WO2022189846A1 - NOVEL ADENOSYLMERCAPTANE DERIVATIVES AS VIRAL mRNA CAP METHYLTRANSFERASE INHIBITORS - Google Patents
NOVEL ADENOSYLMERCAPTANE DERIVATIVES AS VIRAL mRNA CAP METHYLTRANSFERASE INHIBITORS Download PDFInfo
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- WO2022189846A1 WO2022189846A1 PCT/IB2021/061623 IB2021061623W WO2022189846A1 WO 2022189846 A1 WO2022189846 A1 WO 2022189846A1 IB 2021061623 W IB2021061623 W IB 2021061623W WO 2022189846 A1 WO2022189846 A1 WO 2022189846A1
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- nhc
- alkyl
- mrna cap
- derivatives
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- 230000003612 virological effect Effects 0.000 title abstract description 15
- 101710121537 mRNA (guanine-N(7))-methyltransferase Proteins 0.000 title abstract description 14
- 102100040949 mRNA cap guanine-N7 methyltransferase Human genes 0.000 title abstract description 14
- 101710144593 mRNA cap guanine-N7 methyltransferase Proteins 0.000 title abstract description 14
- 101710082804 mRNA cap methyltransferase Proteins 0.000 title abstract description 14
- 101710167437 mRNA-capping enzyme small subunit Proteins 0.000 title abstract description 14
- 239000003697 methyltransferase inhibitor Substances 0.000 title description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- -1 -F Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 208000001528 Coronaviridae Infections Diseases 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 claims description 2
- 125000005841 biaryl group Chemical group 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 13
- 208000036142 Viral infection Diseases 0.000 abstract description 7
- 230000009385 viral infection Effects 0.000 abstract description 7
- 108060004795 Methyltransferase Proteins 0.000 abstract description 5
- 102000016397 Methyltransferase Human genes 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
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- 238000000034 method Methods 0.000 description 11
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
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- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
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- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 6
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- 108090000623 proteins and genes Proteins 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
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- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 3
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- 238000006243 chemical reaction Methods 0.000 description 3
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- 239000003480 eluent Substances 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 108010066733 mRNA (guanine(N7))-methyltransferase Proteins 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- RSFDFESMVAIVKO-UHFFFAOYSA-N 3-sulfanylbenzoic acid Chemical compound OC(=O)C1=CC=CC(S)=C1 RSFDFESMVAIVKO-UHFFFAOYSA-N 0.000 description 2
- IYSNPOMTKFZDHZ-KQYNXXCUSA-N 5'-chloro-5'-deoxyadenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O IYSNPOMTKFZDHZ-KQYNXXCUSA-N 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- 239000002773 nucleotide Substances 0.000 description 2
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
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- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229940123379 Methyltransferase inhibitor Drugs 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
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- 230000002238 attenuated effect Effects 0.000 description 1
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- 230000004071 biological effect Effects 0.000 description 1
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
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- YUHSMQQNPRLEEJ-UHFFFAOYSA-N methyl 3-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=CC(CBr)=C1 YUHSMQQNPRLEEJ-UHFFFAOYSA-N 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
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- 239000013642 negative control Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical class OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
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
- A61K31/13—Amines
- A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
Definitions
- the present invention relates to medicine, and in particular to the treatment of viral infections, more particularly to inhibitors of viral mRNA cap methyltransferases (MTases). Even more particularly, the invention relates to adenosylmercaptane derivatives and pharmaceutical compositions thereof and their use as inhibitors for viral mRNA cap methyltransferases.
- MTases viral mRNA cap methyltransferases
- Coronaviruses have evolved an mRNA capping apparatus to protect their 5 ’-ends with a cap moiety that is indistinguishable from eukaryotic mRNA cap structures (Decroly, et al. Nat Rev. Microbiol. 2011, 10, 51).
- the capping is performed by the MTases Nspl4 and Nspl6, which modify the N7 of the guanosine cap and the 2’ -OH group of the two subsequent nucleotides of viral mRNA, respectively (Bouvet, M et al. PLoS Pathog. 2010, 6, el 000863).
- TheN7-methylguanosine (m7G) cap is required for efficient translation of viral proteins, whereas 2'-O-methylation of the first two nucleotides is important for evasion of host immune response (Decroly, E et al. PLoS Pathog. 2011, 7, el 002059; Chen, Y. at al. Proc. Natl. Acad. Sci. USA 2009, 106, 3484)
- the invention features a method of treating viral infections in humans or animals, comprising administering to a human or animal in need of a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug, wherein the compound is an inhibitor of viral mRNA cap methyltransferase.
- the invention features a pharmaceutical composition for treatment of viral infections comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug; and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of viral mRNA cap methyltransferase.
