AU720458B2 - Substituted biphenyl isoxazole sulfonamides - Google Patents
Substituted biphenyl isoxazole sulfonamides Download PDFInfo
- Publication number
- AU720458B2 AU720458B2 AU22098/97A AU2209897A AU720458B2 AU 720458 B2 AU720458 B2 AU 720458B2 AU 22098/97 A AU22098/97 A AU 22098/97A AU 2209897 A AU2209897 A AU 2209897A AU 720458 B2 AU720458 B2 AU 720458B2
- Authority
- AU
- Australia
- Prior art keywords
- oxazolyl
- biphenyl
- isoxazolyl
- dimethyl
- methyl
- 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.)
- Ceased
Links
- KFJGHVOVYDCDOS-UHFFFAOYSA-N 1,1'-biphenyl;1,2-oxazole-3-sulfonamide Chemical class NS(=O)(=O)C=1C=CON=1.C1=CC=CC=C1C1=CC=CC=C1 KFJGHVOVYDCDOS-UHFFFAOYSA-N 0.000 title 1
- -1 cycloalkenylalkyl Chemical group 0.000 claims abstract description 423
- 150000001875 compounds Chemical class 0.000 claims abstract description 345
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 86
- 125000003118 aryl group Chemical group 0.000 claims abstract description 67
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 40
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 38
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 37
- 239000001257 hydrogen Substances 0.000 claims abstract description 33
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 30
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 27
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 23
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 23
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 21
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 16
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 14
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 14
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 14
- 102000002045 Endothelin Human genes 0.000 claims abstract description 12
- 108050009340 Endothelin Proteins 0.000 claims abstract description 12
- 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 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000004305 biphenyl Substances 0.000 claims description 201
- 229940124530 sulfonamide Drugs 0.000 claims description 169
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 150
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 147
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 118
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 99
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 82
- 238000000034 method Methods 0.000 claims description 76
- 235000010290 biphenyl Nutrition 0.000 claims description 49
- 125000000623 heterocyclic group Chemical group 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 45
- 238000011282 treatment Methods 0.000 claims description 37
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 125000005843 halogen group Chemical group 0.000 claims description 26
- 150000002367 halogens Chemical group 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 206010020772 Hypertension Diseases 0.000 claims description 19
- 208000035475 disorder Diseases 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- SBXDENYROQKXBE-UHFFFAOYSA-N 2-phenylbenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1C1=CC=CC=C1 SBXDENYROQKXBE-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 15
- 241000124008 Mammalia Species 0.000 claims description 14
- 125000004470 heterocyclooxy group Chemical group 0.000 claims description 13
- 102000003729 Neprilysin Human genes 0.000 claims description 12
- 108090000028 Neprilysin Proteins 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 206010019280 Heart failures Diseases 0.000 claims description 9
- 125000002971 oxazolyl group Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 102000005862 Angiotensin II Human genes 0.000 claims description 8
- 101800000733 Angiotensin-2 Proteins 0.000 claims description 8
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 8
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 claims description 8
