RU2246493C2 - Производные индолилпиперидина в качестве антигистаминных и противоаллергических средств - Google Patents

Info

Publication number

RU2246493C2

RU2246493C2 RU2002100073/04A RU2002100073A RU2246493C2 RU 2246493 C2 RU2246493 C2 RU 2246493C2 RU 2002100073/04 A RU2002100073/04 A RU 2002100073/04A RU 2002100073 A RU2002100073 A RU 2002100073A RU 2246493 C2 RU2246493 C2 RU 2246493C2

Authority

RU

Russia

Prior art keywords

piperidin

indol

ethoxy

acid

ethoxyethyl

Prior art date

1999-06-04

Links

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• Global Dossier
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• HNQZRUDJRPSFAU-UHFFFAOYSA-N 2-piperidin-1-yl-1h-indole Chemical class C1CCCCN1C1=CC2=CC=CC=C2N1 HNQZRUDJRPSFAU-UHFFFAOYSA-N 0.000 title claims abstract description 14
• 239000000739 antihistaminic agent Substances 0.000 title claims abstract description 9
• 230000001387 anti-histamine Effects 0.000 title abstract description 3
• 239000000043 antiallergic agent Substances 0.000 title description 4
• 150000001875 compounds Chemical class 0.000 claims abstract description 101
• 238000000034 method Methods 0.000 claims abstract description 92
• 239000000203 mixture Substances 0.000 claims abstract description 90
• 150000003839 salts Chemical class 0.000 claims abstract description 21
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
• 125000005843 halogen group Chemical group 0.000 claims abstract description 17
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 16
• 230000000694 effects Effects 0.000 claims abstract description 14
• 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims abstract description 8
• 208000006673 asthma Diseases 0.000 claims abstract description 7
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 7
• 230000003266 anti-allergic effect Effects 0.000 claims abstract description 6
• 208000024780 Urticaria Diseases 0.000 claims abstract description 5
• 208000026935 allergic disease Diseases 0.000 claims abstract description 5
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 5
• 125000003831 tetrazolyl group Chemical group 0.000 claims abstract description 5
• 206010010741 Conjunctivitis Diseases 0.000 claims abstract description 4
• 201000004624 Dermatitis Diseases 0.000 claims abstract description 3
• 206010039083 rhinitis Diseases 0.000 claims abstract description 3
• -1 methylene, ethylene, propylene, butylene, pentylene, hexylene, ethyleneoxy, propyleneoxy, hydroxybutylene group Chemical group 0.000 claims description 104
• 239000000460 chlorine Substances 0.000 claims description 12
• 125000002947 alkylene group Chemical group 0.000 claims description 11
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
• 125000003545 alkoxy group Chemical group 0.000 claims description 9
• 229910052801 chlorine Inorganic materials 0.000 claims description 9
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
• KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 8
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
• 239000002253 acid Substances 0.000 claims description 7
• 125000003342 alkenyl group Chemical group 0.000 claims description 7
• 125000000304 alkynyl group Chemical group 0.000 claims description 7
• 229910052739 hydrogen Inorganic materials 0.000 claims description 6
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
• 125000005529 alkyleneoxy group Chemical group 0.000 claims description 5
• 210000000748 cardiovascular system Anatomy 0.000 claims description 5
