WO2021204923A1 - Antiviral agents - Google Patents
Antiviral agents Download PDFInfo
- Publication number
- WO2021204923A1 WO2021204923A1 PCT/EP2021/059133 EP2021059133W WO2021204923A1 WO 2021204923 A1 WO2021204923 A1 WO 2021204923A1 EP 2021059133 W EP2021059133 W EP 2021059133W WO 2021204923 A1 WO2021204923 A1 WO 2021204923A1
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- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- pharmaceutically acceptable
- methyl
- acceptable salt
- Prior art date
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- 239000003443 antiviral agent Substances 0.000 title claims description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 230
- 241000711573 Coronaviridae Species 0.000 claims abstract description 28
- 230000009385 viral infection Effects 0.000 claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 73
- 150000002367 halogens Chemical class 0.000 claims description 72
- 150000003839 salts Chemical class 0.000 claims description 53
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 48
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 47
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 26
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 22
- 239000013543 active substance Substances 0.000 claims description 19
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 18
- 244000309467 Human Coronavirus Species 0.000 claims description 15
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 14
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- 241001678559 COVID-19 virus Species 0.000 claims description 10
- ODESSNQHGYOCNW-UHFFFAOYSA-N ClC=1C=C(C#N)C=CC=1N1CCN(CC1)C(=O)C1=C(N=NN1C)C1=C(C=CC=C1OC)OC Chemical compound ClC=1C=C(C#N)C=CC=1N1CCN(CC1)C(=O)C1=C(N=NN1C)C1=C(C=CC=C1OC)OC ODESSNQHGYOCNW-UHFFFAOYSA-N 0.000 claims description 10
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
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- WRIJBJUYZHAWHU-UHFFFAOYSA-N [4-(2-chloro-4-nitrophenyl)piperazin-1-yl]-[5-(2,6-dimethoxyphenyl)-3-methyltriazol-4-yl]methanone Chemical compound COC1=CC=CC(OC)=C1C1=C(C(=O)N2CCN(CC2)C=2C(=CC(=CC=2)[N+]([O-])=O)Cl)N(C)N=N1 WRIJBJUYZHAWHU-UHFFFAOYSA-N 0.000 claims description 7
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 7
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- GRUCZKGGAPJFPL-UHFFFAOYSA-N [4-(2-chloro-4-nitrophenyl)piperazin-1-yl]-[5-(2,6-dimethoxyphenyl)-3-methyltriazol-4-yl]methanethione Chemical compound COC1=CC=CC(OC)=C1C1=C(C(=S)N2CCN(CC2)C=2C(=CC(=CC=2)[N+]([O-])=O)Cl)N(C)N=N1 GRUCZKGGAPJFPL-UHFFFAOYSA-N 0.000 claims description 6
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- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 5
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- FNXYZOLJMOAKIU-UHFFFAOYSA-N [4-(2-chloro-4-nitrophenyl)piperazin-1-yl]-(5-methyl-3-phenyl-1,2-oxazol-4-yl)methanethione Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C(=S)N(CC1)CCN1C1=CC=C([N+]([O-])=O)C=C1Cl FNXYZOLJMOAKIU-UHFFFAOYSA-N 0.000 claims description 2
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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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to compounds for use as antiviral agents, in particular as antivi ral agents in the treatment of coronavirus infections.
- Coronaviruses constitute the subfamily Orthocoronavirinae , in the family Coronaviridae, or der Nidovirales, and realm Riboviria. They are enveloped viruses with a positive-sense sin gle-stranded RNA genome and a nucleocapsid of helical symmetry, having a genome size of coronaviruses ranging from approximately 27 to 34 kilobases.
- SARS-CoV severe Acute Respiratory Syndrome-Corona Virus
- SARS-CoV-1 SARS-CoV-1
- HCoV-NL63 and HCoV-HKU1 were discovered in 2004 and in 2005, respectively, causing more severe lower respiratory tract infections like bronchiolitis and pneumonia, especially in young children, im munocompromised patients and the elderly.
- a first aspect is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is C, Y is O, and Z is C,
- X is C, Y is N, and Z is N, or X is N, Y is N, and Z is C;
- W is O or S; each Ri is independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen;
- R 2 is H or C1-C4 alkyl; each R3 is independently selected from nitro, cyano, C1-C4 alkyl; C1-C4 alkoxy, hydroxy and halogen; m is an integer of from 0 to 3; and n is an integer of from 1 to 3; for use in the treatment of a Coronaviridae virus infection.
- a further aspect relates to improved processes for preparing intermediates useful in the syn thesis of compounds of formula (I).
- a further aspect is compound of formula (I) or salt thereof for use as defined herein, in com bination with at least one further therapeutically active agent.
- a further aspect is a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable ex cipient, for use in the treatment of a Coronaviridae virus infection.
- a further aspect is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a Coronaviridae virus infec tion.
- a further aspect is a method for the treatment of a Coronaviridae virus infection, by admin istration of a therapeutically effective amount of a compound of formula (I) or a pharmaceuti cally acceptable salt thereof to a patient need thereof.
- a further aspect is a kit-of-parts comprising
- (B) a further therapeutically active agent in a pharmaceutical formulation; and a package insert with instructions for the combined use of components (A) and (B), for use in the treatment of a Coronaviridae virus infection.
- X is C
- Y is O
- Z is C
- X is C, Y is N, and Z is N, or X is N, Y is N, and Z is C;
- W is O or S
- Ri is selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen; each Ri a is independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen;
- R 2 is H or C1-C4 alkyl; each R3 is independently selected from nitro, cyano, C1-C4 alkyl; C1-C4 alkoxy, hydroxy and halogen; m is 2 or 3; and n is an integer of from 1 to 3.
- a further aspect is a process for preparing a compound of formula (Iq).
- a still further aspect is a compound of formula (Iq) for use in therapy.
- a still further aspect is a pharmaceutical composition
- a pharmaceutical composition comprising the compound of formula (Iq) and optionally a pharmaceutically acceptable excipient.
- a further aspect is compound of formula (Iq) or salt thereof for use as defined herein, in com bination with at least one further therapeutically active agent.
- a further aspect is a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (Iq), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable ex cipient, for use in the treatment of a Coronaviridae virus infection.
- a further aspect is the use of a compound of formula (Iq) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a Coronaviridae virus infection.
- a further aspect is a method for the treatment of a Coronaviridae virus infection, by admin istration of a therapeutically effective amount of a compound of formula (Iq) or a pharmaceu tically acceptable salt thereof to a patient need thereof.
- Figure 1 is a bar chart showing number of SARS-CoV-2 virus plaques formed in a plaque re duction assay at different concentrations (in mM) of three different compounds of formula (I), compared to untreated control.
- Comp. A is 3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1-methyl- 1 H-1 ,2,3-triazole-5-carbonyl)piperazin-1-yl)benzonitrile;
- Comp. B is (4-(2-chloro-4-nitro- phenyl)piperazin-1 -yl)(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol-5-yl)methanone; and Comp.
- C is (4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(4-(2,6-dimethoxyphenyl)-1 -methyl- 1 H-1 ,2,3-triazol-5-yl)methanethione.
- Figure 2 is a bar chart showing number of SARS-CoV-2 virus plaques formed in a plaque re duction assay at different concentrations (in pM) of three different compounds of formula (I), compared to untreated control.
- Comp. A is 3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1-methyl- 1 H-1 ,2,3-triazole-5-carbonyl)piperazin-1-yl)benzonitrile;
- Comp. B is (4-(2-chloro-4-nitro- phenyl)piperazin-1 -yl)(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol-5-yl)methanone; and Comp.
- C is (4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(4-(2,6-dimethoxyphenyl)-1 -methyl- 1 H-1 ,2,3-triazol-5-yl)methanethione.
- Figure 3 is a graph showing the % of live MDCK cells (Madin-Darby Canine Kidney cells) in the presence of different concentrations (in mM) of two different compounds of formula (I), or DMSO, in a cytotoxicity assay.
- Comp. A is 3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1-methyl- 1H-1,2,3-triazole-5-carbonyl)piperazin-1-yl)benzonitrile; and Comp.
- B is (4-(2-chloro-4-nitro- phenyl)piperazin-1 -yl)(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol-5-yl)methanone.
- “Pharmaceutically acceptable” means being useful in preparing a pharmaceutical composi tion that is generally safe for the intended therapeutic use, and neither biologically nor other wise undesirable, and includes being useful for veterinary use as well as human pharmaceu tical use.
- treating may refer to ameliorating the dis ease or disorder (i.e. , arresting or reducing the development of the disease or at least one of the clinical symptoms thereof), and/or ameliorating at least one physical parameter, which may not be discernible by the patient.
- the term also may refer to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
- treating a disease generally also encompasses preventing the disease.
- preventing refers to preventing and/or delaying the onset of a disease, disorder and/or clinical symptom(s) in a subject and/or a reduction in the severity of the onset of the disease, disorder and/or clinical symptom(s) relative to what would occur in the absence of the preventive activity (e.g. administration of a compound as defined herein in an amount effective to cause a preventive effect).
- the prevention can be complete, e.g., the total absence of the disease, disorder and/or clinical symptom(s).
- the prevention can also be partial, such that the occurrence of the disease, disorder and/or clinical symptom(s) in the subject and/or the severity of onset and/or the time period of symptoms is less than what would occur in the absence of the preventive activity.
- an “effective amount” refers to an amount of a compound that has a therapeutic or preven tive effect on a disorder in a treated subject.
- the therapeutic or preventive effect may be ob jective (i.e. , measurable by some test or marker, e.g. no measurable virus titer in a biological sample from the treated subject) or subjective (i.e., subject gives an indication of or feels an effect).
- excipient refers to a pharmaceutically acceptable chemical, such as known to those of ordinary skill in the art of pharmacy to aid the administration of a medicinal agent. It is a compound that is useful in preparing a pharmaceutical composition, generally safe, non toxic and neither biologically nor otherwise undesirable, and includes excipients that are ac ceptable for veterinary use as well as human pharmaceutical use. Exemplary excipients in clude binders, surfactants, diluents, disintegrants, antiadherents, and lubricants.
- a “viral infection” or “virus infection” refers to an infection by a virus in a bird or a mammal.
- a “Coronaviridae virus infection” means an infection with a virus belonging to the Coronaviridae virus family, more particularly the Orthocoronavirinae subfamily.
- mammal refers to a human or any mammalian animal, e.g. a primate, a farm ani mal, a pet animal, or a laboratory animal. Examples of such animals are monkeys, cows, sheep, goats, horses, pigs, dogs, cats, rabbits, mice, rats etc.
- the mammal is a human.
- the mammal is an animal, e.g. a farm animal, such as a cow, sheep, goat, horse, or pig.
- the animal is a pet, e.g. a dog, a cat, or a rabbit.
- a “bird” as referred to herein e.g. may be poultry, a cage bird or a pet bird.
- C1-C4 alkyl denotes a straight or branched alkyl group having from 1 to 4 carbon atoms, e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl.
- halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
- C1-C4 alkoxy refers to a moiety of formula RO, i.e.
- R'° wherein R is C1-C4 alkyl.
- cyano refers to a moiety of formula NoC — !
- hydroxy refers to a moiety of formula HO— I
- nitro refers to a moiety of formula
- a compound of formula (I) as herein defined contains a 5-membered heteroaromatic ring of formula (II) wherein
- X is C
- Y is O
- Z is C
- X is C, Y is N, and Z is N, or X is N, Y is N, and Z is C.
- X is C, Y is N, and Z is N, or X is N, Y is N, and Z is C.
- Y is N.
- the com pound of formula (I) is a compound of formula (la) wherein X, Z, W, each Ri, R 2 , each R 3 , m and n are as defined herein.
- the compound of formula (I) more particularly is a compound of formula (lb) wherein W, Ri, R 2 , R 3 , m and n are as defined herein.
- W is O or S. In some embodiments, W is O.
- the compound of formula (I) more particularly is a compound of formula (lc) wherein X, Y, Z, Ri, R 2 , R 3 , m and n are as defined herein.
- the compound of formula (I) more particularly is a compound of formula (Id) wherein X, Y, Z, Ri, R 2 , R 3 , m and n are as defined herein.
- each moiety Ri is independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen.
