CN1301264A - 内皮素拮抗剂 - Google Patents

Info

Publication number

CN1301264A

CN1301264A CN98809462A CN98809462A CN1301264A CN 1301264 A CN1301264 A CN 1301264A CN 98809462 A CN98809462 A CN 98809462A CN 98809462 A CN98809462 A CN 98809462A CN 1301264 A CN1301264 A CN 1301264A

Authority

CN

China

Prior art keywords

alkyl

alkoxy

bases

group

aryl

Prior art date

1997-08-04

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.)

Pending

Links

• Espacenet
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• 102000002045 Endothelin Human genes 0.000 title claims abstract description 29
• 108050009340 Endothelin Proteins 0.000 title claims abstract description 28
• 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 28
• 239000005557 antagonist Substances 0.000 title description 4
• JAEIBKXSIXOLOL-UHFFFAOYSA-N pyrrolidin-1-ium-3-carboxylate Chemical class OC(=O)C1CCNC1 JAEIBKXSIXOLOL-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 272
• 238000000034 method Methods 0.000 claims abstract description 134
• 150000003839 salts Chemical class 0.000 claims abstract description 42
• 239000002585 base Substances 0.000 claims description 705
• -1 tetrazole radical Chemical class 0.000 claims description 478
• 125000000217 alkyl group Chemical group 0.000 claims description 403
• FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 259
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 187
• 229910052739 hydrogen Inorganic materials 0.000 claims description 173
• 239000001257 hydrogen Substances 0.000 claims description 173
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 170
• 125000003118 aryl group Chemical group 0.000 claims description 163
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 160
• 125000001118 alkylidene group Chemical group 0.000 claims description 157
• 125000001188 haloalkyl group Chemical group 0.000 claims description 144
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 143
• 125000003545 alkoxy group Chemical group 0.000 claims description 139
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 124
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 103
• 125000003342 alkenyl group Chemical group 0.000 claims description 99
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 88
• 239000000203 mixture Substances 0.000 claims description 85
• 150000002367 halogens Chemical class 0.000 claims description 75
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 73
• 125000004598 dihydrobenzofuryl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 72
• 125000001424 substituent group Chemical group 0.000 claims description 70
• 150000005529 1,3-benzodioxoles Chemical class 0.000 claims description 57
• 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 56
• 125000005154 alkyl sulfonyl amino alkyl group Chemical group 0.000 claims description 52
• BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical class C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 claims description 52
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 49
• 150000002431 hydrogen Chemical class 0.000 claims description 49
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 49
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
• GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 claims description 44
• HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 44
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 43
• 150000002148 esters Chemical class 0.000 claims description 41
• 125000004212 difluorophenyl group Chemical group 0.000 claims description 40
• 125000005805 dimethoxy phenyl group Chemical group 0.000 claims description 40
• 125000005111 carboxyalkoxy group Chemical group 0.000 claims description 37
• 150000003235 pyrrolidines Chemical class 0.000 claims description 37
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 36
• 229910052736 halogen Inorganic materials 0.000 claims description 35
• 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 32
• 125000000304 alkynyl group Chemical group 0.000 claims description 32
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 31
• 125000005309 thioalkoxy group Chemical group 0.000 claims description 30
• 125000005081 alkoxyalkoxyalkyl group Chemical group 0.000 claims description 28
• 125000004171 alkoxy aryl group Chemical group 0.000 claims description 27
• 125000003368 amide group Chemical group 0.000 claims description 26
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 26
• HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical class C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 claims description 25
• 125000002947 alkylene group Chemical group 0.000 claims description 25
• 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 24
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
• 238000011282 treatment Methods 0.000 claims description 23
• 239000002253 acid Substances 0.000 claims description 22
• 125000001589 carboacyl group Chemical group 0.000 claims description 22
• 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 21
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
• 125000003282 alkyl amino group Chemical group 0.000 claims description 20
• 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 20
• 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 19
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 18
• 238000006243 chemical reaction Methods 0.000 claims description 18
• ABADUMLIAZCWJD-UHFFFAOYSA-N 1,3-dioxole Chemical compound C1OC=CO1 ABADUMLIAZCWJD-UHFFFAOYSA-N 0.000 claims description 17
• 241000124008 Mammalia Species 0.000 claims description 17
• PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 17
• 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 17
• 229910018828 PO3H2 Inorganic materials 0.000 claims description 16
• 239000003513 alkali Substances 0.000 claims description 16
• 125000002541 furyl group Chemical group 0.000 claims description 16
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 15
• 239000003054 catalyst Substances 0.000 claims description 15
• 230000000694 effects Effects 0.000 claims description 15
• 201000010099 disease Diseases 0.000 claims description 14
• 229910052757 nitrogen Inorganic materials 0.000 claims description 14
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
• 230000008485 antagonism Effects 0.000 claims description 12
