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WO2022157519A1 - Traitement d'une infection à coronavirus - Google Patents

Traitement d'une infection à coronavirus Download PDF

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Publication number
WO2022157519A1
WO2022157519A1 PCT/GB2022/050194 GB2022050194W WO2022157519A1 WO 2022157519 A1 WO2022157519 A1 WO 2022157519A1 GB 2022050194 W GB2022050194 W GB 2022050194W WO 2022157519 A1 WO2022157519 A1 WO 2022157519A1
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Prior art keywords
alkyl
heteroaryl
aryl
heterocyclyl
cycloalkyl
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Inventor
Ian Timothy William Matthews
Howard Christopher Thomas
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Riotech Pharmaceuticals Ltd
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Riotech Pharmaceuticals Ltd
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    • 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
    • A61K31/33—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
    • A61K31/407—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 other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems

Definitions

  • the present invention relates to compounds for use in the treatment and/or prevention of a coronavirus infection.
  • the present invention relates to compounds for use in the treatment and/or prevention of a SARS-CoV-2 infection (COVID-19).
  • cytokine release syndrome also known as cytokine storm syndrome
  • ARDS acute respiratory distress syndrome
  • Viricidal therapeutics aim to destroy viral infections by deactivating virions, which are single viral particles.
  • viricidal therapeutics aim to destroy viral infections by deactivating virions, which are single viral particles.
  • side effects are often a consequence as a result of interference with the functioning of the host cell.
  • Anti-viral therapeutics work differently by targeting the replication of viral-infected cells, a more common therapeutic technique with fewer side effects.
  • Such therapeutics typically require site-specific and rapid administration, typically within short notice of confirmation of infection, providing problems with practicality, especially in cases of lung treatment, such as required for SARS- CoV-2.
  • Vaccines operate differently by activating an immune response to the viral infection through stimulation of lymphocytes, thereby invoking an antibody response (e.g. IgA, IgM, or IgG).
  • the number of vaccines suitable for treatment and/or prevention of viral infections is limited. Not only this, the viral infections can evolve through mutations in the genes that relate to the viral surface proteins, which may lead to the virus’s outer surface changing appearance to a host previously infected with the ancestor strain of the virus. Such a scenario means that the antibodies produced by previous infection with the ancestor strain cannot effectively fight the mutated virus. As a consequence of this, a number of new vaccines may be required for different mutations of the viral infection, adding to the already significant time required for vaccine development.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment and/or prevention of a coronavirus infection there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment and/or prevention of a coronavirus infection.
  • a method of treating and/or preventing a coronavirus infection in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating and/or preventing the SARS-CoV-2 infection (COVID-19) in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition.
  • “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, pathology or condition, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • the treatment may include one or more of the following: Reduce or eliminate the virus; prevent or reduce viral replication; reduce or eliminate transmission of the virus; reduce or eliminate fever; reduce or eliminate flu-like symptoms, reduce or eliminate coughing, reduce or eliminate muscle and/or joint pain; improve respiratory status of the subject (e.g.
  • the treatment and/or prevention of acute respiratory distress syndrome associated with the coronavirus infection the treatment and/or prevention of pneumonia associated with the coronavirus infection; the treatment and/or prevention of viral pneumonia; the treatment and/or prevention of bacterial pneumonia associated with a coronavirus infection; reducing or eliminating pulmonary edema; reducing or eliminating pulmonary inflammation; preventing or reducing lung fibrosis (e.g.
  • preventing or reducing interstitial fibroblasts reducing one or more inflammatory biomarkers associated with the coronavirus infection; preventing or reducing proteinaceous exudates associated with a coronavirus infection; preventing or reducing fibrin exudates associated with a coronavirus infection; and/or preventing or ameliorating pulmonary bacterial or fungal infections associated with the coronavirus infection.
  • a disease e.g. a coronavirus infection such as the SARS- CoV-2 infection
  • a coronavirus infection such as the SARS- CoV-2 infection
  • the disease is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of the compounds described herein and, which are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable salts of the compounds disclosed herein are well known to skilled persons in the art.
  • solvate is used herein to refer to a complex of solute, such as a compound or salt of the compound, and a solvent. If the solvent is water, the solvate may be termed a hydrate, for example a monohydrate, dihydrate, trihydrate etc., depending on the number of water molecules present per molecule of substrate.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • alkyl includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only.
  • (1-6C)alkyl includes (1- 4C)alkyl, (1 -3C)alkyl, propyl, isopropyl and f-butyl.
  • (m-nC) or "(m-nC) group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • alkylene is an alkyl group that is positioned between and serves to connect two other chemical groups.
  • (1-6C)alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), 2-methylpropylene (-CH2CH(CHs)CH2-), pentylene (-CH2CH2CH2CH2CH2-), and the like.
