IL134905A

IL134905A - Intermediates for endothelin antagonistic pyrrolidine derivatives, their preparation and pharmaceutical compositions comprising them

Intermediates for endothelin antagonistic pyrrolidine derivatives, their preparation and pharmaceutical compositions comprising them

Info

Publication number: IL134905A
Authority: IL; Israel
Prior art keywords: benzodioxol; frans; pyrrolidine; carboxylic acid; methoxyphenyl
Prior art date: 1994-08-19

Application number

IL134905A

Other languages

English (en)

Other versions

IL134905A0 (en

Original Assignee

Abbott Lab

Priority date

1994-08-19

Filing date

1995-08-10

Publication date

2009-06-15

1995-05-30 Priority claimed from US08/442,575 external-priority patent/US5767144A/en

1995-08-10 Application filed by Abbott Lab filed Critical Abbott Lab

2001-05-20 Publication of IL134905A0 publication Critical patent/IL134905A0/xx

2009-06-15 Publication of IL134905A publication Critical patent/IL134905A/en

Links

108050009340 Endothelin Proteins 0.000 title claims abstract description 24
102000002045 Endothelin Human genes 0.000 title claims abstract description 24
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 23
238000002360 preparation method Methods 0.000 title claims description 19
230000003042 antagnostic effect Effects 0.000 title claims description 8
239000008194 pharmaceutical composition Substances 0.000 title claims description 5
239000000543 intermediate Substances 0.000 title abstract description 18
150000003235 pyrrolidines Chemical class 0.000 title description 11
238000000034 method Methods 0.000 claims abstract description 294
150000003839 salts Chemical class 0.000 claims abstract description 28
230000008569 process Effects 0.000 claims abstract description 11
150000001875 compounds Chemical class 0.000 claims description 482
-1 loweralkyi Chemical group 0.000 claims description 222
229910052739 hydrogen Inorganic materials 0.000 claims description 179
239000000203 mixture Substances 0.000 claims description 141
239000001257 hydrogen Substances 0.000 claims description 47
125000002947 alkylene group Chemical group 0.000 claims description 46
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 44
125000000623 heterocyclic group Chemical group 0.000 claims description 43
125000003118 aryl group Chemical group 0.000 claims description 39
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 33
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 32
125000003545 alkoxy group Chemical group 0.000 claims description 29
125000003342 alkenyl group Chemical group 0.000 claims description 18
125000000217 alkyl group Chemical group 0.000 claims description 18
125000003710 aryl alkyl group Chemical group 0.000 claims description 16
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
125000000304 alkynyl group Chemical group 0.000 claims description 13
125000000753 cycloalkyl group Chemical group 0.000 claims description 13
239000003814 drug Substances 0.000 claims description 13
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
125000003282 alkyl amino group Chemical group 0.000 claims description 12
125000004663 dialkyl amino group Chemical group 0.000 claims description 12
125000004183 alkoxy alkyl group Chemical group 0.000 claims description 11
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
125000004450 alkenylene group Chemical group 0.000 claims description 10
201000001320 Atherosclerosis Diseases 0.000 claims description 8
125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 8
125000001188 haloalkyl group Chemical group 0.000 claims description 8
125000005081 alkoxyalkoxyalkyl group Chemical group 0.000 claims description 7
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 7
206010007559 Cardiac failure congestive Diseases 0.000 claims description 6
206010019280 Heart failures Diseases 0.000 claims description 6
206010003162 Arterial injury Diseases 0.000 claims description 5
206010020772 Hypertension Diseases 0.000 claims description 5
125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 5
239000002327 cardiovascular agent Substances 0.000 claims description 5
229940125692 cardiovascular agent Drugs 0.000 claims description 5
125000005020 hydroxyalkenyl group Chemical group 0.000 claims description 5
208000031225 myocardial ischemia Diseases 0.000 claims description 5
208000037803 restenosis Diseases 0.000 claims description 5
201000006474 Brain Ischemia Diseases 0.000 claims description 4
206010008120 Cerebral ischaemia Diseases 0.000 claims description 4
125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 4
206010008118 cerebral infarction Diseases 0.000 claims description 4
IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 claims description 4
239000003937 drug carrier Substances 0.000 claims description 3
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
238000004519 manufacturing process Methods 0.000 claims description 3
125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 3
