TWI458719B - 非核苷反轉錄酶抑制劑 - Google Patents
非核苷反轉錄酶抑制劑 Download PDFInfo
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- TWI458719B TWI458719B TW100110833A TW100110833A TWI458719B TW I458719 B TWI458719 B TW I458719B TW 100110833 A TW100110833 A TW 100110833A TW 100110833 A TW100110833 A TW 100110833A TW I458719 B TWI458719 B TW I458719B
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- Prior art keywords
- compound
- hiv
- alkyl
- formula
- pharmaceutically acceptable
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- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 title description 6
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 205
- 150000003839 salts Chemical class 0.000 claims description 89
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 63
- 208000030507 AIDS Diseases 0.000 claims description 36
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 7
- 208000015181 infectious disease Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229940126062 Compound A Drugs 0.000 claims 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 description 111
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- 125000001424 substituent group Chemical group 0.000 description 76
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 73
- 239000000203 mixture Substances 0.000 description 68
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 51
- 235000019439 ethyl acetate Nutrition 0.000 description 40
- 238000000034 method Methods 0.000 description 38
- -1 3TC Chemical compound 0.000 description 34
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 33
- 150000002367 halogens Chemical class 0.000 description 30
- 125000001188 haloalkyl group Chemical group 0.000 description 28
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 27
- 229910052736 halogen Inorganic materials 0.000 description 27
- 125000005842 heteroatom Chemical group 0.000 description 26
- 229910052799 carbon Inorganic materials 0.000 description 25
- 239000000651 prodrug Substances 0.000 description 25
- 229940002612 prodrug Drugs 0.000 description 25
- 208000031886 HIV Infections Diseases 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 24
- 208000037357 HIV infectious disease Diseases 0.000 description 23
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 23
- 229910052739 hydrogen Inorganic materials 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 23
- 239000007787 solid Substances 0.000 description 22
- 239000000284 extract Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 18
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 17
- 102100034343 Integrase Human genes 0.000 description 16
- 239000003443 antiviral agent Substances 0.000 description 16
- 125000003118 aryl group Chemical group 0.000 description 16
- 125000003709 fluoroalkyl group Chemical group 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 16
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 14
- 239000012267 brine Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- 125000001072 heteroaryl group Chemical group 0.000 description 13
- 125000000623 heterocyclic group Chemical group 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
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- 229940124411 anti-hiv antiviral agent Drugs 0.000 description 12
- 238000003556 assay Methods 0.000 description 12
- 239000003112 inhibitor Substances 0.000 description 12
- 125000000753 cycloalkyl group Chemical group 0.000 description 11
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 229910052794 bromium Inorganic materials 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 125000004122 cyclic group Chemical group 0.000 description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
