NZ730923B2 - 4'-vinyl substituted nucleoside derivatives as inhibitors of respiratory syncytial virus rna replication - Google Patents
4'-vinyl substituted nucleoside derivatives as inhibitors of respiratory syncytial virus rna replication Download PDFInfo
- Publication number
- NZ730923B2 NZ730923B2 NZ730923A NZ73092315A NZ730923B2 NZ 730923 B2 NZ730923 B2 NZ 730923B2 NZ 730923 A NZ730923 A NZ 730923A NZ 73092315 A NZ73092315 A NZ 73092315A NZ 730923 B2 NZ730923 B2 NZ 730923B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- ethyl
- vinylcytidine
- bis
- onaphthyl
- vinyluridine
- Prior art date
Links
- 241000725643 Respiratory syncytial virus Species 0.000 title description 45
- 230000002401 inhibitory effect Effects 0.000 title description 15
- 150000003833 nucleoside derivatives Chemical class 0.000 title description 12
- 239000003112 inhibitor Substances 0.000 title description 10
- 229920000160 (ribonucleotides)n+m Polymers 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 199
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- -1 -N(R ) Chemical group 0.000 claims description 255
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 130
- 125000000217 alkyl group Chemical group 0.000 claims description 78
- 150000008299 phosphorodiamidates Chemical class 0.000 claims description 78
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims description 72
- 125000003118 aryl group Chemical group 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 239000011780 sodium chloride Substances 0.000 claims description 18
- 125000001188 haloalkyl group Chemical group 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical group O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- RTIXFJOJNSXSOB-UHFFFAOYSA-N dipropan-2-yl hydrogen phosphate;propan-2-yl dihydrogen phosphate Chemical compound CC(C)OP(O)(O)=O.CC(C)OP(O)(=O)OC(C)C RTIXFJOJNSXSOB-UHFFFAOYSA-N 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 claims description 13
- 206010061603 Respiratory syncytial virus infection Diseases 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- RWQNBRDOKXIBIV-UHFFFAOYSA-N Thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
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- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 6
- UHDGCWIWMRVCDJ-XVFCMESISA-N Cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-XVFCMESISA-N 0.000 claims description 6
- 229940104302 Cytosine Drugs 0.000 claims description 6
- NYHBQMYGNKIUIF-PXMDKTAGSA-N Guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1O[C@@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-PXMDKTAGSA-N 0.000 claims description 6
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- UYTPUPDQBNUYGX-UHFFFAOYSA-N Guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 5
- 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 claims description 5
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- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 claims description 5
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- 125000005050 dihydrooxazolyl group Chemical group O1C(NC=C1)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 125000005056 dihydrothiazolyl group Chemical group S1C(NC=C1)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000035510 distribution Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 125000002587 enol group Chemical group 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 230000002255 enzymatic Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000006232 ethoxy propyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000002349 favourable Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000005842 heteroatoms Chemical group 0.000 description 1
- 125000001145 hydrido group Chemical group *[H] 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229940121354 immunomodulators Drugs 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000008011 inorganic excipient Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- YBCISJAPWKQOPH-UHFFFAOYSA-N iodoethane Chemical group [CH2]CI YBCISJAPWKQOPH-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000000873 masking Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- XOBKSJJDNFUZPF-UHFFFAOYSA-N methoxyethyl Chemical group CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000003835 nucleoside group Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229940005943 ophthalmologic Antivirals Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000008012 organic excipient Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 230000000275 pharmacokinetic Effects 0.000 description 1
- 230000036231 pharmacokinetics Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000008298 phosphoramidates Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- OEUAEFQARUZYLW-UHFFFAOYSA-N prop-1-en-2-olate Chemical group [CH2+]C([O-])=C OEUAEFQARUZYLW-UHFFFAOYSA-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
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 239000002212 purine nucleoside Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- HBDYSKVKXMUPKV-UHFFFAOYSA-N pyridine;trioxochromium;hydrochloride Chemical compound [H+].[Cl-].O=[Cr](=O)=O.C1=CC=NC=C1 HBDYSKVKXMUPKV-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- UKNAYQWNMMGCNX-UHFFFAOYSA-N sodium;[hydroxy(phenyl)methyl]-oxido-oxophosphanium Chemical compound [Na+].[O-][P+](=O)C(O)C1=CC=CC=C1 UKNAYQWNMMGCNX-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000000153 supplemental Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 229940026754 topical Antivirals Drugs 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000002264 triphosphate group Chemical class [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-I triphosphate(5-) Chemical compound [O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O UNXRWKVEANCORM-UHFFFAOYSA-I 0.000 description 1
- PIEPQKCYPFFYMG-UHFFFAOYSA-N tris acetate Chemical compound CC(O)=O.OCC(N)(CO)CO PIEPQKCYPFFYMG-UHFFFAOYSA-N 0.000 description 1
- 229950010342 uridine triphosphate Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- 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
- C07H19/06—Pyrimidine radicals
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
-
- 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
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- 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
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/11—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate
-
- 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
-
- 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
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- 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
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
-
- 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
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/213—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate
Abstract
The application discloses compounds of Formula (I), wherein the variable substituents are as defined herein. The compounds of Formula (I) and pharmaceutical compositions comprising compounds of Formula I are useful for the treatment of diseases mediated by RSV.
Description
’-VINYL SUBSTITUTED NUCLEOSIDE DERIVATIVES AS INHIBITORS OF
RESPIRATORY SYNCYTIAL VIRUS RNA REPLICATION
FIELD OF THE INVENTION
The application relates to nucleoside derivatives as inhibitors of Respiratory Syncytial
Virus (RSV) RNA replication. In particular, the instant disclosure is concerned with the use of
purine and pyrimidine nucleoside derivatives as inhibitors of RSV RNA replication and
pharmaceutical compositions containing such compounds.
RSV virus is the leading cause of seasonal respiratory disease throughout the world.
Patients infected with RSV are at risk of developing severe respiratory disease, which can result
in long-lasting complications or death (Lee, N. et al. Clin Infect Dis. 2013 57(8):1069-77; Nair,
H. et al. Lancet. 2010 375(9725) 1545-55).
Many of the drugs approved for the treatment of viral infections are nucleosides or
nucleoside analogues and most of these nucleoside analogue drugs inhibit viral replication,
following conversion to the corresponding triphosphates, through inhibition of the viral
polymerase enzymes. The nucleoside triphosphate analogs are therefore the active inhibitors of
the target enzyme. The delivery of nucleoside analogs to virus infected target cells therefore
requires a precursor that can enter the target cells. This may be a nucleoside analog, if the target
cells have the capacity to convert the nucleoside analog to a nucleoside triphosphate derivative,
or a nucleoside phosphate analog that can be converted to the active triphosphate in the target
cell (Klumpp, K. et al. Hepatitis C: Antiviral Drug Discovery and Development, Nucleoside
Inhibitors of Hepatitis C Virus, Caister Academic Press, Norwich, UK, 2011, pp. 293-311).
RSV is a negative strand RNA virus and belongs to the family of Paramyxoviridae.
The viral genome encodes a RNA-dependent RNA polymerase (L protein) that is essential for
transcription and replication of RSV. The RSV polymerase is incorporated into RSV virions and
carried together with the viral negative strand RNA into newly infected cells. Inhibitors of the
RSV L-protein have been shown to possess antiviral activity, consistent with the essential nature
of the L-protein function for RSV replication (Tiong-Yip, C. L. et al. Antimicrob. Agents
Chemother. 2014 58(7) 3867-3873; Xiong, H. et al. Bioorg. Med. Chem. Lett. 2013 23(24)
6789-6793; Mason, S. W. Nucleic Acids Res. 2004 32(16) 4758-4767).
Because RSV virus continues to be the leading cause of seasonal respiratory disease
throughout the world, causes risk of developing severe respiratory disease, which can result in
long-lasting complications or death, there exists a need in the field for new compounds for
treatment of RSV mediated diseases; and/ or compounds which at least provide the public with a
useful choice.
SUMMARY OF THE INVENTION
The compounds of Formula I (below) and pharmaceutical compositions comprising
said compounds are useful for the treatment of diseases mediated by RSV.
[0006a] In a first aspect, the invention relates to a compound of formula I
Base
wherein:
Y is P(=X)(R)(R’);
1 2a 2b 3
R is O-R or NHC(R )(R )C(=O)OR ;
4 2a 2b 3 3
R’ is N(R )C(R )(R )C(=O)OR , –OP(=O)(OH)OP(=O)(OH)OH, or –OR ;
R is H, C alkyl, C haloalkyl, or aryl, wherein aryl is phenyl or
1-7 1-7
naphthyl, optionally substituted with one or more C alkyl, C alkenyl, C alkynyl,
1-7 2-7 2-7
1a 1a 1b
C alkoxy, halo, lower haloalkyl, -N(R ) , acylamino, -SO N(R ) , -C(=O)R , -
1-7 2 2 2
1c 1c 1’’
SO R , -NHSO R , nitro, cyano, or R ;
each R is independently H or lower alkyl;
1b 1a 1a
each R is independently -OR or -N(R ) ;
each R is lower alkyl;
2a 2b 1a
each R and R is independently H, C alkyl, -(CH ) N(R ) , C
1-7 2 r 2 1-
7 hydroxyalkyl, -CH2SH, -(CH2)S(O)pMe, -(CH2)nNHC(=NH)NH2, (1H-indolyl)Me,
(1H-indolyl)Me, -(CH ) C(=O)R , aryl or aryl C alkyl, wherein aryl and aryl C
2 m 1-7 1-7
alkyl are optionally substituted with one or more hydroxy, C alkyl, C alkoxy, halo,
1-7 1-7
nitro or cyano;
m is 0, 1, or 2;
n is 1, 2, or 3;
p is 1 or 2;
r is 1 or 2;
2a 2b 4
or R is H and R and R together form (CH ) ;
each R is independently H, C alkyl, C haloalkyl, phenyl or phenyl C
1-7 1-7 1-
alkyl, wherein phenyl and phenyl C alkyl are optionally substituted with C alkoxy;
7 1-7 1-7
3 1’’
or R and R together form CH2;
each R is independently H, C alkyl;
2b 4
or R and R together form (CH ) ;
w x y
each of R , R , and R is independently H, OH, or F;
R is H or OH;
or R and R together form a bond;
or R and R together form a bond;
X is O or S; and
Base is uracil, cytosine, guanine, adenine, or thymine, each of which may optionally be
substituted with one or more hydroxy, C alkyl, C alkoxy, halo, nitro or cyano;
1-7 1-7
or a pharmacologically acceptable salt thereof.