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 239000011737 fluorine Substances 0.000 claims description 5
• 229910052731 fluorine Inorganic materials 0.000 claims description 5
• 239000001257 hydrogen Substances 0.000 claims description 5
• QIRDLEIUOYJRGZ-UHFFFAOYSA-N 2-methyl-2-[4-[4-[4-[1-(3-methylbutyl)indol-3-yl]piperidin-1-yl]butanoyl]phenyl]propanoic acid Chemical compound C12=CC=CC=C2N(CCC(C)C)C=C1C(CC1)CCN1CCCC(=O)C1=CC=C(C(C)(C)C(O)=O)C=C1 QIRDLEIUOYJRGZ-UHFFFAOYSA-N 0.000 claims description 4
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
• GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims description 4
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• DUCZGLRXKNHEME-UHFFFAOYSA-N 1-(2-ethoxyethyl)-3-[1-[3-[4-(2h-tetrazol-5-yl)phenoxy]propyl]piperidin-4-yl]indole Chemical compound C12=CC=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCCOC(C=C1)=CC=C1C=1N=NNN=1 DUCZGLRXKNHEME-UHFFFAOYSA-N 0.000 claims description 3
• QMFNTTFIGWXQNY-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)-5-fluoroindol-3-yl]piperidin-1-yl]ethoxy]-4-methoxybenzoic acid Chemical compound C12=CC(F)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC(OC)=CC=C1C(O)=O QMFNTTFIGWXQNY-UHFFFAOYSA-N 0.000 claims description 3
• NDRPQPJPFUMFQZ-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)-5-fluoroindol-3-yl]piperidin-1-yl]ethoxy]-5-methylbenzoic acid Chemical compound C12=CC(F)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=C(C)C=C1C(O)=O NDRPQPJPFUMFQZ-UHFFFAOYSA-N 0.000 claims description 3
• DTTZVMYXKPDNIC-UHFFFAOYSA-N 2-[2-[4-[1-[2-(2-methoxyethoxy)ethyl]indol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=CC=CC=C2N(CCOCCOC)C=C1C(CC1)CCN1CCOC1=CC=CC=C1C(O)=O DTTZVMYXKPDNIC-UHFFFAOYSA-N 0.000 claims description 3
• XLIGNZHKWRUBOD-UHFFFAOYSA-N 2-[2-[4-[7-bromo-1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]-5-methylbenzoic acid Chemical compound C12=CC=CC(Br)=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=C(C)C=C1C(O)=O XLIGNZHKWRUBOD-UHFFFAOYSA-N 0.000 claims description 3
• HIKYNJRMLYWZMO-UHFFFAOYSA-N 2-[3-[4-[1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]propoxy]benzoic acid Chemical compound C12=CC=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCCOC1=CC=CC=C1C(O)=O HIKYNJRMLYWZMO-UHFFFAOYSA-N 0.000 claims description 3
• NUYSPCIQLGLALT-UHFFFAOYSA-N 2-[3-[4-[1-[2-(2-methoxyethoxy)ethyl]indol-3-yl]piperidin-1-yl]propoxy]benzoic acid Chemical compound C12=CC=CC=C2N(CCOCCOC)C=C1C(CC1)CCN1CCCOC1=CC=CC=C1C(O)=O NUYSPCIQLGLALT-UHFFFAOYSA-N 0.000 claims description 3
• SUYRJLMLWQRSTJ-UHFFFAOYSA-N 2-[4-[1-hydroxy-4-[4-(1-pentylindol-3-yl)piperidin-1-yl]butyl]phenyl]-2-methylpropanoic acid Chemical compound C12=CC=CC=C2N(CCCCC)C=C1C(CC1)CCN1CCCC(O)C1=CC=C(C(C)(C)C(O)=O)C=C1 SUYRJLMLWQRSTJ-UHFFFAOYSA-N 0.000 claims description 3
• NPNSJRPLUBCWJW-UHFFFAOYSA-N 2-[4-[4-[4-[1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]-1-hydroxybutyl]phenyl]-2-methylpropanoic acid Chemical compound C12=CC=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCCC(O)C1=CC=C(C(C)(C)C(O)=O)C=C1 NPNSJRPLUBCWJW-UHFFFAOYSA-N 0.000 claims description 3
• HBVUBXMUMKERIB-UHFFFAOYSA-N 3-[2-[4-[1-[2-(2-methoxyethoxy)ethyl]indol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=CC=CC=C2N(CCOCCOC)C=C1C(CC1)CCN1CCOC1=CC=CC(C(O)=O)=C1 HBVUBXMUMKERIB-UHFFFAOYSA-N 0.000 claims description 3
• OLYGEFPXSWBWOU-UHFFFAOYSA-N 3-[3-[4-[1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]propoxy]benzoic acid Chemical compound C12=CC=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCCOC1=CC=CC(C(O)=O)=C1 OLYGEFPXSWBWOU-UHFFFAOYSA-N 0.000 claims description 3
