WO1991017148A1 - 1h-substituted-1,2,4-triazole compounds for treatment of cardiovascular disorders - Google Patents
1h-substituted-1,2,4-triazole compounds for treatment of cardiovascular disorders Download PDFInfo
- Publication number
- WO1991017148A1 WO1991017148A1 PCT/US1991/002926 US9102926W WO9117148A1 WO 1991017148 A1 WO1991017148 A1 WO 1991017148A1 US 9102926 W US9102926 W US 9102926W WO 9117148 A1 WO9117148 A1 WO 9117148A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- triazol
- biphenyl
- tetrazole
- phenyl
- Prior art date
Links
- 208000024172 Cardiovascular disease Diseases 0.000 title claims abstract description 12
- 238000011282 treatment Methods 0.000 title abstract description 8
- -1 hydroxy, formyl Chemical group 0.000 claims abstract description 969
- 125000001145 hydrido group Chemical group *[H] 0.000 claims abstract description 178
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 175
- 150000001875 compounds Chemical class 0.000 claims abstract description 156
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 134
- 125000005843 halogen group Chemical group 0.000 claims abstract description 77
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 71
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 48
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 44
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 34
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims abstract description 33
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 33
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 33
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 33
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 33
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 33
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 32
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 30
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 29
- 229910006069 SO3H Inorganic materials 0.000 claims abstract description 26
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims abstract description 24
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims abstract description 24
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 23
- 125000006002 1,1-difluoroethyl group Chemical group 0.000 claims abstract description 20
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims abstract description 20
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 20
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims abstract description 20
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims abstract description 20
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims abstract description 19
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims abstract description 19
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims abstract description 19
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 19
- 125000006343 heptafluoro propyl group Chemical group 0.000 claims abstract description 19
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims abstract description 19
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims abstract description 19
- SYQNQPHXKWWZFS-YFKPBYRVSA-N (4s)-4-amino-5-ethoxy-5-oxopentanoic acid Chemical group CCOC(=O)[C@@H](N)CCC(O)=O SYQNQPHXKWWZFS-YFKPBYRVSA-N 0.000 claims abstract description 17
- SEWIYICDCVPBEW-BYPYZUCNSA-N L-glutamate methyl ester Chemical group COC(=O)[C@@H](N)CCC(O)=O SEWIYICDCVPBEW-BYPYZUCNSA-N 0.000 claims abstract description 17
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 16
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical group CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 claims abstract description 15
- 206010020772 Hypertension Diseases 0.000 claims abstract description 14
- 229940123413 Angiotensin II antagonist Drugs 0.000 claims abstract description 12
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims abstract description 12