[0006b] In a second aspect, the invention relates to a compound selected from the list
consisting of:
4’-Vinyluridine-5’-(O-phenyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(i2,2-dimethylpropoxycarbonyl)ethyl
phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(3,3-dimethylbutoxycarbonyl)ethyl
phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(benzyloxycarbonyl)ethyl phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(hexoxycarbonyl)ethyl phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(cyclopentoxycarbonyl)ethyl phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(cyclohexoxycarbonyl)ethyl phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinyluridine-5’-{ N ,N ’-bis[(S)(isopropoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyluridine-5’-{ N ,N ’-bis[(S)(2,2-
dimethylpropoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyluridine-5’-{ N ,N ’-bis[(S)(3,3-dimethylbutoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyluridine-5’-{ N ,N ’-bis[(S)(benzyloxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyluridine-5’-{ N ,N ’-bis[(S)(hexoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyluridine-5’-{ N ,N ’-bis[(S)(cyclopentoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyluridine-5’-{ N ,N ’-bis[(S)(cyclohexoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyl-5’-O-(2-oxidoH-1,3,2-benzodioxaphosphorinyl)-uridine;
4’-Vinyl-5’-O-[bis(4-methoxyphenoxy)phosphinyl] uridine;
4’-Vinyluridine-3’,5’-cyclic phosphoric acid isopropyl ester;
4’-Vinylcytidine-5’-(O-phenyl-N-(S)(ethoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(O-phenyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(O-phenyl-N-(S)(neopentoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(O-phenyl-N-(S)(benzyloxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(2,2-dimethylpropoxycarbonyl)ethyl
phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(benzyloxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(3,3-dimethybutoxycarbonyl)ethyl
phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(pentoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(hexoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(cyclohexoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-{N ,N ’-bis[(S)(isopropoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinylcytidine-5’-{N ,N ’-bis[(S)(2,2-
dimethylpropoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinylcytidine-5’-{N ,N ’-bis[(S)benzyloxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinylcytidine-5’-{N ,N ’-bis[(S)(3,3-
dimethylbutoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinylcytidine-5’-{N ,N ’-bis[(S)(hexoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinylcytidine-5’-{N ,N ’-bis[(S)(cyclohexoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyl-5’-O-(2-oxidoH-1,3,2-benzodioxaphosphorinyl)-cytidine;
4’-Vinyl-5’-O-[bis(4-methoxyphenoxy)phosphinyl] cytidine;
4’-Vinylcytidine-3’,5’-cyclic phosphoric acid isopropyl ester;
4’-Viyladenosine-5’-(O-phenyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinyladenosine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinyladenosine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinyladenosine-5’-{ N ,N ’-bis[(S)(isopropoxycarbonyl)ethyl]phosphorodiamidate;
4’-Vinyl-5’-O-(2-oxidoH-1,3,2-benzodioxaphosphorinyl)-adenosine;
4’-Vinyl-5’-O-[bis(4-methoxyphenoxy)phosphinyl] adenosine;
4’-Vinyladenosine-3’,5’-cyclic phosphoric acid isopropyl ester;
4’-Vinylguanosine-5’-(O-phenyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinylguanosine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinylguanosine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinylguanosine-5’-{ N ,N ’-bis[(S)(isopropoxycarbonyl)ethyl]phosphorodiamidate;
4’-Vinyl-5’-O-(2-oxidoH-1,3,2-benzodioxaphosphorinyl)-guanosine;
4’-Vinyl-5’-O-[bis(4-methoxyphenoxy)phosphinyl] guanosine;
4’-Vinylguanosine-3’,5’-cyclic phosphoric acid isopropyl ester;
3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl
phosphoramidate;
3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-(Onaphthyl-N-(S)(2,2-
dimethylpropoxycarbonyl)ethyl phosphoramidate;
3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-(Onaphthyl-N-(S)(benzyloxycarbonyl)ethyl
phosphoramidate;
3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-{ N ,N ’-bis[(S)
(isopropoxycarbonyl)ethyl]phosphorodiamidate};
3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-{ N ,N ’-bis[(S)(2,2-
dimethylpropoxycarbonyl)ethyl]phosphorodiamidate};
3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-{ N ,N ’-bis[(S)
(cyclopentoxycarbonyl)ethyl]phosphorodiamidate};
3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl
phosphoramidate;
3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-(Onaphthyl-N-(S)(2,2-
dimethylpropoxycarbonyl)ethyl phosphoramidate;
3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-(Onaphthyl-N-(S)(benzyloxycarbonyl)ethyl
phosphoramidate;
3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-{N ,N ’-bis[(S)
(propoxycarbonyl)ethyl]phosphorodiamidate};
3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-{N ,N ’-bis[(S)(2,2-
dimethylpropoxycarbonyl)ethyl]phosphorodiamidate};
3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-{N ,N ’-bis[(S)
(hexoxycarbonyl)ethyl]phosphorodiamidate}; and
3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-{N ,N ’-bis[(S)
(cyclopentoxycarbonyl)ethyl]phosphorodiamidate}.
[0006c] In a third aspect, the invention relates to use of a compound according to any one of
claims 1 to 17 in the manufacture of a medicament for preventing or treating an RSV infection.
[0006d] In a fourth aspect, the invention relates to a pharmaceutical composition comprising a
compound according to the first or second aspect.
[0006e] In a fifth aspect, the invention relates to a pharmaceutical composition comprising a
compound according to the second aspect.
BRIEF DESCRIPTION OF THE INVENTION
The application describes a compound of Formula I
Base
wherein:
Y is H or P(=X)(R)(R’);
1 2a 2b 3
R is O-R or NHC(R )(R )C(=O)OR ;
4 2a 2b 3 3
R’ is N(R )C(R )(R )C(=O)OR , –OP(=O)(OH)OP(=O)(OH)OH, or –OR ;
R is H, lower alkyl, lower haloalkyl, or aryl, wherein aryl is phenyl or
naphthyl, optionally substituted with one or more lower alkyl, lower alkenyl, lower
1a 1a
alkynyl, lower alkoxy, halo, lower haloalkyl, -N(R ) , acylamino, -SO N(R ) , -
2 2 2
1b 1c 1c 1’’
C(=O)R , -SO R , -NHSO R , nitro, cyano, or R ;
each R is independently H or lower alkyl;
1b 1a 1a
each R is independently -OR or -N(R ) ;
each R is lower alkyl;
2a 2b 1a
each R and R is independently H, lower alkyl, -(CH ) N(R ) ,
2 r 2
lower hydroxyalkyl, -CH SH, -(CH )S(O) Me, -(CH ) NHC(=NH)NH , (1H-indol
2 2 p 2 n 2
yl)Me, (1H-indolyl)Me, -(CH ) C(=O)R , aryl or aryl lower alkyl, wherein aryl and
aryl lower alkyl are optionally substituted with one or more hydroxy, lower alkyl, lower
alkoxy, halo, nitro or cyano;
m is 0, 1, or 2;
n is 1, 2, or 3;
p is 1 or 2;
r is 1 or 2;
2a 2b 4
or R is H and R and R together form (CH ) ;
each R is independently H, lower alkyl, lower haloalkyl, phenyl or phenyl
lower alkyl, wherein phenyl and phenyl lower alkyl are optionally substituted with lower
alkoxy;
3 1’’
or R and R together form CH2;
each R is independently H, lower alkyl;
2b 4
or R and R together form (CH ) ;
w x y
each of R , R , and R is independently H, OH, or F;
R is H or OH;
or R and R together form a bond;
or R and R together form a bond;
X is O or S; and
Base is uracil, cytosine, guanine, adenine, thymine, or heterocycloalkyl, each of which
may optionally be substituted with one or more hydroxy, lower alkyl, lower alkoxy, halo,
nitro or cyano;
or a pharmacologically acceptable salt thereof.
The application describes the compounds of Formula I which are useful for the
prevention or treatment of diseases mediated by RSV, pharmaceutical compositions comprising
compounds of Formula I, compounds that result in the formation of compounds of Formula I in
vivo during said treatment, or pharmaceutical compositions comprising compounds that result in
the formation of compounds of Formula I in vivo during said treatment.
The application describes a method for preventing or treating RSV infection
comprising administering to a patient in need thereof a therapeutically effective amount of a
compound of Formula I or a compound resulting in the formation of a compound of Formula I in
vivo.
The application describes a composition comprising a compound of Formula I, or a
compound resulting in the formation of a compound of Formula I in vivo, and a pharmaceutically
acceptable excipient.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of Formula I are efficacious as antiviral drugs for the treatment of
RSV infections in human. Administration of the compounds of Formula I inhibits RSV
replication in infected cells by the formation of the nucleoside 5’-triphosphate derivatives of the
compounds of Formula I, as inhibitors of RSV polymerase.
Definitions
The term “alkyl” as used herein denotes a straight or branched chain hydrocarbon
residue containing 1 to 12 carbon atoms. Preferably, the term “alkyl” denotes a straight or
branched chain hydrocarbon residue containing 1 to 7 carbon atoms. Most preferred are methyl,
ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl. The alkyl may be unsubstituted or
substituted. The substituents are selected from one or more of cycloalkyl, nitro, amino, alkyl
amino, dialkyl amino, alkyl carbonyl and cycloalkyl carbonyl.
The term “cycloalkyl” as used herein denotes an optionally substituted cycloalkyl
group containing 3 to 7 carbon atoms, e. g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl.
The term “alkoxy” as used herein denotes an optionally substituted straight or
branched chain alkyl-oxy group wherein the "alkyl" portion is as defined above such as methoxy,
ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, tert-butyloxy, pentyloxy, hexyloxy,
heptyloxy including their isomers.
The term “alkoxyalkyl” as used herein denotes an alkoxy group as defined above
which is bonded to an alkyl group as defined above. Examples are methoxymethyl,
methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propyloxypropyl,
methoxybutyl, ethoxybutyl, propyloxybutyl, butyloxybutyl, tert -butyloxybutyl, methoxypentyl,
ethoxypentyl, propyloxypentyl including their isomers.
The term “alkenyl” as used herein denotes an unsubstituted or substituted hydrocarbon
chain radical having from 2 to 7 carbon atoms, preferably from 2 to 4 carbon atoms, and having
one or two olefinic double bonds, preferably one olefinic double bond. Examples are vinyl, 1-
propenyl, 2-propenyl (allyl) or 2-butenyl (crotyl).
The term “alkynyl” as used herein denotes an unsubstituted or substituted hydrocarbon
chain radical having from 2 to 7 carbon atoms, preferably 2 to 4 carbon atoms, and having one or
where possible two triple bonds, preferably one triple bond. Examples are ethynyl, 1-propynyl,
2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl.
The term “hydroxyalkyl” as used herein denotes a straight or branched chain alkyl
group as defined above wherein 1, 2, 3 or more hydrogen atoms are substituted by a hydroxy
group. Examples are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-
hydroxypropyl, 3-hydroxypropyl, hydroxyisopropyl, hydroxybutyl and the like.
The term “haloalkyl” as used herein denotes a straight or branched chain alkyl group
as defined above wherein 1, 2, 3 or more hydrogen atoms are substituted by a halogen.
Examples are 1-fluoromethyl, 1-chloromethyl, 1-bromomethyl, 1-iodomethyl, trifluoromethyl,
trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-
iodoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-dichloroethyl, 3-
bromopropyl or 2,2,2-trifluoroethyl and the like.
The term “alkylthio” as used herein denotes a straight or branched chain (alkyl)S-
group wherein the "alkyl" portion is as defined above. Examples are methylthio, ethylthio, n-
propylthio, i-propylthio, n-butylthio, i-butylthio or tert-butylthio.
The term “aryl” as used herein denotes an optionally substituted phenyl or naphthyl
group (e. g. 1-naphthyl, 2-naphthyl or 3-naphthyl). Suitable substituents for aryl can be selected
from those named for alkyl, in addition however, halogen, hydroxy and optionally substituted
alkyl, haloalkyl, alkenyl, alkynyl and aryloxy are substituents which can be added to the
selection.
The term “heterocycloalkyl” or “heterocyclyl” as used herein denotes optionally
substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic
heterocyclic systems which contain one or more hetero atoms selected from nitrogen, oxygen
and sulfur which can also be fused to an optionally substituted saturated, partially unsaturated or
aromatic monocyclic carbocycle or heterocycle.
Examples of suitable heterocycles are oxazolyl, isoxazolyl, furyl, tetrahydrofuryl, 1,3-
dioxolanyl, dihydropyranyl, 2-thienyl, 3-thienyl, pyrazinyl, isothiazolyl, dihydrooxazolyl,
pyrimidinyl, tetrazolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, pyrrolidinonyl, (N-oxide)-
pyridinyl, 1-pyrrolyl, 2-pyrrolyl, triazolyl e. g. 1,2,3-triazolyl or 1,2,4-triazolyl, 1-pyrazolyl, 2-
pyrazolyl, 4-pyrazolyl, piperidinyl, morpholinyl (e. g. 4-morpholinyl), thiomorpholinyl (e. g. 4-
thiomorpholinyl), thiazolyl, pyridinyl, dihydrothiazolyl, imidazolidinyl, pyrazolinyl, piperazinyl,
1-imidazolyl, 2-imidazolyl, 4-imidazolyl, thiadiazolyl e. g. 1,2,3-thiadiazolyl, 4-
methylpiperazinyl, 4-hydroxypiperidinyl.
Suitable substituents for heterocycloalkyl can be selected from those named for alkyl,
in addition however, optionally substituted alkyl, alkenyl, alkynyl, an oxo group (=O) or
aminosulphonyl are substituents which can be added to the selection.
The term “acyl” ("alkylcarbonyl")as used herein denotes a group of formula C(=O)R
wherein R is hydrogen, an unsubstituted or substituted straight or branched chain hydrocarbon
residue containing 1 to 7 carbon atoms or a phenyl group. Most preferred acyl groups are those
wherein R is hydrogen, an unsubstituted straight chain or branched hydrocarbon residue
containing 1 to 4 carbon atoms or a phenyl group.
The term halogen stands for fluorine, chlorine, bromine or iodine, and preferably
fluorine, chlorine, or bromine.
In the pictorial representation of the compounds given throughout this application, a
thickened tapered line ( ) indicates a substituent which is above the plane of the ring to
which the asymmetric carbon belongs and a dotted line ( ) indicates a substituent which is
below the plane of the ring to which the asymmetric carbon belongs.
