemic regions).
  • the first administration of the medicament may also occur at most 15 days, at most 14 days, at most 13 days, at most 12 days, at most 11 days, at most 10 days, at most 8 days, at most 6 days, at most 5 days, at most 4 days, at most 72 hours, at most 48 hours, at most 36 hours, at most 24 hours or at most 12 hours after being infected by Dengue virus.
  • the medicament comprises an effective amount of compound of formula I or formula II.
  • Said effective amount is selected such that dengue viral load in blood is kept during a prolonged period of time at a level of at most 0 copies/mL, at most 0.5 logio copies/mL, at most 1 logio copies/mL, at most 1.5 logio copies/mL, at most 2 logio copies/mL, at most 2.5 logio copies/mL, at most 3 logio copies/mL, at most 3.5 logio copies/mL, at most 4 logio copies/mL, at most 4.5 logio copies/mL, at most 5 logio copies/mL, at most 5.5 logio copies/mL, at most 6 logio copies/mL, at most 6.5 logio copies/mL, at most 7 logio copies/mL, at most 7.5 logio copies/mL, at most 8 logio copies/mL, at most 8.5 logio copies/mL, at most
  • logio copies/mL at most 9.5 logio copies/mL, at most 10 logio copies/mL, at most 10.5 logio copies/mL, at most 11 logio copies/mL, at most 11.5 logio copies/mL, at most 12 logio copies/mL, at most 12.5 logio copies/mL, at most 13 logio copies/mL, at most 13.5 logio copies/mL, at most 14 logio copies/mL, at most 15 logio copies/mL.
  • Said effective amount is selected such that dengue viral load in blood is kept at a level of at most 0 copies/mL, at most 0.5 logio copies/mL, at most 1 logio copies/mL, at most 1.5 logio copies/mL, at most 2 logio copies/mL, at most 2.5 logio copies/mL, at most 3 logio copies/mL, at most 3.5 logio copies/mL, at most 4 logio copies/mL, at most 4.5 logio copies/mL, at most 5 logio copies/mL, at most 5.5 logio copies/mL, at most 6 logio copies/mL, at most 6.5 logio copies/mL, at most 7 logio copies/mL, at most 7.5 logio copies/mL, at most 8 logio copies/mL, at most 8.5 logio copies/mL, at most 9 logio copies/mL, at most 9.5 logio copies/mL, at most
  • logio copies/mL at most 10.5 logio copies/mL, at most 11 logio copies/mL, at most 11.5 logio copies/mL, at most 12 logio copies/mL, at most 12.5 logio copies/mL, at most 13 logio copies/mL, at most 13.5 logio copies/mL, at most 14 logio copies/mL, at most 15 logio copies/mL.
  • the effective amount of compound of formula I or formula II is selected such that dengue viral load in blood is kept during a prolonged period of time at a level of at most 2 logio copies/mL, at most 2.5 logio copies/mL, at most 3 logio copies/mL, at most 3.5 logio copies/mL, at most 4 logio copies/mL, at most4.5 logiocopies/ml_, at most 5 logio copies/mL, at most 5.5 logio copies/mL, at most 6 logio copies/mL, at most 6.5 logio copies/mL, at most 7 logio copies/mL, at most 7.5 logio copies/mL, at most 8 logio copies/mL, at most 8.5 logio copies/mL, at most 9 logio copies/mL.
  • the effective amount of compound of formula I or formula II is selected such that dengue viral load in blood is kept at a level of at most 2 logio copies/mL, at most 2.5 logio copies/mL, at most 3 logio copies/mL, at most 3.5 logio copies/mL, at most 4 logio copies/mL, at most 4.5 logio copies/mL, at most 5 logio copies/mL, at most 5.5 logio copies/mL, at most 6 logio copies/mL, at most 6.5 logio copies/mL, at most 7 logio copies/mL, at most 7.5 logio copies/mL, at most 8 logio copies/mL, at most 8.5 logio copies/mL, at most 9 logio copies/mL.
  • Prolonged period of time refers to a period of at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours, at least 1 week, at least 2 weeks, at least 3 weeks or at least 4 weeks.
  • Said prolonged period of time refers to a period of at most 1 year, at most 6 months, at most 5 months, at most 4 months, at most 3 months or at most 2 months.
  • the medicament is administered orally, subcutaneously, intramuscularly, or intravenously.
  • the medicament may be formulated into various pharmaceutical forms for different administration purposes.
  • the medicament comprises an effective amount of any compound mentioned above or a mixture thereof, optionally in addition salt form, as the active ingredient.