WOHZPAAHKICDQP-UHFFFAOYSA-N 1-ethyl-3-fluoropyrrolidine Chemical compound CCN1CCC(F)C1 WOHZPAAHKICDQP-UHFFFAOYSA-N 0.000 claims description 2
150000002431 hydrogen Chemical group 0.000 claims 3
230000002490 cerebral effect Effects 0.000 claims 2
125000001589 carboacyl group Chemical group 0.000 claims 1
208000028867 ischemia Diseases 0.000 claims 1
239000005557 antagonist Substances 0.000 abstract description 6
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 307
238000005481 NMR spectroscopy Methods 0.000 description 222
239000002253 acid Substances 0.000 description 187
239000000243 solution Substances 0.000 description 159
229910000069 nitrogen hydride Inorganic materials 0.000 description 149
CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 145
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 140
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 139
229910001868 water Inorganic materials 0.000 description 121
239000007787 solid Substances 0.000 description 105
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 100
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 96
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 92
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 89
JAEIBKXSIXOLOL-UHFFFAOYSA-N pyrrolidin-1-ium-3-carboxylate Chemical compound OC(=O)C1CCNC1 JAEIBKXSIXOLOL-UHFFFAOYSA-N 0.000 description 85
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 79
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 76
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 70
OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 68
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 63
SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 60
239000000047 product Substances 0.000 description 57
235000019439 ethyl acetate Nutrition 0.000 description 55
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 50
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 50
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 48
150000002148 esters Chemical class 0.000 description 45
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 42
230000002829 reductive effect Effects 0.000 description 41
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 38
239000000741 silica gel Substances 0.000 description 37
229910002027 silica gel Inorganic materials 0.000 description 37
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 35
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 33
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 30
239000012043 crude product Substances 0.000 description 30
229940081310 piperonal Drugs 0.000 description 30
238000006243 chemical reaction Methods 0.000 description 29
239000011541 reaction mixture Substances 0.000 description 28
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 27
GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 25
239000012267 brine Substances 0.000 description 24
FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 24
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 22
WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 22
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 21
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
125000004494 ethyl ester group Chemical group 0.000 description 20
238000003818 flash chromatography Methods 0.000 description 20
239000003921 oil Substances 0.000 description 20
235000019198 oils Nutrition 0.000 description 20
239000002904 solvent Substances 0.000 description 20
125000001424 substituent group Chemical group 0.000 description 20
238000003756 stirring Methods 0.000 description 18
239000010410 layer Substances 0.000 description 17
239000000706 filtrate Substances 0.000 description 16
239000012074 organic phase Substances 0.000 description 16
125000006308 propyl amino group Chemical group 0.000 description 16
125000005877 1,4-benzodioxanyl group Chemical group 0.000 description 15
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
125000005871 1,3-benzodioxolyl group Chemical group 0.000 description 14
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 14
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
229960000583 acetic acid Drugs 0.000 description 14
125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 14
238000000746 purification Methods 0.000 description 14
JWEQRJSCTFBRSI-PCLIKHOPSA-N rboxylate Chemical compound COC(=O)C1C(N2C3=O)C4=CC=CC=C4OC1(C)N=C2S\C3=C\C(C=1)=CC=C(OC)C=1COC1=CC=CC=C1C JWEQRJSCTFBRSI-PCLIKHOPSA-N 0.000 description 14
238000007792 addition Methods 0.000 description 13
125000005083 alkoxyalkoxy group Chemical group 0.000 description 13
239000006260 foam Substances 0.000 description 13
229910000104 sodium hydride Inorganic materials 0.000 description 13
229910052938 sodium sulfate Inorganic materials 0.000 description 13
235000011152 sodium sulphate Nutrition 0.000 description 13
238000006467 substitution reaction Methods 0.000 description 13
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
150000001732 carboxylic acid derivatives Chemical class 0.000 description 12
210000004027 cell Anatomy 0.000 description 12
239000012230 colorless oil Substances 0.000 description 12
