WO2021224494A1 - Nouveaux traitements d'infections virales - Google Patents

Nouveaux traitements d'infections virales Download PDF

Info

Publication number
WO2021224494A1
WO2021224494A1 PCT/EP2021/062223 EP2021062223W WO2021224494A1 WO 2021224494 A1 WO2021224494 A1 WO 2021224494A1 EP 2021062223 W EP2021062223 W EP 2021062223W WO 2021224494 A1 WO2021224494 A1 WO 2021224494A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
disease
immune response
treatment
formula
Prior art date
Application number
PCT/EP2021/062223
Other languages
English (en)
Inventor
Thomas Olin
Ali MOSHFEGH
Original Assignee
Kancera Ab
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 Kancera Ab filed Critical Kancera Ab
Publication of WO2021224494A1 publication Critical patent/WO2021224494A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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

  • This invention relates to new uses of known CX3CR1 antagonists.
  • the invention relates to the use of such compounds in the treatment or prevention of an exaggerated host immune response to a viral infection and diseases and disorders caused by the viral infection and/or the host immune response thereto.
  • a virus is a submicroscopic infectious agent comprising genetic material (DNA or RNA) that is capable of infecting a biological organism.
  • a virus invades and attaches itself to a living cell, after which it multiplies to produce more virus particles (virions), which attach to and enter susceptible cells.
  • a virus may either kill a cell or alter its functions, the by-products of which processes lead to the infection of other cells. This will then generally lead to what is termed as viral diseases (or a viral infection).
  • an organism Following viral infection, an organism’s immune defence system is triggered. Lymphocytes and monocytes attempt to attack and destroy the invasive virus. This is referred to as the body’s innate or natural immunity.
  • the innate immune response can often lead a patient feeling unwell or fatigued. If a patient’s immune system is compromised, or not effective enough to prevent the spread of a virus, this can lead to severe illness and, in some instances, morbidity and/or death.
  • Antagonists of the fractal kine receptor are disclosed in WO 2006/107258, Karlstrom et al., J. Med. Chem., 2013, 56, 3177-3190, WO 2019/219771 and WO 2020/008064.
  • compounds of formula I appear to possess properties that render them useful in the treatment or prevention of exaggerated host immune responses to viral infections, such as coronavirus and more particularly severe acute respiratory syndrome coronavirus 2 infections. These properties may be due to the ability of the compounds to act as antagonists of the fractalkine receptor as the exaggerated host immune response may involve increased expression of fractalkine. These properties may also allow the compounds to treat diseases or disorders caused by viruses and/or the host immune response to the viral infection, or to prevent such diseases or disorders from occurring. Similarly, intervention with the compounds described herein may lead to the prevention or reduction in tissue damage occurring as a result of the host immune response, a reduced risk of secondary infections and a better outcome for the subject overall.
  • severe acute respiratory syndrome coronavirus 2 (the causative virus of COVID-19) may block or reduce the function of the ACE2 receptor in endothelial cells after endocytosis of the viral particles, leading to increased expression of CX3CL1 , which in turn promotes thrombosis in COVID-19 patients (Rivas-Fuentes et al. , Medical Hypotheses, 151 (2021) 110570).
  • R 1 represents aryl or pyridyl, both of which are optionally substituted by one or more groups selected from halo, -CN, -C(O)NR 3 R 4 , -S(O) 2 R 5 , C 1 -6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein the latter three groups are optionally substituted by one or more F;
  • R 2 represents H or C 1 -6 alkyl optionally substituted by one or more F;
  • R 3 and R 4 each independently represent H or C 1 -6 alkyl optionally substituted by one of more F;
  • R 5 represents C 1 -6 alkyl optionally substituted by one or more F; wherein indicates a point of attachment to the rest of the molecule;
  • Q 1 and Q 2 each independently represent H or -PO(OR 6 )(OR 7 );
  • Q 3 represents H or -CH 2 OPO(OR 6 )(OR 7 );
  • Q 4 represents -CH 2 OPO(OR 6 )(OR 7 ); wherein R 6 and R 7 each independently represent H, C 1-4 alkyl or C 2-4 alkenyl, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of an exaggerated host immune response to a viral infection.
  • a method of treatment or prevention of an exaggerated host immune response to a viral infection in a subject comprises administering a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • Compounds of the invention include (2R)-2-[(2-amino-5- ⁇ [(1S)-1- phenylethyl]thio ⁇ [1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol and 5- ⁇ [(1S)-1-(5-chloropyridin-2-yl)ethyl]sulfanyl ⁇ -7- ⁇ [(1R)-1-(hydroxymethyl)-3- methylbutyl]amino ⁇ [1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one which are described in WO 2006/107528 and Karlstrom et a!., J. Med. Chem.
  • references herein to compounds of particular aspects of the invention will include references to all embodiments and particular features thereof, which embodiments and particular features may be taken in combination to form further embodiments and features of the invention.
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared using techniques known to those skilled in the art, such as by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • carboxylate salts e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, a-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxy- benzoate, salicylate, ni cotin ate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate,
  • carboxylate salts e.g. formate, acetate, trifluoroacetate, propionate,
  • sulphonate salts e.g. benzenesulphonate, methyl-, bromo- or chloro-benzenesulphonate, xylenesulphonate, methanesulphonate, ethanesulphonate, propanesulphonate, hydroxy- ethanesulphonate, 1 or 2- naphthalene-sulphonate or 1 ,5-naphthalene-disulphonate salts
  • Particular base addition salts include salts formed by reaction with corresponding bases, thus removing a proton from compounds of the invention, to form salts with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine and tromethamine) and inorganic bases (such as ammonia).
  • alkali metals such as Na and K salts
  • alkaline earth metals such as Mg and Ca salts
  • organic bases such as ethanolamine, diethanolamine, triethanolamine and tromethamine
  • inorganic bases such as ammonia
  • More particular salts that may be mentioned include Li, Na, K and ammonium salts (including monosalts and disalts).
  • R 6 and R 7 each represent H particular salts that may be mentioned include diammonium salts, disodium salts, dilithium salts and dipotassium salts.
  • compounds of the invention may exist as solids, and thus the scope of the invention includes all amorphous, crystalline and part crystalline forms thereof, and may also exist as oils. Where compounds of the invention exist in crystalline and part crystalline forms, such forms may include solvates, which are included in the scope of the invention.
  • compounds of the invention may also exist in solution (i.e. in solution in a suitable solvent).
  • compounds of the invention may exist in aqueous solution, in which case compounds of the invention may exist in the form of hydrates thereof.
  • Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism (i.e. existing in enantiomeric or diastereomeric forms).
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers i.e. enantiomers
  • the desired enantiomer or diastereoisomer may be obtained from appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e.
  • C 1-Z alkyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e.
  • cycloalkyl groups that may be mentioned include cyclopropyl, cyclopentyl and cyclohexyl.
  • part cyclic alkyl groups (which may also be referred to as “part cycloalkyl” groups) that may be mentioned include cyclopropylmethyl.
  • such groups may also be multicyclic (e.g. bicyclic or tricyclic) and/or spirocyclic.
  • multicyclic e.g. bicyclic or tricyclic
  • spirocyclic e.g. spirocyclic
  • particular alkyl groups that may be mentioned include straight chain (i.e. not branched and/or cyclic) alkyl groups.
  • C 2-Z alkenyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain, and/or cyclic (so forming a C 4-Z cycloalkenyl group). When there is a sufficient number (i.e. a minimum of five) of carbon atoms, such groups may also be part cyclic.
