ES2536727T3 - Nucleósido ciclofosfatos - Google Patents

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Publication number

ES2536727T3

ES2536727T3 ES09763386.1T ES09763386T ES2536727T3 ES 2536727 T3 ES2536727 T3 ES 2536727T3 ES 09763386 T ES09763386 T ES 09763386T ES 2536727 T3 ES2536727 T3 ES 2536727T3

Authority

ES

Spain

Prior art keywords

alkyl

substituted

optionally substituted

alkenyl

halogenated

Prior art date

2008-06-11

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• 239000002777 nucleoside Substances 0.000 title description 23
• 150000003833 nucleoside derivatives Chemical class 0.000 title description 15
• -1 CO2R ' Chemical group 0.000 claims abstract description 118
• 150000001875 compounds Chemical class 0.000 claims abstract description 92
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 78
• 229910052731 fluorine Inorganic materials 0.000 claims abstract description 45
• 229910052794 bromium Inorganic materials 0.000 claims abstract description 43
• 229910052801 chlorine Inorganic materials 0.000 claims abstract description 41
• 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 39
• 229910052740 iodine Inorganic materials 0.000 claims abstract description 39
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 35
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 32
• 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims abstract description 31
• 125000003118 aryl group Chemical group 0.000 claims abstract description 29
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 28
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 27
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 27
• 150000003839 salts Chemical class 0.000 claims abstract description 27
• 125000003342 alkenyl group Chemical group 0.000 claims abstract description 25
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 23
• 125000002252 acyl group Chemical group 0.000 claims abstract description 23
• 125000001624 naphthyl group Chemical group 0.000 claims abstract description 23
• 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 22
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 20
• 125000005017 substituted alkenyl group Chemical group 0.000 claims abstract description 18
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims abstract description 18
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 17
• 125000004426 substituted alkynyl group Chemical group 0.000 claims abstract description 17
• 125000001424 substituent group Chemical group 0.000 claims abstract description 16
• 125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 15
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 12
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 11
• 239000012453 solvate Substances 0.000 claims abstract description 11
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 8
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 8
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 8
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims abstract description 7
• 125000005865 C2-C10alkynyl group Chemical group 0.000 claims abstract description 7
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims abstract description 7
• VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical group F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims abstract description 7
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims abstract description 7
• XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 claims abstract description 6
• JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical group F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims abstract description 6
• 108010081348 HRT1 protein Hairy Chemical group 0.000 claims abstract description 6
• 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims abstract description 6
• AQIAIZBHFAKICS-UHFFFAOYSA-N methylaminomethyl Chemical compound [CH2]NC AQIAIZBHFAKICS-UHFFFAOYSA-N 0.000 claims abstract description 6
• 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims abstract description 3
• 239000000203 mixture Substances 0.000 claims description 60
• 241000711549 Hepacivirus C Species 0.000 claims description 41
• 238000011282 treatment Methods 0.000 claims description 21
• 241000700605 Viruses Species 0.000 claims description 20
• 125000000304 alkynyl group Chemical group 0.000 claims description 15
• 241000710780 Bovine viral diarrhea virus 1 Species 0.000 claims description 11
• 239000003814 drug Substances 0.000 claims description 11
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
• 241000710842 Japanese encephalitis virus Species 0.000 claims description 7
• 241000710772 Yellow fever virus Species 0.000 claims description 7
• 238000002560 therapeutic procedure Methods 0.000 claims description 7
• 229940051021 yellow-fever virus Drugs 0.000 claims description 7
• 241000709661 Enterovirus Species 0.000 claims description 6
• 241000991587 Enterovirus C Species 0.000 claims description 6
• 241000709721 Hepatovirus A Species 0.000 claims description 6
• 241000710886 West Nile virus Species 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 241000725619 Dengue virus Species 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 206010012310 Dengue fever Diseases 0.000 claims description 3
• 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 2
• 208000001490 Dengue Diseases 0.000 claims description 2
• 208000025729 dengue disease Diseases 0.000 claims description 2
• 208000010710 hepatitis C virus infection Diseases 0.000 claims description 2
• 150000001540 azides Chemical class 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 70