• WJOOEDOCJSIGIS-UHFFFAOYSA-N 3-[4-[2-[4-(1-pentylindol-3-yl)piperidin-1-yl]ethyl]phenyl]prop-2-enoic acid Chemical compound C12=CC=CC=C2N(CCCCC)C=C1C(CC1)CCN1CCC1=CC=C(C=CC(O)=O)C=C1 WJOOEDOCJSIGIS-UHFFFAOYSA-N 0.000 claims description 3
• JWCRKHFKVHMTRJ-UHFFFAOYSA-N 3-[4-[2-[4-[1-[2-(2-methoxyethoxy)ethyl]indol-3-yl]piperidin-1-yl]ethyl]phenyl]prop-2-enoic acid Chemical compound C12=CC=CC=C2N(CCOCCOC)C=C1C(CC1)CCN1CCC1=CC=C(C=CC(O)=O)C=C1 JWCRKHFKVHMTRJ-UHFFFAOYSA-N 0.000 claims description 3
• UMFXWTOKTPDSRO-UHFFFAOYSA-N 4-[3-[4-(1-pentylindol-3-yl)piperidin-1-yl]propoxy]benzoic acid Chemical compound C12=CC=CC=C2N(CCCCC)C=C1C(CC1)CCN1CCCOC1=CC=C(C(O)=O)C=C1 UMFXWTOKTPDSRO-UHFFFAOYSA-N 0.000 claims description 3
• 125000005081 alkoxyalkoxyalkyl group Chemical group 0.000 claims description 3
• 230000003326 anti-histaminergic effect Effects 0.000 claims description 3
• 125000001589 carboacyl group Chemical group 0.000 claims description 3
• 210000003169 central nervous system Anatomy 0.000 claims description 3
• 230000002526 effect on cardiovascular system Effects 0.000 claims description 3
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 3
• YGMUXTWULKXKAO-UHFFFAOYSA-N 1-(2-ethoxyethyl)-3-[1-[3-[2-(2h-tetrazol-5-yl)phenoxy]propyl]piperidin-4-yl]indole Chemical compound C12=CC=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCCOC1=CC=CC=C1C=1N=NNN=1 YGMUXTWULKXKAO-UHFFFAOYSA-N 0.000 claims description 2
• ISRNSOPKRJFRMR-UHFFFAOYSA-N 1-(3-methylbutyl)-3-[1-[3-[2-(2h-tetrazol-5-yl)phenoxy]propyl]piperidin-4-yl]indole Chemical compound C12=CC=CC=C2N(CCC(C)C)C=C1C(CC1)CCN1CCCOC1=CC=CC=C1C=1N=NNN=1 ISRNSOPKRJFRMR-UHFFFAOYSA-N 0.000 claims description 2
• ZDRUIODKMKJGOJ-UHFFFAOYSA-N 1-(3-methylbutyl)-3-[1-[3-[4-(2h-tetrazol-5-yl)phenoxy]propyl]piperidin-4-yl]indole Chemical compound C12=CC=CC=C2N(CCC(C)C)C=C1C(CC1)CCN1CCCOC(C=C1)=CC=C1C=1N=NNN=1 ZDRUIODKMKJGOJ-UHFFFAOYSA-N 0.000 claims description 2
• KTEZZEXASTZNJG-UHFFFAOYSA-N 2-[2-[4-(1-prop-2-enylindol-3-yl)piperidin-1-yl]ethoxy]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1OCCN1CCC(C=2C3=CC=CC=C3N(CC=C)C=2)CC1 KTEZZEXASTZNJG-UHFFFAOYSA-N 0.000 claims description 2
• SPOKTOSVUQLTOH-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)-4-fluoroindol-3-yl]piperidin-1-yl]ethoxy]-5-methylbenzoic acid Chemical compound C12=C(F)C=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=C(C)C=C1C(O)=O SPOKTOSVUQLTOH-UHFFFAOYSA-N 0.000 claims description 2
• QAZVGNJWLJEDFV-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)-4-fluoroindol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=C(F)C=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=CC=C1C(O)=O QAZVGNJWLJEDFV-UHFFFAOYSA-N 0.000 claims description 2
• INVVRCPLVVQOGS-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)-5-fluoroindol-3-yl]piperidin-1-yl]ethoxy]-6-fluorobenzoic acid Chemical compound C12=CC(F)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=CC(F)=C1C(O)=O INVVRCPLVVQOGS-UHFFFAOYSA-N 0.000 claims description 2
• DGVYELQBTIBCMU-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)-5-fluoroindol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=CC(F)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=CC=C1C(O)=O DGVYELQBTIBCMU-UHFFFAOYSA-N 0.000 claims description 2
• HOLMXWXLIIOTTC-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)-5-methoxyindol-3-yl]piperidin-1-yl]ethoxy]-4-methoxybenzoic acid Chemical compound C12=CC(OC)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC(OC)=CC=C1C(O)=O HOLMXWXLIIOTTC-UHFFFAOYSA-N 0.000 claims description 2