  • part cyclic alkenyl groups (which may also be referred to as “part cycloalkenyl” groups) that may be mentioned include cyclopentenylmethyl and cyclohexenylmethyl.
  • such groups may also be multicyclic (e.g. bicyclic or tricyclic) or spirocyclic.
  • multicyclic e.g. bicyclic or tricyclic
  • spirocyclic e.g. spirocyclic
  • alkenyl groups that may be mentioned include straight chain (i.e. not branched and/or cyclic) alkenyl groups.
  • C 2-Z alkynyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, be branched-chain.
  • alkynyl groups that may be mentioned include straight chain (i.e. not branched and/or cyclic) alkynyl groups.
  • alkyl groups referred to herein as “alkyl”, “alkenyl” and/or “alkynyl” will be taken as referring to the highest degree of unsaturation in a bond present in such groups.
  • alkynyl groups referred to herein as “alkynyl”, “alkenyl” and/or “alkynyl” will be taken as referring to the highest degree of unsaturation in a bond present in such groups.
  • alkynyl such a group having a carbon-carbon double bond and, in the same group, a carbon-carbon triple bond
  • alkynyl groups referred to as “alkynyl”.
  • that such groups will comprise only the degree of unsaturation specified (i.e. in one or more bond therein, as appropriate; e.g. in in one bond therein).
  • alkyl, alkenyl and alkynyl groups as described herein may also act as linker groups (i.e. groups joining two or more parts of the compound as described), in which case such groups may be referred to as “alkylene”, “alkenylene” and/or “alkynylene” groups, respectively.
  • aryl may refer to C 6-14 (e.g. Ce-io) aromatic groups. Such groups may be monocyclic or bicyclic and, when bicyclic, be either wholly or partly aromatic. Ce aryl groups that may be mentioned include phenyl, naphthyl, 1 ,2,3,4- tetrahydronaphthyl, indanyl, and the like (e.g. phenyl, naphthyl, and the like). For the avoidance of doubt, the point of attachment of substituents on aryl groups may be via any suitable carbon atom of the ring system.
  • references to polycyclic (e.g. bicyclic or tricyclic) groups will refer to ring systems wherein at least two scissions would be required to convert such rings into a non-cyclic (i.e. straight or branched) chain, with the minimum number of such scissions corresponding to the number of rings defined (e.g. the term bicyclic may indicate that a minimum of two scissions would be required to convert the rings into a straight chain).
  • bicyclic e.g.
  • alkyl groups when employed in the context of alkyl groups may refer to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring, to groups in which two non-adjacent atoms are linked by an alkyl (which, when linking two moieties, may be referred to as alkylene) group (optionally containing one or more heteroatoms), which later groups may be referred to as bridged, or to groups in which the second ring is attached to a single atom, which latter groups may be referred to as spiro compounds.
  • alkyl which, when linking two moieties, may be referred to as alkylene
  • bridged or to groups in which the second ring is attached to a single atom, which latter groups may be referred to as spiro compounds.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention.
  • the compounds of the invention also include deuterated compounds, i.e. compounds of the invention in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.
  • substituents e.g. C 1 -3 alkyl optionally substituted by one or more F
  • substituents e.g. C 1 -3 alkyl optionally substituted by one or more F
  • substituents where possible may be positioned on the same or different atoms.
  • Such optional substituents may be present in any suitable number thereof (e.g. the relevant group may be substituted with one or more such substituents, such as one such substituent).
  • a wavy bond may indicate a (or the) point of attachment of the relevant substituent to the core molecule (i.e. the compound of the compound of formula I to which the substituent is attached).
  • compounds of the invention that are the subject of this invention include those that are obtainable, i.e. those that may be prepared in a stable form. That is, compounds of the invention include those that are sufficiently robust to survive isolation, e.g. from a reaction mixture, to a useful degree of purity.
  • At least one of Q 1 and Q 2 , Q 3 or Q 4 represents -PO(OR 6 )(OR 7 ) or -CH 2 OPO(OR 6 )(OR 7 ).
  • certain compounds of the invention may contain one or two phosphate or phosphoamidic acid groups or esters thereof (-OPO(OR 6 )(OR 7 ) or -N H PO(OR 6 ) (OR 7 )/-NR x PO(OR 6 ) (OR 7 ) , wherein R x represents a carbon- based group (e.g. alkyl)) groups (i.e.
  • Q 1 and Q 2 , Q 3 or Q 4 may represent -PO(OR 6 )(OR 7 ) or -CH 2 OP(OR 6 )(OR 7 ) (as appropriate)). If one of Q 1 and Q 2 , Q 3 or Q 4 represents -PO(OR 6 )(OR 7 ) or -CH 2 OP(OR 6 )(OR 7 ), the remaining group represents H.
  • one of Q 1 and Q 2 , Q 3 or Q 4 represents -PO(OR 6 )(OR 7 ) or -CH 2 OPO(OR 6 )(OR 7 ), and the remainder of Q 1 , and (if present) Q 2 or Q 3 represent H (Q 4 either represents -CH 2 OPO(OR 6 )(OR 7 ) or is absent).
  • Particular compounds of the invention include those in which if one of Q 1 and Q 2 or Q 3 represents -PO(OR 6 )(OR 7 ) or -CH 2 OPO(OR 6 )(OR 7 ) and the other of Q 1 , and Q 2 or Q 3 represents H ; and
  • Q 1 represents H and Q 4 represents -CH 2 OPO(OR 6 )(OR 7 ).
  • Q 1 represents -PO(OR 6 )(OR 7 ). In particular embodiments that may be mentioned,
  • Q 1 represents -PO(OR 6 )(OR 7 ).
  • Q 1 represents -PO(OR 6 )(OR 7 ); and Q 2 or Q 3 (as appropriate) each represent H.
  • Q 1 represents -PO(OR 6 )(OR 7 ).
  • Q 2 represents -PO(OR 6 )(OR 7 ).
  • Q 2 represents -PO(OR 6 )(OR 7 );
  • Q 3 represents -CH 2 PO(OR 6 )(OR 7 ).
  • Q 3 represents -CH2PO(OR 6 )(OR 7 );
  • Q 1 represents H.
  • Q 2 represents H.
  • Q 3 represents H.
  • Q 2 , Q 3 or Q 4 (as appropriate) represents H.
  • Q 1 represents H or -PO(OR 6 )(OR 7 ); and Q 2 represents H.
  • R 1 represents phenyl or pyridyl, both of which are optionally substituted by one or more (e.g. one) fluoro, chloro, bromo, -CN , -C(O)NR 3 R 4 , -S(O) 2 R 5 , C 1-4 alkyl (for example C 1 -3 alkyl, e.g. C 1 -2 alkyl), C 2-6 alkenyl (for example C 2-3 alkenyl, e.g. ethenyl) or C 2-4 alkynyl (for example C 2-3 alkenyl, e.g.
  • R 1 represents phenyl or pyridyl, both of which are optionally substituted by one or more fluoro, chloro, bromo, -CN, -C(O)NR 3 R 4 or -S(O) 2 Me group, wherein R 3 and R 4 are as defined herein.
  • R 1 represents phenyl or pyridyl, both of which are optionally substituted by one or more (e.g. one) fluoro, chloro, bromo or methyl group.
  • R 1 represents phenyl or pyridyl, both of which are optionally substituted by one or more (e.g. one) fluoro, chloro or bromo group.
  • R 1 is selected from wherein indicates the point of attachment to the rest of the molecule.
  • R 1 represents phenyl or pyridyl, both of which are optionally substituted by one or more (e.g. one) chloro group.
  • R 1 represents phenyl (i.e. unsubstituted) or 5- chloropyridin-2-yl (e.g. phenyl).
  • R 2 represents C 1 -6 alkyl optionally substituted by one or more F.
  • R 2 represents C 1 -6 alkyl (i.e. unsubstituted). In more particular embodiments R 2 represents C 1-3 alkyl optionally substituted by one or more F (e.g. unsubstituted). In yet more particular embodiments, R 2 represents trifluoromethyl, difluoromethyl, fluoromethyl or, particularly, methyl.
  • R 2 represents H or, particularly, methyl.
  • R 3 and R 4 each independently represent H or C 1 -6 alkyl (i.e. unsubstituted).
  • R 3 and R 4 each independently represent C 1-3 alkyl optionally substituted by one or more F (e.g. unsubstituted).
  • R 3 and R 4 each independently represent H, trifluoromethyl, difluoromethyl, fluoromethyl or methyl.
  • R 3 and R 4 both represent H.
  • R 5 represents C 1-6 alkyl (i.e. unsubstituted). In more particular embodiments R 5 represents C 1-3 alkyl optionally substituted by one or more F (e.g. unsubstituted). In yet more particular embodiments, R 5 represents trifluoromethyl, difluoromethyl, fluoromethyl or, particularly, methyl.
  • R 6 and R 7 each independently represent C 1-3 alkyl (e.g. C 1-2 alkyl) or H. In more particular embodiments, R 6 and R 7 each represent H.
  • R 6 and R 7 each represent methyl or each represent ethyl.
  • R 6 represents iso-propyl and R 7 represents H.
  • the compound of formula I is a compound of formula IA wherein R 1 , R 2 , Q 1 and are as defined herein, or a pharmaceutically acceptable salt thereof.
  • the compound of formula I is a compound of formula lAa