239000012299 nitrogen atmosphere Substances 0.000 description 12
235000015497 potassium bicarbonate Nutrition 0.000 description 12
229910000028 potassium bicarbonate Inorganic materials 0.000 description 12
239000011736 potassium bicarbonate Substances 0.000 description 12
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 12
239000000843 powder Substances 0.000 description 12
XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 11
125000005111 carboxyalkoxy group Chemical group 0.000 description 11
239000003054 catalyst Substances 0.000 description 11
239000000284 extract Substances 0.000 description 11
230000007062 hydrolysis Effects 0.000 description 11
238000006460 hydrolysis reaction Methods 0.000 description 11
239000007858 starting material Substances 0.000 description 11
238000001665 trituration Methods 0.000 description 11
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 10
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
239000008346 aqueous phase Substances 0.000 description 10
239000002585 base Substances 0.000 description 10
JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 10
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
238000001914 filtration Methods 0.000 description 10
235000011167 hydrochloric acid Nutrition 0.000 description 10
229910052757 nitrogen Inorganic materials 0.000 description 10
238000002953 preparative HPLC Methods 0.000 description 10
229910000029 sodium carbonate Inorganic materials 0.000 description 10
238000004809 thin layer chromatography Methods 0.000 description 10
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
125000002252 acyl group Chemical group 0.000 description 9
125000004453 alkoxycarbonyl group Chemical group 0.000 description 9
HLSNQZQSNWFXET-UHFFFAOYSA-N benzofuran-6-carboxaldehyde Natural products O=CC1=CC=C2C=COC2=C1 HLSNQZQSNWFXET-UHFFFAOYSA-N 0.000 description 9
239000013078 crystal Substances 0.000 description 9
ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 9
KRAHENMBSVAAHD-UHFFFAOYSA-N ethyl 3-(4-methoxyphenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=C(OC)C=C1 KRAHENMBSVAAHD-UHFFFAOYSA-N 0.000 description 9
238000010438 heat treatment Methods 0.000 description 9
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
101800004490 Endothelin-1 Proteins 0.000 description 8
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
125000004432 carbon atom Chemical group C* 0.000 description 8
238000009903 catalytic hydrogenation reaction Methods 0.000 description 8
WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
125000006239 protecting group Chemical group 0.000 description 8
150000003254 radicals Chemical class 0.000 description 8
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 8
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 8
235000009518 sodium iodide Nutrition 0.000 description 8
125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 7
125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 7
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 7
125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
102400000686 Endothelin-1 Human genes 0.000 description 7
DZJXKISLUDYJSV-UHFFFAOYSA-N [N].C1CCNC1 Chemical compound [N].C1CCNC1 DZJXKISLUDYJSV-UHFFFAOYSA-N 0.000 description 7
150000001412 amines Chemical class 0.000 description 7
150000003857 carboxamides Chemical class 0.000 description 7
238000001816 cooling Methods 0.000 description 7
125000004212 difluorophenyl group Chemical group 0.000 description 7
125000005805 dimethoxy phenyl group Chemical group 0.000 description 7
238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 7
125000001207 fluorophenyl group Chemical group 0.000 description 7
230000005764 inhibitory process Effects 0.000 description 7
SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 7
150000002825 nitriles Chemical class 0.000 description 7
239000012044 organic layer Substances 0.000 description 7
239000011369 resultant mixture Substances 0.000 description 7
239000012312 sodium hydride Substances 0.000 description 7
239000000725 suspension Substances 0.000 description 7
125000005309 thioalkoxy group Chemical group 0.000 description 7
WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 6
WEBVDBDZSOJGPB-UHFFFAOYSA-N 2,3-dihydro-1-benzofuran-5-carbaldehyde Chemical group O=CC1=CC=C2OCCC2=C1 WEBVDBDZSOJGPB-UHFFFAOYSA-N 0.000 description 6
MALIONKMKPITBV-UHFFFAOYSA-N 2-(3-chloro-4-hydroxyphenyl)-n-[2-(4-sulfamoylphenyl)ethyl]acetamide Chemical compound C1=CC(S(=O)(=O)N)=CC=C1CCNC(=O)CC1=CC=C(O)C(Cl)=C1 MALIONKMKPITBV-UHFFFAOYSA-N 0.000 description 6
JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 description 6
NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 description 6
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 6
WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
230000027455 binding Effects 0.000 description 6
125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 6
201000010099 disease Diseases 0.000 description 6
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