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 206010007559 Cardiac failure congestive Diseases 0.000 claims abstract description 5
- 206010019280 Heart failures Diseases 0.000 claims abstract description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 258
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 218
- 230000002378 acidificating effect Effects 0.000 claims description 216
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 206
- 125000003118 aryl group Chemical group 0.000 claims description 196
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 193
- 125000000623 heterocyclic group Chemical group 0.000 claims description 183
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 174
- 150000003839 salts Chemical class 0.000 claims description 165
- 125000001188 haloalkyl group Chemical group 0.000 claims description 145
- 229910052717 sulfur Inorganic materials 0.000 claims description 135
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 134
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 133
- 229910052760 oxygen Inorganic materials 0.000 claims description 128
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 127
- 239000001301 oxygen Substances 0.000 claims description 124
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 123
- 125000004434 sulfur atom Chemical group 0.000 claims description 104
- 229910052757 nitrogen Inorganic materials 0.000 claims description 102
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 100
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 98
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 88
- 125000003342 alkenyl group Chemical group 0.000 claims description 87
- 235000010290 biphenyl Nutrition 0.000 claims description 87
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 83
- 125000003545 alkoxy group Chemical group 0.000 claims description 81
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 75
- 239000011593 sulfur Substances 0.000 claims description 75
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 72
- 125000006413 ring segment Chemical group 0.000 claims description 72
- 125000005842 heteroatom Chemical group 0.000 claims description 69
- 150000001408 amides Chemical class 0.000 claims description 68
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 68
- 150000002148 esters Chemical class 0.000 claims description 68
- 125000004414 alkyl thio group Chemical group 0.000 claims description 61
- 125000004104 aryloxy group Chemical group 0.000 claims description 61
- 125000004441 haloalkylsulfonyl group Chemical group 0.000 claims description 60
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 55
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 55
- 125000001072 heteroaryl group Chemical group 0.000 claims description 53
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 48
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 48
- 229920006395 saturated elastomer Polymers 0.000 claims description 46
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 45
- 125000000304 alkynyl group Chemical group 0.000 claims description 44
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 37
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 36
- 125000004691 alkyl thio carbonyl group Chemical group 0.000 claims description 36
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 36
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 36
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 36
- 125000005592 polycycloalkyl group Polymers 0.000 claims description 33
- 125000004945 acylaminoalkyl group Chemical group 0.000 claims description 31
- 125000005110 aryl thio group Chemical group 0.000 claims description 31
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 31
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 30
- 125000003435 aroyl group Chemical group 0.000 claims description 30