  • R 1 , R 2 , Q 1 and are as defined herein, or a pharmaceutically acceptable salt thereof.
  • Q 1 represents H or -PO(OR 6 )(OR 7 );
  • R 1 represents phenyl or pyridyl both of which are optionally substituted by one or more (e.g. one) groups selected from the group consisting of chloro, fluoro, -CN, -CONH2 and - SO 2 Me (particularly phenyl (i.e. unsubstituted));
  • R 2 represents H or C 1-3 alkyl (e.g. methyl);
  • R 6 and R 7 each independently represent C 1-3 alkyl (e.g. Me) or H; more particularly R 6 represents iso-propyl and R 7 represents H or R 6 and R 7 each represent H (e.g. R 6 and R 7 each represent H).
  • the compound of formula I is selected from the group consisting of:
  • the compound of formula I is selected from the group consisting of
  • the compound of formula I is (2R)-2-[(2-amino-5- ⁇ [(1S)-1- phenylethyl]thio ⁇ [1 ,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol
  • the compound of formula I is (2R)-2-[(2-Amino-5- ⁇ [(1 S)-1- phenylethyl]sulfanyl ⁇ [1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate (Compound 2)
  • the compounds of the invention are useful in the treatment or prevention of an exaggerated host immune response to a viral infection induced by the innate immune system.
  • the host immune response is the process by which the body’s immune system interacts with and responds to viruses that it encounters.
  • the host immune response involves an immune response in which virus replication-induced production of cytokines epithelium recruits innate immune cells to the site of infection.
  • cytokines epithelium recruits innate immune cells to the site of infection.
  • leukocytes including, neutrophils, monocytes, macrophages, dendritic cells, eosinophils, natural killer cells, innate lymphoid cells such as gd T cells, become activated in response to the virus, to stop the virus and protect tissues of the host while triggering the adaptive arm of the immune system.
  • An exaggerated host immune response occurs when there is an overactivation of immune cells leading to an extensive tissue infiltration and to over production of inflammatory cytokines. Together, the factors cause a stepwise progression to excessive inflammation and a cytokine storm, leading to damage and fibrosis in tissues including e.g. the heart, vasculature, lung, kidney, liver intestine and nerves.
  • An exaggerated host immune response may also induce coagulation disorder, endotheliitis and vasculitis. If it is not controlled or does not abate naturally, this immune response can result in death.
  • An exaggerated host immune response may also be described as an excessive (host) immune response.
  • the excessive inflammation resulting from the exaggerated host immune response may also be termed hyperinflammation.
  • the compounds of the invention for use in the treatment or prevention (e.g. prevention) of viral infection-induced hyperinflammation.
  • a method of treatment or prevention (e.g. prevention) of viral infection- induced hyperinflammation in a subject comprises administering a therapeutically effective amount the compounds of the invention (including pharmaceutically acceptable salts thereof), to a subject in need thereof.
  • This second wave of innate immunity is thought to be caused by ineffective or inadequate clearance of the virus during the early stage of the infection as a result of the normal immune response. This generally occurs when the subject’s adaptive immune system is not effective in clearing the virus and/or in subjects that are immunosuppressed, as, for example, reflected by lymphopenia.
  • dengue fever (caused by the Dengue virus).
  • the dengue fever develops into severe dengue (also known dengue hemorrhagic fever) and/or dengue shock syndrome. Severe dengue occurs most frequently when subjects are infected for a second time with a different strain of dengue virus to the initial infection. It is believed that the compounds of the invention may be effective in the treatment or prevention of disorders involving a second wave of innate immunity.
  • the compounds of the invention exert their effects through acting as antagonists of the CX3CR1 receptor (fractalkine receptor).
  • the compounds of the invention act as antagonists of the CX3CR1 (fractalkine) receptor.
  • compounds of the invention are therefore useful because they possess pharmacological activity, and/or are metabolised in the body following administration (e.g. oral or parenteral administration) to form compounds that possess pharmacological activity.
  • references to the treatment of a particular condition will take their normal meanings in the field of medicine.
  • the terms may refer to achieving a reduction in the severity and/or frequency of occurrence of one or more clinical symptom associated with the condition, as adjudged by a physician attending a patient having or being susceptible to such symptoms.
  • the term may refer to achieving a reduction in the degree of inflammation or tissue damage in an organ (e.g. the lungs) and/or the reduction in the severity and/or frequency of a symptom associated with inflammation or tissue damage in an organ (e.g. the lungs), (e.g. cough, oxygenation, dyspnea, respiratory distress and/or respiratory failure).
  • the term prevention will include references to the prophylaxis of the disease or disorder (and vice-versa).
  • references to prevention may also be references to prophylaxis, and vice versa.
  • such terms term may refer to achieving a reduction (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction) in the likelihood of the patient (or healthy subject) developing the condition (which may be understood as meaning that the condition of the patient changes such that patient is diagnosed by a physician as having, e.g. requiring treatment for, the relevant disease or disorder).
  • the compounds of the invention may attenuate the host immune response and thereby achieve a reduction in the likelihood of a subject (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction) developing of an exaggerated host immune response to a viral infection.
  • the compounds of the invention may cause a reduction in the severity of the host immune response (e.g. as measured by the degree of inflammation and/or tissue damage and function). Accordingly, the compounds of the invention may prevent the development of disorders and/or complications caused by excessive inflammation and/or tissue damage occurring during the host immune response to a viral infection.
  • the compounds of the invention are for use in the prevention of an exaggerated host immune response to a viral infection (and similarly there is provided a method of prevention of an exaggerated host immune response to a viral infection comprising administering the compounds of the invention as described herein and the use of the compounds of the invention in the manufacture of medicament for the prevention of an exaggerated host immune response to a viral infection).
  • This prevention of an exaggerated host immune response to a viral infection may include the prevention of tissue and/or the prevention of diseases and disorders caused by the virus and/or the host response, as described herein.
  • references to a subject (or patient), or to subjects (or patients), will refer to a living subject being treated, including mammalian (e.g. human) subjects (or patients).
  • references to a subject (or patient) will refer to a human subject (or patient).
  • disease and disorder and, similarly, the terms condition, illness, medical problem, and the like may be used interchangeably.
  • the term effective amount will refer to an amount of a compound that confers a therapeutic effect on the treated patient.
  • the effect may be observed in a manner that is objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and/or feels an effect).
  • the effect may be observed (e.g. measured) in a manner that is objective, using appropriate tests as known to those skilled in the art.
  • the exaggerated host immune response is caused by a virus selected from the group consisting of a coronavirus, Cytomegalovirus, Dengue virus, an influenza virus, a parainfluenza virus and a respiratory syncytial virus.
  • the exaggerated host immune response is caused by a virus selected from the group consisting of a coronavirus, Dengue virus, an influenza virus, and a parainfluenza virus.
  • the exaggerated host immune response is caused by a coronavirus, Cytomegalovirus, Dengue virus or a respiratory syncytial virus.
  • the exaggerated host immune response is caused by a coronavirus, such as severe acute respiratory syndrome coronavirus or severe acute respiratory syndrome coronavirus 2.
