WO1992000068A1 - Substituted histidines - Google Patents
Substituted histidines Download PDFInfo
- Publication number
- WO1992000068A1 WO1992000068A1 PCT/US1991/004561 US9104561W WO9200068A1 WO 1992000068 A1 WO1992000068 A1 WO 1992000068A1 US 9104561 W US9104561 W US 9104561W WO 9200068 A1 WO9200068 A1 WO 9200068A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- chlorophenyl
- compound
- propylthio
- alkyl
- Prior art date
Links
- 235000014304 histidine Nutrition 0.000 title description 5
- 150000002411 histidines Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 110
- 238000000034 method Methods 0.000 claims abstract description 46
- 206010019280 Heart failures Diseases 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 206010007559 Cardiac failure congestive Diseases 0.000 claims abstract description 9
- 206010020772 Hypertension Diseases 0.000 claims abstract description 9
- 241000124008 Mammalia Species 0.000 claims abstract description 9
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 8
- 102000008873 Angiotensin II receptor Human genes 0.000 claims abstract description 7
- 108050000824 Angiotensin II receptor Proteins 0.000 claims abstract description 7
- 208000001647 Renal Insufficiency Diseases 0.000 claims abstract description 7
- 201000006370 kidney failure Diseases 0.000 claims abstract description 7
- -1 C1-C6alkoxy Chemical group 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- WCYQRIDGGHVQFE-AWEZNQCLSA-N (2s)-2-amino-3-[3-[(2-chlorophenyl)methyl]-2-propylimidazol-4-yl]propanethioic s-acid Chemical compound CCCC1=NC=C(C[C@H](N)C(O)=S)N1CC1=CC=CC=C1Cl WCYQRIDGGHVQFE-AWEZNQCLSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 7
- GNCOEGPFZGNSBH-SFHVURJKSA-N (2s)-2-(butanoylamino)-3-[2-butyl-3-[(2-chlorophenyl)methyl]imidazol-4-yl]propanoic acid Chemical compound CCCCC1=NC=C(C[C@H](NC(=O)CCC)C(O)=O)N1CC1=CC=CC=C1Cl GNCOEGPFZGNSBH-SFHVURJKSA-N 0.000 claims description 6
- KZBKSOLOEBLFKO-INIZCTEOSA-N (2s)-2-acetamido-3-[3-[(2-chlorophenyl)methyl]-2-propylsulfanylimidazol-4-yl]propanoic acid Chemical compound CCCSC1=NC=C(C[C@H](NC(C)=O)C(O)=O)N1CC1=CC=CC=C1Cl KZBKSOLOEBLFKO-INIZCTEOSA-N 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- URMIEEZKVGLMOS-KRWDZBQOSA-N (2s)-2-(butanoylamino)-3-[3-[(2-chlorophenyl)methyl]-2-propylsulfanylimidazol-4-yl]propanoic acid Chemical compound CCCSC1=NC=C(C[C@H](NC(=O)CCC)C(O)=O)N1CC1=CC=CC=C1Cl URMIEEZKVGLMOS-KRWDZBQOSA-N 0.000 claims description 5
- DKBNZFWWTGEUNI-FQEVSTJZSA-N (2s)-2-benzamido-3-[3-[(2-chlorophenyl)methyl]-2-propylsulfanylimidazol-4-yl]propanoic acid Chemical compound N([C@@H](CC1=CN=C(N1CC=1C(=CC=CC=1)Cl)SCCC)C(O)=O)C(=O)C1=CC=CC=C1 DKBNZFWWTGEUNI-FQEVSTJZSA-N 0.000 claims description 5
- NNWUGZDMNKTVDV-SFHVURJKSA-N (2s)-3-[3-[(2-chlorophenyl)methyl]-2-propylsulfanylimidazol-4-yl]-2-(3-methylbutanoylamino)propanoic acid Chemical compound CCCSC1=NC=C(C[C@H](NC(=O)CC(C)C)C(O)=O)N1CC1=CC=CC=C1Cl NNWUGZDMNKTVDV-SFHVURJKSA-N 0.000 claims description 5
- 239000004305 biphenyl Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- DRSZJICCKJHXCY-KRWDZBQOSA-N (2s)-3-[2-butyl-3-[(2-chlorophenyl)methyl]imidazol-4-yl]-2-(propanoylamino)propanoic acid Chemical compound CCCCC1=NC=C(C[C@H](NC(=O)CC)C(O)=O)N1CC1=CC=CC=C1Cl DRSZJICCKJHXCY-KRWDZBQOSA-N 0.000 claims description 4
- JDTIADSNMHNCOY-MHZLTWQESA-N (2s)-3-[2-butyl-3-[(2-chlorophenyl)methyl]imidazol-4-yl]-2-[(2,2-diphenylacetyl)amino]propanoic acid Chemical compound N([C@@H](CC1=CN=C(N1CC=1C(=CC=CC=1)Cl)CCCC)C(O)=O)C(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1 JDTIADSNMHNCOY-MHZLTWQESA-N 0.000 claims description 4
- NJOZNRPYDMKTSN-IBGZPJMESA-N (2s)-3-[3-[(2-chlorophenyl)methyl]-2-propylsulfanylimidazol-4-yl]-2-(cyclopentanecarbonylamino)propanoic acid Chemical compound N([C@@H](CC1=CN=C(N1CC=1C(=CC=CC=1)Cl)SCCC)C(O)=O)C(=O)C1CCCC1 NJOZNRPYDMKTSN-IBGZPJMESA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000003042 antagnostic effect Effects 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 229910006069 SO3H Inorganic materials 0.000 claims description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 239000005557 antagonist Substances 0.000 abstract description 10
- 239000002333 angiotensin II receptor antagonist Substances 0.000 abstract description 4
- 230000008485 antagonism Effects 0.000 abstract description 3
- 230000001105 regulatory effect Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 40
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 35