- the invention features the use of a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug, wherein the compound is an inhibitor of viral mRNA cap methyltransferase, in the manufacture of a medicament for treatment or prevention of viral infections.
- the invention features a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug for use in treating or preventing viral infections, wherein the compound is an inhibitor of viral mRNA cap methyltransferase.
- an inhibitor of viral mRNA cap methyltransferase is a compound of Formula I: wherein:
- n is an integer selected from 0 to 1; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; wherein when R 1 , R 2 , R 3 , R 4 are H; n is not 0, and when R 1 , R 2 , R 4 are H; R 3 is NO 2 ; then n is not 0.
- the treatment is treatment of a disease or disorder that is mediated by a viral mRNA cap methyltransferase or human mRNA cap methyltransferase.
- the treatment is treatment of a disease or disorder that is ameliorated by the inhibition of a viral mRNA cap methyltransferase or human mRNA cap methyltransferase.
- the treatment is treatment of a disease or disorder that is treated by a viral mRNA cap methyltransferase or human mRNA cap methyltransferase inhibitor.
- the invention features a kit comprising a adenosylmercaptane derivatives described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging.
- the invention features compounds obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
- the invention features compounds obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
- the invention features novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
- Viral nonstructural proteins (Nsp) group have been identified as a group of promising biological targets for the development of broad-spectrum antiviral drugs against coronaviruses (Chen, ⁇ et al. Proc. Natl. Acad. Sci. USA 2009, 106, 3484; Chen, Y. et al. J. Virol. 2013, 87, 6296.; Menachery, V. D. et al. J. Virol. 2014, 88, 4251, Pugh, C. S. and Borchardt, R. T. Biochemistry 1982, 21, 1535)
- Reagents and conditions (a) i SOCl 2 , pyridine, MeCN, 0°C to rt; ii NH 4 OH, MeOH; (b) 3- mercaptobenzoic acid, CS 2 CO 3 , DMF, rt.
- Reagents and conditions (a) DIAD, PPH 3 , AcSH, THF, 0°C; (b) appropriate RHal, NaOMe, MeOH, -30°C to rt; (c) LiOH, THF, water, rt; (d) HCOOH, water, rt or 50°C.
- Diisopropyl azodicarboxylate (0.6 ml, 3.05 mmol) was added drop wise over 5 min to an ice-cold solution of triphenylphosphine (0.80 g, 3.06 mmol) in dry THF (5 ml). After stirring for 30 min in the ice bath a thick suspension formed, 2 ,3 -O-isopropylideneadenosine 4 (0.47 g, 1.53 mmol) was added, and the stirring was continued for 10 min at 0°C.
- Acetonide 6.1 (70 mg, 0.15 mmol) was dissolved in ice-cold HCOOH solution in water (50%, 1 ml). The reaction mixture was stirred at 50°C for 20 h. The solvent was evaporated, then the residue was co-evaporated with EtOH to remove HCOOH. The residue was washed with small amount of hot MeOH, then with acetonitrile, dried in vacuo to give 46 mg (72%) of the product 1.5 as white solid. HPLC purity 91%.
- Methyltransferase activity was determined with an EPIgeneous Methyltransferase Assay kit by assaying the conversion of SAM to SAH according to the manufacturer’s directions.
- the enzymatic reaction was performed in white ProxiPlate-384 Plus with a final volume of 10 ml.
- the reaction buffer is composed of 40 mM Tris-HCl pH 8.3 (pH 8.0 for nsp 16) and 100mM NaCl (or 10mM KCl only for nspl6), 1 mM DTT, 2mM MgCh, 0.01% Tween20. 4 ml purified recombinant protein Nspl4 at 0.4 mM or Nsp 16 at 3mM final concentration were added in the assay wells, containing previously dispensed inhibitors.
- the reaction was started with 4 ml of a mix containing both 4 mM GpppG (Jena Bioscience, cat.nr. NU854) or ⁇ 5 pM m7GpppA-RNA (for Nsp 16) and SAM at 10 mM final concentrations and incubated at 37°C for 20 min (2h for Nsp 16).
- HTRF signals were measured using a Hidex Sense (Finland) with an excitation filter at 337 nm and fluorescence wavelength measurements at 620 and 665 nm, an integration delay of 150 ms, and an integration time of 400 ms.
- Mean HTRF Ratio Mean Sample HTRF Ratio - Blank HTRF Ratio, where ‘blank’ is the signal with compound (or DMSO in control sample) and Anti-SAH-Lumi4-Tb.
- % Inhibition 100-(max signal comp - min signal comp ) *100 / (max signal control - min signal control), where ‘max signal’ is the signal ratio without protein (negative control) and ‘min signal’ the signal ratio in sample.
- the ICso value was calculated using the program Graph Pad Prism® 8.0.