- 229950006323 angiotensin ii Drugs 0.000 claims description 8
- 230000001434 glomerular Effects 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 7
- 208000037487 Endotoxemia Diseases 0.000 claims description 7
- 208000019695 Migraine disease Diseases 0.000 claims description 7
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 7
- 108090000783 Renin Proteins 0.000 claims description 7
- 102100028255 Renin Human genes 0.000 claims description 7
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 claims description 7
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 7
- 210000003904 glomerular cell Anatomy 0.000 claims description 7
- 210000003584 mesangial cell Anatomy 0.000 claims description 7
- 206010027599 migraine Diseases 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 229940044551 receptor antagonist Drugs 0.000 claims description 7
- 239000002464 receptor antagonist Substances 0.000 claims description 7
- 208000037803 restenosis Diseases 0.000 claims description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 7
- 125000004385 trihaloalkyl group Chemical group 0.000 claims description 7
- 239000005541 ACE inhibitor Substances 0.000 claims description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims description 6
- 208000004248 Familial Primary Pulmonary Hypertension Diseases 0.000 claims description 6
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 6
- 125000004171 alkoxy aryl group Chemical group 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 150000003857 carboxamides Chemical class 0.000 claims description 6
- 239000002368 cardiac glycoside Substances 0.000 claims description 6
- 229940097217 cardiac glycoside Drugs 0.000 claims description 6
- 239000002934 diuretic Substances 0.000 claims description 6
- 230000009977 dual effect Effects 0.000 claims description 6
- 208000028867 ischemia Diseases 0.000 claims description 6
- APVPOHHVBBYQAV-UHFFFAOYSA-N n-(4-aminophenyl)sulfonyloctadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 APVPOHHVBBYQAV-UHFFFAOYSA-N 0.000 claims description 6
- 201000008312 primary pulmonary hypertension Diseases 0.000 claims description 6
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 6
- 239000002461 renin inhibitor Substances 0.000 claims description 6
- 229940086526 renin-inhibitors Drugs 0.000 claims description 6
- 229930002534 steroid glycoside Natural products 0.000 claims description 6
- 150000003456 sulfonamides Chemical class 0.000 claims description 6
- 125000004952 trihaloalkoxy group Chemical group 0.000 claims description 6
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 5
- 229940097420 Diuretic Drugs 0.000 claims description 5
- 125000004419 alkynylene group Chemical group 0.000 claims description 5
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 5
- 230000001882 diuretic effect Effects 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 claims description 5
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 4
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 4
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 4
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 4
- XXUNIGZDNWWYED-UHFFFAOYSA-N 2-methylbenzamide Chemical compound CC1=CC=CC=C1C(N)=O XXUNIGZDNWWYED-UHFFFAOYSA-N 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 8
- AZWFNQKHHGQCET-UHFFFAOYSA-N 2-(2-methylphenyl)acetamide Chemical compound CC1=CC=CC=C1CC(N)=O AZWFNQKHHGQCET-UHFFFAOYSA-N 0.000 claims 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 2
- 230000002685 pulmonary effect Effects 0.000 claims 2
- OYPKKXBKOMAMBY-UHFFFAOYSA-N 1-(4-methoxyphenyl)-n-methylcyclopropane-1-carboxamide Chemical compound C=1C=C(OC)C=CC=1C1(C(=O)NC)CC1 OYPKKXBKOMAMBY-UHFFFAOYSA-N 0.000 claims 1
- ZVXKYWHJBYIYNI-UHFFFAOYSA-N 1h-pyrazole-4-carboxamide Chemical compound NC(=O)C=1C=NNC=1 ZVXKYWHJBYIYNI-UHFFFAOYSA-N 0.000 claims 1
