JP6817217B2 - ウイルス感染症の治療および予防のための３−置換された５−アミノ−６Ｈ−チアゾロ［４，５−ｄ］ピリミジン−２，７−ジオン化合物 - Google Patents
ウイルス感染症の治療および予防のための３−置換された５−アミノ−６Ｈ−チアゾロ［４，５−ｄ］ピリミジン−２，７−ジオン化合物 Download PDFInfo
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- JP6817217B2 JP6817217B2 JP2017548325A JP2017548325A JP6817217B2 JP 6817217 B2 JP6817217 B2 JP 6817217B2 JP 2017548325 A JP2017548325 A JP 2017548325A JP 2017548325 A JP2017548325 A JP 2017548325A JP 6817217 B2 JP6817217 B2 JP 6817217B2
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- Prior art keywords
- amino
- tetrahydrofuran
- thiazolo
- hydroxy
- pyrimidin
- Prior art date
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- -1 3-Substituted 5-amino-6H-thiazolo [4,5-d] pyrimidine-2,7-dione compound Chemical class 0.000 title claims description 376
- 238000011282 treatment Methods 0.000 title claims description 29
- 230000002265 prevention Effects 0.000 title claims description 8
- 208000036142 Viral infection Diseases 0.000 title description 4
- 230000009385 viral infection Effects 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 360
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 130
- 238000004519 manufacturing process Methods 0.000 claims description 117
- 229910052739 hydrogen Inorganic materials 0.000 claims description 108
- 239000001257 hydrogen Substances 0.000 claims description 107
- 125000000217 alkyl group Chemical group 0.000 claims description 104
- 150000003839 salts Chemical class 0.000 claims description 96
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 79
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 75
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 60
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 60
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 59
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 52
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 41
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 41
- 150000001540 azides Chemical class 0.000 claims description 38
- 150000002431 hydrogen Chemical class 0.000 claims description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 30
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 29
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 29
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 27
- 125000001544 thienyl group Chemical group 0.000 claims description 27
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 26
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 claims description 25
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 25
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 25
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 25
- 229920002554 vinyl polymer Polymers 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
- 125000005394 methallyl group Chemical group 0.000 claims description 24
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 24
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 21
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims description 18
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 claims description 18
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 17
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 16
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 229940090181 propyl acetate Drugs 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 208000002672 hepatitis B Diseases 0.000 claims description 13
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 13
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 13
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 12
- 125000002757 morpholinyl group Chemical group 0.000 claims description 12
- 125000003386 piperidinyl group Chemical group 0.000 claims description 12
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 10
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 8
- DAXWDTFMGNGWDN-MPGRNQODSA-N [(2R,3R,5S)-2-(5-amino-2-oxo-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-5-(1-hydroxypropyl)oxolan-3-yl] acetate Chemical compound CCC(O)[C@@H]1C[C@@H](OC(C)=O)[C@@H](O1)N1C(=O)SC2=C1N=C(N)N=C2 DAXWDTFMGNGWDN-MPGRNQODSA-N 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 6
- AVQFGCZUSKVJKK-YNVXMBFESA-N 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-(1-hydroxypropyl)oxolan-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(CC)O AVQFGCZUSKVJKK-YNVXMBFESA-N 0.000 claims description 6
- 150000008065 acid anhydrides Chemical class 0.000 claims description 6
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- FYYAXSGIFXZSLJ-DQSPEZDDSA-N (2R,3S,5S)-2-(5-amino-2,7-dioxo-6H-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)oxolane-3-carbonitrile Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@@H]1O[C@@H](C[C@H]1C#N)CO)=O FYYAXSGIFXZSLJ-DQSPEZDDSA-N 0.000 claims description 5
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 5
- XDFJFHCSLJOEFB-MRCNFZFLSA-N [(1S)-1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxyoxolan-2-yl]propyl] 2-methylpropanoate Chemical compound CC(C(=O)O[C@@H](CC)[C@H]1O[C@H]([C@@H](C1)O)N1C(SC2=C1N=C(NC2=O)N)=O)C XDFJFHCSLJOEFB-MRCNFZFLSA-N 0.000 claims description 5
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- SWKTWVWCSHNIRV-JOAULVNJSA-N 5-amino-3-[(2R,3R,5S)-5-(hydroxymethyl)-3-morpholin-4-yloxolan-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]1N1CCOCC1)CO)=O SWKTWVWCSHNIRV-JOAULVNJSA-N 0.000 claims description 4
- 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 4
- ONQSMTMFFXEKNN-MOEZTCPLSA-N [(1S)-1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxyoxolan-2-yl]propyl] acetate Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@H]1[C@@H](C[C@H](O1)[C@H](CC)OC(C)=O)O)=O ONQSMTMFFXEKNN-MOEZTCPLSA-N 0.000 claims description 4
- ZYPFNBPDNCWMMN-UPBCOZELSA-N [(S)-[(2S,4R,5R)-5-(5-amino-2-oxo-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxyoxolan-2-yl]-cyclopropylmethyl] acetate Chemical compound NC=1N=CC2=C(N=1)N(C(S2)=O)[C@H]1[C@@H](C[C@H](O1)[C@H](C1CC1)OC(C)=O)O ZYPFNBPDNCWMMN-UPBCOZELSA-N 0.000 claims description 4
- UEOONJPGATTXIY-CWWJLMTASA-N [[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxyoxolan-2-yl]-cyclopropylmethyl] acetate Chemical compound NC=1NC(C2=C(N=1)N(C(S2)=O)[C@H]1[C@@H](C[C@H](O1)C(C1CC1)OC(C)=O)O)=O UEOONJPGATTXIY-CWWJLMTASA-N 0.000 claims description 4
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
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- 125000001475 halogen functional group Chemical group 0.000 claims 1
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 96
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- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 65
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Images
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