- 239000000243 solution Substances 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 239000000203 mixture Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 102000005862 Angiotensin II Human genes 0.000 description 14
- 101800000733 Angiotensin-2 Proteins 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 125000000217 alkyl group Chemical group 0.000 description 14
- 229950006323 angiotensin ii Drugs 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 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 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 230000036454 renin-angiotensin system Effects 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical group O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- ZOAIEIGFVKULON-UHFFFAOYSA-N [2-butyl-3-[(2-chlorophenyl)methyl]imidazol-4-yl]methanol Chemical compound CCCCC1=NC=C(CO)N1CC1=CC=CC=C1Cl ZOAIEIGFVKULON-UHFFFAOYSA-N 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 4
- QYNTVRFDSZYJQN-KRWDZBQOSA-N ethyl (2s)-2-amino-3-[2-butyl-3-[(2-chlorophenyl)methyl]imidazol-4-yl]propanoate Chemical compound CCCCC1=NC=C(C[C@H](N)C(=O)OCC)N1CC1=CC=CC=C1Cl QYNTVRFDSZYJQN-KRWDZBQOSA-N 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- WMUIAIJZZCLHBA-INIZCTEOSA-N o-ethyl (2s)-2-amino-3-[3-[(2-chlorophenyl)methyl]-2-propylimidazol-4-yl]propanethioate Chemical compound CCCC1=NC=C(C[C@H](N)C(=S)OCC)N1CC1=CC=CC=C1Cl WMUIAIJZZCLHBA-INIZCTEOSA-N 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 3
- ZOMATQMEHRJKLO-UHFFFAOYSA-N 1h-imidazol-2-ylmethanol Chemical class OCC1=NC=CN1 ZOMATQMEHRJKLO-UHFFFAOYSA-N 0.000 description 3
- QDIAKNVAAGSOEB-UHFFFAOYSA-N 2-butyl-1-[(2-chlorophenyl)methyl]imidazole Chemical compound CCCCC1=NC=CN1CC1=CC=CC=C1Cl QDIAKNVAAGSOEB-UHFFFAOYSA-N 0.000 description 3
- SLLDUURXGMDOCY-UHFFFAOYSA-N 2-butyl-1h-imidazole Chemical compound CCCCC1=NC=CN1 SLLDUURXGMDOCY-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
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- 108090000783 Renin Proteins 0.000 description 3
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- 235000021355 Stearic acid Nutrition 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZLLLNMVZWPISGD-UHFFFAOYSA-N [3-[(2-chlorophenyl)methyl]-2-propylsulfanylimidazol-4-yl]methanol Chemical compound CCCSC1=NC=C(CO)N1CC1=CC=CC=C1Cl ZLLLNMVZWPISGD-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 230000003276 anti-hypertensive effect Effects 0.000 description 3
- 210000000709 aorta Anatomy 0.000 description 3
- 230000004872 arterial blood pressure Effects 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 150000002460 imidazoles Chemical class 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- LPXCHPSTROLSJX-UHFFFAOYSA-N pentanimidamide Chemical compound CCCCC(N)=N LPXCHPSTROLSJX-UHFFFAOYSA-N 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 210000002254 renal artery Anatomy 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008117 stearic acid Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- ZBLMIMYMFNBXDB-UHFFFAOYSA-N (1-acetyl-2-butylimidazol-4-yl)methyl acetate Chemical compound CCCCC1=NC(COC(C)=O)=CN1C(C)=O ZBLMIMYMFNBXDB-UHFFFAOYSA-N 0.000 description 2
- XLFLVGNMUZHTLD-HNNXBMFYSA-N (2s)-2-amino-3-[2-butyl-3-[(2-chlorophenyl)methyl]imidazol-4-yl]propanoic acid Chemical compound CCCCC1=NC=C(C[C@H](N)C(O)=O)N1CC1=CC=CC=C1Cl XLFLVGNMUZHTLD-HNNXBMFYSA-N 0.000 description 2
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- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
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- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
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- 229960004926 chlorobutanol Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
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- LRNLPVGOTJQNGO-DEOSSOPVSA-N ethyl (2s)-2-(benzylamino)-3-[2-butyl-3-[(2-chlorophenyl)methyl]imidazol-4-yl]propanoate Chemical compound N([C@@H](CC1=CN=C(N1CC=1C(=CC=CC=1)Cl)CCCC)C(=O)OCC)CC1=CC=CC=C1 LRNLPVGOTJQNGO-DEOSSOPVSA-N 0.000 description 1
- DKVMATZRWJRGIT-IBGZPJMESA-N ethyl (2s)-2-(butanoylamino)-3-[3-[(2-chlorophenyl)methyl]-2-propylsulfanylimidazol-4-yl]propanoate Chemical compound CCCSC1=NC=C(C[C@H](NC(=O)CCC)C(=O)OCC)N1CC1=CC=CC=C1Cl DKVMATZRWJRGIT-IBGZPJMESA-N 0.000 description 1
- SPLRKAKDPFKQBI-IBGZPJMESA-N ethyl (2s)-2-[butanoyl-[(2-chlorophenyl)methyl]amino]-3-(2-propylsulfanyl-1h-imidazol-5-yl)propanoate Chemical compound N1C(SCCC)=NC=C1C[C@@H](C(=O)OCC)N(C(=O)CCC)CC1=CC=CC=C1Cl SPLRKAKDPFKQBI-IBGZPJMESA-N 0.000 description 1