Compounds of Formula I exhibit stereoisomerism. These compounds can be any
isomer of the compound of Formula I or mixtures of these isomers. The compounds and
intermediates of the present invention having one or more asymmetric carbon atoms may be
obtained as racemic mixtures of stereoisomers which can be resolved.
Compounds of Formula I may exhibit tautomerism, which means that the compounds
of Formula I can exist as two or more chemical compounds that are capable of facile
interconversion. In many cases it merely means the exchange of a hydrogen atom between two
other atoms, to either of which it forms a covalent bond. Tautomeric compounds exist in a
mobile equilibrium with each other, so that attempts to prepare the separate substances usually
result in the formation of a mixture that shows all the chemical and physical properties to be
expected on the basis of the structures of the components.
The most common type of tautomerism is that involving carbonyl, or keto, compounds
and unsaturated hydroxyl compounds, or enols. The structural change is the shift of a hydrogen
atom between atoms of carbon and oxygen, with the rearrangement of bonds. For example, in
many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form is the predominant
one; in phenols, the enol form is the major component.
Compounds of Formula I which are basic can form pharmaceutically acceptable salts
with inorganic acids such as hydrohalic acids (e.g. hydrochloric acid and hydrobromic acid),
sulfuric acid, nitric acid and phosphoric acid, and the like, and with organic acids (e.g. with
acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric
acid, methanesulfonic acid and p-toluene sulfonic acid, and the like). The formation and isolation
of such salts can be carried out according to methods known in the art.
[0031a] The term “comprising” as used in this specification and claims means “consisting at
least in part of”. When interpreting statements in this specification, and claims which include the
term “comprising”, it is to be understood that other features that are additional to the features
prefaced by this term in each statement or claim may also be present. Related terms such as
“comprise” and “comprised” are to be interpreted in similar manner.
Inhibitors of RSV
The application describes a compound of Formula I
Bas e
wherein:
Y is H or P(=X)(R)(R’);
1 2a 2b 3
R is O-R or NHC(R )(R )C(=O)OR ;
4 2a 2b 3 3
R’ is N(R )C(R )(R )C(=O)OR , –OP(=O)(OH)OP(=O)(OH)OH, or –OR ;
R is H, lower alkyl, lower haloalkyl, or aryl, wherein aryl is phenyl or
naphthyl, optionally substituted with one or more lower alkyl, lower alkenyl, lower
1a 1a
alkynyl, lower alkoxy, halo, lower haloalkyl, -N(R ) , acylamino, -SO N(R ) , -
2 2 2
1b 1c 1c 1’’
C(=O)R , -SO R , -NHSO R , nitro, cyano, or R ;
each R is independently H or lower alkyl;
1b 1a 1a
each R is independently -OR or -N(R ) ;
each R is lower alkyl;
2a 2b 1a
each R and R is independently H, lower alkyl, -(CH2)rN(R )2,
lower hydroxyalkyl, -CH SH, -(CH )S(O) Me, -(CH ) NHC(=NH)NH , (1H-indol
2 2 p 2 n 2
yl)Me, (1H-indolyl)Me, -(CH ) C(=O)R , aryl or aryl lower alkyl, wherein aryl and
aryl lower alkyl are optionally substituted with one or more hydroxy, lower alkyl, lower
alkoxy, halo, nitro or cyano;
m is 0, 1, or 2;
n is 1, 2, or 3;
p is 1 or 2;
r is 1 or 2;
2a 2b 4
or R is H and R and R together form (CH ) ;
each R is independently H, lower alkyl, lower haloalkyl, phenyl or phenyl
lower alkyl, wherein phenyl and phenyl lower alkyl are optionally substituted with lower
alkoxy;
3 1’’
or R and R together form CH ;
each R is independently H, lower alkyl;
2b 4
or R and R together form (CH ) ;
w x y z
each of R , R , R and R is independently H, OH, or F;
or R and R together form a bond;
or R and R together form a bond;
X is O or S;
Base is uracil, cytosine, guanine, adenine, thymine, or heterocycloalkyl, each of which
may optionally be substituted with one or more hydroxy, lower alkyl, lower alkoxy, halo,
nitro or cyano;
y x z
with the proviso that when R is H or F and R is OH, R is not F; and
x z w y
with the proviso that when R and R are both H, and R is OH, R is not F;
or a pharmacologically acceptable salt thereof.
The application describes a compound of Formula I
Base
wherein:
Y is H or P(=X)(R)(R’);
1 2a 2b 3
R is O-R or NHC(R )(R )C(=O)OR ;
4 2a 2b 3 3
R’ is N(R )C(R )(R )C(=O)OR , –OP(=O)(OH)OP(=O)(OH)OH, or –OR ;
R is H, lower alkyl, lower haloalkyl, or aryl, wherein aryl is phenyl or
naphthyl, optionally substituted with one or more lower alkyl, lower alkenyl, lower
1a 1a
alkynyl, lower alkoxy, halo, lower haloalkyl, -N(R ) , acylamino, -SO N(R ) , -
2 2 2
1b 1c 1c 1’’
C(=O)R , -SO R , -NHSO R , nitro, cyano, or R ;
each R is independently H or lower alkyl;
1b 1a 1a
each R is independently -OR or -N(R ) ;
each R is lower alkyl;
2a 2b 1a
each R and R is independently H, lower alkyl, -(CH ) N(R ) ,
2 r 2
lower hydroxyalkyl, -CH SH, -(CH )S(O) Me, -(CH ) NHC(=NH)NH , (1H-indol
2 2 p 2 n 2
yl)Me, (1H-indolyl)Me, -(CH ) C(=O)R , aryl or aryl lower alkyl, wherein aryl and
aryl lower alkyl are optionally substituted with one or more hydroxy, lower alkyl, lower
alkoxy, halo, nitro or cyano;
m is 0, 1, or 2;
n is 1, 2, or 3;
p is 1 or 2;
r is 1 or 2;
2a 2b 4
or R is H and R and R together form (CH ) ;
each R is independently H, lower alkyl, lower haloalkyl, phenyl or phenyl
lower alkyl, wherein phenyl and phenyl lower alkyl are optionally substituted with lower
alkoxy;
3 1’’
or R and R together form CH ;
each R is independently H, lower alkyl;
2b 4
or R and R together form (CH ) ;
w x y
each of R , R , and R is independently H, OH, or F;
R is H or OH;
or R and R together form a bond;
or R and R together form a bond;
X is O or S; and
Base is uracil, cytosine, guanine, adenine, thymine, or heterocycloalkyl, each of which
may optionally be substituted with one or more hydroxy, lower alkyl, lower alkoxy, halo,
nitro or cyano;
or a pharmacologically acceptable salt thereof.
The application describes the above compound of Formula I, wherein R is H.
The application describes either of the above compounds of Formula I, wherein R is
The application describes any one of the above compounds of Formula I, wherein R
is H.
The application describes any one of the above compounds of Formula I, wherein R
is OH.
The application alternatively describes any one of the above compounds of Formula I,
3 3 1 1 x
wherein R’ is O-R , R is lower alkyl, R is –OR , and R and R together form a bond.
The application alternatively describes any one of the above compounds of Formula I,
1 1 1’’ 3 3 1’’
wherein R is –OR , R is phenyl substituted with R , R’ is –OR , and R and R together form
The application describes any one of the above compounds of Formula I, wherein X is
The application alternatively describes any one of the above compounds of Formula I,
wherein X is S.
The application describes any one of the above compounds of Formula I, wherein R is
O-R , and R is phenyl optionally substituted with methoxy.
The application alternatively describes any one of the above compounds of Formula I,
wherein R is O-R , and R is naphthyl.
The application describes any one of the above compounds of Formula I, wherein R’
4 2a 2b 3 4 2a 2b 3
is N(R )C(R )(R )C(=O)OR , R is H, R is H, R is methyl, and R is isopropyl.
The application alternatively describes any one of the above compounds of Formula I,
wherein R’ is -OP(=O)(OH)OP(=O)(OH)OH.
The application describes any one of the above compounds of Formula I, wherein
Base is cytidine optionally substituted with halo.
The application alternatively describes any one of the above compounds of Formula I,
wherein Base is uridine optionally substituted with halo.
The application alternatively describes any one of the above compounds of Formula I,
wherein Base is guanosine.
The application alternatively describes any one of the above compounds of Formula I,
wherein Base is adenosine.
The application provides a compound of Formula I selected from the group consisting
4’-Vinyluridine-5’-(O-phenyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(i2,2-dimethylpropoxycarbonyl)ethyl
phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(3,3-dimethylbutoxycarbonyl)ethyl
phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(benzyloxycarbonyl)ethyl phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(hexoxycarbonyl)ethyl phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(cyclopentoxycarbonyl)ethyl phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(cyclohexoxycarbonyl)ethyl phosphoramidate;
4’-Vinyluridine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinyluridine-5’-{N ,N ’-bis[(S)(isopropoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyluridine-5’-{N ,N ’-bis[(S)(2,2-
dimethylpropoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyluridine-5’-{N ,N ’-bis[(S)(3,3-dimethylbutoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyluridine-5’-{N ,N ’-bis[(S)(benzyloxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyluridine-5’-{N ,N ’-bis[(S)(hexoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyluridine-5’-{N ,N ’-bis[(S)(cyclopentoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyluridine-5’-{N ,N ’-bis[(S)(cyclohexoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyl-5’-O-(2-oxidoH-1,3,2-benzodioxaphosphorinyl)-uridine;
4’-Vinyl-5’-O-[bis(4-methoxyphenoxy)phosphinyl] uridine;
4’-Vinyluridine-3’,5’-cyclic phosphoric acid isopropyl ester;
4’-Vinylcytidine-5’-(O-phenyl-N-(S)(ethoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(O-phenyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(O-phenyl-N-(S)(neopentoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(O-phenyl-N-(S)(benzyloxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(2,2-dimethylpropoxycarbonyl)ethyl
phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(benzyloxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(3,3-dimethybutoxycarbonyl)ethyl
phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(pentoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(hexoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(cyclohexoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinylcytidine-5’-{N ,N ’-bis[(S)(isopropoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinylcytidine-5’-{N ,N ’-bis[(S)(2,2-
dimethylpropoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinylcytidine-5’-{N ,N ’-bis[(S)benzyloxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinylcytidine-5’-{N ,N ’-bis[(S)(3,3-dimethylbutoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinylcytidine-5’-{N ,N ’-bis[(S)(hexoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinylcytidine-5’-{N ,N ’-bis[(S)(cyclohexoxycarbonyl)ethyl]phosphorodiamidate};
4’-Vinyl-5’-O-(2-oxidoH-1,3,2-benzodioxaphosphorinyl)-cytidine;
4’-Vinyl-5’-O-[bis(4-methoxyphenoxy)phosphinyl] cytidine;
4’-Vinylcytidine-3’,5’-cyclic phosphoric acid isopropyl ester;
4’-Viyladenosine-5’-(O-phenyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinyladenosine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinyladenosine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinyladenosine-5’-{N ,N ’-bis[(S)(isopropoxycarbonyl)ethyl]phosphorodiamidate;
4’-Vinyl-5’-O-(2-oxidoH-1,3,2-benzodioxaphosphorinyl)-adenosine;
4’-Vinyl-5’-O-[bis(4-methoxyphenoxy)phosphinyl] adenosine;
4’-Vinyladenosine-3’,5’-cyclic phosphoric acid isopropyl ester;
4’-Vinylguanosine-5’-(O-phenyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinylguanosine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinylguanosine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate;
4’-Vinylguanosine-5’-{N ,N ’-bis[(S)(isopropoxycarbonyl)ethyl]phosphorodiamidate;
4’-Vinyl-5’-O-(2-oxidoH-1,3,2-benzodioxaphosphorinyl)-guanosine;
4’-Vinyl-5’-O-[bis(4-methoxyphenoxy)phosphinyl] guanosine;
4’-Vinylguanosine-3’,5’-cyclic phosphoric acid isopropyl ester;
3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl
phosphoramidate;
3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-(Onaphthyl-N-(S)(2,2-
dimethylpropoxycarbonyl)ethyl phosphoramidate;
3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-(Onaphthyl-N-(S)(benzyloxycarbonyl)ethyl
phosphoramidate;
3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-{N ,N ’-bis[(S)
(isopropoxycarbonyl)ethyl]phosphorodiamidate};
3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-{ N ,N ’-bis[(S)(2,2-
dimethylpropoxycarbonyl)ethyl]phosphorodiamidate};
3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-{ N ,N ’-bis[(S)
(cyclopentoxycarbonyl)ethyl]phosphorodiamidate};
3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl
phosphoramidate;
3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-(Onaphthyl-N-(S)(2,2-
dimethylpropoxycarbonyl)ethyl phosphoramidate;
3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-(Onaphthyl-N-(S)(benzyloxycarbonyl)ethyl
phosphoramidate;
3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-{ N ,N ’-bis[(S)
(propoxycarbonyl)ethyl]phosphorodiamidate};
3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-{ N ,N ’-bis[(S)(2,2-
dimethylpropoxycarbonyl)ethyl]phosphorodiamidate};
3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-{ N ,N ’-bis[(S)
(hexoxycarbonyl)ethyl]phosphorodiamidate}; and
3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-{N ,N ’-bis[(S)
(cyclopentoxycarbonyl)ethyl]phosphorodiamidate}.
