KR102109061B1 - 고요산혈증 또는 통풍을 치료 또는 예방하는 화합물 - Google Patents
고요산혈증 또는 통풍을 치료 또는 예방하는 화합물 Download PDFInfo
- Publication number
- KR102109061B1 KR102109061B1 KR1020187010142A KR20187010142A KR102109061B1 KR 102109061 B1 KR102109061 B1 KR 102109061B1 KR 1020187010142 A KR1020187010142 A KR 1020187010142A KR 20187010142 A KR20187010142 A KR 20187010142A KR 102109061 B1 KR102109061 B1 KR 102109061B1
- Authority
- KR
- South Korea
- Prior art keywords
- pyridine
- ethyl
- hydroxyphenyl
- pyridin
- methylketone
- Prior art date
- 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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- 150000001875 compounds Chemical class 0.000 title claims abstract description 77
- 201000005569 Gout Diseases 0.000 title claims abstract description 17
- 201000001431 Hyperuricemia Diseases 0.000 title claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- -1 cyano, hydroxy Chemical group 0.000 claims description 138
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- 229910052805 deuterium Inorganic materials 0.000 claims description 34
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 32
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- MJZHZCIYMVJHNB-UHFFFAOYSA-N 1-(2-ethylimidazo[1,2-a]pyridin-3-yl)ethanone Chemical compound C1=CC=CN2C(C(C)=O)=C(CC)N=C21 MJZHZCIYMVJHNB-UHFFFAOYSA-N 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- DWUMLGJEZBNWCZ-UHFFFAOYSA-N 3-chloro-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile Chemical compound ClC=1C(=C(C#N)C=C(C=1)C(=O)C1=C(N=C2N1C=CC=C2)CC)O DWUMLGJEZBNWCZ-UHFFFAOYSA-N 0.000 claims description 7
- APYMAIQXUQXLIP-UHFFFAOYSA-N CC(=O)C1=C(N=C2N1C(=CC=C2)C1=CC(=C(C(=C1)Br)O)Br)CC Chemical compound CC(=O)C1=C(N=C2N1C(=CC=C2)C1=CC(=C(C(=C1)Br)O)Br)CC APYMAIQXUQXLIP-UHFFFAOYSA-N 0.000 claims description 7
- ZNWPTJSBHHIXLJ-UHFFFAOYSA-N 1-(3,5-dibromo-4-hydroxyphenyl)ethanone Chemical compound CC(=O)C1=CC(Br)=C(O)C(Br)=C1 ZNWPTJSBHHIXLJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- NSHIHGWTBXXTNH-UHFFFAOYSA-N CC(=O)C1=C(C(=C(C(=C1)Br)O)Br)C1=C(N=C2N1C=CC=C2)C1CC1 Chemical compound CC(=O)C1=C(C(=C(C(=C1)Br)O)Br)C1=C(N=C2N1C=CC=C2)C1CC1 NSHIHGWTBXXTNH-UHFFFAOYSA-N 0.000 claims description 6
- NETCTFCNPLEWCL-UHFFFAOYSA-N CC(=O)C1=C(N=C2N1C(=C(C=C2)OC)C1=CC(=C(C(=C1)Br)O)Br)CC Chemical compound CC(=O)C1=C(N=C2N1C(=C(C=C2)OC)C1=CC(=C(C(=C1)Br)O)Br)CC NETCTFCNPLEWCL-UHFFFAOYSA-N 0.000 claims description 6
- VZNSNYKUTZDTCA-UHFFFAOYSA-N 3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile hydron chloride Chemical compound [H+].[Cl-].CCc1nc2ccccn2c1C(=O)c1cc(Br)c(O)c(c1)C#N VZNSNYKUTZDTCA-UHFFFAOYSA-N 0.000 claims description 5
- FCNMXRCNKXIQMQ-UHFFFAOYSA-N CC(=O)C1=C(C(=C(C(=C1)C)O)I)C1=C(N=C2N1C=CC=C2)CC Chemical compound CC(=O)C1=C(C(=C(C(=C1)C)O)I)C1=C(N=C2N1C=CC=C2)CC FCNMXRCNKXIQMQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- PGGVRVAVZNXVFZ-UHFFFAOYSA-N 3-(3,5-dibromo-4-hydroxyphenyl)-2-ethylimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound BrC=1C=C(C=C(C=1O)Br)C1=C(N=C2N1C=C(C=C2)C#N)CC PGGVRVAVZNXVFZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 150000002825 nitriles Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- HTQSPIOYJOBAQP-UHFFFAOYSA-N 5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxy-3-iodobenzonitrile Chemical compound C(C)C=1N=C2N(C=CC=C2)C=1C(=O)C=1C=C(C(=C(C#N)C=1)O)I HTQSPIOYJOBAQP-UHFFFAOYSA-N 0.000 claims description 3
- CBCPZQYRTQJETM-UHFFFAOYSA-N CC(=O)C1=C(C(=C(C(=C1)I)O)I)C1=C(N=C2N1C=CC=C2)CC Chemical compound CC(=O)C1=C(C(=C(C(=C1)I)O)I)C1=C(N=C2N1C=CC=C2)CC CBCPZQYRTQJETM-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- MDQAWRAKHWBLOG-UHFFFAOYSA-N 1-[5-(3,5-dibromo-4-hydroxyphenyl)-2-ethyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]ethanone Chemical compound CC(=O)C1=C(N=C2N1C(=CC(=C2)C(F)(F)F)C1=CC(=C(C(=C1)Br)O)Br)CC MDQAWRAKHWBLOG-UHFFFAOYSA-N 0.000 claims description 2
- RQGCKMOCOOAGEG-UHFFFAOYSA-N 3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile Chemical compound BrC=1C(=C(C#N)C=C(C=1)C(=O)C1=C(N=C2N1C=CC=C2)CC)O RQGCKMOCOOAGEG-UHFFFAOYSA-N 0.000 claims description 2