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Abstract
The present invention relates to medicine, and in particular to the treatment of viral infections, more particularly to inhibitors of viral mRNA cap methyltransf erases (MTases). Even more particularly, the invention relates to adenosylmercaptane derivatives and pharmaceutical compositions thereof and their use as inhibitors for viral mRNA cap methyltransferases.
Description
Novel adenosylmercaptane derivatives as viral mRNA cap methyltransferase inhibitors
Field of invention
[001] The present invention relates to medicine, and in particular to the treatment of viral infections, more particularly to inhibitors of viral mRNA cap methyltransferases (MTases). Even more particularly, the invention relates to adenosylmercaptane derivatives and pharmaceutical compositions thereof and their use as inhibitors for viral mRNA cap methyltransferases.
Background of invention
[002] Coronaviruses have evolved an mRNA capping apparatus to protect their 5 ’-ends with a cap moiety that is indistinguishable from eukaryotic mRNA cap structures (Decroly, et al. Nat Rev. Microbiol. 2011, 10, 51). The capping is performed by the MTases Nspl4 and Nspl6, which modify the N7 of the guanosine cap and the 2’ -OH group of the two subsequent nucleotides of viral mRNA, respectively (Bouvet, M et al. PLoS Pathog. 2010, 6, el 000863). TheN7-methylguanosine (m7G) cap is required for efficient translation of viral proteins, whereas 2'-O-methylation of the first two nucleotides is important for evasion of host immune response (Decroly, E et al. PLoS Pathog. 2011, 7, el 002059; Chen, Y. at al. Proc. Natl. Acad. Sci. USA 2009, 106, 3484)
[003] Studies on SARS-CoV-1 have shown that mutations in the Nspl4 and Nspl6 genes lead to a significantly attenuated virus that is recognized by the innate immune system. (Chen, Y et al. Proc. Natl. Acad. Sci. USA 2009, 106, 3484; Chen, Y. etal. J. Virol. 2013, 87, 6296.; Menachery, V. D. etal. J. Virol. 2014, 88, 4251.)
[004] In addition, the studies with the Nspl4 and Nspl6 SAM analogues have shown that the inhibition of Nspl4 or Nspl6 can be used to treat coronavirus infections (Pugh, C. S. and Borchardt, R T. Biochemistry 1982, 21, 1535) However, despite the efforts made so far, none of the methyltransferase inhibitors have been advanced into clinical development
Summary of the invention
[005] In a first aspect, the invention features a method of treating viral infections in humans or animals, comprising administering to a human or animal in need of a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug, wherein the compound is an inhibitor of viral mRNA cap methyltransferase.
[006] In another aspect, the invention features a pharmaceutical composition for treatment of viral infections comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug; and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of viral mRNA cap methyltransferase.
[007] In another aspect, the invention features the use of a compound or prodrug thereof, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph of said compound or prodrug, wherein the compound is an inhibitor of viral mRNA cap methyltransferase, in the manufacture of a medicament for treatment or prevention of viral infections.
[008] In another aspect, the invention features a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug for use in treating or preventing viral infections, wherein the compound is an inhibitor of viral mRNA cap methyltransferase.
[009] In one embodiment an inhibitor of viral mRNA cap methyltransferase is a compound of Formula I:
wherein:
R1, R2, R3 R4 are independently H, C1-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl- C1-6alkyl, C2- 6alkenyl, C2-6alkynyl, aryl, biaryl, arylC1-6alkyl, aryl C2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylC1-6alkyl, heteroarylC2-6alkenyl, R5O(CH2)n, R5S(CH2)n, R5OC(=O)(CH2)n, R5N(R6)C(=O)(CH2)n, R5N(R6)(CH2)n, -F, -Cl, -Br, -I, -CF3, -CH2CF3, -CF2CF2H, -OH, -L-OH,-O-L-OH, -OR5, -O-L-NH2, -O-L-NHR5, -O-L-N(R5)R6, -L-OR5,-O-L-OR5,-OCF3, -OCH2CF3, -OCF2CF2H, -L-OR5,-O-L-OR5,-OCF3, -OCH2CF3, -OCF2CF2H, SR5, SCF3, CN, -NO2, -NO2, -NH2, -NHR5, -NR52, -N(R5)R6, -L-NH2, -L-NHR5, -L-NR5 2, -L-N(R5)R6,-NH-L-NH2, -NH-L-NHR5, -NH-L-N(R5)R6, -NH-L-N(R5)R6,-NR5-L-NH2, -NR5-L-NHR5, -NR5-L-N(R5)R6,
-NR5-L-N(R5)R6, -N(R5)R6, -C(=O)OH, -C(=O)OR5, -C(=O)NH2, -C(=O)NHR5, -C(=O)N(R5)R6,
-C(=O)N(R5)R6,-NHC(=O)R5, -NR5C(=O)R6, -NHC(=O)OR5,
-NR5C(=O)OR6, -OC(=O)NH2, -OC(=O)NHR5, -OC(=O)N(R5)R6,
-OC(=O) R5NR6,-OC(=O)R5, -C(=O)R5,-NHC(=O)NH2, -NHC(=O)NHR6,
-NHC(=O)NR5 2, -NHC(=O)N(R5)R6, -NR5C(=O)NH2, -N(R5)C(=O)NHR6,
-NR5C(=O)N (R5)R6
[010] wherein: n is an integer selected from 0 to 1; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; wherein when R1, R2, R3, R4 are H; n is not 0, and when R1 , R2, R4 are H; R3 is NO2; then n is not 0.