  • the exaggerated host immune response is caused by a combination of viruses selected from the group consisting of a coronavirus, Cytomegalovirus, Dengue virus, an influenza virus, a parainfluenza virus and a respiratory syncytial virus.
  • the exaggerated host immune response is caused by a combination of coronavirus and Cytomegalovirus, for example, a combination of severe acute respiratory syndrome coronavirus and Cytomegalovirus or a combination of severe acute respiratory syndrome coronavirus 2 and Cytomegalovirus.
  • the exaggerated host immune response occurs as a result of a patient being infected by Cyromegalovirus, then subsequently infected with a second virus (particularly a coronavirus and more particularly, severe acute respiratory syndrome coronavirus 2), which infections may be concurrent or sequential.
  • a second virus particularly a coronavirus and more particularly, severe acute respiratory syndrome coronavirus 2
  • the treatment or prevention (e.g. prevention) of an exaggerated host immune response to a viral infection includes the treatment or prevention (e.g. prevention) of tissue damage caused by the viral infection and/or the exaggerated host immune response.
  • the tissue damage is damage to heart tissue, lung tissue, kidney tissue or liver tissue. More particularly, the tissue damage is damage to lung tissue.
  • the treatment or prevention (e.g. prevention) of an exaggerated host immune response to a viral infection includes the treatment or prevention (e.g. prevention) of a disease or disorder caused by the viral infection and/or the exaggerated host immune response.
  • references to a disease or disorder (or tissue damage) being caused by the viral infection and/or the exaggerated host immune response to a viral infection indicates the disease or disorder (or tissue damage) occurring as a result of the host immune response.
  • the disease or disorder may occur, and thus be treated, concurrently with the exaggerated host immune response or may persist once the exaggerated host immune response is no longer present, and thus be treatment may continue once the host immune response is no longer present.
  • the administration of the compounds of the invention may prevent the disease or disorder (or tissue damage) from occurring as a result of the exaggerated host immune response or may cause the disease or disorder to manifest less severely, thereby causing the patient to experience milder and/or less frequent symptoms and/or to experience a reduced risk of mortality.
  • a compound of formula I for use in the treatment or prevention of a viral infection-induced disease or disorder, (e.g. a viral infection-induced inflammatory disease or disorder).
  • a viral infection-induced disease or disorder e.g. a viral infection-induced inflammatory disease or disorder
  • a method of treatment or prevention of a viral infection-induced disease or disorder e.g. a viral infection-induced inflammatory disease or disorder
  • a method of treatment or prevention of a viral infection-induced disease or disorder comprises administering a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a viral infection-induced disease or disorder (e.g. a viral infection-induced inflammatory disease or disorder).
  • a viral infection-induced disease or disorder e.g. a viral infection-induced inflammatory disease or disorder
  • the disease or disorder caused by the viral infection and/or the exaggerated host immune response is selected from the list consisting of a heart disorder (e.g. myocarditis, endocarditis, heart failure, ventricular hypertrophy, cardiac fibrosis, arrythmia), a lung disorder (e.g. acute respiratory distress syndrome, severe acute respiratory syndrome, pulmonary embolism, pulmonary hypertension, lung fibrosis), a kidney disorder (e.g. acute kidney injury, glomerulonephritis, renal fibrosis), a liver disorder (e.g.
  • a heart disorder e.g. myocarditis, endocarditis, heart failure, ventricular hypertrophy, cardiac fibrosis, arrythmia
  • a lung disorder e.g. acute respiratory distress syndrome, severe acute respiratory syndrome, pulmonary embolism, pulmonary hypertension, lung fibrosis
  • a kidney disorder e.g. acute kidney injury, glomerulonephritis, renal fibrosis
  • hepatitis hepatitis, acute liver failure, liver fibrosis/cirrhosis
  • gastrointestinal inflammatory disease a vascular disorder (e.g. coagulation disorder, vasculitis, endotheliitis, hypertension), a neurological disorder (e.g. stroke and seizures, neuritis, pain), sepsis, cytokine release syndrome and/or systemic inflammatory response syndrome.
  • a vascular disorder e.g. coagulation disorder, vasculitis, endotheliitis, hypertension
  • a neurological disorder e.g. stroke and seizures, neuritis, pain
  • sepsis cytokine release syndrome and/or systemic inflammatory response syndrome.
  • the disease or disoder is dengue fever.
  • the treatment or prevention of dengue fever comprisies the treatment or prevention of severe dengue and/or dengue shock syndrome.
  • Such treatment may include the treatment or prevention (e.g. prevention) of tissue damage caused by the viral infection and/or the exaggerated host immune response
  • the disease or disorder is selected from the list consisting of pneumonia, severe acute respiratory syndrome, acute respiratory distress syndrome, vasculitis, sepsis, cytokine release syndrome and/or systemic inflammatory response syndrome.
  • the disease or disorder is selected from sepsis, severe acute respiratory syndrome (e.g. coronavirus disease 2019 (COVID-19)) and acute respiratory distress syndrome.
  • severe acute respiratory syndrome e.g. coronavirus disease 2019 (COVID-19)
  • acute respiratory distress syndrome e.g. coronavirus disease 2019 (COVID-19)
  • the disease or disorder is severe acute respiratory syndrome.
  • the disease is coronavirus disease 2019 (COVID-19).
  • COVID-19 appears to process through different stages of increasing disease severity.
  • COVID-19 Illness in Native and Immunosuppressed States A Clinical-Therapeutic Staging Proposal, https://doi.Org/10.1016/j.healun.2020.03.012).
  • Stage I of COVID-19 refers to the early stages of infection and initial immune response to the virus associated with mild symptoms. If the subject is unable to adequately clear the viral infection during stage I the disease progresses to stage II, which is characterised by an escalating systemic host immune response leading to a severe pulmonary inflammation. During stage II, patients develop viral pneumonia and may also begin to develop hypoxia. Markers of systemic inflammation also become elevated during stage II. During this stage inflammatory biomarkers are significantly elevated, typically including IL- 1, IL-6 , Interferon gamma, TNFa, C-reactive protein. A minority of subjects then transition into stage III of the disease, which involves systemic acute life threatening hyperinflammation. Treatment in intensive care is necessary during this stage and there is a risk of shock, repiratory failure, multiple organ failure and death.
  • treatment with the compounds of the invention may reduce the likelihood of the disease progressing to stage II, and, parti cuarly, stage III, and therefore prevent severe disease from occuring.
  • the compound of the invention or pharmaceutically acceptable salt thereof is administered during stage I (viral response) and/or stage II (host immune response) of the disease. More particularly, the compound is administered during stage I (viral response) and stage II (host immune response). More particularly, the compound is administered during first administered during late stage I (viral response) or during stage II (host immune response) of the disease but prior to intensive care (stage III).
  • the treatment comprises the treatment or prevention (e.g. prevention) of acute respiratory distress syndrome, systemic inflammatory response syndrome and/or cardiac failure.
  • the treatment of COVID-19 is in a hypoxic subject.
  • a subject may be considered to be hypoxic if they have an arterial oxygen saturation level of below 94% (e.g. below 90%).
  • the treatment of COVI D-19 is in a subject with a clinically significant viral titre after 5 or more days from the initial infection (for example after 7 or more days, e.g. after 7 to 10 days).
  • the treatment of COVID-19 is: in a subject that has an oxygen saturation level of below 94% (e.g. below 90%); and/or in a subject with a clinically-significant viral titre after 5 or more days from the initial infection (for example after 7 or more days, e.g. after 7 to 10 days); and/or in a subject with a C- reactive protein (CRP) level of 10 mg/L or more.
