JP2006506373A - 医薬アリールエタノールアミン化合物 - Google Patents

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Publication number

JP2006506373A

JP2006506373A JP2004545914A JP2004545914A JP2006506373A JP 2006506373 A JP2006506373 A JP 2006506373A JP 2004545914 A JP2004545914 A JP 2004545914A JP 2004545914 A JP2004545914 A JP 2004545914A JP 2006506373 A JP2006506373 A JP 2006506373A

Authority

JP

Japan

Prior art keywords

ethyl

benzodioxin

methyl

dihydro

amino

Prior art date

2002-10-22

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.)

Pending

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 245
• 238000000034 method Methods 0.000 claims abstract description 74
• 150000003839 salts Chemical class 0.000 claims abstract description 59
• 239000012453 solvate Substances 0.000 claims abstract description 45
• 238000002360 preparation method Methods 0.000 claims abstract description 12
• 230000002265 prevention Effects 0.000 claims abstract description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
• 230000008569 process Effects 0.000 claims abstract description 4
• 239000000203 mixture Substances 0.000 claims description 86
• -1 SR 14 Chemical compound 0.000 claims description 85
• 125000000217 alkyl group Chemical group 0.000 claims description 70
• 229910052739 hydrogen Inorganic materials 0.000 claims description 62
• 239000001257 hydrogen Substances 0.000 claims description 61
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 42
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 39
• 125000003118 aryl group Chemical group 0.000 claims description 37
• 125000006239 protecting group Chemical group 0.000 claims description 33
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 32
• 229910052757 nitrogen Inorganic materials 0.000 claims description 30
• 150000002431 hydrogen Chemical class 0.000 claims description 27
• PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 claims description 24
• CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 20
• 125000001072 heteroaryl group Chemical group 0.000 claims description 19
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
• 125000003545 alkoxy group Chemical group 0.000 claims description 16
• 229910052736 halogen Inorganic materials 0.000 claims description 15
• 150000002367 halogens Chemical class 0.000 claims description 15
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 14
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 13
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
• 239000000048 adrenergic agonist Substances 0.000 claims description 11
• 229940126157 adrenergic receptor agonist Drugs 0.000 claims description 11
• 239000003814 drug Substances 0.000 claims description 11
• 229920006395 saturated elastomer Polymers 0.000 claims description 10
• 208000024891 symptom Diseases 0.000 claims description 10
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
• 239000003795 chemical substances by application Substances 0.000 claims description 7
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 7
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
• 239000004615 ingredient Substances 0.000 claims description 6
• 230000001225 therapeutic effect Effects 0.000 claims description 6
• 125000004432 carbon atom Chemical group C* 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 4
• LGKNRGURKRQRRL-NOZRDPDXSA-N 4-[(1r)-2-[2-[(3r)-3-[(4-chlorophenyl)methoxymethyl]-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCC=2C=C3O[C@H](COCC=4C=CC(Cl)=CC=4)COC3=CC=2)=C1 LGKNRGURKRQRRL-NOZRDPDXSA-N 0.000 claims description 4
• WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 claims description 4
