JPH10513158A - エンドセリンアンタゴニストとしての置換されたフェニル化合物 - Google Patents
エンドセリンアンタゴニストとしての置換されたフェニル化合物Info
- Publication number
- JPH10513158A JPH10513158A JP8522708A JP52270896A JPH10513158A JP H10513158 A JPH10513158 A JP H10513158A JP 8522708 A JP8522708 A JP 8522708A JP 52270896 A JP52270896 A JP 52270896A JP H10513158 A JPH10513158 A JP H10513158A
- Authority
- JP
- Japan
- Prior art keywords
- acetic acid
- cyano
- phenoxy
- methylphenyl
- mixture
- 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.)
- Granted
Links
- 108050009340 Endothelin Proteins 0.000 title claims description 56
- 102000002045 Endothelin Human genes 0.000 title claims description 56
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 title claims description 55
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims description 14
- 239000005557 antagonist Substances 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 305
- 150000003839 salts Chemical class 0.000 claims abstract description 64
- 239000002253 acid Substances 0.000 claims abstract description 54
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 28
- 125000003118 aryl group Chemical group 0.000 claims abstract description 20
- 239000000651 prodrug Substances 0.000 claims abstract description 13
- 229940002612 prodrug Drugs 0.000 claims abstract description 13
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 239000001301 oxygen Substances 0.000 claims abstract description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052717 sulfur Chemical group 0.000 claims abstract description 5
- 239000011593 sulfur Chemical group 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 225
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 186
- -1 aryl-lower Kirthio Chemical group 0.000 claims description 183
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 58
- 238000000034 method Methods 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 17
- APLORBWHYKOKCO-UHFFFAOYSA-N 2-[(2-methylphenyl)-(2h-tetrazol-5-yl)methoxy]-4-(pyridin-4-ylmethoxy)benzonitrile Chemical compound CC1=CC=CC=C1C(C1=NNN=N1)OC1=CC(OCC=2C=CN=CC=2)=CC=C1C#N APLORBWHYKOKCO-UHFFFAOYSA-N 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- KUSKJEWEPSLVPY-UHFFFAOYSA-N 2-[2-cyano-5-(pyridin-4-ylmethoxy)phenoxy]-2-(2-methylphenyl)acetic acid Chemical compound CC1=CC=CC=C1C(C(O)=O)OC1=CC(OCC=2C=CN=CC=2)=CC=C1C#N KUSKJEWEPSLVPY-UHFFFAOYSA-N 0.000 claims description 8
- 150000001204 N-oxides Chemical class 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 150000004677 hydrates Chemical class 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- PWFARXSGRUQKRX-QHCPKHFHSA-N (2s)-2-[5-(1,3-benzodioxol-5-ylmethoxy)-2-cyanophenoxy]-2-(2-methylphenyl)acetic acid Chemical compound CC1=CC=CC=C1[C@@H](C(O)=O)OC1=CC(OCC=2C=C3OCOC3=CC=2)=CC=C1C#N PWFARXSGRUQKRX-QHCPKHFHSA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- TZCSIHYODNZXAN-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-[2-cyano-3-fluoro-5-(pyridin-4-ylmethoxy)phenoxy]acetic acid Chemical compound C=1C=CC=C(Cl)C=1C(C(=O)O)OC(C(=C(F)C=1)C#N)=CC=1OCC1=CC=NC=C1 TZCSIHYODNZXAN-UHFFFAOYSA-N 0.000 claims description 3