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 30
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 30
- 125000004440 haloalkylsulfinyl group Chemical group 0.000 claims description 30
- 125000006850 spacer group Chemical group 0.000 claims description 30
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims description 27
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 25
- 239000004305 biphenyl Substances 0.000 claims description 25
- 235000013922 glutamic acid Nutrition 0.000 claims description 25
- 239000004220 glutamic acid Substances 0.000 claims description 25
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 24
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 24
- 125000004043 oxo group Chemical group O=* 0.000 claims description 24
- ILYSAKHOYBPSPC-UHFFFAOYSA-N 2-phenylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=CC=C1 ILYSAKHOYBPSPC-UHFFFAOYSA-N 0.000 claims description 22
- 229910018828 PO3H2 Inorganic materials 0.000 claims description 22
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 22
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 20
- 239000000460 chlorine Substances 0.000 claims description 20
- 229910052801 chlorine Inorganic materials 0.000 claims description 20
- 125000004692 haloalkylcarbonyl group Chemical group 0.000 claims description 18
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 16
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 13
- 125000001589 carboacyl group Chemical group 0.000 claims description 13
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 13
- LFMFPKKYRXFHHZ-UHFFFAOYSA-N R24 Chemical compound C1=C(Cl)C(C)=CC=C1NC1=NC(N)=C(C=CC=C2)C2=N1 LFMFPKKYRXFHHZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000005130 alkyl carbonyl thio group Chemical group 0.000 claims description 12
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 12
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 claims description 12
- 125000004122 cyclic group Chemical group 0.000 claims description 11
- 125000004983 dialkoxyalkyl group Chemical group 0.000 claims description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 7
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 6
- 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
- 239000011574 phosphorus Substances 0.000 claims description 6
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 claims description 6
- 229910004727 OSO3H Inorganic materials 0.000 claims description 5
- 125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 5
- 125000005009 perfluoropropyl group Chemical group FC(C(C(F)(F)F)(F)F)(F)* 0.000 claims description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000005557 antagonist Substances 0.000 claims description 4
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- VYAYHSWYTUXSCW-UHFFFAOYSA-N 2-[4-[(3-butyl-5-chloro-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound N1=C(CCCC)N=C(Cl)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 VYAYHSWYTUXSCW-UHFFFAOYSA-N 0.000 claims description 3
- YVCOAIBWHWAQER-UHFFFAOYSA-N 2-[4-[(5-butyl-3-chloro-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(Cl)=NN1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 YVCOAIBWHWAQER-UHFFFAOYSA-N 0.000 claims description 3
- ZCZISCZYYCJCRV-UHFFFAOYSA-N methyl 2-[4-[(3,5-dibutyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoate Chemical compound N1=C(CCCC)N=C(CCCC)N1CC1=CC=C(C=2C(=CC=CC=2)C(=O)OC)C=C1 ZCZISCZYYCJCRV-UHFFFAOYSA-N 0.000 claims description 3
- PZGXIEZXCZFRQC-UHFFFAOYSA-N 2-[4-[(3,5-dipropyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound N1=C(CCC)N=C(CCC)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 PZGXIEZXCZFRQC-UHFFFAOYSA-N 0.000 claims description 2
- KQKXXTDHQVRRPZ-UHFFFAOYSA-N 2-[4-[(3-butanoyl-5-butyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(C(=O)CCC)=NN1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 KQKXXTDHQVRRPZ-UHFFFAOYSA-N 0.000 claims description 2