- CRKOSGNZDZJPJU-UHFFFAOYSA-N 2-(2-methoxyphenyl)-n-methylacetamide Chemical compound CNC(=O)CC1=CC=CC=C1OC CRKOSGNZDZJPJU-UHFFFAOYSA-N 0.000 claims 1
- GHMBGSQGEDPNPA-UHFFFAOYSA-N 2-(2-phenylphenyl)-1,3-oxazole Chemical compound C1=COC(C=2C(=CC=CC=2)C=2C=CC=CC=2)=N1 GHMBGSQGEDPNPA-UHFFFAOYSA-N 0.000 claims 1
- JVTZVDKMTZUJFY-UHFFFAOYSA-N 2-ethylnonanamide Chemical compound CCCCCCCC(CC)C(N)=O JVTZVDKMTZUJFY-UHFFFAOYSA-N 0.000 claims 1
- NAGFMACWWJYORB-UHFFFAOYSA-N 2-fluoro-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1F NAGFMACWWJYORB-UHFFFAOYSA-N 0.000 claims 1
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- WVHWEIFXJOJSKH-UHFFFAOYSA-N 3-(1h-benzimidazol-2-yl)propanamide Chemical compound C1=CC=C2NC(CCC(=O)N)=NC2=C1 WVHWEIFXJOJSKH-UHFFFAOYSA-N 0.000 claims 1
- RPCUHNOWPGCYGH-UHFFFAOYSA-N 3-(trifluoromethyl)-1,2-oxazole-4-carboxamide Chemical compound NC(=O)C1=CON=C1C(F)(F)F RPCUHNOWPGCYGH-UHFFFAOYSA-N 0.000 claims 1
- YNSCKPCDFIDINW-UHFFFAOYSA-N 3-[[2-[[1-[2-(dimethylamino)acetyl]-6-methoxy-4,4-dimethyl-2,3-dihydroquinolin-7-yl]amino]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]amino]thiophene-2-carboxamide Chemical compound COC1=CC(C(CCN2C(=O)CN(C)C)(C)C)=C2C=C1NC(N=C1NC=CC1=1)=NC=1NC=1C=CSC=1C(N)=O YNSCKPCDFIDINW-UHFFFAOYSA-N 0.000 claims 1
- KJTRXVXWSSPHRV-UHFFFAOYSA-N 4-benzoyl-5-methyl-2-phenyl-1h-pyrazol-3-one Chemical compound O=C1C(C(=O)C=2C=CC=CC=2)=C(C)NN1C1=CC=CC=C1 KJTRXVXWSSPHRV-UHFFFAOYSA-N 0.000 claims 1
- 102000015427 Angiotensins Human genes 0.000 claims 1
- 108010064733 Angiotensins Proteins 0.000 claims 1
- 102100025027 E3 ubiquitin-protein ligase TRIM69 Human genes 0.000 claims 1
- 101000830203 Homo sapiens E3 ubiquitin-protein ligase TRIM69 Proteins 0.000 claims 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims 1
- ZYVXHFWBYUDDBM-UHFFFAOYSA-N N-methylnicotinamide Chemical compound CNC(=O)C1=CC=CN=C1 ZYVXHFWBYUDDBM-UHFFFAOYSA-N 0.000 claims 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims 1
- LDECUSDQMXVUMP-UHFFFAOYSA-N benzyl 3-[6-[[2-(butylamino)-1-[3-methoxycarbonyl-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]-hexylamino]-6-oxohexyl]-4-methyl-2-oxo-6-(4-phenylphenyl)-1,6-dihydropyrimidine-5-carboxylate Chemical compound O=C1NC(C=2C=CC(=CC=2)C=2C=CC=CC=2)C(C(=O)OCC=2C=CC=CC=2)=C(C)N1CCCCCC(=O)N(CCCCCC)C(C(=O)NCCCC)C1=CC=C(OCC(=O)OC)C(C(=O)OC)=C1 LDECUSDQMXVUMP-UHFFFAOYSA-N 0.000 claims 1
- 239000004202 carbamide Substances 0.000 claims 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- IICOVGJZZYTZLU-UHFFFAOYSA-N n,2-dimethylpropanamide Chemical compound [CH2]C(C)C(=O)NC IICOVGJZZYTZLU-UHFFFAOYSA-N 0.000 claims 1
- GFWZPTGIVKRQNM-UHFFFAOYSA-N n,3-dimethylbutanamide Chemical compound CNC(=O)CC(C)C GFWZPTGIVKRQNM-UHFFFAOYSA-N 0.000 claims 1
- QKUDHKCFODBAOC-UHFFFAOYSA-N n,5-dimethyl-2-phenyltriazole-4-carboxamide Chemical compound N1=C(C)C(C(=O)NC)=NN1C1=CC=CC=C1 QKUDHKCFODBAOC-UHFFFAOYSA-N 0.000 claims 1
- YVVNRNOCXWXOLJ-UHFFFAOYSA-N n-(1,3-oxazol-2-yl)-2-phenylbenzenesulfonamide Chemical compound C=1C=CC=C(C=2C=CC=CC=2)C=1S(=O)(=O)NC1=NC=CO1 YVVNRNOCXWXOLJ-UHFFFAOYSA-N 0.000 claims 1
- RKEXPBCMGJAOLM-UHFFFAOYSA-N n-methyl-2-phenylacetamide Chemical compound CNC(=O)CC1=CC=CC=C1 RKEXPBCMGJAOLM-UHFFFAOYSA-N 0.000 claims 1
- NCCHARWOCKOHIH-UHFFFAOYSA-N n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1 NCCHARWOCKOHIH-UHFFFAOYSA-N 0.000 claims 1
- MXGRCIBAPXPYMA-UHFFFAOYSA-N n-methylfuran-2-carboxamide Chemical compound CNC(=O)C1=CC=CO1 MXGRCIBAPXPYMA-UHFFFAOYSA-N 0.000 claims 1
- KYKDOARTYFGHPC-UHFFFAOYSA-N n-propan-2-ylpropanamide Chemical compound CCC(=O)NC(C)C KYKDOARTYFGHPC-UHFFFAOYSA-N 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical group O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims 1
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- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 2
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 504
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- 239000000243 solution Substances 0.000 description 196