• RJSOFPFJWDXFOG-RDGATRHJSA-N n-[2-hydroxy-5-[(1r)-1-hydroxy-2-[2-[(3r)-3-(phenylmethoxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]ethyl]phenyl]formamide Chemical compound C([C@@H]1COC2=CC=C(C=C2O1)CCNC[C@H](O)C=1C=C(NC=O)C(O)=CC=1)OCC1=CC=CC=C1 RJSOFPFJWDXFOG-RDGATRHJSA-N 0.000 claims description 4
• TVAKVBAPSAPQNU-RDGATRHJSA-N n-[2-hydroxy-5-[(1r)-1-hydroxy-2-[2-[(3r)-3-(phenylmethoxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]ethyl]phenyl]methanesulfonamide Chemical compound C1=C(O)C(NS(=O)(=O)C)=CC([C@@H](O)CNCCC=2C=C3O[C@H](COCC=4C=CC=CC=4)COC3=CC=2)=C1 TVAKVBAPSAPQNU-RDGATRHJSA-N 0.000 claims description 4
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• 125000001424 substituent group Chemical group 0.000 claims description 4
• GNOUEFPUIBRVPP-NLFFAJNJSA-N 4-[(1r)-2-[2-[(3r)-3-[(2,6-dichlorophenyl)methoxymethyl]-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCC=2C=C3O[C@H](COCC=4C(=CC=CC=4Cl)Cl)COC3=CC=2)=C1 GNOUEFPUIBRVPP-NLFFAJNJSA-N 0.000 claims description 3
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
• 241000124008 Mammalia Species 0.000 claims description 3
• 125000001624 naphthyl group Chemical group 0.000 claims description 3
• IWSPKHYWOOYAOU-OFNKIYASSA-N (1r)-1-(4-amino-3,5-dichlorophenyl)-2-[2-[(3r)-3-(phenylmethoxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]ethanol Chemical compound C1=C(Cl)C(N)=C(Cl)C=C1[C@@H](O)CNCCC1=CC=C(OC[C@@H](COCC=2C=CC=CC=2)O2)C2=C1 IWSPKHYWOOYAOU-OFNKIYASSA-N 0.000 claims description 2
• 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims description 2
• VSVNCOSQAVVWAE-YMINUMGASA-N 2-(hydroxymethyl)-4-[(1r)-1-hydroxy-2-[2-[(3r)-3-(1-phenylethoxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]ethyl]phenol Chemical compound C1([C@@H](O)CNCCC2=CC=C3OC[C@H](OC3=C2)COC(C)C=2C=CC=CC=2)=CC=C(O)C(CO)=C1 VSVNCOSQAVVWAE-YMINUMGASA-N 0.000 claims description 2
• KAHONMCTSMKOLY-NOZRDPDXSA-N 2-(hydroxymethyl)-4-[(1r)-1-hydroxy-2-[2-[(3r)-3-(phenylmethoxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]ethyl]phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCC=2C=C3O[C@H](COCC=4C=CC=CC=4)COC3=CC=2)=C1 KAHONMCTSMKOLY-NOZRDPDXSA-N 0.000 claims description 2
• OPSQZFXQIFFMMQ-VWNXMTODSA-N 2-(hydroxymethyl)-4-[(1r)-1-hydroxy-2-[2-[(3r)-3-(pyridin-3-ylmethoxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]ethyl]phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCC=2C=C3O[C@H](COCC=4C=NC=CC=4)COC3=CC=2)=C1 OPSQZFXQIFFMMQ-VWNXMTODSA-N 0.000 claims description 2
• DTORYSDPBVKPCI-BVAGGSTKSA-N 2-(hydroxymethyl)-4-[(1r)-1-hydroxy-2-[2-[(3r)-3-[(3-methylsulfonylphenyl)methoxymethyl]-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]ethyl]phenol Chemical compound CS(=O)(=O)C1=CC=CC(COC[C@H]2OC3=CC(CCNC[C@H](O)C=4C=C(CO)C(O)=CC=4)=CC=C3OC2)=C1 DTORYSDPBVKPCI-BVAGGSTKSA-N 0.000 claims description 2
• GXQPBAUTCSQSIT-IMDOIRSXSA-N 2-(hydroxymethyl)-4-[(1r)-1-hydroxy-2-[2-[(3r)-3-[[5-(4-methylsulfinylphenyl)pyridin-3-yl]methoxymethyl]-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]ethyl]phenol Chemical compound C1=CC(S(=O)C)=CC=C1C1=CN=CC(COC[C@H]2OC3=CC(CCNC[C@H](O)C=4C=C(CO)C(O)=CC=4)=CC=C3OC2)=C1 GXQPBAUTCSQSIT-IMDOIRSXSA-N 0.000 claims description 2
• KAHONMCTSMKOLY-ZCYQVOJMSA-N 2-(hydroxymethyl)-4-[(1r)-1-hydroxy-2-[2-[(3s)-3-(phenylmethoxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]ethyl]phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCC=2C=C3O[C@@H](COCC=4C=CC=CC=4)COC3=CC=2)=C1 KAHONMCTSMKOLY-ZCYQVOJMSA-N 0.000 claims description 2
• GVIFLLPHLPIVLU-YNMFNDETSA-N 2-(hydroxymethyl)-4-[(1r)-1-hydroxy-2-[2-[2-(phenylmethoxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]ethyl]phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCC=2C=C3OCC(COCC=4C=CC=CC=4)OC3=CC=2)=C1 GVIFLLPHLPIVLU-YNMFNDETSA-N 0.000 claims description 2