- each moiety Ri is independently selected from C1-C4 alkyl, C1-C4 alkoxy, and halogen.
- each moiety Ri is independently selected from C1-C4 alkoxy, hy droxy and halogen.
- each moiety Ri is independently selected from C1-C4 alkyl and C1- C4 alkoxy.
- each moiety Ri is independently selected from C1-C4 alkoxy, and halogen.
- each moiety Ri is independently selected from C1-C4 alkoxy.
- said C1-C4 alkyl particularly is C1-C3 alkyl, or more particularly methyl or ethyl, e.g. methyl.
- said C1-C4 alkoxy particularly is C1-C3 alkoxy, or more particularly C1-C2 alkoxy, even more particularly methoxy.
- Ri when Ri is halogen, said halogen is selected from F, Cl, Br and I; e.g. from F, Cl, and Br, or from F and Cl, or from Cl and Br. In some embodiments, when Ri is halogen, said halogen is Cl. In some embodiments, when Ri is halogen, said halogen is F. In a compound of formula (I) as defined herein, R2 is H or C1-C4 alkyl.
- R2 is H or C1-C3 alkyl. In some embodiments, R2 is H, methyl or ethyl; e.g. H or methyl.
- R2 is C1-C4 alkyl, e.g. C1-C3 alkyl. In some embodiments, R2 is me thyl or ethyl. In some embodiments, R2 is methyl.
- each moiety R3 is independently selected from nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen.
- each moiety R3 is independently selected from nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, and halogen.
- each moiety R3 is independently selected from nitro, cyano, C1-C4 alkoxy, hydroxy and halogen.
- each moiety R3 is independently selected from nitro, cyano, C1-C4 alkyl, hydroxy and halogen.
- each moiety R3 is independently selected from nitro, cyano, C1-C4 alkyl, and halogen.
- each moiety R3 is independently selected from nitro, cyano, C1-C4 alkoxy, and halogen.
- each moiety R3 is independently selected from nitro, cyano, hydroxy and halogen.
- each moiety R3 is independently selected from nitro, cyano, and halo gen.
- each moiety R3 is independently selected from nitro and halogen.
- each moiety R3 is independently selected from cyano and halogen.
- said C1-C4 alkyl particularly is C1-C3 alkyl, or more particularly methyl or ethyl, e.g. methyl.
- said C1-C4 alkoxy particularly is C1-C3 alkoxy, or more particularly methoxy or ethoxy, even more particularly methoxy.
- said halogen is selected from F, Cl, Br and I; e.g. from F, Cl, and Br, or from F and Cl, or from Cl and Br. In some embodiments, when R 3 is halogen, said halogen is Cl.
- m is an integer 0, 1 , 2 or 3, denoting the number of moieties Ri present in the compound.
- m is 0, 1 , or 2; e.g. m is 1 or 2.
- m is 1 , 2, or 3; e.g. m is 2 or 3.
- m is 2.
- a compound of formula (I) more particularly may be represented by formula (le) wherein m is 2 or 3; each Ri a is independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen; and X, Y, Z, W, Ri, R 2 , each R 3 , and n are as defined herein.
- each moiety Ri a is independently se lected from C1-C4 alkyl, C1-C4 alkoxy, and halogen.
- each moiety Ri a is independently selected from C1-C4 alkoxy, hy droxy and halogen. In some embodiments, each moiety Ri a is independently selected from C1-C4 alkyl and C1- C4 alkoxy.
- each moiety Ri a is independently selected from C1-C4 alkoxy, and halogen.
- each moiety Ri a is independently selected from C1-C4 alkoxy.
- Ri a when Ri a is C1-C4 alkyl, said C1-C4 alkyl particularly is C1-C3 alkyl, or more particularly methyl or ethyl.
- Ri a is C1-C4 alkoxy
- said C1-C4 alkoxy particularly is C1-C3 alkoxy, or more particularly C1-C2 alkoxy, even more particularly methoxy.
- Ri a when Ri a is halogen, said halogen is selected from F, Cl, Br and I; e.g. from F, Cl, and Br, or from F and Cl, or from Cl and Br. In some embodiments, when Ri a is halogen, said halogen is Cl. In some embodiments, when Ri a is halogen, said halogen is F.
- m is 2, i.e. the compound of more par ticularly may be represented by formula (If) wherein X, Y, Z, W, each Ri a , R 2 , each R 3 , and n are as defined herein.
- n is an integer 1, 2 or 3 that denotes the number of moieties R3 present in the compound. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 2. In some embodiments, the compound of formula (I) more particularly is a compound of for mula (Ig) wherein R3 a is selected from nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen; and X, Y, Z, W, each Ri, R 2 , each R 3 , m and n are as defined herein.
- R3 a is selected from nitro, cyano, C1- C4 alkoxy, hydroxy and halogen.
- R3 a is selected from nitro, cyano, C1- C4 alkyl, C1-C4 alkoxy, and halogen.
- R3 a is selected from nitro, cyano, C1- C4 alkoxy, and halogen.
- R3 a is selected from nitro, cyano, and halogen.
- R3 a is selected from nitro, cyano, C1- C4 alkyl, C1-C4 alkoxy, and hydroxy.
- R3 a is selected from nitro, cyano, and C1-C4 alkoxy.
- R3 a is selected from nitro and cyano. In some embodiments of a compound of formula (Ig), R3 a is nitro.
- R3 a is cyano.
- said C1-C4 alkyl particularly is C1-C3 alkyl, or more particularly methyl or ethyl, e.g. methyl.
- R3 a is C1-C4 alkoxy
- said C1-C4 alkoxy particularly is C1-C3 alkoxy, or more particularly methoxy or ethoxy, even more particularly methoxy.
- R3 a when R3 a is halogen, said halogen is selected from F, Cl, Br and I; e.g. from F, Cl, and Br, or from F and Cl, or from Cl and Br. In some embodiments, when R3 a is halogen, said halogen is Cl.
- the compound of formula (I) more particularly is a compound of formula (Ih) wherein n is 2 or 3;
- R3 b is selected from nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen; and X, Y, Z, W, each Ri, R2, R3, R3 a , and are as defined herein.
- R3 b is selected from C1-C4 alkyl, C1- C4 alkoxy, hydroxy and halogen.
- R3 b is selected from C1-C4 alkoxy, hy droxy and halogen.
- R3 b is selected from C1-C4 alkyl, C1- C4 alkoxy, and halogen.
- R3 b is selected from C1-C4 alkyl, and halogen. In some embodiments of a compound of formula (Ih), R3 b is selected from C1-C4 alkoxy, and halogen.
- R3 b is halogen
- R3 b is C1-C4 alkyl
- said C1-C4 alkyl particularly is C1-C3 alkyl, or more particularly methyl or ethyl.
- R3 b is C1-C4 alkoxy
- said C1-C4 alkoxy particularly is C1-C3 alkoxy, or more particularly methoxy or ethoxy, even more particularly methoxy.
- R3 b when R3 b is halogen, said halogen is selected from F, Cl, Br and I; e.g. from F, Cl, and Br, or from F and Cl, or from Cl and Br.
- R3 b when R3 b is halogen, said halogen is Cl.
- n is 2, i.e. the compound of formula (Ih) more particularly may be represented by formula (Ij) wherein X, Y, Z, W, each Ri, R2, R3 a , R3 b and m are as defined herein.
- the compound of formula (le) is also a compound of for mula (Ig)
- the compound of formula (I) is as represented by formula (Ik) wherein m is 2 or 3, e.g. m is 2;
- X, Y, Z, W, Ri, each Ri a , R 2 , each R 3 , R 3a , and n are as defined herein.
- the compound of formula (I) is as represented by formula (Im) wherein m is 2 or 3, e.g. m is 2; n is 2 or 3, e.g. n is 2; and
- X, Y, Z, W, Ri, each Ri a , R 2 , R 3 , R 3a , and R 3b are as defined herein.
- the compound of formula (If) is also a compound of for- mula (Ij)
- the compound of formula (I) is as represented by formula (In) wherein X, Y, Z, W, each Ri a , R 2 , R 3a , and R 3b are as defined herein.
- the compound of formula (In) is also a compound of for mula (la), i.e. a compound that may be represented by formula (lo) wherein X, Z, W, each Ri a , R2, R3 a , and R3 b are as defined herein.
- the compound of formula (In) is also a compound of formula (lb), i.e. a compound that may be represented by formula (Ip) wherein W, each Ri a , R2, R3 a , and R3 b are as defined herein.
- the compound for use as described herein is selected from: 3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1 , 2, 3-triazole-5-carbonyl)piperazin-1- yl)benzonitrile,
- the compound for use as defined herein is selected from: 3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazole-5-carbonyl)piperazin-1- yl)benzonitrile,
- the compound for use as defined herein is selected from: 3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazole-5-carbonyl)piperazin-1- yl)benzonitrile,
- Compounds of formula (I) may also be prepared by a method as illustrated in Reaction Scheme 1, involving a Suzuki coupling reaction of compound 1 with compound 2, to give compound 3, followed by carbonylation of compound 3 using CO2 in the presence of a base such as LDA at a temperature of about 0°C, to give compound 4, and further reacting com pound 4 in a multi-step procedure as generally described in WO 2013/171334 (vide supra), to provide a compound of formula (I) as defined herein.
- Reaction Scheme 1 involving a Suzuki coupling reaction of compound 1 with compound 2, to give compound 3, followed by carbonylation of compound 3 using CO2 in the presence of a base such as LDA at a temperature of about 0°C, to give compound 4, and further reacting com pound 4 in a multi-step procedure as generally described in WO 2013/171334 (vide supra), to provide a compound of formula (I) as defined herein.
- a further aspect therefore is a process for preparing a compound of formula (V), by reacting a compound of formula (III) with a compound of formula (IV), wherein X, Y, Z, each Ri, R2 and m are as defined herein, in the presence of a palladium-containing catalyst, such as tetrakis (triphenylphosphine)palla- dium, and in the presence of a base, such as potassium carbonate.
- a palladium-containing catalyst such as tetrakis (triphenylphosphine)palla- dium
- the compound of formula (V) may be used as an intermediate in the synthesis of a com pound of formula (I) as defined herein.
- WO 2013/171334 describes car- bonylation of a compound of the type of formula (V) with CO2 in the presence of a base, such as lithium diisopropylamide (LDA), at a reaction temperature of -70°C or lower.
- a base such as lithium diisopropylamide (LDA)
- carbonylation of the compound of formula (V) may suitably be performed by performing such carbonylation reaction at a substantially higher temperature, viz. at a temperature of about 0°C.
- a substantially higher temperature viz. at a temperature of about 0°C.
- Such reaction temperature provides a reaction mixture having improved characteristics, e.g. of being much easier to stir, which is considered very advantageous for large scale production. Indeed, at the lower temperature of -70°C, the re action mixture formed a thick slurry, which is avoided at the higher temperature.
- a further aspect therefore is a process for preparing a compound of formula (VI), by reacting a compound of formula (V) with CO2 in the presence of a base, such LDA, at a temperature of about 0°C, wherein X, Y, Z, each Ri, R2 and m are as defined herein.
- the compound of formula (VI) is an intermediate in the synthesis of a compound of formula (I) as defined herein.
- a still further aspect therefore is a process for preparing a compound of formula (VI), by re acting a compound of formula (III) with a compound of formula (IV), in the presence of a pal ladium based catalyst, such as tetrakis (triphenylphosphine)palladium and in the presence of a base, such as potassium carbonate, to obtain a compound of formula (V) and reacting the obtained compound of formula (V) with CO2 in the presence of a base, such as LDA, at a temperature of about 0°C, to obtain a compound of formula (VI), wherein X, Y, Z, each Ri, R2 and m are as defined herein.
- a pal ladium based catalyst such as tetrakis (triphenylphosphine)palladium
- a base such as potassium carbonate
- a further aspect is a novel compound as defined in any one of formulas (Ik), (Im), (In), (lo) or (Ip), wherein R3 a is cyano.
- X, Y, Z, W, Ri, each Ri a , R 2 , each R 3 , and n are as defined herein.
