[go: up one dir, main page]

WO2019070709A1 - Composés pour le traitement ou la prévention d'infections à flavivirus - Google Patents

Composés pour le traitement ou la prévention d'infections à flavivirus Download PDF

Info

Publication number
WO2019070709A1
WO2019070709A1 PCT/US2018/053968 US2018053968W WO2019070709A1 WO 2019070709 A1 WO2019070709 A1 WO 2019070709A1 US 2018053968 W US2018053968 W US 2018053968W WO 2019070709 A1 WO2019070709 A1 WO 2019070709A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
optionally substituted
alkyl
subject
virus
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2018/053968
Other languages
English (en)
Other versions
WO2019070709A8 (fr
Inventor
Piotr Pawel RUCHALA
Ewa Dorota MICEMICZ
Ronil KHACHATOORIAN
Samuel Wheeler FRENCH
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.)
University of California Berkeley
University of California San Diego UCSD
Original Assignee
University of California Berkeley
University of California San Diego UCSD
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of California Berkeley, University of California San Diego UCSD filed Critical University of California Berkeley
Publication of WO2019070709A1 publication Critical patent/WO2019070709A1/fr
Publication of WO2019070709A8 publication Critical patent/WO2019070709A8/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/4015—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 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • 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
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/433—Thidiazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • 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

