HRP940346A2

HRP940346A2 - Imidazole 5-position substituted angiotensin ii antagonists

Imidazole 5-position substituted angiotensin ii antagonists Download PDF

Info

Publication number: HRP940346A2
Authority: HR; Croatia
Prior art keywords: alkyl; ethyl; biphenyl; methyl; propyl
Prior art date: 1993-06-10

Application number

HR08/072,977A

Other languages

English (en)

Croatian (hr)

Original Assignee

Du Pont Merck Pharma

Priority date

1993-06-10

Filing date

1994-06-09

Publication date

1996-12-31

1994-06-09 Application filed by Du Pont Merck Pharma filed Critical Du Pont Merck Pharma

1996-12-31 Publication of HRP940346A2 publication Critical patent/HRP940346A2/hr

Links

RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title description 58
229940123413 Angiotensin II antagonist Drugs 0.000 title description 3
239000002333 angiotensin II receptor antagonist Substances 0.000 title description 3
238000000034 method Methods 0.000 claims description 129
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 110
150000001875 compounds Chemical class 0.000 claims description 97
-1 C1-C4-alkyl Chemical group 0.000 claims description 94
ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 78
125000003118 aryl group Chemical group 0.000 claims description 66
125000005843 halogen group Chemical group 0.000 claims description 52
235000010290 biphenyl Nutrition 0.000 claims description 46
125000001072 heteroaryl group Chemical group 0.000 claims description 45
125000001424 substituent group Chemical group 0.000 claims description 44
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 43
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 37
150000003839 salts Chemical class 0.000 claims description 36
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 33
125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 claims description 32
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 31
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 22
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 22
229910052801 chlorine Inorganic materials 0.000 claims description 18
239000004305 biphenyl Substances 0.000 claims description 17
229910052794 bromium Inorganic materials 0.000 claims description 17
229910052731 fluorine Inorganic materials 0.000 claims description 17
229910052740 iodine Inorganic materials 0.000 claims description 17
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 14
125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 13
125000005010 perfluoroalkyl group Chemical group 0.000 claims description 12
206010020772 Hypertension Diseases 0.000 claims description 11
229910018828 PO3H2 Inorganic materials 0.000 claims description 10
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 8
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
229910052736 halogen Inorganic materials 0.000 claims description 8
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 claims description 7
150000002367 halogens Chemical class 0.000 claims description 7
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 6
125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
241001465754 Metazoa Species 0.000 claims description 5
125000000732 arylene group Chemical group 0.000 claims description 5
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 5
125000001624 naphthyl group Chemical group 0.000 claims description 5
239000000825 pharmaceutical preparation Substances 0.000 claims description 5
XXEQGYPNXJWJLV-UHFFFAOYSA-N (3-anilino-3-oxopropyl) 5-ethyl-2-propyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylate Chemical compound C=1C=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=CC=1CN1C(CCC)=NC(CC)=C1C(=O)OCCC(=O)NC1=CC=CC=C1 XXEQGYPNXJWJLV-UHFFFAOYSA-N 0.000 claims description 4
125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
229910004727 OSO3H Inorganic materials 0.000 claims description 4
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
229910006069 SO3H Inorganic materials 0.000 claims description 4
125000006347 bis(trifluoromethyl)hydroxymethyl group Chemical group [H]OC(*)(C(F)(F)F)C(F)(F)F 0.000 claims description 4
239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 4
125000005549 heteroarylene group Chemical group 0.000 claims description 4
VGCFKIQQCCIPGR-UHFFFAOYSA-N propyl 5-ethyl-2-propyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylate Chemical compound CCCOC(=O)C1=C(CC)N=C(CCC)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 VGCFKIQQCCIPGR-UHFFFAOYSA-N 0.000 claims description 4
ZUUBORJFIVFRAP-UHFFFAOYSA-N butyl n-[2-[4-[[4-ethyl-5-[2-(2-phenoxyphenoxy)acetyl]-2-propylimidazol-1-yl]methyl]-3-fluorophenyl]phenyl]sulfonylcarbamate Chemical compound CCCCOC(=O)NS(=O)(=O)C1=CC=CC=C1C(C=C1F)=CC=C1CN1C(C(=O)COC=2C(=CC=CC=2)OC=2C=CC=CC=2)=C(CC)N=C1CCC ZUUBORJFIVFRAP-UHFFFAOYSA-N 0.000 claims description 3
CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 3
208000019622 heart disease Diseases 0.000 claims description 3
125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 2
125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 2
125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 2
125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 2
208000020446 Cardiac disease Diseases 0.000 claims description 2
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 2
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
125000002877 alkyl aryl group Chemical group 0.000 claims description 2
YMWOHWOUQZNMOK-UHFFFAOYSA-N butyl n-[2-[4-[[4-ethyl-2-propyl-5-[3-[pyridine-4-carbonyl(pyridin-3-yl)amino]propanoyl]imidazol-1-yl]methyl]-3-fluorophenyl]phenyl]sulfonylcarbamate Chemical compound CCCCOC(=O)NS(=O)(=O)C1=CC=CC=C1C(C=C1F)=CC=C1CN1C(C(=O)CCN(C(=O)C=2C=CN=CC=2)C=2C=NC=CC=2)=C(CC)N=C1CCC YMWOHWOUQZNMOK-UHFFFAOYSA-N 0.000 claims description 2
UFDNVPGOVBPTGU-UHFFFAOYSA-N butyl n-[2-[4-[[5-[3-[acetyl(pyridin-3-yl)amino]propanoyl]-4-ethyl-2-propylimidazol-1-yl]methyl]-3-fluorophenyl]phenyl]sulfonylcarbamate Chemical compound CCCCOC(=O)NS(=O)(=O)C1=CC=CC=C1C(C=C1F)=CC=C1CN1C(C(=O)CCN(C(C)=O)C=2C=NC=CC=2)=C(CC)N=C1CCC UFDNVPGOVBPTGU-UHFFFAOYSA-N 0.000 claims description 2
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 2
SXPUVBFQXJHYNS-UHFFFAOYSA-N α-furil Chemical compound C=1C=COC=1C(=O)C(=O)C1=CC=CO1 SXPUVBFQXJHYNS-UHFFFAOYSA-N 0.000 claims description 2
101100440695 Dictyostelium discoideum corB gene Proteins 0.000 claims 1
JUDBPCYNUQJHIU-UHFFFAOYSA-N butyl n-[2-[4-[[4-ethyl-2-propyl-5-[3-[pyridine-3-carbonyl(pyridin-3-yl)amino]propanoyl]imidazol-1-yl]methyl]-3-fluorophenyl]phenyl]sulfonylcarbamate Chemical compound CCCCOC(=O)NS(=O)(=O)C1=CC=CC=C1C(C=C1F)=CC=C1CN1C(C(=O)CCN(C(=O)C=2C=NC=CC=2)C=2C=NC=CC=2)=C(CC)N=C1CCC JUDBPCYNUQJHIU-UHFFFAOYSA-N 0.000 claims 1
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 178
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 140
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 126
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 106
238000002360 preparation method Methods 0.000 description 98
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 86
238000005160 1H NMR spectroscopy Methods 0.000 description 72
238000006243 chemical reaction Methods 0.000 description 72
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 68
239000000243 solution Substances 0.000 description 68
239000000047 product Substances 0.000 description 63
239000000203 mixture Substances 0.000 description 62
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 53
235000019439 ethyl acetate Nutrition 0.000 description 53
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 47
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
238000003786 synthesis reaction Methods 0.000 description 45
230000015572 biosynthetic process Effects 0.000 description 44
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
150000001412 amines Chemical class 0.000 description 39
150000001732 carboxylic acid derivatives Chemical class 0.000 description 39
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
239000002904 solvent Substances 0.000 description 36
239000011541 reaction mixture Substances 0.000 description 35
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
125000004178 (C1-C4) alkyl group Chemical group 0.000 description 31
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 30
102000005862 Angiotensin II Human genes 0.000 description 28
101800000733 Angiotensin-2 Proteins 0.000 description 28
150000002576 ketones Chemical group 0.000 description 28
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
229950006323 angiotensin ii Drugs 0.000 description 27
239000012267 brine Substances 0.000 description 27
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 27
238000003818 flash chromatography Methods 0.000 description 26
CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox 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](C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 25
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 25
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
230000029936 alkylation Effects 0.000 description 24
238000005804 alkylation reaction Methods 0.000 description 24
150000001299 aldehydes Chemical class 0.000 description 23
150000001408 amides Chemical class 0.000 description 23
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
238000005481 NMR spectroscopy Methods 0.000 description 22
239000003921 oil Substances 0.000 description 22
235000019198 oils Nutrition 0.000 description 22
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
125000000217 alkyl group Chemical group 0.000 description 21