- QRFDQAOGOMZTKQ-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-[2-cyano-3-fluoro-5-(thiophen-3-ylmethoxy)phenoxy]acetic acid Chemical compound C=1C=CC=C(Cl)C=1C(C(=O)O)OC(C(=C(F)C=1)C#N)=CC=1OCC=1C=CSC=1 QRFDQAOGOMZTKQ-UHFFFAOYSA-N 0.000 claims description 3
- UVFWKUJETWVIOR-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-[2-cyano-5-(1,2-thiazol-4-ylmethoxy)phenoxy]acetic acid Chemical compound C=1C=CC=C(Cl)C=1C(C(=O)O)OC(C(=CC=1)C#N)=CC=1OCC=1C=NSC=1 UVFWKUJETWVIOR-UHFFFAOYSA-N 0.000 claims description 3
- MCLHLEYBESOJIH-UHFFFAOYSA-N 2-[(2-chlorophenyl)-(2h-tetrazol-5-yl)methoxy]-4-(pyridin-4-ylmethoxy)benzonitrile Chemical compound ClC1=CC=CC=C1C(C1=NNN=N1)OC1=CC(OCC=2C=CN=CC=2)=CC=C1C#N MCLHLEYBESOJIH-UHFFFAOYSA-N 0.000 claims description 3
- ZOHQPXPUZCOPSH-UHFFFAOYSA-N 2-[2-cyano-5-(furan-3-ylmethoxy)phenoxy]-2-(2-methylphenyl)acetic acid Chemical compound CC1=CC=CC=C1C(C(O)=O)OC1=CC(OCC2=COC=C2)=CC=C1C#N ZOHQPXPUZCOPSH-UHFFFAOYSA-N 0.000 claims description 3
- BTNZSRJALSENFA-UHFFFAOYSA-N 2-[2-cyano-5-(pyridin-3-ylmethoxy)phenoxy]-2-phenylacetic acid Chemical compound C=1C=CC=CC=1C(C(=O)O)OC(C(=CC=1)C#N)=CC=1OCC1=CC=CN=C1 BTNZSRJALSENFA-UHFFFAOYSA-N 0.000 claims description 3
- IUJPCCWWYKTZCX-UHFFFAOYSA-N 2-[2-cyano-5-(thiophen-3-ylmethoxy)phenoxy]-2-(2-fluorophenyl)acetic acid Chemical compound C=1C=CC=C(F)C=1C(C(=O)O)OC(C(=CC=1)C#N)=CC=1OCC=1C=CSC=1 IUJPCCWWYKTZCX-UHFFFAOYSA-N 0.000 claims description 3
- LGTPDJNKVKGRTG-UHFFFAOYSA-N 2-[2-cyano-5-(thiophen-3-ylmethoxy)phenoxy]-2-(2-methylphenyl)acetic acid Chemical compound CC1=CC=CC=C1C(C(O)=O)OC1=CC(OCC2=CSC=C2)=CC=C1C#N LGTPDJNKVKGRTG-UHFFFAOYSA-N 0.000 claims description 3
- DOBAMTNAGGMTSB-UHFFFAOYSA-N 2-[2-cyano-5-(thiophen-3-ylmethoxy)phenoxy]-2-[2-(trifluoromethyl)phenyl]acetic acid Chemical compound C=1C=CC=C(C(F)(F)F)C=1C(C(=O)O)OC(C(=CC=1)C#N)=CC=1OCC=1C=CSC=1 DOBAMTNAGGMTSB-UHFFFAOYSA-N 0.000 claims description 3
- AXRWHVQKSIEFTF-UHFFFAOYSA-N 2-[2-cyano-5-(thiophen-3-ylmethoxy)phenoxy]-2-phenylacetic acid Chemical compound C=1C=CC=CC=1C(C(=O)O)OC(C(=CC=1)C#N)=CC=1OCC=1C=CSC=1 AXRWHVQKSIEFTF-UHFFFAOYSA-N 0.000 claims description 3
- WAJLYZFNIUWBKI-UHFFFAOYSA-N 2-[5-(1,3-benzoxazol-6-ylmethoxy)-2-cyano-3-fluorophenoxy]-2-(2-methylphenyl)acetic acid Chemical compound CC1=CC=CC=C1C(C(O)=O)OC1=CC(OCC=2C=C3OC=NC3=CC=2)=CC(F)=C1C#N WAJLYZFNIUWBKI-UHFFFAOYSA-N 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- ANJKWRNGBULYMW-UHFFFAOYSA-N 2-[2-cyano-5-(pyridin-4-ylmethoxy)phenoxy]-2-[2-(trifluoromethyl)phenyl]acetic acid Chemical compound C=1C=CC=C(C(F)(F)F)C=1C(C(=O)O)OC(C(=CC=1)C#N)=CC=1OCC1=CC=NC=C1 ANJKWRNGBULYMW-UHFFFAOYSA-N 0.000 claims description 2
