TWI733656B - 用於治療及預防病毒感染之新穎3-經取代5-胺基-6H-噻唑并[4,5-d]嘧啶-2,7-二酮化合物 - Google Patents
用於治療及預防病毒感染之新穎3-經取代5-胺基-6H-噻唑并[4,5-d]嘧啶-2,7-二酮化合物 Download PDFInfo
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- TWI733656B TWI733656B TW104140978A TW104140978A TWI733656B TW I733656 B TWI733656 B TW I733656B TW 104140978 A TW104140978 A TW 104140978A TW 104140978 A TW104140978 A TW 104140978A TW I733656 B TWI733656 B TW I733656B
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- Prior art keywords
- tetrahydrofuran
- amino
- thiazolo
- pyrimidine
- compound
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- -1 3-SUBSTITUTED 5-AMINO-6H-THIAZOLO[4,5-d]PYRIMIDINE-2,7-DIONE COMPOUNDS Chemical class 0.000 title claims description 94
- 238000011282 treatment Methods 0.000 title claims description 34
- 230000009385 viral infection Effects 0.000 title description 4
- 238000011321 prophylaxis Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 320
- 150000003839 salts Chemical class 0.000 claims abstract description 69
- 238000000034 method Methods 0.000 claims abstract description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 315
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 122
- 238000002360 preparation method Methods 0.000 claims description 107
- 150000002148 esters Chemical class 0.000 claims description 88
- 125000000217 alkyl group Chemical group 0.000 claims description 68
- 239000001257 hydrogen Substances 0.000 claims description 66
- 229910052739 hydrogen Inorganic materials 0.000 claims description 66
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 56
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 50
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 50
- 238000006243 chemical reaction Methods 0.000 claims description 40
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 32
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims description 32
- 239000004305 biphenyl Substances 0.000 claims description 29
- 235000010290 biphenyl Nutrition 0.000 claims description 29
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 29
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 24
- 239000002585 base Substances 0.000 claims description 21
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 20
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 19
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 19
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 16
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 14
- 125000001544 thienyl group Chemical group 0.000 claims description 14
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 claims description 13
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 13
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 12
- 229920002554 vinyl polymer Polymers 0.000 claims description 12
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000006267 biphenyl group Chemical group 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 208000002672 hepatitis B Diseases 0.000 claims description 7
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- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
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- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 229920001296 polysiloxane Polymers 0.000 claims description 6
- ZMTKCUWAZUIQSB-TZVDFBJISA-N 5-amino-3-[(2R,3R,5S)-5-[cyclopropyl(hydroxy)methyl]-3-hydroxyoxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1O)C(O)C1CC1)=O ZMTKCUWAZUIQSB-TZVDFBJISA-N 0.000 claims description 5
- FMXMRHPDGUJOQZ-LYEZXKSPSA-N C[C@@H]1C[C@H](O[C@H]1N1C(=O)SC2C1=NC(N)=NC2=O)[C@@H](O)C1CC1 Chemical compound C[C@@H]1C[C@H](O[C@H]1N1C(=O)SC2C1=NC(N)=NC2=O)[C@@H](O)C1CC1 FMXMRHPDGUJOQZ-LYEZXKSPSA-N 0.000 claims description 5
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- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 5
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- 125000006248 tosyl amino group Chemical group [H]N(*)S(=O)(=O)C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 5
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 4
- CSCCBXFBWDXYLV-BAJZRUMYSA-N 5-amino-3-[(2R,3R,5S)-3-(2-fluoropropan-2-yl)-5-(hydroxymethyl)oxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1C(C)(C)F)CO)=O CSCCBXFBWDXYLV-BAJZRUMYSA-N 0.000 claims description 3
- BXLRBSLTDVGIIR-RGNHYFCHSA-N 5-amino-3-[(2R,3R,5S)-5-(hydroxymethyl)-3-(2-methylprop-2-enyl)oxolan-2-yl]-6H-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound CC(=C)C[C@@H]1C[C@@H](CO)O[C@H]1N1C(=O)SC2=C1N=C(N)NC2=O BXLRBSLTDVGIIR-RGNHYFCHSA-N 0.000 claims description 3
- BAPUBUNRCUYTJG-RUFHJGMRSA-N C[C@H](O)[C@@H]1C[C@@H](C)[C@@H](O1)N1C(=O)SC2C1=NC(N)=NC2=O Chemical compound C[C@H](O)[C@@H]1C[C@@H](C)[C@@H](O1)N1C(=O)SC2C1=NC(N)=NC2=O BAPUBUNRCUYTJG-RUFHJGMRSA-N 0.000 claims description 3
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 3
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 2
- DCSLKYLPOSSKFY-UHFFFAOYSA-N 3h-[1,3]thiazolo[4,5-d]pyrimidin-2-one Chemical compound C1=NC=C2SC(=O)NC2=N1 DCSLKYLPOSSKFY-UHFFFAOYSA-N 0.000 claims description 2
- RFHAKLORKVEFPL-XWXUBSDMSA-N 5-amino-3-[(2R,3R,5S)-5-[cyclopropyl(hydroxy)methyl]-3-hydroxyoxolan-2-yl]-[1,3]thiazolo[4,5-d]pyrimidin-2-one Chemical compound NC=1N=CC2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1O)C(O)C1CC1 RFHAKLORKVEFPL-XWXUBSDMSA-N 0.000 claims description 2
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Classifications
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- 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
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
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| BR112019007450A2 (pt) | 2016-10-14 | 2020-07-07 | Precision Biosciences, Inc. | meganucleases modificadas específicas para sequências de reconhecimento no genoma do vírus da hepatite b |
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| US12012421B2 (en) | 2017-07-07 | 2024-06-18 | Hoffmann-La Roche Inc. | Solid forms of [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate |
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| WO2006066080A1 (en) * | 2004-12-17 | 2006-06-22 | Anadys Pharmaceuticals, Inc. | 3, 5-DISUBSTITUTED AND 3,5,7-TRISUBSTITUTED-3H-OXAZOLO AND 3H-THIAZOLO [4,5-d]PYRIMIDIN-2-ONE COMPOUNDS AND PRODRUGS THEREOF |
| WO2007150002A2 (en) * | 2006-06-22 | 2007-12-27 | Anadys Pharmaceuticals, Inc. | PRODRUGS OF 5-AMINO-3-(3'-DEOXY-β-D-RIBOFURANOSYL)-THIAZOLO[4,5-d] PYRIMIDIN-2,7-DIONE |
| WO2009026292A1 (en) * | 2007-08-20 | 2009-02-26 | Anadys Pharmaceuticals, Inc. | Dosing methods for treating disease |
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