- XOHQUKCTURLJAV-UHFFFAOYSA-N 2-[4-[(3-butyl-5-propyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound N1=C(CCCC)N=C(CCC)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 XOHQUKCTURLJAV-UHFFFAOYSA-N 0.000 claims description 2
- SEEYLLXKAZYWEQ-UHFFFAOYSA-N 2-[4-[(5-butyl-3-ethyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(CC)=NN1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 SEEYLLXKAZYWEQ-UHFFFAOYSA-N 0.000 claims description 2
- INYDHBPERXKSPG-UHFFFAOYSA-N 2-[4-[(5-butyl-3-pentanoyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound N1=C(C(=O)CCCC)N=C(CCCC)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 INYDHBPERXKSPG-UHFFFAOYSA-N 0.000 claims description 2
- FLHSSZFOTPVKRQ-UHFFFAOYSA-N 2-[4-[(5-butyl-3-propyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(CCC)=NN1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 FLHSSZFOTPVKRQ-UHFFFAOYSA-N 0.000 claims description 2
- ZMGVLFRSFLQLKZ-UHFFFAOYSA-N 2-[4-[[3-(1,1-difluorobutyl)-5-propyl-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCC1=NC(C(F)(F)CCC)=NN1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 ZMGVLFRSFLQLKZ-UHFFFAOYSA-N 0.000 claims description 2
- RLEPYXSYYHCKEE-UHFFFAOYSA-N 2-[4-[[3-(1,1-difluoroethyl)-5-propyl-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCC1=NC(C(C)(F)F)=NN1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 RLEPYXSYYHCKEE-UHFFFAOYSA-N 0.000 claims description 2
- MJONFACZNULNKS-UHFFFAOYSA-N 2-[4-[[3-(1,1-difluoropentyl)-5-propyl-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(C(F)(F)CCCC)N=C(CCC)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 MJONFACZNULNKS-UHFFFAOYSA-N 0.000 claims description 2
- BHQNHPNISQQNIF-UHFFFAOYSA-N 2-[4-[[3-(1,1-difluoropropyl)-5-propyl-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCC1=NC(C(F)(F)CC)=NN1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 BHQNHPNISQQNIF-UHFFFAOYSA-N 0.000 claims description 2
- FDNCKOIQBCVKIR-UHFFFAOYSA-N 2-[4-[[3-butyl-5-(1,1-difluorobutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(CCCC)N=C(C(F)(F)CCC)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 FDNCKOIQBCVKIR-UHFFFAOYSA-N 0.000 claims description 2
- YFQLOQAGULIHSR-UHFFFAOYSA-N 2-[4-[[5-butyl-3-(1,1-difluorobutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(C(F)(F)CCC)=NN1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 YFQLOQAGULIHSR-UHFFFAOYSA-N 0.000 claims description 2
- XYOSLSVTKUGLGR-UHFFFAOYSA-N 2-[4-[[5-butyl-3-(1,1-difluoroethyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(C(C)(F)F)=NN1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 XYOSLSVTKUGLGR-UHFFFAOYSA-N 0.000 claims description 2
- DZDDYXDKLMAHAF-UHFFFAOYSA-N 2-[4-[[5-butyl-3-(1,1-difluoropentyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(C(F)(F)CCCC)=NN1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 DZDDYXDKLMAHAF-UHFFFAOYSA-N 0.000 claims description 2
- RWIJNLFFMCKDDC-UHFFFAOYSA-N 2-[4-[[5-butyl-3-(1,1-difluoropropyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(C(F)(F)CC)=NN1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 RWIJNLFFMCKDDC-UHFFFAOYSA-N 0.000 claims description 2
- BEHNLXZVSLKPTH-UHFFFAOYSA-N 2-[4-[[5-butyl-3-(1,1-dimethoxybutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(C(CCC)(OC)OC)=NN1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 BEHNLXZVSLKPTH-UHFFFAOYSA-N 0.000 claims description 2
- BJVQHGQLZGFHNH-UHFFFAOYSA-N 2-[4-[[5-butyl-3-(3-methylbutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(CCC(C)C)=NN1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 BJVQHGQLZGFHNH-UHFFFAOYSA-N 0.000 claims description 2
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 claims 85
- 239000005711 Benzoic acid Substances 0.000 claims 9
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 claims 9