- LFPYTZFMTUTKQN-UHFFFAOYSA-N 2-[2-cyano-5-(pyridin-4-ylmethoxy)phenoxy]-2-phenylacetic acid Chemical compound C=1C=CC=CC=1C(C(=O)O)OC(C(=CC=1)C#N)=CC=1OCC1=CC=NC=C1 LFPYTZFMTUTKQN-UHFFFAOYSA-N 0.000 claims description 2
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 239000000556 agonist Substances 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 230000002785 anti-thrombosis Effects 0.000 claims description 2
- 239000003146 anticoagulant agent Substances 0.000 claims description 2
- 239000003524 antilipemic agent Substances 0.000 claims description 2
- 239000003420 antiserotonin agent Substances 0.000 claims description 2
- 229960004676 antithrombotic agent Drugs 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 102000015005 beta-adrenergic receptor activity proteins Human genes 0.000 claims description 2
- 108040006818 beta-adrenergic receptor activity proteins Proteins 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 239000002934 diuretic Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000002857 endothelin converting enzyme inhibitor Substances 0.000 claims description 2
- 239000003527 fibrinolytic agent Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 claims description 2
- 239000004041 inotropic agent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000000612 proton pump inhibitor Substances 0.000 claims description 2
- 229940126409 proton pump inhibitor Drugs 0.000 claims description 2
- 239000002461 renin inhibitor Substances 0.000 claims description 2
- 229940086526 renin-inhibitors Drugs 0.000 claims description 2
- 239000000952 serotonin receptor agonist Substances 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 229960000103 thrombolytic agent Drugs 0.000 claims description 2
- 239000012190 activator Substances 0.000 claims 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 claims 1
- 102000015427 Angiotensins Human genes 0.000 claims 1
- 108010064733 Angiotensins Proteins 0.000 claims 1
- 229940127291 Calcium channel antagonist Drugs 0.000 claims 1
- 108091006146 Channels Proteins 0.000 claims 1
- 229940122601 Esterase inhibitor Drugs 0.000 claims 1
- 229940122236 Histamine receptor antagonist Drugs 0.000 claims 1
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 claims 1
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 claims 1
- 102000015007 alpha-adrenergic receptor activity proteins Human genes 0.000 claims 1
- 108040006816 alpha-adrenergic receptor activity proteins Proteins 0.000 claims 1
- 239000002416 angiotensin derivative Substances 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 claims 1
- 229940088710 antibiotic agent Drugs 0.000 claims 1