• UOYZKGZGKHEACD-QPPBQGQZSA-N 2-fluoro-4-[(1r)-1-hydroxy-2-[2-[(3r)-3-(phenylmethoxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]ethyl]phenol Chemical compound C([C@@H]1COC2=CC=C(C=C2O1)CCNC[C@H](O)C=1C=C(F)C(O)=CC=1)OCC1=CC=CC=C1 UOYZKGZGKHEACD-QPPBQGQZSA-N 0.000 claims description 2
• ZGYJBLHKCAJDIX-RSXGOPAZSA-N 3-[[(3r)-6-[2-[[(2r)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]ethyl]-2,3-dihydro-1,4-benzodioxin-3-yl]methoxymethyl]benzonitrile Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCC=2C=C3O[C@H](COCC=4C=C(C=CC=4)C#N)COC3=CC=2)=C1 ZGYJBLHKCAJDIX-RSXGOPAZSA-N 0.000 claims description 2
• BQPPGLWIIUGNKB-NOZRDPDXSA-N 4-[(1r)-1-hydroxy-2-[2-[(3r)-3-(phenylmethoxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]ethyl]-3-methylphenol Chemical compound CC1=CC(O)=CC=C1[C@@H](O)CNCCC1=CC=C(OC[C@@H](COCC=2C=CC=CC=2)O2)C2=C1 BQPPGLWIIUGNKB-NOZRDPDXSA-N 0.000 claims description 2
• XVFVDBAZXYZAKW-IRLDBZIGSA-N 4-[(1r)-2-[2-[(3r)-3-[(2,6-dichloropyridin-3-yl)methoxymethyl]-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCC=2C=C3O[C@H](COCC=4C(=NC(Cl)=CC=4)Cl)COC3=CC=2)=C1 XVFVDBAZXYZAKW-IRLDBZIGSA-N 0.000 claims description 2
• UCXYWNVJHMRWEP-VPUSJEBWSA-N 4-[(1r)-2-[2-[(3r)-3-[(3,5-dimethylphenyl)methoxymethyl]-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol Chemical compound CC1=CC(C)=CC(COC[C@H]2OC3=CC(CCNC[C@H](O)C=4C=C(CO)C(O)=CC=4)=CC=C3OC2)=C1 UCXYWNVJHMRWEP-VPUSJEBWSA-N 0.000 claims description 2
• VQGKMDUXRXRKAR-VIZCGCQYSA-N 4-[(1r)-2-[2-[(3r)-3-[(3-cyclopentylsulfanylphenyl)methoxymethyl]-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCC=2C=C3O[C@H](COCC=4C=C(SC5CCCC5)C=CC=4)COC3=CC=2)=C1 VQGKMDUXRXRKAR-VIZCGCQYSA-N 0.000 claims description 2
• UYFAWFCRMQTTTL-VIZCGCQYSA-N 4-[(1r)-2-[2-[(3r)-3-[(3-cyclopentylsulfonylphenyl)methoxymethyl]-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCC=2C=C3O[C@H](COCC=4C=C(C=CC=4)S(=O)(=O)C4CCCC4)COC3=CC=2)=C1 UYFAWFCRMQTTTL-VIZCGCQYSA-N 0.000 claims description 2
• XEYZFUOKQKMSPH-NOZRDPDXSA-N 4-[(1r)-2-[2-[(3r)-3-[(4-fluorophenyl)methoxymethyl]-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCC=2C=C3O[C@H](COCC=4C=CC(F)=CC=4)COC3=CC=2)=C1 XEYZFUOKQKMSPH-NOZRDPDXSA-N 0.000 claims description 2
• YHSXTPIFVQCNAA-VWNXMTODSA-N 4-[(1r)-2-[2-[(3r)-3-[(5-bromopyridin-3-yl)methoxymethyl]-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCC=2C=C3O[C@H](COCC=4C=C(Br)C=NC=4)COC3=CC=2)=C1 YHSXTPIFVQCNAA-VWNXMTODSA-N 0.000 claims description 2
• FIADYWSJYQQBIO-GGAORHGYSA-N 4-[(1r)-2-[2-[(3r)-3-[(6-chloropyridin-3-yl)methoxymethyl]-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCC=2C=C3O[C@H](COCC=4C=NC(Cl)=CC=4)COC3=CC=2)=C1 FIADYWSJYQQBIO-GGAORHGYSA-N 0.000 claims description 2
• QBLMBMNXROVXHL-AMGIVPHBSA-N 4-[(1r)-2-[2-[(3r)-3-[3-(2,6-dichlorophenyl)propoxymethyl]-2,3-dihydro-1,4-benzodioxin-6-yl]ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCC=2C=C3O[C@H](COCCCC=4C(=CC=CC=4Cl)Cl)COC3=CC=2)=C1 QBLMBMNXROVXHL-AMGIVPHBSA-N 0.000 claims description 2
• KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 2
• WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical group C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 2
• RFGYBENEOUTBJN-NOZRDPDXSA-N [3-[[(3r)-6-[2-[[(2r)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]ethyl]-2,3-dihydro-1,4-benzodioxin-3-yl]methoxymethyl]phenyl]urea Chemical compound NC(=O)NC1=CC=CC(COC[C@H]2OC3=CC(CCNC[C@H](O)C=4C=C(CO)C(O)=CC=4)=CC=C3OC2)=C1 RFGYBENEOUTBJN-NOZRDPDXSA-N 0.000 claims description 2
• 125000004104 aryloxy group Chemical group 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 125000000623 heterocyclic group Chemical group 0.000 claims description 2
