ES2987744T3 - Inhibidores de calicreína plasmática y usos de los mismos - Google Patents
Inhibidores de calicreína plasmática y usos de los mismos Download PDFInfo
- Publication number
- ES2987744T3 ES2987744T3 ES20785878T ES20785878T ES2987744T3 ES 2987744 T3 ES2987744 T3 ES 2987744T3 ES 20785878 T ES20785878 T ES 20785878T ES 20785878 T ES20785878 T ES 20785878T ES 2987744 T3 ES2987744 T3 ES 2987744T3
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- Prior art keywords
- nitrogen
- oxygen
- sulfur
- membered
- methyl
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- 102000003827 Plasma Kallikrein Human genes 0.000 title abstract description 7
- 108090000113 Plasma Kallikrein Proteins 0.000 title abstract description 7
- 229940127379 Kallikrein Inhibitors Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 156
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 483
- 229910052757 nitrogen Inorganic materials 0.000 claims description 258
- 125000005842 heteroatom Chemical group 0.000 claims description 236
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 233
- 229910052760 oxygen Inorganic materials 0.000 claims description 233
- 239000001301 oxygen Substances 0.000 claims description 233
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 219
- 229910052717 sulfur Chemical group 0.000 claims description 219
- 239000011593 sulfur Chemical group 0.000 claims description 219
- 125000001931 aliphatic group Chemical group 0.000 claims description 132
- 229920006395 saturated elastomer Polymers 0.000 claims description 132
- 229910052739 hydrogen Inorganic materials 0.000 claims description 91
- 239000001257 hydrogen Substances 0.000 claims description 91
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 68
- 229910052736 halogen Inorganic materials 0.000 claims description 54
- 150000002367 halogens Chemical class 0.000 claims description 40
- 125000002619 bicyclic group Chemical group 0.000 claims description 38
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 37
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 29
- 125000002950 monocyclic group Chemical group 0.000 claims description 28
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 125000005549 heteroarylene group Chemical group 0.000 claims description 17
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
- 125000004429 atom Chemical group 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 5
- 150000002431 hydrogen Chemical group 0.000 claims 10
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 145
- 239000003112 inhibitor Substances 0.000 abstract description 5
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- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 171
- 239000012043 crude product Substances 0.000 description 128
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- 238000000034 method Methods 0.000 description 103
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- 238000010586 diagram Methods 0.000 description 95
- -1 which inhibits pKal Proteins 0.000 description 90
- 235000019439 ethyl acetate Nutrition 0.000 description 85
- 239000000047 product Substances 0.000 description 73
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 72
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 70
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 60
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- 238000002953 preparative HPLC Methods 0.000 description 46
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 44
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 42
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 33
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- 206010019860 Hereditary angioedema Diseases 0.000 description 27
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 26
- 125000003118 aryl group Chemical group 0.000 description 26
- 125000001072 heteroaryl group Chemical group 0.000 description 23
- 125000001424 substituent group Chemical group 0.000 description 23
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 18
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 18
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 18
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- 101100485158 Salmonella typhimurium (strain LT2 / SGSC1412 / ATCC 700720) wzzE gene Proteins 0.000 description 16
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
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- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 11
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 11
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- 235000010378 sodium ascorbate Nutrition 0.000 description 11
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 11
- 229960005055 sodium ascorbate Drugs 0.000 description 11
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 11
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- C07—ORGANIC CHEMISTRY
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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| DK4031547T3 (da) | 2019-09-18 | 2024-09-09 | Takeda Pharmaceuticals Co | Plasmakallikreininhibitorer og anvendelser deraf |
| EP4031245A1 (en) | 2019-09-18 | 2022-07-27 | Takeda Pharmaceutical Company Limited | Heteroaryl plasma kallikrein inhibitors |
| MX2022007376A (es) | 2019-12-20 | 2022-09-02 | Tenaya Therapeutics Inc | Fluoroalqull-oxadiazoles y sus usos. |
| TW202144331A (zh) * | 2020-02-13 | 2021-12-01 | 德商百靈佳殷格翰國際股份有限公司 | 作為血漿激肽釋放酶抑制劑之雜芳族甲醯胺衍生物 |
| TWI873290B (zh) | 2020-02-13 | 2025-02-21 | 德商百靈佳殷格翰國際股份有限公司 | 作為血漿激肽釋放酶抑制劑之雜芳族甲醯胺衍生物 |
| CN114262322B (zh) * | 2020-09-16 | 2026-01-06 | 中国科学院上海有机化学研究所 | 一类细胞程序性坏死抑制剂及其制备方法和用途 |
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| CN114907260A (zh) * | 2022-05-27 | 2022-08-16 | 河南省科学院高新技术研究中心 | 一种利用离子液体制备4-溴甲基喹啉酮的方法 |
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| WO2025001956A1 (zh) * | 2023-06-30 | 2025-01-02 | 远森制药（杭州）有限公司 | 杂芳族甲酰胺类化合物及其在医药上的应用 |
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| WO2026008750A1 (en) | 2024-07-05 | 2026-01-08 | Syngenta Crop Protection Ag | Novel carboxamide compounds |
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- 2020-09-17 PL PL20785878.8T patent/PL4031547T3/pl unknown
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| CN114728962B (zh) | 2025-09-19 |
| EP4477220A3 (en) | 2025-02-26 |
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| PL4031547T3 (pl) | 2024-10-07 |
| US20210078999A1 (en) | 2021-03-18 |
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| CN114728962A (zh) | 2022-07-08 |
| US12221441B2 (en) | 2025-02-11 |
| PT4031547T (pt) | 2024-08-27 |
| DK4031547T3 (da) | 2024-09-09 |
| JP2022548696A (ja) | 2022-11-21 |
| US20230391773A1 (en) | 2023-12-07 |
| US11787796B2 (en) | 2023-10-17 |
| EP4477220A2 (en) | 2024-12-18 |
| WO2021055621A1 (en) | 2021-03-25 |
| EP4031547A1 (en) | 2022-07-27 |
| JP7777519B2 (ja) | 2025-11-28 |
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