DK2632927T3 - Boronates AS ARGINSASEINHIBITORER - Google Patents
Boronates AS ARGINSASEINHIBITORER Download PDFInfo
- Publication number
- DK2632927T3 DK2632927T3 DK11779904.9T DK11779904T DK2632927T3 DK 2632927 T3 DK2632927 T3 DK 2632927T3 DK 11779904 T DK11779904 T DK 11779904T DK 2632927 T3 DK2632927 T3 DK 2632927T3
- Authority
- DK
- Denmark
- Prior art keywords
- mmol
- stirred
- pyrrolidine
- amino
- alkylene
- Prior art date
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- 125000005621 boronate group Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 195
- 102000004452 Arginase Human genes 0.000 claims description 114
- 108700024123 Arginases Proteins 0.000 claims description 114
- 229920006395 saturated elastomer Polymers 0.000 claims description 71
- 125000000217 alkyl group Chemical group 0.000 claims description 56
- 125000002947 alkylene group Chemical group 0.000 claims description 51
- 230000000694 effects Effects 0.000 claims description 49
- 125000003118 aryl group Chemical group 0.000 claims description 48
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 46
- 201000010099 disease Diseases 0.000 claims description 37
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 206010020772 Hypertension Diseases 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 19
- 230000014509 gene expression Effects 0.000 claims description 18
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 18
- 102100030356 Arginase-2, mitochondrial Human genes 0.000 claims description 17
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 17
- 201000001881 impotence Diseases 0.000 claims description 17
- 101710186578 Arginase-2, mitochondrial Proteins 0.000 claims description 16
- 208000006673 asthma Diseases 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
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- 208000028867 ischemia Diseases 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
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- 125000004450 alkenylene group Chemical group 0.000 claims description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
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- 125000002993 cycloalkylene group Chemical group 0.000 claims description 8
- 230000004064 dysfunction Effects 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 229910052796 boron Inorganic materials 0.000 claims description 7
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 6
- 125000004419 alkynylene group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
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- 125000004103 aminoalkyl group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
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- 230000004770 neurodegeneration Effects 0.000 claims description 5
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 5
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- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 206010016654 Fibrosis Diseases 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims 1
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims 1
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 claims 1
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- 239000003112 inhibitor Substances 0.000 description 32
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 27
- 229910000029 sodium carbonate Inorganic materials 0.000 description 26
- 238000003756 stirring Methods 0.000 description 25
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 24
- 125000004432 carbon atom Chemical group C* 0.000 description 23
- 239000000706 filtrate Substances 0.000 description 23
- 239000012362 glacial acetic acid Substances 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 22
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- 235000014852 L-arginine Nutrition 0.000 description 21
- 229930064664 L-arginine Natural products 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 20
- 241000699670 Mus sp. Species 0.000 description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 19
- 239000011347 resin Substances 0.000 description 19
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- 239000004475 Arginine Substances 0.000 description 18
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| HUE048859T2 (hu) | 2010-08-10 | 2020-08-28 | Rempex Pharmaceuticals Inc | Gyûrûs bórsavészter származékok, eljárás elõállításukra, és terápiás alkalmazásuk |
| AU2011320732B2 (en) | 2010-10-26 | 2018-07-05 | Mars Incorporated | Boronates as arginase inhibitors |
| EP2852598B3 (en) * | 2012-04-18 | 2016-10-19 | Mars, Incorporated | Ring constrained analogs as arginase inhibitors |
| EA201591003A1 (ru) | 2013-01-04 | 2015-12-30 | Ремпекс Фармасьютикалз, Инк. | Производные бороновой кислоты и их терапевтическое применение |
| EP3134546A4 (en) * | 2014-04-24 | 2017-12-06 | Dana-Farber Cancer Institute, Inc. | Tumor suppressor and oncogene biomarkers predictive of anti-immune checkpoint inhibitor response |
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| PT3140310T (pt) | 2014-05-05 | 2019-11-18 | Rempex Pharmaceuticals Inc | Síntese de sais de boronato e utilizações dos mesmos |
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| US10662205B2 (en) | 2014-11-18 | 2020-05-26 | Qpex Biopharma, Inc. | Cyclic boronic acid ester derivatives and therapeutic uses thereof |
| PL410665A1 (pl) | 2014-12-29 | 2016-07-04 | Oncoarendi Therapeutics Spółka Z Ograniczoną Odpowiedzialnością | Inhibitory arginazy oraz ich zastosowania terapeutyczne |
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| SG11201811549UA (en) | 2016-06-30 | 2019-01-30 | Qpex Biopharma Inc | Boronic acid derivatives and therapeutic uses thereof |
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| CN111212843B (zh) | 2017-10-11 | 2025-05-16 | Qpex生物制药有限公司 | 硼酸衍生物及其合成 |
| WO2019120296A1 (en) * | 2017-12-22 | 2019-06-27 | Guangdong Newopp Biopharmaceuticals Co., Ltd. | Heterocyclic compounds as arginase inhibitors |
| DK3752251T3 (da) | 2018-02-17 | 2025-12-15 | Astrazeneca Ab | Arginasehæmmere og fremgangsmåder til anvendelse deraf |
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| EP3765006A4 (en) * | 2018-03-13 | 2022-02-23 | Merck Sharp & Dohme Corp. | ARGINASE INHIBITORS AND METHODS OF USE |
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| CN111770756B (zh) * | 2018-04-27 | 2023-03-31 | 四川科伦博泰生物医药股份有限公司 | 非天然氨基酸类衍生物、包含其的药物组合物及其制备方法和用途 |
| WO2019218904A1 (zh) * | 2018-05-18 | 2019-11-21 | 四川科伦博泰生物医药股份有限公司 | 非天然氨基酸类衍生物、其制备方法及用途 |
| WO2019245890A1 (en) | 2018-06-20 | 2019-12-26 | Merck Sharp & Dohme Corp. | Arginase inhibitors and methods of use |
| TWI828800B (zh) * | 2018-11-16 | 2024-01-11 | 美商阿克思生物科學有限公司 | Arg1及/或arg2之抑制劑 |
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| EP3897622A4 (en) * | 2018-12-18 | 2022-09-28 | Merck Sharp & Dohme Corp. | Arginase inhibitors and methods of use |
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| PT3921033T (pt) * | 2019-02-08 | 2023-10-11 | Astrazeneca Ab | Inibidores de arginase e métodos de utilização dos mesmos |
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| CN110734456A (zh) * | 2019-11-06 | 2020-01-31 | 南京谷睿生物科技有限公司 | 一种化合物及其制备方法和医药上的应用 |
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| US11919908B2 (en) | 2020-12-21 | 2024-03-05 | Incyte Corporation | Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors |
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| SG10201911243WA (en) | 2016-12-22 | 2020-02-27 | Calithera Biosciences Inc | Compositions and methods for inhibiting arginase activity |
| EA201992695A1 (ru) | 2017-05-12 | 2020-05-15 | Калитера Байосайнсиз, Инк. | Способ получения (3r,4s)-3-ацетамидо-4-аллил-n-(трет-бутил)пирролидин-3-карбоксамида |
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