  • Flavivirus is a genus of viruses that include West Nile virus, dengue virus, yellow fever virus, Zika virus, and several others.
  • Zika Virus Zika Virus (ZIKV) is an emerging pathogen that is linked to fetal developmental abnormalities such as microcephaly, eye defects, and impaired growth. Animal model studies also suggest that Zika- infection may lead to male infertility (Cell, 2016; 167: 1511-1524; Nature, 2016; 540:438-442) and severe neurological and other systemic complications in adults.
  • ZIKV Zika's replication
  • ICso bioactivity reported to date for small molecules is in the micromolar range and for most active peptides in low nanomolar range with ICso values for antibodies ⁇ 1 ng/mL, depending on antibody and viral strain tested. Therefore further development of inexpensive and orally available anti-Zika drugs is of critical importance, with small organic compounds being obvious candidates for versatile use as a prophylactic, post-exposure prophylactic, and treatment option for Zika virus infections in general and high-risk populations, including infected pregnant women.
  • the flavivirus may be Zika virus, Dengue virus, West Nile virus, Yellow fever virus, Japanese encephalitis virus or St. Louis encephalitis virus, preferably, Zika virus.
  • the methods comprise administering a compound disclosed herein or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • the compositions disclosed herein further comprise a pharmaceutically acceptable carrier.
  • the compounds disclosed herein have a structure of Formula I or Formula II:
  • a method of treating or preventing a virus infection from a virus from the Flaviviridae family in a subject comprising administering to the subject a compound having the structure of Formula III or Formula IV
  • the methods disclosed herein treat or prevent a flavivirus infection in a subject, e.g., by administering to the subject a compound of Formula I, Formula II, Formula III or Formula IV.
  • the methods disclosed herein treat or prevent a Zika virus infection, Dengue virus infection, West Nile virus infection, Yellow fever virus infection, Japanese encephalitis virus infection or St. Louis encephalitis virus infection.
  • the flavivirus is Zika virus.
  • FIG. 1 is a bar graph showing anti-Zika activity of compounds 57X, 57Y, 57Z, 78X, 78 Y, 78Z, and 9 (NE9) at 5 ⁇ compared to a DMSO control.
  • FIG. 3 shows an overlay of minimized structures of NE9 (top), ASN 07115854 (middle) and (S)-(+)-rolipram (bottom).
  • FIG. 4 shows a screen of selected PDE4 inhibitors and adenosine receptors' antagonists.
  • FIG. 5 shows the corresponding dose response curves of selected PDE4 inhibitors and adenosine receptors' antagonists.
  • FIG. 6 shows the screening results for ASN compounds at 5 ⁇ concentration.
  • FIG. 7 shows representative examples of dose response curves.
  • a flavivirus infection such as a Zika virus infection, Dengue virus infection, West Nile virus infection, Yellow fever virus infection, Japanese encephalitis virus infection or St. Louis encephalitis virus infection.
  • the flavivirus is Zika virus.
  • R 12 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, or optionally substituted aryloxyalkyl;
  • R 13 is H or optionally substituted alkyl
  • R 14 is optionally substituted alkyl
  • X is selected from O or S
  • ene e.g., methylene
  • p is an integer selected from 1, 2, 3, 4 or 5.
  • each R 11 is independently selected from -F, -CI, -Br, -I, -CF3, and acyl.
  • each R 11 is independently selected from -F, -CI, -Br
  • the compound comprises one occurrence of R in the para position. In some embodiments, the compound comprises an occurrence of R 11 is in a meta position. In other embodiments, at least one occurrence of R 11 , e.g., an occurrence of R 11 in the para position, is halo. In preferred embodiments, the compound comprises an occurrence of R 1 in the para position, where R 11 is halo, e.g., -F, -CI, -Br or -I, preferably CI.
  • At least one occurrence of R 11 is substituted alkyl, preferably haloalkyl, most preferably -CF3.
  • R is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, or optionally substituted aryloxyalkyl.
  • R is optionally substituted alkenyl, e.g.
  • R is optionally substituted alkynyl, e.g.
  • R 12 is optionally substituted aralkyl.
  • R optionally substituted aryloxyalkyl e.g.,
  • X is O. In some embodiments, X is S.
  • Y is S or -NH-.
  • Th i In certain embodime In certain embodiments, Th i In
  • R 12 is optionally substituted alkenyl or optionally substituted alkynyl, preferably allyl or propargyl;
  • X is selected from O or S
  • Y is selected from S or -NH- p is 1 or 2.
  • the compound is selected from a compound of Formula I identified in Table 1 or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • A is O or S
  • R 4 is selected from optionally substituted aryl or heteroaryl
  • R 5 is selected from CR 6 R 7 , OR 6 , NR 6 and optionally substituted alkyl;
  • R 6 is selected from H or optionally substituted alkyl
  • R 7 is selected from H or optionally substituted alkyl.
  • A is O.
  • R 4 is optionally substituted aryl, e.g., optionally substituted phenyl.
  • the aryl or phenyl is substituted with one or more substituents selected from halo, nitro, cyano, hydroxy, carboxy, alkyl, alkoxy, ester, sulfonate, sulfone, sulfoxide, and -C(0)R 8 and R 8 is alkyl.
  • R 8 is lower alkyl
  • R 4 is , e.g.
  • R 5 is selected from CHR 6 and OR 6 .
  • R 6 is substituted alkyl. In some embodim R 6 is substituted with an alkynyl or alkyl group.
  • R 6 is or an integer selected from 1, 2, 3, or 4, e.g., 1, 2, or 3; and n is an integer selected from 1, 2, 3, or 4, e.g., 1, 2, or 3.
  • the compound is selected from:
  • R 1 is selected from optionally substituted aryl and heteroaryl
  • R 2 is selected from H and optionally substituted alkyl
  • R 3 is selected from optionally substituted aryl, heteroaryl or alkyl.
  • R 1 is optionally substituted aryl, e.g., phenyl.
  • the phenyl is substituted with at least one of halo, e.g., CI, alkoxy or nitro,
  • R 1 preferably nitro.
  • R 1 preferably nitro.
  • R 2 is optionally substituted alkyl.
  • the alkyl is substituted with a sulfonate, e.g., wherein R 2 is -(CH2)3-SC H.
  • R 3 is optionally substituted aryl, e.g., phenyl.
  • the phenyl is substituted with at least one of halo e.g., -F, nitro and heteroaryl.
  • R is
  • R 3 is optionally substituted heteroaryl.
  • the heteroaryl substituted with alkyl e.g., methyl.
  • R 3 is optionally substituted aryl. In some embodiments, R 3 is optionally substituted phenyl, e.g., para-substituted phenyl.
  • R 3 is phenyl substituted with at least one of halo, nitro, heteroaryl, acyl, acylamino, alkyl, -SC Me, cyano, carboxy, -CF3 and -OCF3.
  • R 3 is phenyl substituted with at least one -F, -CI, or alkyl selected from methyl, iso-propyl, tert-butyl or n-hexyl.
  • the compound is selected from the compounds identified in Table 2 or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising any one of the aforementioned compounds and a pharmaceutically acceptable carrier.
  • Patients including but not limited to humans, can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrug or salt thereof in the presence of a pharmaceutically acceptable carrier or diluent.
  • the active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form.
  • the concentration of active compound in the drug composition will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated, and possible drug-drug interactions with antiretroviral medications. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient can be administered at once, or can be divided into a number of smaller doses to be administered at varying intervals of time.
  • the mode of administration of the active compound is oral.