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- 230000002265 prevention Effects 0.000 description 10
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 9
- 108020004414 DNA Proteins 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
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- 229910052731 fluorine Inorganic materials 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- 239000002777 nucleoside Substances 0.000 description 9
- 150000003833 nucleoside derivatives Chemical class 0.000 description 9
- 230000010076 replication Effects 0.000 description 9
- 229910052801 chlorine Inorganic materials 0.000 description 8
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
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- 238000012986 modification Methods 0.000 description 8
- 125000001624 naphthyl group Chemical group 0.000 description 8
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- 230000008569 process Effects 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 7
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
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- HWTORHRJFMRBLG-UHFFFAOYSA-N 3-chloro-5-[[2-oxo-4-(trifluoromethyl)-1h-pyridin-3-yl]oxy]benzonitrile Chemical compound OC1=NC=CC(C(F)(F)F)=C1OC1=CC(Cl)=CC(C#N)=C1 HWTORHRJFMRBLG-UHFFFAOYSA-N 0.000 description 6
- 206010001513 AIDS related complex Diseases 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
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- 210000004027 cell Anatomy 0.000 description 6
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- 239000004615 ingredient Substances 0.000 description 6
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 241000894007 species Species 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000001931 aliphatic group Chemical group 0.000 description 5
- FMHPFOIODIOBIC-UHFFFAOYSA-N 3-(3-bromo-5-chlorophenoxy)-2-chloro-4-nitro-1-oxidopyridin-1-ium Chemical compound [O-][N+](=O)C1=CC=[N+]([O-])C(Cl)=C1OC1=CC(Cl)=CC(Br)=C1 FMHPFOIODIOBIC-UHFFFAOYSA-N 0.000 description 4
- KLFRYOYHJGWKAU-UHFFFAOYSA-N 3-[(4-bromo-2-oxo-1h-pyridin-3-yl)oxy]-5-chlorobenzonitrile Chemical compound OC1=NC=CC(Br)=C1OC1=CC(Cl)=CC(C#N)=C1 KLFRYOYHJGWKAU-UHFFFAOYSA-N 0.000 description 4
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- 101900297506 Human immunodeficiency virus type 1 group M subtype B Reverse transcriptase/ribonuclease H Proteins 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- 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
- A61P31/18—Antivirals for RNA viruses for HIV
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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| US31882410P | 2010-03-30 | 2010-03-30 | |
| US32157310P | 2010-04-07 | 2010-04-07 |
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| TW201139409A TW201139409A (en) | 2011-11-16 |
| TWI458719B true TWI458719B (zh) | 2014-11-01 |
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| TW100110833A TWI458719B (zh) | 2010-03-30 | 2011-03-29 | 非核苷反轉錄酶抑制劑 |
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| MX2012011379A (es) * | 2010-03-30 | 2012-11-30 | Merck Canada Inc | Inhibidores no nucleosidicos de la transcriptasa inversa. |
| WO2012048113A2 (en) | 2010-10-07 | 2012-04-12 | The General Hospital Corporation | Biomarkers of cancer |
| EP2900240B1 (en) * | 2012-09-26 | 2020-01-08 | Merck Sharp & Dohme Corp. | Crystalline form of a reverse transcriptase inhibitor |
| JO3470B1 (ar) | 2012-10-08 | 2020-07-05 | Merck Sharp & Dohme | مشتقات 5- فينوكسي-3h-بيريميدين-4-أون واستخدامها كمثبطات ناسخ عكسي ل hiv |
| CN104994855B (zh) * | 2012-12-05 | 2018-06-05 | 默沙东公司 | 制备逆转录酶抑制剂的方法 |
| EP3071037A4 (en) * | 2013-11-22 | 2017-08-02 | Merck Sharp & Dohme Corp. | Composition of a non-nucleoside reverse transcriptase inhibitor |