• 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 11
• 206010002383 Angina Pectoris Diseases 0.000 claims description 11
• 206010063837 Reperfusion injury Diseases 0.000 claims description 11
• 230000002460 anti-migrenic effect Effects 0.000 claims description 11
• 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 11
• 206010009887 colitis Diseases 0.000 claims description 11
• 208000002815 pulmonary hypertension Diseases 0.000 claims description 11
• 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 10
• 230000009467 reduction Effects 0.000 claims description 10
• 125000004104 aryloxy group Chemical group 0.000 claims description 9
• 238000006467 substitution reaction Methods 0.000 claims description 9
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 8
• 229910052759 nickel Inorganic materials 0.000 claims description 8
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 7
• PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 7
• 229930105110 Cyclosporin A Natural products 0.000 claims description 7
• 108010036949 Cyclosporine Proteins 0.000 claims description 7
• 229960001265 ciclosporin Drugs 0.000 claims description 7
• 229930182912 cyclosporin Natural products 0.000 claims description 7
• 238000006345 epimerization reaction Methods 0.000 claims description 7
• 238000005984 hydrogenation reaction Methods 0.000 claims description 7
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 7
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 6
• 208000003782 Raynaud disease Diseases 0.000 claims description 6
• 208000012322 Raynaud phenomenon Diseases 0.000 claims description 6
• 208000007107 Stomach Ulcer Diseases 0.000 claims description 6
• 230000006378 damage Effects 0.000 claims description 6
• 201000005917 gastric ulcer Diseases 0.000 claims description 6
• 230000006698 induction Effects 0.000 claims description 6
• OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 6
• 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 5
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
• 102000004506 Blood Proteins Human genes 0.000 claims description 4
• 108010017384 Blood Proteins Proteins 0.000 claims description 4
• 239000001273 butane Substances 0.000 claims description 4
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 4
• 238000001727 in vivo Methods 0.000 claims description 4
• 230000029936 alkylation Effects 0.000 claims description 3
• 238000005804 alkylation reaction Methods 0.000 claims description 3
• 230000027455 binding Effects 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
• ZKNHDJMXIUOHLX-UHFFFAOYSA-N 2-ethoxy-1,1,1-trifluoroethane Chemical compound CCOCC(F)(F)F ZKNHDJMXIUOHLX-UHFFFAOYSA-N 0.000 claims description 2
• AAPXFUYUGJQZQE-UHFFFAOYSA-N C(CCC)[C]N Chemical compound C(CCC)[C]N AAPXFUYUGJQZQE-UHFFFAOYSA-N 0.000 claims description 2
• 125000002521 alkyl halide group Chemical group 0.000 claims description 2
• 235000013847 iso-butane Nutrition 0.000 claims description 2
• 231100000417 nephrotoxicity Toxicity 0.000 claims description 2
• 230000001154 acute effect Effects 0.000 claims 10
• 201000001320 Atherosclerosis Diseases 0.000 claims 8
• 201000006474 Brain Ischemia Diseases 0.000 claims 8
• 206010007559 Cardiac failure congestive Diseases 0.000 claims 8
• 206010019280 Heart failures Diseases 0.000 claims 8
• 206010020772 Hypertension Diseases 0.000 claims 8
• 210000004556 brain Anatomy 0.000 claims 8
• 208000031225 myocardial ischemia Diseases 0.000 claims 8
• 231100000419 toxicity Toxicity 0.000 claims 8
• 230000001988 toxicity Effects 0.000 claims 8
• 206010003162 Arterial injury Diseases 0.000 claims 7
• 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims 7
• 208000009304 Acute Kidney Injury Diseases 0.000 claims 5
• 206010051055 Deep vein thrombosis Diseases 0.000 claims 5
• 108010002350 Interleukin-2 Proteins 0.000 claims 5
• 102000004895 Lipoproteins Human genes 0.000 claims 5
• 108090001030 Lipoproteins Proteins 0.000 claims 5
• 206010028980 Neoplasm Diseases 0.000 claims 5
• 208000001647 Renal Insufficiency Diseases 0.000 claims 5
• 208000033626 Renal failure acute Diseases 0.000 claims 5
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• 208000006673 asthma Diseases 0.000 claims 5
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• 230000002062 proliferating effect Effects 0.000 claims 5
• 208000010110 spontaneous platelet aggregation Diseases 0.000 claims 5
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• 239000008194 pharmaceutical composition Substances 0.000 claims 4
• 230000002526 effect on cardiovascular system Effects 0.000 claims 2
• 239000002327 cardiovascular agent Substances 0.000 claims 1
• 229940125692 cardiovascular agent Drugs 0.000 claims 1
• 230000005611 electricity Effects 0.000 claims 1
• IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims 1
• 231100000572 poisoning Toxicity 0.000 claims 1
• 230000000607 poisoning effect Effects 0.000 claims 1
• BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical group [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 1
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• 238000002360 preparation method Methods 0.000 abstract description 6
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• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 109
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• 238000005160 1H NMR spectroscopy Methods 0.000 description 69
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• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 33
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 32
• 229910000069 nitrogen hydride Inorganic materials 0.000 description 30
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• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
• 235000002639 sodium chloride Nutrition 0.000 description 24
• 230000002902 bimodal effect Effects 0.000 description 22
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• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 21
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• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 13
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 13
• XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 13
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• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
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