The application describes a method for preventing or treating an RSV infection
comprising administering to a patient in need thereof a therapeutically effective amount of a
compound of Formula I.
The application describes the above method, further comprising administering an
immune system modulator or an antiviral agent that inhibits replication of RSV, or a
combination thereof.
The application describes the above method, wherein the immune system modulator is
an RSV vaccine, therapeutic vaccine, adjuvant, an interferon or a chemically derivatized
interferon.
The application describes the above method for inhibiting replication of RSV in a cell
comprising administering a compound of Formula I.
The application describes a composition comprising the compound of Formula I.
The application describes the above method for inhibiting replication of RSV in a cell
comprising administering a composition comprising the compound of Formula I.
The application describes the above composition, admixed with at least one carrier,
diluent or excipient.
The application describes a use of the compound of Formula I in the manufacture of a
medicament for the treatment of RSV.
The application describes a compound, composition, or method as described herein.
Examples of representative compounds encompassed by the present invention and
within the scope of the invention are provided in the following Tables. These examples and
preparations which follow are provided to enable those skilled in the art to more clearly
understand and to practice the present invention. They should not be considered as limiting the
scope of the invention, but merely as being illustrative and representative thereof.
In general, the nomenclature used in this Application is based on standard nucleic acid
nomenclature common to one of ordinary skill in the art. If there is a discrepancy between a
depicted structure and a name given that structure, the depicted structure is to be accorded more
weight. In addition, if the stereochemistry of a structure or a portion of a structure is not
indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be
interpreted as encompassing all stereoisomers of it.
Table 1. Examples of compounds of generic Formula I.
Compound
Structure Name
Number
4’-Vinyluridine-5’-(O-phenyl-N-(S)-
I-1 1-(isopropoxycarbonyl)ethyl
phosphoramidate
4’-Vinyluridine-5’-(Onaphthyl-N-
I-2 (S)(isopropoxycarbonyl)ethyl
phosphoramidate
4’-Vinyluridine-5’-(Onaphthyl-N-
(S)(i2,2-
dimethylpropoxycarbonyl)ethyl
phosphoramidate
4’-Vinyluridine-5’-(Onaphthyl-N-
(S)(3,3-
dimethylbutoxycarbonyl)ethyl
phosphoramidate
4’-Vinyluridine-5’-(Onaphthyl-N-
I-5 (S)(benzyloxycarbonyl)ethyl
phosphoramidate
Table 1. Examples of compounds of generic Formula I.
Compound
Structure Name
Number
4’-Vinyluridine-5’-(Onaphthyl-N-
I-6 (S)(hexoxycarbonyl)ethyl
phosphoramidate
4’-Vinyluridine-5’-(Onaphthyl-N-
(S)(cyclopentoxycarbonyl)ethyl
phosphoramidate
4’-Vinyluridine-5’-(Onaphthyl-N-
I-8 (S)(cyclohexoxycarbonyl)ethyl
phosphoramidate
4’-Vinyluridine-5’-(Onaphthyl-N-
I-9 (S)(isopropoxycarbonyl)ethyl
phosphoramidate
Table 1. Examples of compounds of generic Formula I.
Compound
Structure Name
Number
4’-Vinyluridine-5’-{ N , N ’-bis[(S)
(isopropoxycarbonyl)ethyl]phosphoro
I-10
diamidate}
4’-Vinyluridine-5’-{ N , N ’-bis[(S)
(2,2-
dimethylpropoxycarbonyl)ethyl]phos
I-11
phorodiamidate}
4’-Vinyluridine-5’-{ N , N ’-bis[(S)
(3,3-
dimethylbutoxycarbonyl)ethyl]phosp
I-12
horodiamidate}
4’-Vinyluridine-5’-{ N , N ’-bis[(S)
(benzyloxycarbonyl)ethyl]phosphoro
I-13
diamidate}
Table 1. Examples of compounds of generic Formula I.
Compound
Structure Name
Number
4’-Vinyluridine-5’-{ N , N ’-bis[(S)
(hexoxycarbonyl)ethyl]phosphorodia
I-14
midate}
4’-Vinyluridine-5’-{ N , N ’-bis[(S)
(cyclopentoxycarbonyl)ethyl]phospho
I-15
rodiamidate}
4’-Vinyluridine-5’-{ N , N ’-bis[(S)
(cyclohexoxycarbonyl)ethyl]phosphor
I-16
odiamidate}
4’-Vinyl-5’-O-(2-oxidoH-1,3,2-
I-17
benzodioxaphosphorinyl)-uridine
Table 1. Examples of compounds of generic Formula I.
Compound
Structure Name
Number
4’-Vinyl-5’-O-[bis(4-
I-18
methoxyphenoxy)phosphinyl] uridine
4’-Vinyluridine-3’,5’-cyclic
I-19
phosphoric acid isopropyl ester
4’-Vinylcytidine-5’-(O-phenyl-N-(S)-
I-20 1-(ethoxycarbonyl)ethyl
phosphoramidate
4’-Vinylcytidine-5’-(O-phenyl-N-(S)-
I-21 1-(isopropoxycarbonyl)ethyl
phosphoramidate
4’-Vinylcytidine-5’-(O-phenyl-N-(S)-
I-22 1-(neopentoxycarbonyl)ethyl
phosphoramidate
Table 1. Examples of compounds of generic Formula I.
Compound
Structure Name
Number
4’-Vinylcytidine-5’-(O-phenyl-N-(S)-
I-23 1-(benzyloxycarbonyl)ethyl
phosphoramidate
4’-Vinylcytidine-5’-(Onaphthyl-N-
I-24 (S)(isopropoxycarbonyl)ethyl
phosphoramidate
4’-Vinylcytidine-5’-(Onaphthyl-N-
(S)(2,2-
I-25
dimethylpropoxycarbonyl)ethyl
phosphoramidate
4’-Vinylcytidine-5’-(Onaphthyl-N-
(S)(benzyloxycarbonyl)ethyl
I-26
phosphoramidate
4’-Vinylcytidine-5’-(Onaphthyl-N-
(S)(3,3-
I-27
dimethybutoxycarbonyl)ethyl
phosphoramidate
Table 1. Examples of compounds of generic Formula I.
Compound
Structure Name
Number
4’-Vinylcytidine-5’-(Onaphthyl-N-
I-28 (S)(pentoxycarbonyl)ethyl
phosphoramidate
4’-Vinylcytidine-5’-(Onaphthyl-N-
(S)(hexoxycarbonyl)ethyl
I-29
phosphoramidate
4’-Vinylcytidine-5’-(Onaphthyl-N-
I-30 (S)(cyclohexoxycarbonyl)ethyl
phosphoramidate
4’-Vinylcytidine-5’-(Onaphthyl-N-
I-31 (S)(isopropoxycarbonyl)ethyl
phosphoramidate
4’-Vinylcytidine-5’-{ N , N ’-bis[(S)
(isopropoxycarbonyl)ethyl]phosphoro
I-32
diamidate}
Table 1. Examples of compounds of generic Formula I.
Compound
Structure Name
Number
4’-Vinylcytidine-5’-{ N , N ’-bis[(S)
(2,2-
I-33
dimethylpropoxycarbonyl)ethyl]phos
phorodiamidate}
4’-Vinylcytidine-5’-{ N , N ’-bis[(S)
I-34 benzyloxycarbonyl)ethyl]phosphorodi
amidate}
4’-Vinylcytidine-5’-{ N , N ’-bis[(S)
(3,3-
I-35
dimethylbutoxycarbonyl)ethyl]phosp
horodiamidate}
4’-Vinylcytidine-5’-{ N , N ’-bis[(S)
I-36 (hexoxycarbonyl)ethyl]phosphorodia
midate}
4’-Vinylcytidine-5’-{ N , N ’-bis[(S)
I-37 (cyclohexoxycarbonyl)ethyl]phosphor
odiamidate}
Table 1. Examples of compounds of generic Formula I.
Compound
Structure Name
Number
4’-Vinyl-5’-O-(2-oxidoH-1,3,2-
I-38
benzodioxaphosphorinyl)-cytidine
4’-Vinyl-5’-O-[bis(4-
I-39 methoxyphenoxy)phosphinyl]
cytidine
4’-Vinylcytidine-3’,5’-cyclic
I-40
phosphoric acid isopropyl ester
4’-Viyladenosine-5’-(O-phenyl-N-
I-41 (S)(isopropoxycarbonyl)ethyl
phosphoramidate
4’-Vinyladenosine-5’-(Onaphthyl-
I-42 N-(S)(isopropoxycarbonyl)ethyl
phosphoramidate
Table 1. Examples of compounds of generic Formula I.
Compound
Structure Name
Number
4’-Vinyladenosine-5’-(Onaphthyl-
I-43 N-(S)(isopropoxycarbonyl)ethyl
phosphoramidate
4’-Vinyladenosine-5’-{ N , N ’-bis[(S)-
(isopropoxycarbonyl)ethyl]phosphoro
I-44
diamidate
4’-Vinyl-5’-O-(2-oxidoH-1,3,2-
I-45 benzodioxaphosphorinyl)-
adenosine
4’-Vinyl-5’-O-[bis(4-
I-46 methoxyphenoxy)phosphinyl]
adenosine
4’-Vinyladenosine-3’,5’-cyclic
I-47
phosphoric acid isopropyl ester
Table 1. Examples of compounds of generic Formula I.
Compound
Structure Name
Number
4’-Vinylguanosine-5’-(O-phenyl-N-
I-48 (S)(isopropoxycarbonyl)ethyl
phosphoramidate
4’-Vinylguanosine-5’-(Onaphthyl-
I-49 N-(S)(isopropoxycarbonyl)ethyl
phosphoramidate
4’-Vinylguanosine-5’-(Onaphthyl-
I-50 N-(S)(isopropoxycarbonyl)ethyl
phosphoramidate
4’-Vinylguanosine-5’-{ N , N ’-bis[(S)-
(isopropoxycarbonyl)ethyl]phosphoro
I-51
diamidate
4’-Vinyl-5’-O-(2-oxidoH-1,3,2-
I-52 benzodioxaphosphorinyl)-
guanosine
Table 1. Examples of compounds of generic Formula I.
Compound
Structure Name
Number
4’-Vinyl-5’-O-[bis(4-
I-53 methoxyphenoxy)phosphinyl]
guanosine
4’-Vinylguanosine-3’,5’-cyclic
I-54
phosphoric acid isopropyl ester
3’-Deoxy-3’-fluoro-4’-vinyluridine-
’-(Onaphthyl-N-(S)
I-55
(isopropoxycarbonyl)ethyl
phosphoramidate
3’-Deoxy-3’-fluoro-4’-vinyluridine-
’-(Onaphthyl-N-(S)(2,2-
I-56
dimethylpropoxycarbonyl)ethyl
phosphoramidate
3’-Deoxy-3’-fluoro-4’-vinyluridine-
’-(Onaphthyl-N-(S)
I-57
(benzyloxycarbonyl)ethyl
phosphoramidate
Table 1. Examples of compounds of generic Formula I.
Compound
Structure Name
Number
3’-Deoxy-3’-fluoro-4’-vinyluridine-
’-{ N , N ’-bis[(S)
I-58
(isopropoxycarbonyl)ethyl]phosphoro
diamidate}
3’-Deoxy-3’-fluoro-4’-vinyluridine-
’-{ N , N ’-bis[(S)(2,2-
I-59
dimethylpropoxycarbonyl)ethyl]phos
phorodiamidate}
3’-Deoxy-3’-fluoro-4’-vinyluridine-
’-{ N , N ’-bis[(S)
I-60
(cyclopentoxycarbonyl)ethyl]phospho
rodiamidate}
3’-Deoxy-3’-fluoro-4’-vinylcytidine-
’-(Onaphthyl-N-(S)
I-61
(isopropoxycarbonyl)ethyl
phosphoramidate
Table 1. Examples of compounds of generic Formula I.