[011] In one embodiment, the treatment is treatment of a disease or disorder that is mediated by a viral mRNA cap methyltransferase or human mRNA cap methyltransferase.
[012] In one embodiment, the treatment is treatment of a disease or disorder that is ameliorated by the inhibition of a viral mRNA cap methyltransferase or human mRNA cap methyltransferase. [013] In one embodiment, the treatment is treatment of a disease or disorder that is treated by a viral mRNA cap methyltransferase or human mRNA cap methyltransferase inhibitor.
[014] In another aspect, the invention features a kit comprising a adenosylmercaptane derivatives described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging.
[015] In another aspect, the invention features compounds obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
[016] In another aspect, the invention features compounds obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
[017] In another aspect, the invention features novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
[018] As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention.
Description of invention
[019] Viral nonstructural proteins (Nsp) group have been identified as a group of promising biological targets for the development of broad-spectrum antiviral drugs against coronaviruses (Chen, ¥ et al. Proc. Natl. Acad. Sci. USA 2009, 106, 3484; Chen, Y. et al. J. Virol. 2013, 87, 6296.; Menachery, V. D. et al. J. Virol. 2014, 88, 4251, Pugh, C. S. and Borchardt, R. T. Biochemistry 1982, 21, 1535)
[020] When testing the novel adenosylmercaptane derivatives with general formula I for their ability to inhibit Nspl4 and Nspl6 we have unexpectedly discovered, that said derivatives exhibit pronounced inhibitory properties toward said nonstructural proteins, and thus are useful in treatment of viral infections.
[021] According to this invention, the results from nonstructural protein inhibition studies demonstrate that adenosylmercaptane derivatives with general formula I are novel class inhibitors of nonstructural proteins. Several example compounds from the present invention display nanomolar to low micromolecular nonstructural protein inhibitory potency.
Stereochemistry
[022] Many of the chemical structures shown herein indicate one or more specific stereoisomeric configurations. Similarly, many of the chemical structures shown herein are silent in this respect, and do not indicate any stereoisomeric configuration. Similarly, many of the chemical structures shown herein indicate the specific stereoisomeric configurations at one or more positions, but are silent with respect to one or more other positions. Where a chemical structure herein is silent with respect to the stereoisomeric configuration at a position, that structure is intended to depict all possible stereoisomeric configurations at that position, both individually, as if each possible stereoisomeric configuration was individually recited, and also as a mixture (e.g., a racemic mixture) of stereoisomers.
Combinations
[023] Each and every compatible combination of the embodiments described above is explicitly disclosed herein, as if each and every combination was individually and explicitly recited.
Examples of Specific Embodiments
[024] The following examples further illustrate the invention, but should not be construed to limit the scope of the invention in any way.
[025] The following adenosylmercaptane derivatives with general formula I were prepared as examples of the current invention:
General Synthesis
[026] Compounds 1.1-1.4 were prepared according to Scheme 1. Adenosine 2 was first transformed to chloride 3 which was subsequently used for the alkylation of mercaptobenzoic acids.
Scheme 1
Reagents and conditions: (a) i SOCl2, pyridine, MeCN, 0°C to rt; ii NH4OH, MeOH; (b) 3- mercaptobenzoic acid, CS2CO3, DMF, rt.
[027] For the synthesis of 1.5, protected adenosine 4 was used as a starting material. This was first transformed to S-acetyl mercapto derivative 5 which was deacylated and S-alkylated to give intermediate 6. Finally, deprotection of diol provided target compound 1.5.
Scheme 2
Reagents and conditions: (a) DIAD, PPH3, AcSH, THF, 0°C; (b) appropriate RHal, NaOMe, MeOH, -30°C to rt; (c) LiOH, THF, water, rt; (d) HCOOH, water, rt or 50°C.