- 239000000739 antihistaminic agent Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 239000000480 calcium channel blocker Substances 0.000 claims 1
- 238000002648 combination therapy Methods 0.000 claims 1
- 229940030606 diuretics Drugs 0.000 claims 1
- 239000002329 esterase inhibitor Substances 0.000 claims 1
- 229940044551 receptor antagonist Drugs 0.000 claims 1
- 239000002464 receptor antagonist Substances 0.000 claims 1
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 1
- 239000002550 vasoactive agent Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- 239000002308 endothelin receptor antagonist Substances 0.000 abstract description 2
- 239000012039 electrophile Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 585
- 239000000243 solution Substances 0.000 description 185
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 185
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 178
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 178
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 146
- 239000007787 solid Substances 0.000 description 145
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 138
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 126
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 124
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
- 239000011541 reaction mixture Substances 0.000 description 94
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 90
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 89
- 235000019341 magnesium sulphate Nutrition 0.000 description 89
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
- 239000000284 extract Substances 0.000 description 81
- 239000000047 product Substances 0.000 description 79
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 68
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 66
- 239000000377 silicon dioxide Substances 0.000 description 62
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 59
- 239000003921 oil Substances 0.000 description 58
- 239000012267 brine Substances 0.000 description 57
- 238000003756 stirring Methods 0.000 description 53
- 229960000583 acetic acid Drugs 0.000 description 49
- 235000019198 oils Nutrition 0.000 description 49
- 238000010992 reflux Methods 0.000 description 49
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 48
- 235000011054 acetic acid Nutrition 0.000 description 48
- 238000000921 elemental analysis Methods 0.000 description 48
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 45
- 238000003818 flash chromatography Methods 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- 239000012074 organic phase Substances 0.000 description 37
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 33
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 33
- 229910000027 potassium carbonate Inorganic materials 0.000 description 33
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 33