• ZEARTZKNFQZDKX-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)-5-methoxyindol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=CC(OC)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=CC=C1C(O)=O ZEARTZKNFQZDKX-UHFFFAOYSA-N 0.000 claims description 2
• WYMKMMPHJBIHRY-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)-6-fluoroindol-3-yl]piperidin-1-yl]ethoxy]-4-methoxybenzoic acid Chemical compound C12=CC=C(F)C=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC(OC)=CC=C1C(O)=O WYMKMMPHJBIHRY-UHFFFAOYSA-N 0.000 claims description 2
• XUQURAFGTLVXHN-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)-6-fluoroindol-3-yl]piperidin-1-yl]ethoxy]-6-fluorobenzoic acid Chemical compound C12=CC=C(F)C=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=CC(F)=C1C(O)=O XUQURAFGTLVXHN-UHFFFAOYSA-N 0.000 claims description 2
• BVRIYQUZSCWOSG-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)-6-fluoroindol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=CC=C(F)C=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=CC=C1C(O)=O BVRIYQUZSCWOSG-UHFFFAOYSA-N 0.000 claims description 2
• WUAPZVZDCHYLGI-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)-7-methylindol-3-yl]piperidin-1-yl]ethoxy]-5-methylbenzoic acid Chemical compound C12=CC=CC(C)=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=C(C)C=C1C(O)=O WUAPZVZDCHYLGI-UHFFFAOYSA-N 0.000 claims description 2
• XUYOZHRTHKAKTL-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]-5-methylbenzoic acid Chemical compound C12=CC=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=C(C)C=C1C(O)=O XUYOZHRTHKAKTL-UHFFFAOYSA-N 0.000 claims description 2
• FGOSLGBBJZIYHE-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]-6-fluorobenzoic acid Chemical compound C12=CC=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=CC(F)=C1C(O)=O FGOSLGBBJZIYHE-UHFFFAOYSA-N 0.000 claims description 2
• LVAJRQDSXRFOTR-UHFFFAOYSA-N 2-[2-[4-[1-(2-methoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=CC=CC=C2N(CCOC)C=C1C(CC1)CCN1CCOC1=CC=CC=C1C(O)=O LVAJRQDSXRFOTR-UHFFFAOYSA-N 0.000 claims description 2
• PLUCWLKTQPYMOJ-UHFFFAOYSA-N 2-[2-[4-[4-fluoro-1-(2-methoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]-5-methylbenzoic acid Chemical compound C12=C(F)C=CC=C2N(CCOC)C=C1C(CC1)CCN1CCOC1=CC=C(C)C=C1C(O)=O PLUCWLKTQPYMOJ-UHFFFAOYSA-N 0.000 claims description 2
• DGEZDVIEJXDCQA-UHFFFAOYSA-N 2-[2-[4-[4-fluoro-1-(2-methoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=C(F)C=CC=C2N(CCOC)C=C1C(CC1)CCN1CCOC1=CC=CC=C1C(O)=O DGEZDVIEJXDCQA-UHFFFAOYSA-N 0.000 claims description 2
• MWHMBIYNCCYPQI-UHFFFAOYSA-N 2-[2-[4-[5-bromo-1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]-4-methoxybenzoic acid Chemical compound C12=CC(Br)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC(OC)=CC=C1C(O)=O MWHMBIYNCCYPQI-UHFFFAOYSA-N 0.000 claims description 2
• GOWPJVSOMIHDDM-UHFFFAOYSA-N 2-[2-[4-[5-bromo-1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]-5-methylbenzoic acid Chemical compound C12=CC(Br)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=C(C)C=C1C(O)=O GOWPJVSOMIHDDM-UHFFFAOYSA-N 0.000 claims description 2
• LYQYDLDTHBVSBI-UHFFFAOYSA-N 2-[2-[4-[5-bromo-1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]-6-fluorobenzoic acid Chemical compound C12=CC(Br)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=CC(F)=C1C(O)=O LYQYDLDTHBVSBI-UHFFFAOYSA-N 0.000 claims description 2