  • an oxygen saturation level of below 94% (e.g. below 90%)
  • a subject with a clinically-significant viral titre after 5 or more days from the initial infection (for example after 7 or more days, e.g. after 7 to 10 days)
  • CRP C- reactive protein
  • the treatment may continue once the host immune response is no longer present.
  • Long COVID may otherwise be referred to as post-acute sequelae of SARS-CoV-2 infection, post-acute sequelae of COVID-19 (PASC), chronic COVID syndrome (CCS), and long-haul COVID.
  • PASC post-acute sequelae of SARS-CoV-2 infection
  • CCS chronic COVID syndrome
  • long-haul COVID long-haul COVID.
  • long COVID relates to a disorder characterized by long-term effects that persist after the typical convalescence period from COVID-19. Symptoms accociated with long COVID (i.e.
  • symptoms that occur after a COVID-19 infection in a subject include extreme tiredness (fatigue), shortness of breath, chest pain or tightness, problems with memory and concentration (i.e. "brain fog"), difficulty sleeping (e.g. insomnia), heart palpitations, dizziness, pins and needles, joint pain, depression and anxiety, tinnitus, earaches, nausia , diarrhoea, stomach aches, loss of appetite, high temperature, cough, headaches, sore throat, changes to sense of smell or taste, and rashes.
  • the subject recieving treatment for long COVID may have received (or be receiving) treatment for COVID-19, for example, any of the treatments defined herein.
  • the subject receiving treatment for long COVID may not have received (or be receiving) any treatment for COVID-19.
  • the treatment or prevention (e.g. prevention) of an exaggerated host immune response to a viral infection is in a subject with an increased risk of experiencing an exaggerated host immune response and/or other complications as a result of viral infections.
  • Subjects at increased risk of experiencing an exaggerated host immune response and/or other complications in response to a viral infection include those with weakened immune systems, for example as a result of advanced age and/or chronic or long-term illness.
  • the treatment is in an immunosuppressed subject, for example characterized by lymphopenia.
  • the treatment is in a subject who is 65 years old or over.
  • Particular subjects at increased risk of experiencing an exaggerated host immune response and/or other complications as a result of viral infections include subjects who are:
  • Particular subjects at increased risk of experiencing an exaggerated host immune response and/or other complications as a result of viral infections include subjects who are in a group characterized by elevated levels of CX3CL1 and/or circulating CX3CR1 positive cells, particularly T-cells and/or monocytes.
  • Particular subjects at increased risk of experiencing an exaggerated host immune response and/or other complications as a result of viral infections include subjects who are:
  • subjects at increased risk of experiencing an exaggerated host immune response and/or other complications as a result of infectious illnesses include subjects who are:
  • compositions/formulations may include a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipient, for use in the treatment and/or prevention of infection-induced inflammation.
  • a method of treatment and/or prevention of infection-induced inflammation in a subject comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipient, to a subject in need thereof.
  • a pharmaceutical composition comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipient, for the manufacture of a medicament for the treatment and/or prevention of infection- induced inflammation.
  • the term pharmaceutically acceptable excipients includes vehicles, adjuvants, carriers, diluents, pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like.
  • excipients may include adjuvants, diluents or carriers.
  • the pharmaceutical compositions comprise at least one pharmaceutically acceptable excipient.
  • compounds of the invention act systemically and/or locally (i.e. at a particular site), and may therefore be administered accordingly using suitable techniques known to those skilled in the art.
  • the compounds of the invention may act systemically.
  • compositions as described herein will normally be administered orally, intravenously, intraocularly, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
  • the compounds may be administered orally (i.e. through per oral administration) or intravenously.
  • compositions as described herein will include compositions in the form of tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral (e.g. intravenous) or intramuscular administration, and the like.
  • the pharmaceutical formulation is provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, inhalants (e.g. to be applied intranasally), or forms suitable for topical administration (e.g. eye drops).
  • a pharmaceutically acceptable dosage form including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, inhalants (e.g. to be applied intranasally), or forms suitable for topical administration (e.g. eye drops).
  • compounds of the invention may be present as a solid (e.g. a solid dispersion), liquid (e.g. in solution) or in other forms, such as in the form of micelles.
  • the compound in the preparation of pharmaceutical formulations for oral administration, may be mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • the mixture may then be processed into granules or compressed into tablets.
  • Soft gelatin capsules may be prepared with capsules containing one or more active compounds (e.g. compounds of the first and, therefore, second and third aspects of the invention, and optionally additional therapeutic agents), together with, for example, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules.
  • active compounds e.g. compounds of the first and, therefore, second and third aspects of the invention, and optionally additional therapeutic agents
  • hard gelatine capsules may contain such compound(s) in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the compound(s) mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the compound(s) and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent.
  • Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
  • Solutions for parenteral administration may be prepared as a solution of the compound(s) in a pharmaceutically acceptable solvent (e.g. water). These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
  • a pharmaceutically acceptable solvent e.g. water
  • pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in an amount that is at least 1% (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.
  • compositions/formulations as described hereinabove may be administered (for example, as compositions/formulations as described hereinabove) at varying doses, with suitable doses being determined by one of skill in the art.
  • Oral, pulmonary and topical dosages may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 30 mg/kg/day, preferably about 0.1 to about 5.0 mg/kg/day, and more preferably about 0.5 to about 3.0 mg/kg/day.
  • treatment with such compounds may comprise administration of a formulations typically containing between about 0.01 mg to about 5000 mg, for example between about 0.1 mg to about 500 mg, or between 1 mg to about 400 mg (e.g. about 20 mg to about 200 mg), of the active ingredient(s).
  • a formulations typically containing between about 0.01 mg to about 5000 mg, for example between about 0.1 mg to about 500 mg, or between 1 mg to about 400 mg (e.g. about 20 mg to about 200 mg), of the active ingredient(s).
  • the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion.
  • the compounds of the invention may be administered orally at a dose of 100 to 600 mg per day (e.g. 50 to 300 mg twice daily) and/or intravenously at a dose sufficient to achieve a steady state plasma concentration of 300 nM to 2 mM for a period of at least 6 hours.
  • the compound of formula I, or pharmaceutically acceptable salt thereof is administered:
  • references to the active compound may be understood to refer to the compound that binds to and exerts the effect at the relevant receptor (the CX3CR1 receptor).
  • the active compound refers to the corresponding compound in which the relevant group(s) of Q 1 , and Q 2 , Q 3 and Q 4 represents H.
  • references to the active ingredient in a composition/formulation may refer to the compound that exerts the effect at the relevant receptor (i.e. the active compound) or the relevant salt form or derivative thereof present in the composition/formulation. When dosages are expressed in milligrams, this may refer to the weight of the relevant salt form or derivative, or, alternatively, may refer to the weight of the active compound within the salt form/derivative. In particular, references to the active ingredient refer to the compound that exerts the effect at the relevant receptor.