- QUGJYNGNUBHTNS-UHFFFAOYSA-N ethyl 2-(benzhydrylideneamino)acetate Chemical compound C=1C=CC=CC=1C(=NCC(=O)OCC)C1=CC=CC=C1 QUGJYNGNUBHTNS-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
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- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007701 flash-distillation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
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- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- YWGHUJQYGPDNKT-UHFFFAOYSA-N hexanoyl chloride Chemical compound CCCCCC(Cl)=O YWGHUJQYGPDNKT-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
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- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
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- 239000008101 lactose Substances 0.000 description 1
- 229940041476 lactose 100 mg Drugs 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 210000003975 mesenteric artery Anatomy 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- DNMZJIGSDQVGSA-UHFFFAOYSA-N methoxymethane;hydrochloride Chemical compound Cl.COC DNMZJIGSDQVGSA-UHFFFAOYSA-N 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229960005141 piperazine Drugs 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- 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
- C07D233/66—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 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
- C07D233/68—Halogen atoms
-
- 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
- C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- 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
- C07D233/66—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 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
- C07D233/84—Sulfur atoms
Definitions
- the present invention relates to new substituted histidines which are angiotensin II receptor antagonists and are useful in regulating hypertension induced or exacerbated by angiotensin II and in the treatment of congestive heart failure, renal failure, and glaucoma.
- This invention also relates to pharmaceutical compositions containing substituted histidines and methods for using these compounds as antagonists of angiotensin II, as anti-hypertensive agents and. as agents for treating congestive heart failure, renal failure, and glaucoma.
- angiotensin is responsible for a vasopressor action that is implicated in the etiology of hypertension in man.
- AII angiotensin II
- the renin-angiotensin system by virtue of its participation in the control of renal sodium handling, plays an important role in cardiovascular homostasis.
- the compounds of this invention inhibit, block and antagonize the action of the hormone All, and are therefore useful in regulating and moderating angiotensin induced hypertension, congestive heart failure, renal failure, glaucoma, and other disorders attributed to the actions of AII.
- compounds of this invention are administered to mammals, the elevated blood pressure due to All is reduced and other manifestations based on All intercession are minimized and controlled.
- Compounds of this invention is also expected to exhibit diuretic activity.
- R is lower alkyl or phenylC 1-2 alkyl optionally substituted with halogen or nitro;
- R 2 is lower alkyl, cycloalkyl, or phenyl optionally substituted; one of R 3 and
- R 4 is -(CH 2 ) n COR 5 , where R 5 is amino, lower alkoxy or hydroxy and n is 0-2, and the other of R 3 and R 4 is
- Examples include 1-benzyl-2-n-butyl- 4-chloroimidazole-5-acetamide and 1-benzyl-2-n-butyl-5- chloroimidazole-4-acetic acid.
- R 1 is lower alkyl, cycloalkyl, or phenyl optionally substituted
- X 1 , X 2 and X 3 are each hydrogen, halogen, nitro, amino, lower alkyl, lower alkoxy, benzyloxy, or hydroxy
- Y is halogen and R 2 is hydrogen or lower alkyl.
- a compound specifically disclosed is 1-(2-chlorobenzyl)-2-n- butyl-4-chloro-imidazole-5-acetic acid.
- R is lower alkyl.
- the disclosure includes 4-chloro-1-(4-methoxy-3-methylbenzyl)-2-phenyl-imidazole-5-acetic acid.
- R wherein is a single or double bond; one of R is present and includes groups such as (CH 2 ) 1-6 naphthyl,
- R 2 includes groups such as hydrogen, lower alkyl, and
- R 3 includes groups such as COC 1-15 alkyl or
- R 4 includes CO 2 R 9 , wherein R 9 is hydrogen, lower alkyl or benzyl; and n is 0- 3.
- a compound specifically disclosed is 5-[(4-nitrophenyl)acetyl]-1-(phenylmethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid.