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- 239000000203 mixture Substances 0.000 description 154
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 127
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- 239000007787 solid Substances 0.000 description 109
- 239000002904 solvent Substances 0.000 description 108
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 102
- 239000012267 brine Substances 0.000 description 98
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 98
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 93
- 239000000741 silica gel Substances 0.000 description 90
- 229910002027 silica gel Inorganic materials 0.000 description 90
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 89
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 72
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 68
- 239000011541 reaction mixture Substances 0.000 description 68
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- 229940126062 Compound A Drugs 0.000 description 53
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 53
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- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/06—Antimigraine agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- 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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- A—HUMAN NECESSITIES
- 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
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/38—Nitrogen atoms
- C07D231/42—Benzene-sulfonamido pyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60397596A | 1996-02-20 | 1996-02-20 | |
| US08/603975 | 1996-02-20 | ||
| US75471596A | 1996-11-21 | 1996-11-21 | |
| US08/754715 | 1996-11-21 | ||
| US08/799616 | 1997-02-13 | ||
| US08/799,616 US5846990A (en) | 1995-07-24 | 1997-02-13 | Substituted biphenyl isoxazole sulfonamides |
| PCT/US1997/003956 WO1997029748A1 (en) | 1996-02-20 | 1997-02-20 | Substituted biphenyl isoxazole sulfonamides |
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| AU2209897A AU2209897A (en) | 1997-09-02 |
| AU720458B2 true AU720458B2 (en) | 2000-06-01 |
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| AU22098/97A Ceased AU720458B2 (en) | 1996-02-20 | 1997-02-20 | Substituted biphenyl isoxazole sulfonamides |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US5846990A (enExample) |
| EP (1) | EP0921800B1 (enExample) |
| JP (1) | JP2002500619A (enExample) |
| AT (1) | ATE264324T1 (enExample) |
| AU (1) | AU720458B2 (enExample) |
| CA (1) | CA2240043A1 (enExample) |
| DE (1) | DE69728673T2 (enExample) |
| ES (1) | ES2219762T3 (enExample) |
| WO (1) | WO1997029748A1 (enExample) |
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-
1997
- 1997-02-13 US US08/799,616 patent/US5846990A/en not_active Expired - Lifetime
- 1997-02-20 AT AT97915055T patent/ATE264324T1/de not_active IP Right Cessation
- 1997-02-20 WO PCT/US1997/003956 patent/WO1997029748A1/en not_active Ceased
- 1997-02-20 JP JP52962097A patent/JP2002500619A/ja not_active Ceased
- 1997-02-20 CA CA002240043A patent/CA2240043A1/en not_active Abandoned
- 1997-02-20 ES ES97915055T patent/ES2219762T3/es not_active Expired - Lifetime
- 1997-02-20 EP EP97915055A patent/EP0921800B1/en not_active Expired - Lifetime
- 1997-02-20 AU AU22098/97A patent/AU720458B2/en not_active Ceased
- 1997-02-20 DE DE69728673T patent/DE69728673T2/de not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP0921800A1 (en) | 1999-06-16 |
| ATE264324T1 (de) | 2004-04-15 |
| JP2002500619A (ja) | 2002-01-08 |
| DE69728673D1 (de) | 2004-05-19 |
| WO1997029748A1 (en) | 1997-08-21 |
| EP0921800B1 (en) | 2004-04-14 |
| AU2209897A (en) | 1997-09-02 |
| DE69728673T2 (de) | 2005-03-31 |
| ES2219762T3 (es) | 2004-12-01 |
| EP0921800A4 (en) | 2000-12-06 |
| US5846990A (en) | 1998-12-08 |
| CA2240043A1 (en) | 1997-08-21 |
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