• XADGZRXEEIMQPN-UHFFFAOYSA-N 2-[2-[4-[5-bromo-1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=CC(Br)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=CC=C1C(O)=O XADGZRXEEIMQPN-UHFFFAOYSA-N 0.000 claims description 2
• MYXRAYCZYBLISE-UHFFFAOYSA-N 2-[2-[4-[5-chloro-1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]-4-methoxybenzoic acid Chemical compound C12=CC(Cl)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC(OC)=CC=C1C(O)=O MYXRAYCZYBLISE-UHFFFAOYSA-N 0.000 claims description 2
• LLHPGPJNBDMHJH-UHFFFAOYSA-N 2-[2-[4-[5-chloro-1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]-5-methylbenzoic acid Chemical compound C12=CC(Cl)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=C(C)C=C1C(O)=O LLHPGPJNBDMHJH-UHFFFAOYSA-N 0.000 claims description 2
• ZXVAQCXPJFHKGW-UHFFFAOYSA-N 2-[2-[4-[5-chloro-1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]-6-fluorobenzoic acid Chemical compound C12=CC(Cl)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=CC(F)=C1C(O)=O ZXVAQCXPJFHKGW-UHFFFAOYSA-N 0.000 claims description 2
• AKNGDPJHNUTJDE-UHFFFAOYSA-N 2-[2-[4-[6-bromo-1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]-5-methylbenzoic acid Chemical compound C12=CC=C(Br)C=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=C(C)C=C1C(O)=O AKNGDPJHNUTJDE-UHFFFAOYSA-N 0.000 claims description 2
• LPNLDHOWPWSASA-UHFFFAOYSA-N 2-[2-[4-[6-bromo-1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=CC=C(Br)C=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=CC=C1C(O)=O LPNLDHOWPWSASA-UHFFFAOYSA-N 0.000 claims description 2
• VUUZVHPYUMSGRB-UHFFFAOYSA-N 2-[2-[4-[7-bromo-1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]-4-methoxybenzoic acid Chemical compound C12=CC=CC(Br)=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC(OC)=CC=C1C(O)=O VUUZVHPYUMSGRB-UHFFFAOYSA-N 0.000 claims description 2
• OMSYYPWHMFLIDI-UHFFFAOYSA-N 2-[2-[4-[7-bromo-1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]-6-fluorobenzoic acid Chemical compound C12=CC=CC(Br)=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=CC(F)=C1C(O)=O OMSYYPWHMFLIDI-UHFFFAOYSA-N 0.000 claims description 2
• QWQRGXJHFQEOOM-UHFFFAOYSA-N 2-[2-[4-[7-bromo-1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=CC=CC(Br)=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=CC=C1C(O)=O QWQRGXJHFQEOOM-UHFFFAOYSA-N 0.000 claims description 2
• LEBSVPBBFMPHOV-UHFFFAOYSA-N 2-[3-[2-[4-[1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]phenyl]acetic acid Chemical compound C12=CC=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=CC(CC(O)=O)=C1 LEBSVPBBFMPHOV-UHFFFAOYSA-N 0.000 claims description 2
• FUDVVNJRXLXUKM-UHFFFAOYSA-N 2-[3-[2-[4-[1-(3-methylbutyl)indol-3-yl]piperidin-1-yl]ethoxy]phenyl]acetic acid Chemical compound C12=CC=CC=C2N(CCC(C)C)C=C1C(CC1)CCN1CCOC1=CC=CC(CC(O)=O)=C1 FUDVVNJRXLXUKM-UHFFFAOYSA-N 0.000 claims description 2
• LCYYTYJEGJBMTO-UHFFFAOYSA-N 2-[3-[3-[4-[1-(3-methylbutyl)indol-3-yl]piperidin-1-yl]propoxy]phenyl]acetic acid Chemical compound C12=CC=CC=C2N(CCC(C)C)C=C1C(CC1)CCN1CCCOC1=CC=CC(CC(O)=O)=C1 LCYYTYJEGJBMTO-UHFFFAOYSA-N 0.000 claims description 2
• HCBSJRILLFNCKC-UHFFFAOYSA-N 2-[4-[2-[4-[1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]phenyl]acetic acid Chemical compound C12=CC=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=C(CC(O)=O)C=C1 HCBSJRILLFNCKC-UHFFFAOYSA-N 0.000 claims description 2
• LFHWAHCXXMHIDU-UHFFFAOYSA-N 2-[4-[2-[4-[1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethyl]phenyl]-2-methylpropanoic acid Chemical compound C12=CC=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCC1=CC=C(C(C)(C)C(O)=O)C=C1 LFHWAHCXXMHIDU-UHFFFAOYSA-N 0.000 claims description 2