- R 1 includes groups such as phenyl optionally substituted or adamantylmethyl
- R 2 includes groups such as hydrogen, halo, NO 2 , C 1-4 alkyl, or C 1-4 alkoxy
- R 3 is hydrogen, halo, C 1-4 alkyl, or C 1-4 alkoxy
- R 6 includes groups such as C 2 _ 10 alkyl, C 3-10 alkenyl, C 3-8 cycloalkyl, benzyl optionally substituted or Z(CH 2 ) 1-5 -R 5 , wherein 2 is
- R 5 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or alkenyl
- R 7 is hydrogen, halo, NO 2 , CF 3 , or CN
- R 8 includes groups such as C 1-10 alkanoic acids, esters and amides and alkyl N-alkyl carbamates. Examples include 2-n- butyl-5-chloro-1-(4-nitrobenzyl)imidazole-4-acetic acid and 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-n-butyl-4-chloro-5- (dimethylcarbamoyl) imidazole.
- X is 0-3.
- Examples include N-(2-(4(5)-imidazolyl)-ethyl)glycine and 1-benzyl-5-(2-aminoethyl)imidazole.
- the compounds of the present invention that are blockers of angiotensin II receptors are represented by the following Formula (I) :
- R 1 is adamantyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C 1 -C 6 alkyl, nitro, CO 2 R 7 , tetrazol-5-yl, C.-Cgalkoxy, hydroxy, SC 1 -C 6 alkyl, SO 2 NR 7 R 7 , NHSO 2 R 7 , SO 3 H, CONR 7 R 7 , CN,
- R 2 is C 2 -C 10 alkyl unsubstituted or substituted by
- X is a single bond, S, or O
- R is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR 7 , CONR 7 R 7 , NO 2 , or C n F 2n+1 ;
- each n is 1-3;
- n 0-4;
- R 4 is CO 2 R 7 , CONR 7 R 7 , or tetrazol-5-yl
- Y is a single bond or a carbonyl group
- R 5 is hydrogen, C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl,
- each phenyl group independently is unsubstituted or substituted by one to t ⁇ ree substituents selected from C 1 -C 6 alkyl, nitro, Cl,
- R 6 is hydrogen or C 1-6 alkyl
- each R independently is hydrogen, C 1 -C 4 alkyl, or
- alkyl, alkenyl, alkoxy, and alkynyl mean carbon chains which are branched or unbranched with the length of the chain determined by the descriptor preceding the term.
- Preferred compounds of the invention are represented by Formula (I) when:
- R 1 is phenyl unsubstituted or substituted by one to three substituents selected from chloro, fluoro,
- X is a single bond or S
- R 2 is C 2 -C 8 alkyl
- R 3 is hydrogen, chloro, fluoro, or trifluoromethyl; m is 0-2;
- R 4 is CO 2 R 7 ;
- each R 7 independently is hydrogen or C 1 -C 4 alkyl
- Particular compounds of the invention include, but are not limited to, the following:
- the invention also relates to pharmaceutical
- compositions comprising a pharmaceutical carrier and an effective amount of a compound of Formula (I).
- Also included in the present invention are methods for antagonizing angiotensin II receptors which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I).
- Methods of treating hypertension, congestive heart failure, renal failure, and glaucoma by administering these compounds are also included in this invention.
- compositions and methods of this invention are prepared by procedures described herein and illustrated by the examples. Reagents, protecting groups and
- R 1 is 2-chlorophenyl or 4-carboxyphenyl
- m is one
- R 2 is n-propyl or n-butyl
- X is S or a single bond
- R 3 is hydrogen, chloro, fluoro, or trifluoromethyl
- R 4 is CO 2 H
- R 6 is hydrogen
- Y is a carbonyl group or a single bond
- R 5 is hydrogen, (CH 2 ) 0-2 phenyl, or CH-diphenyl.
- halo-R 8 compound wherein R 8 is C 2-10 alkyl, C 3-10 alkenyl,
- a suitable base such as sodium carbonate
- halogenating agent such as refluxing thionyl
- Formula (I) compounds which had been pre-treated with a deprotonating agent, for example, sodium hydride, yielded formula (9) compounds.
- a deprotonating agent for example, sodium hydride
- formula (9) compounds, wherein R 6 is H are alkylated with a C 1-6 alkyl halide, such as methyl iodide, to give the formula (9) compounds, wherein R 6 is C 1-6 alkyl.
- Formula (10) compounds which are
- Formula (I) compounds are prepared from formula (9) ester compounds using aqueous base, such as aqueous sodium carbonate solution, in a suitable organic solvent, such as methanol or ethanol.
- aqueous base such as aqueous sodium carbonate solution
- a suitable organic solvent such as methanol or ethanol.
- Scheme II depicts an alternate route to Formula (I) compounds. According to Scheme II, chloromethyl
- imidazoles of formula (8) are converted to formula (11) compounds in a reaction with a N-diphenylmethylene glycine C 1-4 alkyl ester in the presence of a base, such as lithium diisopropylamide, in a suitable solvent, such as
- the amine alkyl ester compounds of formula (12) are prepared from formula (11) compounds by hydrolysis with 'a suitable aqueous acid such as aqueous hydrochloric acid.
- formula (14) amide compounds are prepared by reacting formula (12) amine compounds with an acylating agent R 5CO- halo in the presence of a base, such as triethylamine.
- formulae (12) amines are monoalkylated by reacting said amines with an appropriately substituted aldehyde, such as benzaldehyde, in the presence of sodium cyanoborohydride.
- formulae (14) and (16) compounds, wherein R 6 is H are alkylated with a C 1-6 alkyl, such as methyl iodide, to give the formulae (14) and (16) compounds, wherein R 6 is C 1-6 alkyl.