  • alkyenyl refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon double bond is present within the group.
  • alkenyl groups include ethenyl, propenyl and but-2, 3-enyl and includes all possible geometric (E/Z) isomers.
  • alkynyl refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon triple bond is present within the group.
  • alkynyl groups include acetylenyl and propynyl.
  • (3-10C)cycloalkyl means a hydrocarbon ring containing from 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo[2.2.1]heptyl.
  • alkoxy refers to O-linked straight and branched chain alkyl groups. Examples of alkoxy groups include methoxy, ethoxy and t-butoxy.
  • haloalkyl is used herein to refer to an alkyl group in which one or more hydrogen atoms have been replaced by halogen (e.g. fluorine) atoms.
  • halogen e.g. fluorine
  • alkyl groups include -CH2F, -CHF2 and -CF3.
  • halo or “halogeno” refers to fluoro, chloro, bromo and iodo, suitably fluoro, chloro and bromo, more suitably, fluoro and chloro.
  • Carbocyclyl means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbon-containing ring system(s).
  • Monocyclic carbocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms.
  • Bicyclic carbocycles contain from 6 to 17 member atoms, suitably 7 to 12 member atoms, in the ring.
  • Bicyclic carbocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl and spiro[3.3]heptanyl.
  • heterocyclyl means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s).
  • Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring.
  • Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring.
  • Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems.
  • heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers.
  • Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like.
  • Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1 , 3-dithiol, tetrahydro-2/7-thiopyran, and hexahydrothiepine.
  • heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl.
  • heterocycles containing sulfur the oxidized sulfur heterocycles containing SO or SO2 groups are also included.
  • examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1 ,1 -dioxide and thiomorpholinyl 1 ,1 -dioxide.
  • heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1 ,1 -dioxide, thiomorpholinyl, thiomorpholinyl 1 ,1 -dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl.
  • any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom.
  • reference herein to piperidino or morpholino refers to a piperidin-1 - yl or morpholin-4-yl ring that is linked via the ring nitrogen.
  • bridged ring systems is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131-133, 1992.
  • bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza- bicyclo[3.2.1]octane and quinuclidine.
  • spiro bi-cyclic ring systems we mean that the two ring systems share one common spiro carbon atom, i.e. the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom.
  • spiro ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptanes, 2-oxa-
  • heteroaryl or “heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur.
  • heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members.
  • the heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings.
  • Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen.
  • the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • heteroaryl examples include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthy
  • Heteroaryl also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur.
  • partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-
  • heteroaryl groups examples include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • a bicyclic heteroaryl group may be, for example, a group selected from: a benzene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.
  • aryl means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms.
  • aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In a particular embodiment, an aryl is phenyl.
  • the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, for use in the treatment and/or prevention of a coronavirus infection.
  • the compounds of interest for use in the treatment of a coronavirus infection have been defined and described in International PCT Publication No. WO 2012/046030 A2, the entire contents of which are incorporated herein by reference. While it is known that the compounds disclosed in WO 2012/046030 A2 are particularly useful as 2’5’- phosphodiesterase inhibitors, specifically targeting phosphodiesterase-12, their use in treating and/preventing a coronavirus infection, such as the SARS-CoV-2 infection (COVID-19) is unknown.
  • Ri is selected from H, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-4C)alkyl, carbocyclyl, carbocyclyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl, heterocyclyl(1-4C)alkyl, (CH 2 ) q iCHR a bRac, (CH 2 )q1 N RabRac, (CH 2 )ql ORab, (CH 2 )ql C(O)Rab, (CH 2 )q1 C(O)ORab, (CH 2 )ql OC(O)Rab, (CH 2 )ql C(O) N(Rac)Rab, (CH 2 )q1 N(R ac )C(