• KBRRQKNQGRVNGK-UHFFFAOYSA-N 2-[4-[2-[4-[1-(cyclopropylmethyl)indol-3-yl]piperidin-1-yl]ethoxy]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1OCCN1CCC(C=2C3=CC=CC=C3N(CC3CC3)C=2)CC1 KBRRQKNQGRVNGK-UHFFFAOYSA-N 0.000 claims description 2
• VTWFKEXRCDULPU-UHFFFAOYSA-N 2-[4-[3-[4-[1-(3-methylbutyl)indol-3-yl]piperidin-1-yl]propoxy]phenyl]acetic acid Chemical compound C12=CC=CC=C2N(CCC(C)C)C=C1C(CC1)CCN1CCCOC1=CC=C(CC(O)=O)C=C1 VTWFKEXRCDULPU-UHFFFAOYSA-N 0.000 claims description 2
• DXTGTULLPMCNRT-UHFFFAOYSA-N 2-[4-[3-[4-[1-(cyclopropylmethyl)indol-3-yl]piperidin-1-yl]propoxy]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1OCCCN1CCC(C=2C3=CC=CC=C3N(CC3CC3)C=2)CC1 DXTGTULLPMCNRT-UHFFFAOYSA-N 0.000 claims description 2
• LTDFGOPQQANPNG-UHFFFAOYSA-N 2-[4-[4-[4-[1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]butanoyl]phenyl]-2-methylpropanoic acid Chemical compound C12=CC=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCCC(=O)C1=CC=C(C(C)(C)C(O)=O)C=C1 LTDFGOPQQANPNG-UHFFFAOYSA-N 0.000 claims description 2
• MBKSDCJSGRTHKE-UHFFFAOYSA-N 2-[4-[4-[4-[1-(cyclopropylmethyl)indol-3-yl]piperidin-1-yl]butanoyl]phenyl]-2-methylpropanoic acid Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(=O)CCCN1CCC(C=2C3=CC=CC=C3N(CC3CC3)C=2)CC1 MBKSDCJSGRTHKE-UHFFFAOYSA-N 0.000 claims description 2
• XFWCYOUPAMWZIT-UHFFFAOYSA-N 2-[4-[4-[4-[1-[(4-fluorophenyl)methyl]indol-3-yl]piperidin-1-yl]-1-hydroxybutyl]phenyl]-2-methylpropanoic acid Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C=2C3=CC=CC=C3N(CC=3C=CC(F)=CC=3)C=2)CC1 XFWCYOUPAMWZIT-UHFFFAOYSA-N 0.000 claims description 2
• ZIXKCKFYIITNOA-UHFFFAOYSA-N 2-methyl-2-[4-[2-[4-[1-(3-methylbutyl)indol-3-yl]piperidin-1-yl]ethyl]phenyl]propanoic acid Chemical compound C12=CC=CC=C2N(CCC(C)C)C=C1C(CC1)CCN1CCC1=CC=C(C(C)(C)C(O)=O)C=C1 ZIXKCKFYIITNOA-UHFFFAOYSA-N 0.000 claims description 2
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• VDNIYYAUQYHPBV-UHFFFAOYSA-N 3,5-dibromo-2-[2-[4-[1-(2-ethoxyethyl)-5-methoxyindol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=CC(OC)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=C(Br)C=C(Br)C=C1C(O)=O VDNIYYAUQYHPBV-UHFFFAOYSA-N 0.000 claims description 2
• XQWHUXXNURFZIU-UHFFFAOYSA-N 3,5-dibromo-2-[2-[4-[1-(2-ethoxyethyl)-6-fluoroindol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=CC=C(F)C=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=C(Br)C=C(Br)C=C1C(O)=O XQWHUXXNURFZIU-UHFFFAOYSA-N 0.000 claims description 2
• FAWAGJVGOIPRSX-UHFFFAOYSA-N 3,5-dibromo-2-[2-[4-[1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=CC=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=C(Br)C=C(Br)C=C1C(O)=O FAWAGJVGOIPRSX-UHFFFAOYSA-N 0.000 claims description 2
• ATXRPHCEPHCREN-UHFFFAOYSA-N 3,5-dibromo-2-[2-[4-[5-bromo-1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=CC(Br)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=C(Br)C=C(Br)C=C1C(O)=O ATXRPHCEPHCREN-UHFFFAOYSA-N 0.000 claims description 2
• QWEBBOUXWRCKQN-UHFFFAOYSA-N 3-[3-[4-[1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]propoxy]propanoic acid Chemical compound C12=CC=CC=C2N(CCOCC)C=C1C1CCN(CCCOCCC(O)=O)CC1 QWEBBOUXWRCKQN-UHFFFAOYSA-N 0.000 claims description 2
• 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 2
• 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 2
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• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