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
• COWNFYYYZFRNOY-UHFFFAOYSA-N oxazolidinedione Chemical compound O=C1COC(=O)N1 COWNFYYYZFRNOY-UHFFFAOYSA-N 0.000 claims description 2
• 125000000160 oxazolidinyl group Chemical group 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims 9
• ZJRBRKUGRKKZOO-UHFFFAOYSA-N 2-(hydroxymethyl)pyridin-3-ol Chemical compound OCC1=NC=CC=C1O ZJRBRKUGRKKZOO-UHFFFAOYSA-N 0.000 claims 1
• 230000002152 alkylating effect Effects 0.000 claims 1
• 238000013160 medical therapy Methods 0.000 claims 1
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 13
• 201000010099 disease Diseases 0.000 abstract description 6
• 230000000241 respiratory effect Effects 0.000 abstract 1
• 238000002560 therapeutic procedure Methods 0.000 abstract 1
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 109
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 83
• 239000000243 solution Substances 0.000 description 66
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 63
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 62
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 52
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
• 239000002904 solvent Substances 0.000 description 42
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 41
• 239000002253 acid Substances 0.000 description 38
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
• 239000000377 silicon dioxide Substances 0.000 description 35
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 34
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
• 235000019439 ethyl acetate Nutrition 0.000 description 30
• 239000011541 reaction mixture Substances 0.000 description 27
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 26
• 239000000284 extract Substances 0.000 description 24
• 239000011734 sodium Substances 0.000 description 24
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 22
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
• 238000006243 chemical reaction Methods 0.000 description 19
• 238000009472 formulation Methods 0.000 description 18
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
• 239000003921 oil Substances 0.000 description 17
• 239000002585 base Substances 0.000 description 16
• 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 15
• 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 15
• 239000004480 active ingredient Substances 0.000 description 14
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 13
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
• 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 11
• 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 11
• 238000004587 chromatography analysis Methods 0.000 description 11
• 125000005843 halogen group Chemical group 0.000 description 11
• MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 10
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 10
• 239000012267 brine Substances 0.000 description 10
• 238000004440 column chromatography Methods 0.000 description 10
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 10
• 102000005962 receptors Human genes 0.000 description 10
• 108020003175 receptors Proteins 0.000 description 10
• HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 10
• 229950005741 rolipram Drugs 0.000 description 10
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
• 239000005557 antagonist Substances 0.000 description 9
• 210000004027 cell Anatomy 0.000 description 9
• WACQKHWOTAEEFS-UHFFFAOYSA-N cyclohexane;ethyl acetate Chemical compound CCOC(C)=O.C1CCCCC1 WACQKHWOTAEEFS-UHFFFAOYSA-N 0.000 description 9
• 150000002148 esters Chemical class 0.000 description 9
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