  • Rab is selected from hydrogen, (1-4C)alkyl, (1-4C)aminoalkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-4C)alkyl, carbocyclyl, carbocyclyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl and heterocyclyl(1-4C)alkyl,
  • R ac is selected from hydrogen, (1-4C)alkyl, (1-4C)aminoalkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-4C)alkyl, carbocyclyl, carbocyclyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl and heterocyclyl(1-4C)alkyl, and wherein Ri, R aP and/or R ac is optionally substituted by one or more substituent groups independently selected from oxo, (1 -4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-4C)alkyl, carbocyclyl, carbocyclyl(1-4C)al
  • R2 is selected from H, (1-8C)alkyl, (1-8C)alkoxy, (2-8C)alkenyl, (2-8C)alkynyl, halo, (1- 8C)haloalkyl, (1-8C)haloalkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, carbocyclyl, carbocyclyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl or heterocyclyl(1-4C)alkyl, wherein R2 is optionally substituted by one or more substituent groups independently selected from oxo, (1 -4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1- 4C)hydroxyalkyl, cyano, nitro, hydroxy, NR ad R
  • R3 is optionally substituted by one or more substituent groups independently selected from oxo, (1 -4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1- 4C)hydroxyalkyl, cyano, nitro, hydroxy, NR ad Rae,
  • R4 is is selected from H, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-4C)alkyl, carbocyclyl, carbocyclyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl or heterocyclyl(1-4C)alkyl, wherein R4 is optionally substituted by one or more substituent groups independently selected from oxo, (1 -4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1- 4C)hydroxyalkyl, cyano, nitro, hydroxy, NR ad Rae, OR ad , C(O)R ad , C(O)OR ad , OC(
  • Particular compounds for use in the invention include, for example, compounds of the Formula (la) or (lb), or pharmaceutically acceptable salts, hydrates and/or solvates thereof, wherein, unless otherwise stated, each of Ri, R2, R3 and R4 and any associated substituent groups has any of the meanings defined hereinbefore or in any of paragraphs (1) to (24) hereinafter:
  • R1 is selected from H, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-4C)alkyl, carbocyclyl, carbocyclyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl, heterocyclyl(1-4C)alkyl, (CH2)qiCHR a bRac, (CH 2 )q1 N RabRac, (CH 2 )qlORab, (CH 2 )qlC(O)Rab, (CH 2 )q1 C(O)ORab, (CH 2 )qlOC(O)Rab, (CH 2 )qiC(O)N(Rac)Rab, or (CH 2 )q1 N(Rac)C(O)Rab
  • Rab is selected from hydrogen, (1-4C)alkyl, (1-4C)aminoalkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-4C)alkyl, carbocyclyl, carbocyclyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl and heterocyclyl(1-4C)alkyl,
  • R ac is selected from hydrogen, (1-4C)alkyl, (1-4C)aminoalkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-4C)alkyl, carbocyclyl, carbocyclyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl and heterocyclyl(1-4C)alkyl, and wherein R1, R a b and/or R ac is optionally substituted by one or more substituent groups independently selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-4C)alkyl, carbocyclyl, carbocyclyl(1-4C
  • Ri is selected from (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-4C)alkyl, carbocyclyl, carbocyclyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl, heterocyclyl(1-4C)alkyl, (CH2) q iCHR a bR ac , (CH2)qiNR a bR ac or (CH2)qiOR a b, and wherein: q1 is 0, 1 , 2, 3 or 4;
  • R a b is selected from hydrogen, (1-4C)alkyl, (1-4C)aminoalkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-4C)alkyl, carbocyclyl, carbocyclyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl and heterocyclyl(1-4C)alkyl,
  • R ac is selected from hydrogen, (1-4C)alkyl, (1-4C)aminoalkyl, (3-8C)cycloalkyl, (3- 8C)cycloalkyl(1-4C)alkyl, carbocyclyl, carbocyclyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl and heterocyclyl(1-4C)alkyl, and wherein Ri, R a b and/or R ac is optionally substituted by one or more substituent groups independently selected from oxo, (1-4C)alkyl, halo, cyano, nitro, hydroxy, (CH2)q2CH RadRae, N RadRae, ORad, C(O)R a d, C(O)OR a d, OC(O)R a d, C(O)N(R ae )Rad and N(Rae
  • Ri is selected from (1-6C)alkyl, (3-8C)cycloalkyl(1-2C)alkyl, phenyl, aryl(1-2C)alkyl, heteroaryl(1-2C)alkyl or heterocyclyl(1-2C)alkyl, and wherein Ri is optionally substituted by one or more substituent groups independently selected from (1 -4C)alkyl, N RadRae, ORad and C(O)R a d; wherein Rad and R ae are each independently selected from hydrogen, (1 -2C)alkyl, halo, (1-4C)haloalkyl, amino or (1-4C)aminoalkyl;
  • Ri is selected from (1-4C)alkyl, phenyl or phenyl(1-2C)alkyl, and wherein Ri is optionally substituted by one or more substituent groups independently selected from N RadRae and ORad; wherein Rad and R ae are each independently selected from hydrogen or (1 -2C)alkyl;
  • Ri is selected from (3-4C)alkyl, phenyl or phenyl(1C)alkyl, and wherein Ri is optionally substituted by one or more substituent groups independently selected from N RadRae and ORad; wherein Rad and R ae are each independently selected from methyl;