  • the daily dose may be administered in divided doses of two, three or four times daily. More particularly, the compound may be administered at a twice daily dose of between 205 and 300 mg (e.g. 250 mg).
  • the compound is administered orally at a twice daily dose of 125 mg of the active ingredient.
  • the compound of formula I, or pharmaceutically acceptable salt thereof may be administered for a period of between 5 to 30 days (for example 5 to 25 days, e.g. 10 to 21 days). In particular embodiments, the treatment is continued for 7 days.
  • the compound of formula I is administered for a period of 10 to 21 days:
  • the term “about” (or similar terms, such as “approximately”) will be understood as indicating that such values may vary by up to 10% (particularly, up to 5%, such as up to 1%) of the value defined. It is contemplated that, at each instance, such terms may be replaced with the notation “ ⁇ 10%”, or the like (or by indicating a variance of a specific amount calculated based on the relevant value). It is also contemplated that, at each instance, such terms may be deleted.
  • treatment with compounds of the invention may further comprise (i.e. be combined with) further treatment(s) or preventative methods for the same condition, or related conditions.
  • treatment with compounds of the invention may be combined with other means for the treatment of patients with viral infections, such as treatment with one or more other therapeutic agent that is useful in the in the treatment of patients with viral infections, as known to those skilled in the art.
  • compounds of the invention may also be combined with one or more other (i.e. different) therapeutic agents (i.e. agents that are not compounds of the invention) that are useful in the treatment of patients with viral infections.
  • Such combination products that provide for the administration of a compound of the invention in conjunction with one or more other therapeutic agent may be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the one or more other therapeutic agent).
  • Therapeutic agents that may be used in conjunction with the compounds of the invention include one or more of the variously-applied standard treatments for viral infections, including antiviral medicines (e.g. oseltamivir, remdesivir, favilavir, simeprevir, daclatasvir, sofosbuvir, ribavirin, umifenovir, lopinavir, ritonavir, teicoplanin, the TMPRSS2 inhibitor, camostat, Actembra (Roche), TZLS-501 , AT-100 (rhSP-D), OYA1 (OyaGen9), BPI-002 (BeyondSpring), NP-120 (Ifenprodil; Algernon Pharmaceuticals), Galidesivir (Biocryst Pharma), REGN3048-3051 and Kevzara (SNG001 ; Synairgen Research), antiinflammatory agents (e.g.
  • antiviral medicines e.g. oseltamivir,
  • NSAIDs such as ibuprofen, ketorolac, naproxen and the like, chloroquine, hydroxychloroquine, interferons, tocilizumab, lenalidomide, pomalidomide and thalidomide), analgesics (e.g. paracetamol or opioids), antitussive agents (e.g. dextromethorphan).
  • each of components (I) and (II) is formulated in admixture, optionally with one or more a pharmaceutically acceptable excipient.
  • kit-of-parts comprising:
  • a pharmaceutical formulation as hereinbefore defined (a) a pharmaceutical formulation as hereinbefore defined; and (b) one or more other therapeutic agent that is useful in the treatment of patients with viral infections, optionally in admixture with one or more pharmaceutically acceptable excipient, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction (i.e. concomitantly or sequentially) with the other.
  • kits-of-parts as described herein, by “administration in conjunction with” (and similarly “administered in conjunction with”) we include that respective formulations are administered, sequentially, separately or simultaneously, as part of a medical intervention directed towards treatment of the relevant condition.
  • the term “administration in conjunction with” includes that the two active ingredients (i.e. a compound of the invention and a further agent for the treatment and/or prevention of fractalkine-related diseases, or compositions comprising the same) are administered (optionally repeatedly) either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment and/or prevention of the relevant condition, than if either agent is administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment and/or prevention. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of, treatment and/or prevention of a particular condition will depend upon the condition to be treated and/or prevented, but may be achieved routinely by the skilled person.
  • the term “in conjunction with” includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration of the other component.
  • the terms “administered simultaneously” and “administered at the same time as” includes instances where the individual doses of the compound of the invention and the additional compound for the treatment patients with viral infections, or pharmaceutically acceptable salts thereof, are administered within 48 hours (e.g. within 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes or 10 minutes) of each other.
  • references to other therapeutic agents that are “useful” in a certain manner will refer to agents that are known to be suitable for use in that manner (e.g. agents commonly used for that purpose). Such references may therefore be replaced with references to agents “suitable for” the relevant purpose.
  • compositions/formulations, combination products and kits as described herein may be prepared in accordance with standard and/or accepted pharmaceutical practice.
  • a process for the preparation of a pharmaceutical composition/formulation which process comprises bringing into association a compound of the invention, as hereinbefore defined, with one or more pharmaceutically acceptable excipient.
  • a process for the preparation of a combination product or kit-of- parts as hereinbefore defined comprises bringing into association a compound of the invention, as hereinbefore defined, with the other therapeutic agent that is useful in the treatment of the relevant disease or disorder, and at least one pharmaceutically-acceptable excipient.
  • references to bringing into association will mean that the two components are rendered suitable for administration in conjunction with each other.
  • kit-of-parts as hereinbefore defined, by bringing the two components “into association with” each other, we include that the two components of the kit-of-parts may be:
  • these effects may also be relevant during the second wave of the immune response associated with exaggerated inflammation, leading to reduced tissue damage ocurring during this stage of the infection.
  • the uses and methods described herein may also have the advantage that they attenuate the host immune response without affecting the antibody response to the virus antigen, such that the desired virus-directed host response is retained.
  • the uses and methods described herein may also have the advantage that, in the treatment or prevention of an exaggerated host response to a viral infection , they may be more convenient for the subject than, be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or that it/they may have other useful pharmacological properties over, similar methods (treatments) known in the prior art, whether for use in the treatment of an exaggerated host immune response to a viral infection, diseases or disorders caused by such a host immune response, viral infections generally, or otherwise.
  • Figure 1 shows mean plasma concentration-time profiles of Compound 2 and Compound 1 after 30 min IV infusion of Compound 2 at 25 mg/kg or a PO dose of Compound 2 at 35 mg/kg in male Beagle dogs.
  • AUC inf Area under the plasma concentration-time curve extrapolated to infinity
  • AUC last Area under the plasma concentration-time curve from time zero to last quantifiable concentration bid: twice daily
  • DPBS Dulbecco's phosphate-buffered saline
  • EDTA-K2 Ethylenediaminetetraacetic acid dipotassium salt dihydrate
  • FACS Fluorescence-activated cell sorting
  • the primary objective is to determine and compare the effects of oral administration of Compound 1 versus placebo, on oxygen exchange and respiration in subjects admitted to the hospital for care of COVID-19 infection.
  • AEs adverse events
  • SAEs serious adverse events
  • Ferritin > 300 ng/mL for men and > 150 ng/mL for women