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• 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 claims description 2
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• 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000006229 isopropoxyethyl group Chemical group [H]C([H])([H])C([H])(OC([H])([H])C([H])([H])*)C([H])([H])[H] 0.000 claims description 2
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
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• 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 2
• 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 2
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims 1
• HHITYXUJELSBPS-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)-4-fluoroindol-3-yl]piperidin-1-yl]ethoxy]-4-methoxybenzoic acid Chemical compound C12=C(F)C=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC(OC)=CC=C1C(O)=O HHITYXUJELSBPS-UHFFFAOYSA-N 0.000 claims 1
• WYMUGVSTXZEYIJ-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)-5-methoxyindol-3-yl]piperidin-1-yl]ethoxy]-6-fluorobenzoic acid Chemical compound C12=CC(OC)=CC=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=CC=CC(F)=C1C(O)=O WYMUGVSTXZEYIJ-UHFFFAOYSA-N 0.000 claims 1
• OBUAFUJPNYUMEW-UHFFFAOYSA-N 2-[2-[4-[1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethylsulfanyl]acetic acid Chemical compound C12=CC=CC=C2N(CCOCC)C=C1C1CCN(CCSCC(O)=O)CC1 OBUAFUJPNYUMEW-UHFFFAOYSA-N 0.000 claims 1
• VPOOFOBSBKIDGC-UHFFFAOYSA-N 3,5-dibromo-2-[2-[4-[7-bromo-1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C12=CC=CC(Br)=C2N(CCOCC)C=C1C(CC1)CCN1CCOC1=C(Br)C=C(Br)C=C1C(O)=O VPOOFOBSBKIDGC-UHFFFAOYSA-N 0.000 claims 1
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• UFSQXEDNTIJGMA-UHFFFAOYSA-N 3-[4-[2-[4-[1-[2-(2-methoxyethoxy)ethyl]indol-3-yl]piperidin-1-yl]ethyl]phenyl]propanoic acid;4-[4-(1-pentylindol-3-yl)piperidin-1-yl]butanoic acid Chemical compound C12=CC=CC=C2N(CCCCC)C=C1C1CCN(CCCC(O)=O)CC1.C12=CC=CC=C2N(CCOCCOC)C=C1C(CC1)CCN1CCC1=CC=C(CCC(O)=O)C=C1 UFSQXEDNTIJGMA-UHFFFAOYSA-N 0.000 claims 1
• UCBOXYPDTNDQOX-UHFFFAOYSA-N 4-[3-[4-[1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]propoxy]benzoic acid 4-[3-[4-[1-[2-(2-methoxyethoxy)ethyl]indol-3-yl]piperidin-1-yl]propoxy]benzoic acid Chemical compound CCOCCn1cc(C2CCN(CCCOc3ccc(cc3)C(O)=O)CC2)c2ccccc12.COCCOCCn1cc(C2CCN(CCCOc3ccc(cc3)C(O)=O)CC2)c2ccccc12 UCBOXYPDTNDQOX-UHFFFAOYSA-N 0.000 claims 1
• UZLXEGUTODDCEO-UHFFFAOYSA-N 5-[[4-[1-(2-ethoxyethyl)indol-3-yl]piperidin-1-yl]methyl]furan-2-carboxylic acid;5-[[4-[1-[(4-fluorophenyl)methyl]indol-3-yl]piperidin-1-yl]methyl]furan-2-carboxylic acid Chemical compound C12=CC=CC=C2N(CCOCC)C=C1C(CC1)CCN1CC1=CC=C(C(O)=O)O1.O1C(C(=O)O)=CC=C1CN1CCC(C=2C3=CC=CC=C3N(CC=3C=CC(F)=CC=3)C=2)CC1 UZLXEGUTODDCEO-UHFFFAOYSA-N 0.000 claims 1
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• RISXHQOWLNWCBC-UHFFFAOYSA-N C(CCCC)N1C=C(C2=CC=CC=C12)C1CCN(CC1)CC=1C=C(C(=O)O)C=CC1.C1(CC1)CN1C=C(C2=CC=CC=C12)C1CCN(CC1)CCOC=1C=C(C=CC1)CC(=O)O Chemical compound C(CCCC)N1C=C(C2=CC=CC=C12)C1CCN(CC1)CC=1C=C(C(=O)O)C=CC1.C1(CC1)CN1C=C(C2=CC=CC=C12)C1CCN(CC1)CCOC=1C=C(C=CC1)CC(=O)O RISXHQOWLNWCBC-UHFFFAOYSA-N 0.000 claims 1
• GGHYRNXJUKNCRV-UHFFFAOYSA-N C(CCCC)N1C=C(C2=CC=CC=C12)C1CCN(CC1)CCOC1=C(C(=O)O)C=CC=C1.FC1=CC=C(CN2C=C(C3=CC=CC=C23)C2CCN(CC2)CCOC2=C(C(=O)O)C=CC=C2)C=C1 Chemical compound C(CCCC)N1C=C(C2=CC=CC=C12)C1CCN(CC1)CCOC1=C(C(=O)O)C=CC=C1.FC1=CC=C(CN2C=C(C3=CC=CC=C23)C2CCN(CC2)CCOC2=C(C(=O)O)C=CC=C2)C=C1 GGHYRNXJUKNCRV-UHFFFAOYSA-N 0.000 claims 1