  • Ri is selected from: wherein denotes the point of attachment
  • Ri is selected from: wherein denotes the point of attachment
  • R2 is selected from (1-6C)alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C)alkynyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, carbocyclyl, carbocyclyl(1-4C)alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl or heterocyclyl(1-4C)alkyl, wherein R2 is optionally substituted by one or more substituent groups independently selected from (1 -4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, nitro, hydroxy, NRadRae, ORad, C
  • R2 is selected from (3-6C)cycloalkyl, phenyl, (5-6C)heteroaryl or (3-7C)heterocyclyl, wherein R2 is optionally substituted by one or more substituent groups independently selected from NR ad Rae, OR ad , C(O)R ad , C(O)OR ad , (CH2)q2CHR ad Rae and (CH2)q2N Rad Rae, wherein R ad and R ae are each independently selected from hydrogen or (1 -6C)alkyl and q2 is 0, 1 , 2 or 3;
  • R2 is selected from phenyl, wherein R2 is optionally substituted by one or more substituent groups independently selected from NR ad Rae, OR ad , C(O)R ad and C(O)OR ad ; wherein R ad and R ae are each independently selected from hydrogen or (1 -6C)alkyl;
  • R2 is selected from phenyl, wherein R2 is optionally substituted by one or more substituent groups independently selected from OR ad ; wherein R ad and R ae are each independently selected from hydrogen or methyl;
  • R2 is selected from: wherein denotes the point of attachment;
  • R3 is selected from (1-6C)alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C)alkynyl, halo, (1- 6C)haloalkyl, (1-6C)haloalkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, carbocyclyl, carbocyclyl(1-4C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl or heterocyclyl(1-2C)alkyl, wherein R3 is optionally substituted by one or more substituent groups independently selected from oxo, (1-4C)alkyl, halo, cyano, nitro, hydroxy, NRadRae, ORad, C(O)R a d and C(O)ORad; wherein Rad and R ae are each independently selected from hydrogen or (1 -6C
  • R3 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, (3- 12C)carbocyclyl, (3-12C)carbocyclyl(1-4C)alkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl or heterocyclyl(1-2C)alkyl, wherein R3 is optionally substituted by one or more substituent groups independently selected from oxo, (1-4C)alkyl, halo, cyano, nitro, hydroxy, NRadRae, ORad, C(O)R a d and C(O)ORad; wherein Rad and R ae are each independently selected from hydrogen or (1 -6C)alkyl;
  • R3 is selected from (3-6C)cycloalkyl, (5-6C)aryl, (5-6C)heteroaryl or (3- 7C)heterocyclyl, wherein R3 is optionally substituted by one or more substituent groups independently selected from hydroxy, NRadRae, ORad, C(O)R a d and C(O)OR a d; wherein Rad and R ae are each independently selected from hydrogen or (1 -4C)alkyl;
  • R3 is selected from phenyl, wherein R3 is optionally substituted by one or more substituent groups independently selected from hydroxy and ORad; wherein Rad and R ae are each independently selected from hydrogen or (1 -4C)alkyl;
  • R3 is selected from: wherein denotes the point of attachment;
  • R4 is selected from H, (1-8C)alkyl, (3-8C)cycloalkyl, carbocyclyl, carbocyclyl(1-
  • R4 is optionally substituted by one or more substituent groups independently selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1- 4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, nitro, hydroxy, N RadRae, ORad, C(O)R a d, C(O)ORad, OC(O)Rad, C(O)N(Rae)Rad, N(R ae )C(O)Rad, S(O)pRad, SO 2 N(Rae)Rad, N(Rae)SO 2 Rad and (CH 2 ) q2 N RadRae, wherein Rad and R ae are each independently selected from hydrogen or (1 -6C)alkyl, p is 0, 1 or 2, and q2 is
  • R4 is is selected from H, (1-8C)alkyl, (3-8C)cycloalkyl, (3-12C)carbocyclyl, (3- 12C)carbocyclyl(1-4C)alkyl, aryl, (5-6C)heteroaryl or (3-7C)heterocyclyl, wherein R4 is optionally substituted by one or more substituent groups independently selected from oxo, (1 -4C)alkyl, halo, cyano, nitro and hydroxy;
  • R4 is is selected from H, (1 -4C)alkyl or (5-6C)aryl, wherein R4 is optionally substituted by one or more substituent groups independently selected from oxo, (1 -4C)alkyl, halo, cyano, nitro and hydroxy;
  • R4 is selected from H, methyl or phenyl, wherein R4 is optionally substituted by one or more substituent groups independently selected from oxo, (1 -4C)alkyl, halo, cyano, nitro and hydroxy
  • R4 is selected from: wherein denotes the point of attachment.
  • R1 is as defined in any one of paragraphs (1) to (8) above. Most suitably, R1 is as defined in paragraph (6), paragraph (7) or paragraph (8) above.
  • R 2 is as defined in paragraphs (9) to (14) above. Most suitably, R 2 is as defined in paragraph (12), paragraph (13) or paragraph (14) above.
  • R3 is as defined in paragraphs (15) and (19) above. Most suitably, R3 is as defined in paragraph (17), paragraph (18) or paragraph (19) above.
