NO314503B1 - N-Heteroarylpyridinsulfonamidderivater, anvendelse og fremstilling derav samt farmasöytisk preparat - Google Patents

Info

Publication number

NO314503B1

NO314503B1 NO19975700A NO975700A NO314503B1 NO 314503 B1 NO314503 B1 NO 314503B1 NO 19975700 A NO19975700 A NO 19975700A NO 975700 A NO975700 A NO 975700A NO 314503 B1 NO314503 B1 NO 314503B1

Authority

NO

Norway

Prior art keywords

methoxy

sulfonamide

alkyl

pyridine

phenyl

Prior art date

1995-06-07

Links

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• 238000002360 preparation method Methods 0.000 title claims description 11
• DWJMBQYORXLGAE-UHFFFAOYSA-N pyridine-2-sulfonamide Chemical class NS(=O)(=O)C1=CC=CC=N1 DWJMBQYORXLGAE-UHFFFAOYSA-N 0.000 title claims description 3
• 239000008194 pharmaceutical composition Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 142
• 238000000034 method Methods 0.000 claims description 120
• 125000000217 alkyl group Chemical group 0.000 claims description 87
• -1 3-hydroxy-2-methyl-propyl Chemical group 0.000 claims description 84
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 57
• 150000003839 salts Chemical class 0.000 claims description 43
• 125000003545 alkoxy group Chemical group 0.000 claims description 38
• NKFLEFWUYAUDJV-UHFFFAOYSA-N pyridine-3-sulfonamide Chemical compound NS(=O)(=O)C1=CC=CN=C1 NKFLEFWUYAUDJV-UHFFFAOYSA-N 0.000 claims description 29
• 229940124530 sulfonamide Drugs 0.000 claims description 29
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 27
• 239000000460 chlorine Substances 0.000 claims description 26
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
• 125000006239 protecting group Chemical group 0.000 claims description 19
• 125000001424 substituent group Chemical group 0.000 claims description 19
• 238000006243 chemical reaction Methods 0.000 claims description 18
• 125000004076 pyridyl group Chemical group 0.000 claims description 15
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
• 150000001412 amines Chemical class 0.000 claims description 13
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
• 239000002253 acid Substances 0.000 claims description 12
• 239000002585 base Substances 0.000 claims description 10
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
• 229910052794 bromium Inorganic materials 0.000 claims description 10
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
• 229910052801 chlorine Inorganic materials 0.000 claims description 9
• 125000003342 alkenyl group Chemical group 0.000 claims description 8
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
• 150000003461 sulfonyl halides Chemical class 0.000 claims description 8
• 229910052783 alkali metal Inorganic materials 0.000 claims description 7
• 239000001257 hydrogen Substances 0.000 claims description 7
• 229910052739 hydrogen Inorganic materials 0.000 claims description 7
• 229910003827 NRaRb Inorganic materials 0.000 claims description 6
• 125000003282 alkyl amino group Chemical group 0.000 claims description 6
• 125000004414 alkyl thio group Chemical group 0.000 claims description 6
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
• 125000000524 functional group Chemical group 0.000 claims description 6
• 229910052736 halogen Inorganic materials 0.000 claims description 6
• 150000002367 halogens Chemical class 0.000 claims description 6
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
• 206010020772 Hypertension Diseases 0.000 claims description 5
• 230000001154 acute effect Effects 0.000 claims description 5
• 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
• 150000001450 anions Chemical class 0.000 claims description 5
• 230000015572 biosynthetic process Effects 0.000 claims description 5
• 239000003814 drug Substances 0.000 claims description 5
• 125000005843 halogen group Chemical group 0.000 claims description 5