- 235000010233 benzoic acid Nutrition 0.000 claims 9
- 239000000203 mixture Substances 0.000 claims 9
- HBCVUIYTGIRGCG-UHFFFAOYSA-N 5-[2-[4-[[5-butyl-3-(difluoromethyl)-1,2,4-triazol-1-yl]methyl]phenyl]phenyl]-2h-tetrazole Chemical compound CCCCC1=NC(C(F)F)=NN1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 HBCVUIYTGIRGCG-UHFFFAOYSA-N 0.000 claims 8
- OWYMRAJKPMBNEX-UHFFFAOYSA-N 2-[4-[(3,5-dibutyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound N1=C(CCCC)N=C(CCCC)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 OWYMRAJKPMBNEX-UHFFFAOYSA-N 0.000 claims 6
- XNLWJFYYOIRPIO-UHFFFAOYSA-N 3-phenylbenzoic acid Chemical compound OC(=O)C1=CC=CC(C=2C=CC=CC=2)=C1 XNLWJFYYOIRPIO-UHFFFAOYSA-N 0.000 claims 5
- LRZYXWIVLLNUPK-UHFFFAOYSA-N 5-[2-[4-[(3,5-dibutyl-1,2,4-triazol-1-yl)methyl]phenyl]phenyl]-2h-tetrazole Chemical compound N1=C(CCCC)N=C(CCCC)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 LRZYXWIVLLNUPK-UHFFFAOYSA-N 0.000 claims 5
- BDCKGTKJEKEFDM-UHFFFAOYSA-N 5-[2-[4-[(3,5-dipentyl-1,2,4-triazol-1-yl)methyl]phenyl]phenyl]-2h-tetrazole Chemical compound N1=C(CCCCC)N=C(CCCCC)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 BDCKGTKJEKEFDM-UHFFFAOYSA-N 0.000 claims 5
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- ODNNANZJEGBGGS-UHFFFAOYSA-N 1-[5-propyl-1-[[4-[3-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]-1,2,4-triazol-3-yl]butan-1-one Chemical compound N1=C(C(=O)CCC)N=C(CCC)N1CC1=CC=C(C=2C=C(C=CC=2)C=2NN=NN=2)C=C1 ODNNANZJEGBGGS-UHFFFAOYSA-N 0.000 claims 1
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- FEBPOEPZVAFNNN-UHFFFAOYSA-N 2-[4-[(3,5-dibutoxy-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound N1=C(OCCCC)N=C(OCCCC)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 FEBPOEPZVAFNNN-UHFFFAOYSA-N 0.000 claims 1
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- SSTLUNVYYPJKAR-UHFFFAOYSA-N 2-[4-[(5-butyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC=NN1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 SSTLUNVYYPJKAR-UHFFFAOYSA-N 0.000 claims 1
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- SWAKIRRXKOAHHT-UHFFFAOYSA-N 3-[4-[(3,5-dibutoxy-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound N1=C(OCCCC)N=C(OCCCC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 SWAKIRRXKOAHHT-UHFFFAOYSA-N 0.000 claims 1
- AERABRJUORNGAQ-UHFFFAOYSA-N 3-[4-[(3,5-diethoxy-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound N1=C(OCC)N=C(OCC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 AERABRJUORNGAQ-UHFFFAOYSA-N 0.000 claims 1
- BBSYZXZMARCCJK-UHFFFAOYSA-N 3-[4-[(3,5-dipentyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound N1=C(CCCCC)N=C(CCCCC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 BBSYZXZMARCCJK-UHFFFAOYSA-N 0.000 claims 1
- TYXNFAAHJYCQMU-UHFFFAOYSA-N 3-[4-[(3,5-dipropoxy-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound N1=C(OCCC)N=C(OCCC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 TYXNFAAHJYCQMU-UHFFFAOYSA-N 0.000 claims 1
- AOSVTFPAUIDSNY-UHFFFAOYSA-N 3-[4-[(3,5-dipropyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound N1=C(CCC)N=C(CCC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 AOSVTFPAUIDSNY-UHFFFAOYSA-N 0.000 claims 1
- WGXPCDJSSQJGME-UHFFFAOYSA-N 3-[4-[(3,5-ditert-butyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound N1=C(C(C)(C)C)N=C(C(C)(C)C)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 WGXPCDJSSQJGME-UHFFFAOYSA-N 0.000 claims 1
- ZJGLWIQSWJJUQJ-UHFFFAOYSA-N 3-[4-[(3-butanoyl-5-butyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(C(=O)CCC)=NN1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 ZJGLWIQSWJJUQJ-UHFFFAOYSA-N 0.000 claims 1
- YJTOUCSVZNORBH-UHFFFAOYSA-N 3-[4-[(3-butyl-5-chloro-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound N1=C(CCCC)N=C(Cl)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 YJTOUCSVZNORBH-UHFFFAOYSA-N 0.000 claims 1