  • Said active ingredient may be combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • the medicament may be in unitary dosage form suitable, for example, for oral, topical, rectal or any other administration route known to the person skilled in the art.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets.
  • the medicament may also be in solid form preparations that can be converted, shortly before use, to liquid forms.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • the effective amount of compound of formula I or formula II comprised in the medicament is of from 0.05 mg/kg to 500 mg/kg body weight, from 0.1 mg/kg to 400 mg/kg body weight, from 0.5 mg/kg to 300 mg/kg body weight, from 1 mg/kg to 200 mg/kg body weight, from 1.5 to 180 mg/kg body weight, from 3 mg/kg to 150 mg/kg body weight, from 5 mg/kg to 120 mg/kg body weight, from 6 mg/kg to 110 mg/kg body weight, from 10 mg/kg to 100 mg/kg body weight, from 15 mg/kg to 90 mg/kg body weight, from 20 mg/kg to 80 mg/kg body weight, from 25 mg/kg to 70 mg/kg body weight, from 30 mg/kg to 60 mg/kg body weight, from 35 mg/kg to 55 mg/kg body weight, from 40 mg/kg to 50 mg/kg body weight, from 42 to 45 mg/kg body weight or around 43 mg/kg body weight.
  • the effective daily amount of compound of formula I or formula II is of from 0.1 to 2400 mg, from 0.2 to 2000 mg, from 0.3 mg to 1600 mg, 0.5 mg to 1500 mg, from 1 mg to 1400 mg, from 2 mg to 1300 mg, from 3 mg to 1200 mg, from 4 mg to 1100 mg, from 5 mg to 1000 mg, from 6 mg to 950 mg, from 7 mg to 900 mg, from 8 mg to 850 mg, from 9 mg to 800 mg, from 10 mg to 750 mg, from 11 mg to 700 mg, from 12 mg to 650 mg, from 13 mg to 600 mg, from 14 mg to 550 mg, from 15 mg to 500 mg, from 16 mg to 450 mg, from 17 mg to 400 mg, from 18 mg to 350 mg, from 19 mg to 300 mg, from 20 mg to 250 mg, from 21 mg to 200 mg, from 22 mg to 150 mg, from 23 mg to 100 mg, from 24 mg to 95 mg, from 25 mg to 90 mg, from 26 mg to 85 mg, from 27 mg to 80 mg, from 28 mg to 75 mg, from 29 mg
  • the effective daily amount of compound may remain unchanged during the prophylaxis treatment period.
  • Said effective daily dose or amount may also be variable such that it may decrease and/or increase during the indicated prophylaxis treatment period.
  • Said effective daily amount may be reached by administration of medicaments which comprise unchanged or different concentrations (or effective amount) of compound of the invention.
  • Compounds of formula I or II as described herein may also be used in the manufacture of a medicament for the treatment of dengue disease.
  • the medicament is preferably administered 1 , 2, 3 or 4 times per day.
  • the effective amount of compound of formula I or formula II comprised in the medicament for example a single tablet or dosage form
  • the effective daily amount of compound may remain unchanged during the treatment period.
  • Said effective daily dose or amount may also be variable such that it may decrease and/or increase during the indicated treatment period.
  • Said effective daily amount may be reached by administration of medicaments which comprise unchanged or different concentrations of compound of the invention.
  • the present invention provides a method for the treatment of dengue disease in an individual infected by Dengue virus or the prevention of dengue disease in an individual at risk of being infected by Dengue virus, said method comprising the step of administering to said individual a medicament comprising compound of formula I or formula II, wherein the medicament is administered intermittently at a time interval of at least 6 hours, preferably at least 12 hours, preferably at least 20 hours, more preferably at least 24 hours, more preferably at least 36 hours, more preferably at least 48 hours, more preferably at least 72 hours, and wherein the compounds of formula I and formula II are as described above in the first aspect of the invention.
  • the medicament is administered as specified above in the first aspect of the invention including the administration timing of the medicament.
  • the medicament comprises an effective amount of compound of formula I or formula II, said effective amount is selected and has a value as specified above in the first aspect of the invention.
  • the AG 129 mouse model is a well-established model to study the antiviral effect of compounds against DENV in vivo (Zompi and Harris, 2012). These 129/Sv mice are deficient for both IFN-a/b and IFN-y receptors, enabling peripheral viral replication upon intravenous (i.v.) or subcutaneous (s.c.) infection with DENV (Johnson and Roehrig, 1999).
  • mice age- and sex-matched (6 to 10 weeks of age), were used to assess the antiviral effect of compound (a) on viral RNA levels in the serum.