5'-Chloro-5'-deoxyadenosine 3
[028] To a suspension of adenosine (2) (1.50 g, 5.61 mmol) in dry acetonitrile (6 ml) under an argon atmosphere was added thionyl chloride (1.2 ml, 16.5 mmol) dropwise cooling in the ice bath and keeping the temperature below 4°C. Pyridine (0.9 ml, 11.1 mmol) was added keeping temperature below 4°C and the mixture was stirred in the ice bath for 3 h, then the mixture was allowed to warm to room temperature and stirred 16 h. The precipitate was dissolved by adding water (15 ml) to the reaction mixture. The solution was neutralized to pH 5 by the slow addition of sodium bicarbonate.
[029] The precipitate was collected by vacuum filtration, washed with cold water (2x5 ml), and dried in vacuo to give 1.36 g (77%) of the sulfinyladenosine intermediate. A suspension containing 1.36 g of the sulfinyladenosine in MeOH (15 ml) was treated with 1.5 ml of ammonium hydroxide. Precipitate was formed upon stirring at room temperature for 1 h, the precipitate was filtered, washed with cold MeOH/ammonium hydroxide solution (10:1, 2x5 ml), and dried under vacuum to give 1.11 g (69%) of the product 3 as a white solid.
[030] 1H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.15 (s, 1H), 7.29 (br s, 2H), 5.93 (d, J = 5.6 Hz, 1H), 5.60 (br d, 1H), 5.46 (br d, 1H), 4.75 (q, J = 5.2 Hz, 1H), 4.22 (d, J = 4.5 Hz, 1H), 4.26 - 4.18 (m, 1H), 4.14 - 4.05 (m, 1fH), 3.94 (dd, J = 11.6, 5.0 Hz, 1H), 3.84 (dd, J = 11.6, 6.3 Hz, 1H). Data are consistent with literature values.
[031] Synthesis of products 1.1-1.4, general method A. Exemplified by the synthesis of 3-
((((2S,3S,4R,5R )-5-(6-Amino-9H -purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)thio)benzoic acid 1.4
[032] A suspension of 5'-chloro-5'-deoxyadenosine 3 (70 mg, 0.25 mmol), 3 -mercaptobenzoic acid (42 mg, 0.27 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in dry DMF (1.2 ml) were stirred in a closed vial under argon atmosphere for 5 h. The solvent was evaporated under reduced pressure. The residue was treated with water (5 ml), cooled in the ice bath and neutralized to pH 5 with 1 M HC1. The precipitate was filtered off, washed with water (2x2 ml), dried in vacuo. The residue was chromatographed on Cl 8 silica on Biotage, eluent acetonitrile in 0.1% HCOOH, gradient 5-80%, and then freeze-dried to give 30 mg (30%) of the product 1.4. as a white solid. HPLC purity 97%.
[033] NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.15 (s, 1H), 7.85 (t, J = 1.6 Hz, 1H), 7.73 (dt, J = 7.8, 1.3 Hz, 1H), 7.59 (ddd, J = 7.8, 1.9, 1.1 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.29 (s, 2H), 5.89 (d, J = 5.9 Hz, 1H), 5.53 (d, J = 6.1 Hz, 1H), 5.41 (d, J = 4.9 Hz, 1H), 4.82 (q, J = 5.6 Hz, 1H), 4.23 - 4.18 (m, 1H), 4.01 (ddd, J = 7.0, 5.9, 3.3 Hz, 1H), 3.53-3.30 (m, 2H, overlapped with water). 13C NMR (100 MHz, DMSO-d6) δ 166.9, 156.1, 152.7, 149.5, 140.0, 136.8, 132.3, 131.7, 129.4, 128.4, 126.7, 119.3, 87.6, 82.8, 72.8, 72.6, 35.1. HRMS (ESI/TOF-Q) m/z: [M + H]+ calcd for C17H18N5O5S, 404.1029; found, 404.1036.
By the method analogues to method A the following compounds were obtained:
[034] 5 -Acetylthio-5 -deoxy- 2.3 -O-isopropylideneadenosine 5
Diisopropyl azodicarboxylate (0.6 ml, 3.05 mmol) was added drop wise over 5 min to an ice-cold solution of triphenylphosphine (0.80 g, 3.06 mmol) in dry THF (5 ml). After stirring for 30 min in the ice bath a thick suspension formed, 2 ,3 -O-isopropylideneadenosine 4 (0.47 g, 1.53 mmol) was added, and the stirring was continued for 10 min at 0°C. A solution of thioacetic acid (0.22 ml, 3.08 mmol) in dry THF (1 ml) was added dropwise to the resulting yellow suspension and stirring was continued for another 1 h at 0°C, then allowed to warm to room temperature. The solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel on Biotage, eluent EtOAc:EtOH 3: 1 in petroleum ether, gradient 20-80% to give 0.44 g (78%) of the product 5 as a white solid.