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 29
- 239000012312 sodium hydride Substances 0.000 description 29
- 229910000104 sodium hydride Inorganic materials 0.000 description 29
- 239000002480 mineral oil Substances 0.000 description 28
- 235000010446 mineral oil Nutrition 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 239000006185 dispersion Substances 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000010410 layer Substances 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- 239000008346 aqueous phase Substances 0.000 description 19
- 238000004587 chromatography analysis Methods 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- 239000011734 sodium Substances 0.000 description 18
- 239000011780 sodium chloride Substances 0.000 description 18
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 17
- 239000002585 base Substances 0.000 description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
- 229910052708 sodium Inorganic materials 0.000 description 17
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 16
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- 102400000686 Endothelin-1 Human genes 0.000 description 12
- 101800004490 Endothelin-1 Proteins 0.000 description 12
- KWGRBVOPPLSCSI-WPRPVWTQSA-N L-Ephedrine Natural products CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
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- ZHNFLHYOFXQIOW-LPYZJUEESA-N quinine sulfate dihydrate Chemical compound [H+].[H+].O.O.[O-]S([O-])(=O)=O.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 ZHNFLHYOFXQIOW-LPYZJUEESA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 description 1
- 229910052911 sodium silicate Inorganic materials 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000003883 substance clean up Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid group Chemical class S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 239000003848 thrombocyte activating factor antagonist Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- UMFCIIBZHQXRCJ-NSCUHMNNSA-N trans-anol Chemical compound C\C=C\C1=CC=C(O)C=C1 UMFCIIBZHQXRCJ-NSCUHMNNSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000012855 volatile organic compound Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/12—Radicals substituted by oxygen atoms
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/54—Radicals substituted by oxygen atoms
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D411/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1. 式(I) 式中、 R1は、CN、CH2CN、CH=CHCN、CHO、またはCH=CHCO2 Hであり、 R2は、アリール及びヘテロアリール部分の各々が場合によっては置換される 、アリール低級アルコキシ、ヘテロアリール低級アルコキシ、アリール低級アル キルチオ、またはヘテロアリール低級アルキルチオであり、 R3は、ハロゲンであり、 R4は、場合によっては置換されたアリールまたは場合によっては置換された ヘテロアリールであり、 R5は、カルボキシまたは酸同配体であり、 Xは、酸素または硫黄であり、そして nは、0または1である、の化合物並びにこれらのN−酸化物及びプロドラッ グ、並びにこれらの製薬学的に許容できる塩。 2. R1が環の2位で結合される、請求の範囲1に記載の化合物。 