- the ester compounds of formulae (12), (14), and (16) are hydrolyzed to formulae (13), (15), and (17) compounds, for example, using base, such as potassium hydroxide, lithium hydroxide, or sodium hydroxide, in a suitable solvent system, such as aqueous methanol or ethanol.
- base such as potassium hydroxide, lithium hydroxide, or sodium hydroxide
- a suitable solvent system such as aqueous methanol or ethanol.
- Formula (I) compounds are also prepared by the procedures of Scheme III.
- the starting 2-R 2 X-imidazoles of formula (18) are known to the art (J. Org. Chem. 45:4038, 1980) or are synthesized by known procedures.
- imidazole is converted to 2-n-butylimidazole by reacting imidazole with triethylorthoformate and p-toluenesulfonic acid to give 1-diethoxyorthoamide imidazole and then treating with n-butyl lithium to give the 2-lithium
- the 1-R 1 (CH 2 ) m -group is incorporated onto the 2-R 2 X- imidazole of formula (18) by known procedures, for example, by reaction with an R 1 -(CH 2 ) m halide, mesylate or acetate, such as 2-chlorobenzyl bromide, in a suitable solvent, such as dimethylformamide, in the presence of a suitable acid acceptor, such as sodium alkylate, potassium or sodium carbonate, or a metal hydride, preferably sodium hydride, at a reaction temperature of about 25oC to about 100oC, preferably at about 50oC.
- a suitable acid acceptor such as sodium alkylate, potassium or sodium carbonate
- a metal hydride preferably sodium hydride
- imidazole is hydroxymethylated in the 5-position, for example, by reacting with formaldehyde in the presence of sodium acetate in acetic acid to provide the 1-R 1 (CH 2 ) -2- R 2 X-5-hydroxymethylimidazole intermediates of formula (20).
- Chloromethyl formula (21) compounds are prepared from formula (20) these hydroxymethyl imidazoles in a reaction with a halogenating agent, for example, refluxing thionyl chloride.
- a halogenating agent for example, refluxing thionyl chloride.
- Formula (I) compounds are prepared from the chloromethyl imidazoles by the methods described in
- Formula (I) compounds wherein the alkylene bridge at the 5 position of the imidazole ring is defined as n equal to 2 or 3 are prepared from the corresponding alkanoic esters, which are disclosed in U.S. Patent Number
- compositions of Formula (I) are formed with appropriate organic or inorganic acids by methods known in the art.
- the base is reacted with a suitable inorganic or organic acid in an aqueous miscible solvent such as ethanol with isolation of the salt by removing the solvent or in an aqueous immiscible solvent when the acid is soluble therein, such as ethyl ether or chloroform, with the desired salt separating directly or isolated by
- Suitable acids are maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic,
- ethanedisulfonic acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
- Pharmaceutically acceptable base addition salts of compounds of Formula (I) which have an acidic group are prepared by known methods from organic and inorganic bases, including nontoxic alkali metal and alkaline earth bases, for example, calcium, lithium, sodium, and potassium hydroxide; ammonium hydroxide, and nontoxic organic bases, such as triethylamine, butylamine, piperazine, meglumine, choline, diethanolamine, and tromethamine.
- organic and inorganic bases including nontoxic alkali metal and alkaline earth bases, for example, calcium, lithium, sodium, and potassium hydroxide; ammonium hydroxide, and nontoxic organic bases, such as triethylamine, butylamine, piperazine, meglumine, choline, diethanolamine, and tromethamine.
- Angiotensin II antagonist activity of the compounds of Formula (I) is assessed by in vitro and in vivo methods.
- In vitro antagonist activity is determined by the ability of the compounds to compete with 125 I-angiotensm II for binding to vascular angiotensin II receptors and by their ability to antagonize the contractile response to
- angiotensin II in the isolated rabbit aorta in vivo activity is evaluated by the efficacy of the compounds to inhibit the pressor response to exogenous angiotensin II in conscious rats and to lower blood pressure in a rat model of renin dependent hypertension.
- the radioligand binding assay is a modification of a method previously described in detail (Gunther et al., Circ. Res. 47:278, 1980).
- a particular fraction from rat mesenteric arteries is incubated in Tris buffer with 80 pM of 125 I-angiotensm II wi.th or without angi.otensin II antagonists for 1 hour at 25oC.
- the incubation is
- angiotensin II antagonists is expressed as the IC 50 which is the concentration of antagonist needed to displace 50% of the total specifically bound angiotensin II.
- IC 50 of compounds of the invention is about 1.0 to about 70 ⁇ m.
- Ring segments are cut from the rabbit thoracic aorta and suspended in organ baths containing physiological salt solution. The ring segments are mounted over metal supports and attached to force displacement transducers which are connected to a recorder. Cumulative
- Antagonists were performed in the absence of antagonist or following a 30-minute incubation with antagonist.
- disassociation constants (K B ) of compounds of the invention is about 0.05 to about 50 ⁇ M.