- a novel compound is provided which is a compound of for mula (Im) wherein R 3a is cyano, i.e. a compound according to formula (Ir) wherein m is 2 or 3, e.g. m is 2; n is 2 or 3, e.g. n is 2; and X, Y, Z, W, Ri, each Ri a , R2, R3, and R 3b .
- the compound of formula (Ir) more particularly is a compound of formula (Is) wherein X, Y, Z, W, each Ri a , R2, and R 3b are as defined herein.
- a compound of formula (Is) more particularly may be represented by for mula (It) wherein X, Z, W, each Ri a , R2, and R 3b are as defined herein.
- each Ri a is inde pendently selected from C1-C4 alkoxy and halogen, or from C1-C3 alkoxy and halogen, e.g. from methoxy and halogen, such as from methoxy and F; and R3 b is halogen, e.g. Cl or Br, in particular Cl.
- each Ri a is inde pendently selected from C1-C4 alkoxy, or from C1-C3 alkoxy, e.g. each is methoxy; and R3 b is halogen, e.g. Cl or Br, in particular Cl.
- the novel compound is one as represented by formula (lu) wherein X, Z, W and R2 are as defined herein.
- X is N and Z is C. In some embodiments of a compound of formula (Iq), (Ir), (Is), (It), or (lu), X is C and Z is N.
- W is O. In some other embodiments of a compound of formula (Iq), (Ir), (Is), (It), or (lu), W is S. In some embodiments, a compound of formula (Iv) is provided, wherein W is as defined herein. In some embodiments, W is S, i.e. the compound is 3- chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1 , 2, 3-triazole-5-carbonothioyl)piperazin-1- yl)benzonitrile. In some further embodiments, W is O, i.e. the compound is 3-chloro-4-(4-(4- (2, 6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazole-5-carbonyl)piperazin-1-yl)benzonitrile.
- a further aspect is a process for preparing a compound of formula (Iq)
- n 2 or 3, e.g. m is 2;
- X, Y, Z, W, Ri, each Ri a , R 2 , each R 3 , and n are as defined herein, by: reacting a compound of formula (III) with a compound of formula (IVa) to obtain a compound of formula (Va) reacting a compound of formula (Va) with CO2 in the presence of a base, such as LDA, pref erably at a temperature of about 0°C; to obtain a compound of formula (Via) reacting a compound of formula (Via) with SOCI2, to obtain a compound of formula (VII)
- a reference to a compound of formula (Iq) made herein should also be understood as a reference to any of the embodiments of such compound, e.g. as illustrated by any one of the formulas (Ir), (Is), (It), (lu) and (Iv).
- a pharmaceutically acceptable salt of the compound of formula (I) examples include those derived from mineral acids, such as hy drochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, suc cinic, and arylsulfonic acids.
- mineral acids such as hy drochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids
- organic acids such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, suc cinic, and arylsulfonic acids.
- the pharmaceutical composition provided herein may be for enteral administration, such as rectal or oral administration, or for parenteral administration to a mammal (especially a hu man) and comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as active ingredient, optionally in association with a pharmaceutically acceptable excipient, e.g. a pharmaceutically acceptable carrier.
- enteral administration such as rectal or oral administration
- parenteral administration to a mammal (especially a hu man) and comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as active ingredient, optionally in association with a pharmaceutically acceptable excipient, e.g. a pharmaceutically acceptable carrier.
- the therapeutically effective amount of the active ingredient is as defined herein above and depends e.g. on the body weight of the treated subject, the age, the individual condition, indi vidual pharmacokinetic data, and the mode of administration.
- the compound of formula (I) may be formulated in a wide variety of dosage forms.
- the pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, lozenges, capsules, cachets, suppositories, and dispersible granules.
- a solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
- the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely di vided active component.
- the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
- suitable carriers include but are not limited to magnesium carbonate, mag nesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methyl- cellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
- liquid form preparations including emul sions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.
- Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions, or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia.
- Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents.
- Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
- Solid form preparations include solutions, suspen sions, and emulsions, and may contain, in addition to the active component, colorants, fla vors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubiliz ing agents, and the like.
- compositions for rectal administration include suppositories which can contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
- a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
- the compound of formula (I) also may be administered parenterally, e.g. by injection or infu sion, e.g. by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intracere- broventricular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial, intratumoral, intracutaneous, intraperitoneal and subcutaneous injection or infusion, by pulmonary admin istration, by inhalation administration or by nasal administration.
- the pharmaceutical compositions may be in the form of a sterile injectable or infusi ble preparation, for example, as a sterile aqueous or oleaginous suspension.
- This suspen sion may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80), and suspending agents.
- compositions for pulmonary administration include liquid solutions or powders, for administration in an aerosolized or nebulized form, contain, for example, non-irritating excipi ents to enable formation of droplets and particle sizes, which enable an effective dispersion of the drug into the deeper parts of the lungs.
- suitable pharmaceutical formulations are as particles, aerosols, powders, mists or droplets, e.g. with an average size of about 10 pm in diameter or less.
- compositions for inhalation may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.
- the sterile injectable or infusible preparation may also be a sterile injectable or infusible solu tion or suspension in a non-toxic parenterally acceptable diluent or solvent.
- the pharmaceutical composition may be a solution in 1,3-butanediol.
- accepta ble vehicles and solvents that may be employed in the compositions of the present invention include, but are not limited to, mannitol, water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspend ing medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as ol ive oil or castor oil, especially in their polyoxyethylated versions.
- oils such as ol ive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or sus pensions may also contain a long-chain alcohol diluent or dispersant.
- Suitable stabilizing agents include antioxidizing agents, such as sodium bisulfate, sodium sulfite or ascorbic acid, either alone or combined, citric acid and its salts and sodium EDTA.
- Suitable stabilizing agents may also contain preservatives, such as ben- zalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
- the pharmaceutical compositions may comprise from approximately 1 % to approximately 95%, preferably from approximately 20 % to approximately 90 % of a compound of formula (I), together with at least one pharmaceutically acceptable excipient.
- the com pounds of formula (I) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
- Also provided herein is a method for the treatment of a viral infection, by administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically accepta ble salt thereof to a patient need thereof.
- the dosage level and frequency will generally be as determined by the treating physician, with due regard to factors such as and the sex, age, corporal weight and relative health of the treated subject, the state of progression of the viral disease, the selected route and form of administration, the additional use of other drugs, e.g. in a combination therapy.
- a daily dosage ranging from a minimum of 0.001 mg/kg body weight, or 0.002 mg/kg body weight or 0.005 mg/kg body weight or 0.01 mg/kg body weight, to a maximum of 1000 mg/kg body weight, or 100 mg/kg body weight, or 50 mg/kg body weight, or 10 mg/kg body weight, or 5 mg/kg body weight, or 2 mg/kg body weight, or 1 mg/kg body weight may be contemplated.
- the compound of formula (I) preferably is administrated on a daily basis during the treatment period, e.g. 1-3 times a day, or 1-2 times a day, such as once daily.
- the drug is administrated on a less frequent basis, e.g. every two days, once a week etc.
- the compound of formula (I) is used in combination with at least one further therapeutically active agent, e.g. a further antiviral agent, an antibiotic agent, an anti inflammatory agent, an analgesic agent (a “pain-killer”), or an antipyretic agent (a fever-re ducing agent).
- a further antiviral agent e.g. selected from ribavirin, remdesivir, lopinavir, and ritonavir, or chloroquine or hydroxychloroquine.
- the compound of formula (I) is used in combination with an antibiotic, such an antibiotic selected from macrolide antibiotics, e.g. azithromycin (Zithromax) or clarithromycin (Biaxin XL); tetracycline antibiotics, e.g. doxycycline; fluoroquinolone antibiot ics, e.g. levofloxacin (Levaquin); or combined antibiotics therapy of a beta-lactam such as amoxicillin or amoxicillin/clavulanate (Augmentin) with a macrolide antibiotic.
- an antibiotic such as macrolide antibiotics, e.g. azithromycin (Zithromax) or clarithromycin (Biaxin XL); tetracycline antibiotics, e.g. doxycycline; fluoroquinolone antibiot ics, e.g. levofloxacin (Levaquin); or combined antibiotics therapy of a beta-lactam such as am
- the compound of formula (I) is used in combination with an anti-in flammatory agent, such as a nonsteroidal anti-inflammatory drug (NSAID), e.g. selected from aspirin, ibuprofen, and naproxen.
- an anti-in flammatory agent such as a nonsteroidal anti-inflammatory drug (NSAID), e.g. selected from aspirin, ibuprofen, and naproxen.
- NSAID nonsteroidal anti-inflammatory drug
- the compound of formula (I) is used in combination with an antipyretic and/or analgesic (antiphlogistic) agent, such as paracetamol.
- an antipyretic and/or analgesic (antiphlogistic) agent such as paracetamol.
- a combination comprising a compound of for mula (I) as defined herein and at least one further therapeutically active compound e.g. se lected from a further antiviral agent, an antibiotic agent, an anti-inflammatory agent, an anal gesic agent (a “pain-killer”), or an antipyretic agent (a fever-reducing agent).
- a further antiviral agent e.g. se lected from a further antiviral agent, an antibiotic agent, an anti-inflammatory agent, an anal gesic agent (a “pain-killer”), or an antipyretic agent (a fever-reducing agent).
- combination as used herein is meant that the compound of formula (I) and the further therapeutically active agent(s) may be administered simultaneously in one and the same for mulation or in separate formulations.
- the combination of the compound of formula (I) and the further agent further includes administration of the two or more compounds separately, e.g. sequentially or at different time points.
- kits which may also referred to as a kit-of-parts
- a kit-of-parts com prising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a suitable pharmaceutical formulation, and a package insert with instructions for use of the compound together with at least one further therapeutically active agent, e.g. one such as mentioned herein above.
- a kit is useful for the treatment of a viral infection, e.g. a viral infection as mentioned herein.
- a kit comprising:
- the patient treated herein is one in need of antiviral treatment.
- the patient has been tested for virus infection and found to be infected by a virus, such as a virus belonging to the Coronaviridae virus family.
- the patient is one suffer ing from one or more symptoms of coronavirus infection, such as fever, coughing, headache, respiratory distress, pneumonia, etc.
- the patient is a subject belong ing to a risk group, e.g.
- an elderly subject an immunocompromised subject, a subject suffer ing from an underlying health problem, such as diabetes, a long-term respiratory condition such as asthma or COPD, a long-term coronary condition, such as a person with weak heart or carrying a pacemaker, etc.
- the treated subject is one having come into contact with someone carrying the viral infection.
- treatment is prophylactic.
- the virus treated according to the present invention belongs to the virus belonging to the Coronaviridae virus family, more particularly the Orthocoronavirinae subfamily.
- the virus is a human coronavirus.
- the human coronavirus is selected from HCoV-NL63, HCoV-OC43, HCoV-229E, HCoV-HKlM, SARS-CoV (Severe Acute Respiratory Syndrome-Corona Virus), SARS-CoV-2, and CoV MERS (Middle East Respiratory Syndrome virus).
- the human coronavirus is HCoV-NL63. In some embodiments, the human coronavirus is HCoV-OC43. In some embodiments, the human coronavirus is HCoV- 229E. In some embodiments, the human coronavirus is HCoV-HKlM. In some embodiments, the human coronavirus is SARS-CoV. In some embodiments, the human coronavirus is SARS-CoV-2. In some embodiments, the human coronavirus is CoV MERS.
- Flash column chromatography was performed on a Teledyne ISCO, Combi Flash Rf+ Lumen using a RediSep Rf silica column.
- Analytical HPLC-MS was performed using an Agilent 1100 series Liquid Chromatograph/Mass Selective Detector (MSD) (Single Quadropole) equipped with an electrospray interface and a UV diode array detector.
- MSD Liquid Chromatograph/Mass Selective Detector
- Step 1 4-(2,6-Dimethoxyphenyl)-1 -methyl-triazole
- Step 2 5-(2,6-Dimethoxyphenyl)-3-methyl-triazole-4-carboxylic acid
- LDA base 1.5 eq
- CO2 generated from dry ice
- the reaction was monitored by LCMS.
- the reaction was warmed to 20°C over 1 hour. Water was added and the solvent was removed under reduced pressure. The water phase was washed with EtOAc (2 x 40 ml) and acidified with HCI 35%.
- Step 3 5-(2,6-dimethoxyphenyl)-3-methyl-triazole-4-carbonyl chloride
- the compound 5-(2,6-dimethoxyphenyl)-3-methyl-triazole-4-carbonyl chloride was prepared by reaction with SOCI2, according to the general procedure described in WO 2013/171334 (cf. first step in Reaction Scheme 2).
- the obtained 5-(2,6-dimethoxyphenyl)-3-methyl-tria- zole-4-carbonyl chloride was used in step 4.
- Step 4 3-Chloro-4-[4-[5-(2, 6-dimethoxyphenyl)-3-methyl-triazole-4-carbonyl] piperazin-1-yl] benzonitrile
- the antiviral activity against SARS-CoV-2 of some compounds of formula (I) was tested in two plaque reduction assays. The tested compounds are shown in Table 1.
- Vero cells were grown in Minimum Essential Medium supplemented with Fetal Bovine Se rum, antibiotics and HEPES (MEM +FBS, Abx, HEPES) at 37 °C in 5% CO2. The cells were seeded in either 12-well plates, or 6-well plates, 1 day prior to the start of experiment. Intact (95% or more) monolayers were verified, prior to starting infection protocol. The growth me dium was removed, and the cells were washed with 2x Infection medium (MEM+Abx+HEPES, No FBS). The samples were diluted in serum free medium (SF me dium) with 500mI per dilution for plating in triplicate.
- MEM +FBS Fetal Bovine Se rum, antibiotics and HEPES
- the test compounds (150mI) were added 30 min post infection and the incuba tion was performed for 30 min before the wells were overlaid with 2X L-15 medium and aga rose (0.9%w/v final concentration), containing trypsin to a final concentration of 2 pg/pl.
- test included wells that did not receive any test compound.
- the plates were incu bated for 3 days before counting the plaques.
- the results are illustrated in Figure 1 and Fig ure 2.
- Tables 2 and 3 the results, in terms of number of plaques, are shown for Com pounds A, B and C at different dilutions.
- Figure 1 illustrates number of plaques from Table 2
- Figure 2 illustrates number of plaques from Table 3.
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Abstract
A compound of formula (I) for use in the treatment of a Coronaviridae virus infection. A novel compound of formula (I), and a process for preparing the compound.
Description
ANTIVIRAL AGENTS
FIELD OF THE INVENTION
The present invention relates to compounds for use as antiviral agents, in particular as antivi ral agents in the treatment of coronavirus infections.
BACKGROUND OF THE INVENTION
Coronaviruses constitute the subfamily Orthocoronavirinae , in the family Coronaviridae, or der Nidovirales, and realm Riboviria. They are enveloped viruses with a positive-sense sin gle-stranded RNA genome and a nucleocapsid of helical symmetry, having a genome size of coronaviruses ranging from approximately 27 to 34 kilobases.
Coronaviruses cause diseases in both mammals and birds. It is estimated that human coro naviruses cause approximately 10-15% of all upper and lower respiratory tract infections and account for significant hospitalizations of both children, and elderly, as well as immunocom promised individuals.
Thus, SARS-CoV (Severe Acute Respiratory Syndrome-Corona Virus) is a highly aggressive virus causing the lung disease SARS in humans, often with fatal outcome. The virus SARS- CoV (or SARS-CoV-1) appeared as an epidemic in 2003 after it had crossed the species bar rier from bats to civet cats and humans, demonstrating the potential of coronaviruses to cause high morbidity and mortality in humans. Further virus strains, i.e. HCoV-NL63 and HCoV-HKU1 were discovered in 2004 and in 2005, respectively, causing more severe lower respiratory tract infections like bronchiolitis and pneumonia, especially in young children, im munocompromised patients and the elderly. In 2012, a new human CoV MERS (Middle East Respiratory Syndrome virus, previously called "EMC") emerged from the Middle East with clinical outcomes such as renal failure and acute pneumonia, similar to those of SARS-CoV but with an even higher mortality rate of about 50%. In December 2019, a novel SARS-CoV, viz. SARS-CoV-2, caused an outbreak of disease (Covid-19) starting in China, and rapidly spreading across the globe, causing high numbers of fatalities and suffering.
Clearly, there is an urgent need for new antiviral drugs to combat the coronavirus infections.
International patent application No. PCT/CN2010/001187, published as WO 2011/015037, is directed to compounds which exhibit antiviral activity, in particular against influenza virus. In one embodiment, the compounds described therein are represented by the formula
International patent application No. PCT/US2011/052965, published as WO/2012/044531, discloses compounds of formula:
wherein Het is a 5 or 6-membered heterocycle, as useful for the treatment of influenza virus infections.
International patent application No. PCT/EP2013/060266, published as WO 2013/171334, discloses compounds of formula
as useful for the treatment of in particular influenza virus infections.
SUMMARY OF THE INVENTION
It has now been found that certain heterocyclic compounds have a surprising antiviral effect against viruses belonging to the Coronaviridae family.
A first aspect is a compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein X is C, Y is O, and Z is C,
X is C, Y is N, and Z is N, or X is N, Y is N, and Z is C;
W is O or S; each Ri is independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen;
R2 is H or C1-C4 alkyl; each R3 is independently selected from nitro, cyano, C1-C4 alkyl; C1-C4 alkoxy, hydroxy and halogen; m is an integer of from 0 to 3; and n is an integer of from 1 to 3; for use in the treatment of a Coronaviridae virus infection.
A further aspect relates to improved processes for preparing intermediates useful in the syn thesis of compounds of formula (I).
A further aspect is compound of formula (I) or salt thereof for use as defined herein, in com bination with at least one further therapeutically active agent.
A further aspect is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable ex cipient, for use in the treatment of a Coronaviridae virus infection.
A further aspect is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a Coronaviridae virus infec tion.
A further aspect is a method for the treatment of a Coronaviridae virus infection, by admin istration of a therapeutically effective amount of a compound of formula (I) or a pharmaceuti cally acceptable salt thereof to a patient need thereof.
A further aspect is a kit-of-parts comprising
(A) a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation; and
(B) a further therapeutically active agent in a pharmaceutical formulation; and a package insert with instructions for the combined use of components (A) and (B), for use in the treatment of a Coronaviridae virus infection.
Some compounds according to formula (I) are novel. Therefore, a further aspect is a com pound of formula (Iq)
or a pharmaceutically acceptable salt thereof, wherein
X is C, Y is O, and Z is C,
X is C, Y is N, and Z is N, or X is N, Y is N, and Z is C;
W is O or S;
Ri is selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen; each Ria is independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen;
R2 is H or C1-C4 alkyl; each R3 is independently selected from nitro, cyano, C1-C4 alkyl; C1-C4 alkoxy, hydroxy and halogen; m is 2 or 3; and n is an integer of from 1 to 3.
A further aspect is a process for preparing a compound of formula (Iq).
A still further aspect is a compound of formula (Iq) for use in therapy.
A still further aspect is a pharmaceutical composition comprising the compound of formula (Iq) and optionally a pharmaceutically acceptable excipient.
A further aspect is compound of formula (Iq) or salt thereof for use as defined herein, in com bination with at least one further therapeutically active agent.
A further aspect is a pharmaceutical composition comprising a compound of formula (Iq), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable ex cipient, for use in the treatment of a Coronaviridae virus infection.
A further aspect is the use of a compound of formula (Iq) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a Coronaviridae virus infection.
A further aspect is a method for the treatment of a Coronaviridae virus infection, by admin istration of a therapeutically effective amount of a compound of formula (Iq) or a pharmaceu tically acceptable salt thereof to a patient need thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a bar chart showing number of SARS-CoV-2 virus plaques formed in a plaque re duction assay at different concentrations (in mM) of three different compounds of formula (I), compared to untreated control. Comp. A is 3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1-methyl- 1 H-1 ,2,3-triazole-5-carbonyl)piperazin-1-yl)benzonitrile; Comp. B is (4-(2-chloro-4-nitro- phenyl)piperazin-1 -yl)(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol-5-yl)methanone; and Comp. C is (4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(4-(2,6-dimethoxyphenyl)-1 -methyl- 1 H-1 ,2,3-triazol-5-yl)methanethione.
Figure 2 is a bar chart showing number of SARS-CoV-2 virus plaques formed in a plaque re duction assay at different concentrations (in pM) of three different compounds of formula (I), compared to untreated control. Comp. A is 3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1-methyl- 1 H-1 ,2,3-triazole-5-carbonyl)piperazin-1-yl)benzonitrile; Comp. B is (4-(2-chloro-4-nitro- phenyl)piperazin-1 -yl)(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol-5-yl)methanone;
and Comp. C is (4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(4-(2,6-dimethoxyphenyl)-1 -methyl- 1 H-1 ,2,3-triazol-5-yl)methanethione.
Figure 3 is a graph showing the % of live MDCK cells (Madin-Darby Canine Kidney cells) in the presence of different concentrations (in mM) of two different compounds of formula (I), or DMSO, in a cytotoxicity assay. Comp. A is 3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1-methyl- 1H-1,2,3-triazole-5-carbonyl)piperazin-1-yl)benzonitrile; and Comp. B is (4-(2-chloro-4-nitro- phenyl)piperazin-1 -yl)(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol-5-yl)methanone.
DETAILED DESCRIPTION OF THE INVENTION Definitions
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Some definitions are provided herein below, but any such definition is not intended to be limiting of the invention.
“Pharmaceutically acceptable” means being useful in preparing a pharmaceutical composi tion that is generally safe for the intended therapeutic use, and neither biologically nor other wise undesirable, and includes being useful for veterinary use as well as human pharmaceu tical use.
The term “treating" (or "treatment of") a disease or disorder may refer to ameliorating the dis ease or disorder (i.e. , arresting or reducing the development of the disease or at least one of the clinical symptoms thereof), and/or ameliorating at least one physical parameter, which may not be discernible by the patient. The term also may refer to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. Unless specifically indicated or apparent from the context, treating a disease generally also encompasses preventing the disease.
The term "preventing" (or "prevention", etc.), refers to preventing and/or delaying the onset of a disease, disorder and/or clinical symptom(s) in a subject and/or a reduction in the severity of the onset of the disease, disorder and/or clinical symptom(s) relative to what would occur in the absence of the preventive activity (e.g. administration of a compound as defined herein in an amount effective to cause a preventive effect). The prevention can be complete, e.g., the total absence of the disease, disorder and/or clinical symptom(s). The prevention can
also be partial, such that the occurrence of the disease, disorder and/or clinical symptom(s) in the subject and/or the severity of onset and/or the time period of symptoms is less than what would occur in the absence of the preventive activity.
An “effective amount” refers to an amount of a compound that has a therapeutic or preven tive effect on a disorder in a treated subject. The therapeutic or preventive effect may be ob jective (i.e. , measurable by some test or marker, e.g. no measurable virus titer in a biological sample from the treated subject) or subjective (i.e., subject gives an indication of or feels an effect).
The term “excipient” refers to a pharmaceutically acceptable chemical, such as known to those of ordinary skill in the art of pharmacy to aid the administration of a medicinal agent. It is a compound that is useful in preparing a pharmaceutical composition, generally safe, non toxic and neither biologically nor otherwise undesirable, and includes excipients that are ac ceptable for veterinary use as well as human pharmaceutical use. Exemplary excipients in clude binders, surfactants, diluents, disintegrants, antiadherents, and lubricants.
A “viral infection” or “virus infection” refers to an infection by a virus in a bird or a mammal.
As used herein a "Coronaviridae virus infection" means an infection with a virus belonging to the Coronaviridae virus family, more particularly the Orthocoronavirinae subfamily.
The term “mammal” refers to a human or any mammalian animal, e.g. a primate, a farm ani mal, a pet animal, or a laboratory animal. Examples of such animals are monkeys, cows, sheep, goats, horses, pigs, dogs, cats, rabbits, mice, rats etc. Preferably, the mammal is a human. In some embodiments, however, the mammal is an animal, e.g. a farm animal, such as a cow, sheep, goat, horse, or pig. In some other embodiments, the animal is a pet, e.g. a dog, a cat, or a rabbit.
A “bird” as referred to herein e.g. may be poultry, a cage bird or a pet bird.