• 125000000623 heterocyclic group Chemical group 0.000 claims description 5
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 5
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
• 208000002815 pulmonary hypertension Diseases 0.000 claims description 5
• 208000009304 Acute Kidney Injury Diseases 0.000 claims description 4
• 201000001320 Atherosclerosis Diseases 0.000 claims description 4
• 206010007559 Cardiac failure congestive Diseases 0.000 claims description 4
• 206010019280 Heart failures Diseases 0.000 claims description 4
• 208000032382 Ischaemic stroke Diseases 0.000 claims description 4
• 208000033626 Renal failure acute Diseases 0.000 claims description 4
• 208000032851 Subarachnoid Hemorrhage Diseases 0.000 claims description 4
• 201000011040 acute kidney failure Diseases 0.000 claims description 4
• 208000012998 acute renal failure Diseases 0.000 claims description 4
• 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 4
• 208000006673 asthma Diseases 0.000 claims description 4
• 125000001589 carboacyl group Chemical group 0.000 claims description 4
• 150000001768 cations Chemical class 0.000 claims description 4
• 208000020832 chronic kidney disease Diseases 0.000 claims description 4
• 208000022831 chronic renal failure syndrome Diseases 0.000 claims description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• QDLQHGLUNGMAKG-UHFFFAOYSA-N n-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-pyridin-2-ylphenyl)pyridine-3-sulfonamide Chemical compound COC1=NC(C)=CN=C1NS(=O)(=O)C1=CC=CN=C1C1=CC=C(C=2N=CC=CC=2)C=C1 QDLQHGLUNGMAKG-UHFFFAOYSA-N 0.000 claims description 4
• 229910052705 radium Inorganic materials 0.000 claims description 4
• 229910052701 rubidium Inorganic materials 0.000 claims description 4
• 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 3
• WMEJLSWILDWHNN-UHFFFAOYSA-N 2-[4-(1-hydroxyethyl)phenyl]-n-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide Chemical compound COC1=NC(C)=CN=C1NS(=O)(=O)C1=CC=CN=C1C1=CC=C(C(C)O)C=C1 WMEJLSWILDWHNN-UHFFFAOYSA-N 0.000 claims description 3
• MHWPGYSKTFVVDQ-UHFFFAOYSA-N 2-[4-[3-[(3-methoxy-5-methylpyrazin-2-yl)sulfamoyl]pyridin-2-yl]phenoxy]propanoic acid Chemical compound COC1=NC(C)=CN=C1NS(=O)(=O)C1=CC=CN=C1C1=CC=C(OC(C)C(O)=O)C=C1 MHWPGYSKTFVVDQ-UHFFFAOYSA-N 0.000 claims description 3
• 208000032928 Dyslipidaemia Diseases 0.000 claims description 3
• 206010022562 Intermittent claudication Diseases 0.000 claims description 3
• 206010053159 Organ failure Diseases 0.000 claims description 3
• 150000007513 acids Chemical class 0.000 claims description 3
• 230000002950 deficient Effects 0.000 claims description 3
• 229940079593 drug Drugs 0.000 claims description 3
• 150000002391 heterocyclic compounds Chemical class 0.000 claims description 3
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
• 208000021156 intermittent vascular claudication Diseases 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
• ZWLRFKXOUHKNLI-UHFFFAOYSA-N n-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-pyridin-3-ylphenyl)pyridine-3-sulfonamide Chemical compound COC1=NC(C)=CN=C1NS(=O)(=O)C1=CC=CN=C1C1=CC=C(C=2C=NC=CC=2)C=C1 ZWLRFKXOUHKNLI-UHFFFAOYSA-N 0.000 claims description 3
• OWRXTBUPEKJMPQ-UHFFFAOYSA-N n-(5-chloro-3-methoxypyrazin-2-yl)-2-[4-(2-methylpropyl)phenyl]pyridine-3-sulfonamide Chemical compound COC1=NC(Cl)=CN=C1NS(=O)(=O)C1=CC=CN=C1C1=CC=C(CC(C)C)C=C1 OWRXTBUPEKJMPQ-UHFFFAOYSA-N 0.000 claims description 3
• MWSDMYZTAMBGKE-UHFFFAOYSA-N propyl 3-[4-[3-[(3-methoxy-5-methylpyrazin-2-yl)sulfamoyl]pyridin-2-yl]phenyl]-2,2-dimethylpropanoate Chemical compound C1=CC(CC(C)(C)C(=O)OCCC)=CC=C1C1=NC=CC=C1S(=O)(=O)NC1=NC=C(C)N=C1OC MWSDMYZTAMBGKE-UHFFFAOYSA-N 0.000 claims description 3
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 208000037803 restenosis Diseases 0.000 claims description 3
• BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 3
• 238000002054 transplantation Methods 0.000 claims description 3