Compound
Structure Name
Number
3’-Deoxy-3’-fluoro-4’-vinylcytidine-
’-(Onaphthyl-N-(S)(2,2-
I-62
dimethylpropoxycarbonyl)ethyl
phosphoramidate
3’-Deoxy-3’-fluoro-4’-vinylcytidine-
’-(Onaphthyl-N-(S)
I-63
(benzyloxycarbonyl)ethyl
phosphoramidate
3’-Deoxy-3’-fluoro-4’-vinylcytidine-
’-{ N , N ’-bis[(S)
I-64
(propoxycarbonyl)ethyl]phosphorodia
midate}
3’-Deoxy-3’-fluoro-4’-vinylcytidine-
’-{ N , N ’-bis[(S)(2,2-
I-65
dimethylpropoxycarbonyl)ethyl]phos
phorodiamidate}
3’-Deoxy-3’-fluoro-4’-vinylcytidine-
’-{ N , N ’-bis[(S)
I-66
(hexoxycarbonyl)ethyl]phosphorodia
midate}
Table 1. Examples of compounds of generic Formula I.
Compound
Structure Name
Number
3’-Deoxy-3’-fluoro-4’-vinylcytidine-
’-{ N , N ’-bis[(S)
I-67
(cyclopentoxycarbonyl)ethyl]phospho
rodiamidate}
EXAMPLES
Abbreviations used in this application include: acetyl (Ac), acetic acid (HOAc), azo-
bis-isobutyrylnitrile (AIBN), 1-N-hydroxybenzotriazole (HOBt), atmospheres (Atm), high
pressure liquid chromatography (HPLC), 9-borabicyclo[3.3.1]nonane (9-BBN or BBN), methyl
(Me), tert-butoxycarbonyl (Boc), acetonitrile (MeCN), di-tert-butyl pyrocarbonate or boc
anhydride (BOC O), 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (EDCI),
benzoyl (Bz), benzyl (Bn), m-chloroperbenzoic acid (MCPBA), butyl (Bu), methanol (MeOH),
benzyloxycarbonyl (cbz or Z), melting point (mp), carbonyl diimidazole (CDI), MeSO - (mesyl
or Ms), 1,4-diazabicyclo[2.2.2]octane (DABCO), mass spectrum (ms) diethylaminosulfur
trifluoride (DAST), methyl t-butyl ether (MTBE), dibenzylideneacetone (Dba), N-
carboxyanhydride (NCA), 1,5-diazabicyclo[4.3.0]nonene (DBN), N-bromosuccinimide
(NBS), 1,8-diazabicyclo[5.4.0]undecene (DBU), N-methylmorpholine (NMM), N-
methylpyrrolidone (NMP), 1,2-dichloroethane (DCE), pyridinium chlorochromate (PCC), N,N'-
dicyclohexylcarbodiimide (DCC), pyridinium dichromate (PDC), dichloromethane (DCM),
propyl (Pr), diethyl azodicarboxylate (DEAD), phenyl (Ph), di-iso-propylazodicarboxylate ,
DIAD, pounds per square inch (psi), di-iso-propylethylamine (DIPEA), pyridine (pyr), di-iso-
butylaluminumhydride , DIBAL-H, room temperature, rt or RT, N,N-dimethyl acetamide
(DMA), tert-butyldimethylsilyl or t-BuMe Si, (TBDMS), 4-N,N-dimethylaminopyridine
(DMAP), triethylamine (Et N or TEA), N,N-dimethylformamide (DMF), triflate or CF SO -
3 3 2
(Tf), dimethyl sulfoxide (DMSO), trifluoroacetic acid (TFA), 1,1'-bis-
(diphenylphosphino)ethane (dppe), 2,2,6,6-tetramethylheptane-2,6-dione (TMHD), 1,1'-bis-
(diphenylphosphino)ferrocene (dppf), thin layer chromatography (TLC), ethyl acetate (EtOAc),
tetrahydrofuran (THF), diethyl ether (Et O), trimethylsilyl or Me Si (TMS), ethyl (Et), p-
toluenesulfonic acid monohydrate (TsOH or pTsOH), lithium hexamethyl disilazane (LiHMDS),
4-Me-C H SO - or tosyl (Ts), iso-propyl (i-Pr), N-urethane-N-carboxyanhydride (UNCA),
6 4 2
ethanol (EtOH). Conventional nomenclature including the prefixes normal (n), iso (i-),
secondary (sec-), tertiary (tert-) and neo have their customary meaning when used with an alkyl
moiety. (J. Rigaudy and D. P. Klesney, Nomenclature in Organic Chemistry, IUPAC 1979
Pergamon Press, Oxford.).
General Conditions
Compounds of the invention can be made by a variety of methods depicted in the
illustrative synthetic reactions described below in the Examples section.
The starting materials and reagents used in preparing these compounds generally are
either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by
methods known to those skilled in the art following procedures set forth in references such as
Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-
; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5
and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. It
should be appreciated that the synthetic reaction schemes shown in the Examples section are
merely illustrative of some methods by which the compounds of the invention can be
synthesized, and various modifications to these synthetic reaction schemes can be made and will
be suggested to one skilled in the art having referred to the disclosure contained in this
application.
The starting materials and the intermediates of the synthetic reaction schemes can be
isolated and purified if desired using conventional techniques, including but not limited to,
filtration, distillation, crystallization, chromatography, and the like. Such materials can be
characterized using conventional means, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein are typically conducted
under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about
-78 °C to about 150 °C, often from about 0 °C to about 125 °C, and more often and conveniently
at about room (or ambient) temperature, e.g., about 20 °C.
Various substituents on the compounds of the invention can be present in the starting
compounds, added to any one of the intermediates or added after formation of the final products
by known methods of substitution or conversion reactions. If the substituents themselves are
reactive, then the substituents can themselves be protected according to the techniques known in
the art. A variety of protecting groups are known in the art, and can be employed. Examples of
many of the possible groups can be found in “Protective Groups in Organic Synthesis” by Green
et al., John Wiley and Sons, 1999. For example, nitro groups can be added by nitration and the
nitro group can be converted to other groups, such as amino by reduction, and halogen by
diazotization of the amino group and replacement of the diazo group with halogen. Acyl groups
can be added by Friedel-Crafts acylation. The acyl groups can then be transformed to the
corresponding alkyl groups by various methods, including the Wolff-Kishner reduction and
Clemmenson reduction. Amino groups can be alkylated to form mono- and di-alkylamino
groups; and mercapto and hydroxy groups can be alkylated to form corresponding ethers.
Primary alcohols can be oxidized by oxidizing agents known in the art to form carboxylic acids
or aldehydes, and secondary alcohols can be oxidized to form ketones. Thus, substitution or
alteration reactions can be employed to provide a variety of substituents throughout the molecule
of the starting material, intermediates, or the final product, including isolated products.
The starting material of type 1 was prepared according to the literature (J. Med.
Chem., 2000, 43, 4516) and converted to the vinyl derivative 2 by Wittig reaction. Deprotection
and acetolysis provide 3 that underwent Vorbrüggen reaction to the cytidine analogue 4. Further
deprotection by ammonia followed by boron trichloride provided 4’-vinylcytidine 6 (Scheme 1).
Scheme 1
4’-Vinyluridine was synthesized according to the procedure outlined in Scheme 2. 4’-
Vinylcytidine 6 was converted to the corresponding phosphoramidates of type 12 according to
the procedure in Scheme 3. Compounds of type 15 are prepared according to the standard
procedure outlined in Scheme 4.
Scheme 2.
Scheme 3.
Scheme 4.
3’-Deoxy-3’-fluoro-4’-vinyl nucleosides of type 26 should be readily prepared as outlined in
Scheme 5.
Scheme 5.
General Preparations
Synthesis of compound (3aR,5R,6S,6aR)(benzyloxy)(benzyloxymethyl)-2,2-
dimeth ylvinyl-tetrahydrofuro[2,3-d][1,3]dioxole (2)
n-BuLi (3.7 mL, 2.5 mmol) was added into the solution of Ph PCH I (4.0 g, 10 mmol) in dry
THF (25 mL) at 25 °C, after addition, the reaction mixture was stirred at 40 °C for 2 hrs, then the
solution was cooled to 0 °C and compound 1 (1.0 g, 2.5 mmol) was added into the mixture,
removed the ice-bath, the reaction was stirred at 30 °C. After 2 h, the reaction mixture was
quenched by saturated aqueous NH Cl solution (10 mL), extracted with ether, washed with
water, brine solution, dried (Na SO ) and evaporated to dryness under reduced pressure.
Chromatography (petroleum ether:ethyl acetate 20:1 to 15:1) afforded 2 (0.72 g, 72%) as a
colorless oil.
LC-MS: (M+Na) = 419.2
H NMR (300 MHz, CDCl ) δ 7.35–7.33 (m, 10H), 6.19 (dd, J = 11.1 and 17.7 Hz, 1 H), 5.76–
.75 (m, 1H), 5.51 (dd, J = 1.8 and 17.7 Hz, 1H), 5.24 (dd, J = 1.8 and 11.1 Hz, 1H), 4.76 (d, J =
12.3 Hz, 1H), 4.60–4.24 (m, 4H), 1.51 (s, 4H), 1.28 (s, 6H).
Synthesis of compound (3R,4S,5R)(benzyloxy)(benzyloxymethyl)vinyl-
tetra hydrofuran-2,3-diyl diacetate (3)
To a solution of 2 (0.72 g, 1.82 mmol) in AcOH/Ac O (16.5 mL/2 mL) was added H SO (0.35
2 2 4
mL). After stirring at room temperature for 3 h, the reaction mixture was poured into ice-water
and then treated with saturated aqueous NaHCO (5 mL). The organic phase was extracted with
ethyl acetate was washed with water, brine solution, dried (Na SO ) and evaporated to dryness
under reduced pressure. Chromatography column (Chromatography (petroleum ether:ethyl
acetate 20:1 to 10:1) to afford the product 3 (0.471 g, 58%) as a white solid.
LC-MS: (M+Na) = 463.1
H NMR (300 MHz, CDCl ) δ 7.32–7.30 (m, 10H), 6.191 (s, 1H), 6.00–5.94 (m, 1H), 5.50 (dd, J
= 1.5 and 17.1 Hz, 1H), 5.31–5.23 (m, 2H), 4.66 (d, J = 11.7 Hz, 1H), 4.51–4.42 (m, 4H), 3.42
(s, 2H), 2.06 (s, 3H), 1.87 (s, 3H).
Synthesis of compound (2R,3R,4S,5R)(4-aminooxopyrimidin-1(2H)-yl)
(benzyloxy)(benzyloxymethyl)vinyl-tetrahydrofuranyl acetate (4)
BSA (0.976 g, 4.8 mmol) was added to a mixture of 4-aminopyrimidin-2(1H)-one (0.266 g, 2.4
mmol) in CH CN (15 mL) at room temperature. After 3 h, 3 (0.53 g, 1.2 mmol) and SnCl (1.35
g) were added into the mixture. Once complete, the mixture was stirred at 65 °C for 1 h, cooled
and then poured into a saturated aqueous solution of NaHCO (20 mL). The organic phase was
extracted with ethyl acetate, washed with water, brine solution, dried (Na SO ) and evaporated to
dryness. Chromatography (dichloromethane:methanol 15:1) afforded 4 (0.564 g, 95%) as a
brown solid.
LC-MS: (M+H) = 492.2
Synthesis of compound 4-amino((2R,3R,4S,5R)(benzyloxy)
(benzyloxymethy l)hydroxyvinyl-tetrahydrofuranyl)pyrimidin-2(1H)-one (5)
A solution of compound 4 (0.56 g, 1.14 mmol) in NH ·MeOH (20 mL) was stirred at room
temperature for 24 h and then evaporated to dryness under reduced pressure. Chromatography
(dichloromethane:MeOH 15:1) provided 5 (0.5 g, 97%) as a white solid.
LC-MS: (M+H) = 450.2
Synthesis of compound 4-amino((2R,3R,4S,5R)-3,4-dihydroxy(hydroxymeth
yl)vinyl-tetrahydrofuranyl)pyrimidin-2(1H)-one (6)
To a solution of compound 5 (0.112 g, 0.249 mmol) in dry dichloromethane (10 mL) was added
BCl (2.1 mL, 2.1 mmol) at –78 °C. After stirring at –78 °C for 2 h, the reaction mixture was
quenched by the addition of MeOH (1 mL), warmed to room temperature and evaporated to
dryness under reduced pressure. Purification by prep-HPLC provided 6 (0.05 g, 74%) as a white
solid.
