HRP20010515A2 - 4-(heterocyclylsulfonamido)-5-methoxy-6-(2-methoxyphenoxy)-2-phenyl- or pyridylpyrimidines as endothelin receptor antagonists - Google Patents

Info

Publication number

HRP20010515A2

HRP20010515A2 HR20010515A HRP20010515A HRP20010515A2 HR P20010515 A2 HRP20010515 A2 HR P20010515A2 HR 20010515 A HR20010515 A HR 20010515A HR P20010515 A HRP20010515 A HR P20010515A HR P20010515 A2 HRP20010515 A2 HR P20010515A2

Authority

HR

Croatia

Prior art keywords

methoxy

pyridine

phenoxy

pyrimidin

methyl

Prior art date

1999-01-18

Links

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• 229940118365 Endothelin receptor antagonist Drugs 0.000 title description 3
• 239000002308 endothelin receptor antagonist Substances 0.000 title description 3
• -1 amidino, hydroxyamidino Chemical group 0.000 claims description 148
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 114
• 125000000217 alkyl group Chemical group 0.000 claims description 109
• 150000001875 compounds Chemical class 0.000 claims description 106
• 238000006243 chemical reaction Methods 0.000 claims description 55
• 239000002904 solvent Substances 0.000 claims description 36
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
• 238000011282 treatment Methods 0.000 claims description 25
• 239000001257 hydrogen Substances 0.000 claims description 24
• 229910052739 hydrogen Inorganic materials 0.000 claims description 24
• 229940124530 sulfonamide Drugs 0.000 claims description 24
• PWSQPYYJRFUQNY-UHFFFAOYSA-N 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-methylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxylic acid Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C(O)=O)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 PWSQPYYJRFUQNY-UHFFFAOYSA-N 0.000 claims description 23
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 23
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 20
• 238000000034 method Methods 0.000 claims description 20
• 125000000623 heterocyclic group Chemical group 0.000 claims description 17
• XYDHSCZUHCZWHJ-UHFFFAOYSA-N 5-methylpyridine-2-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)N=C1 XYDHSCZUHCZWHJ-UHFFFAOYSA-N 0.000 claims description 16
• 125000003342 alkenyl group Chemical group 0.000 claims description 15
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
• 150000002431 hydrogen Chemical class 0.000 claims description 14
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
• 150000002148 esters Chemical class 0.000 claims description 12
• USAZCYCMURFAHN-UHFFFAOYSA-N n-[2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(O)C=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 USAZCYCMURFAHN-UHFFFAOYSA-N 0.000 claims description 12
• 150000003456 sulfonamides Chemical class 0.000 claims description 11
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 10
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 10
• 238000004519 manufacturing process Methods 0.000 claims description 10
• 150000003839 salts Chemical class 0.000 claims description 10
• BDDSPURWPWLXQX-UHFFFAOYSA-N 1-acetyloxyethyl 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-methylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxylate Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C(=O)OC(C)OC(C)=O)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 BDDSPURWPWLXQX-UHFFFAOYSA-N 0.000 claims description 9
• DSPWOBHBGWPXJE-UHFFFAOYSA-N 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-propan-2-ylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxylic acid Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C(O)=O)OC)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 DSPWOBHBGWPXJE-UHFFFAOYSA-N 0.000 claims description 9
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
• HXAZFIXWZPERHB-UHFFFAOYSA-N 5-propan-2-ylpyridine-2-sulfonic acid Chemical compound CC(C)C1=CC=C(S(O)(=O)=O)N=C1 HXAZFIXWZPERHB-UHFFFAOYSA-N 0.000 claims description 8
• TZGPRVZHYJHRJM-UHFFFAOYSA-N n-[2-(2-cyanopyridin-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C#N)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 TZGPRVZHYJHRJM-UHFFFAOYSA-N 0.000 claims description 8
• 125000000335 thiazolyl group Chemical group 0.000 claims description 8
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 7
• 206010048554 Endothelial dysfunction Diseases 0.000 claims description 7
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
• 230000002159 abnormal effect Effects 0.000 claims description 7
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 7
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
• 125000001589 carboacyl group Chemical group 0.000 claims description 7
• 239000003814 drug Substances 0.000 claims description 7
• 230000008694 endothelial dysfunction Effects 0.000 claims description 7
