TW492966B - Thienylsulfonamides and derivatives thereof that modulate the activity of endothelin - Google Patents

Info

Publication number

TW492966B

TW492966B TW085112218A TW85112218A TW492966B TW 492966 B TW492966 B TW 492966B TW 085112218 A TW085112218 A TW 085112218A TW 85112218 A TW85112218 A TW 85112218A TW 492966 B TW492966 B TW 492966B

Authority

TW

Taiwan

Prior art keywords

methyl

thiophene

scope

isoxazolyl

item

Prior art date

1995-04-04

Links

• Espacenet
• Global Dossier
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• 108050009340 Endothelin Proteins 0.000 title claims abstract description 198
• 102000002045 Endothelin Human genes 0.000 title claims abstract description 193
• 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 abstract description 169
• 230000000694 effects Effects 0.000 title claims abstract description 117
• 229940124530 sulfonamide Drugs 0.000 claims abstract description 129
• 230000027455 binding Effects 0.000 claims abstract description 42
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 9
• 230000001404 mediated effect Effects 0.000 claims abstract description 7
• 125000001544 thienyl group Chemical group 0.000 claims abstract description 6
• -1 butanedioxy Chemical group 0.000 claims description 530
• 150000001875 compounds Chemical class 0.000 claims description 265
• 125000000217 alkyl group Chemical group 0.000 claims description 152
• 125000003118 aryl group Chemical group 0.000 claims description 134
• 229910052799 carbon Inorganic materials 0.000 claims description 130
• 150000001412 amines Chemical class 0.000 claims description 111
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 102
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 87
• 229910052739 hydrogen Inorganic materials 0.000 claims description 84
• 239000001257 hydrogen Substances 0.000 claims description 84
• 239000000203 mixture Substances 0.000 claims description 65
• 125000001424 substituent group Chemical group 0.000 claims description 61
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 60
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 57
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 56
• 150000002431 hydrogen Chemical class 0.000 claims description 51
• BWJZHYWAXLWLTB-UHFFFAOYSA-N thiophene-3-sulfonamide Chemical compound NS(=O)(=O)C=1C=CSC=1 BWJZHYWAXLWLTB-UHFFFAOYSA-N 0.000 claims description 50
• 125000003545 alkoxy group Chemical group 0.000 claims description 47
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 46
• 125000003342 alkenyl group Chemical group 0.000 claims description 44
• 125000000304 alkynyl group Chemical group 0.000 claims description 44
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 42
• 239000008194 pharmaceutical composition Substances 0.000 claims description 42
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 38
• 229910052736 halogen Inorganic materials 0.000 claims description 37
• 201000010099 disease Diseases 0.000 claims description 36
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 33
• 238000011049 filling Methods 0.000 claims description 32
• NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 32
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
• 150000002367 halogens Chemical class 0.000 claims description 28
• 229930192474 thiophene Natural products 0.000 claims description 25
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 22
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 22
• 230000001105 regulatory effect Effects 0.000 claims description 22
• 125000004432 carbon atom Chemical group C* 0.000 claims description 20
• 238000011282 treatment Methods 0.000 claims description 20
• RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 17
• 206010020772 Hypertension Diseases 0.000 claims description 16
• 206010047139 Vasoconstriction Diseases 0.000 claims description 16
• 230000025033 vasoconstriction Effects 0.000 claims description 16
• IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 claims description 15
• 239000000460 chlorine Substances 0.000 claims description 15
• 229910052801 chlorine Inorganic materials 0.000 claims description 15
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 14
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
• WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 14
• 239000003814 drug Substances 0.000 claims description 12
• 208000024891 symptom Diseases 0.000 claims description 12
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 11
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
• 239000007789 gas Substances 0.000 claims description 11
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
• 208000006673 asthma Diseases 0.000 claims description 10
• 208000001647 Renal Insufficiency Diseases 0.000 claims description 9
• 229940079593 drug Drugs 0.000 claims description 9
• 201000006370 kidney failure Diseases 0.000 claims description 9
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 8
• 125000001246 bromo group Chemical group Br* 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• 125000005530 alkylenedioxy group Chemical group 0.000 claims description 7
• 229910052786 argon Inorganic materials 0.000 claims description 7
• 125000003943 azolyl group Chemical group 0.000 claims description 7
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
• 125000002971 oxazolyl group Chemical group 0.000 claims description 7
• 229950010879 phenamine Drugs 0.000 claims description 7