  • Oral compositions will generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such
  • the compound can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
  • a syrup can contain, in addition to the active compound(s), sucrose or sweetener as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the compound or a pharmaceutically acceptable prodrug or salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, anti-inflammatories or other antivirals, including but not limited to nucleoside compounds.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;
  • chelating agents such as ethylenediaminetetraacetic acid
  • buffers such as acetates, citrates or phosphates
  • agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • carriers include physiological saline and phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including but not limited to implants and microencapsulated delivery systems, such as those disclosed in International Publication No. WO 2010/093944, hereby incorporated by reference in its entirety, and specifically with respect to the formulations disclosed therein.
  • a controlled release formulation including but not limited to implants and microencapsulated delivery systems, such as those disclosed in International Publication No. WO 2010/093944, hereby incorporated by reference in its entirety, and specifically with respect to the formulations disclosed therein.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid.
  • enterically coated compounds can be used to protect cleavage by stomach acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Suitable materials can also be obtained commercially.
  • Liposomal suspensions are also preferred as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (incorporated by reference).
  • liposome formulations can be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container.
  • compositions and methods of the present invention may be utilized to treat a subject in need thereof.
  • the subject is a mammal such as a human, or a non- human mammal.
  • the composition is preferably administered as a pharmaceutical composition comprising, for example, a composition of the invention and a pharmaceutically acceptable carrier.
  • compositions include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil or injectable organic esters.
  • aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, powder, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration,
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • polymers of the present invention may also be optically active.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and -S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize or to increase the absorption of a compound of the invention.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases "pharmaceutically acceptable carrier” as used herein means a
  • composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • a liquid or solid filler such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue);
  • routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue);
  • oral mucosa e.g., sublingually
  • anally, rectally or vaginally for example, as a pessary, cream or foam
  • parenterally including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension
  • nasally e.g., a sterile solution or suspension
  • compositions may also be formulated for inhalation.
  • a composition may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Patent Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • composition that is suitable for use in the invention may be administered orally, topically or parenterally, and in particular topically.
  • Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the composition may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an antibiotic, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of the invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • composition of the invention may be formulated with an excipient and component that is common for such oral compositions or food supplements, e.g., especially fatty and/or aqueous components, humectants, thickeners, preserving agents, texturizers, flavor enhancers and/or coating agents, antioxidants and preserving agents.
  • an excipient and component that is common for such oral compositions or food supplements, e.g., especially fatty and/or aqueous components, humectants, thickeners, preserving agents, texturizers, flavor enhancers and/or coating agents, antioxidants and preserving agents.
  • an ingestible support is preferred.
  • the ingestible support may be of diverse nature according to the type of composition under consideration. Tablets, gel capsules or lozenges, suspensions, oral supplements in dry form and oral supplements in liquid form are especially suitable for use as food supports.
  • Formulation of the oral compositions according to the invention may be performed via any usual process known to those skilled in the art for producing drinkable solutions, sugar- coated tablets, gel capsules, gels, emulsions, tablets to be swallowed or chewed, wafer capsules, especially soft or hard wafer capsules, granules to be dissolved, syrups, solid or liquid foods, and hydrogels allowing controlled release.
  • Formulation of the oral compositions according to the invention may be incorporated into any form of food supplement or enriched food, for example food bars, or compacted or loose powders.
  • the powders may be diluted with water, with soda, with dairy products or soybean derivatives, or may be incorporated into food bars.
  • the composition according to the invention administered orally may be formulated in the form of sugar-coated tablets, gel capsules, gels, emulsions, tablets, wafer capsules, hydrogels, food bars, compacted or loose powders, liquid suspensions or solutions, confectioneries, fermented milks, fermented cheeses, chewing gum, toothpaste or spray solutions.
  • An effective amount of the composition may be administered in a single dose per day or in fractional doses over the day, for example two to three times a day.
  • the administration of a composition according to the invention may be performed at a rate, for example, of 3 times a day or more, generally over a prolonged period of at least a week, 2 weeks, 3 weeks, 4 weeks, or even 4 to 15 weeks, optionally comprising one or more periods of stoppage or being repeated after a period of stoppage.
  • the compound may be administered at a dose between 1 mg and 1,500 mg per day, such as between 5 mg and 1,300 mg per day, such as between 10 mg and 900 mg per day, such as between 20 mg and 600 mg per day, such as between 40 mg and 300 mg per day, such as between 150 mg and 350 mg per day , such as between 40 and 150 mg per day, such as between 25 mg and 150 mg per day , such as between 2.5 mg and 150 mg per day, such as between 20 mg and 80 mg per day, or such as between 1 mg and 30 mg per day.
  • 1 mg and 1,500 mg per day such as between 5 mg and 1,300 mg per day, such as between 10 mg and 900 mg per day, such as between 20 mg and 600 mg per day, such as between 40 mg and 300 mg per day, such as between 150 mg and 350 mg per day , such as between 40 and 150 mg per day, such as between 25 mg and 150 mg per day , such as between 2.5 mg and 150 mg per day, such as between 20 mg and 80 mg per day, or such as between 1 mg and 30 mg
  • the compound may be administered at a dose of 1,300 mg/day, 900 mg/day, 600 mg/day, 350 mg/day, 300 mg/day, 250mg/day, 200 mg/day, 150 mg/day, 80 mg/day, 75 mg/day, 60 mg/day, 40 mg/day, 30 mg/day, 20 mg/day, 15 mg/day, 10 mg/day, 5 mg/day, or 2.5 mg/day.
  • compositions and methods of the present invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention.