[035] NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 7.90 (s, 1H), 6.06 (d, J = 2.1 Hz, 1H), 5.72 (br s, 2H), 5.51 (dd, J = 6.4, 2.1 Hz, 1H), 4.97 (dd, J = 6.4, 3.1 Hz, 1H), 4.34 (td, J = 6.9, 3.1 Hz, 1H), 3.29 (dd, J = 13.8, 7.2 Hz, 1H), 3.18 (dd, J = 13.8, 6.6 Hz, 1H), 2.34 (s, 3H), 1.60 (s, 3H), 1.39 (s, 3H).
[036] Synthesis of intermediate 6, general method B. Exemplified bv the synthesis of 3- (((((3aS,4S,6R, 6aR)-6-(6-Amino-9H-purin-9-yl)-2.2-dimethvltetrahvdrofuro[3,4-d][3,1dioxol-4- yl)methyl)thio)methyl)benzoic acid 6.1.
[037] To a solution of 5 -acetylthio-5 -deoxy-2 ,3 -O-isopropylideneadenosine (5) (0.11 g, 0.30 mmol) and methyl 3-(bromomethyl)benzoate (76 mg, 0.33 mmol) sodium methoxide solution in
MeOH (5.4 M, 0.12 ml, 0.65 mmol) was added dropwise under argon atmosphere cooling reaction mixture in the dry ice-acetone bath (bath temperature -30°C). The reaction mixture was stirred at - 30°C for 1 h, then allowed to warm to room temperature and stirred for 3 h. The solvent was evaporated under reduced pressure. The residue was diluted with EtOAc (20 ml), washed with saturated NH4CI solution, water, dried over anhydrous Na2SO4 and concentrated.
[038] The residue was purified by chromatography on silica gel on Biotage, eluent EtOAc:EtOH 3: 1 in petroleum ether, gradient 20-60% to give 90 mg of the product with impurities, which was used in the next step without additional purification. This residue was vigorously stirred with LiOH (14 mg, 0.58 mmol) in THF (2 ml) and water (1 ml) mixture at room temperature for 22 h. The reaction mixture was concentrated, diluted with water (3 ml) and acidified with IN HCl to pH 3, white precipitate was extracted with EtOAc (2x15 ml), washed with brine, dried over anhydrous Na2SO4 and evaporated. The residue was washed with small volume of MeOH to give 70 mg (50% in 2 steps) of the product 6.1 as white solid.
[039] 1H NMR (400 MHz, Methanol-d4 ) δ 8.24 (s, 1H), 8.15 (s, 1H), 7.92 (t, J = 1.5 Hz, 1H), 7.83 (dt, J = 7.7, 1.4 Hz, 1H), 7.37 (dt, J = 7.7, 1.6 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 6.12 (d, J = 2.4 Hz, 1H), 5.42 (dd, J = 6.4, 2.4 Hz, 1H), 4.94 (dd, J = 6.4, 3.2 Hz, 1H), 4.27 (td, J = 6.7, 3.2 Hz, 1H), 3.73 (s, 2H), 2.73 (dd, J = 13.8, 6.8 Hz, 1H), 2.66 (dd, J = 13.8, 6.6 Hz, 1H), 1.54 (s, 3H), 1.33 (s, 3H). 13C NMR (100 MHz, Methanol-d4 ) δ 169.6, 156.7, 152.9, 150.0, 142.2, 140.3, 134.5, 132.2, 131.1, 129.5, 129.4, 120.6, 115.5, 91.6, 88.2, 85.2, 85.1, 36.8, 34.5, 27.4, 25.5. HRMS (ESI/TOF-Q) m/z: [M + H]+ calcd for C22H24N5O5S, 458.1493; found, 458.1500.
[040] Synthesis of product 1.5, general method C. 3-(((((2S,3S,4R,5R)-5-(6-Amino-9H-purin-
9-yl)-3.4-dihvdroxvtetrahvdrofuran-2-yl)methyl)thio)methyl)benzoic acid 1.5
Acetonide 6.1 (70 mg, 0.15 mmol) was dissolved in ice-cold HCOOH solution in water (50%, 1 ml). The reaction mixture was stirred at 50°C for 20 h. The solvent was evaporated, then the residue was co-evaporated with EtOH to remove HCOOH. The residue was washed with small amount of hot MeOH, then with acetonitrile, dried in vacuo to give 46 mg (72%) of the product 1.5 as white solid. HPLC purity 91%.