• 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 2
• WOIGGUHJFVDVEY-UHFFFAOYSA-N 2-(4-ethylphenyl)-n-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide Chemical compound C1=CC(CC)=CC=C1C1=NC=CC=C1S(=O)(=O)NC1=NC=C(C)N=C1OC WOIGGUHJFVDVEY-UHFFFAOYSA-N 0.000 claims description 2
• NVMWIBZFTMDUHO-UHFFFAOYSA-N 2-[4-(2-hydroxyethoxy)phenyl]-n-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide Chemical compound COC1=NC(C)=CN=C1NS(=O)(=O)C1=CC=CN=C1C1=CC=C(OCCO)C=C1 NVMWIBZFTMDUHO-UHFFFAOYSA-N 0.000 claims description 2
• FUZRZKMHKFCQRI-UHFFFAOYSA-N 2-[4-(cyclopropylmethyl)phenyl]-n-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide Chemical compound COC1=NC(C)=CN=C1NS(=O)(=O)C1=CC=CN=C1C(C=C1)=CC=C1CC1CC1 FUZRZKMHKFCQRI-UHFFFAOYSA-N 0.000 claims description 2
• FJHHZXWJVIEFGJ-UHFFFAOYSA-N N-(3-methoxy-5-methyl-2-pyrazinyl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]-3-pyridinesulfonamide Chemical compound COC1=NC(C)=CN=C1NS(=O)(=O)C1=CC=CN=C1C1=CC=C(C=2OC=NN=2)C=C1 FJHHZXWJVIEFGJ-UHFFFAOYSA-N 0.000 claims description 2
• 206010034576 Peripheral ischaemia Diseases 0.000 claims description 2
• ZSJDZWHBWHUZAA-UHFFFAOYSA-N [3-[4-[3-[(3-methoxy-5-methylpyrazin-2-yl)sulfamoyl]pyridin-2-yl]phenyl]-2-methylpropyl] acetate Chemical compound COC1=NC(C)=CN=C1NS(=O)(=O)C1=CC=CN=C1C1=CC=C(CC(C)COC(C)=O)C=C1 ZSJDZWHBWHUZAA-UHFFFAOYSA-N 0.000 claims description 2
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 2
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
• 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
• 239000003085 diluting agent Substances 0.000 claims description 2
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
• MAQAIMQRQPBRPD-UHFFFAOYSA-N n-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(1,2,4-oxadiazol-3-yl)phenyl]pyridine-3-sulfonamide Chemical compound COC1=NC(C)=CN=C1NS(=O)(=O)C1=CC=CN=C1C1=CC=C(C2=NOC=N2)C=C1 MAQAIMQRQPBRPD-UHFFFAOYSA-N 0.000 claims description 2
• 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 2
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 10
• GRPBLCVLKWBMRV-UHFFFAOYSA-N 2-[4-(2-hydroxyethoxymethyl)phenyl]-n-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide Chemical compound COC1=NC(C)=CN=C1NS(=O)(=O)C1=CC=CN=C1C1=CC=C(COCCO)C=C1 GRPBLCVLKWBMRV-UHFFFAOYSA-N 0.000 claims 1
• 208000017170 Lipid metabolism disease Diseases 0.000 claims 1
• USPRGUCKBIXGIG-UHFFFAOYSA-N n-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-pyrimidin-2-ylphenyl)pyridine-3-sulfonamide Chemical compound COC1=NC(C)=CN=C1NS(=O)(=O)C1=CC=CN=C1C1=CC=C(C=2N=CC=CN=2)C=C1 USPRGUCKBIXGIG-UHFFFAOYSA-N 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 408
• 239000000243 solution Substances 0.000 description 218
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 215
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 172
• 238000001819 mass spectrum Methods 0.000 description 136
• 239000000203 mixture Substances 0.000 description 130
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 122
• 238000005481 NMR spectroscopy Methods 0.000 description 115
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 110
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 86
• 235000019341 magnesium sulphate Nutrition 0.000 description 86
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 79
• 238000001704 evaporation Methods 0.000 description 79
• 230000008020 evaporation Effects 0.000 description 79
• 239000007787 solid Substances 0.000 description 75
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 65
• 239000007858 starting material Substances 0.000 description 64
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 59
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 56
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 55
• 239000000284 extract Substances 0.000 description 54
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 50
