JP2012500805A - 免疫抑制のための６−置換２−（ベンズイミダゾリル）プリンおよびプリノン誘導体ならびに６−置換２−（イミダゾロ［４，５−ｃ］ピリジニル）プリンおよびプリノン誘導体 - Google Patents
免疫抑制のための６−置換２−（ベンズイミダゾリル）プリンおよびプリノン誘導体ならびに６−置換２−（イミダゾロ［４，５−ｃ］ピリジニル）プリンおよびプリノン誘導体 Download PDFInfo
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- JP2012500805A JP2012500805A JP2011524034A JP2011524034A JP2012500805A JP 2012500805 A JP2012500805 A JP 2012500805A JP 2011524034 A JP2011524034 A JP 2011524034A JP 2011524034 A JP2011524034 A JP 2011524034A JP 2012500805 A JP2012500805 A JP 2012500805A
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- Prior art keywords
- substituted
- alkyl
- mmol
- aryl
- heterocyclyl
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- -1 6-Substituted 2- (benzimidazolyl) purine Chemical class 0.000 title claims description 139
- UFZNZKGKBWOSJG-UHFFFAOYSA-N purin-2-one Chemical class O=C1N=CC2=NC=NC2=N1 UFZNZKGKBWOSJG-UHFFFAOYSA-N 0.000 title description 5
- 206010062016 Immunosuppression Diseases 0.000 title description 3
- 230000001506 immunosuppresive effect Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 97
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 70
- 125000000623 heterocyclic group Chemical group 0.000 claims description 45
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 239000001257 hydrogen Substances 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 31
- 125000003118 aryl group Chemical group 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical group 0.000 claims description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000003107 substituted aryl group Chemical group 0.000 claims description 16
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- 150000002431 hydrogen Chemical group 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000003725 azepanyl group Chemical group 0.000 claims description 6
- 125000002393 azetidinyl group Chemical group 0.000 claims description 6
- QYJXLKYOBNZROU-UHFFFAOYSA-N carboxysulfonylformic acid Chemical group OC(=O)S(=O)(=O)C(O)=O QYJXLKYOBNZROU-UHFFFAOYSA-N 0.000 claims description 6
- 125000005959 diazepanyl group Chemical group 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
- 150000004820 halides Chemical class 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 4
- JAAJQSRLGAYGKZ-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-1-ol Chemical compound C1=CC=C2C(O)CCCC2=C1 JAAJQSRLGAYGKZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 3
- 125000000676 alkoxyimino group Chemical group 0.000 claims description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 3
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 claims description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical group OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- UHHKSVZZTYJVEG-UHFFFAOYSA-N oxepane Chemical compound C1CCCOCC1 UHHKSVZZTYJVEG-UHFFFAOYSA-N 0.000 claims description 2
- 125000003551 oxepanyl group Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 125000002619 bicyclic group Chemical group 0.000 claims 2
- 125000002950 monocyclic group Chemical group 0.000 claims 2
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- 150000003212 purines Chemical class 0.000 abstract description 4
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- 230000002265 prevention Effects 0.000 abstract 1
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- 239000000243 solution Substances 0.000 description 63
- 239000002904 solvent Substances 0.000 description 62
- 238000006243 chemical reaction Methods 0.000 description 59
- 235000019439 ethyl acetate Nutrition 0.000 description 56
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 49
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- 238000000746 purification Methods 0.000 description 37
- 238000004128 high performance liquid chromatography Methods 0.000 description 34
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
- 101150069380 JAK3 gene Proteins 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 27
- 239000000741 silica gel Substances 0.000 description 26
- 229910002027 silica gel Inorganic materials 0.000 description 26
- 238000001035 drying Methods 0.000 description 25
- 238000012544 monitoring process Methods 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
- 239000011734 sodium Substances 0.000 description 22
- 238000010828 elution Methods 0.000 description 21
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 21
- 238000001704 evaporation Methods 0.000 description 20
- 230000008020 evaporation Effects 0.000 description 20
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- 238000002953 preparative HPLC Methods 0.000 description 17
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- 0 *c(cc1)cc2*1nc[n]2-c(nc1*)nc(N2*)c1N(*)C2=O Chemical compound *c(cc1)cc2*1nc[n]2-c(nc1*)nc(N2*)c1N(*)C2=O 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- 239000004677 Nylon Substances 0.000 description 13
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 13