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
• 239000000047 product Substances 0.000 description 53
• 239000000243 solution Substances 0.000 description 53
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
• 230000002829 reductive effect Effects 0.000 description 42
• 239000007787 solid Substances 0.000 description 41
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
• 238000006243 chemical reaction Methods 0.000 description 38
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
• 239000000460 chlorine Substances 0.000 description 33
• 235000019439 ethyl acetate Nutrition 0.000 description 30
• 238000000034 method Methods 0.000 description 25
• 238000005160 1H NMR spectroscopy Methods 0.000 description 24
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
• 230000015572 biosynthetic process Effects 0.000 description 23
• 238000003756 stirring Methods 0.000 description 22
• 238000003786 synthesis reaction Methods 0.000 description 22
• 239000000741 silica gel Substances 0.000 description 20
• 229910002027 silica gel Inorganic materials 0.000 description 20
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
• 239000000706 filtrate Substances 0.000 description 18
• 238000002360 preparation method Methods 0.000 description 18
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
• 125000003545 alkoxy group Chemical group 0.000 description 16
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
• 241000710778 Pestivirus Species 0.000 description 15
• 229910052757 nitrogen Inorganic materials 0.000 description 15
• 208000015181 infectious disease Diseases 0.000 description 14
• 239000002904 solvent Substances 0.000 description 14
• KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 13
• 241000711557 Hepacivirus Species 0.000 description 13
• 201000010099 disease Diseases 0.000 description 13
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
• 239000003112 inhibitor Substances 0.000 description 13
• 108091032973 (ribonucleotides)n+m Proteins 0.000 description 12
• 238000004679 31P NMR spectroscopy Methods 0.000 description 12
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 12
• 239000000725 suspension Substances 0.000 description 12
• 239000003795 chemical substances by application Substances 0.000 description 11
• 229910052760 oxygen Inorganic materials 0.000 description 11
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 10
• 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 10
• 238000009472 formulation Methods 0.000 description 10
• 239000001257 hydrogen Substances 0.000 description 10
• 239000011541 reaction mixture Substances 0.000 description 10
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 9
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
• 239000007858 starting material Substances 0.000 description 9
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
• 229910019142 PO4 Inorganic materials 0.000 description 8
• ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 8
• 125000005843 halogen group Chemical group 0.000 description 8
• 235000021317 phosphate Nutrition 0.000 description 8
• 238000011321 prophylaxis Methods 0.000 description 8
• 229910052717 sulfur Inorganic materials 0.000 description 8
• HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 8
• 238000005481 NMR spectroscopy Methods 0.000 description 7
• 239000004480 active ingredient Substances 0.000 description 7
• 229910052799 carbon Inorganic materials 0.000 description 7
• 238000004440 column chromatography Methods 0.000 description 7
• QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 7
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
• 239000003981 vehicle Substances 0.000 description 7
• 230000003612 virological effect Effects 0.000 description 7
• KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 6
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
• 241000283690 Bos taurus Species 0.000 description 6
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
• JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
• 101710144111 Non-structural protein 3 Proteins 0.000 description 6
• 108700026244 Open Reading Frames Proteins 0.000 description 6
• 101710172711 Structural protein Proteins 0.000 description 6
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
• 150000001413 amino acids Chemical class 0.000 description 6
• 239000003443 antiviral agent Substances 0.000 description 6
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
• 238000004587 chromatography analysis Methods 0.000 description 6
• 230000008034 disappearance Effects 0.000 description 6
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• 229910052736 halogen Inorganic materials 0.000 description 6
• 150000002367 halogens Chemical class 0.000 description 6
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• 102000004169 proteins and genes Human genes 0.000 description 6
• 230000010076 replication Effects 0.000 description 6
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• CEZAHINTASCQLC-GSWPYSDESA-N (2r,3r,4r,5r)-5-(2-amino-6-methoxypurin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyloxolan-3-ol Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)F CEZAHINTASCQLC-GSWPYSDESA-N 0.000 description 5
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
• 241000282412 Homo Species 0.000 description 5
• 108060004795 Methyltransferase Proteins 0.000 description 5
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• UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 5
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• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
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