  • R4 is as defined in any one of paragraphs (20) to (24) above. Most suitably, R4 is as defined in paragraph (22), paragraph (23) or paragraph (24) above. [0054] In a particular group of compounds for use in the invention, the compounds have structural formula la shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
  • R1 is as defined in any one of paragraphs (1) to (8) above;
  • R2 is as defined in any one of paragraphs (9) to (14) above;
  • R3 is as defined in any one of paragraphs (15) to (19) above;
  • R4 is as defined in any one of paragraphs (20) to (24) above.
  • R1 is as defined in any one of paragraphs (3) to (8) above;
  • R2 is as defined in any one of paragraphs (10) to (14) above;
  • R3 is as defined in any one of paragraphs (16) to (19) above;
  • R4 is as defined in any one of paragraphs (21) to (24) above.
  • R1 is as defined in any one of paragraphs (5) to (8) above;
  • R2 is as defined in any one of paragraphs (11) to (14) above;
  • R3 is as defined in any one of paragraphs (17) to (19) above;
  • R4 is as defined in any one of paragraphs (22) to (24) above.
  • R1 is as defined in any one of paragraphs (6) to (8) above;
  • R2 is as defined in any one of paragraphs (12) to (14) above;
  • R3 is as defined in any one of paragraphs (18) or (19) above;
  • R4 is as defined in any one of paragraphs (23) or (24) above.
  • R1 is as defined in any one of paragraphs (7) or (8) above;
  • R2 is as defined in any one of paragraphs (13) or (14) above;
  • R3 is as defined in any one of paragraphs (18) or (19) above;
  • R4 is as defined in any one of paragraphs (23) or (24) above.
  • R1 is as defined in paragraph (8) above;
  • R2 is as defined in paragraph (14) above;
  • R3 is as defined in paragraph (19) above;
  • R4 is as defined in paragraph (24) above.
  • the compounds have structural formula lb shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: wherein each of R1, R2, R3 and R4 are as defined hereinbefore.
  • R1 is as defined in any one of paragraphs (1) to (8) above;
  • R2 is as defined in any one of paragraphs (9) to (14) above;
  • R3 is as defined in any one of paragraphs (15) to (19) above;
  • R4 is as defined in any one of paragraphs (20) to (24) above. [0063] In another embodiment of the compounds of Formula lb:
  • Ri is as defined in any one of paragraphs (3) to (8) above;
  • R2 is as defined in any one of paragraphs (10) to (14) above;
  • R3 is as defined in any one of paragraphs (16) to (19) above;
  • R4 is as defined in any one of paragraphs (21) to (24) above.
  • R1 is as defined in any one of paragraphs (5) to (8) above;
  • R2 is as defined in any one of paragraphs (11) to (14) above;
  • R3 is as defined in any one of paragraphs (17) to (19) above;
  • R4 is as defined in any one of paragraphs (22) to (24) above.
  • R1 is as defined in any one of paragraphs (6) to (8) above;
  • R2 is as defined in any one of paragraphs (12) to (14) above;
  • R3 is as defined in any one of paragraphs (18) or (19) above;
  • R4 is as defined in any one of paragraphs (23) or (24) above.
  • R1 is as defined in any one of paragraphs (7) or (8) above;
  • R2 is as defined in any one of paragraphs (13) or (14) above;
  • R3 is as defined in any one of paragraphs (18) or (19) above;
  • R4 is as defined in any one of paragraphs (23) or (24) above.
  • R1 is as defined in paragraph (8) above;
  • R2 is as defined in paragraph (14) above;
  • R3 is as defined in paragraph (19) above;
  • R4 is as defined in paragraph (24) above.
  • Particular compounds for use in the treatment and/or prevention of a coronavirus infection include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, in particular, any of the following: 4-(4-hydroxy-3-methoxy-phenyl)-3,5-diphenyl-4,5-dihydro-1 H-pyrrolo[3,4-c]pyrazol-6-one (compound 1);
  • compounds for use in the treatment and/or prevention of a coronavirus infection include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, in particular, any of the following:
  • Particular compounds for use in the treatment and/or prevention of a coronavirus infection include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, in particular, any of the following:
  • compounds for use in the treatment and/or prevention of a coronavirus infection include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, in particular, any of the following:
  • the various functional groups and substituents making up the compounds of the Formula (la) or (lb), are typically chosen such that the molecular weight of the compound of the formula (la) or (lb) does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600 and, for example, is 550 or less.
  • a suitable pharmaceutically acceptable salt of a compound for the use of the invention is, for example, an acid-addition salt of a compound for the use of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • an inorganic or organic acid for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound for the use of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • the compounds for use in this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual ( )- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • Some of the compounds for the use of the invention may have geometric isomeric centres (E- and Z- isomers).
  • the compounds for use in the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that treat and/or prevent a coronavirus infection, such as the SARS-CoV-2 infection.