  • Animals were infected intraperitoneally (i.p.) with high viral input of 10 6 plaque-forming units (PFU) DENV-2/Rega lab strain. Animals were treated by administering compound (a) by oral gavage with a first administration at one hour prior to infection. The treatment continued for three consecutive days with one administration of compound (a) every 12 hours (twice daily or b.i.d.). At day 3 post infection (p.i.), the mice were sacrificed, and blood was collected and stored at -80°C for viral load determination (Figure 1).
  • reference compound (2’CMC) 50 mg/kg/dose b.i.d., administered subcutaneously (s.c.),
  • RNA from serum was extracted using the NucleoSpin RNA virus kit according to the manufacturer’s protocol (Macherey-Nagel, Duren, Germany). The viral RNA load was determined by one-step TaqMan RT-qPCR (master mix from Eurogentec, Seraing, Belgium).
  • a dose-dependent reduction in mean viral load was estimated for the dose-range of 0.1 , 0.3, 1, 3, 10, and 30 mg/kg/dose b.i.d., compound (a) in serum ( Figure 2). All doses, except 0.1 mg/kg/dose b.i.d., resulted in a significant viral load reduction in serum compared with the vehicle-treated group (p ⁇ 0.001). In serum at 30 mg/kg/dose b.i.d., a viral load reduction of 4.4 logio copies/mL was observed, and at the lowest dose of compound (a) (0.1 mg/kg/dose b.i.d.), a viral load reduction of 0.47 logio copies/mL was still achieved.
  • mice reached their peak viral load at day 4 to day 5 p.i., while for the mice treated with 0.1 mg/kg/dose b.i.d. compound (a), the peak was delayed by about ⁇ 1 day.
  • a dose of 0.1 mg/kg/dose b.i.d. compound (a) reduced the viral load with 0.50 logio copies/mL compared with vehicle.
  • the two higher doses (10 and 1 mg/kg/dose b.i.d. compound (a)) reduced the viral load in the mice, over all the days, to undetectable levels (Figure 6).
  • mice age and sex matched (6 to 10 weeks of age), were used to assess the activity of compound (a) on viral RNA levels in serum.
  • Animals were i.p. infected with 10 2 PFU DENV-2/Rega lab strain in a volume of 200 mI_. Animals were treated by administering compound (a) by oral gavage with a first administration at one hour prior to infection. The treatment continued for six consecutive days with one administration of compound (a) every 24 hours (once a day or q.d.) ( Figure 7).
  • mice were divided in 4 treatment groups (n 16/group) representing the following treatment regimens:
  • experiment 1 compound (a) administrated q.d. p.o. at 0.1 , 0.6 and 30 mg/kg/dose q.d. (results in Figure 8)
  • experiment 2 compound (a) administrated q.d. p.o. at 0.1 , 0.3 and 1 mg/kg/dose q.d. (results in Figure 9)
  • experiment 3 compound (a) administrated q.d. p.o. at 1, 3 and 10 mg/kg/dose q.d. (results in Figure 10)
  • Alternating sub-groups were used to enable daily blood collections.
  • mice reached peak viral load generally at day 5 to days 6 p.i. with median viral loads of 4.3, 7.1, and 6.6 logio copies/mL, respectively, in experiments 1, 2, and 3 ( Figure 8, Figure 9, and Figure 10, respectively).
  • the rhesus monkeys were divided in 7 groups representing the following treatment regimens:
  • Table 1 The Median Estimated Change in Peak Viral Load (on Logio Scale) Versus Vehicle by Dose Group.
  • the antiviral activity of compound (a) DENV in a prophylactic setting was assessed in rhesus monkeys (Macaca mulatta) infected with strain DENV 1/45AZ5. Oral dosing of compound (a) (6 mg/kg) was started 3 days before infection with DENV (day -3) and continued with daily dosing until 10 days post infection. On day 0, the animals were intradermally inoculated with 0.5 mL of DENV 1/45AZ5 (1.2x105 plaque-forming units [PFU/mL]). Animals were followed up until day 28 post infection (Figure 13 X).
  • the rhesus monkeys were divided in 2 groups representing the following treatment regimens:
  • mice age- and sex-matched (6 to 9 weeks of age), were used to assess the activity of compound (b) on viral RNA levels in the serum of the mice and on virus-induced disease or mortality of the mice.
  • mice age and sex matched (6 to 10 weeks of age), were used to assess the activity of compound (b) on viral RNA levels in serum.
  • Animals were i.p. infected with 10 2 PFU DENV-2/Rega lab strain in a volume of 200 mI_. Animals were treated by administering compound (b) by oral gavage with a first administration at one hour prior to infection. The treatment continued for six consecutive days with one administration of compound (b) every 12 hours (twice daily or b.i.d.) ( Figure 16 Y).