Unless otherwise stated or indicated, the term “C1-C4 alkyl” denotes a straight or branched alkyl group having from 1 to 4 carbon atoms, e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl.
Unless otherwise stated or indicated, the term “halogen” (or “halo”) refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term “C1-C4 alkoxy” refers to a moiety of formula RO, i.e.
R'° wherein R is C1-C4 alkyl.
The term “cyano” (or “CN”) refers to a moiety of formula NºC — !
The term “hydroxy” (or “OH”) refers to a moiety of formula HO— I
A compound of formula (I) as herein defined, contains a 5-membered heteroaromatic ring of formula (II)
wherein
X is C, Y is O, and Z is C,
X is C, Y is N, and Z is N, or X is N, Y is N, and Z is C.
In some embodiments in a ring of formula (II),
X is C, Y is N, and Z is N, or X is N, Y is N, and Z is C.
In some embodiments, in a ring of formula (II), Y is N. Thus, in some embodiments, the com pound of formula (I) is a compound of formula (la)
wherein X, Z, W, each Ri, R2, each R3, m and n are as defined herein.
In some embodiments, in a ring of formula (II) X is C, Y is N, and Z is N. Thus, in some em- bodiments, the compound of formula (I) more particularly is a compound of formula (lb)
wherein W, Ri, R2, R3, m and n are as defined herein.
In a compound of formula (I) as defined herein, W is O or S. In some embodiments, W is O. Thus, in some embodiments, the compound of formula (I) more particularly is a compound of formula (lc)
wherein X, Y, Z, Ri, R2, R3, m and n are as defined herein.
In some other embodiments, W is S. Thus, in some embodiments, the compound of formula (I) more particularly is a compound of formula (Id)
wherein X, Y, Z, Ri, R2, R3, m and n are as defined herein.
In a compound of formula (I) as defined herein, each moiety Ri is independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen.
In some embodiments, each moiety Ri is independently selected from C1-C4 alkyl, C1-C4 alkoxy, and halogen.
In some embodiments, each moiety Ri is independently selected from C1-C4 alkoxy, hy droxy and halogen.
In some embodiments, each moiety Ri is independently selected from C1-C4 alkyl and C1- C4 alkoxy.
In some embodiments, each moiety Ri is independently selected from C1-C4 alkoxy, and halogen.
In some embodiments, each moiety Ri is independently selected from C1-C4 alkoxy.
In some embodiments, when Ri is C1-C4 alkyl, said C1-C4 alkyl particularly is C1-C3 alkyl, or more particularly methyl or ethyl, e.g. methyl.
In some embodiments, when Ri is C1-C4 alkoxy, said C1-C4 alkoxy particularly is C1-C3 alkoxy, or more particularly C1-C2 alkoxy, even more particularly methoxy.
In some embodiments, when Ri is halogen, said halogen is selected from F, Cl, Br and I; e.g. from F, Cl, and Br, or from F and Cl, or from Cl and Br. In some embodiments, when Ri is halogen, said halogen is Cl. In some embodiments, when Ri is halogen, said halogen is F.
In a compound of formula (I) as defined herein, R2 is H or C1-C4 alkyl.
In some embodiments, R2 is H or C1-C3 alkyl. In some embodiments, R2 is H, methyl or ethyl; e.g. H or methyl.
In some embodiments, R2 is C1-C4 alkyl, e.g. C1-C3 alkyl. In some embodiments, R2 is me thyl or ethyl. In some embodiments, R2 is methyl.
In a compound of formula (I) as defined herein, each moiety R3 is independently selected from nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen.
In some embodiments, each moiety R3 is independently selected from nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, and halogen.
In some embodiments, each moiety R3 is independently selected from nitro, cyano, C1-C4 alkoxy, hydroxy and halogen.
In some embodiments, each moiety R3 is independently selected from nitro, cyano, C1-C4 alkyl, hydroxy and halogen.
In some embodiments, each moiety R3 is independently selected from nitro, cyano, C1-C4 alkyl, and halogen.
In some embodiments, each moiety R3 is independently selected from nitro, cyano, C1-C4 alkoxy, and halogen.
In some embodiments, each moiety R3 is independently selected from nitro, cyano, hydroxy and halogen.
In some embodiments, each moiety R3 is independently selected from nitro, cyano, and halo gen.
In some embodiments, each moiety R3 is independently selected from nitro and halogen.
In some embodiments, each moiety R3 is independently selected from cyano and halogen.
In some embodiments, when R3 is C1-C4 alkyl, said C1-C4 alkyl particularly is C1-C3 alkyl, or more particularly methyl or ethyl, e.g. methyl.
In some embodiments, when R3 is C1-C4 alkoxy, said C1-C4 alkoxy particularly is C1-C3 alkoxy, or more particularly methoxy or ethoxy, even more particularly methoxy.
In some embodiments, when R3 is halogen, said halogen is selected from F, Cl, Br and I; e.g. from F, Cl, and Br, or from F and Cl, or from Cl and Br. In some embodiments, when R3 is halogen, said halogen is Cl.
In a compound of formula (I) as defined herein, m is an integer 0, 1 , 2 or 3, denoting the number of moieties Ri present in the compound. In some embodiments, m is 0, 1 , or 2; e.g. m is 1 or 2. In some embodiments, m is 1 , 2, or 3; e.g. m is 2 or 3. In some embodiments, m is 2.
In some embodiments, a compound of formula (I) more particularly may be represented by formula (le)
wherein m is 2 or 3; each Ria is independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen; and X, Y, Z, W, Ri, R2, each R3, and n are as defined herein.
In some embodiments of a compound of formula (le), each moiety Ria is independently se lected from C1-C4 alkyl, C1-C4 alkoxy, and halogen.
In some embodiments, each moiety Ria is independently selected from C1-C4 alkoxy, hy droxy and halogen.
In some embodiments, each moiety Ria is independently selected from C1-C4 alkyl and C1- C4 alkoxy.
In some embodiments, each moiety Ria is independently selected from C1-C4 alkoxy, and halogen.
In some embodiments, each moiety Ria is independently selected from C1-C4 alkoxy.
In some embodiments, when Ria is C1-C4 alkyl, said C1-C4 alkyl particularly is C1-C3 alkyl, or more particularly methyl or ethyl.
In some embodiments, when Ria is C1-C4 alkoxy, said C1-C4 alkoxy particularly is C1-C3 alkoxy, or more particularly C1-C2 alkoxy, even more particularly methoxy.
In some embodiments, when Ria is halogen, said halogen is selected from F, Cl, Br and I; e.g. from F, Cl, and Br, or from F and Cl, or from Cl and Br. In some embodiments, when Ria is halogen, said halogen is Cl. In some embodiments, when Ria is halogen, said halogen is F.
In some embodiments of a compound of formula (le), m is 2, i.e. the compound of more par ticularly may be represented by formula (If)
wherein X, Y, Z, W, each Ria, R2, each R3, and n are as defined herein.
In a compound of formula (I) as defined herein, n is an integer 1, 2 or 3 that denotes the number of moieties R3 present in the compound. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 2.
In some embodiments, the compound of formula (I) more particularly is a compound of for mula (Ig)
wherein R3a is selected from nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen; and X, Y, Z, W, each Ri, R2, each R3, m and n are as defined herein.
In some embodiments of a compound of formula (Ig), R3a is selected from nitro, cyano, C1- C4 alkoxy, hydroxy and halogen.
In some embodiments of a compound of formula (Ig), R3a is selected from nitro, cyano, C1- C4 alkyl, C1-C4 alkoxy, and halogen.
In some embodiments of a compound of formula (Ig), R3a is selected from nitro, cyano, C1- C4 alkoxy, and halogen.
In some embodiments of a compound of formula (Ig), R3a is selected from nitro, cyano, and halogen.
In some embodiments of a compound of formula (Ig), R3a is selected from nitro, cyano, C1- C4 alkyl, C1-C4 alkoxy, and hydroxy.
In some embodiments of a compound of formula (Ig), R3a is selected from nitro, cyano, and C1-C4 alkoxy.
In some embodiments of a compound of formula (Ig), R3a is selected from nitro and cyano. In some embodiments of a compound of formula (Ig), R3a is nitro.
In some embodiments of a compound of formula (Ig), R3a is cyano.
In some embodiments, when R3a is C1-C4 alkyl, said C1-C4 alkyl particularly is C1-C3 alkyl, or more particularly methyl or ethyl, e.g. methyl.
In some embodiments, when R3a is C1-C4 alkoxy, said C1-C4 alkoxy particularly is C1-C3 alkoxy, or more particularly methoxy or ethoxy, even more particularly methoxy.
In some embodiments, when R3a is halogen, said halogen is selected from F, Cl, Br and I; e.g. from F, Cl, and Br, or from F and Cl, or from Cl and Br. In some embodiments, when R3a is halogen, said halogen is Cl.
In some further embodiments, the compound of formula (I) more particularly is a compound of formula (Ih)
wherein n is 2 or 3;
R3bis selected from nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen; and X, Y, Z, W, each Ri, R2, R3, R3a, and are as defined herein.
In some embodiments of a compound of formula (Ih), R3b is selected from C1-C4 alkyl, C1- C4 alkoxy, hydroxy and halogen.
In some embodiments of a compound of formula (Ih), R3b is selected from C1-C4 alkoxy, hy droxy and halogen.
In some embodiments of a compound of formula (Ih), R3b is selected from C1-C4 alkyl, C1- C4 alkoxy, and halogen.
In some embodiments of a compound of formula (Ih), R3b is selected from C1-C4 alkyl, and halogen.
In some embodiments of a compound of formula (Ih), R3b is selected from C1-C4 alkoxy, and halogen.
In some embodiments of a compound of formula ((Ih), R3b is halogen.
In some embodiments, when R3b is C1-C4 alkyl, said C1-C4 alkyl particularly is C1-C3 alkyl, or more particularly methyl or ethyl.
In some embodiments, when R3b is C1-C4 alkoxy, said C1-C4 alkoxy particularly is C1-C3 alkoxy, or more particularly methoxy or ethoxy, even more particularly methoxy.
In some embodiments, when R3b is halogen, said halogen is selected from F, Cl, Br and I; e.g. from F, Cl, and Br, or from F and Cl, or from Cl and Br.
In some embodiments, when R3b is halogen, said halogen is Cl.
In some embodiments of a compound of formula (Ih), n is 2, i.e. the compound of formula (Ih) more particularly may be represented by formula (Ij)
wherein X, Y, Z, W, each Ri, R2, R3a, R3b and m are as defined herein.
It should be realized that unless mutually exclusive or incompatible, the various features of the embodiments described herein, e.g. as illustrated by formulas (la) to (Ij), may be freely combined to give rise to further embodiments within the scope of formula (I).
Thus, in some embodiments, where the compound of formula (le) is also a compound of for mula (Ig), the compound of formula (I) is as represented by formula (Ik)
wherein m is 2 or 3, e.g. m is 2; and
X, Y, Z, W, Ri, each Ria, R2, each R3, R3a, and n are as defined herein.
In some further embodiments, where the compound of formula (le) is also a compound of for mula (Ih), the compound of formula (I) is as represented by formula (Im)
wherein m is 2 or 3, e.g. m is 2; n is 2 or 3, e.g. n is 2; and
X, Y, Z, W, Ri, each Ria, R2, R3, R3a, and R3b are as defined herein.
In some further embodiments, where the compound of formula (If) is also a compound of for- mula (Ij), the compound of formula (I) is as represented by formula (In)
wherein X, Y, Z, W, each Ria, R2, R3a, and R3b are as defined herein.
In some particular embodiments, the compound of formula (In) is also a compound of for mula (la), i.e. a compound that may be represented by formula (lo)
wherein X, Z, W, each Ria, R2, R3a, and R3b are as defined herein.
In still further particular embodiments, the compound of formula (In) is also a compound of formula (lb), i.e. a compound that may be represented by formula (Ip)
wherein W, each Ria, R2, R3a, and R3b are as defined herein.
