JP2018510184A5 - - Google Patents

Info

Publication number

JP2018510184A5

JP2018510184A5 JP2017551197A JP2017551197A JP2018510184A5 JP 2018510184 A5 JP2018510184 A5 JP 2018510184A5 JP 2017551197 A JP2017551197 A JP 2017551197A JP 2017551197 A JP2017551197 A JP 2017551197A JP 2018510184 A5 JP2018510184 A5 JP 2018510184A5

Authority

JP

Japan

Prior art keywords

methoxy

benzaldehyde

hydroxy

lysine

piperazinyl

Prior art date

2016-03-29

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.)

Granted

Links

• Espacenet
• Global Dossier
• Discuss

• HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 14
• -1 (S) -2- hydroxy-6 - ((1- (6-methyl-nicotinoyl) piperazinyl lysine-2-yl) methoxy) benzaldehyde Chemical compound 0.000 claims description 12
• 150000001875 compounds Chemical class 0.000 claims description 10
• QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 7
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
• 208000019693 Lung disease Diseases 0.000 claims description 4
• ATRDITXXERVYLU-TUXUZCGSSA-N OC1=C(C=O)C(=CC=C1)OC[C@@](NC1N(CCNC1)C(C1=CC(=NC=C1)C)=O)(CCCCN)C(=O)O Chemical compound OC1=C(C=O)C(=CC=C1)OC[C@@](NC1N(CCNC1)C(C1=CC(=NC=C1)C)=O)(CCCCN)C(=O)O ATRDITXXERVYLU-TUXUZCGSSA-N 0.000 claims description 4
• RMFGBZNBRKQIPK-QBGQUKIHSA-N OC1=C(C=O)C(=CC=C1)OC[C@@](NC1N(CCNC1)C(C1=CC(=NC=C1)OC)=O)(CCCCN)C(=O)O Chemical compound OC1=C(C=O)C(=CC=C1)OC[C@@](NC1N(CCNC1)C(C1=CC(=NC=C1)OC)=O)(CCCCN)C(=O)O RMFGBZNBRKQIPK-QBGQUKIHSA-N 0.000 claims description 4
• WKIFXDPQCJCNCL-QBGQUKIHSA-N OC1=C(C=O)C(=CC=C1)OC[C@@](NC1N(CCNC1)C(C1=CN=C(C=C1)OC)=O)(CCCCN)C(=O)O Chemical compound OC1=C(C=O)C(=CC=C1)OC[C@@](NC1N(CCNC1)C(C1=CN=C(C=C1)OC)=O)(CCCCN)C(=O)O WKIFXDPQCJCNCL-QBGQUKIHSA-N 0.000 claims description 4
• 206010021143 Hypoxia Diseases 0.000 claims description 3
• 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 3
• 230000004761 fibrosis Effects 0.000 claims description 2
• 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 2
• 239000003814 drug Substances 0.000 claims 11
• FWCVZAQENIZVMY-UHFFFAOYSA-N 2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]benzaldehyde Chemical compound CC(C)N1N=CC=C1C1=NC=CC=C1COC1=CC=CC(O)=C1C=O FWCVZAQENIZVMY-UHFFFAOYSA-N 0.000 claims 5
• 150000003839 salts Chemical class 0.000 claims 4
• MQZCNVXUMGPPGB-UHFFFAOYSA-N 2-hydroxy-6-[[3-(2-propan-2-ylpyrazol-3-yl)pyrazin-2-yl]methoxy]benzaldehyde Chemical compound OC1=C(C=O)C(=CC=C1)OCC1=NC=CN=C1C1=CC=NN1C(C)C MQZCNVXUMGPPGB-UHFFFAOYSA-N 0.000 claims 3
• BMGMIXABCSIXCI-UHFFFAOYSA-N 3-chloro-2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]benzaldehyde Chemical compound CC(C)N1N=CC=C1C1=NC=CC=C1COC1=CC=C(Cl)C(O)=C1C=O BMGMIXABCSIXCI-UHFFFAOYSA-N 0.000 claims 3
• XKJFHQZGEDYFDB-AWEZNQCLSA-N OC1=C(C=O)C(=CC=C1)OC[C@H]1N(C(CC1)=O)C1=CC=CC=C1 Chemical compound OC1=C(C=O)C(=CC=C1)OC[C@H]1N(C(CC1)=O)C1=CC=CC=C1 XKJFHQZGEDYFDB-AWEZNQCLSA-N 0.000 claims 3
• 206010016654 Fibrosis Diseases 0.000 claims 1
• 230000007954 hypoxia Effects 0.000 claims 1
• 239000008194 pharmaceutical composition Substances 0.000 claims 1
• 239000000546 pharmaceutical excipient Substances 0.000 claims 1