- BRPBOEOUNKXCGI-UHFFFAOYSA-N 3-[4-[(3-butyl-5-propyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound N1=C(CCCC)N=C(CCC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 BRPBOEOUNKXCGI-UHFFFAOYSA-N 0.000 claims 1
- MSONLNYNCXTJEA-UHFFFAOYSA-N 3-[4-[(5-butyl-3-pentanoyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound N1=C(C(=O)CCCC)N=C(CCCC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 MSONLNYNCXTJEA-UHFFFAOYSA-N 0.000 claims 1
- RECHSRJZHOEYHN-UHFFFAOYSA-N 3-[4-[(5-butyl-3-propyl-1,2,4-triazol-1-yl)methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(CCC)=NN1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 RECHSRJZHOEYHN-UHFFFAOYSA-N 0.000 claims 1
- RLPMXTKGTPVFFI-UHFFFAOYSA-N 3-[4-[[3,5-bis(2-methylpropyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(CC(C)C)N=C(CC(C)C)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 RLPMXTKGTPVFFI-UHFFFAOYSA-N 0.000 claims 1
- WMKWWXCUTJSWCN-UHFFFAOYSA-N 3-[4-[[3,5-bis(but-1-enyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(C=CCC)N=C(C=CCC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 WMKWWXCUTJSWCN-UHFFFAOYSA-N 0.000 claims 1
- HRHFWEIUTHPPKG-UHFFFAOYSA-N 3-[4-[[3,5-bis(but-1-ynyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(C#CCC)N=C(C#CCC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 HRHFWEIUTHPPKG-UHFFFAOYSA-N 0.000 claims 1
- OHNQDMZPJNOSFB-UHFFFAOYSA-N 3-[4-[[3,5-bis(but-2-enyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(CC=CC)N=C(CC=CC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 OHNQDMZPJNOSFB-UHFFFAOYSA-N 0.000 claims 1
- SSKNKTFNHFBEEH-UHFFFAOYSA-N 3-[4-[[3,5-bis(but-2-ynyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(CC#CC)N=C(CC#CC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 SSKNKTFNHFBEEH-UHFFFAOYSA-N 0.000 claims 1
- FFFUCGRTVZXILG-UHFFFAOYSA-N 3-[4-[[3,5-bis(but-3-enyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(C=2C=CC(CN3C(=NC(CCC=C)=N3)CCC=C)=CC=2)=C1 FFFUCGRTVZXILG-UHFFFAOYSA-N 0.000 claims 1
- IZQJSDCATFKPNF-UHFFFAOYSA-N 3-[4-[[3,5-bis(but-3-ynyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(C=2C=CC(CN3C(=NC(CCC#C)=N3)CCC#C)=CC=2)=C1 IZQJSDCATFKPNF-UHFFFAOYSA-N 0.000 claims 1
- ANXLCZUWTHBGHI-UHFFFAOYSA-N 3-[4-[[3,5-di(butan-2-yl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(C(C)CC)N=C(C(C)CC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 ANXLCZUWTHBGHI-UHFFFAOYSA-N 0.000 claims 1
- PBEXJLLDPUYTEM-UHFFFAOYSA-N 3-[4-[[3,5-di(propan-2-yloxy)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(OC(C)C)N=C(OC(C)C)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 PBEXJLLDPUYTEM-UHFFFAOYSA-N 0.000 claims 1
- KBKJFRKEIKTZCN-UHFFFAOYSA-N 3-[4-[[3-(1,1-difluorobutyl)-5-(2-methylpropyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(C(F)(F)CCC)N=C(CC(C)C)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 KBKJFRKEIKTZCN-UHFFFAOYSA-N 0.000 claims 1
- CVMSBAKLTNRYJI-UHFFFAOYSA-N 3-[4-[[3-(1,1-difluorobutyl)-5-(3-methylbutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(C(F)(F)CCC)N=C(CCC(C)C)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 CVMSBAKLTNRYJI-UHFFFAOYSA-N 0.000 claims 1
- DUBHPSDFPFUGBK-UHFFFAOYSA-N 3-[4-[[3-(1,1-difluorobutyl)-5-ethyl-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(C(F)(F)CCC)N=C(CC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 DUBHPSDFPFUGBK-UHFFFAOYSA-N 0.000 claims 1
- FRFLUPFITFSLPV-UHFFFAOYSA-N 3-[4-[[3-(1,1-difluorobutyl)-5-pentyl-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCCC1=NC(C(F)(F)CCC)=NN1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 FRFLUPFITFSLPV-UHFFFAOYSA-N 0.000 claims 1
- DZMMBGGHNNIJTH-UHFFFAOYSA-N 3-[4-[[3-(1,1-difluorobutyl)-5-propyl-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCC1=NC(C(F)(F)CCC)=NN1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 DZMMBGGHNNIJTH-UHFFFAOYSA-N 0.000 claims 1