• LXNTVTQZKZHOQG-UHFFFAOYSA-N methyl 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-propan-2-ylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxylate Chemical compound C1=NC(C(=O)OC)=CC(C=2N=C(OC)C(OC=3C(=CC=CC=3)OC)=C(NS(=O)(=O)C=3N=CC(=CC=3)C(C)C)N=2)=C1 LXNTVTQZKZHOQG-UHFFFAOYSA-N 0.000 claims description 7
• 125000004076 pyridyl group Chemical group 0.000 claims description 7
• 230000006442 vascular tone Effects 0.000 claims description 7
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 6
• 229910003827 NRaRb Inorganic materials 0.000 claims description 6
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 6
• 229910052736 halogen Inorganic materials 0.000 claims description 6
• 150000002367 halogens Chemical group 0.000 claims description 6
• HWDVVFJLGKKDDY-UHFFFAOYSA-N n-[2-[2-(hydroxymethyl)pyridin-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(CO)N=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 HWDVVFJLGKKDDY-UHFFFAOYSA-N 0.000 claims description 6
• 230000008569 process Effects 0.000 claims description 6
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
• JBOAZACHEBUCCG-UHFFFAOYSA-N ethyl 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-methylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxylate Chemical compound C1=NC(C(=O)OCC)=CC(C=2N=C(OC)C(OC=3C(=CC=CC=3)OC)=C(NS(=O)(=O)C=3N=CC(C)=CC=3)N=2)=C1 JBOAZACHEBUCCG-UHFFFAOYSA-N 0.000 claims description 5
• FFIICJXAEMQRPV-UHFFFAOYSA-N ethyl 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-propan-2-ylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxylate Chemical compound C1=NC(C(=O)OCC)=CC(C=2N=C(OC)C(OC=3C(=CC=CC=3)OC)=C(NS(=O)(=O)C=3N=CC(=CC=3)C(C)C)N=2)=C1 FFIICJXAEMQRPV-UHFFFAOYSA-N 0.000 claims description 5
• 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 claims description 5
• JBMOXASJKXMRQK-UHFFFAOYSA-N methyl 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-methylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxylate Chemical compound C1=NC(C(=O)OC)=CC(C=2N=C(OC)C(OC=3C(=CC=CC=3)OC)=C(NS(=O)(=O)C=3N=CC(C)=CC=3)N=2)=C1 JBMOXASJKXMRQK-UHFFFAOYSA-N 0.000 claims description 5
• BUIBBWMIISPCPE-UHFFFAOYSA-N 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-propan-2-ylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C(N)=O)OC)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 BUIBBWMIISPCPE-UHFFFAOYSA-N 0.000 claims description 4
• DTVHASKEQAUBMN-UHFFFAOYSA-N N'-hydroxy-4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-propan-2-ylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboximidamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C(=N)NO)OC)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 DTVHASKEQAUBMN-UHFFFAOYSA-N 0.000 claims description 4
• 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 4
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
• 125000002883 imidazolyl group Chemical group 0.000 claims description 4
• IPCRQNKALGQPEY-UHFFFAOYSA-N n-[6-methoxy-5-(2-methoxyphenoxy)-2-[2-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-4-yl]pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C=2N=C(C)ON=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 IPCRQNKALGQPEY-UHFFFAOYSA-N 0.000 claims description 4
• 125000002971 oxazolyl group Chemical group 0.000 claims description 4
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 4
• 239000003963 antioxidant agent Substances 0.000 claims description 3
• 239000003153 chemical reaction reagent Substances 0.000 claims description 3
• IHKAXUYWYVTCEJ-UHFFFAOYSA-N ethyl 2-[3-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-methylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]phenoxy]acetate Chemical compound CCOC(=O)COC1=CC=CC(C=2N=C(OC)C(OC=3C(=CC=CC=3)OC)=C(NS(=O)(=O)C=3N=CC(C)=CC=3)N=2)=C1 IHKAXUYWYVTCEJ-UHFFFAOYSA-N 0.000 claims description 3
• ILWORCFVIJMBEH-UHFFFAOYSA-N n-[2-[2-(2-hydroxyethoxy)pyridin-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-methyl-1,3-thiazole-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(OCCO)N=CC=2)OC)=C1NS(=O)(=O)C1=NC=C(C)S1 ILWORCFVIJMBEH-UHFFFAOYSA-N 0.000 claims description 3
• IQCNZVLOUOHMKZ-UHFFFAOYSA-N n-[2-[2-(2-hydroxyethoxy)pyridin-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-propan-2-ylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(OCCO)N=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 IQCNZVLOUOHMKZ-UHFFFAOYSA-N 0.000 claims description 3
• PTOBBLWJHXHHBN-UHFFFAOYSA-N n-[2-[2-(hydroxymethyl)pyridin-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-propan-2-ylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(CO)N=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 PTOBBLWJHXHHBN-UHFFFAOYSA-N 0.000 claims description 3