• 238000000634 powder X-ray diffraction Methods 0.000 claims 1
• 230000002685 pulmonary effect Effects 0.000 claims 1
• 230000005855 radiation Effects 0.000 claims 1
• 239000012453 solvate Substances 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
• 239000000243 solution Substances 0.000 description 14
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
• 239000007787 solid Substances 0.000 description 6
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
• 239000000741 silica gel Substances 0.000 description 5
• 229910002027 silica gel Inorganic materials 0.000 description 5
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
• DGXAGETVRDOQFP-UHFFFAOYSA-N 2,6-dihydroxybenzaldehyde Chemical compound OC1=CC=CC(O)=C1C=O DGXAGETVRDOQFP-UHFFFAOYSA-N 0.000 description 3
• 239000007821 HATU Substances 0.000 description 3
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
• FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 3
• 239000012267 brine Substances 0.000 description 3
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
• 229910052757 nitrogen Inorganic materials 0.000 description 3
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
• 238000003756 stirring Methods 0.000 description 3
• PMDHIMMPXRSDML-UHFFFAOYSA-N 2-methylpyridine-4-carboxylic acid Chemical compound CC1=CC(C(O)=O)=CC=N1 PMDHIMMPXRSDML-UHFFFAOYSA-N 0.000 description 2
• 229910021529 ammonia Inorganic materials 0.000 description 2
• 238000010171 animal model Methods 0.000 description 2
• 229940125904 compound 1 Drugs 0.000 description 2
• 239000012043 crude product Substances 0.000 description 2
• 208000018875 hypoxemia Diseases 0.000 description 2
• 239000003208 petroleum Substances 0.000 description 2
• 239000012071 phase Substances 0.000 description 2
• 125000004193 piperazinyl group Chemical group 0.000 description 2
• 238000002953 preparative HPLC Methods 0.000 description 2
• 208000005069 pulmonary fibrosis Diseases 0.000 description 2
• 239000003643 water by type Substances 0.000 description 2
• IDFPQEHZYBXIFO-GFCCVEGCSA-N (R)-(4-fluoro-2-propylphenyl)-(1H-imidazol-2-yl)methanol Chemical compound CCCc1cc(F)ccc1[C@@H](O)c1ncc[nH]1 IDFPQEHZYBXIFO-GFCCVEGCSA-N 0.000 description 1
• VOCKNCWQVHJMAE-UHFFFAOYSA-N 2-methoxypyridine-4-carbaldehyde Chemical compound COC1=CC(C=O)=CC=N1 VOCKNCWQVHJMAE-UHFFFAOYSA-N 0.000 description 1
• DPNDWFVORIGXQO-UHFFFAOYSA-N 2-methoxypyridine-4-carboxylic acid Chemical compound COC1=CC(C(O)=O)=CC=N1 DPNDWFVORIGXQO-UHFFFAOYSA-N 0.000 description 1
• NVDJVEQITUWZDT-UHFFFAOYSA-N 6-Methoxy-pyridine-3-carboxylic acid Chemical compound COC1=CC=C(C(O)=O)C=N1 NVDJVEQITUWZDT-UHFFFAOYSA-N 0.000 description 1
• 108010006654 Bleomycin Proteins 0.000 description 1
• 206010035664 Pneumonia Diseases 0.000 description 1
• 229960001561 bleomycin Drugs 0.000 description 1
• OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
• 238000010828 elution Methods 0.000 description 1
• 230000003176 fibrotic effect Effects 0.000 description 1
• WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 1
• 239000012074 organic phase Substances 0.000 description 1
• 238000012746 preparative thin layer chromatography Methods 0.000 description 1