238000006482 condensation reaction Methods 0.000 description 21
229910052943 magnesium sulfate Inorganic materials 0.000 description 21
235000019341 magnesium sulphate Nutrition 0.000 description 21
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
239000010410 layer Substances 0.000 description 20
239000012442 inert solvent Substances 0.000 description 19
239000000741 silica gel Substances 0.000 description 17
229910002027 silica gel Inorganic materials 0.000 description 17
230000002378 acidificating effect Effects 0.000 description 16
239000011521 glass Substances 0.000 description 16
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 15
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
230000003647 oxidation Effects 0.000 description 15
238000007254 oxidation reaction Methods 0.000 description 15
229910000027 potassium carbonate Inorganic materials 0.000 description 15
238000010992 reflux Methods 0.000 description 15
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 14
239000002253 acid Substances 0.000 description 14
229910052757 nitrogen Chemical group 0.000 description 13
150000003141 primary amines Chemical class 0.000 description 13
239000007787 solid Substances 0.000 description 13
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 12
239000000460 chlorine Substances 0.000 description 12
150000002460 imidazoles Chemical class 0.000 description 12
238000000746 purification Methods 0.000 description 12
239000007858 starting material Substances 0.000 description 12
241000700159 Rattus Species 0.000 description 11
XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 11
239000000284 extract Substances 0.000 description 11
239000012299 nitrogen atmosphere Substances 0.000 description 11
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
150000001345 alkine derivatives Chemical class 0.000 description 10
239000003153 chemical reaction reagent Substances 0.000 description 10
238000001914 filtration Methods 0.000 description 10
238000005984 hydrogenation reaction Methods 0.000 description 10
150000002513 isocyanates Chemical class 0.000 description 10
229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 10
239000012044 organic layer Substances 0.000 description 10
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
102000005962 receptors Human genes 0.000 description 10
108020003175 receptors Proteins 0.000 description 10
230000002829 reductive effect Effects 0.000 description 10
102100040372 Type-2 angiotensin II receptor Human genes 0.000 description 9
235000013877 carbamide Nutrition 0.000 description 9
239000012043 crude product Substances 0.000 description 9
239000000543 intermediate Substances 0.000 description 9
239000012948 isocyanate Substances 0.000 description 9
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 9
229940093956 potassium carbonate Drugs 0.000 description 9
235000011181 potassium carbonates Nutrition 0.000 description 9
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
238000007239 Wittig reaction Methods 0.000 description 8
150000001336 alkenes Chemical class 0.000 description 8
239000002934 diuretic Substances 0.000 description 8
239000000706 filtrate Substances 0.000 description 8
238000010438 heat treatment Methods 0.000 description 8
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 8
239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 8
NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 8
LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 8
150000003254 radicals Chemical class 0.000 description 8
229940124530 sulfonamide Drugs 0.000 description 8
150000003456 sulfonamides Chemical class 0.000 description 8
KLVDUSUYBDMJKR-SANMLTNESA-N (6s)-1-[(4-amino-3-methylphenyl)methyl]-5-(2,2-diphenylacetyl)-6,7-dihydro-4h-imidazo[4,5-c]pyridine-6-carboxylic acid Chemical compound C1=C(N)C(C)=CC(CN2C=3C[C@H](N(CC=3N=C2)C(=O)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C(O)=O)=C1 KLVDUSUYBDMJKR-SANMLTNESA-N 0.000 description 7
125000003342 alkenyl group Chemical group 0.000 description 7
125000000304 alkynyl group Chemical group 0.000 description 7
239000003054 catalyst Substances 0.000 description 7
239000003814 drug Substances 0.000 description 7
HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 7
OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 7
239000012266 salt solution Substances 0.000 description 7
235000017557 sodium bicarbonate Nutrition 0.000 description 7
229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
101150116411 AGTR2 gene Proteins 0.000 description 6
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
150000004703 alkoxides Chemical class 0.000 description 6
239000005557 antagonist Substances 0.000 description 6
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