  • the present invention also encompasses compounds for use in the invention as defined herein which comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2H(D), and 3H (T);
  • C may be in any isotopic form, including 12C, 13C, and 14C; and
  • O may be in any isotopic form, including 160 and 180; and the like.
  • certain compounds of the Formulae (la) or (lb) may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the compounds for use in the invention encompasses all such solvated forms that treat and/or prevent a coronavirus infection, such as the SARS-CoV-2 infection.
  • keto-, enol-, and enolate-forms examples include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • keto enol enolate as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • N-oxides Compounds of the Formulae (la) or (lb) containing an amine function may also form N-oxides.
  • a reference herein to a compound of the Formulae (la) or (lb) that contains an amine function also includes the N-oxide.
  • one or more than one nitrogen atom may be oxidised to form an N-oxide.
  • Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogencontaining heterocycle.
  • N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g.
  • a peroxycarboxylic acid see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m- chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.
  • mCPBA m- chloroperoxybenzoic acid
  • the compounds of Formula (la) or (lb) may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound for the use of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound for use in the invention.
  • a pro-drug can be formed when the compound for use in the invention contains a suitable group or substituent to which a propertymodifying group can be attached.
  • pro-drugs examples include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formulae (la) or (lb) and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formulae (la) or (lb).
  • the compounds for use in the present invention includes those compounds of the Formulae (la) or (lb) as defined hereinbefore, when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the compounds for use in the present invention includes those compounds of the Formulae (la) or (lb) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formulae (la) or (lb) may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formulae (la) or (lb) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • pro-drug Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formulae (la) or (lb) that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the Formulae (la) or (lb) containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically acceptable esters for carboxy include (1 -6C)alkyl esters such as methyl, ethyl and tert-butyl, (1-6C)alkoxymethyl esters such as methoxymethyl esters, (1-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1 -cyclohexylcarbonyloxyethyl esters, 2-oxo-1 ,3- dioxolenylmethyl esters such as 5-methyl-2-oxo-1 ,3-dioxolen-4-ylmethyl esters and (1- 6C)alkoxycarbonyloxy-(1-6C)alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formulae (la) or (lb) that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the Formulae (la) or (lb) containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include (1- 10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1-10C)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(1- 6C)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formulae (la) or (lb) that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a (1-4C)alkylamine such as methylamine, a [(1-4C)alkyl]2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a (1-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(1- 4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a (1-4C)alkylamine such as methylamine
  • a [(1-4C)alkyl]2amine such as dimethylamine, N-ethyl-N-methylamine or diethyl
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formulae (la) or (lb) that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with (1-10C)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1 -ylmethyl and 4-(1-4C)alkyl)piperazin-1- ylmethyl.
  • the in vivo effects of a compound of the Formulae (la) or (lb) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formulae (la) or (lb). As stated hereinbefore, the in vivo effects of a compound of the Formulae (la) or (lb) may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • the compounds for use in the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the compounds for use in the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
  • the compounds for use in the present invention excludes any individual compounds not possessing the biological activity defined herein.
  • the compounds for use in the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in International PCT Publication No. WO 2012/046030 A2.
  • protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons).
  • Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.
  • reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a terf-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
  • a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • Resins may also be used as a protecting group.
  • compositions for use in the present invention are provided.
  • a pharmaceutical composition for use in the treatment and/or prevention of a coronavirus infection which comprises a compound as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition for use in the treatment and/or prevention of the SARS-Cov-2 infection which comprises a compound as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • compositions for use in the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrup
  • compositions for use in the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • An effective amount of a compound or pharmaceutically acceptable salt, hydrate or solvate thereof as described herein for use in therapy is an amount sufficient to treat and/or prevent a coronavirus infection referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formulae (la) or (lb) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well- known principles of medicine.
  • a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration may also be suitable, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound or pharmaceutically acceptable salt, hydrate or solvate thereof as described herein.
  • Coronaviridae viruses are a family of enveloped, positive-stranded, single-stranded, spherical RNA viruses.
  • the Coronaviridae family includes coronavirus, the genus of which has a helical nucleocapsid.
  • Within the Coronavirus sub-family are the following genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment and/or prevention of a coronavirus infection.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment and/or prevention of the SARS-CoV-2 infection (COVID-19).
  • the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment and/or prevention of a coronavirus infection.
  • the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment and/or prevention of the SARS-CoV-2 infection (COVID-19).
  • the present invention provides a method of treating and/or preventing a coronavirus infection in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • the present invention provides a method of treating and/or preventing the SARS- CoV-2 infection (COVID-19) in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • the subject infected with a coronavirus infection may be asymptomatic at the early stages of infection. T reatment of asymptomatic subjects may prevent the coronavirus infection becoming symptomatic and/or developing diseases or medical conditions associated with the coronavirus infection. Accordingly also provided is a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment and/or prevention of an asymptomatic subject infected with a coronavirus infection.