- KLCGWOCFGXXLBY-UHFFFAOYSA-N 3-[4-[[3-(1,1-difluoroethyl)-5-propyl-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCC1=NC(C(C)(F)F)=NN1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 KLCGWOCFGXXLBY-UHFFFAOYSA-N 0.000 claims 1
- SENPGMKQNKFKAG-UHFFFAOYSA-N 3-[4-[[3-(1,1-difluoropentyl)-5-propyl-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(C(F)(F)CCCC)N=C(CCC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 SENPGMKQNKFKAG-UHFFFAOYSA-N 0.000 claims 1
- LCZDQZLYTPZTSO-UHFFFAOYSA-N 3-[4-[[3-butyl-5-(1,1-difluorobutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(CCCC)N=C(C(F)(F)CCC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 LCZDQZLYTPZTSO-UHFFFAOYSA-N 0.000 claims 1
- YWMAGYQWVADLKR-UHFFFAOYSA-N 3-[4-[[5-but-1-enyl-3-(1,1-difluorobutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(C(F)(F)CCC)N=C(C=CCC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 YWMAGYQWVADLKR-UHFFFAOYSA-N 0.000 claims 1
- CGHHCOYUGBJYHX-UHFFFAOYSA-N 3-[4-[[5-but-1-ynyl-3-(1,1-difluorobutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(C(F)(F)CCC)N=C(C#CCC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 CGHHCOYUGBJYHX-UHFFFAOYSA-N 0.000 claims 1
- IGUBVPBDGSRNGW-UHFFFAOYSA-N 3-[4-[[5-but-2-enyl-3-(1,1-difluorobutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(C(F)(F)CCC)N=C(CC=CC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 IGUBVPBDGSRNGW-UHFFFAOYSA-N 0.000 claims 1
- ODTWHHANIPPTDB-UHFFFAOYSA-N 3-[4-[[5-but-2-ynyl-3-(1,1-difluorobutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(C(F)(F)CCC)N=C(CC#CC)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 ODTWHHANIPPTDB-UHFFFAOYSA-N 0.000 claims 1
- LXCSMTJPWCWISV-UHFFFAOYSA-N 3-[4-[[5-but-3-enyl-3-(1,1-difluorobutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(C(F)(F)CCC)N=C(CCC=C)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 LXCSMTJPWCWISV-UHFFFAOYSA-N 0.000 claims 1
- AWJSXHUMVUBRPZ-UHFFFAOYSA-N 3-[4-[[5-but-3-ynyl-3-(1,1-difluorobutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(C(F)(F)CCC)N=C(CCC#C)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 AWJSXHUMVUBRPZ-UHFFFAOYSA-N 0.000 claims 1
- HZUHYMDFZHICJZ-UHFFFAOYSA-N 3-[4-[[5-butyl-3-(1,1-difluorobutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(C(F)(F)CCC)=NN1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 HZUHYMDFZHICJZ-UHFFFAOYSA-N 0.000 claims 1
- JIOWPQYDAYMRDR-UHFFFAOYSA-N 3-[4-[[5-butyl-3-(1,1-difluoroethyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(C(C)(F)F)=NN1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 JIOWPQYDAYMRDR-UHFFFAOYSA-N 0.000 claims 1
- CWKXEXGXNBTFKL-UHFFFAOYSA-N 3-[4-[[5-butyl-3-(1,1-difluoropentyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(C(F)(F)CCCC)=NN1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 CWKXEXGXNBTFKL-UHFFFAOYSA-N 0.000 claims 1
- TYLBTGCDJAPKCM-UHFFFAOYSA-N 3-[4-[[5-butyl-3-(1,1-difluoropropyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(C(F)(F)CC)=NN1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 TYLBTGCDJAPKCM-UHFFFAOYSA-N 0.000 claims 1
- PNWXDQCHORIXDP-UHFFFAOYSA-N 3-[4-[[5-butyl-3-(1,1-dimethoxybutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(C(CCC)(OC)OC)=NN1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 PNWXDQCHORIXDP-UHFFFAOYSA-N 0.000 claims 1
- WUWNFHNBNGGKHB-UHFFFAOYSA-N 3-[4-[[5-butyl-3-(3-methylbutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(CCC(C)C)=NN1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 WUWNFHNBNGGKHB-UHFFFAOYSA-N 0.000 claims 1
- ZULKUCAUZNUJEP-UHFFFAOYSA-N 3-[4-[[5-tert-butyl-3-(1,1-difluorobutyl)-1,2,4-triazol-1-yl]methyl]phenyl]benzoic acid Chemical compound N1=C(C(F)(F)CCC)N=C(C(C)(C)C)N1CC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1 ZULKUCAUZNUJEP-UHFFFAOYSA-N 0.000 claims 1
- QJUFSSUYLIFCNW-UHFFFAOYSA-N 3-[5-butyl-2-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]-1,2,4-triazol-3-yl]propanoic acid Chemical compound N1=C(CCCC)N=C(CCC(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 QJUFSSUYLIFCNW-UHFFFAOYSA-N 0.000 claims 1