  • pharmaceutically acceptable salt includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic,
  • salt forms can include forms wherein the ratio of molecules comprising the salt is not 1 : 1.
  • the salt may comprise more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of a compound.
  • the salt may comprise less than one inorganic or organic acid molecule per molecule of base, such as two molecules of a compound per molecule of tartaric acid.
  • contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N- methylglucamine, hydrabamine, lH-imidazole, L-lysine, magnesium, 4-(2- hydroxy ethyl)morpholine, piperazine, potassium, 1 -(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.
  • contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In further embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • the pharmaceutically acceptable salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • compositions of the present invention may be administered daily to the subject.
  • provided herein is a method for protecting a subject from flavivirus, comprising administering to the subject a compound (e.g., compound of Formula I, compound of Formula II, compound of Formula III, compound of Formula IV) or a composition disclosed herein.
  • a method of treating a subject for a flavivirus infection comprising administering to the subject a compound (e.g., compound of Formula I, compound of Formula II, compound of Formula III, compound of Formula IV) or a composition disclosed herein.
  • a method of preventing a subject from a flavivirus infection comprising administering to the subject a compound (e.g., compound of Formula I, compound of Formula II, compound of Formula III, compound of Formula IV) or a composition disclosed herein.
  • the flavivirus is Zika virus, Dengue virus, West Nile virus, Yellow fever virus, Japanese encephalitis virus or St. Louis encephalitis virus.
  • the flavivirus is Zika virus.
  • provided herein is a method for protecting a subject from Zika virus, comprising administering to the subject a compound (e.g., compound of Formula I, compound of Formula II, compound of Formula III, compound of Formula IV) or a composition disclosed herein.
  • a method of treating a subject for a Zika virus infection comprising administering to the subject a compound (e.g., compound of Formula I, compound of Formula II, compound of Formula III, compound of Formula IV) or a composition disclosed herein.
  • provided herein is a method of preventing a subject for a Zika virus infection comprising administering to the subject a compound (e.g., compound of Formula I, compound of Formula II, compound of Formula III, compound of Formula IV) or a composition disclosed herein.
  • a compound e.g., compound of Formula I, compound of Formula II, compound of Formula III, compound of Formula IV
  • provided herein are compounds (e.g., compound of Formula I, compound of Formula II, compound of Formula III, compound of Formula IV) or a composition disclosed herein for use in secondary clinical application as antivirals against flavivirus infections.
  • a “subject,” as used herein, can be any mammal.
  • a subject can be a human, a non-human primate (e.g., monkey, baboon, or chimpanzee), a horse, a cow, a pig, a sheep, a goat, a dog, a cat, a rabbit, a guinea pig, a gerbil, a hamster, a rat, or a mouse.
  • the subject is an infant (e.g., a human infant).
  • the subject is female (e.g., a human female).
  • a subject can be a human female of child-bearing age or a human female who is pregnant.
  • the subject is exposed to Zika virus due to the subject's exposure to a mosquito comprising the Zika virus.
  • the subject may be exposed to a Aedes mosquitoes, particularly aegypti.
  • Such a subject may be at risk of developing a Zika virus infection and disease states related to or caused by such an infection.
  • a method of treating or preventing a virus infection from a virus from the Flaviviridae family in a subject comprising administering to the subject a compound (e.g., compound of Formula I, compound of Formula II, compound of Formula III, compound of Formula IV) or a composition disclosed herein.
  • a compound e.g., compound of Formula I, compound of Formula II, compound of Formula III, compound of Formula IV
  • a composition disclosed herein. e.g., a compound of Formula I, compound of Formula II, compound of Formula III, compound of Formula IV
  • the virus is Zika, Dengue, West Nile, Yellow fever, Japanese encephalitis or St. Louis encephalitis viruses, preferably Zika.
  • acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
  • acylamino is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(0)NH-.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(0)0-, preferably alkylC(0)0-.
  • alkoxy refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, tert- butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkenyl refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and “substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • alkyl group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A Ci-C 6 straight chained or branched alkyl group is also referred to as a "lower alkyl” group. An alkyl group with two open valences is sometimes referred to as an alkylene group, such as methylene, ethylene, propylene and the like.
  • alkyl (or “lower alkyl) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
  • a halogen
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like.
  • Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.
  • C x - y when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • Cx- y alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2- tirfluoroethyl, etc.
  • Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • C2- y alkenyl and C2- y alkynyl refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • C x - y indicates that the group contains from x to y carbons and heteroatoms in the chain.
  • C x - y indicates that the ring comprises x to y carbon atoms.
  • C x - y indicates that the ring contains from x to y carbons and heteroatoms.
  • groups such as aralkyl and heterocyclylalkyl groups, that have both ring and chain components, “C x - y " indicates that the ring and the chain together contain from x to y carbon atoms and, as appropriate heteroatoms.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • alkynyl refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and “substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • amide refers to a group
  • each R 10 independently represent a hydrogen or hydrocarbyl group, or two R 10 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by
  • each R 10 independently represents a hydrogen or a hydrocarbyl group, or two R 10 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7-membered ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • R 9 and R 10 independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R 9 and R 10 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • carbocycle refers to a saturated or unsaturated ring in which each atom of the ring is carbon.
  • carbocycle includes both aromatic carbocycles and non-aromatic carbocycles.
  • Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.
  • Carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term "fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring.
  • Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g., phenyl
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic.
  • Exemplary "carbocycles" include cyclopentane, cyclohexane,
  • a "cycloalkyl” group is a cyclic hydrocarbon which is completely saturated.
  • Cycloalkyl includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined.
  • the second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring.
  • the second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.