• GBVBKQUMFUNJSX-UHFFFAOYSA-N n-[2-[2-(methanesulfonamidomethyl)pyridin-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(CNS(C)(=O)=O)N=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 GBVBKQUMFUNJSX-UHFFFAOYSA-N 0.000 claims description 3
• LEPZHONWBRDTIQ-UHFFFAOYSA-N n-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-oxo-1h-pyridin-4-yl)pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(O)N=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 LEPZHONWBRDTIQ-UHFFFAOYSA-N 0.000 claims description 3
• OCZRIJKYGLCQGB-UHFFFAOYSA-N propan-2-yl 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-propan-2-ylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxylate Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C(=O)OC(C)C)OC)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 OCZRIJKYGLCQGB-UHFFFAOYSA-N 0.000 claims description 3
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
• 125000002769 thiazolinyl group Chemical group 0.000 claims description 3
• BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical class C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 claims description 2
• 241001465754 Metazoa Species 0.000 claims description 2
• JVISYACOKHFQLD-UHFFFAOYSA-N N'-hydroxy-4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-methylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboximidamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C(=N)NO)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 JVISYACOKHFQLD-UHFFFAOYSA-N 0.000 claims description 2
• ZDLIYCVDCFABIY-UHFFFAOYSA-N [3-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-methylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]phenyl] acetate Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(OC(C)=O)C=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 ZDLIYCVDCFABIY-UHFFFAOYSA-N 0.000 claims description 2
• 230000003288 anthiarrhythmic effect Effects 0.000 claims description 2
• 239000004004 anti-anginal agent Substances 0.000 claims description 2
• 230000002785 anti-thrombosis Effects 0.000 claims description 2
• 239000003416 antiarrhythmic agent Substances 0.000 claims description 2
• 239000002220 antihypertensive agent Substances 0.000 claims description 2
• 229940127088 antihypertensive drug Drugs 0.000 claims description 2
• 239000003524 antilipemic agent Substances 0.000 claims description 2
• 229960004676 antithrombotic agent Drugs 0.000 claims description 2
• 239000012752 auxiliary agent Substances 0.000 claims description 2
• 229910052799 carbon Inorganic materials 0.000 claims description 2
• 201000010099 disease Diseases 0.000 claims description 2
• MGOPRDLMTJAUDR-UHFFFAOYSA-N n-[2-[3-(2-hydroxyethoxy)phenyl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(OCCO)C=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 MGOPRDLMTJAUDR-UHFFFAOYSA-N 0.000 claims description 2
• ZAPIXIFQZPXOQX-UHFFFAOYSA-N n-[6-methoxy-5-(2-methoxyphenoxy)-2-[2-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-4-yl]pyrimidin-4-yl]-5-propan-2-ylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C=2N=C(C)ON=2)OC)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 ZAPIXIFQZPXOQX-UHFFFAOYSA-N 0.000 claims description 2
• ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 claims description 2
• 230000000069 prophylactic effect Effects 0.000 claims description 2
• 238000011321 prophylaxis Methods 0.000 claims description 2
• 230000001225 therapeutic effect Effects 0.000 claims description 2
• 125000005270 trialkylamine group Chemical group 0.000 claims description 2
• FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims 2
• 229940124345 antianginal agent Drugs 0.000 claims 1
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• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
• 239000000243 solution Substances 0.000 description 48
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
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• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
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• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 25
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• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
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• 239000007858 starting material Substances 0.000 description 22
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• 238000004809 thin layer chromatography Methods 0.000 description 21
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• RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 9
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• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
• 238000002844 melting Methods 0.000 description 9
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