• JZGFMQRGBPIPMW-UHFFFAOYSA-N C1(CCCCC1)CN1C=C(C2=CC=CC=C12)C1CCN(CC1)CCOC1=C(C(=O)O)C=CC=C1.C1(CC1)CN1C=C(C2=CC=CC=C12)C1CCN(CC1)CCCOC=1C=C(C(=O)O)C=CC1 Chemical compound C1(CCCCC1)CN1C=C(C2=CC=CC=C12)C1CCN(CC1)CCOC1=C(C(=O)O)C=CC=C1.C1(CC1)CN1C=C(C2=CC=CC=C12)C1CCN(CC1)CCCOC=1C=C(C(=O)O)C=CC1 JZGFMQRGBPIPMW-UHFFFAOYSA-N 0.000 claims 1
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
• UPMSNTQYMTUNQH-UHFFFAOYSA-N FC1=CC=C(CN2C=C(C3=CC=CC=C23)C2CCN(CC2)CCCOC=2C=C(C(=O)O)C=CC2)C=C1.C(C)OCCN1C=C(C2=CC=CC=C12)C1CCN(CC1)CCCC(=O)O Chemical compound FC1=CC=C(CN2C=C(C3=CC=CC=C23)C2CCN(CC2)CCCOC=2C=C(C(=O)O)C=CC2)C=C1.C(C)OCCN1C=C(C2=CC=CC=C12)C1CCN(CC1)CCCC(=O)O UPMSNTQYMTUNQH-UHFFFAOYSA-N 0.000 claims 1
• DVTVOFCOWDDUMS-UHFFFAOYSA-N N1C=C(C2=CC=CC=C12)C1CCN(CC1)CCCC(=O)C1=CC=C(C=C1)C(C(=O)O)(C)C.N1C=C(C2=CC=CC=C12)C1CCN(CC1)CCC1=CC=C(C=C1)C(C(=O)O)(C)C Chemical compound N1C=C(C2=CC=CC=C12)C1CCN(CC1)CCCC(=O)C1=CC=C(C=C1)C(C(=O)O)(C)C.N1C=C(C2=CC=CC=C12)C1CCN(CC1)CCC1=CC=C(C=C1)C(C(=O)O)(C)C DVTVOFCOWDDUMS-UHFFFAOYSA-N 0.000 claims 1
• TVXBUQQKESWDKN-UHFFFAOYSA-N N1C=C(C2=CC=CC=C12)C1CCN(CC1)CCOC1=CC=C(C=C1)CC(=O)O.N1C=C(C2=CC=CC=C12)C1CCN(CC1)CCCOC=1C=C(C=CC1)CC(=O)O Chemical compound N1C=C(C2=CC=CC=C12)C1CCN(CC1)CCOC1=CC=C(C=C1)CC(=O)O.N1C=C(C2=CC=CC=C12)C1CCN(CC1)CCCOC=1C=C(C=CC1)CC(=O)O TVXBUQQKESWDKN-UHFFFAOYSA-N 0.000 claims 1
• SUYWGFCLISUEHA-UHFFFAOYSA-N N1N=NN=C1C=1C=C(OCCCN2CCC(CC2)C2=CNC3=CC=CC=C23)C=CC1.N1C=C(C2=CC=CC=C12)C1CCN(CC1)CCCOC1=CC=C(C=C1)CC(=O)O Chemical compound N1N=NN=C1C=1C=C(OCCCN2CCC(CC2)C2=CNC3=CC=CC=C23)C=CC1.N1C=C(C2=CC=CC=C12)C1CCN(CC1)CCCOC1=CC=C(C=C1)CC(=O)O SUYWGFCLISUEHA-UHFFFAOYSA-N 0.000 claims 1
• QEWIQPNBZXSRLH-UHFFFAOYSA-N OC(=O)c1ccccc1OCCN1CCC(CC1)c1cn(CC2CC2)c2cc(F)ccc12.CCCCCCn1cc(C2CCN(CCOc3ccccc3C(O)=O)CC2)c2ccccc12 Chemical compound OC(=O)c1ccccc1OCCN1CCC(CC1)c1cn(CC2CC2)c2cc(F)ccc12.CCCCCCn1cc(C2CCN(CCOc3ccccc3C(O)=O)CC2)c2ccccc12 QEWIQPNBZXSRLH-UHFFFAOYSA-N 0.000 claims 1
• 125000005083 alkoxyalkoxy group Chemical group 0.000 claims 1
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• 150000001540 azides Chemical class 0.000 claims 1
• 125000001246 bromo group Chemical group Br* 0.000 claims 1
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• 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
• 125000004705 ethylthio group Chemical group C(C)S* 0.000 claims 1
• 230000007062 hydrolysis Effects 0.000 claims 1
• 238000006460 hydrolysis reaction Methods 0.000 claims 1
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
• SMNDYUVBFMFKNZ-UHFFFAOYSA-N pyromucic acid Natural products OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 claims 1
• 208000030603 inherited susceptibility to asthma Diseases 0.000 abstract description 5
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• 239000000126 substance Substances 0.000 abstract 1
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• 239000012043 crude product Substances 0.000 description 45
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• 239000000047 product Substances 0.000 description 42
• 239000002904 solvent Substances 0.000 description 42
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• 239000000243 solution Substances 0.000 description 34
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• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
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• 229910000104 sodium hydride Inorganic materials 0.000 description 23
• 238000002844 melting Methods 0.000 description 21
• 230000008018 melting Effects 0.000 description 21
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