- OFYGZDIUFPAFPA-UHFFFAOYSA-N 5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxy-3-iodobenzonitrile hydron chloride Chemical compound [H+].[Cl-].CCc1nc2ccccn2c1C(=O)c1cc(I)c(O)c(c1)C#N OFYGZDIUFPAFPA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 abstract description 60
- 229940116269 uric acid Drugs 0.000 abstract description 58
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 abstract description 57
- 230000029142 excretion Effects 0.000 abstract description 26
- 230000001737 promoting effect Effects 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 174
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 61
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- 239000000203 mixture Substances 0.000 description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000002904 solvent Substances 0.000 description 39
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- 238000004440 column chromatography Methods 0.000 description 26
- SRKGZXIJDGWVAI-GVAVTCRGSA-M (e,3r)-7-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)C1=NC(C(C)(C)C)=CC(C=2C=CC(F)=CC=2)=C1\C=C\C(O)C[C@@H](O)CC([O-])=O SRKGZXIJDGWVAI-GVAVTCRGSA-M 0.000 description 25
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- 238000000034 method Methods 0.000 description 20
- 238000010828 elution Methods 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510576110 | 2015-09-10 | ||
| CN201510576110.7 | 2015-09-10 | ||
| PCT/CN2016/098468 WO2017041732A1 (zh) | 2015-09-10 | 2016-09-08 | 一类用于治疗或预防高尿酸血症或痛风的化合物 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20180044426A KR20180044426A (ko) | 2018-05-02 |
| KR102109061B1 true KR102109061B1 (ko) | 2020-05-11 |
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| KR1020187010142A Active KR102109061B1 (ko) | 2015-09-10 | 2016-09-08 | 고요산혈증 또는 통풍을 치료 또는 예방하는 화합물 |
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| EP (1) | EP3348557B1 (https=) |
| JP (1) | JP6635527B2 (https=) |
| KR (1) | KR102109061B1 (https=) |
| CN (1) | CN106432229B (https=) |
| AU (1) | AU2016320073B2 (https=) |
| BR (1) | BR112018004863B1 (https=) |
| CA (1) | CA2998034C (https=) |
| CY (1) | CY1123137T1 (https=) |
| DK (1) | DK3348557T3 (https=) |
| EA (1) | EA037280B1 (https=) |
| ES (1) | ES2803223T3 (https=) |
| HR (1) | HRP20201094T1 (https=) |
| HU (1) | HUE051448T2 (https=) |
| IL (1) | IL257960A (https=) |
| LT (1) | LT3348557T (https=) |
| MX (1) | MX375068B (https=) |
| MY (1) | MY195675A (https=) |
| NZ (1) | NZ741318A (https=) |
| PL (1) | PL3348557T3 (https=) |
| PT (1) | PT3348557T (https=) |
| RS (1) | RS60697B1 (https=) |
| SG (1) | SG11201802010QA (https=) |
| SI (1) | SI3348557T1 (https=) |
| TW (1) | TWI681772B (https=) |
| WO (1) | WO2017041732A1 (https=) |
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Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018090921A1 (zh) * | 2016-11-16 | 2018-05-24 | 江苏新元素医药科技有限公司 | Urat1抑制剂及其应用 |
| CN108084186B (zh) * | 2016-11-16 | 2021-06-25 | 江苏新元素医药科技有限公司 | Urat1抑制剂及其应用 |
| EP3632904B1 (en) * | 2017-05-26 | 2022-04-20 | Jiangsu Atom Bioscience and Pharmaceutical Co., Ltd. | Urat1 inhibitors for promoting uric acid excretion |
| CN114213331B (zh) * | 2017-05-26 | 2024-06-21 | 江苏新元素医药科技有限公司 | 一类urat1抑制剂及其应用 |
| CN112979661B (zh) * | 2018-01-19 | 2022-05-17 | 苏州信诺维医药科技股份有限公司 | 杂环化合物、制备方法及其在医药上的应用 |
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| WO2022169974A1 (en) | 2021-02-05 | 2022-08-11 | Nexys Therapeutics, Inc. | Inhibitors of urat1 and pharmaceutical uses thereof |
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| CN116715633B (zh) * | 2022-04-27 | 2025-08-12 | 杭州新元素药业股份有限公司 | 可用于降尿酸的化合物 |
| WO2023221078A1 (en) * | 2022-05-20 | 2023-11-23 | Jiangsu Atom Bioscience And Pharmaceutical Co., Ltd. | Solid forms of a compound for treating or preventing hyperuricemia or gout |
| TWI898321B (zh) * | 2023-11-17 | 2025-09-21 | 大陸商杭州新元素藥業有限公司 | 用於治療或預防高尿酸血症或痛風的化合物的固體晶型 |
| WO2025237171A1 (zh) * | 2024-05-11 | 2025-11-20 | 广州市联瑞制药有限公司 | 嘧啶并五元氮杂环酚类化合物及其应用 |
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