JP5587790B2 - 化合物 - Google Patents
化合物 Download PDFInfo
- Publication number
- JP5587790B2 JP5587790B2 JP2010541840A JP2010541840A JP5587790B2 JP 5587790 B2 JP5587790 B2 JP 5587790B2 JP 2010541840 A JP2010541840 A JP 2010541840A JP 2010541840 A JP2010541840 A JP 2010541840A JP 5587790 B2 JP5587790 B2 JP 5587790B2
- Authority
- JP
- Japan
- Prior art keywords
- furo
- benzamide
- pyrrole
- oxodihydro
- oxopentan
- 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.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims description 218
- 239000000203 mixture Substances 0.000 claims description 307
- -1 tert- butylmethyl Chemical group 0.000 claims description 120
- 238000002360 preparation method Methods 0.000 claims description 89
- 238000000034 method Methods 0.000 claims description 85
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 64
- 229910052739 hydrogen Inorganic materials 0.000 claims description 61
- 102000005927 Cysteine Proteases Human genes 0.000 claims description 48
- 108010005843 Cysteine Proteases Proteins 0.000 claims description 48
- 102000035195 Peptidases Human genes 0.000 claims description 42
- 108091005804 Peptidases Proteins 0.000 claims description 42
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical group C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 42
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 42
- 235000019833 protease Nutrition 0.000 claims description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 201000010099 disease Diseases 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 26
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- 239000003814 drug Substances 0.000 claims description 24
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- 230000027455 binding Effects 0.000 claims description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 21
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
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- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 10
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 208000029725 Metabolic bone disease Diseases 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- 238000012544 monitoring process Methods 0.000 claims description 6
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- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
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- 230000003993 interaction Effects 0.000 claims description 4
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
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- 125000002355 alkine group Chemical group 0.000 claims description 3
- 238000010171 animal model Methods 0.000 claims description 3
- 238000012875 competitive assay Methods 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
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- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 4
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims 1
- BLMYFOVRPAQMPC-UHFFFAOYSA-N n-(4-methylpiperazin-1-yl)benzamide Chemical compound C1CN(C)CCN1NC(=O)C1=CC=CC=C1 BLMYFOVRPAQMPC-UHFFFAOYSA-N 0.000 claims 1
- 238000000159 protein binding assay Methods 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 363
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 336
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 258
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 175
- 239000011734 sodium Substances 0.000 description 171
- 239000000243 solution Substances 0.000 description 167
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 148
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 138
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 137
- 235000019439 ethyl acetate Nutrition 0.000 description 132
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 116
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 87
- 239000000377 silicon dioxide Substances 0.000 description 72
- 125000003118 aryl group Chemical group 0.000 description 71
- 238000003818 flash chromatography Methods 0.000 description 69
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 64
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 61
- 239000012267 brine Substances 0.000 description 60
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 60
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 53
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 52
- 238000004128 high performance liquid chromatography Methods 0.000 description 52
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 50
- 101150065749 Churc1 gene Proteins 0.000 description 50
- 102100038239 Protein Churchill Human genes 0.000 description 50
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 50
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 50
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 48
- 150000002576 ketones Chemical class 0.000 description 48
- 239000012044 organic layer Substances 0.000 description 48
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 46
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- 239000003921 oil Substances 0.000 description 41
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 40
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- 239000007787 solid Substances 0.000 description 40
- 239000012300 argon atmosphere Substances 0.000 description 39
- 239000000725 suspension Substances 0.000 description 39
- 239000002904 solvent Substances 0.000 description 37
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 37
- 239000003112 inhibitor Substances 0.000 description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 36
- 239000012230 colorless oil Substances 0.000 description 35
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 34
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 34
- 239000012074 organic phase Substances 0.000 description 34
- 239000012065 filter cake Substances 0.000 description 30