- Rats are prepared with indwelling femoral arterial and venous catheters and a stomach tube (Gellai et al., Kidney Int. 15:419, 1979). Two to three days following surgery the rats are placed in a restrainer and blood pressure is continuously monitored from the arterial catheter with a pressure transducer and recorded on a polygraph. The change in mean arterial pressure in response to intravenous injections of 250 mg/kg angiotensin II is compared at various time points prior to and following the
- angiotensin II (IC 50 ) is used to estimate the potency of the compounds.
- the IC 50 of 3- [(2-chlorophenyl)methyl]-2-n-butyl-N-butyrylhistidine is 10 mg/kg i.v.
- the antihypertensive activity of the compounds is measured by their ability to reduce mean arterial pressure in conscious rats made renin-dependent hypertensive by ligation of the left renal artery (Cangiano et al., J.
- Renal artery ligated rats are prepared with indwelling catheters as described above. Seven to eight days following renal artery
- the intraocular pressure lowering effects employed in this invention may be measured by the procedure described by Watkins, et al., J. Ocular Pharmacol., 1 (2):161-168 (1985).
- the compounds of Formula (I) are incorporated into convenient dosage forms, such as injectable preparations, or for orally active compounds, capsules or tablets.
- Solid or liquid pharmaceutical carriers are employed. Solid carriers include starch, lactose, calcium sulfate
- Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
- the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
- the amount of solid carrier varies but, preferably, will be from about 25 mg to about 1 g per dosage unit.
- the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid, such as an ampoule, or an aqueous or nonaqueous liquid suspension.
- compositions adapted include solutions, suspensions, ointments, and solid inserts.
- pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or vegatable oils, and water soluble ophthalmologically acceptable non-toxic polymers, for example, cellulose derivatives such as methyl cellulose.
- the pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting, and bodying agents, as for example, polyethylene glycols; antibacterial components, such as quarternary ammonium compounds; buffering ingredients, such as alkali metal chloride; antioxidants, such as sodium metabisulfite; and other conventional ingredients, such as sorbitan monolaurate.
- suitable ophthalmic vehicles may be used as carrier media for the present purpose including
- the pharmaceutical preparation may also be in the form of a solid insert.
- a solid water soluble polymer as the carrier for the medicament.
- Solid water insoluble inserts such as those prepared from ethylene vinyl acetate copolymer, may also be utilized.
- Doses of the compounds of Formula (I) in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity selected from the range of .01-200 mg/kg of active compound, preferably 1-100 mg/kg.
- the selected dose is administered to a human patient in need of angiotensin II receptor antagonism from 1-6 times daily, orally, rectally, topically, by injection, or continuously by infusion.
- Oral dosage units for human administration preferably contain from 1 to 500 mg of active compound. Lower dosages are used generally for parenteral administration. Oral administration, is used when safe, effective and convenient for the patient.
- Topical formulations contain the active compound in an amount selected from 0.0001 to 0.1 (w/v%) , preferably from 0.0001 to 0.01. As a topical dosage unit form, an amount of active compound from between 50 ng to 0.05 mg,
- preferably 50 ng to 5 mg is applied to the human eye.
- angiotensin II receptors in mammals comprises administering to a subject in need of such antagonism an effective amount of a compound of Formula (I).
- antihypertensive activity and the method of treating congestive heart failure, glaucoma, and renal failure comprise administering a compound of Formula (I) to a subject in need thereof an effective amount to produce said activity.
- hydrochloric acid (14.3 mL of 12 N, 0.171 mol) was added slowly to this solution followed by a solution of potassium thiocyanate (8.6 g, 0.0885 mol) in water (20mL) .
- the mixture was heated in an oil bath held at 90oC for 2.5 hours, then cooled to -10oC.
- the precipitated solid was filtered, washed with cold ethanol-water and dried at 60oC to provide 14.7 g (74%) of 5-carboxymethyl-1-1-(2- chlorophenyl)methyl-2-thio-1H-imidazole; m.p. 72-74oC.
- This crude product was purified over silica gel with 1:1 hexane/ethyl acetate to afford 0.27 g of the malonate addition product.
- This product was hydrolyzed in 50% aqueous ethanol (20 mL) and sodium carbonate (0.85 g) in water (20 mL) on the steam bath for 3 hours. The reaction mixture was poured into water and extracted with methylene chloride.
- tetrahydrofuran 100 mL was cooled to -78oC under argon and a solution of n-butyl lithium (30 mL of 2.5 M in hexane) was added. The mixture was stirred at -78oC for 30 minutes and at 0oC for 10 minutes. After being recooled to -78°C, a solution of N-(diphenylmethylene)-glycine ethyl ester (Tetra.
- Example 2 (ii-iii) was followed using isovaleryl chloride in place of butyryl chloride to give 3- [(2-chlorophenyl)methyl]-2-propylthiohistidine.
- the title compound is a white solid obtained in 58% overall yield; m.p. 151o-154oC.
- Example 5 The procedure of Example 2 (ii-iii) was followed using benzoyl chloride in place of butyryl chloride. The title compound is a white solid; m.p. 210o-212oC (from methanol) .
- Example 5 The procedure of Example 2 (ii-iii) was followed using benzoyl chloride in place of butyryl chloride. The title compound is a white solid; m.p. 210o-212oC (from methanol) .
- Example 5 The procedure of Example 2 (ii-iii) was followed using benzoyl chloride in place of butyryl chloride. The title compound is a white solid; m.p. 210o-212oC (from methanol) .
