JP6850396B2 - ［１，２，４］トリアゾロ［４，３−ａ］ピラジン−６（５ｈ）−オン誘導体 - Google Patents
［１，２，４］トリアゾロ［４，３−ａ］ピラジン−６（５ｈ）−オン誘導体 Download PDFInfo
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- JP6850396B2 JP6850396B2 JP2020505232A JP2020505232A JP6850396B2 JP 6850396 B2 JP6850396 B2 JP 6850396B2 JP 2020505232 A JP2020505232 A JP 2020505232A JP 2020505232 A JP2020505232 A JP 2020505232A JP 6850396 B2 JP6850396 B2 JP 6850396B2
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- Prior art keywords
- compound
- pharmaceutically acceptable
- mmol
- acceptable salt
- pyrazine
- Prior art date
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- DIZPOCWXIWENOQ-UHFFFAOYSA-N 5H-[1,2,4]triazolo[4,3-a]pyrazin-6-one Chemical class C1=NC(=O)CN2C=NN=C21 DIZPOCWXIWENOQ-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 143
- 150000003839 salts Chemical class 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- -1 Y is H Chemical group 0.000 claims description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 12
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 11
- 208000020832 chronic kidney disease Diseases 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 64
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 58
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- 235000019439 ethyl acetate Nutrition 0.000 description 23
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
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- LAQJGAKLLZAETL-UHFFFAOYSA-N 2h-pyrazin-3-one Chemical compound O=C1CN=CC=N1 LAQJGAKLLZAETL-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
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- 239000007821 HATU Substances 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 239000013058 crude material Substances 0.000 description 4
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- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 4
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000003828 vacuum filtration Methods 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- 229920000936 Agarose Polymers 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- GPQWXNATEQUEGO-UHFFFAOYSA-N CCCCNc1cc(C)cnc1N Chemical compound CCCCNc1cc(C)cnc1N GPQWXNATEQUEGO-UHFFFAOYSA-N 0.000 description 3
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- WLYAPNZTYZDHRG-UHFFFAOYSA-N Cl.NNC(=O)C1(CC1)C1CC1 Chemical compound Cl.NNC(=O)C1(CC1)C1CC1 WLYAPNZTYZDHRG-UHFFFAOYSA-N 0.000 description 3
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 3
- JFYKIEHOOZWARC-UHFFFAOYSA-N cyclopropanecarbohydrazide Chemical compound NNC(=O)C1CC1 JFYKIEHOOZWARC-UHFFFAOYSA-N 0.000 description 3
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
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- ZYOYYQRWXITKFF-UHFFFAOYSA-N pyrazine-2,3-dione Chemical compound O=C1N=CC=NC1=O ZYOYYQRWXITKFF-UHFFFAOYSA-N 0.000 description 3
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
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- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
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Classifications
-
- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201762540122P | 2017-08-02 | 2017-08-02 | |
| US62/540,122 | 2017-08-02 | ||
| PCT/US2018/043845 WO2019027783A1 (en) | 2017-08-02 | 2018-07-26 | DERIVATIVES OF [1,2,4] TRIAZOLO [4,3-A] PYRAZIN-6 (5H) -ONE |
