KR20200041315A - 아데노신 길항제로서의 헤테로시클릭 화합물 - Google Patents
아데노신 길항제로서의 헤테로시클릭 화합물 Download PDFInfo
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- KR20200041315A KR20200041315A KR1020207004248A KR20207004248A KR20200041315A KR 20200041315 A KR20200041315 A KR 20200041315A KR 1020207004248 A KR1020207004248 A KR 1020207004248A KR 20207004248 A KR20207004248 A KR 20207004248A KR 20200041315 A KR20200041315 A KR 20200041315A
- Authority
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- South Korea
- Prior art keywords
- alkylene
- halogen
- optionally substituted
- compound
- alkyl
- 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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- 239000000296 purinergic P1 receptor antagonist Substances 0.000 title description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 466
- 201000010099 disease Diseases 0.000 claims abstract description 45
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 45
- 239000003814 drug Substances 0.000 claims abstract description 25
- 108050000203 Adenosine receptors Proteins 0.000 claims abstract description 23
- 102000009346 Adenosine receptors Human genes 0.000 claims abstract description 23
- 238000011282 treatment Methods 0.000 claims abstract description 21
- 230000019491 signal transduction Effects 0.000 claims abstract description 18
- 230000001404 mediated effect Effects 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims description 233
- 229910052736 halogen Inorganic materials 0.000 claims description 199
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 139
- 150000002367 halogens Chemical class 0.000 claims description 134
- 229910052739 hydrogen Inorganic materials 0.000 claims description 125
- 239000001257 hydrogen Substances 0.000 claims description 125
- 125000000623 heterocyclic group Chemical group 0.000 claims description 108
- 150000002431 hydrogen Chemical class 0.000 claims description 91
- -1 4-hydroxy-2-pyridyl Chemical group 0.000 claims description 86
- 206010028980 Neoplasm Diseases 0.000 claims description 84
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 64
- 229910052757 nitrogen Inorganic materials 0.000 claims description 63
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 60
- 238000000034 method Methods 0.000 claims description 55
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 50
- 125000003118 aryl group Chemical group 0.000 claims description 50
- 201000011510 cancer Diseases 0.000 claims description 49
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 43
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 39
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- 125000004429 atom Chemical group 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 30
- 229960005305 adenosine Drugs 0.000 claims description 30
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 28
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 22
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000004043 oxo group Chemical group O=* 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 13
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
- 125000000335 thiazolyl group Chemical group 0.000 claims description 9
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 6
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims description 6
- 125000002619 bicyclic group Chemical group 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 6
- 125000001425 triazolyl group Chemical group 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 5
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 3
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 2
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 abstract description 18
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 abstract description 18
- 229940124597 therapeutic agent Drugs 0.000 abstract description 12
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical class NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 403
- 239000011541 reaction mixture Substances 0.000 description 275
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 223
- 238000006243 chemical reaction Methods 0.000 description 199
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 183
- 230000015572 biosynthetic process Effects 0.000 description 179
- 238000003786 synthesis reaction Methods 0.000 description 179
- 239000007787 solid Substances 0.000 description 169
- 239000000243 solution Substances 0.000 description 148
- 235000019439 ethyl acetate Nutrition 0.000 description 139
- 239000011734 sodium Substances 0.000 description 136
- 239000012044 organic layer Substances 0.000 description 126
- 239000000203 mixture Substances 0.000 description 119
- 239000000047 product Substances 0.000 description 111
- 239000012267 brine Substances 0.000 description 93
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 93
- 238000004440 column chromatography Methods 0.000 description 87