  • a "cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds.
  • Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • carbonate is art-recognized and refers to a group -OCO2-R 10 , wherein R 10 represents a hydrocarbyl group.
  • esters refers to a group -C(0)OR 10 wherein R 10 represents a hydrocarbyl group.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • heteroalkyl and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroalkyl refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.
  • heteroalkyl groups with two open valences are sometimes referred to as heteroalkylene groups.
  • the heteroatoms in heteroalkyl groups are selected from O and N.
  • heteroaryl and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and “heterocyclic” also include poly cyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer.
  • acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • mitigating means reducing the negative effects caused by exposure to ionizing radiation, relative to a cell, organ, tissue, or organism exposed to the same level of radiation for the same amount of time, but untreated.
  • a "therapeutically effective amount” is an amount sufficient to mitigate the effects of the ionizing radiation.
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are "fused rings".
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • a polycyclic substituent When a polycyclic substituent is attached through an aryl or heteroaryl ring, that substituent may be referred to herein as an aryl or heteroaryl group, while if the polycyclic substituent is attached through a cycloalkyl or heterocyclyl group, that substituent may be referred to herein as a cycloalkyl or heterocyclyl group.
  • a 1,2,3,4-tetrahydronaphthalen-l-yl group would be a cycloalkyl group, while a l,2,3,4-tetrahydronaphthalen-5-yl group would be an aryl group.
  • sil refers to a silicon moiety with three hydrocarbyl moieties attached thereto.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the moiety. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic mo
  • sulfate is art-recognized and refers to the group -OSO3H, or a
  • R 9 and R 10 independently represents hydrogen or hydrocarbyl, such as alkyl, or R 9 and R 10 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • sulfoxide is art-recognized and refers to the group -S(0)-R 10 , wherein R 10 represents a hydrocarbyl.
  • sulfonate is art-recognized and refers to the group SO3H, or a
  • sulfone is art-recognized and refers to the group -S(0)2-R 10 , wherein R 10 represents a hydrocarbyl.
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(0)SR or -SC(0)R wherein R 10 represents a hydrocarbyl.
  • thioether is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
  • urea is art-recognized and may be represented by the general formula
  • R 9 and R 10 independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R 9 taken together with R 10 and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • administering means the actual physical introduction of a composition into or onto (as appropriate) a subject. Any and all methods of introducing the composition into subject are contemplated according to the invention; the method is not dependent on any particular means of introduction and is not to be so construed. Means of introduction are well known to those skilled in the art, and also are exemplified herein.
  • the terms "effective amount”, “effective dose”, “sufficient amount”, “amount effective to”, “therapeutically effective amount” or grammatical equivalents thereof mean a dosage sufficient to produce a desired result, to ameliorate, or in some manner, reduce a symptom or stop or reverse progression of a condition and provide either a subjective relief of a symptom(s) or an objectively identifiable improvement as noted by a clinician or other qualified observer.
  • Amelioration of a symptom of a particular condition by administration of a pharmaceutical composition described herein refers to any lessening, whether permanent or temporary, lasting, or transitory, that can be associated with the administration of the
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present invention.
  • a common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal.
  • esters or carbonates e.g., esters or carbonates of alcohols or carboxylic acids
  • some or all of the compounds in a formulation represented above can be replaced with the corresponding suitable prodrug, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid present in the parent compound is presented as an ester.
  • the term “pharmaceutically acceptable” refers to compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction when administered to a subject, preferably a human subject.
  • pharmaceutically acceptable means approved by a regulatory agency of a federal or state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • a therapeutic that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • treating is art-recognized and includes administration to the host of one or more of the subject compositions, e.g., to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof.
  • Precipitated intermediate D was collected by filtration, washed twice with absolute ethanol (2x25 mL) and dried under the vacuum (overnight) giving 12.9 g (37.14 mmoles) of solid material (92.8% yield). Crude D was re-crystallized from hot ethyl acetate (88.6% yield). Subsequently intermediate D (1 equivalent) was reacted with 3 equivalents of 1,3- propanesultone in anhydrous 1,4-dioxane (75°C/72h). Next, reaction mixture was evaporated using rotary evaporator and remaining residue extracted with hot water (95°C, 3 x). Combined extracts were lyophilized and obtained solid residue purified using preparative reversed-phase liquid chromatography giving pure 19 (36.7% yield for betainization).
  • Table 4 summarizes the characterization data for compounds disclosed herein.
  • LC-MS analytical data were acquired using Agilent 6460 Triple Quadrupole LC/MS System (Agilent Technologies, Santa Clara, CA) with mobile phases consisted of solvent A, 0.1% formic acid (FA) in water, and solvent B, 0.1% FA in acetonitrile (ACN). Analysis was performed with an analytical reversed-phase CORTECS ® UPLC ® Phenyl 1.6 ⁇ 2.1 x 100 mm Column (Waters, Milford, MA) applying linear gradient of solvent B from 0% to 100% over 50 min (flow rate: 200 ⁇ 7 ⁇ ).
  • Mass spectra were acquired using Applied Biosystems Voyager-DE STR MALDI-TOF instrument.
  • Example 5 In vitro screening against Zika virus infection by plaque assay
  • Naive A549 cells were seeded at concentration of 2* 10 5 cells per well using a 48-well plate, and allowed to grow for 48 hours to form a confluent monolayer. Subsequently, the tested compounds were added at indicated concentrations (using Opti-MEM medium) in biological triplicates. The cells were infected immediately after compound treatment, (MOI of 10, 1, 0.1, 0.01, 0.001, and 0.0001) in 100 ⁇ per well and plates were incubated at 37°C with 5% CO2 for 4 hours. At 4 hr post-infection, the viral inoculum was replaced with serum supplemented media (250 ⁇ per well, including the same concentration of the compounds) and plates incubated at 37°C for additional 44 hours. At 48 hr post-infection, the plaques in each well were counted using a phase contrast microscope.
  • the dose response anti-Zika activity of compounds 9, 19 and 39 using the plaque assay are shown in Table 5 and the dose response anti-Zika activity of compounds 61, 63, 89, 91, 92, 93, 95, 96, 98, 99 and 102 using the plaque assay are shown in Table 6.
  • Table 6 summarizes the chemical and assay data for certain compounds disclosed herein.