  • CRP C-reactive protein
  • age-related calculated as follows: 0.5 mg/L FEU + 0.01 mg/L FEU for every year over 50 (i.e. one who is 70 years old has thus a reference limit of ⁇ 0.7 mg/L FEU; on who is 90 years old has a reference limit of ⁇ 0.9 mg/L FEU)
  • the study is a phase II, randomized, 2-arm parallel-group, double-blind study to explore the efficacy, safety, tolerability and pharmacokinetics of Compound 1 versus placebo in COVID-19 subjects in need of oxygen treatment.
  • the subject is then enrolled and randomized into one of two arms. After randomization, the subjects will receive Compound 1 or placebo. The Compound 1 or placebo treatment will continue for one week. After the treatment period the subjects will return to ordinary clinical follow-up, but a study follow-up visit will be planned for Day 21 and 90.
  • Compound 1 is provided as 125 mg capsules (2 capsules BID) or a placebo.
  • the IV infusion dose was conducted via cephalic vein for 30 min.
  • the oral (PO) administration was conducted via oral gavage.
  • the animals were restrained manually, and approximately 0.5 mL blood/time point was collected from non-dosed cephalic vein into pre-chilled EDTA-K2 tubes at designated time points. Blood samples were put on wet ice and centrifuged at 4 °C to obtain plasma within 15 minutes of sample collection.
  • Plasma samples were snap frozen in dry ice for temporary storage and transferred into - 80 °C freezer until analysis. The backup samples were discarded one month after in-life completion.
  • the objective was to determine (amongst other things) the pharmacodynamics of
  • Compound 1 in healthy female and male volunteers (elderly included).
  • the study design included both single ascending dose (SAD) and multiple ascending dose (MAD) where each cohort included a total of 8 subjects.
  • SAD single ascending dose
  • MAD multiple ascending dose
  • Subjects were screened for eligibility within 21 days prior to start of study treatment and according to the following study-specific eligibility criteria.
  • Both the SAD and MAD parts were performed in a randomized and double-blind manner except the first two subjects in the initial dose part.
  • Body Mass Index (BMI) ⁇ 19 and ⁇ 30 kg/m 2 at screening. 4. Healthy male and female subjects aged ⁇ 18 and ⁇ 65 years at screening, or healthy elderly male and female subjects aged > 65 at screening (for one elderly MAD cohort).
  • Female subject must be of non-childbearing potential (defined as pre-menopausal females with a documented tubal ligation or hysterectomy or bilateral oophorectomy; or as post-menopausal females defined as 12 months’ amenorrhoea [in questionable cases a blood sample with simultaneous follicle stimulation hormone 25-140 IE/L and estradiol ⁇ 200 pmol/L is confirmatory]).
  • Part 2 Women of non-childbearing potential were recruited and included in Part 2 (SAD), from cohort 2:2 and onwards. The aim was to have at least two female subjects in each cohort from cohort 2:2, throughout Part 2 (SAD) and in Part 3 (MAD).
  • OTC drugs including herbals, vitamins and minerals
  • Subject has an eGFR ⁇ 90 mL/min/1.73m2 at screening for 18-65 years and an eGFR ⁇ 80 for subjects older than 65 years.
  • SAD study subjects were admitted to the study clinic from the day before dosing (Day -1) and until at least 24 hours post-dosing (Day 2) or longer at the discretion of the Investigator. Subjects returned to the clinic for a follow-up visit during day 6-10.
  • Blood sampling was performed on Day -1 or Day 1 pre-dose; and at estimated Cmax (1 h).
  • the MAD study included four cohorts (per cohort: 6 with dosed with Compound 1 ; 2 dosed with placebo, administrated during 7 consecutive days).
  • the forth cohort was a panel in elderly (> 65 years old) volunteers.
  • the MAD study had the possibility to be extended with two optional cohorts depending on the results from the previous cohorts. No additional cohorts were dosed.
  • the selection of starting dose and dosing regimen was based on safety and tolerability and PK simulations on the data from the first four SAD cohorts. Subjects were enrolled to the subsequent cohorts and dose escalation was based on the safety and pharmacokinetics from previous cohorts.
  • Blood sampling was performed on Day -1 or Day 1 pre-dose; Day 1 at estimated Cmax; Day 2 at estimated Cmax; and Day 7 at estimated Cmax.
  • Compound 1 (2 mg/mL, 5 mg/mL and 10 mg/mL) or placebo was administrated as oral suspension in single dose or as multiple dose for 7 days.
  • Compound 1 or placebo was administrated as drug in capsule 100 mg.
  • the site personnel administrated the IP as a single dose in fasted condition.
  • the total volume of water (250 mL) administered with the IP was adjusted so that all subjects received the same total volume.
  • the maximum time for administration of suspension was 2 minutes from start of administration.
  • the IP was administered in the morning between 08:00 and 11:00.
  • the second dose was administered within a 12- hour interval from the morning dose.
  • Compound 1 was provided from Kancera AB to QPS, Netherlands.
  • the IP was provided as Compound 1 2 mg/mL, 5 mg/mL and 10 mg/mL, or placebo, oral suspensions.
  • Compound 1 or placebo was provided as drug in capsule 100 mg.
  • IP active and placebo
  • the collected human whole blood was stimulated ex vivo in PBS with 110 nM CX3CL1 (fractalkine/FKN) or H20/0.1%BSA (non-stimulated control) for 1 minute.
  • Actin polymerization was assessed in lymphocytes and monocytes by staining of filamentous actin with phalloidin-A488, immunostaining of lymphocyte and monocyte with anti-CD3-PE CY7, anti-CD45 APC-Cy7, anti-CD19 BV421 , anti-HLA-DR PE, anti-CD14 BV510, and anti-CD16 APC and cells were examined using flow cytometry.
  • CX3CR1 on lymphocytes and monocytes was assessed in non-stimulated samples (H20/0.1 % BSA) by surface immunostaining with anti-CX3CR1 PerCp-Cy5.5, immunostaining of lymphocyte and monocyte with anti-CD3-PE CY7, anti-CD45 APC-Cy7, anti-CD19 BV421, anti-CD14-BV510 and anti-CD16 APC and cells were examined using flow cytometry.
  • the objective was to determine subsets of lymphocytes and monocytes expressing fractal kine receptor CX3CR1 (CX3CR1+ cells) and the level (density) of this receptor on the cell surface of these cells in whole blood of healthy subjects treated with Compound 1.
  • One-way Anova was used to study sampled data relationship for frequency of CX3CR1 + cells (%) and surface density (MFI) of the CX3CR1 raw data.
  • a two-tailed parallel t-test analysis was performed on frequency of CX3CR1+ cells (%) and surface density (MFI) of CX3CR1 raw data.
  • a two-tailed unpaired t-test analysis was performed on frequency of CX3CR1+ cells (%) and surface density (MFI) of CX3CR1 normalised data.
  • CM Classical monocytes
  • IM Intermediate monocytes
  • NCM Non-classical monocytes.
  • P values *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001, ****P ⁇ 0.0001.
  • NS stands for not statistically significant.
  • CM Classical monocytes
  • IM Intermediate monocytes
  • NCM Non-classical monocytes.
  • the significance levels are presented by P values. *P ⁇ 0.05, **P ⁇ 0.01 , ***P ⁇ 0.001 , ****P ⁇ 0.0001.
  • NS stands for not statistically significant.
  • MAD Cohort 3 400 mg bid elderly (65 years old and over) subjects Mean baseline normalized -frequency of CX3CR1+ cells and -surface density of CX3CR1 on lymphocytes (NK-cells, T-cells and B-cells) and monocyte subtypes (classical, intermediate and non-classical monocytes) after 300 mg bid in the elderly subject cohort between placebo and Compound 1 treatments are shown in Table 9. A significant decrease in frequency of CX3CR1+ NK and T-cells was observed on days 2 and 7 in Compound 1 treated elderly subjects vs placebo with maximal decrease on day 2 (-99%) for T-cells and day 7 (-30%) for NK cells.
  • CM Classical monocytes
  • IM Intermediate monocytes
  • NCM Non-classical monocytes.
  • the significance levels are presented by P values. *P ⁇ 0.05, **P ⁇ 0.01 , ***P ⁇ 0.001 , ****P ⁇ 0.0001.
  • NS stands for not statistically significant.
  • the ability of the compounds of the invention to decreasing the surface density of CX3CR1 on NK, T-cells and monocytes suggests that they may be useful in modulating the immune response and thereforeare believed to be likely to be useful in the treatment or prevention of an exaggerated host immune response to a viral infection, as defined hereinabove.
  • the fact that the compounds have also been shown to have this effect in the elderly patient group is also significant as it suggests likely utility in this higher risk patient group.