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 30
- 238000000746 purification Methods 0.000 description 29
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 28
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 28
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 102000004171 Cathepsin K Human genes 0.000 description 26
- 108090000625 Cathepsin K Proteins 0.000 description 26
- 239000000047 product Substances 0.000 description 26
- 229910052708 sodium Inorganic materials 0.000 description 25
- 229910000029 sodium carbonate Inorganic materials 0.000 description 25
- 229910052786 argon Inorganic materials 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 24
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 23
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- 235000002639 sodium chloride Nutrition 0.000 description 23
- 150000001412 amines Chemical class 0.000 description 21
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- 125000002619 bicyclic group Chemical group 0.000 description 20
- 239000010949 copper Substances 0.000 description 20
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 20
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 19
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 19
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- UKHQUUMINBTTGU-UHFFFAOYSA-N bromo 4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(=O)(=O)OBr)C=C1 UKHQUUMINBTTGU-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
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- 150000001413 amino acids Chemical group 0.000 description 17
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- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 13
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
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- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
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| GB0800338A GB0800338D0 (en) | 2008-01-09 | 2008-01-09 | Compounds |
| GB0800338.6 | 2008-01-09 | ||
| GB0808669.6 | 2008-05-13 | ||
| GB0808669A GB0808669D0 (en) | 2008-05-13 | 2008-05-13 | Compounds |
| PCT/GB2009/000039 WO2009087379A2 (en) | 2008-01-09 | 2009-01-07 | Tetrahydrofuro (3, 2 -b) pyrrol- 3 -one derivatives as inhibitors of cysteine proteinases |
Publications (3)
| Publication Number | Publication Date |
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| JP2011509282A JP2011509282A (ja) | 2011-03-24 |
| JP2011509282A5 JP2011509282A5 (enExample) | 2012-02-23 |
| JP5587790B2 true JP5587790B2 (ja) | 2014-09-10 |
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| JP2010541840A Expired - Fee Related JP5587790B2 (ja) | 2008-01-09 | 2009-01-07 | 化合物 |
Country Status (4)
| Country | Link |
|---|---|
| US (3) | US8501744B2 (enExample) |
| EP (2) | EP2719700A1 (enExample) |
| JP (1) | JP5587790B2 (enExample) |
| WO (1) | WO2009087379A2 (enExample) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU581929B2 (en) * | 1985-09-16 | 1989-03-09 | Schering Corporation | Antihypertensive agents, pharmaceutical compositions containing them and processes for the preparation of the agents and compositions |
| GB0817424D0 (en) | 2008-09-24 | 2008-10-29 | Medivir Ab | Protease inhibitors |
| KR20150046259A (ko) | 2012-08-23 | 2015-04-29 | 앨리오스 바이오파마 인크. | 파라믹소바이러스 바이러스성 감염의 치료용 화합물 |
| EP2945950B1 (en) | 2013-01-17 | 2017-03-01 | Sanofi | Isomannide derivatives as inhibitors of soluble epoxide hydrolase |
| CA2921294C (en) * | 2013-08-21 | 2023-05-16 | Alios Biopharma, Inc. | Antiviral compounds |
| CN105764904B (zh) | 2013-09-12 | 2020-02-11 | 詹森生物制药有限公司 | 氮杂-吡啶酮化合物及其用途 |
| MA41614A (fr) | 2015-02-25 | 2018-01-02 | Alios Biopharma Inc | Composés antiviraux |
| GB201506660D0 (en) | 2015-04-20 | 2015-06-03 | Cellcentric Ltd | Pharmaceutical compounds |
| GB201506658D0 (en) | 2015-04-20 | 2015-06-03 | Cellcentric Ltd | Pharmaceutical compounds |
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| US6043218A (en) | 1996-10-22 | 2000-03-28 | Medical University Of South Carolina | Positively charged non-natural amino acids, methods of making thereof, and use thereof in peptides |
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| ATE339404T1 (de) | 1999-12-24 | 2006-10-15 | Hoffmann La Roche | Nitrilderivate als cathepsin k hemmer |
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| CN100354276C (zh) | 2002-07-16 | 2007-12-12 | 阿姆拉医疗有限公司 | 生物活性化合物 |
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| WO2006064286A1 (en) | 2004-12-13 | 2006-06-22 | Medivir Uk Ltd | Cathepsin s inhibitors |
| GB0614044D0 (en) * | 2006-07-14 | 2006-08-23 | Amura Therapeutics Ltd | Compounds |
| GB0614042D0 (en) * | 2006-07-14 | 2006-08-23 | Amura Therapeutics Ltd | Compounds |
-
2009
- 2009-01-07 JP JP2010541840A patent/JP5587790B2/ja not_active Expired - Fee Related
- 2009-01-07 WO PCT/GB2009/000039 patent/WO2009087379A2/en not_active Ceased
- 2009-01-07 EP EP20130189094 patent/EP2719700A1/en not_active Withdrawn
- 2009-01-07 EP EP09700614.2A patent/EP2240491B1/en not_active Not-in-force
-
2010
- 2010-06-25 US US12/823,558 patent/US8501744B2/en not_active Expired - Fee Related
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2013
- 2013-05-23 US US13/901,479 patent/US9045492B2/en not_active Expired - Fee Related
-
2015
- 2015-04-10 US US14/683,913 patent/US20150209349A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US20110077254A1 (en) | 2011-03-31 |
| US8501744B2 (en) | 2013-08-06 |
| US20150209349A1 (en) | 2015-07-30 |
| WO2009087379A3 (en) | 2009-09-03 |
| EP2240491A2 (en) | 2010-10-20 |
| JP2011509282A (ja) | 2011-03-24 |
| US20130252969A1 (en) | 2013-09-26 |
| WO2009087379A2 (en) | 2009-07-16 |
| EP2240491B1 (en) | 2015-07-15 |
| US9045492B2 (en) | 2015-06-02 |
| EP2719700A1 (en) | 2014-04-16 |
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