In some embodiments, the compound for use as described herein is selected from: 3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1 , 2, 3-triazole-5-carbonyl)piperazin-1- yl)benzonitrile,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(5-methyl-3-phenylisoxazol-4-yl)methanone, (5-methyl-3-phenylisoxazol-4-yl)(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methanone, (4-(2-chloro-4-nitrophenyl)piperazin-1 -yl)(4-(2-methoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol-5- yl)methanone,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(4-(2-fluoro-6-methoxyphenyl)-1 -methyl-1 H-1, 2, 3- triazol-5-yl)methanone,
(4-(2-chloro-4-nitrophenyl)piperazin-1 -yl)(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol- 5-yl)methanone,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(1-(2-methoxyphenyl)-4-methyl-1 H-1,2,3-triazol-5- yl)methanone,
(4-(2-chloro-4-(trifluoromethyl)phenyl)piperazin-1-yl)(1-(2-methoxyphenyl)-4-methyl-1 H-1 ,2,3- triazol-5-yl)methanone,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(1-(2,4-dimethoxyphenyl)-4-methyl-1H-1,2,3-triazol-
5-yl)methanone,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(1-(2,6-dimethoxyphenyl)-4-methyl-1H-1,2,3-triazol-
5-yl)methanone,
3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazole-5- carbonothioyl)piper- azin-1-yl)benzonitrile,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(5-methyl-3-phenylisoxazol-4-yl)methanethione, (5-methyl-3-phenylisoxazol-4-yl)(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methanethione, (4-(2-chloro-4-nitrophenyl)piperazin-1 -yl)(4-(2-methoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol-5- yl)methanethione,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(4-(2-fluoro-6-methoxyphenyl)-1 -methyl-1 H-1, 2, 3- triazol-5-yl)methanethione,
(4-(2-chloro-4-nitrophenyl)piperazin-1 -yl)(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol- 5-yl)methanethione,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(1-(2-methoxyphenyl)-4-methyl-1H-1,2,3-triazol-5- yl)methanethione,
(4-(2-chloro-4-(trifluoromethyl)phenyl)piperazin-1-yl)(1-(2-methoxyphenyl)-4-methyl-1H-1,2,3- triazol-5-yl)methanethione,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(1-(2,4-dimethoxyphenyl)-4-methyl-1H-1,2,3-triazol- 5-yl)methanethione, and
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(1-(2,6-dimethoxyphenyl)-4-methyl-1H-1,2,3-triazol-
5-yl)methanethione.
In some particular embodiments, the compound for use as defined herein is selected from: 3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazole-5-carbonyl)piperazin-1- yl)benzonitrile,
(4-(2-chloro-4-nitrophenyl)piperazin-1 -yl)(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol- 5-yl)methanone,
3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazole-5- carbonothioyl)piper- azin-1-yl)benzonitrile, and
(4-(2-chloro-4-nitrophenyl)piperazin-1 -yl)(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol- 5-yl)methanethione.
In some particular embodiments, the compound for use as defined herein is selected from:
3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazole-5-carbonyl)piperazin-1- yl)benzonitrile,
(4-(2-chloro-4-nitrophenyl)piperazin-1 -yl)(4-(2,6-di ethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol- 5-yl)methanone, and (4-(2-chloro-4-nitrophenyl)piperazin-1 -yl)(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol-
5-yl)methanethione.
General methods for preparing compounds for use as disclosed herein are as described in WO 2013/171334 ( vide supra) and in the publications referred to therein, the contents of which are incorporated herein by reference.
Compounds of formula (I) may also be prepared by a method as illustrated in Reaction Scheme 1, involving a Suzuki coupling reaction of compound 1 with compound 2, to give compound 3, followed by carbonylation of compound 3 using CO2 in the presence of a base such as LDA at a temperature of about 0°C, to give compound 4, and further reacting com pound 4 in a multi-step procedure as generally described in WO 2013/171334 (vide supra), to provide a compound of formula (I) as defined herein.
Reaction Scheme 1
A further aspect therefore is a process for preparing a compound of formula (V), by reacting a compound of formula (III) with a compound of formula (IV),
wherein X, Y, Z, each Ri, R2 and m are as defined herein, in the presence of a palladium-containing catalyst, such as tetrakis (triphenylphosphine)palla- dium, and in the presence of a base, such as potassium carbonate.
The compound of formula (V) may be used as an intermediate in the synthesis of a com pound of formula (I) as defined herein. Thus, WO 2013/171334 ( vide supra) describes car- bonylation of a compound of the type of formula (V) with CO2 in the presence of a base, such as lithium diisopropylamide (LDA), at a reaction temperature of -70°C or lower.
It has now been found that carbonylation of the compound of formula (V) may suitably be performed by performing such carbonylation reaction at a substantially higher temperature, viz. at a temperature of about 0°C. Such reaction temperature provides a reaction mixture having improved characteristics, e.g. of being much easier to stir, which is considered very advantageous for large scale production. Indeed, at the lower temperature of -70°C, the re action mixture formed a thick slurry, which is avoided at the higher temperature.
A further aspect therefore is a process for preparing a compound of formula (VI), by reacting a compound of formula (V) with CO2 in the presence of a base, such LDA, at a temperature of about 0°C,
wherein X, Y, Z, each Ri, R2 and m are as defined herein.
The compound of formula (VI) is an intermediate in the synthesis of a compound of formula (I) as defined herein.
A still further aspect therefore is a process for preparing a compound of formula (VI), by re acting a compound of formula (III) with a compound of formula (IV), in the presence of a pal ladium based catalyst, such as tetrakis (triphenylphosphine)palladium and in the presence of a base, such as potassium carbonate, to obtain a compound of formula (V)
and reacting the obtained compound of formula (V) with CO2 in the presence of a base, such as LDA, at a temperature of about 0°C, to obtain a compound of formula (VI),
wherein X, Y, Z, each Ri, R2 and m are as defined herein.
A further aspect is a novel compound as defined in any one of formulas (Ik), (Im), (In), (lo) or (Ip), wherein R3a is cyano.
One aspect, thus, is a novel compound of formula (Ik) wherein R3a is cyano, i.e. a compound as represented by formula (Iq)
m is 2 or 3, e.g. m is 2; and
X, Y, Z, W, Ri, each Ria, R2, each R3, and n are as defined herein.
Likewise, in some embodiments a novel compound is provided which is a compound of for mula (Im) wherein R3a is cyano, i.e. a compound according to formula (Ir)
wherein m is 2 or 3, e.g. m is 2; n is 2 or 3, e.g. n is 2; and X, Y, Z, W, Ri, each Ria, R2, R3, and R3b.
In some embodiments of a compound of formula (Iq) or (Ir), m is 2 and n is 2. Thus, in some embodiments, the compound of formula (Ir) more particularly is a compound of formula (Is)
wherein X, Y, Z, W, each Ria, R2, and R3bare as defined herein.
In some particular embodiments of a compound of formula (Iq), (Ir) or (Is), Y is N. Thus, in some embodiments, a compound of formula (Is) more particularly may be represented by for mula (It)
wherein X, Z, W, each Ria, R2, and R3bare as defined herein.
In some embodiments of a compound of formula (Iq), (Ir), (Is), or (It), each Ria is inde pendently selected from C1-C4 alkoxy and halogen, or from C1-C3 alkoxy and halogen, e.g. from methoxy and halogen, such as from methoxy and F; and R3b is halogen, e.g. Cl or Br, in particular Cl.
In some embodiments of a compound of formula (Iq), (Ir), (Is), or (It), each Ria is inde pendently selected from C1-C4 alkoxy, or from C1-C3 alkoxy, e.g. each is methoxy; and R3b is halogen, e.g. Cl or Br, in particular Cl. Thus, in some embodiments, the novel compound is one as represented by formula (lu)
wherein X, Z, W and R2 are as defined herein.
In some embodiments of a compound of formula (Iq), (Ir), (Is), (It), or (lu), X is N and Z is C. In some embodiments of a compound of formula (Iq), (Ir), (Is), (It), or (lu), X is C and Z is N.
In some embodiments of a compound of formula (Iq), (Ir), (Is), (It), or (lu) W is O. In some other embodiments of a compound of formula (Iq), (Ir), (Is), (It), or (lu), W is S. In some embodiments, a compound of formula (Iv) is provided,
wherein W is as defined herein. In some embodiments, W is S, i.e. the compound is 3- chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1 , 2, 3-triazole-5-carbonothioyl)piperazin-1- yl)benzonitrile. In some further embodiments, W is O, i.e. the compound is 3-chloro-4-(4-(4- (2, 6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazole-5-carbonyl)piperazin-1-yl)benzonitrile.
A further aspect is a process for preparing a compound of formula (Iq)
X, Y, Z, W, Ri, each Ria, R2, each R3, and n are as defined herein, by: reacting a compound of formula (III) with a compound of formula (IVa) to obtain a compound of formula (Va)
reacting a compound of formula (Va) with CO2 in the presence of a base, such as LDA, pref erably at a temperature of about 0°C; to obtain a compound of formula (Via)
reacting a compound of formula (Via) with SOCI2, to obtain a compound of formula (VII)
reacting a compound of formula (VII) with a compound of formula (VIII) to obtain a compound of formula (Iq) wherein W is O
if W is S, reacting a compound of formula (Iq), wherein W is O, with a thionating agent, such as P2S5.2C5H5N
It is noted that unless otherwise specified or clearly apparent from the context, a reference to a compound of formula (I) made herein should also be understood as a reference to any of the embodiments of such compound, e.g. as illustrated by any of the above formulas (la),
(lb), (lc), (Id), (le), (If), (Ig), (Ih), (Ij), (Ik), (Im), (In), (lo), (Ip), (Iq), (Ir), (Is), (It), (lu) and (Iv).
Likewise, unless otherwise specified or clearly apparent from the context, a reference to a compound of formula (Iq) made herein should also be understood as a reference to any of
the embodiments of such compound, e.g. as illustrated by any one of the formulas (Ir), (Is), (It), (lu) and (Iv).
In some embodiments there is provided a pharmaceutically acceptable salt of the compound of formula (I). Examples of pharmaceutically acceptable salts for use in the pharmaceutical compositions of the present invention include those derived from mineral acids, such as hy drochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, suc cinic, and arylsulfonic acids.
The pharmaceutical composition provided herein may be for enteral administration, such as rectal or oral administration, or for parenteral administration to a mammal (especially a hu man) and comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as active ingredient, optionally in association with a pharmaceutically acceptable excipient, e.g. a pharmaceutically acceptable carrier.
The therapeutically effective amount of the active ingredient is as defined herein above and depends e.g. on the body weight of the treated subject, the age, the individual condition, indi vidual pharmacokinetic data, and the mode of administration.
For enteral, e.g. oral, administration, the compound of formula (I) may be formulated in a wide variety of dosage forms. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, lozenges, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely di vided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, mag nesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methyl- cellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
Other forms suitable for oral administration include liquid form preparations including emul sions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations
which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions, or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Solid form preparations include solutions, suspen sions, and emulsions, and may contain, in addition to the active component, colorants, fla vors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubiliz ing agents, and the like.
Exemplary compositions for rectal administration include suppositories which can contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
The compound of formula (I) also may be administered parenterally, e.g. by injection or infu sion, e.g. by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intracere- broventricular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial, intratumoral, intracutaneous, intraperitoneal and subcutaneous injection or infusion, by pulmonary admin istration, by inhalation administration or by nasal administration. Thus, for parenteral admin istration, the pharmaceutical compositions may be in the form of a sterile injectable or infusi ble preparation, for example, as a sterile aqueous or oleaginous suspension. This suspen sion may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80), and suspending agents.
Exemplary compositions for pulmonary administration include liquid solutions or powders, for administration in an aerosolized or nebulized form, contain, for example, non-irritating excipi ents to enable formation of droplets and particle sizes, which enable an effective dispersion of the drug into the deeper parts of the lungs.
For inhalation or nasal administration, suitable pharmaceutical formulations are as particles, aerosols, powders, mists or droplets, e.g. with an average size of about 10 pm in diameter or less. For example, compositions for inhalation may be prepared as solutions in saline,
employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.
The sterile injectable or infusible preparation may also be a sterile injectable or infusible solu tion or suspension in a non-toxic parenterally acceptable diluent or solvent. For example, the pharmaceutical composition may be a solution in 1,3-butanediol. Other examples of accepta ble vehicles and solvents that may be employed in the compositions of the present invention include, but are not limited to, mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspend ing medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as ol ive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or sus pensions may also contain a long-chain alcohol diluent or dispersant.