Landscapes

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

Abstract

L'invention concerne un composé de formule (I), dans laquelle R1, R2 et Q1 sont tels que définis dans la description, destiné à être utilisé dans le traitement ou la prévention d'une réponse immunitaire d'hôte exagérée à une infection virale, et des maladies et des troubles provoqués par des infections virales et/ou la réponse immunitaire de l'hôte à celles-ci, y compris la maladie du coronavirus 2019.
PCT/EP2021/062223 2020-05-08 2021-05-07 Nouveaux traitements d'infections virales WO2021224494A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB2006849.0 2020-05-08
GBGB2006849.0A GB202006849D0 (en) 2020-05-08 2020-05-08 New use

Publications (1)

Publication Number Publication Date
WO2021224494A1 true WO2021224494A1 (fr) 2021-11-11

Family

ID=71134892

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2021/062223 WO2021224494A1 (fr) 2020-05-08 2021-05-07 Nouveaux traitements d'infections virales

Country Status (2)

Country Link
GB (1) GB202006849D0 (fr)
WO (1) WO2021224494A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006107258A1 (fr) 2005-04-06 2006-10-12 Astrazeneca Ab NOUVEAUX DÉRIVÉS DE 7-AMINO-[1,3]THIAZOLO[4,5-d]PYRIMIDINE 5 SUBSTITUÉ
WO2006107528A1 (fr) 2005-03-30 2006-10-12 Watson Pharmaceuticals, Inc. Nouvelle formulation pharmaceutique contenant un biguanide et un derive de thiazolidinedione
WO2019219771A1 (fr) 2018-05-15 2019-11-21 Kancera Ab Procédé de préparation stéréosélective de 2-[(hétéro)arylalkylsulfanyl]pyrimidines chirales et produits pouvant être obtenus à partir de celles-ci
WO2020008064A1 (fr) 2018-07-06 2020-01-09 Kancera Ab Dérivés de phosphate et de phosphonate de 7-amino-5-thio-thiazolo[4,5-d]pyrimidines et leur utilisation dans le traitement d'états associés à des niveaux élevés de cx3cr1 et/ou cx3cl1

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006107528A1 (fr) 2005-03-30 2006-10-12 Watson Pharmaceuticals, Inc. Nouvelle formulation pharmaceutique contenant un biguanide et un derive de thiazolidinedione
WO2006107258A1 (fr) 2005-04-06 2006-10-12 Astrazeneca Ab NOUVEAUX DÉRIVÉS DE 7-AMINO-[1,3]THIAZOLO[4,5-d]PYRIMIDINE 5 SUBSTITUÉ
WO2019219771A1 (fr) 2018-05-15 2019-11-21 Kancera Ab Procédé de préparation stéréosélective de 2-[(hétéro)arylalkylsulfanyl]pyrimidines chirales et produits pouvant être obtenus à partir de celles-ci
WO2020008064A1 (fr) 2018-07-06 2020-01-09 Kancera Ab Dérivés de phosphate et de phosphonate de 7-amino-5-thio-thiazolo[4,5-d]pyrimidines et leur utilisation dans le traitement d'états associés à des niveaux élevés de cx3cr1 et/ou cx3cl1

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
ALIJOTAS-REIG JAUME ET AL: "Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: A comprehensive review", AUTOIMMUNITY REVIEWS, ELSEVIER, AMSTERDAM, NL, vol. 19, no. 7, 3 May 2020 (2020-05-03), XP086161711, ISSN: 1568-9972, [retrieved on 20200503], DOI: 10.1016/J.AUTREV.2020.102569 *
ANONYMOUS: "Kanceras drug development projects February 2019", 1 February 2019 (2019-02-01), pages 1 - 19, XP055823904, Retrieved from the Internet <URL:http://media.kancera.com/2019/02/ENGLISH-Project-status-Q4-2019.pdf> [retrieved on 20210713] *
CEDERBLAD LINDA ET AL: "AZD8797 is an allosteric non-competitive modulator of the human CX3CR1 receptor", BIOCHEMICAL JOURNAL, vol. 473, no. 5, 1 March 2016 (2016-03-01), GB, pages 641 - 649, XP055823702, ISSN: 0264-6021, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764977/pdf/bj4730641.pdf> DOI: 10.1042/BJ20150520 *
CHIOH ET AL., MEDRXIV PREPRINT, 18 November 2020 (2020-11-18)
COVID-19 ILLNESS IN NATIVE AND IMMUNOSUPPRESSED STATES: A CLINICAL-THERAPEUTIC STAGING PROPOSAL, Retrieved from the Internet <URL:https://doi.org/10.1016/j.healun.2020.03.012>
ELIFE, vol. 10, 2021, pages e64909
GARAU ET AL., ESC HEART FAILURE, vol. 8, 2021, pages 766 - 773
KANCERA AB: "KAND567-A candidate to counteract hyperinflammation in COVID-19 and heart attack", NATURE, 1 December 2020 (2020-12-01), England, pages B33 - B33, XP055823885, Retrieved from the Internet <URL:https://media.nature.com/original/magazine-assets/d43747-020-01156-3/d43747-020-01156-3.pdf> [retrieved on 20210713], DOI: 10.1039/C7CP08364E *
KARLSTROM ET AL., J. MED. CHEM., vol. 56, 2013, pages 3177 - 3190
RIVAS-FUENTES ET AL., MEDICAL HYPOTHESES, vol. 151, 2021, pages 110570
SOFIA KARLSTR?M ET AL: "Substituted 7-Amino-5-thio-thiazolo[4,5- d ]pyrimidines as Potent and Selective Antagonists of the Fractalkine Receptor (CX 3 CR1)", JOURNAL OF MEDICINAL CHEMISTRY, vol. 56, no. 8, 25 April 2013 (2013-04-25), pages 3177 - 3190, XP055334582, ISSN: 0022-2623, DOI: 10.1021/jm3012273 *
TONG ET AL., THE JOURNAL OF INFECTIOUS DISEASES, vol. 222, 2020, pages 894 - 8

Also Published As

Publication number Publication date
GB202006849D0 (en) 2020-06-24

Similar Documents

Publication Publication Date Title
JPH10513463A (ja) うっ血性心不全の治療へのカルバゾール化合物の利用
JP2012001558A (ja) ロテプレドノールと抗ヒスタミン薬の新規な組み合わせ物
KR100445946B1 (ko) 폐고혈압 치료법
JP2020507610A (ja) 腸管外症状を伴う炎症性腸疾患の治療のための化合物および方法
TW202203917A (zh) 治療細胞激素釋放症候群之方法
US20220211674A1 (en) Thromboxane Receptor Antagonists in AERD/Asthma
CA2605923C (fr) Utilisation d&#39;antagonistes d&#39;oxytocine et/ou de vasopressine
US20210353648A1 (en) Grapiprant unit dosage forms
US20230151093A1 (en) Methods of treating immune mediated pulmonary injury
WO2021224494A1 (fr) Nouveaux traitements d&#39;infections virales
WO2023025220A1 (fr) Composition pharmaceutique d&#39;ibuprofène et d&#39;antagoniste d&#39;ions calcium, et application
JP2024519835A (ja) タウロデオキシコール酸またはその薬学的に許容される塩を有効成分として含む新型コロナウイルス感染症（ｃｏｖｉｄ－１９）の治療用組成物
KR20210126515A (ko) 니클로사마이드를 포함하는 폐고혈압의 예방 및 치료용 조성물
WO2015160249A2 (fr) Utilisation d&#39;énoximone pour le traitement d&#39;affections topiques associées au système immunitaire, dans une composition pharmaceutique ainsi que dans une préparation pharmaceutique
WO2023220396A1 (fr) Procédés de traitement utilisant un inhibiteur de kinase 1a à double spécificité régulée par la phosphorylation de la tyrosine (dyrk1a)
US20230089371A1 (en) Combination comprising alpelisib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid
TW202245742A (zh) 預防、治療或改善潰瘍性結腸炎的方法
WO2005063253A1 (fr) Composition medicinale pour le traitement de symptomes allergiques
JP2024535095A (ja) タウロデオキシコリン酸またはその薬学的に許容可能な塩および抗ウイルス剤を有効成分として含有するコロナウイルス感染症－１９（ｃｏｖｉｄ－１９）治療用組成物
AU2022342537A1 (en) Pharmaceutical composition for treating solid tumors
WO2020207355A1 (fr) Composition pharmaceutique contenant de l&#39;amlodipine, de la chlortalidone et de l&#39;amiloride
TW202339727A (zh) 使用１ｈ－１，２，３－三唑－４－羧酸之治療方法
CN117479936A (zh) 用奥瑞司特治疗化脓性汗腺炎
MOTION Rick Hansen
JPH10513472A (ja) 心臓血管疾患の治療を目的とするアンギオテンシン変換酵素抑制物質、副作用軽減量のアルドステロン拮抗物質および利尿剤のコンビネーション療法

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: 21724670

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: 21724670

Country of ref document: EP

Kind code of ref document: A1