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 7
• KTFDYVNEGTXQCV-UHFFFAOYSA-N 2-Thiophenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CS1 KTFDYVNEGTXQCV-UHFFFAOYSA-N 0.000 claims description 6
• 206010061218 Inflammation Diseases 0.000 claims description 6
• 125000005605 benzo group Chemical group 0.000 claims description 6
• 230000036772 blood pressure Effects 0.000 claims description 6
• 125000001188 haloalkyl group Chemical group 0.000 claims description 6
• 230000004054 inflammatory process Effects 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
• 230000000670 limiting effect Effects 0.000 claims description 6
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
• 206010040070 Septic Shock Diseases 0.000 claims description 5
• 125000000732 arylene group Chemical group 0.000 claims description 5
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 5
• 150000007857 hydrazones Chemical class 0.000 claims description 5
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 5
• 208000018522 Gastrointestinal disease Diseases 0.000 claims description 4
• AVRWEULSKHQETA-UHFFFAOYSA-N Thiophene-2 Chemical compound S1C=2CCCCCC=2C(C(=O)OC)=C1NC(=O)C1=C(F)C(F)=C(F)C(F)=C1F AVRWEULSKHQETA-UHFFFAOYSA-N 0.000 claims description 4
• 229910052794 bromium Inorganic materials 0.000 claims description 4
• 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 4
• 206010002199 Anaphylactic shock Diseases 0.000 claims description 3
• 208000032456 Hemorrhagic Shock Diseases 0.000 claims description 3
• 208000019255 Menstrual disease Diseases 0.000 claims description 3
• 206010049771 Shock haemorrhagic Diseases 0.000 claims description 3
• PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 claims description 3
• 208000003455 anaphylaxis Diseases 0.000 claims description 3
• 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 3
• 208000010643 digestive system disease Diseases 0.000 claims description 3
• 208000018685 gastrointestinal system disease Diseases 0.000 claims description 3
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
• HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 3
• 208000036236 obstetric disease Diseases 0.000 claims description 3
• 230000004088 pulmonary circulation Effects 0.000 claims description 3
• PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 claims description 3
• 235000021286 stilbenes Nutrition 0.000 claims description 3
• 150000001335 aliphatic alkanes Chemical group 0.000 claims description 2
• 125000004429 atom Chemical group 0.000 claims description 2
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 2
• DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 claims description 2
• 208000014674 injury Diseases 0.000 claims description 2
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
• 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 241000790917 Dioxys <bee> Species 0.000 claims 11
• XRUNQUOBZSSTNJ-UHFFFAOYSA-N n-phenyl-3-sulfamoylthiophene-2-carboxamide Chemical compound C1=CSC(C(=O)NC=2C=CC=CC=2)=C1S(=O)(=O)N XRUNQUOBZSSTNJ-UHFFFAOYSA-N 0.000 claims 9
• 239000004575 stone Substances 0.000 claims 4
• 230000005856 abnormality Effects 0.000 claims 3
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 2
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
• 229940106189 ceramide Drugs 0.000 claims 2
• PJTZZRIWZAUVBJ-UHFFFAOYSA-N n-benzyl-3-sulfamoylthiophene-2-carboxamide Chemical compound C1=CSC(C(=O)NCC=2C=CC=CC=2)=C1S(=O)(=O)N PJTZZRIWZAUVBJ-UHFFFAOYSA-N 0.000 claims 2
• JKCKRNYECSTMLV-UHFFFAOYSA-N thiophene-3-carboximidamide Chemical compound NC(=N)C=1C=CSC=1 JKCKRNYECSTMLV-UHFFFAOYSA-N 0.000 claims 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
• QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims 1
• REJHVSOVQBJEBF-OWOJBTEDSA-N 5-azaniumyl-2-[(e)-2-(4-azaniumyl-2-sulfonatophenyl)ethenyl]benzenesulfonate Chemical compound OS(=O)(=O)C1=CC(N)=CC=C1\C=C\C1=CC=C(N)C=C1S(O)(=O)=O REJHVSOVQBJEBF-OWOJBTEDSA-N 0.000 claims 1
• KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims 1
• 229930192334 Auxin Natural products 0.000 claims 1
• HAOWLBTYJJBGAF-UHFFFAOYSA-N C(=C)C=1SC=CC=1S(=O)(=O)N Chemical compound C(=C)C=1SC=CC=1S(=O)(=O)N HAOWLBTYJJBGAF-UHFFFAOYSA-N 0.000 claims 1
• XTSQBBUNBAWTQE-UHFFFAOYSA-N C1(=CC=CC=C1)C=1SC=CC=1S(=O)(=O)N=NO Chemical compound C1(=CC=CC=C1)C=1SC=CC=1S(=O)(=O)N=NO XTSQBBUNBAWTQE-UHFFFAOYSA-N 0.000 claims 1
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
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• 206010062016 Immunosuppression Diseases 0.000 claims 1
• 229920000877 Melamine resin Polymers 0.000 claims 1
• RFYTZXNMAIENJD-UHFFFAOYSA-N N-thiophen-3-ylsulfonyl-1,3-benzodioxole-5-carboxamide Chemical compound S1C=C(C=C1)S(=O)(=O)NC(C1=CC2=C(C=C1)OCO2)=O RFYTZXNMAIENJD-UHFFFAOYSA-N 0.000 claims 1
• DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical group C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims 1
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• 239000001273 butane Substances 0.000 claims 1
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• QFMCFKUEOJJQLJ-UHFFFAOYSA-N methyl 2-[[3-[(4-chloro-3-methyl-1,2-oxazol-5-yl)sulfamoyl]thiophene-2-carbonyl]amino]-4,5-dimethoxybenzoate Chemical compound COC(=O)C1=CC(OC)=C(OC)C=C1NC(=O)C1=C(S(=O)(=O)NC2=C(C(C)=NO2)Cl)C=CS1 QFMCFKUEOJJQLJ-UHFFFAOYSA-N 0.000 claims 1
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• 238000000034 method Methods 0.000 abstract description 74
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