LC-MS (M+H) = 270.2
H NMR (300 MHz, DMSO-d ) δ 7.84 (d, J = 7.2 Hz, 1H), 7.17 (d, J = 11.1 Hz , 1H), 5.93 (dd, J
= 10.5 and 17.1 Hz, 1H), 5.84 (d, J = 5.4 Hz, 1H) 5.73 (d, J = 7.5 Hz, 1H), 5.29–5.22 (m, 2H),
.11–5.05 (m, 2H), 4.93–4.91 (d, J = 5.1 Hz, 1H), 4.13–4.09 (m, 2H), 3.48–3.42 (m, 1H), 3.28
(d, J = 11.7 Hz, 1H).
Synthesis of compound (2R,3R,4S,5R)(benzyloxy)(benzyloxymethyl)(2,4-
diox o-3,4-dihydropyrimidin-1(2H)-yl)vinyl-tetrahydrofuranyl acetate (7)
To a solution of pyrimidine-2,4(1H,3H)-dione (0.2 g, 1.8 mmol) in anhydrous CH CN was
slowly added BSA (0.73 mL, 3.6 mmol), maintaining a reaction temperature below 25 C. Once
the reaction mixture solubilized, compound 6 (0.4 g, 0.9 mmol) in CH CN (5 mL) was added at
0 C followed by SnCl (1.17 g, 3.6 mmol). The mixture was stirred at 65 C for 1 h and then
poured into saturated NaHCO (5 mL) at 0 C. The organic phase was extracted with ethyl
acetate, washed with water, brine solution, dried (Na SO ) and evaporated to dryness under
reduced pressure. Chromatography (Petroleum ether: thyl acetate 1:1) gave 7 as an colorless oil
(0.4 g, 90%).
LC-MS: (M+H) = 493;
Synthesis of compound 1-((2R,3R,4S,5R)(benzyloxy)(benzyloxymethyl)
hydro xyvinyl-tetrahydrofuranyl)pyrimidine-2,4(1H,3H)-dione (8)
A mixture of compound 7 (0.4 g, 0.81 mmol) in NH ·MeOH (16 mL) was stirred at 25 C for 16
h and then evaporated to dryness under reduced pressure. Chromatography
(dichloromethance:methanol; 20:1) provided 8 as an colorless oil (0.285 g, 78%).
LC-MS (M+H) = 451;
Synthesis of compound 1-((2R,3R,4S,5R)-3,4-dihydroxy(hydroxymethyl)
vinyl-te trahydrofuranyl)pyrimidine-2,4(1H,3H)-dione (9)
To a solution of compound 8 (0.36 g, 0.8 mmol) in dry dichloromethane (20 mL), cooled to –78
C, was added BCl (6 mL, 6 mmol). After stirring at –78 C for 2 h, the reaction mixture was
quenched by MeOH (0.5 mL), warmed to room temperature and evaporated to dryness under
reduced pressure. Purification by prep-HPLC provided 9 (0.06 g, 25%) as a white solid.
LC-MS (M+H) = 271.1
H NMR (300MHz, d -DMSO) δ 11.317 (brs, 1H), 7.93 (d, J = 8.1 Hz, 1 H), 5.97–5.84 (m, 2 H),
.68 (d, J = 8.1 Hz, 1 H), 5.29–5.02 (m, 5 H), 4.17–4.10 (m, 2 H), 3.50–3.46 (m, 1 H), 3.34–3.27
(m, 1 H).
Synthesis of compound (10)
To a mixture of compound 6 (0.08 g, 0.3 mmol) and 1,1-dimethoxycyclop entane (0.387 g, 3
mmol) in anhydrous 1,2-dichloroethane was added p-toluenesulfonic acid (0.04 g, 0.24 mmol).
The resulting mixture was stirred at 65 C for 1 h, cooled to room temperature and evaporated to
dryness under reduced pressure. Chromatography (dichloromethance:methanol 5:1) gave 10 as a
white solid (0.08 g, 82%).
LC-MS (M+H) = 270.1
Synthesis of (S)(benzyloxy)oxopropanaminium chloride (27)
To a solution of (S)-alanine (5.0 g, 56 mmol) in dry EtOH (100 mL) was added SOCl (8.0 g, 60
mmol) dropwise at –20 C over 20 min. Once complete, the resulting mixture was stirred at 78
C for 5 h, cooled and then evaporated to dryness under reduced pressure. The residue was
triturated with Et O, filtered and dried under vacuum to give the crude product 27, which was
used directly without further purification (8.0 g, 90%).
LC-MS (M) = 118.2
Synthesis of (2S)-benzyl 2-(chloro(phenoxy)phosphorylamino)propanoate (28)
To a solution of 27 (5.0 g, 33 mmol) and Et N (3.6 g, 36 mmol) in dry dichloromethane (100
mL), at –78 C under a nitrogen atmosphere, was added phenyl phosphorodichloridate (6.85 g,
33 mmol). The resulting mixture was stirred at –78 C for 1 h and then warmed to room
temperature. After stirring for further 5 h, the reaction mixture was evaporated to dryness under
reduced pressure. Chromatography (petroleum ether:ethyl acetate 5:1) gave 28 as an colorless oil
(9.0 g, 95%).
LC-MS (M+H) = 292.1
Synthesis of compound (29)
To a suspension of compound 10 (0.08 g, 0.23 mmol) in anhydrous THF, cooled to 0 C and
under nitrogen atmosphere, was added t-BuMgBr (1.84 mL, 1.84 mmol). The resulting mixture
was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was then
cooled to 0 C and (2S)-ethyl 2-(chloro(phenoxy)phosphorylamino)propanoate 28 (0.267 g, 0.92
mmol) was added drop-wise over 10 min. The resulting mixture was stirred at room temperature
for 2 h and then quenched with 1 mL MeOH followed by evaporation to dryness under reduced
pressure. Chromatography (dichloromethane:methanol 20:1 to 15:1) afforded 29 as a white solid
(0.14 g, crude).
LC-MS (M+H) = 591.2
Synthesis of compound (S)-benzyl 2-((((2R,3S,4R,5R)(4-aminooxopyrimid
in-1(2H)-yl)(difluoromethyl)-3,4-dihydroxy-tetrahydrofuran
yl)methoxy)(phenoxy)phosphorylamino)propanoate (30)
A solution of compound 29 (0.14 g, 0.26 mmol) in HCO H (80%, v/v; 10 mL) was stirred at 25
C for 18 h and then evaporated to dryness under reduced pressure. Purification by pre-HPLC
provided 30 as a white solid (28 mg, 22%).
LC-MS (M+H) = 525.2
H NMR (300 MHz, DMSO-d ) δ 7.58 (m, 1H), 7.39 (m, 2H), 7.21 (m, 5H), 6.10–5.91 (m, 3H),
.69 (m, 1H), 5.37–5.19 (m, 4H), 4.13–3.90 (m, 7H), 1.25–1.16 (m, 6H).
Synthesis of compound (31)
t-BuMgBr (1.6 mL, 1.6 mmol) was added to a cooled (0 C ) suspension of compound 10 (0.09
g, 0.27 mmol) in dry THF (36 mL). The reaction mixture was left to stir under a nitrogen
atmosphere for 30 min. (2S)-Benzyl 2-(chloro(phenoxy)pho sphorylamino)propanoate (0.285 g,
0.807 mmol) was added drop-wise at 0 C over 10 min. Once complete, the reaction mixture was
stirred for16 h at room temperature and then quenched with 1 mL MeOH. The resulting mixture
was evaporated to dryness under reduced pressure. Chromatography (dichloromethane:methanol
:1 to 10:1) afforded 31 as a white solid (0.15 g, crude).
LC-MS (M+H) = 653.2
Synthesis of compound (S)-benzyl 2-((((2R,3S,4R,5R)(4-aminooxopyrimid
in-1(2H)-yl)(difluoromethyl)-3,4-dihydroxy-tetrahydrofuran
yl)methoxy)(phenoxy)phosphorylamino)propanoate (32)
A solution of compound 31 (0.15 g, 0.23 mmol) in HCO H (80%, v/v, 30 mL) was stirred at
room temperature for 18 h and then evaporated to dryness under reduced pressure. The residue
was treated with saturated aqueous NaHCO solution until pH = 7 persisted. The organic phase
was extracted with ethyl acetate, washed water, brine solution, dried (Na SO ) and evaporated to
dryness under reduced pressure. Purification by prep-HPLC provided 32 as a white solid (17 mg,
9%).
LC-MS (M+H) = 587.2
H NMR (300 MHz, DMSO-d ) δ 7.56 (m, 1H), 7.34 (m, 7H), 7.34–7.17 (m, 5 H), 6.19-6.15 (m,
1H), 6.12–5.90 (m, 2H), 5.72–5.66 (dd, 1H), 5.35 (m, 1 H), 5.20–5.09 (m, 5H), 4.15–3.89 (m,
5H), 1.25 (t, J = 7.5 Hz, 3H)
Synthesis of compound (2R,3R,4S,5R)(6-amino-9H-purinyl)(benzy loxy)-
-(benzyloxymethyl)vinyl-tetrahydrofuranyl acetate (33).
To a solution of compound 9H-purinamine (0.307 g, 2.28 mmol) and 3 (0.5 g, 1.14 mmol) in
anhydrous CH CN was added SnCl (0.57 mL, 4.9 mmol) portion-wise while maintaining the
reaction temperature at 25 °C. Once complete, the reaction mixture was stired for 16 h and then
poured into saturated aqueous solution of NaHCO at 0 °C. The organic phase was extracted with
ethyl acetate, washed with water, brine solution, dried (Na SO ) and evaporated to dryness under
reduced pressure. Chromatography (petroleum ether:ethyl acetate 1:1) provided 33 as a white
solid (0.395 g, 67%).
LC-MS: (M+H) = 516
Synthesis of compound (2R,3R,4S,5R)(6-amino-9H-purinyl)(benzylox y)-
-(benzyloxymethyl)vinyl-tetrahydrofuranol (34)
A mixture of compound 33 (0.395 g, 0.77 mmol) in NH ·MeOH/dioxane (15 mL/15 mL) was
stirred at 25 °C for 16 h and then evaporated to dryness under reduced pressure. Chromatography
(petroleum ether:ethyl acetate 1:1) afforded 34 as a white solid (0.324 g, 96%).
LC-MS (M+H) = 474
Synthesis of compound (2R,3S,4R,5R)(6-amino-9H-purinyl)(hydroxyme
thyl)vinyl-tetrahydrofuran-3,4-diol (35)
To a solution of compound 34 (0.304 g, 0.64 mmol) in anhydrous dichloromethane (20 mL), at –
78 °C and under a nitrogen atmosphere, was added BCl (5.4 mL, 5.4 mmol). After stirring at –
78 °C for 4 h, the reaction mixture was quenched by the addition of MeOH. The resulting
mixture was allowed to warm to room temperature and then evaporated to dryness under reduced
pressure. Purification by prep-HPLC provided 35 (0.058 g, 29%) as a white solid.
LC-MS (M+H) = 294.1
H NMR (300 MHz, d -DMSO) δ 8.35 (s, 1H), 8.14 (s, 1H), 7.39 (s, 2H), 6.02–5.85 (m, 3 H),
.33–5.26 (m, 2H), 5.15–5.10 (m, 2H), 4.81–4.79 (m, 1H), 4.23 (t, J = 4.8 Hz, 1H), 3.48–3.44
(m, 2H).
Synthesis of compound (2R,3R,4S,5R)(benzyloxy)(benzyloxymethyl)(2-
isob utyramidooxo-1,6-dihydropurinyl)vinyl-tetrahydrofuranyl acetate (36)
Compound 3 (1 g, 2.27 mmol) was added to a mixture of BSA (1.38 g, 6.81 mmol) and N-(6-
oxo-6,9-dihydro-1H-purinyl)isobutyramide (0.752 g, 3.4 mmol) in CH CN (15 mL), under
nitrogen atmosphere, in one portion. Once complete, the mixture was stirred for 3 h. To the
resulting clear solution was added TMSOTf (1.51 g, 6.81 mmol). The reaction mixture was
stirred at 60 °C for 16 h, cooled to 0 °C and then poured onto saturated aqueous solution of
NaHCO . The organic phase was extracted with ethyl acetate, washed with water, brine solution,
dried (Na2SO4) and evaporated to dryness. Chromatography (petroleum ether:ethyl acetate 1:1)
provided 36 (0.7 g, 51%) as a white solid.