- 229910000024 caesium carbonate Inorganic materials 0.000 description 13
- 229920001778 nylon Polymers 0.000 description 13
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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 12
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- 150000003839 salts Chemical class 0.000 description 12
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- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 10
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- YLKYOEVXPMJDQM-UHFFFAOYSA-N 6-chloropurin-2-one Chemical compound ClC1=NC(=O)N=C2N=CN=C12 YLKYOEVXPMJDQM-UHFFFAOYSA-N 0.000 description 9
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Classifications
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- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
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- Pharmacology & Pharmacy (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12/196,516 US7902187B2 (en) | 2006-10-04 | 2008-08-22 | 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression |
| US12/196,516 | 2008-08-22 | ||
| PCT/US2009/054663 WO2010022358A1 (en) | 2008-08-22 | 2009-08-21 | 6-substituted 2-(benzimidazolyl)purine and purinone derivatives and 6-substituted 2-(imidazoio[4,5- c]pyridinyl)purine and purinone derivatives for immunosuppression |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2012500805A true JP2012500805A (ja) | 2012-01-12 |
| JP2012500805A5 JP2012500805A5 (enExample) | 2012-09-27 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2011524034A Pending JP2012500805A (ja) | 2008-08-22 | 2009-08-21 | 免疫抑制のための６−置換２−（ベンズイミダゾリル）プリンおよびプリノン誘導体ならびに６−置換２−（イミダゾロ［４，５−ｃ］ピリジニル）プリンおよびプリノン誘導体 |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US7902187B2 (enExample) |
| EP (1) | EP2326647A4 (enExample) |
| JP (1) | JP2012500805A (enExample) |
| CA (1) | CA2735048A1 (enExample) |
| WO (1) | WO2010022358A1 (enExample) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20190092573A (ko) * | 2016-12-20 | 2019-08-07 | 아스트라제네카 아베 | 아미노-트리아졸로피리딘 화합물 및 암 치료에서의 이의 용도 |
| WO2025234404A1 (ja) * | 2024-05-07 | 2025-11-13 | 全薬工業株式会社 | ピリミジン含有縮合環化合物及びその用途 |
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| CN101304748A (zh) | 2005-08-22 | 2008-11-12 | 加利福尼亚大学董事会 | Tlr激动剂 |
| WO2007030438A2 (en) * | 2005-09-06 | 2007-03-15 | Pharmacopeia, Inc. | Aminopurine derivatives for treating neurodegenerative diseases |
| EP2012791A4 (en) * | 2006-02-07 | 2010-09-22 | Conforma Therapeutics Corp | 7,9-DIHYDRO-PURIN-8-ONE AND RELATED ANALOGUES AS INHIBITORS OF HSP90 |
| US7989459B2 (en) * | 2006-02-17 | 2011-08-02 | Pharmacopeia, Llc | Purinones and 1H-imidazopyridinones as PKC-theta inhibitors |
| US20090281075A1 (en) * | 2006-02-17 | 2009-11-12 | Pharmacopeia, Inc. | Isomeric purinones and 1h-imidazopyridinones as pkc-theta inhibitors |
| WO2007104053A2 (en) * | 2006-03-09 | 2007-09-13 | Pharmacopeia, Inc. | 8-heteroarylpurine mnk2 inhibitors for treating metabolic disorders |
| EP2700638A1 (en) * | 2006-05-31 | 2014-02-26 | The Regents Of the University of California | Purine analogs |
| US7767685B2 (en) * | 2006-06-29 | 2010-08-03 | King Pharmaceuticals Research And Development, Inc. | Adenosine A2B receptor antagonists |
| US7919490B2 (en) * | 2006-10-04 | 2011-04-05 | Wyeth Llc | 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression |
| US7902187B2 (en) | 2006-10-04 | 2011-03-08 | Wyeth Llc | 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression |
| TW200837064A (en) * | 2006-10-04 | 2008-09-16 | Pharmacopeia Inc | 8-substituted 2-(benzimidazolyl)purine derivatives for immunosuppression |
| CA2666624C (en) * | 2006-10-19 | 2015-12-29 | Signal Pharmaceuticals, Llc | Heteroaryl compounds, compositions thereof, and use thereof as protein kinase inhibitors |
| US20080119496A1 (en) * | 2006-11-16 | 2008-05-22 | Pharmacopeia Drug Discovery, Inc. | 7-Substituted Purine Derivatives for Immunosuppression |
| CN101790380B (zh) | 2007-02-07 | 2013-07-10 | 加利福尼亚大学董事会 | 合成tlr激动剂的缀合物及其应用 |
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| JP2020504107A (ja) * | 2016-12-20 | 2020-02-06 | アストラゼネカ・アクチエボラーグＡｓｔｒａｚｅｎｅｃａ Ａｋｔｉｅｂｏｌａｇ | アミノ−トリアゾロピリジン化合物および癌の治療におけるその使用 |
| KR102220971B1 (ko) | 2016-12-20 | 2021-02-25 | 아스트라제네카 아베 | 아미노-트리아졸로피리딘 화합물 및 암 치료에서의 이의 용도 |
| US11136340B2 (en) | 2016-12-20 | 2021-10-05 | Astrazeneca Ab | Amino-triazolopyridine compounds and their use in treating cancer |
| US11746118B2 (en) | 2016-12-20 | 2023-09-05 | Astrazeneca Ab | Amino-triazolopyridine compounds and their use in treating cancer |
| WO2025234404A1 (ja) * | 2024-05-07 | 2025-11-13 | 全薬工業株式会社 | ピリミジン含有縮合環化合物及びその用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2326647A1 (en) | 2011-06-01 |
| WO2010022358A8 (en) | 2011-03-24 |
| EP2326647A4 (en) | 2012-12-26 |
| US7902187B2 (en) | 2011-03-08 |
| US20090069289A1 (en) | 2009-03-12 |
| WO2010022358A1 (en) | 2010-02-25 |
| CA2735048A1 (en) | 2010-02-25 |
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