- Example 6 3-[(2-Chlorophenyl)methyl]-2-propylthio-N- [(cyclopentyl)carbonyl]histidine The procedure of Example 2 (ii-iii) was followed using cyclopentanecarbonyl chloride in place of butyryl chloride. The title compound is white solid; m.p. 173o-175oC (from ethanol) .
- Example 6
- Example 2 (ii-iii) was followed using hexanoyl chloride in place of butyryl chloride.
- the title compound is a white solid; m.p. 118o-121oC (from ethyl acetate).
- Example 7 3-[(2-Chlorophenyl)methyl]-2-propylthiohistidine A solution of 3-[(2-chlorophenyl)methyl]-2-propylthiohistidine ethyl ester (Example 2 (i)) (0.48 g, 1.26 mmol), ethanol (4 mL) , water (4 mL) and potassium hydroxide (0.111 g, 1.97 mmol) was stirred at 25oC for 1 hour. The mixture was treated with concentrated
- Imidazole was converted to the 1-diethoxyortho-amide derivative by the method of Curtis and Brown, J. Org.
- n-butyl iodide (31.1 g, 0.169 mol) was added at -40oC, and the reaction was stirred overnight at ambient temperature.
- the reaction was partitioned between ether and 0.3 N hydrochloric acid, and the organic layer was repeatedly extracted with dilute hydrochloric acid.
- the combined aqueous extracts were neutralized with sodium bicarbonate solution, extracted with methylene chloride, dried over magnesium sulfate and concentrated.
- a mixture of valeramidine methyl ether hydrochloride (250 g, 1.66 mol) and dihydroxyacetone (150 g, 0.83 mol) dissolved in liquid ammonia was allowed to stand overnight at room temperature in a pressure vessel, and then heated at 65oC for 4 hours at 375 psi. The ammonia was allowed to evaporate, and the residue was dissolved in methanol (3L). The resulting slurry was refluxed with added acetonitrile (1L). The solution was decanted from the solid ammonium chloride while hot.
- This crude alcohol (253 g) was treated with acetic anhydride (400 mL) at -15oC and then was allowed to warm to ambient temperature with stirring, and then stirred an additional 19 hours.
- the acetic anhydride was evaporated at reduced pressure, the residue taken up in methylene chloride, and the organic phase was washed with 5% sodium bicarbonate solution and water.
- the extract was dried over sodium ⁇ ulfate and concentrated to give 323 g (83%) of 1-acetyl-4-acetoxymethyl-2-n-butylimidazole.
- This diacetate was N-alkylated by the following procedure. To a solution of triflic anhydride (120 mL, 0.71 mol) in methylene chloride (200 mL) at -78oC under argon was added a solution of diisopropyl ethylamine (128 mL, 0.73 mol) and 2-chlorobenzyl alcohol (104 g, 0.72 mol) in methylene chloride (350 mL) over a period of 20 minutes.
- Example 8 The procedure of Example 8 was followed using 3-phenylpropionyl chloride in place of butyryl chloride to give 2-n-butyl-3-(2-chlorophenyl)methylhistidine. After trituration with cyclohexane, the title compound (as the hydrochloride salt) is a white solid; m.p. 194-196oC.
- Example 12
- the title compound is prepared according to Example 8 using phenylacetyl chloride in place of butyl chloride.
- the title compound is prepared by reductive alkylation of 2-n-butyl-3-(2-chlorophenyl)methylhistidine ethyl ester with benzaldehyde in the presence of sodium
- Example 16 An oral dosage form for administering orally active Formula (I) compounds is produced by screening, mixing and filling into hard gelatin capsules the ingredients in proportions, for example, as shown below.
- sucrose calcium sulfate dihydrate and orally active Formula (I) compounds are mixed and granulated with a 10% gelatin solution.
- the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
- a topical opthamological solution for administering Formula (I) compounds is produced by mixing under sterile conditions the ingredients in proportions, for example, as shown below.