Synthesis of compound 2-amino((2R,3R,4S,5R)(benzyloxy)(benzyloxy
methyl)hydroxyvinyl-tetrahydrofuranyl)-1H-purin-6(9H)-one (37)
A solution of compound 36 (0.65 g, 1.08 mmol) in NH ·MeOH (10 mL) was stirred at room
temperature for 48 h and then evaporated to dryness under reduced pressure to give 37 (0.5 g,
crude) as a white solid, which was used directly without further purification.
Synthesis of compound 2-amino((2R,3R,4S,5R)-3,4-dihydroxy(hydroxymeth
yl)vinyl-tetrahydrofuranyl)-1H-purin-6(9H)-one (38)
To a solution of 37 (0.5 g, 1.02 mmol) in anhydrous dichloromethane (10 mL) was added BCl
(10 mL, 10.2 mmol) at –50 °C under a nitrogen atmosphere. Once complete, the reaction was
stirred at –20 °C for 3 h and then quenched by the addition of MeOH (6 mL), warmed to room
temperature and then evaporated to dryness under reduced pressure. Purification by prep-HPLC
afforded 38 (0.054 g, 17%) as a white solid.
LC-MS (M+H) = 310.1
H NMR (300 MHz, DMSO-d ) δ 10.59 (s, 1 H), 7.98 (s, 1H), 6.46 (s, 2H), 6.03–5.94 (q, 1 H),
.75–5.73 (d, 1H), 5.33–5.26 (m, 3H), 5.15–5.11 (dd, 1H), 5.05–5.04 (d, 1H), 4.62–4.56 (q, 1H),
4.24–4.20 (t, 1H), 3.50–3.36 (m, 2H).
Biological Examples
Table 2. Activity of nucleoside triphosphate analogs
as inhibitors of RNA synthesis by RSV polymerase.
Compound Number a
Structure IC
II-1 A
II-2 A
II-3 A
II-4
II-5
II-6
RSV polymerase inhibition with A = IC < 1 µM
RSV Assays
The RSV polymerase assay measures the ability of the nucleoside triphosphates
derived from compounds of formula I to inhibit the RSV polymerase. RSV polymerase was
obtained from RSV infected A549 cells. RSV polymerase activity was measured using RSV
polymerase preparation (stored in 10 mM Tris-acetate (pH 8), 10 mM K-acetate, 1.5 mM MgCl2,
0.5% deoxycholate and 1% Tween-40) in the a buffer containing 50 mM Tris-HCL, pH8, 100
mM KCl, 5 mM MgCl , 1 mM DTT and 0.2 mg/ml BSA in the presence of 50 µM ATP, GTP
and UTP, 1 µM CTP and 3.5 µCi P-labeled CTP (10 mCi/mL). The amount of nucleotides
incorporated into nascent RSV RNA was determined TCA precipitation and scintillation
counting.
RSV replication was measured in cell culture in RSV infected Hep-2 or Huh-7 cells.
Cell culture supernatant containing RSV particles was collected and the RSV virus concentration
was determined using ELISA, RT-PCR and plaque assays.
The polymerase and replication activities of RSV were measured in the presence and
absence of different concentrations of compounds to determine the degree of inhibition by the
compounds.
The compound concentration at which the enzyme-catalyzed rate is reduced by 50 %
(IC ) was calculated by fitting the data to equation (1),
(%Max − %Min)
Y = %Min +
(1 + )
(IC )
where “Y” corresponds to the relative enzyme activity (in %), “%Min” is the residual relative
activity at saturating compound concentration, “%Max” is the relative maximum enzymatic
activity, X corresponds to the compound concentration, and “S” is the Hill coefficient (or slope).
Dosage and Administration:
As shown in above Table the compounds of formula I have the potential to be
efficacious as antiviral drugs for the treatment of RSV infections in humans, or are metabolized
to a compound that exhibit such activity.
In another embodiment, the active compound or its prodrug derivative or salt can be
administered in combination with another antiviral agent, such as an anti-hepatitis agent,
including those of formula I. When the active compound or its derivative or salt are administered
in combination with another antiviral agent the activity may be increased over the parent
compound. This can easily be assessed by preparing the derivative and testing its anti-RSV
activity according to the method described herein.
Administration of the active compound may range from continuous (intravenous drip)
to several oral administrations per day (for example, Q.I.D) and may include oral, topical
parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a
penetration enhancement agent), buccal and suppository administration, among other routes of
administration.
The 4'-vinyl substituted nucleoside derivatives as well as their pharmaceutically
useable salts, can be used as medicaments in the form of any pharmaceutical formulation. The
pharmaceutical formulation can be administered enterally, either orally, e.g. in the form of
tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions, syrups, or
suspensions, or rectally, e.g. in the form of suppositories. They can also be administered
parenterally (intramuscularly, intravenously, subcutaneously or intrasternal injection or infusion
techniques), e.g. in the form of injection solutions, nasally, e.g. in the form of nasal sprays, or
inhalation spray, topically and so forth.
For the manufacture of pharmaceutical preparations, the 4'-substituted nucleoside
derivatives, as well as their pharmaceutically useable salts, can be formulated with a
therapeutically inert, inorganic or organic excipient for the production of tablets, coated tablets,
dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions.
The compounds of formula I can be formulated in admixture with a pharmaceutically
acceptable carrier. For example, the presently described compounds can be administered orally
as pharmacologically acceptable salts. Because the presently described compounds are mostly
water soluble, they can be administered intravenously in physiological saline solution (e.g.,
buffered to a pH of about 7.2 to 7.5). Conventional buffers such as phosphates, bicarbonates or
citrates can be used for this purpose. Of course, one of ordinary skill in the art may modify the
formulations within the teachings of the specification to provide numerous formulations for a
particular route of administration without rendering the compositions of the present invention
unstable or compromising their therapeutic activity. In particular, the modification of the present
compounds to render them more soluble in water or other vehicle, for example, may be easily
accomplished by minor modifications (salt formulation, esterification, etc.) which are well within
the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route
of administration and dosage regimen of a particular compound in order to manage the
pharmacokinetics of the present compounds for maximum beneficial effect in patients.
For parenteral formulations, the carrier will usually comprise sterile water or aqueous
sodium chloride solution, though other ingredients including those which aid dispersion may be
included. Of course, where sterile water is to be used and maintained as sterile, the compositions
and carriers must also be sterilized. Injectable suspensions may also be prepared, in which case
appropriate liquid carriers, suspending agents and the like may be employed.
Suitable excipients for tablets, coated tablets, dragées, and hard gelatin capsules are,
for example, lactose, corn starch and derivatives thereof, talc, and stearic acid or its salts.
If desired, the tablets or capsules may be enteric-coated or sustained release by
standard techniques.
Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes,
fats, semi-solid and liquid polyols.
Suitable excipients for injection solutions are, for example, water, saline, alcohols,
polyols, glycerin or vegetable oils.
Suitable excipients for suppositories are, for example, natural and hardened oils,
waxes, fats, semi-liquid or liquid polyols.
Suitable excipients for solutions and syrups for enteral use are, for example, water,
polyols, saccharose, invert sugar and glucose.
The presently described pharmaceutical preparations may also be provided as
sustained release formulations or other appropriate formulations.
The pharmaceutical preparations can also contain preservatives, solubilizers,
stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavourants, salts for adjustment of
the osmotic pressure, buffers, masking agents or antioxidants.
The pharmaceutical preparations may also contain other therapeutically active agents
known in the art.
The dosage can vary within wide limits and will, of course, be adjusted to the
individual requirements in each particular case. For oral administration, a daily dosage of
between about 0.01 and about 100 mg/kg body weight per day should be appropriate in
monotherapy and/or in combination therapy. A preferred daily dosage is between about 0.1 and
about 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg body weight and most
preferred 1.0 and about 100 mg/kg body weight per day. A typical preparation will contain from
about 5% to about 95% active compound (w/w). The daily dosage can be administered as a
single dosage or in divided dosages, typically between 1 and 5 dosages per day.
In certain pharmaceutical dosage forms, the pro-drug form of the compounds,
especially including acylated (acetylated or other) derivatives, pyridine esters and various salt
forms of the present compounds are preferred. One of ordinary skill in the art will recognize how
to readily modify the present compounds to pro-drug forms to facilitate delivery of active
compounds to a target site within the host organism or patient. One of ordinary skill in the art
will also take advantage of favorable pharmacokinetic parameters of the pro-drug forms, where
applicable, in delivering the present compounds to targeted site within the host organism or
patient to maximize the intended effect of the compound.
Indications and Method of Treatment
The application describes a method for treating an RSV infection comprising
administering to a patient in need thereof a therapeutically effective amount of a compound of
Formula I.
The application describes the above method, further comprising administering an
immune system modulator or one or more antiviral agents that inhibits replication of RSV, or a
combination thereof.
The application describes the above method for inhibiting replication of RSV in a cell
comprising administering a compound of Formula I.
Combination Therapy
The compounds of the description and their isomeric forms and pharmaceutically
acceptable salts thereof are useful in treating and preventing RSV infection alone or when used
in combination with other compounds targeting viral or cellular elements or functions involved
in the RSV lifecycle or immunomodulators. Classes of compounds useful as described include,
without limitation, all classes of RSV antivirals.
Additionally, combinations of, for example, with an interferon, may be administered
as multiple combination therapy with at least one of the described compounds. The present
description is not limited to the aforementioned classes or compounds and contemplates known
and new compounds and combinations of biologically active agents. It is intended that
combination therapies of the present description include any chemically compatible combination
of a compound of this inventive group with other compounds of the inventive group or other
compounds outside of the inventive group, as long as the combination does not eliminate the
anti-viral activity of the compound of this inventive group or the anti-viral activity of the
pharmaceutical composition itself.
Combination therapy can be sequential, that is treatment with one agent first and then
a second agent (for example, where each treatment comprises a different compound of the
present description or where one treatment comprises a compound of the description and the
other comprises one or more biologically active agents) or it can be treatment with both agents at
the same time (concurrently). Sequential therapy can include a reasonable time after the
completion of the first therapy before beginning the second therapy. Treatment with both agents
at the same time can be in the same daily dose or in separate doses. Combination therapy need
not be limited to two agents and may include three or more agents. The dosages for both
concurrent and sequential combination therapy will depend on absorption, distribution,
metabolism and excretion rates of the components of the combination therapy as well as other
factors known to one of skill in the art. Dosage values will also vary with the severity of the
condition to be alleviated. It is to be further understood that for any particular subject, specific
dosage regimens and schedules may be adjusted over time according to the individual's need and
the judgment of the one skilled in the art administering or supervising the administration of the
combination therapy.
The application describes a method for treating an RSV infection comprising
administering to a patient in need thereof a therapeutically effective amount of a compound of
any one of Formula I.
The application describes the above method, further comprising administering an
immune system modulator or an antiviral agent that inhibits replication of RSV, or a
combination thereof.
The application describes the above method, wherein the immune system modulator is
an interferon or chemically derivatized interferon.
It will be understood that references herein to treatment extend to prophylaxis as well
as to the treatment of existing conditions, and that the treatment of animals includes the treatment
of humans as well as other mammals. Furthermore, treatment of an RSV infection, as used
herein, also includes treatment or prophylaxis of a disease or a condition associated with or
mediated by an RSV infection, or the clinical symptoms thereof.
The features disclosed in the foregoing description, or the following claims, or the
accompanying drawings, expressed in their specific forms or in terms of a means for performing
the disclosed function, or a method or process for attaining the disclosed result, as appropriate,
may, separately, or in any combination of such features, be utilized for realizing the invention in
diverse forms thereof.
The foregoing invention has been described in some detail by way of illustration and
example, for purposes of clarity and understanding. It will be obvious to one of skill in the art
that changes and modifications may be practiced within the scope of the appended claims.
Therefore, it is to be understood that the above description is intended to be illustrative and not
restrictive. The scope of the invention should, therefore, be determined not with reference to the
above description, but should instead be determined with reference to the following appended
claims, along with the full scope of equivalents to which such claims are entitled.
[0123a] In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission that such
documents, or such sources of information, in any jurisdiction, are prior art, or form part of the
common general knowledge in the art.
All patents, patent applications and publications cited in this application are hereby
incorporated by reference in their entirety for all purposes to the same extent as if each individual
patent, patent application or publication were so individually denoted.