  • the compounds of Formula III take advantage of diversity and commercial availability of relatively rigid 1-phenylpiperazine scaffold which is present in compound 9. With 100+ analogs of substituted 1-phenylpiperazine available, a small library of compounds of Formula III can be easily created using either 3-butenyl chloroformate, 4-isothiocyanato-l-butene or 5-hexenoic acid, giving as a result urethanes, thiourethanes or piperazides respectively, with slightly different geometry/orientation of alkene-containing moiety. Preliminary experiments toward development of a library was performed to determine the optimal size and saturation (alkene versus alkyne) to ascertain bioactive hybrids. A group of compounds of Formula III were synthesized and tested. Compound 57Z showed significant anti-Zika inhibitory effects
  • Newly found compounds were both proprietary (NE9) as well as commercially available entities (ASN07115854, rolipram, preladenant) with potential for further pharmaceutically - relevant modifications.
  • the "hits” show certain common structural features, namely they contain an assembly of 3 aromatic/aliphatic rings (or 2 rings with rigid linker, see compound 2) in para- or meta-configuration and with or without additional peripheral modifications (acetyl, S-allyl, O- Me, etc.) which are usually small.
  • An additional common denominator is the presence of N- phenyl-substituted piperazine or phenyl-substituted-piperazine-like moiety (4-phenyl-2- pyrrolidone in case of rolipram (compound 3)).
  • Molecular modeling studies have shown that at least 3 of the leading compounds which possess similar size (namely compounds 1, 2 and 3) can adopt certain conformations allowing them to occupy dimmensionaly similar binding cavities (See FIG. 3).
  • a small group of adenosine receptors' antagonists (preladenant (compound 91), SLV 320 (compound 89), DPCPX (compound 203), SCH 442416 (compound 92), PSB 603 (compound 93), ZM 241385 (compound 63) and MRS 1220 (compound 204) were tested in the plaque assays to see whether specific receptor subtypes are involved in anti-Zika inhibitory effects. The major criteria for selection was specific receptor subtype selectivity.
  • the group comprised the following molecules: SLV 320 (Al antagonist), DPCPX (Al antagonist), SCH 442416 (A2A antagonist), PSB 603 (A2B antagonist), ZM 241385 (A2A and A2B antagonist) and MRS 1220 (A3 antagonist).
  • Table 8 shows the activity of selected PDE4 inhibitors and adenosine receptors' antagonists at 5 ⁇ concentration.
  • IC50 43.8 ⁇ 8.8 nM
  • SLV 32060 Al antagonists
  • IC50 58.6 ⁇ 10.2 nM
  • PSB 603 which is selective A2B receptor antagonist with very low activity against A2A subtype is also highly active, precluding neither of AR subtypes, A2A and A2B as the important players in the Zika virus life cycle.
  • A3 adenosine receptor subtype as its selective antagonist MRS 1220 shows no anti-Zika potency even though it is also partially active against A2B subtype like PSB 603.
  • the latter is also particularly similar to our hit compound 1 (NE9) with additional bulky xanthine substituent in benzenesulfonyl moiety, emphasizing again the role of structural similarities between the identified compounds.
  • compound 2 is 1,3-disubstituted urea, containing on the one side the acetophenone and on the other 3-allylthio-l,2,4-thiadiazole moieties. Due to the presence of urea linker which is positioned between two aromatic rings, the entire structure is relatively rigid, providing convenient scaffold for synthesis of compound 2-related derivatives.
  • a number of such derivatives is commercially available (Asinex Corp., Winston- Salem, NC), and a small group of compounds was selected to further delineate anti-Zika SAR properties within this class of compounds in plaque assays (ASN 07115854 (compound 61), ASN 07115861 (compound 351), ASN 07115862 (compound 352), ASN 07115865 (compound 353), ASN 07115866 (compound 354), ASN 07115873 (compound 355), ASN 07115881 (compound 356), ASN 07115764 (compound 357), ASN 07115629 (compound 358), ASN 07114909 (compound 359), ASN 07115449 (compound 360), ASN 07114414 (compound 361), ASN 08966910 (compound 362), ASN 07114826 (compound 363), ASN 08966916 (compound 364), ASN 08966912 (compound 365), ASN 07115927 (
  • the compounds can occupy the same binding cavity and, by extension, possess the same mechanism of action.
  • the model is based on the data obtained for the compounds, the study provides a general direction for the design of Zika inhibitors.
  • Effective Zika antivirals (compounds 9, 61, 96, 205, 206, 207 and 208) should contain an assembly of 3 aromatic/aliphatic rings (or 2 rings with rigid linker) in para- or meta-configuration and with or without additional peripheral modifications (acetyl, S-allyl, O- Me, etc.).
  • Ring A should be a six-membered aromatic or aliphatic entity.
  • ring B should be 5- or 6-membered cycloaliphatic ring with or without heteroatoms (pyrrolidin-2-one, 2-oxazolidinone, tetrahydro-2-pyrimidinone) and linker X should be positioned in meta-configuration (X bottom).
  • A is a non-aromatic ring (e.g. piperazine)
  • B ring is likely to be 5- or 6-membered aromatic moiety which may contain small substituents (-Ac, - CH3, -CF3, -CI) with X-linker in para-configuration (X top).
  • the linker X-ring A ensemble may be substituted by urea moiety, provided both rings B and C are aromatic.
  • Linker X may be: - CH2-, -0-, -S-, -SO2- but not an amide, especially when ring A is an aromatic entity.
  • the ring C may be both 5- or 6-membered aromatic, heteroaromatic or cycloaliphatic ring which may contain alkylating groups (allyl- or propargyl-).
  • a group of small-molecule inhibitors of Zika virus infection was identified using plaque assays and the A549 human lung carcinoma cell line.
  • the identified compounds belong to 3 different classes of chemicals, namely simple sulfonamides, 1,3-disubstituted urea derivatives, and generally multi-cyclic entities containing an assembly of 3 or more aromatic/aliphatic rings, often containing N-phenyl-substituted piperazine or phenyl-substituted-piperazine-like moieties.
  • hits several compounds exhibited high inhibitory activity against Zika virus showing IC50 values in low nanomolar and sub-nanomolar range.
  • substrates for the synthesis of analogs are (A) 4-chlorophenyl isocyanate, (B) 4-chlorophenyl isothiocyanate, (C) 4-bromophenyl isocyanate, (D) 4-bromophenyl isothiocyanate, (E) 4-iodophenyl isocyanate, (F) 4-iodophenyl isothiocyanate, (G) 4-chloro-3- (trifluoromethyl)phenyl isocyanate, (H) 4-chloro-3-(trifluoromethyl)phenyl isothiocyanate, (I) 4- bromo-2-(trifluoromethyl)phenyl isocyanate, (J) 4-bromo-2-(trifluoromethyl)phenyl
  • isothiocyanate (1) 3-(prop-2-en-l-ylsulfanyl)-l,2,4-thiadiazol-5-amine, (2) 3-(prop-2-yn-l- ylthio)-l,2,4-thiadiazol-5-amine, (3) 3-amino-5-allylthio-l,2,4-thiadiazole, (4) 5-(prop-2-en-l- ylsulfanyl)- 1 ,3 ,4-thiadiazol-2-amine, (5) 3 -amino-5-allylamino- 1 ,2,4-thiadiazole.
  • Example 9 In vitro screening against Zika virus infection by plaque assay
  • Naive A549 cells were seeded at concentration of 2* 10 5 cells per well using a 48-well plate, and allowed to grow for 48 hours to form a confluent monolayer. Subsequently, the tested compounds were added at indicated concentrations (using Opti-MEM medium) in biological triplicates. The cells were infected immediately after compound treatment, (MOI of 10, 1, 0.1, 0.01, 0.001, and 0.0001) in 100 ⁇ L ⁇ per well and plates were incubated at 37°C with 5% CC for 4 hours. At 4 hr post-infection, the viral inoculum was replaced with serum supplemented media (250 ⁇ L ⁇ per well, including the same concentration of the compounds) and plates incubated at 37°C for additional 44 hours. At 48 hr post-infection, the plaques in each well were counted using a phase contrast microscope.