[041] 1H NMR (400 MHz, DMSO-d6) δ 12.95 (br zs, 1H), 8.33 (s, 1H), 8.12 (s, 1H), 7.89 (t, J = 1.5 Hz, 1H), 7.80 (dt, J = 7.7, 1.5 Hz, 1H), 7.46 (dt, J = 7.7, 1.5 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.28 (s, 2H), 5.87 (d, J = 5.6 Hz, 1H), 5.48 (d, J = 6.0 Hz, 1H), 5.30 (d, J = 5.1 Hz, 1H), 4.73 (q, J = 5.6 Hz, 1H), 4.18 -4.13 (m, 1H), 4.01 (td, J = 6.4, 3.9 Hz, 1H), 3.82 (s, 2H), 2.84 (dd, J = 13.9,
5.9 Hz, 1H), 2.70 (dd, J = 13.9, 6.9 Hz, 1H). 13CNMR(100MHz, DMSO-d6) δ 167.2, 156.1, 152.7, 149.4, 140.0, 139.2, 133.3, 131.0, 129.7, 128.6, 127.8, 119.2, 87.6, 83.6, 72.6, 72.5, 35.2, 33.4. HRMS (ESI/TOF-Q) m/z: [M + H]+ calcd for C18H20N5O5S, 418.1180; found, 418.1189.
In vitro Assay
[042] The compounds have been tested for potential antiviral activity in vitro as Nspl4 and Nspl6 inhibitors according to the following process.
[043] Methyltransferase activity was determined with an EPIgeneous Methyltransferase Assay kit by assaying the conversion of SAM to SAH according to the manufacturer’s directions.
[044] The enzymatic reaction was performed in white ProxiPlate-384 Plus with a final volume of 10 ml. The reaction buffer is composed of 40 mM Tris-HCl pH 8.3 (pH 8.0 for nsp 16) and 100mM NaCl (or 10mM KCl only for nspl6), 1 mM DTT, 2mM MgCh, 0.01% Tween20. 4 ml purified recombinant protein Nspl4 at 0.4 mM or Nsp 16 at 3mM final concentration were added in the assay wells, containing previously dispensed inhibitors. The reaction was started with 4 ml of a mix containing both 4 mM GpppG (Jena Bioscience, cat.nr. NU854) or ~5 pM m7GpppA-RNA (for Nsp 16) and SAM at 10 mM final concentrations and incubated at 37°C for 20 min (2h for Nsp 16).
[045] All compounds suspended in 100% DMSO (0.1 % final DMSO) and were tested at 100 μM in duplicate. ICso values were determined for compounds with a higher than 50% inhibitory effect [046] For the detection of released SAH, 2 ml of EPIgeneous detection buffer one was then added in order to stop the reaction. After 10 min of incubation at room temperature, detection reagents were added: 4 ml of a 1/16 dilution of SAH-d2 conjugate in a first place then 4 ml of Anti-SAH- Lumi4-Tb at a 1/100 dilution. HTRF signals were measured using a Hidex Sense (Finland) with an excitation filter at 337 nm and fluorescence wavelength measurements at 620 and 665 nm, an integration delay of 150 ms, and an integration time of 400 ms.
[047] Results were analysed with a two-wavelength signal ratio: [intensity (665 nm)/intensity (620 nm)] *104 (HTRF Ratio).
Calculate the mean HTRF Ratio for each sample:
Mean HTRF Ratio = Mean Sample HTRF Ratio - Blank HTRF Ratio, where ‘blank’ is the signal with compound (or DMSO in control sample) and Anti-SAH-Lumi4-Tb.
[048] Percent inhibition calculated using the following the formula for each inhibitor dilution:
% Inhibition = 100-(max signalcomp - min signalcomp) *100 / (max signal control - min signal control), where ‘max signal’ is the signal ratio without protein (negative control) and ‘min signal’ the signal ratio in sample. The ICso value was calculated using the program Graph Pad Prism® 8.0.
[049] Table 1 Biological activity of adenosylmercaptane derivatives
Claims
1. A compound selected from general formula I:
wherein:
R1, R2, R3 R4 are independently H, C1-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl- C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, arylC1-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroaryl C1-6alkyl, heteroarylC2-6alkenyl, R5O(CH2)n, R5S(CH2)n, R5OC(=O)(CH2)n, R5N(R6) C(= O)(CH2)n , R5N(R6) (CH2)n,
-F, -Cl, -Br, -I, -CF3, -CH2CF3, -CF2CF2H, -OH, -L-OH.-O-L-OH, -OR5, -O-L-NH2, -O-L-NHR5, -O-L-N(R5)R6, -L-OR5,-O-L-OR5,-OCF3, -OCH2CF3, -OCF2CF2H, -L-OR5,-O-L-OR5,-OCF3, -OCH2CF3, -OCF2CF2H, SR5, SCF3, - CN, -NO2, -NO2, -NH2, -NHR5, -NR52, -N(R5)R6,
-L-NH2, -L-NHR5, -L-NR52, -L-N(R5)R6,-NH-L-NH2, -NH-L-NHR5, -NH-L-N(R5)R6, -NH-L-N(R5)R6,-NR5-L-NH2, -NR5-L-NHR5, -NR5-L-N(R5)R6, -NR5-L-N(R5)R6, -N(R5)R6, -C(=O)OH, -C(=O)OR5, -C(=O)NH2, -C(=O)NHR5, -C(
=O)N(R5)6,
-C(=O)N(R5)R6,-NHC(=O)R5, -NR5C(=O)R6, -NHC(=O)OR5,
-NR5C(=O)OR6, -OC(=O)NH2, -OC(=O)NHR5, -OC(=O)N(R5)R6,
-OC(=O) R5NR6,-OC(=O)R5, -C(=O)R5,-NHC(=O)NH2, -NHC(=O)NHR6, -NHC(=O)NR52, -NHC(=O)N(R5)R6, -NR5C(=O)NH2, -N(R5)C(=O)NHR6, -NR5C(=O)N (R5)R6 wherein: n is an integer selected from 0 to 1; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; wherein when R1, R2, R3, R4 are H; n is not 0,
and when R1, R2, R4 are H; R3 is NO2; then n is not 0.