  • Some coronavirus infections may become contagious before symptoms emerge in a subject infected with the coronavirus. This can result in high rates of transmission of the coronavirus in a population, because the infected host does not know that they are contagious and inadvertently spreads the coronavirus through social contact etc. Transmission of a coronavirus by asymptomatic subjects can be particularly dangerous after an initial infection is contained in a population, because asymptomatic, but contagious, subjects can trigger a resurgence of infections and a “second wave” of viral infection.
  • the detection of a coronavirus infection in an asymptomatic subject may be achieved using known testing methods, for example tests which detect the presence of the coronavirus in saliva samples such as realtime reverse transcription polymerase chain reaction (rRT-PCR) or PCR methods.
  • coronavirus or “coronavirus infection” pertains to a family of viruses which are the source of illness and diseases in humans and animals.
  • Coronaviruses form the subfamily Orthocoronavirinae, which is one of two sub-families in the family Coronaviridae, order Nidovirales, and realm Riboviria. They are divided into the four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus.
  • Alphacoronaviruses and betacoronaviruses infect mammals, while gammacoronaviruses and deltacoronaviruses primarily infect birds.
  • alphacoronavirus species include: Alphacoronavirus 1 (TGEV, Feline coronavirus, Canine coronavirus), Human coronavirus 229E, Human coronavirus NL63, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, Porcine epidemic diarrhea virus, Rhinolophus bat coronavirus HKU2, Scotophilus bat coronavirus 512.
  • TGEV Feline coronavirus
  • Canine coronavirus Human coronavirus 229E
  • Human coronavirus NL63 Human coronavirus NL63
  • Miniopterus bat coronavirus 1 Miniopterus bat coronavirus 1
  • Miniopterus bat coronavirus HKU8 Porcine epidemic diarrhea virus
  • Rhinolophus bat coronavirus HKU2 Scotophilus bat coronavirus 512.
  • betacoronavirus species include: Betacoronavirus 1 (Bovine Coronavirus, Human coronavirus OC43), Hedgehog coronavirus 1, Human coronavirus HKU1, Middle East respiratory syndrome-related coronavirus, Murine coronavirus, Pipistrellus bat coronavirus HKU5, Rousettus bat coronavirus HKU9, Severe acute respiratory syndrome-related coronavirus (SARS-CoV, SARS-CoV-2), Tylonycteris bat coronavirus HKU4.
  • gammacoronavirus species include: Avian coronavirus, Beluga whale coronavirus SW1.
  • deltacoronavirus species include: Bulbul coronavirus HKU11, Porcine coronavirus HKU15.
  • human coronavirus infections include, but are not limited to, human coronavirus infections, animal coronavirus infections, SARS-CoV (Severe acute respiratory syndrome coronavirus), SARS-CoV-2 (also known herein as the 2019 novel coronavirus, COVID-19), MERS-CoV (Middle East respiratory syndrome coronavirus) or common cold-caused coronavirus; the common cold-caused coronavirus is Human coronavirus OC43, Human coronavirus 229E, Human coronavirus NL63 and Human coronavirus HKU1.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • SARS-CoV-2 also known herein as the 2019 novel coronavirus, COVID-19
  • MERS-CoV Middle East respiratory syndrome coronavirus
  • common cold-caused coronavirus is Human coronavirus OC43, Human coronavirus 229E, Human coronavirus NL63 and Human coronavirus HKU1.
  • the aforementioned list highlights
  • a compound of formula (la) or (lb), or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment and/or prevention of a coronavirus infection is provided.
  • a compound of formula (la) or (lb), or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment and/or prevention of the SARS-CoV infection there is provided a compound of formula (la) or (lb), or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment and/or prevention of the SARS-CoV infection.
  • SARS-CoV is the virus that causes severe acute respiratory syndrome (SARS).
  • SARS is an airborne virus, and can spread by the inhalation of small droplets of water that an infected individual releases into the air, touching a contaminated surface and/or by being in close proximity of an infected individual.
  • Middle East respiratory syndrome coronavirus (MERS-CoV) is a member of the Betacoronavirus genus, and causes Middle East Respiratory Syndrome (MERS). MERS is an acute respiratory illness.
  • a compound of formula (la) or (lb), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment and/or prevention of a common cold-caused coronavirus infection.
  • a method of treating and/or preventing a coronavirus infection in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating and/or preventing a human coronavirus infection in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating and/or preventing the Human coronavirus OC43 infection in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating and/or preventing the Human coronavirus 229E infection in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating and/or preventing the Human coronavirus NL63 infection in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating and/or preventing the Human coronavirus HKU1 infection in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating and/or preventing an animal coronavirus infection in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating and/or preventing the SARS-CoV infection in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating and/or preventing the SARS-CoV-2 infection in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating and/or preventing the MERS-CoV infection in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating and/or preventing a common cold-caused coronavirus infection in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • the compounds for use in the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically, peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcut
  • Figure 1 shows example data of the positive control - Chloroquine biphosphate.