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 50
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 45
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 42
• 239000000741 silica gel Substances 0.000 description 41
• 229910002027 silica gel Inorganic materials 0.000 description 41
• 239000003039 volatile agent Substances 0.000 description 38
• 238000004587 chromatography analysis Methods 0.000 description 34
• 239000011541 reaction mixture Substances 0.000 description 34
• 239000002904 solvent Substances 0.000 description 33
• 239000003921 oil Substances 0.000 description 30
• CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 28
• 229910052786 argon Inorganic materials 0.000 description 25
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 25
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 24
• 238000010828 elution Methods 0.000 description 23
• 239000012074 organic phase Substances 0.000 description 23
• AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 22
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 20
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
• 238000012360 testing method Methods 0.000 description 20
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 18
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
• 229920006395 saturated elastomer Polymers 0.000 description 17
• 238000003756 stirring Methods 0.000 description 17
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 16
• 238000005160 1H NMR spectroscopy Methods 0.000 description 15
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 238000004452 microanalysis Methods 0.000 description 15
• 230000000694 effects Effects 0.000 description 14
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 14
• 239000010410 layer Substances 0.000 description 14
• 239000012044 organic layer Substances 0.000 description 14
• HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 14
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
• 229910000029 sodium carbonate Inorganic materials 0.000 description 14
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 13
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
• 241000700159 Rattus Species 0.000 description 12
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 12
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 12
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
• 239000012312 sodium hydride Substances 0.000 description 12
• 229910000104 sodium hydride Inorganic materials 0.000 description 12
• 102000002045 Endothelin Human genes 0.000 description 11
• 108050009340 Endothelin Proteins 0.000 description 11
• 210000004027 cell Anatomy 0.000 description 11
• 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 10
• NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 10
• 239000011780 sodium chloride Substances 0.000 description 10
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
• 201000010099 disease Diseases 0.000 description 9
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
• 239000000706 filtrate Substances 0.000 description 9
• 239000000047 product Substances 0.000 description 9
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
• CDVMCGIOTMQKOU-UHFFFAOYSA-N 2-methylpropyl n-(2-chloropyridin-3-yl)sulfonyl-n-(3-methoxy-5-methylpyrazin-2-yl)carbamate Chemical compound COC1=NC(C)=CN=C1N(C(=O)OCC(C)C)S(=O)(=O)C1=CC=CN=C1Cl CDVMCGIOTMQKOU-UHFFFAOYSA-N 0.000 description 8
• 101800004490 Endothelin-1 Proteins 0.000 description 8
• 102100033902 Endothelin-1 Human genes 0.000 description 8
• 241001465754 Metazoa Species 0.000 description 8
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
• 239000007864 aqueous solution Substances 0.000 description 8
• 238000001816 cooling Methods 0.000 description 8
• 239000002308 endothelin receptor antagonist Substances 0.000 description 8
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