- 238000004809 thin layer chromatography Methods 0.000 description 86
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 85
- 125000005843 halogen group Chemical group 0.000 description 75
- 230000002829 reductive effect Effects 0.000 description 66
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 53
- 102000005962 receptors Human genes 0.000 description 53
- 108020003175 receptors Proteins 0.000 description 53
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 50
- 239000000460 chlorine Substances 0.000 description 50
- 230000002441 reversible effect Effects 0.000 description 44
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 35
- 239000002904 solvent Substances 0.000 description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 26
- 239000012043 crude product Substances 0.000 description 26
- KSLJFTIIOVZSHW-UHFFFAOYSA-N 5-bromo-6-phenylpyrazin-2-amine Chemical compound NC1=CN=C(Br)C(C=2C=CC=CC=2)=N1 KSLJFTIIOVZSHW-UHFFFAOYSA-N 0.000 description 24
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- 230000027455 binding Effects 0.000 description 22
- 238000009739 binding Methods 0.000 description 22
- 230000000694 effects Effects 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 235000011152 sodium sulphate Nutrition 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000013058 crude material Substances 0.000 description 20
- 239000012299 nitrogen atmosphere Substances 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
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- 206010027476 Metastases Diseases 0.000 description 14
- 230000009401 metastasis Effects 0.000 description 14
- 101150003085 Pdcl gene Proteins 0.000 description 13
- 125000000217 alkyl group Chemical group 0.000 description 13
- 125000001309 chloro group Chemical group Cl* 0.000 description 13
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 13
- 239000003480 eluent Substances 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- 230000028993 immune response Effects 0.000 description 13
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- 238000004808 supercritical fluid chromatography Methods 0.000 description 13
- 125000001246 bromo group Chemical group Br* 0.000 description 12
- 125000001153 fluoro group Chemical group F* 0.000 description 12
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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 11
- 229940045513 CTLA4 antagonist Drugs 0.000 description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
- 230000004614 tumor growth Effects 0.000 description 10
- JTPXVCKCLBROOJ-UHFFFAOYSA-N 2-amino-6-chloropyrazine Chemical compound NC1=CN=CC(Cl)=N1 JTPXVCKCLBROOJ-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- JLAAXFZDIGLONV-UHFFFAOYSA-N BrC=1C(=NC(=C(N=1)C=1C=C2C=CC=NC2=CC=1)C1=CC=CC=C1)N Chemical compound BrC=1C(=NC(=C(N=1)C=1C=C2C=CC=NC2=CC=1)C1=CC=CC=C1)N JLAAXFZDIGLONV-UHFFFAOYSA-N 0.000 description 9
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- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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| JP7540996B2 (ja) * | 2018-08-17 | 2024-08-27 | ディザル(ジァンスー)ファーマシューティカル・カンパニー・リミテッド | ピラジン化合物およびその使用 |
| CN111377906B (zh) * | 2018-12-28 | 2022-09-02 | 四川科伦博泰生物医药股份有限公司 | 取代的吡嗪化合物及其制备方法和用途 |
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| CA3126931A1 (en) | 2019-01-18 | 2020-07-23 | Nuvation Bio Inc. | 1,8-naphthyridinone compounds and uses thereof |
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| EP4167982A4 (en) | 2020-06-22 | 2024-08-07 | PMV Pharmaceuticals, Inc. | METHODS AND COMPOUNDS FOR RESTORING FUNCTION OF P53 MUTANTS |
| WO2022268520A1 (de) * | 2021-06-21 | 2022-12-29 | Bayer Aktiengesellschaft | Verwendung von substituierten pyrrolidinonen oder deren salzen zur steigerung der stresstoleranz in pflanzen. |
| US12492178B2 (en) | 2021-09-01 | 2025-12-09 | Empathbio, Inc. | Stable polymorph of R-MDMA HCl |
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- 2018-07-18 KR KR1020207004248A patent/KR20200041315A/ko not_active Ceased
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2020
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2021
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022203267A1 (ko) * | 2021-03-24 | 2022-09-29 | 주식회사 스탠다임 | 아데노신 a2a 수용체 및 아데노신 a2b 수용체의 이중 길항제, 및 이의 용도 |
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| SG11202000418XA (en) | 2020-02-27 |
| WO2019018584A1 (en) | 2019-01-24 |
| AU2018302179A1 (en) | 2020-02-13 |
| JP2020527588A (ja) | 2020-09-10 |
| US20210292285A1 (en) | 2021-09-23 |
| CA3070273A1 (en) | 2019-01-24 |
| US20190023666A1 (en) | 2019-01-24 |
| EP3654978A1 (en) | 2020-05-27 |
| US11028058B2 (en) | 2021-06-08 |
| EP3654978A4 (en) | 2021-03-31 |
| IL272056A (en) | 2020-03-31 |
| CN111163780A (zh) | 2020-05-15 |
| MX2020000690A (es) | 2020-07-29 |
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