2. The compound according to Claim 1 for use in the treatment of disease caused by coronavirus infection.
3. A pharmaceutical composition comprising the compound according to Claim 1 (i) a pharmaceutically acceptable salt, solvate thereof, and (ii) a pharmaceutically acceptable carrier.
4. The pharmaceutical composition according to Claim 3 for use as a human or veterinary medicament.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LVLVP2021000016 | 2021-03-10 | ||
| LVP-21-16A LV15670B (en) | 2021-03-10 | 2021-03-10 | Novel adenosylmercaptane derivatives as viral mrna cap methyltransferase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2022189846A1 true WO2022189846A1 (en) | 2022-09-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2021/061623 WO2022189846A1 (en) | 2021-03-10 | 2021-12-13 | NOVEL ADENOSYLMERCAPTANE DERIVATIVES AS VIRAL mRNA CAP METHYLTRANSFERASE INHIBITORS |
Country Status (2)
| Country | Link |
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| LV (1) | LV15670B (en) |
| WO (1) | WO2022189846A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003074083A1 (en) * | 2002-03-04 | 2003-09-12 | Pfizer Inc. | Combination therapies for treating methylthioadenosine phosphorylase deficient cells |
| US20130023491A1 (en) * | 2009-12-18 | 2013-01-24 | President And Fellows Of Harvard College | Beta-cell replication promoting compounds and methods of their use |
-
2021
- 2021-03-10 LV LVP-21-16A patent/LV15670B/en unknown
- 2021-12-13 WO PCT/IB2021/061623 patent/WO2022189846A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003074083A1 (en) * | 2002-03-04 | 2003-09-12 | Pfizer Inc. | Combination therapies for treating methylthioadenosine phosphorylase deficient cells |
| US20130023491A1 (en) * | 2009-12-18 | 2013-01-24 | President And Fellows Of Harvard College | Beta-cell replication promoting compounds and methods of their use |
Non-Patent Citations (9)
| Title |
|---|
| BOBILEVA OLGA ET AL: "Potent SARS-CoV-2 mRNA Cap Methyltransferase Inhibitors by Bioisosteric Replacement of Methionine in SAM Cosubstrate", ACS MEDICINAL CHEMISTRY LETTERS, vol. 12, no. 7, 8 July 2021 (2021-07-08), US, pages 1102 - 1107, XP055855723, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.1c00140 * |
| BOUVET: "Metal", PLOS PATHOG, vol. 6, 2010, pages e1000863 |
| CHEN, Y ET AL., PROC. NATL. ACAD. SCI. USA, vol. 106, 2009, pages 3484 |
| CHEN, Y. ET AL., J. VIROL., vol. 87, 2013, pages 6296 |
| DECROLY ET AL., NAT. REV. MICROBIOL., vol. 10, 2011, pages 51 |
| DECROLY, E ET AL., PLOS PATHOG, vol. 7, 2011, pages e1002059 |
| MAHALAPBUTR PANUPONG ET AL: "Structural insight into the recognition of S-adenosyl-L-homocysteine and sinefungin in SARS-CoV-2 Nsp16/Nsp10 RNA cap 2'-O-Methyltransferase", COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL, vol. 18, 1 October 2020 (2020-10-01), Sweden, pages 2757 - 2765, XP055855730, ISSN: 2001-0370, DOI: 10.1016/j.csbj.2020.09.032 * |
| MENACHERY, V. D. ET AL., J. VIROL., vol. 88, 2014, pages 4251 |
| PUGH, C. S.BORCHARDT, R. T., BIOCHEMISTRY, vol. 21, 1982, pages 1535 |
Also Published As
| Publication number | Publication date |
|---|---|
| LV15670B (en) | 2023-11-20 |
| LV15670A (en) | 2022-09-20 |
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