Landscapes

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

Abstract

La présente invention concerne des composés, des compositions et des procédés pour le traitement et/ou la prévention d'une infection à flavivirus par administration de tels composés et de telles compositions.
PCT/US2018/053968 2017-10-02 2018-10-02 Composés pour le traitement ou la prévention d'infections à flavivirus Ceased WO2019070709A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US201762566663P 2017-10-02 2017-10-02
US201762566667P 2017-10-02 2017-10-02
US62/566,667 2017-10-02
US62/566,663 2017-10-02
US201762593787P 2017-12-01 2017-12-01
US62/593,787 2017-12-01

Publications (2)

Publication Number Publication Date
WO2019070709A1 true WO2019070709A1 (fr) 2019-04-11
WO2019070709A8 WO2019070709A8 (fr) 2019-09-06

Family

ID=65994743

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2018/053968 Ceased WO2019070709A1 (fr) 2017-10-02 2018-10-02 Composés pour le traitement ou la prévention d'infections à flavivirus

Country Status (1)

Country Link
WO (1) WO2019070709A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110590708A (zh) * 2019-09-24 2019-12-20 中国医学科学院医药生物技术研究所 芳酰基哌嗪类化合物及其制备方法和在抗病毒中的应用
EP4563146A1 (fr) * 2023-11-28 2025-06-04 Irbm S.P.A. Inhibiteurs de flavivirus

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD241740A1 (de) * 1985-10-15 1986-12-24 Univ Rostock Verfahren zur herstellung von substituierten 2-ureido-1,3,4-thiadiazolen
WO2010073011A2 (fr) * 2008-12-23 2010-07-01 Betagenon Ab Composés utiles comme médicaments
WO2014164667A1 (fr) * 2013-03-11 2014-10-09 Georgetown University Inhibiteurs de protéases des virus west nile et de la dengue
CN107494574A (zh) * 2017-09-05 2017-12-22 河南农业大学 一种硫脲类化合物的新用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD241740A1 (de) * 1985-10-15 1986-12-24 Univ Rostock Verfahren zur herstellung von substituierten 2-ureido-1,3,4-thiadiazolen
WO2010073011A2 (fr) * 2008-12-23 2010-07-01 Betagenon Ab Composés utiles comme médicaments
WO2014164667A1 (fr) * 2013-03-11 2014-10-09 Georgetown University Inhibiteurs de protéases des virus west nile et de la dengue
CN107494574A (zh) * 2017-09-05 2017-12-22 河南农业大学 一种硫脲类化合物的新用途