3. R2が環の5位で結合される、請求の範囲1または2に記載の化合物。 4. R3が環の3位で結合される、先行するいずれかの請求の範囲に記載の化 合物。 5. 式(Ia) 式中、R1、R2、R3、R4、R5、n、及びXは、請求の範囲1において定義さ れたとおりである、の化合物並びにこれらのN−酸化物及びプロドラッグ、並び にこれらの製薬学的に許容できる塩。 6. R1がCNである、先行するいずれかの請求の範囲に記載の化合物。 7. R2がヘテロアリール低級アルコキシである、先行するいずれかの請求の 範囲に記載の化合物。 8. R2がヘテロアリールメトキシである、請求の範囲7に記載の化合物。 9. R4が場合によっては置換されたアリールである、先行するいずれかの請 求の範囲に記載の化合物。 10. R5がカルボキシである、先行するいずれかの請求の範囲に記載の化合 物。 11. Xが酸素である、先行するいずれかの請求の範囲に記載の化合物。 12. 式(Ib) 式中、R2、R3、R4、及びnはあらゆる関係のある先行する請求の範囲におい て定義されたとおりである、の化合物並びにこれらのN−酸化物及びプロドラッ グ、並びにこれらの製薬学的に許容できる塩。 13. R2がピリジルメトキシ、ピリダジニルメトキシ、チエニルメトキシ、 イソチアゾリルメトキシ、または1,3−ベンゾジオキソリルメトキシである、 先行するいずれかの請求の範囲に記載の化合物。 14. R3がフッ素原子である、先行するいずれかの請求の範囲に記載の化合 物。 15. R4が、低級アルキル、CF3、または塩素により、R4部分の残りの部 分へのフェニル基の結合に対してオルトの位置において置換されるフェニルであ り、そして場合によっては一つまたはそれより多いハロゲン、低級アルキル、C N、または低級アルコキシによりさらに置換される、先行するいずれかの請求の 範囲に記載の化合物。 16. 基−X−CHR4R5内の部分Xに対する炭素原子α、または基−O−C HR4CO2H内の酸素原子に対する炭素原子αに関係したキラル中心が(S)配 置を有する、先行するいずれかの請求の範囲に記載の化合物。 17. (RS)−(2−クロロフェニル)−[2−シアノ−5−(4−ピリジ ルメトキシ)フェノキシ]酢酸、 (RS)−[2−シアノ−5−(3−チエニルメトキシ)フェノキシ]−フェニ ル酢酸、 (RS)−(2−クロロフェニル)−[2−シアノ−5−(3−チエニルメトキ シ)フェノキシ]酢酸、 (RS)−[5−(1,3−ベンゾジオキソール−5−イルメトキシ)−2−シ アノフェノキシ]フェニル酢酸、 (RS)−[5−(1,3−ベンゾジオキソール−5−イルメトキシ)−2−シ アノフェノキシ]−(2−トリフルオロメチルフェニル)酢酸、 (RS)−[2−シアノ−5−(3−チエニルメトキシ)フェノキシ]−(2− メチルフェニル)酢酸、 (RS)−[5−(1,3−ベンゾジオキソール−5−イルメトキシ)−2−シ アノフェノキシ]−(2−クロロフェニル)酢酸、 (RS)−(2−ブロモフェニル)−[2−シアノ−5−(3−チエニルメトキ シ)フェノキシ]酢酸、 (RS)−(3−クロロフェニル)−[2−シアノ−5−(3−チエニルメトキ シ)フェノキシ]酢酸、 (R)−(2−クロロフェニル)−[2−シアノ−5−(3−チエニルメトキシ )フェノキシ]酢酸、 (S)−(2−クロロフェニル)−[2−シアノ−5−(3−チエニルメトキシ )フェノキシ]酢酸、 (RS)−[2−シアノ−5−(4−ピリジルメトキシ)フェノキシ]−フェニ ル酢酸、 (RS)−[2−シアノ−5−(3−チエニルメトキシ)フェノキシ]−(2− フルオロフェニル)酢酸、 (RS)−[2−シアノ−5−(4−ピリジルメトキシ)フェノキシ]−(2− メチルフェニル)酢酸、 (RS)−[2−シアノ−5−(3−チエニルメトキシ)フェノキシ]−(2− トリフルオロメチルフェニル)酢酸、 (RS)−(2−ブロモフェニル)−[2−シアノ−5−(4−ピリジルメトキ シ)フェノキシ]酢酸、 (RS)−[2−シアノ−5−(4−ピリジルメトキシ)フェノキシ]−(2− トリフルオロメチルフェニル)酢酸、 (S)−[2−シアノ−5−(4−ピリジルメトキシ)フェノキシ]−(2−メ チルフェニル)酢酸、 (RS)−(2−クロロフェニル)−[2−シアノ−5−(ピリダジン−4−イ ルメトキシ)フェノキシ]酢酸、 (RS)−[5−(1,3−ベンゾジオキソール−5−イルメトキシ)−2−シ アノフェノキシ]−(2−メチルフェニル)酢酸、 (RS)−(2−クロロフェニル)−[2−シアノ−5−(イソチアゾール−4 −イルメトキシ)フェノキシ]酢酸、 (RS)−[2−シアノ−5−(3−ピリジルメトキシ)フェノキシ]フェニル 酢酸、 (RS)−[2−ホルミル−5−(3−チエニルメトキシ)フェノキシ]フェニ ル酢酸、 (RS)−N−{[2−シアノ−5−(3−チエニルメトキシ)フェノキシ]フ ェニルアセチル}−4−イソプロピルベンゼンスルホンアミド、 (RS)−[2−シアノ−5−(4−ピリジルメトキシ)フェノキシ]−(2− メチルフェニル)酢酸、アセトキシメチルエステル、 (RS)−(2−クロロフェニル)−[2−シアノ−3−フルオロ−5−(3− チエニルメトキシ)フェノキシ]酢酸、 (RS)−[5−(ベンゾオキサゾール−6−イルメトキシ)−2−シアノフェ ノキシ]−(2−クロロフェニル)酢酸、 (RS)−[2−シアノ−5−(4−ピリジルメトキシ)フェノキシ]−[2− (3−メチル)チエニル]酢酸、 (RS)−[(2−シアノ−5−(チアゾール−5−イルメトキシ)フェノキシ ]−(2−メチルフェニル)酢酸、 (RS)−(2−クロロフェニル)−[2−シアノ−3−フルオロ−5−(4− ピリジルメトキシ)フェノキシ]酢酸、 (RS)−2−[(2−クロロフェニル)−(1H−テトラゾール−5−イル) メトキシ]−4−(4−ピリジルメトキシ)ベンゾニトリル、 (RS)−[3−クロロ−2−シアノ−5−(4−ピリジルメトキシ)フェノキ シ]−(2−クロロフェニル)酢酸、 (RS)−[5−(ベンゾオキサゾール−6−イルメトキシ)−2−シアノフェ ノキシ]−(2−メチルフェニル)酢酸、 (S)−[5−(1,3−ベンゾジオキソール−5−イルメトキシ)−2−シア ノフェノキシ]−(2−メチルフェニル)酢酸、 (S)−[5−(1,3−ベンゾジオキソール−5−イルメトキシ)−2−シア ノ−3−フルオロフェノキシ]−(2−メチルフェニル)酢酸、 (RS)−[2−シアノ−5−(4−(3−フルオロピリジル)メトキシ)フェ ノキシ]−(2−メチルフェニル)酢酸、 (RS)−2−[(2−メチルフェニル)−(1H−テトラゾール−5−イル) メトキシ]−4−(4−ピリジルメトキシ)ベンゾニトリル、 (RS)−4−(1,3−ベンゾジオキソール−5−イルメトキシ)−2−[( 2−メチルフェニル)−(1H−テトラゾール−5−イル)メトキシ]ベンゾニ トリル、 (RS)−[2−シアノ−3−フルオロ−5−(4−ピリジルメトキシ)フェノ キシ]−(2−メチルフェニル)酢酸、 (RS)−[5−(ベンゾオキサゾール−6−イルメトキシ)−2−シアノ−3 −フルオロフェノキシ]−(2−メチルフェニル)酢酸、 (RS)−[5−(1,3−ベンゾジオキソール−5−イルメトキシ)−2−シ アノ−3−フルオロフェノキシ]−(2−メチルフェニル)酢酸、 (RS)−[5−(ベンゾオキサゾール−5−イル)メトキシ−2−シアノフェ ノキシ]−(2−メチルフェニル)酢酸、 (RS)−(5−ベンジルオキシ−2−シアノフェノキシ)−(2−メチルフェ ニル)酢酸、 (RS)−[2−シアノ−5−(フラン−3−イルメトキシ)フェノキシ]−( 2−メチルフェニル)酢酸、 (RS)−N−メトキシ−[2−シアノ−5−(3−チエニルメトキシ)フェノ キシ]−(2−メチルフェニル)アセトアミド、及び溶媒和物(例えば、水和物 )、及びこれらの製薬学的に許容できる塩から選択される化合物。 18. (RS)−(2−クロロフェニル)−[2−シアノ−5−(4−ピリジ ルメトキシ)フェノキシ]酢酸、 (S)−[5−(1,3−ベンゾジオキソール−5−イルメトキシ)−2−シア ノフェノキシ]−(2−メチルフェニル)酢酸、 (RS)−[5−(1,3−ベンゾジオキソール−5−イルメトキシ)−2−シ アノフェノキシ]−(2−メチルフェニル)酢酸、 (RS)−[2−シアノ−5−(4−ピリジルメトキシ)フェノキシ]−(2− メチルフェニル)酢酸、 (S)−[2−シアノ−5−(4−ピリジルメトキシ)フェノキシ]−(2−メ チルフェニル)酢酸、 (RS)−[5−(1,3−ベンゾジオキソール−5−イルメトキシ)−2−シ アノ−3−フルオロフェノキシ]−(2−メチルフェニル)酢酸、 (S)−[5−(1,3−ベンゾジオキソール−5−イルメトキシ)−2−シア ノ−3−フルオロフェノキシ]−(2−メチルフェニル)酢酸、及び溶媒和物( 例えば、水和物)、及びこれらの製薬学的に許容できる塩から選択される化合物 。 19. (S)−[5−(1,3−ベンゾジオキソール−5−イルメトキシ)− 2−シアノフェノキシ]−(2−メチルフェニル)酢酸、及び溶媒和物(例えば 、水和物)、及びこれらの製薬学的に許容できる塩。 20. 製薬学的に許容できるキャリヤーまたは添加剤と共に、請求の範囲1に 記載の化合物を含んでなる製薬学的組成。 21. 請求の範囲1に記載の化合物の有効量を含んでなる、生理学的に有害な 過剰のエンドセリンに関係した疾病状態、またはエンドセリンを阻害することに より和らげられる病状に関係した疾病状態の治療における使用のための製薬学的 組成。 22. 治療における使用のための請求の範囲1に記載の化合物。 23. 生理学的に有害な過剰のエンドセリンに関係した疾病状態、ま たはエンドセリンを阻害することにより和らげられる病状に関係した疾病状態の 治療のための薬剤の製造のための、請求の範囲1に記載の化合物の使用。 24. 生理学的に有害な過剰のエンドセリンに関係した疾病状態、またはエン ドセリンを阻害することにより和らげられる病状に関係した疾病状態の治療のた めの、一つまたはそれより多い、エンドセリン変換酵素阻害剤、アンキオテンシ ンIIレセプターアンタゴニスト、レニン阻害剤、アンギオテンシン変換酵素阻害 剤、α−及びβ−アドレノセプターアゴニスト及びアンタゴニスト、利尿薬、カ リウムチャネル活性化剤、カルシウムチャネルアンタゴニスト、硝酸塩、抗不整 脈剤、陽性変力剤、セロトニンレセプターアゴニスト及びアンタゴニスト、血小 板活性化因子アンタゴニスト、ヒスタミンレセプターアンタゴニストプロトンポ ンプ阻害剤、抗血栓形成及び血栓溶解剤、脂質低下剤、抗生物質剤、及びホスホ ジエステラーゼ阻害剤との組み合わせ治療における、請求の範囲1に記載の化合 物の使用。 25. (A)式(II)の化合物、 を式(III)の化合物、 Y−CHR4R5a (III) 式中、Yはハロゲン原子またはアリール−もしくはアルキル−スルホニ ルオキシ基(例えば、メタン−もしくはp−トルエン−スルホニルオキシ)のよ うな脱離基であり、そしてR5aは、カルボン酸アンモニウム塩を含むR5の保護 された誘導体である、と反応させ、続いて保護基を除去する、あるいは、 (B)R1が環の2位で結合したCNである場合、式(IV)の化合物、 を式(V)の化合物、 HOCHR4R5 (V) または対応するチオールと反応させる、あるいは、 (C)Xが酸素であり、そしてR2がアリール低級アルコキシまたはヘテロアリ ール低級アルコキシである場合、式(VI)の化合物、 式中、R5aはR5の保護された誘導体である、を適当な塩基の存在下で、アリー ルアルキルまたはヘテロアリールアルキルのハロゲン化物で処理し、続いて、必 要な場合、存在するあらゆる保護基を除去する、 ことを含んでなり、塩及びプロドラッグの生成、並びに場合よっては次 の工程としてカルボン酸等電子体へのR5の転化を含む、請求の範囲1において 記載されたような式(I)の化合物の製造方法。 26. エンドセリンの阻害剤の投与により改善されることのできる疾病状態に かかっている患者に、請求の範囲1の化合物の有効量を投与することを含んでな る、該疾病状態を治療するための方法。 27. 実施例に関係して実質的に以上に記述されたような化合物。
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GBGB9501635.8A GB9501635D0 (en) | 1995-01-27 | 1995-01-27 | Chemical compounds |
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NZ298853A (en) | 1998-07-28 |
HUP9801938A3 (en) | 1999-10-28 |
EA199700147A1 (ru) | 1997-12-30 |
EA000061B1 (ru) | 1998-04-30 |
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