Solutions for parenteral use also may contain suitable stabilizing agents, and if necessary, buffer substances. Suitable stabilizing agents include antioxidizing agents, such as sodium bisulfate, sodium sulfite or ascorbic acid, either alone or combined, citric acid and its salts and sodium EDTA. Parenteral solutions may also contain preservatives, such as ben- zalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
Conventional procedures for the selection and preparation of suitable pharmaceutical formu lations are described, for example, in “Pharmaceutics - The Science of Dosage Form De sign”, M.B. Aulton, Churchill Livingstone, 2nd ed. 2002 (ISBN 0443055173, 9780443055171). Suitable pharmaceutical excipients, e.g. carriers, and methods of preparing pharmaceutical dosage forms also are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in art of drug formulation.
The pharmaceutical compositions may comprise from approximately 1 % to approximately 95%, preferably from approximately 20 % to approximately 90 % of a compound of formula (I), together with at least one pharmaceutically acceptable excipient. In general, the com pounds of formula (I) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
Also provided herein is a method for the treatment of a viral infection, by administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically accepta ble salt thereof to a patient need thereof.
While e.g. injection or rectal administration of a compound of formula (I) may be contem plated if necessary, oral administration generally is considered the most convenient.
The dosage level and frequency will generally be as determined by the treating physician, with due regard to factors such as and the sex, age, corporal weight and relative health of the treated subject, the state of progression of the viral disease, the selected route and form of administration, the additional use of other drugs, e.g. in a combination therapy.
Generally, a daily dosage ranging from a minimum of 0.001 mg/kg body weight, or 0.002 mg/kg body weight or 0.005 mg/kg body weight or 0.01 mg/kg body weight, to a maximum of 1000 mg/kg body weight, or 100 mg/kg body weight, or 50 mg/kg body weight, or 10 mg/kg body weight, or 5 mg/kg body weight, or 2 mg/kg body weight, or 1 mg/kg body weight may be contemplated.
The compound of formula (I) preferably is administrated on a daily basis during the treatment period, e.g. 1-3 times a day, or 1-2 times a day, such as once daily. In some embodiments, the drug is administrated on a less frequent basis, e.g. every two days, once a week etc.
It should also be noted that if a pharmaceutically acceptable salt of the compound of formula (I) is administered, an equivalent dosage would be one resulting in the indicated dosage of the compound in non-salt form.
In some embodiments, the compound of formula (I) is used in combination with at least one further therapeutically active agent, e.g. a further antiviral agent, an antibiotic agent, an anti inflammatory agent, an analgesic agent (a “pain-killer”), or an antipyretic agent (a fever-re ducing agent). For example, in some embodiments, the compound of formula (I) is used in combination with a further antiviral agent, e.g. selected from ribavirin, remdesivir, lopinavir, and ritonavir, or chloroquine or hydroxychloroquine.
In some embodiments, the compound of formula (I) is used in combination with an antibiotic, such an antibiotic selected from macrolide antibiotics, e.g. azithromycin (Zithromax) or
clarithromycin (Biaxin XL); tetracycline antibiotics, e.g. doxycycline; fluoroquinolone antibiot ics, e.g. levofloxacin (Levaquin); or combined antibiotics therapy of a beta-lactam such as amoxicillin or amoxicillin/clavulanate (Augmentin) with a macrolide antibiotic.
In some embodiments, the compound of formula (I) is used in combination with an anti-in flammatory agent, such as a nonsteroidal anti-inflammatory drug (NSAID), e.g. selected from aspirin, ibuprofen, and naproxen.
In some embodiments, the compound of formula (I) is used in combination with an antipyretic and/or analgesic (antiphlogistic) agent, such as paracetamol.
Therefore, in some embodiments, a combination is provided, comprising a compound of for mula (I) as defined herein and at least one further therapeutically active compound e.g. se lected from a further antiviral agent, an antibiotic agent, an anti-inflammatory agent, an anal gesic agent (a “pain-killer”), or an antipyretic agent (a fever-reducing agent).
By “combination” as used herein is meant that the compound of formula (I) and the further therapeutically active agent(s) may be administered simultaneously in one and the same for mulation or in separate formulations. The combination of the compound of formula (I) and the further agent further includes administration of the two or more compounds separately, e.g. sequentially or at different time points.
In some embodiments, a kit (which may also referred to as a kit-of-parts) is provided, com prising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a suitable pharmaceutical formulation, and a package insert with instructions for use of the compound together with at least one further therapeutically active agent, e.g. one such as mentioned herein above. Such a kit is useful for the treatment of a viral infection, e.g. a viral infection as mentioned herein.
In some embodiments, a kit is provided, comprising:
(A) a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a suitable pharmaceutical formulation; and
(B) a further therapeutically active agent in a suitable pharmaceutical formulation; and a package insert with instructions for the combined use of components (A) and (B).
The patient treated herein is one in need of antiviral treatment. In some embodiments, the patient has been tested for virus infection and found to be infected by a virus, such as a virus belonging to the Coronaviridae virus family. In some embodiments, the patient is one suffer ing from one or more symptoms of coronavirus infection, such as fever, coughing, headache, respiratory distress, pneumonia, etc. In some embodiments, the patient is a subject belong ing to a risk group, e.g. an elderly subject, an immunocompromised subject, a subject suffer ing from an underlying health problem, such as diabetes, a long-term respiratory condition such as asthma or COPD, a long-term coronary condition, such as a person with weak heart or carrying a pacemaker, etc. In some embodiments, the treated subject is one having come into contact with someone carrying the viral infection. In some embodiments, treatment is prophylactic.
The virus treated according to the present invention belongs to the virus belonging to the Coronaviridae virus family, more particularly the Orthocoronavirinae subfamily. In some em bodiments, the virus is a human coronavirus. In some embodiments, the human coronavirus is selected from HCoV-NL63, HCoV-OC43, HCoV-229E, HCoV-HKlM, SARS-CoV (Severe Acute Respiratory Syndrome-Corona Virus), SARS-CoV-2, and CoV MERS (Middle East Respiratory Syndrome virus).
In some embodiments, the human coronavirus is HCoV-NL63. In some embodiments, the human coronavirus is HCoV-OC43. In some embodiments, the human coronavirus is HCoV- 229E. In some embodiments, the human coronavirus is HCoV-HKlM. In some embodiments, the human coronavirus is SARS-CoV. In some embodiments, the human coronavirus is SARS-CoV-2. In some embodiments, the human coronavirus is CoV MERS.
EXAMPLES
The invention is further illustrated in the following non-limiting examples.
EXAMPLE 1
3-Chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazole-5-carbonyl)piperazin-1- vDbenzonitrile
Flash column chromatography was performed on a Teledyne ISCO, Combi Flash Rf+ Lumen using a RediSep Rf silica column. Analytical HPLC-MS was performed using an Agilent 1100 series Liquid Chromatograph/Mass Selective Detector (MSD) (Single Quadropole) equipped with an electrospray interface and a UV diode array detector. Analyses were performed by
two methods using either an ACE 3 C8 (3.0 x 50 m ) column with a gradient of acetonitrile in 0.1% aqueous TFA over 3 min and a flow of 1 mL/min, or an Xbridge C18 (3.0 x 50 mm) column with a gradient of acetonitrile in 10 mM ammonium bicarbonate over 3 min and a flow of 1 mL/min. NMR spectra were recorded on a Bruker 400 MHz instrument at 25°C.
Step 1: 4-(2,6-Dimethoxyphenyl)-1 -methyl-triazole
A mixture of (1 eq) 4-bromo-1 -methyl-triazole, (1.1 eq) (2,6-dimethoxyphenyl) boronic acid,
(3 eq) potassium carbonate and (0.05 eq) tetrakis (triphenylphosphine)palladium was added to round bottom flask. Under an inert atmosphere the solvents Dioxane/Water 10:1 was added, and the mixture was stirred in a closed vessel at 100°C for 24 hours. The reaction was followed by LCMS at different time points. Reaction mixture was concentrated and then purified by silica (ether/ethyl acetate as eluents) to obtain a white solid 4-(2,6-dimethoxy- phenyl)-1 -methyl-triazole (55% yield), which was used as starting material in step 2.
Step 2: 5-(2,6-Dimethoxyphenyl)-3-methyl-triazole-4-carboxylic acid To a solution of (1 eq) 4-(2,6-dimethoxyphenyl)-1 -methyl-triazole in tetrahydrofuran at 0 °C was added LDA base (1.5 eq). The mixture was stirred at 0 °C for 30 min. CO2 (generated from dry ice) was bubbled through the mixture for 1 hour. The reaction was monitored by LCMS. The reaction was warmed to 20°C over 1 hour. Water was added and the solvent was removed under reduced pressure. The water phase was washed with EtOAc (2 x 40 ml) and acidified with HCI 35%. The aqueous phases were extracted with EtOAc (2 x 50 ml) dried and evaporated under reduced pressure to obtain a white solid 5-(2,6-dimethoxyphenyl)-3- methyl-triazole-4-carboxylic acid which was used directly in step 3.
Step 3: 5-(2,6-dimethoxyphenyl)-3-methyl-triazole-4-carbonyl chloride The compound 5-(2,6-dimethoxyphenyl)-3-methyl-triazole-4-carbonyl chloride was prepared by reaction with SOCI2, according to the general procedure described in WO 2013/171334 (cf. first step in Reaction Scheme 2). The obtained 5-(2,6-dimethoxyphenyl)-3-methyl-tria- zole-4-carbonyl chloride was used in step 4.
Step 4: 3-Chloro-4-[4-[5-(2, 6-dimethoxyphenyl)-3-methyl-triazole-4-carbonyl] piperazin-1-yl] benzonitrile
The compound 3-chloro-4-[4-[5-(2,6-dimethoxyphenyl)-3-methyl-triazole-4-carbonyl] piper- azin-1-yl] benzonitrile was prepared by reacting 5-(2,6-dimethoxyphenyl)-3-methyl-triazole-4- carbonyl chloride with 5-(2,6-dimethoxyphenyl)-3-methyl-triazole-4-carbonyl chloride
according to the general procedure described in WO 2013/171334 (cf. last step in Reaction Scheme 2). Yield: 11.3% (yellowish oil); 400 MHz dH (CDCI3) 7.61 (d, J = 1.9 Hz, 1 H), 7.48 (dd, J = 2.0, 8.3, Hz, 1 H), 7.38 (t, J = 8.3 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 1 H), 6.67 (d, J = 8.4 Hz, 2H), 4.21 (s, 3H), 3.77 (s, 7H), 3.28 (s, 2H), 2.95 (s, 2H), 2.44 (s, 2H), 2.21 (s, 2H), 2.00 (s, 2H), 1.26 (s, 3H), 0.91-0.75 (m, 2H). HPLC/MS (M + H)+ = 467; Rt= 2.49 min.
EXAMPLE 2.
SARS-CoV-2 Plaque Reduction Assay
The antiviral activity against SARS-CoV-2 of some compounds of formula (I) was tested in two plaque reduction assays. The tested compounds are shown in Table 1.
Compound A was obtained as described in Example 1 herein above, whereas Compounds B and C were prepared as described in Examples 6 and 7, respectively, in WO 2013/171334.
Samples (600mI_) of solutions of compound A, B or C in DMSO and serum free medium, at a concentration of 100 mM, 50 mM, 33 mM, 11 mM, or 3.67 mM were used and the final concen trations after dilution in the wells were 5.5 mM, 2.75 mM, 1.8 mM, 0.6 mM, and 0.2 mM, respec tively
Vero cells were grown in Minimum Essential Medium supplemented with Fetal Bovine Se rum, antibiotics and HEPES (MEM +FBS, Abx, HEPES) at 37 °C in 5% CO2. The cells were seeded in either 12-well plates, or 6-well plates, 1 day prior to the start of experiment. Intact (95% or more) monolayers were verified, prior to starting infection protocol. The growth me dium was removed, and the cells were washed with 2x Infection medium (MEM+Abx+HEPES, No FBS). The samples were diluted in serum free medium (SF me dium) with 500mI per dilution for plating in triplicate.