  • mice were divided in 6 treatment groups (n 16/group) representing the following treatment regimens:
  • Alternating sub-groups were used to enable daily blood collections.
  • mice age- and sex-matched (6 to 9 weeks of age), were used to assess the activity of compound (b) on viral RNA levels in the serum of the mice.
  • the animals were infected intraperitoneally (i.p.) with 1 *10 2 PFU DENV-2/Rega lab strain and treated for five consecutive days with compound (b) which was administered by oral gavage.
  • Compound (b) was administered every 12 hours (twice daily or b.i.d.).
  • mice reached their peak viral load of 7.0 logio copies/mL at day 7 post infection.
  • the viral RNA in the serum of mice belonging to groups 2, group 3 and group 4 was reduced to undetectable levels (below the imputed value of negative values of 2.6 logio copies/mL), except for two measurements in group 4, where a viral rebound was observed at day 9 (3.0 logio copies/mL) and day 14 (4.7 logio copies/mL) post infection (Figure 15Z).
  • group 5 where treatment started at day 3 post infection and stopped at day 9 post infection, undetectable viral load was observed until day 9 post infection, but viral RNA was detected (5.0 logio copies/mL) at day 12 post infection (Figure 17Z).
  • This experiment further comprises an additional treatment group, i.e. group 8, in which the animals were treated with 30 mg/kg/dose of compound (b) b.i.d.
  • the first administration of compound (b) took place 6 days after infection.
  • the peak viral load was similar to the vehicle treated group, but undetectable viral load was reached earlier than for the vehicle treated mice ( Figure 17Z).

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CN202080093897.0A CN114980884A (zh) 2019-11-15 2020-11-13 登革热疾病的治疗和预防
IL292970A IL292970A (en) 2019-11-15 2020-11-13 Treatment and prevention of dengue disease
BR112022009199A BR112022009199A2 (pt) 2019-11-15 2020-11-13 Tratamento e prevenção da dengue
AU2020382911A AU2020382911A1 (en) 2019-11-15 2020-11-13 Treatment and prevention of Dengue disease
UAA202202003A UA129409C2 (uk) 2019-11-15 2020-11-13 Лікування та профілактика хвороби денге
MX2022005879A MX2022005879A (es) 2019-11-15 2020-11-13 Tratamiento y prevencion de la enfermedad del dengue.
EP20803432.2A EP4058019A1 (en) 2019-11-15 2020-11-13 Treatment and prevention of dengue disease
JP2022528008A JP2023502053A (ja) 2019-11-15 2020-11-13 デング病の治療及び予防
US17/777,019 US20220409583A1 (en) 2019-11-15 2020-11-13 Treatment and Prevention of Dengue Disease
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Cited By (3)

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WO2023218285A1 (en) * 2022-05-12 2023-11-16 Janssen Pharmaceuticals, Inc. Treatment or prevention of dengue viral infection
WO2025248536A1 (en) * 2024-05-29 2025-12-04 Zydus Lifesciences Limited Novel oxime derivatives to treat viral infections
WO2025253267A1 (en) 2024-06-06 2025-12-11 Janssen Pharmaceuticals, Inc. Combination of mosnodenvir and close analogs with nitd-688 for use in the treatment and prevention of dengue disease

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WO2016180696A1 (en) 2015-05-08 2016-11-17 Janssen Pharmaceuticals, Inc. Mono- or di-substituted indole derivatives as dengue viral replication inhibitors
WO2017167951A1 (en) 2016-04-01 2017-10-05 Janssen Pharmaceuticals, Inc. Substituted indoline derivatives as dengue viral replication inhibitors

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WO2016180696A1 (en) 2015-05-08 2016-11-17 Janssen Pharmaceuticals, Inc. Mono- or di-substituted indole derivatives as dengue viral replication inhibitors
WO2017167951A1 (en) 2016-04-01 2017-10-05 Janssen Pharmaceuticals, Inc. Substituted indoline derivatives as dengue viral replication inhibitors

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023218285A1 (en) * 2022-05-12 2023-11-16 Janssen Pharmaceuticals, Inc. Treatment or prevention of dengue viral infection
WO2025248536A1 (en) * 2024-05-29 2025-12-04 Zydus Lifesciences Limited Novel oxime derivatives to treat viral infections
WO2025253267A1 (en) 2024-06-06 2025-12-11 Janssen Pharmaceuticals, Inc. Combination of mosnodenvir and close analogs with nitd-688 for use in the treatment and prevention of dengue disease

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