WE
Claims (25)
1. A compound of formula I Base wherein: Y is P(=X)(R)(R’); 1 2a 2b 3 R is O-R or NHC(R )(R )C(=O)OR ; 4 2a 2b 3 3 R’ is N(R )C(R )(R )C(=O)OR , –OP(=O)(OH)OP(=O)(OH)OH, or –OR ; R is H, C alkyl, C haloalkyl, or aryl, wherein aryl is phenyl or 1-7 1-7 naphthyl, optionally substituted with one or more C alkyl, C alkenyl, C alkynyl, 1-7 2-7 2-7 1a 1a 1b C alkoxy, halo, lower haloalkyl, -N(R ) , acylamino, -SO N(R ) , -C(=O)R , - 1-7 2 2 2 1c 1c 1’’ SO R , -NHSO R , nitro, cyano, or R ; each R is independently H or lower alkyl; 1b 1a 1a each R is independently -OR or -N(R ) ; each R is lower alkyl; 2a 2b 1a each R and R is independently H, C alkyl, -(CH ) N(R ) , C 1-7 2 r 2 1- hydroxyalkyl, -CH SH, -(CH )S(O) Me, -(CH ) NHC(=NH)NH , (1H-indolyl)Me, 7 2 2 p 2 n 2 (1H-indolyl)Me, -(CH ) C(=O)R , aryl or aryl C alkyl, wherein aryl and aryl C 2 m 1-7 1-7 alkyl are optionally substituted with one or more hydroxy, C alkyl, C alkoxy, halo, 1-7 1-7 nitro or cyano; m is 0, 1, or 2; n is 1, 2, or 3; p is 1 or 2; r is 1 or 2; 2a 2b 4 or R is H and R and R together form (CH ) ; each R is independently H, C alkyl, C haloalkyl, phenyl or phenyl C 1-7 1-7 1- alkyl, wherein phenyl and phenyl C alkyl are optionally substituted with C alkoxy; 7 1-7 1-7 3 1’’ or R and R together form CH ; each R is independently H, C alkyl; 2b 4 or R and R together form (CH ) ; w x y each of R , R , and R is independently H, OH, or F; R is H or OH; or R and R together form a bond; or R and R together form a bond; X is O or S; and Base is uracil, cytosine, guanine, adenine, or thymine, each of which may optionally be substituted with one or more hydroxy, C alkyl, C alkoxy, halo, nitro or cyano; 1-7 1-7 or a pharmacologically acceptable salt thereof.
2. The compound of claim 1, wherein R is OH.
3. The compound of either claim 1 or claim 2, wherein R is H.
4. The compound of any one of claims 1-3, wherein R is H.
5. The compound of any one of claims 1-4, wherein R is OH or F.
6. The compound of any one of claims 1-5, wherein Y is P(=X)(R)(R’), 3 3 1 1 x R’ is O-R , R is C alkyl, R is –OR , and R and R together form a bond.
7. The compound of any one of claims 1-5, wherein R is –OR , R is phenyl 1’’ 3 3 1’’ substituted with R , R’ is –OR , and R and R together form CH2.
8. The compound of any one of claims 1-7, wherein X is O.
9. The compound of any one of claims 1-7, wherein X is S.
10. The compound of any one of claims 1-5, wherein R is O-R , and R is phenyl optionally substituted with methoxy.
11. The compound of any one of claims 1-5, wherein R is O-R , and R is naphthyl.
12. The compound of any one of claims 1-5, wherein R’ is 4 2a 2b 3 4 2a 2b 3 N(R )C(R )(R )C(=O)OR , R is H, R is H, R is methyl, and R is isopropyl.
13. The compound of any one of claims 1-5, wherein R’ is - OP(=O)(OH)OP(=O)(OH)OH.
14. The compound of any one of claims 1-13, wherein Base is cytosine optionally substituted with halo.
15. The compound of any one of claims 1-13, wherein Base is uracil optionally substituted with halo.
16. The compound of any one of claims 1-15, wherein R is F.
17. A compound selected from the list consisting of: 4’-Vinyluridine-5’-(O-phenyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate; 4’-Vinyluridine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate; 4’-Vinyluridine-5’-(Onaphthyl-N-(S)(i2,2-dimethylpropoxycarbonyl)ethyl phosphoramidate; 4’-Vinyluridine-5’-(Onaphthyl-N-(S)(3,3-dimethylbutoxycarbonyl)ethyl phosphoramidate; 4’-Vinyluridine-5’-(Onaphthyl-N-(S)(benzyloxycarbonyl)ethyl phosphoramidate; 4’-Vinyluridine-5’-(Onaphthyl-N-(S)(hexoxycarbonyl)ethyl phosphoramidate; 4’-Vinyluridine-5’-(Onaphthyl-N-(S)(cyclopentoxycarbonyl)ethyl phosphoramidate; 4’-Vinyluridine-5’-(Onaphthyl-N-(S)(cyclohexoxycarbonyl)ethyl phosphoramidate; 4’-Vinyluridine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate; 4’-Vinyluridine-5’-{ N ,N ’-bis[(S)(isopropoxycarbonyl)ethyl]phosphorodiamidate}; 4’-Vinyluridine-5’-{ N ,N ’-bis[(S)(2,2- dimethylpropoxycarbonyl)ethyl]phosphorodiamidate}; 4’-Vinyluridine-5’-{ N ,N ’-bis[(S)(3,3-dimethylbutoxycarbonyl)ethyl]phosphorodiamidate}; 4’-Vinyluridine-5’-{ N ,N ’-bis[(S)(benzyloxycarbonyl)ethyl]phosphorodiamidate}; 4’-Vinyluridine-5’-{ N ,N ’-bis[(S)(hexoxycarbonyl)ethyl]phosphorodiamidate}; 4’-Vinyluridine-5’-{ N ,N ’-bis[(S)(cyclopentoxycarbonyl)ethyl]phosphorodiamidate}; 4’-Vinyluridine-5’-{ N ,N ’-bis[(S)(cyclohexoxycarbonyl)ethyl]phosphorodiamidate}; 4’-Vinyl-5’-O-(2-oxidoH-1,3,2-benzodioxaphosphorinyl)-uridine; 4’-Vinyl-5’-O-[bis(4-methoxyphenoxy)phosphinyl] uridine; 4’-Vinyluridine-3’,5’-cyclic phosphoric acid isopropyl ester; 4’-Vinylcytidine-5’-(O-phenyl-N-(S)(ethoxycarbonyl)ethyl phosphoramidate; 4’-Vinylcytidine-5’-(O-phenyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate; 4’-Vinylcytidine-5’-(O-phenyl-N-(S)(neopentoxycarbonyl)ethyl phosphoramidate; 4’-Vinylcytidine-5’-(O-phenyl-N-(S)(benzyloxycarbonyl)ethyl phosphoramidate; 4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate; 4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(2,2-dimethylpropoxycarbonyl)ethyl phosphoramidate; 4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(benzyloxycarbonyl)ethyl phosphoramidate; 4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(3,3-dimethybutoxycarbonyl)ethyl phosphoramidate; 4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(pentoxycarbonyl)ethyl phosphoramidate; 4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(hexoxycarbonyl)ethyl phosphoramidate; 4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(cyclohexoxycarbonyl)ethyl phosphoramidate; 4’-Vinylcytidine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate; 4’-Vinylcytidine-5’-{N ,N ’-bis[(S)(isopropoxycarbonyl)ethyl]phosphorodiamidate}; 4’-Vinylcytidine-5’-{N ,N ’-bis[(S)(2,2- dimethylpropoxycarbonyl)ethyl]phosphorodiamidate}; 4’-Vinylcytidine-5’-{N ,N ’-bis[(S)benzyloxycarbonyl)ethyl]phosphorodiamidate}; 4’-Vinylcytidine-5’-{N ,N ’-bis[(S)(3,3- dimethylbutoxycarbonyl)ethyl]phosphorodiamidate}; 4’-Vinylcytidine-5’-{N ,N ’-bis[(S)(hexoxycarbonyl)ethyl]phosphorodiamidate}; 4’-Vinylcytidine-5’-{N ,N ’-bis[(S)(cyclohexoxycarbonyl)ethyl]phosphorodiamidate}; 4’-Vinyl-5’-O-(2-oxidoH-1,3,2-benzodioxaphosphorinyl)-cytidine; 4’-Vinyl-5’-O-[bis(4-methoxyphenoxy)phosphinyl] cytidine; 4’-Vinylcytidine-3’,5’-cyclic phosphoric acid isopropyl ester; 4’-Viyladenosine-5’-(O-phenyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate; 4’-Vinyladenosine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate; 4’-Vinyladenosine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate; 4’-Vinyladenosine-5’-{ N ,N ’-bis[(S)(isopropoxycarbonyl)ethyl]phosphorodiamidate; 4’-Vinyl-5’-O-(2-oxidoH-1,3,2-benzodioxaphosphorinyl)-adenosine; 4’-Vinyl-5’-O-[bis(4-methoxyphenoxy)phosphinyl] adenosine; 4’-Vinyladenosine-3’,5’-cyclic phosphoric acid isopropyl ester; 4’-Vinylguanosine-5’-(O-phenyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate; 4’-Vinylguanosine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate; 4’-Vinylguanosine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate; 4’-Vinylguanosine-5’-{ N ,N ’-bis[(S)(isopropoxycarbonyl)ethyl]phosphorodiamidate; 4’-Vinyl-5’-O-(2-oxidoH-1,3,2-benzodioxaphosphorinyl)-guanosine; 4’-Vinyl-5’-O-[bis(4-methoxyphenoxy)phosphinyl] guanosine; 4’-Vinylguanosine-3’,5’-cyclic phosphoric acid isopropyl ester; 3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate; 3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-(Onaphthyl-N-(S)(2,2- dimethylpropoxycarbonyl)ethyl phosphoramidate; 3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-(Onaphthyl-N-(S)(benzyloxycarbonyl)ethyl phosphoramidate; 3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-{ N ,N ’-bis[(S) (isopropoxycarbonyl)ethyl]phosphorodiamidate}; 3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-{ N ,N ’-bis[(S)(2,2- dimethylpropoxycarbonyl)ethyl]phosphorodiamidate}; 3’-Deoxy-3’-fluoro-4’-vinyluridine-5’-{ N ,N ’-bis[(S) (cyclopentoxycarbonyl)ethyl]phosphorodiamidate}; 3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-(Onaphthyl-N-(S)(isopropoxycarbonyl)ethyl phosphoramidate; 3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-(Onaphthyl-N-(S)(2,2- dimethylpropoxycarbonyl)ethyl phosphoramidate; 3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-(Onaphthyl-N-(S)(benzyloxycarbonyl)ethyl phosphoramidate; 3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-{N ,N ’-bis[(S) (propoxycarbonyl)ethyl]phosphorodiamidate}; 3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-{N ,N ’-bis[(S)(2,2- dimethylpropoxycarbonyl)ethyl]phosphorodiamidate}; 3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-{N ,N ’-bis[(S) (hexoxycarbonyl)ethyl]phosphorodiamidate}; and 3’-Deoxy-3’-fluoro-4’-vinylcytidine-5’-{N ,N ’-bis[(S) (cyclopentoxycarbonyl)ethyl]phosphorodiamidate}.
18. Use of a compound according to any one of claims 1 to 17 in the manufacture of a medicament for preventing or treating an RSV infection.
19. A pharmaceutical composition comprising the compound of any one of claims 1 to 17.
20. A pharmaceutical composition comprising the compound of claim 17.
21. A compound of formula I as claimed in any one of claims 1-16, substantially as herein described with reference to any example thereof.
22. A compound as claimed in claim 17, substantially as herein described with reference to any example thereof.
23. A use as claimed in claim 18, substantially as herein described with reference to any example thereof.
24. A pharmaceutical composition as claimed in claim 19, substantially as herein described with reference to any example thereof.
25. A pharmaceutical composition as claimed in claim 20, substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462055704P | 2014-09-26 | 2014-09-26 | |
US62/055,704 | 2014-09-26 | ||
PCT/US2015/052144 WO2016049415A1 (en) | 2014-09-26 | 2015-09-25 | 4'-vinyl substituted nucleoside derivatives as inhibitors of respiratory syncytial virus rna replication |
Publications (2)
Publication Number | Publication Date |
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NZ730923A NZ730923A (en) | 2020-09-25 |
NZ730923B2 true NZ730923B2 (en) | 2021-01-06 |
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