  • the number of viral foci decreased with increasing concentration of chloroquine biphosphate.
  • the IC50 was 0.243 pM with a 95% confidence interval range of 0.164 - 0.348. Dashed lines are the 95% confidence intervals.
  • the SARS-CoV-2 infection (hCoV-19/Australia/VIC01/2020) was generously provided by The Doherty Institute, Melbourne, Australia at P1 and passaged twice in Vero/hSLAM cells [ECACC 04091501], Whole genome sequencing was performed, on the working stock at Passage 3, using both Nanopore and Illumina technologies and no significant changes in the viral sequence were observed.
  • Virus titre was determined by a plaque assay on Vero E6 cells [ECACC 85020206], Cell lines were obtained from the European Collection of Authenticated Cell Cultures (ECACC) PHE, Porton Down, UK. Cell cultures were maintained at 37 °C in minimal essential media (MEM) (Life Technologies, California, USA) supplemented with 10% foetal bovine serum (FBS) (Sigma, Dorset, UK) and 25 mM HEPES (Life Technologies).
  • MEM minimal essential media
  • FBS foetal bovine serum
  • a microplaque inhibition assay was used to assess the inhibitory effect of various compounds. All compounds were dissolved in DMSO (Sigma) and diluted out in water. Compounds were diluted 2-fold to achieve a concentration range 100 pM -.0.05 pM, in duplicate. A fixed concentration of wildtype SARS-CoV-2 was added to the diluted compounds. Additional assay wells included virus-free and untreated virus-only controls. The plates (diluted compound & virus) were then incubated for 1 hr at 37°C to allow the compounds to neutralise the virus. The contents of the neutralisation plates were then transferred into 96- well plates containing Vero-E6 cells and the virus adsorbed to the cells for 1 hr at 37°C.
  • the inocula were removed from the cell plates and a viscous overlay (1 % CMC) added (test compound was added to the overlay media). The plates were then incubated for 24 hours. The cells were then fixed using 8% formalin for >8 hrs and an immunostaining protocol performed on the fixed cells. Stained foci were counted using an ELISpot counter (Cellular Technology Limited(CTL)). The counted foci data were then imported into R-Bioconductor. A positive control, chloroquine biphosphate (50 - 0.02 pM), was run alongside test compounds, on each assay plate.
  • CTL Cellular Technology Limited
  • a mid-point probit analysis (written in R programming language for statistical computing and graphics) was used to determine the amount of compound (pM) required to inhibit SARS-CoV-2 infectious viral foci by 50% (IC50) compared with the virus only control. All outliers were included in the mid-point probit analysis.
  • the IC50 (Table 1) was derived from the mid-point probit plot where the % viral foci reduction was plotted against compound concentration. In some wells exogenous IFNa was added to the overlay media.
  • IFNa type I interferons (eg human interferon a and P) on the SARS-CoV-2 infection in Vero E6 cells has been previously documented (Mantlo et al, 2020; Felgenhauer et al, 2020). IFNa was added to CO17/CO63 compounds at 2 different concentrations 10 pg/ml and 100 pg/ml. When IFNa (10 pg/ml) was added to Vero E6 cells and incubated alone with the virus in replicate wells and the number of foci were reduced by a factor of 2.5.
  • type I interferons eg human interferon a and P
  • This reduction factor was applied to the virus only control in the compound assays with 10 pg/ml IFNa, to normalise the data. The mid-point probit was then re-calculated and a new IC50 derived. In the presence of 100 pg/ml of IFNa the number of foci were reduced by 4.3-fold. This reduction factor was applied to the virus only control (VOC) in the compound assays incubated with 100 pg/ml IFNa, and a new probit IC50 calculated.
  • VOC virus only control

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Abstract

La présente invention concerne des composés destinés à être utilisés dans le traitement et/ou la prévention d'une infection à coronavirus. En particulier, la présente invention concerne des composés destinés à être utilisés dans le traitement et/ou la prévention de l'infection par le SARS-CoV-2 (COVID-19).
PCT/GB2022/050194 2021-01-25 2022-01-25 Traitement d'une infection à coronavirus Ceased WO2022157519A1 (fr)

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WO2012046030A2 (fr) 2010-10-07 2012-04-12 Riotech Pharmaceuticals Ltd Inhibiteurs de phosphodiestérase

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WO2012046030A2 (fr) 2010-10-07 2012-04-12 Riotech Pharmaceuticals Ltd Inhibiteurs de phosphodiestérase

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