| KR101803671B1 (ko) * | 2013-12-04 | 2017-11-30 | 머크 샤프 앤드 돔 코포레이션 | 역전사효소 억제제의 제조 방법 |
| SI3125894T1 (sl) | 2014-04-01 | 2020-12-31 | Merck Sharp & Dohme Corp. | Predzdravila inhibitorjev reverzne transkriptaze HIV |
| EP3161159B1 (en) | 2014-06-25 | 2020-08-05 | The General Hospital Corporation | Targeting human satellite ii (hsatii) |
| RU2736941C2 (ru) | 2015-12-02 | 2020-11-23 | Мерк Шарп энд Доум Корп. | Фармацевтические композиции, содержащие доравирин, тенофовира дизопроксила фумарат и ламивудин |
| WO2018175271A1 (en) * | 2017-03-24 | 2018-09-27 | Merck Sharp & Dohme Corp. | Formulation for parenteral administration |
| RU2019136678A (ru) | 2017-04-18 | 2021-05-18 | Сипла Лимитед | Комбинированная терапия для применения в лечении ретровирусных инфекций |
| EP4317972A3 (en) | 2018-02-06 | 2024-03-13 | The General Hospital Corporation | Repeat rna as biomarkers of tumor immune response |
| WO2020018352A1 (en) | 2018-07-17 | 2020-01-23 | Merck Sharp & Dohme Corp. | Hiv drug combination for increasing barrier against resistance |
| MX2021007382A (es) | 2018-12-18 | 2021-07-15 | Merck Sharp & Dohme Llc | Derivados de pirimidona como agentes citotoxicos selectivos contra celulas infectadas por vih. |
| CN110801455B (zh) * | 2019-11-12 | 2020-06-02 | 河北医科大学第二医院 | 用于治疗mrsa的药物组合物及其应用 |
| CN114163309B (zh) * | 2021-12-27 | 2023-04-25 | 甘肃皓天医药科技有限责任公司 | 一种多拉韦林中间体的制备方法 |
| CN114349690B (zh) * | 2022-02-15 | 2023-04-25 | 甘肃皓天医药科技有限责任公司 | 一种多拉韦林中间体合成方法 |
| CN116903590A (zh) * | 2023-06-06 | 2023-10-20 | 延边大学 | 一种含杂环结构的吡啶酮类化合物及其制备方法和用途 |
| CN120157613A (zh) * | 2023-12-15 | 2025-06-17 | 山东诚创蓝海医药科技有限公司 | 多拉韦林中间体及其应用和合成方法 |
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| WO2004085411A1 (en) * | 2003-03-24 | 2004-10-07 | F. Hoffmann-La Roche Ag | Non-nucleoside reverse transcriptase inhibitors i for treating hiv mediated diseases |
| WO2009067166A2 (en) * | 2007-11-20 | 2009-05-28 | Merck & Co., Inc. | Non-nucleoside reverse transcriptase inhibitors |
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| SE9904045D0 (sv) | 1999-11-09 | 1999-11-09 | Astra Ab | Compounds |
| TW200423930A (en) * | 2003-02-18 | 2004-11-16 | Hoffmann La Roche | Non-nucleoside reverse transcriptase inhibitors |
| WO2004085406A1 (en) | 2003-03-24 | 2004-10-07 | F. Hoffmann-La Roche Ag | Benzyl-pyridazinons as reverse transcriptase inhibitors |
| US7166738B2 (en) | 2004-04-23 | 2007-01-23 | Roche Palo Alto Llc | Non-nucleoside reverse transcriptase inhibitors |
| AU2005235692B2 (en) | 2004-04-23 | 2011-11-10 | F. Hoffmann-La Roche Ag | Non-nucleoside reverse transcriptase inhibitors |
| JP2008525419A (ja) | 2004-12-22 | 2008-07-17 | ファイザー・リミテッド | Ｈｉｖ−１逆転写酵素の非ヌクレオシド阻害剤 |
| AR057455A1 (es) | 2005-07-22 | 2007-12-05 | Merck & Co Inc | Inhibidores de la transcriptasa reversa de vih y composicion farmaceutica |
| ES2320042T3 (es) | 2005-10-19 | 2009-05-18 | F. Hoffmann-La Roche Ag | Inhibidores de transcriptasa reversa con nucleosidos de n-fenil fenilacetamida. |
| EP1940781A1 (en) | 2005-10-19 | 2008-07-09 | F.Hoffmann-La Roche Ag | Phenyl-acetamide nnrt inhibitors |
| TW200831085A (en) | 2006-12-13 | 2008-08-01 | Merck & Co Inc | Non-nucleoside reverse transcriptase inhibitors |
| MX2012011379A (es) * | 2010-03-30 | 2012-11-30 | Merck Canada Inc | Inhibidores no nucleosidicos de la transcriptasa inversa. |
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Patent Citations (2)
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| WO2004085411A1 (en) * | 2003-03-24 | 2004-10-07 | F. Hoffmann-La Roche Ag | Non-nucleoside reverse transcriptase inhibitors i for treating hiv mediated diseases |
| WO2009067166A2 (en) * | 2007-11-20 | 2009-05-28 | Merck & Co., Inc. | Non-nucleoside reverse transcriptase inhibitors |
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