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
BARROWS, N. J. ET AL.: "A screen of FDA-approved drugs for inhibitors of Zika virus infection", CELL HOST & MICROBE, vol. 20, no. 2, 10 August 2016 (2016-08-10), pages 259 - 270, XP029682741, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993926> DOI: doi:10.1016/j.chom.2016.07.004 *
DATABASE CAS 12 December 2003 (2003-12-12), "CA Index Name: Urea, N-(2,4-difluorophenyl)-N'-[3-(2- propen-1-y1thio)-1,2,4-thiadiazol-5-y1", retrieved from STN Database accession no. 626220-75-5 *
DATABASE CAS 12 December 2003 (2003-12-12), "CA Index Name: Urea, N-(4-chlorophenyl)-N'-[3-(2- propen-1-ylthio)-1,2,4-thiadiazol-5-yl", retrieved from STN Database accession no. 626220-97-1 *
DATABASE CAS 12 December 2003 (2003-12-12), "CA Index Name: Urea, N-[4-chloro-2-(trifluoromethyl) phenyl]-N'-[3-(2-p-pen-1-ylthio)-1,2,4-thiadiazol-5-yl", retrieved from STN Database accession no. 626221-05-4 *
DATABASE CAS 12 December 2003 (2003-12-12), "CA Index Name: Urea, N-[4-chloro-3-(trifluoromethyl) phenyl]-N'-[3-(2-propyn-l-ylthio)-l,2,4-thiadiazol-5-yl", retrieved from STN Database accession no. 626221-17-8 *
DATABASE CAS 22 July 2007 (2007-07-22), "CA Index Name: Urea, N-(2,4-difluorophenyl)-N'-[3- [(2-phenoxyethyl)thio]-l,2,4-thiadiazol-5-yl", retrieved from STN Database accession no. 943087-93-2 *
DATABASE CAS 3 February 2009 (2009-02-03), "CA Index Name: Urea, N-(2-chlorophenyl)-N'-[3-(2- propyn-1-ylthio)-1,2,4-thiadiazol-5-y1", retrieved from STN Database accession no. 1100321-85-4 *
DATABASE PubChem BioAssay 28 November 2012 (2012-11-28), ANONYMOUS: "QHTS Assay For Inhibitors Of Hepatitis C Virus (HCV", XP055588428, retrieved from NCBI Database accession no. AID 651820 *
GURJAR, A. S. ET AL.: "Design, synthesis, in silico and in vitro screening of 1, 2, 4-thiadiazole analogues as non-peptide inhibitors of beta-secretase", BIOORGANIC CHEMISTRY, vol. 57, 17 September 2014 (2014-09-17) - December 2014 (2014-12-01), pages 90 - 98, XP055588410, ISSN: 0045-2068, DOI: 10.1016/j.bioorg.2014.09.002 *
HUSSEIN, A.H. ET AL.: "Synthesis of 2-[N-alkyl(aryl)carbamoylamino]-5-alkyl(alkenyl)thio-l,3,4- thiadiazoles", BULGARIAN CHEMICAL COMMUNICATIONS, vol. 28, no. 1, 31 December 1995 (1995-12-31), pages 166 - 169 *
KAMPMANN, T. ET AL.: "In silico screening of small molecule libraries using the dengue virus envelope E protein has identified compounds with antiviral activity against multiple flaviviruses", ANTIVIRAL RESEARCH, vol. 84, no. 3, 23 September 2009 (2009-09-23), pages 234 - 241, XP026763773, DOI: doi:10.1016/j.antiviral.2009.09.007 *
LI, Z. ET AL.: "Design, synthesis, and biological evaluation of antiviral agents targeting flavivirus envelope proteins", JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, no. 15, 14 August 2008 (2008-08-14), pages 4660 - 4671, XP055015056, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562352/pdf/nihms57124.pdf> DOI: doi:10.1021/jm800412d *
MICEWICZ, E. D. ET AL.: "Identification of novel small-molecule inhibitors of Zika virus infection", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 28, no. 3, 1 February 2018 (2018-02-01), pages 452 - 458, XP055588435, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2017.12.019 *
WANG, C. ET AL.: "Design, synthesis and antifungal activity of novel thioureas containing 1, 3, 4- thiadiazole and thioether skeleton", CHEMICAL RESEARCH IN CHINESE UNIVERSITIES, vol. 32, no. 4, 23 June 2016 (2016-06-23), pages 615 - 620 *
XU, M. ET AL.: "Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen", NATURE MEDICINE, vol. 22, no. 10, October 2016 (2016-10-01), pages 1101 - 1107, XP055383662, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386783> DOI: doi:10.1038/nm.4184 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110590708A (zh) * 2019-09-24 2019-12-20 中国医学科学院医药生物技术研究所 芳酰基哌嗪类化合物及其制备方法和在抗病毒中的应用
CN110590708B (zh) * 2019-09-24 2021-08-17 中国医学科学院医药生物技术研究所 芳酰基哌嗪类化合物及其制备方法和在抗病毒中的应用
EP4563146A1 (fr) * 2023-11-28 2025-06-04 Irbm S.P.A. Inhibiteurs de flavivirus
WO2025114399A1 (fr) 2023-11-28 2025-06-05 Irbm S.P.A. Inhibiteurs de flavivirus

Also Published As

Publication number Publication date
WO2019070709A8 (fr) 2019-09-06

Similar Documents

Publication Publication Date Title
JP2022513959A (ja) 大環状化合物及び疾患の処置におけるそれらの使用
KR101640263B1 (ko) 세라마이드 유도체로 다낭성 신장질환을 치료하는 방법
CA3087262A1 (fr) Composes benzamide
US20250074873A1 (en) Compounds
JP6270848B2 (ja) ベータ−クロロシクロペンタンの親水性エステルプロドラッグの使用による角膜中央部肥厚の低下
CA3225135A1 (fr) 3,4-methylenedioxymethamphetamine et composes psychedeliques apparentes et leurs utilisations
TW201309666A (zh) 一種取代桂皮醯胺衍生物、製備方法及其應用
JP2022507117A (ja) 呼吸器疾患の処理のための新規な化合物
JPWO2020128925A5 (fr)
WO2019070709A1 (fr) Composés pour le traitement ou la prévention d&#39;infections à flavivirus
SK18182000A3 (sk) Kryštalický efavirenz
US20250361233A1 (en) Compounds For Activating Serotonin Receptor
CN113272272A (zh) Rip1抑制剂
JP2021514347A (ja) 抗ｒｓｖ活性を有するシクロアルキル置換ピラゾロピリミジン
ES2280379T3 (es) Derivados de la hidroxiformamidina y medicinas que lo contienen.
EP3972601A1 (fr) Formulation de nanoparticules d&#39;inhibiteur de la bcl-2
NL2031332B1 (en) Transmucosal delivery of psychoactive compounds
EP3050871B1 (fr) Nouveau dérivé de bis-amide et son utilisation
US20230159439A1 (en) Arylamides and methods of use thereof
WO2022056068A1 (fr) Inhibiteurs à petites molécules d&#39;enpp1
US12428380B2 (en) Compounds
JP2022515549A (ja) パントテンアミドアナログ
CN109503569B (zh) 噻唑类衍生物及其制备方法和应用
AU2015327817B2 (en) Ester prodrugs of gamma-lactams and their use
WO2025118034A1 (fr) Composés actifs au niveau du récepteur sérotonergique 5-ht2a

Legal Events

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

Ref document number: 18864048

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18864048

Country of ref document: EP

Kind code of ref document: A1