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| JP2020529413A JP2020529413A (ja) | 2020-10-08 |
| JP2020529413A5 JP2020529413A5 (https=) | 2020-11-19 |
| JP6850396B2 true JP6850396B2 (ja) | 2021-03-31 |
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|---|---|
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| EP (1) | EP3661936B1 (https=) |
| JP (1) | JP6850396B2 (https=) |
| CN (1) | CN110914268B (https=) |
| AR (1) | AR112457A1 (https=) |
| ES (1) | ES2904938T3 (https=) |
| TW (1) | TWI670271B (https=) |
| WO (1) | WO2019027783A1 (https=) |
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| US11453673B2 (en) | 2018-02-06 | 2022-09-27 | Eli Lilly And Company | Substituted [1,2,4]triazolo[4,3-a]pyrazines as phosphodiesterase inhibitors |
| AU2024341364A1 (en) | 2023-09-14 | 2026-03-26 | Eli Lilly And Company | Pde1 inhibitors |
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| US4354027A (en) | 1980-05-19 | 1982-10-12 | Usv Pharmaceutical Corporation | Triazoloquinoxalin-4-ones |
| WO2007150025A2 (en) * | 2006-06-23 | 2007-12-27 | Incyte Corporation | Purinone derivatives as hm74a agonists |
| CA2671980C (en) * | 2006-12-13 | 2015-05-05 | Aska Pharmaceutical Co., Ltd. | Quinoxaline derivatives |
| WO2008103357A1 (en) | 2007-02-21 | 2008-08-28 | E. I. Du Pont De Nemours And Company | Fungicidal tricyclic 1,2,4-triazoles |
| EP2509983B1 (en) * | 2009-11-16 | 2014-09-17 | Merck Sharp & Dohme Corp. | FUSED TRICYCLIC COMPOUNDS WITH ADENOSINE A2a RECEPTOR ANTAGONIST ACTIVITY |
| BR112013005439A2 (pt) | 2010-09-07 | 2017-09-19 | Astellas Pharma Inc | compostos de quinoxalina |
| CN103874701A (zh) * | 2011-09-09 | 2014-06-18 | H.隆德贝克有限公司 | 吡啶化合物和其用途 |
| MX357320B (es) | 2012-06-18 | 2018-07-04 | Dart Neuroscience Cayman Ltd | Compuestos de la azolopirimidina-5-(6h)-ona de piridina sustituida. |
| US20140045856A1 (en) * | 2012-07-31 | 2014-02-13 | Boehringer Ingelheim International Gmbh | 4-Methyl-2,3,5,9,9b-pentaaza-cyclopenta[a]naphthalenes |
| TW201629064A (zh) * | 2014-10-10 | 2016-08-16 | Ｈ 朗德貝克公司 | 作爲ｐｄｅ１抑制劑之三唑並吡酮 |
| TWI609870B (zh) * | 2016-02-12 | 2018-01-01 | 美國禮來大藥廠 | Pde1抑制劑 |
| JOP20170164A1 (ar) * | 2016-08-25 | 2019-01-30 | Lilly Co Eli | مشتق ترايازولو بيرازينون مفيد كمثبط لـ pde1 بشري |
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2018
- 2018-07-17 AR ARP180101984 patent/AR112457A1/es unknown
- 2018-07-19 TW TW107124931A patent/TWI670271B/zh not_active IP Right Cessation
- 2018-07-26 WO PCT/US2018/043845 patent/WO2019027783A1/en not_active Ceased
- 2018-07-26 EP EP18752976.3A patent/EP3661936B1/en active Active
- 2018-07-26 ES ES18752976T patent/ES2904938T3/es active Active
- 2018-07-26 JP JP2020505232A patent/JP6850396B2/ja active Active
- 2018-07-26 CN CN201880050277.1A patent/CN110914268B/zh active Active
- 2018-07-26 US US16/624,545 patent/US11180503B2/en active Active
Also Published As
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|---|---|
| CN110914268B (zh) | 2022-04-19 |
| US11180503B2 (en) | 2021-11-23 |
| EP3661936B1 (en) | 2021-12-22 |
| TW201920175A (zh) | 2019-06-01 |
| AR112457A1 (es) | 2019-10-30 |
| CN110914268A (zh) | 2020-03-24 |
| EP3661936A1 (en) | 2020-06-10 |
| JP2020529413A (ja) | 2020-10-08 |
| ES2904938T3 (es) | 2022-04-06 |
| US20200123154A1 (en) | 2020-04-23 |
| TWI670271B (zh) | 2019-09-01 |
| WO2019027783A1 (en) | 2019-02-07 |
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