The SARS-CoV-2 virus stock solutions (titre = 9.78 x 105 plaque forming units/mL (PFU/ml)) were diluted in SF medium to 167 PFU/ml (Example 1) or 334 PFU/ml (Example 2) (in tripli cate), and 150 mI were used to infect each well (25PFU, in Experiment 1) or (50 PFU, in Ex periment 2). The test compounds (150mI) were added 30 min post infection and the incuba tion was performed for 30 min before the wells were overlaid with 2X L-15 medium and aga rose (0.9%w/v final concentration), containing trypsin to a final concentration of 2 pg/pl. As a control, the test included wells that did not receive any test compound. The plates were incu bated for 3 days before counting the plaques. The results are illustrated in Figure 1 and Fig ure 2. In Tables 2 and 3 the results, in terms of number of plaques, are shown for Com pounds A, B and C at different dilutions. Figure 1 illustrates number of plaques from Table 2, and Figure 2 illustrates number of plaques from Table 3.
Table 2
areas. 5.5mM corresponds to 100mM undiluted drug that the monolayer is incubated in for 30 min before overlay media is added. Table 3
EXAMPLE 3
Cytotoxicity assay
Compounds A and B (as identified in Example 2) were tested in a cytotoxicity assay, as fol lows: Madin-Darby Canine Kidney (MDCK) cells were seeded, 4000 cells per well in a 96- well plate. One day later, the test compounds were diluted in serum-free media. The growth media was replaced with 100mI of the new media containing the drug dilution. 3 days later,
10mI of Cell Counting Kit-8 (CCK-8, Sigma Aldrich) reagent was added to every well and in cubate for 2h at 37°C and absorbance was measured at 450nm using a plate reader. Ab- sorbance data was plotted and normalized using Graphpad Prism. 10% DMSO was defined as 0% live cells, and cells in media alone as 100% live cells.
The experiment showed dose-dependent cytotoxicity, with some variation between the con centrations. Compound A appears less cytotoxic than Compound B (Figure 2).
Claims
1. A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein X is C, Y is O, and Z is C,
X is C, Y is N, and Z is N, or X is N, Y is N, and Z is C;
W is O or S; each Ri is independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, and halogen;
R2 is H or C1-C4 alkyl; each R3 is independently selected from nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, and halogen; m is an integer of from 0 to 3; and n is an integer of from 1 to 3; for use in the treatment of a Coronaviridae virus infection.
2. The compound or pharmaceutically acceptable salt for use according to claim 1 , wherein Y is N.
3. The compound or pharmaceutically acceptable salt for use according to claim 2, wherein X is C and Z is N.
4. The compound or pharmaceutically acceptable salt for use according to any one of claims 1 to 3, wherein m is an integer of from 1 to 3.
5. The compound or pharmaceutically acceptable salt for use according to any one of claims 1 to 4, wherein R2 is C1-C4 alkyl.
6. The compound or pharmaceutically acceptable salt for use according to any one of claims 1 to 5, wherein W is O.
7. The compound or pharmaceutically acceptable salt for use according to any one of claims 1 to 5, wherein W is S.
8. The compound or pharmaceutically acceptable salt for use according to any one of claims 1 to 7, of formula (Ig)
wherein
R3a is selected from nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen; and X, Y, Z, W, Ri, R2, R3, and m are as defined in any one of claims 1 to 7.
9. The compound or pharmaceutically acceptable salt for use according to claim 8, of formula (Im)
wherein each Ria is independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, and halogen; R3b is selected from halogen, C1-C4 alkyl, and C1-C4 alkoxy; m is 2 or 3; n is 2 or 3; and
X, Y, Z, W, Ri, R2, R3, and R3a, are as defined in claim 8.
10. The compound or pharmaceutically acceptable salt for use according to claim 9, wherein m is 2 and n is 2.
11. The compound or pharmaceutically acceptable salt for use according to any one of claims 8 to 10, wherein R3a is selected from nitro and cyano.
12. The compound or pharmaceutically acceptable salt for use according to claim 1 , wherein the compound is selected from
3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1 , 2, 3-triazole-5-carbonyl)piperazin-1- yl)benzonitrile,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(5-methyl-3-phenylisoxazol-4-yl)methanone, (5-methyl-3-phenylisoxazol-4-yl)(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methanone, (4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(4-(2-methoxyphenyl)-1 -methyl-1 H-1 , 2, 3-triazol-5- yl)methanone,
(4-(2-chloro-4-nitrophenyl)piperazin-1 -yl)(4-(2-fluoro-6-methoxyphenyl)-1 -methyl-1 H-1, 2,3- triazol-5-yl)methanone,
(4-(2-chloro-4-nitrophenyl)piperazin-1 -yl)(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol- 5-yl)methanone,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(1-(2-methoxyphenyl)-4-methyl-1 H-1,2,3-triazol-5- yl)methanone,
(4-(2-chloro-4-(trifluoromethyl)phenyl)piperazin-1-yl)(1-(2-methoxyphenyl)-4-methyl-1 H-1 ,2,3- triazol-5-yl)methanone,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(1-(2,4-dimethoxyphenyl)-4-methyl-1 H-1,2,3-triazol-
5-yl)methanone,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(1-(2,6-dimethoxyphenyl)-4-methyl-1 H-1,2,3-triazol-
5-yl)methanone,
3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1 , 2, 3-triazole-5-carbonothioyl)piperazin- 1-yl)benzonitrile,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(5-methyl-3-phenylisoxazol-4-yl)methanethione, (5-methyl-3-phenylisoxazol-4-yl)(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methanethione, (4-(2-chloro-4-nitrophenyl)piperazin-1 -yl)(4-(2-methoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol-5- yl)methanethione,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(4-(2-fluoro-6-methoxyphenyl)-1 -methyl-1 H-1, 2, 3- triazol-5-yl)methanethione,
(4-(2-chloro-4-nitrophenyl)piperazin-1 -yl)(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol- 5-yl)methanethione,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(1-(2-methoxyphenyl)-4-methyl-1 H-1,2,3-triazol-5- yl)methanethione,
(4-(2-chloro-4-(trifluoromethyl)phenyl)piperazin-1-yl)(1-(2-methoxyphenyl)-4-methyl-1 H-1 ,2,3- triazol-5-yl)methanethione,
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(1-(2,4-dimethoxyphenyl)-4-methyl-1 H-1,2,3-triazol- 5-yl)methanethione, and
(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(1-(2,6-dimethoxyphenyl)-4-methyl-1 H-1,2,3-triazol-
5-yl)methanethione.
13. The compound or pharmaceutically acceptable salt for use according to claim 1, wherein the compound is selected from
(4-(2-chloro-4-nitrophenyl)piperazin-1 -yl)(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol- 5-yl)methanethione,
(4-(2-chloro-4-nitrophenyl)piperazin-1 -yl)(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazol- 5-yl)methanone,
3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1 , 2, 3-triazole-5-carbonyl)piperazin-1- yl)benzonitrile, and
3-chloro-4-(4-(4-(2,6-dimethoxyphenyl)-1 -methyl-1 H-1 , 2, 3-triazole-5- carbonothioyl)piper- azin-1-yl)benzonitrile.
14. The compound or pharmaceutically acceptable salt for use according to any one of claims 1 to 13, wherein the Coronaviridae virus is a human coronavirus.
15. The compound or pharmaceutically acceptable salt for use according to claim 14, wherein the human coronavirus is selected from HCoV-NL63, HCoV-OC43, HCoV-229E, HCoV-HKLH, SARS-CoV-1 , SARS-CoV-2, and CoV MERS.
16. A combination comprising a compound or pharmaceutically acceptable salt for use as de fined in any one of claims 1 to 15, and a further therapeutically active agent.
17. The combination of claim 16, wherein the further therapeutically active agent is selected from further antiviral agents, antibiotic agents, anti-inflammatory agents, analgesic agents, and antipyretic agents.
18. The combination of claim 17, wherein the further therapeutically active agent is selected from further antiviral agents.
19. A kit-of-parts comprising (A) a compound or salt for use as defined in any one of claims 1 to 15, in a pharmaceutical formulation; and
(B) a further therapeutically active agent in a pharmaceutical formulation; and a package insert with instructions for the combined use of components (A) and (B).
20. The kit-of-parts according to claim 19, wherein the further therapeutically active agent is selected from further antiviral agents, antibiotic agents, anti-inflammatory agents, analgesic agents, and antipyretic agents.
21. The kit-of-parts according to claim 20, wherein the further therapeutically active agent is selected from further antiviral agents.
22. A compound of formula (Iq)
or a pharmaceutically acceptable salt thereof, wherein X is C, Y is O, and Z is C,
X is C, Y is N, and Z is N, or X is N, Y is N, and Z is C;
W is O or S;
Ri is selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, and halogen; each Ria is independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, and halogen;
R2 is H or C1-C4 alkyl; each R3 is independently selected from nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, and halogen; m is 2 or 3; and n is an integer of from 1 to 3.
23. The compound or pharmaceutically acceptable salt according to claim 22, wherein Y is N.
24. The compound or pharmaceutically acceptable salt according to claim 23, wherein X is C and Z is N.
25. The compound or pharmaceutically acceptable salt according to any one of claims 22 to
24, wherein m is 2 and n is 2.
26. The compound or pharmaceutically acceptable salt according to any one of claims 22 to
25, wherein R2 is C1-C4 alkyl.
27. The compound or pharmaceutically acceptable salt according to any one of claims 22 to
26, wherein W is O.
28. The compound or pharmaceutically acceptable salt according to any one of claims 22 to 26, wherein W is S.
29. The compound or pharmaceutically acceptable salt according to claim 22, wherein the compound is 3-chloro-4-(4-(4-(2, 6-dimethoxyphenyl)-1 -methyl-1 H-1, 2, 3-triazole-5-car- bonyl)piperazin-1-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
30. The compound or pharmaceutically acceptable salt according to any one of claims 22 to 29, for use in therapy.
31. A pharmaceutical formulation comprising a compound or pharmaceutically acceptable salt according to any one of claims 22 to 29, and optionally a pharmaceutically acceptable excipient.
32. A compound or pharmaceutically acceptable salt according to any one of claims 22 to 29, for use in the treatment of a Coronaviridae virus infection.
33. The compound or pharmaceutically acceptable salt for use according claim 32, wherein the Coronaviridae virus is a human coronavirus.
34. The compound or pharmaceutically acceptable salt for use according to claim 33, wherein the human coronavirus is selected from HCoV-NL63, HCoV-OC43, HCoV-229E, HCoV-HKlM , SARS-CoV-1 , SARS-CoV-2, and CoV MERS.
35. A combination comprising the compound or pharmaceutically acceptable salt according to any one of claims 22 to 29, and a further therapeutically active agent.
36. The combination of claim 35, wherein the further therapeutically active agent is selected from antiviral agents, antibiotic agents, anti-inflammatory agents, analgesic agents, and anti pyretic agents.
37. The combination of claim 36, wherein the further therapeutically active agent is selected from antiviral agents.
38. A kit-of-parts comprising:
(A) a compound according to any one of claims 22 to 29, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation; and
(B) a further therapeutically active agent in a pharmaceutical formulation; and a package insert with instructions for the combined use of components (A) and (B).
39. The kit-of-parts according to claim 38, wherein the further therapeutically active agent is selected from antiviral agents, antibiotic agents, anti-inflammatory agents, analgesic agents and antipyretic agents.
40. The kit-of-parts according to claim 39, wherein the further therapeutically active agent is selected from antiviral agents.
41. A process for preparing a compound of formula (Iq)
wherein X, Y, Z, W, Ri, each Ria, R2, each R3, m, and n are as defined in any one of claims 22 to 29, by
reacting a compound of formula (III) with a compound of formula (IVa) to obtain a compound of formula (Va);
reacting the compound of formula (Va) with CO2 in the presence of a base, such as LDA, preferably at a temperature of about 0°C; to obtain a compound of formula (Via);
reacting the compound of formula (Via) with SOCI2, to obtain a compound of formula (VII);
and reacting the compound of formula (VII) with a compound of formula (VIII) to obtain a compound of formula (Iq) wherein W is O; and, if W is S, reacting the compound of formula (Iq), wherein W is O, with a thionating agent, such as P2S5.2C5H5N, to obtain a compound of formula (Iq) wherein W is S.
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