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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US07/965,370 US5444081A (en) | 1990-06-28 | 1991-06-26 | Substituted histidines having angiotension II receptor antagonist activity |
AU81059/91A AU650890B2 (en) | 1990-06-28 | 1991-06-26 | Substituted histidines |
JP91511951A JPH05508642A (en) | 1990-06-28 | 1991-06-26 | substituted histidines |
KR1019920703381A KR930701411A (en) | 1990-06-28 | 1991-06-26 | Substituted histidine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US54525390A | 1990-06-28 | 1990-06-28 | |
US545,253 | 1990-06-28 |
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WO1992000068A1 true WO1992000068A1 (en) | 1992-01-09 |
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PCT/US1991/004561 WO1992000068A1 (en) | 1990-06-28 | 1991-06-26 | Substituted histidines |
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US (2) | US5444081A (en) |
EP (1) | EP0536262A4 (en) |
JP (1) | JPH05508642A (en) |
KR (1) | KR930701411A (en) |
AU (1) | AU650890B2 (en) |
CA (1) | CA2084776A1 (en) |
IE (1) | IE912248A1 (en) |
MX (1) | MX9100018A (en) |
NZ (1) | NZ238688A (en) |
PT (1) | PT98143A (en) |
WO (1) | WO1992000068A1 (en) |
ZA (1) | ZA914960B (en) |
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US5444080A (en) * | 1990-07-31 | 1995-08-22 | Smithkline Beecham Corporation | Substituted [1H-imidazol-5-ylialkanoic acids having angiotension II receptor antagonist activity |
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- 1991-06-26 KR KR1019920703381A patent/KR930701411A/en not_active Application Discontinuation
- 1991-06-26 US US07/965,370 patent/US5444081A/en not_active Expired - Fee Related
- 1991-06-26 AU AU81059/91A patent/AU650890B2/en not_active Expired - Fee Related
- 1991-06-26 WO PCT/US1991/004561 patent/WO1992000068A1/en not_active Application Discontinuation
- 1991-06-26 JP JP91511951A patent/JPH05508642A/en active Pending
- 1991-06-26 EP EP91912453A patent/EP0536262A4/en not_active Withdrawn
- 1991-06-26 CA CA002084776A patent/CA2084776A1/en not_active Abandoned
- 1991-06-27 ZA ZA914960A patent/ZA914960B/en unknown
- 1991-06-27 IE IE224891A patent/IE912248A1/en unknown
- 1991-06-28 PT PT98143A patent/PT98143A/en not_active Application Discontinuation
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1995
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EP0438869B1 (en) * | 1989-11-30 | 1994-12-14 | Eli Lilly And Company | Improvements in and relating to angiotensin II antagonists |
US5444080A (en) * | 1990-07-31 | 1995-08-22 | Smithkline Beecham Corporation | Substituted [1H-imidazol-5-ylialkanoic acids having angiotension II receptor antagonist activity |
US5530017A (en) * | 1990-07-31 | 1996-06-25 | Smithkline Beecham Corp | Method of antagonizing angiotensin II receptors in mammals using substituted [1H-Imidazol-5-YL] alkenoic acids |
LT3612B (en) | 1992-08-29 | 1995-12-27 | Boots Co Plc | Therapeutic agents |
FR2770538A1 (en) * | 1997-11-06 | 1999-05-07 | Bio Merieux | METHOD AND AGENT FOR DETECTION AND IDENTIFICATION AND / OR QUANTIFICATION OF DESAMINASE-TYPE ENZYMA ACTIVITY |
WO1999024604A1 (en) * | 1997-11-06 | 1999-05-20 | Bio Merieux | Method and agent for determining an enzymatic activity such as deaminase |
US6733986B1 (en) | 1997-11-06 | 2004-05-11 | Bio Merieux | Method and agent for determining a deaminase enzymatic activity |
EP1925303A2 (en) | 1999-08-27 | 2008-05-28 | Sanofi-Aventis Deutschland GmbH | Use of Angiotensin II type 1 receptor antagonists for the prevention of stroke, diabetes and/or congestive heart failure |
EP2277519A2 (en) | 1999-08-27 | 2011-01-26 | Sanofi-Aventis Deutschland GmbH | Use of Angiotensin II type 1 receptor antagonists for the prevention of stroke, diabetes and/or congestive heart failure |
JP4866233B2 (en) * | 2003-04-29 | 2012-02-01 | ウニヴェルジテート・チューリッヒ | Metal- and organic-protected L derivatized with Nε and / or Nα for coupling to biomolecules for highly efficient [M (OH2) 3 (CO) 3] + labeling via fac coordination -Histidine |
WO2004097406A3 (en) * | 2003-04-29 | 2005-05-19 | Univ Zuerich | Nϵ AND/OR Nα DERIVATIZED, METAL AND ORGANIC PROTECTED L-HISTIDINE FOR COUPLING TO BIOMOLECULES FOR HIGHLY EFFICIENT LABELING WITH [M(OH2)3(CO)3]+ BY FAC COORDINATION |
US8512675B2 (en) | 2003-04-29 | 2013-08-20 | Mallinckrodt Llc | N and/or Nα derivatized, metal and organic protected L-histidine for coupling to biomolecules for highly efficient labeling with [M(OH2)3 (CO)3]+ by fac coordination |
JP2006527167A (en) * | 2003-04-29 | 2006-11-30 | ウニヴェルジテート・チューリッヒ | Metal- and organic-protected L derivatized with Nε and / or Nα for coupling to biomolecules for highly efficient [M (OH2) 3 (CO) 3] + labeling via fac coordination -Histidine |
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WO2013138352A1 (en) | 2012-03-15 | 2013-09-19 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
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Also Published As
Publication number | Publication date |
---|---|
NZ238688A (en) | 1992-05-26 |
KR930701411A (en) | 1993-06-11 |
ZA914960B (en) | 1992-07-29 |
EP0536262A4 (en) | 1996-08-14 |
US5444081A (en) | 1995-08-22 |
CA2084776A1 (en) | 1991-12-29 |
IE912248A1 (en) | 1992-01-01 |
EP0536262A1 (en) | 1993-04-14 |
AU650890B2 (en) | 1994-07-07 |
AU8105991A (en) | 1992-01-23 |
PT98143A (en) | 1992-04-30 |
MX9100018A (en) | 1992-02-03 |
US5565480A (en) | 1996-10-15 |
JPH05508642A (en) | 1993-12-02 |
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