- DHTPMHPSBYTUID-UHFFFAOYSA-N 3-[[4-[(3,5-dibutoxy-1,2,4-triazol-1-yl)methyl]phenyl]methyl]benzoic acid Chemical compound N1=C(OCCCC)N=C(OCCCC)N1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 DHTPMHPSBYTUID-UHFFFAOYSA-N 0.000 claims 1
- PYQLMFDZRKSJHC-UHFFFAOYSA-N 3-[[4-[(3,5-diethoxy-1,2,4-triazol-1-yl)methyl]phenyl]methyl]benzoic acid Chemical compound N1=C(OCC)N=C(OCC)N1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 PYQLMFDZRKSJHC-UHFFFAOYSA-N 0.000 claims 1
- OYRHNGWEESUDAW-UHFFFAOYSA-N 3-[[4-[(3,5-dipentyl-1,2,4-triazol-1-yl)methyl]phenyl]methyl]benzoic acid Chemical compound N1=C(CCCCC)N=C(CCCCC)N1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 OYRHNGWEESUDAW-UHFFFAOYSA-N 0.000 claims 1
- RORGHAAJYVVCJQ-UHFFFAOYSA-N 3-[[4-[(3,5-dipropoxy-1,2,4-triazol-1-yl)methyl]phenyl]methyl]benzoic acid Chemical compound N1=C(OCCC)N=C(OCCC)N1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 RORGHAAJYVVCJQ-UHFFFAOYSA-N 0.000 claims 1
- ZCWVRKYBHMPKFH-UHFFFAOYSA-N 3-[[4-[(3,5-dipropyl-1,2,4-triazol-1-yl)methyl]phenyl]methyl]benzoic acid Chemical compound N1=C(CCC)N=C(CCC)N1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 ZCWVRKYBHMPKFH-UHFFFAOYSA-N 0.000 claims 1
- BABARQTUJAFAPZ-UHFFFAOYSA-N 3-[[4-[(3,5-ditert-butyl-1,2,4-triazol-1-yl)methyl]phenyl]methyl]benzoic acid Chemical compound N1=C(C(C)(C)C)N=C(C(C)(C)C)N1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 BABARQTUJAFAPZ-UHFFFAOYSA-N 0.000 claims 1
- BVYREQSODVYOQH-UHFFFAOYSA-N 3-[[4-[(3-butanoyl-5-butyl-1,2,4-triazol-1-yl)methyl]phenyl]methyl]benzoic acid Chemical compound CCCCC1=NC(C(=O)CCC)=NN1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 BVYREQSODVYOQH-UHFFFAOYSA-N 0.000 claims 1
- VCVGVBSVDKVURH-UHFFFAOYSA-N 3-[[4-[(3-butyl-5-chloro-1,2,4-triazol-1-yl)methyl]phenyl]methyl]benzoic acid Chemical compound N1=C(CCCC)N=C(Cl)N1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 VCVGVBSVDKVURH-UHFFFAOYSA-N 0.000 claims 1
- IAHBCIDXAANYCM-UHFFFAOYSA-N 3-[[4-[(3-butyl-5-propyl-1,2,4-triazol-1-yl)methyl]phenyl]methyl]benzoic acid Chemical compound N1=C(CCCC)N=C(CCC)N1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 IAHBCIDXAANYCM-UHFFFAOYSA-N 0.000 claims 1
- ZCQXJQPSTUEBML-UHFFFAOYSA-N 3-[[4-[(5-butyl-3-chloro-1,2,4-triazol-1-yl)methyl]phenyl]methyl]benzoic acid Chemical compound CCCCC1=NC(Cl)=NN1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 ZCQXJQPSTUEBML-UHFFFAOYSA-N 0.000 claims 1
- HMYGCWVHUXZDKU-UHFFFAOYSA-N 3-[[4-[(5-butyl-3-pentanoyl-1,2,4-triazol-1-yl)methyl]phenyl]methyl]benzoic acid Chemical compound N1=C(C(=O)CCCC)N=C(CCCC)N1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 HMYGCWVHUXZDKU-UHFFFAOYSA-N 0.000 claims 1
- BOYSWKZLKGIITA-UHFFFAOYSA-N 3-[[4-[(5-butyl-3-propyl-1,2,4-triazol-1-yl)methyl]phenyl]methyl]benzoic acid Chemical compound CCCCC1=NC(CCC)=NN1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 BOYSWKZLKGIITA-UHFFFAOYSA-N 0.000 claims 1
- RPURKSUQUCWMTO-UHFFFAOYSA-N 3-[[4-[[3,5-bis(2-methylpropyl)-1,2,4-triazol-1-yl]methyl]phenyl]methyl]benzoic acid Chemical compound N1=C(CC(C)C)N=C(CC(C)C)N1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 RPURKSUQUCWMTO-UHFFFAOYSA-N 0.000 claims 1
- FAKPSXRIIXJMSY-UHFFFAOYSA-N 3-[[4-[[3,5-bis(3-methylbutyl)-1,2,4-triazol-1-yl]methyl]phenyl]methyl]benzoic acid Chemical compound N1=C(CCC(C)C)N=C(CCC(C)C)N1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 FAKPSXRIIXJMSY-UHFFFAOYSA-N 0.000 claims 1
- VWQGCKBZEOTGKP-UHFFFAOYSA-N 3-[[4-[[3,5-bis(but-1-enyl)-1,2,4-triazol-1-yl]methyl]phenyl]methyl]benzoic acid Chemical compound N1=C(C=CCC)N=C(C=CCC)N1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 VWQGCKBZEOTGKP-UHFFFAOYSA-N 0.000 claims 1
- YWIJVBXQRFGCJI-UHFFFAOYSA-N 3-[[4-[[3,5-bis(but-1-ynyl)-1,2,4-triazol-1-yl]methyl]phenyl]methyl]benzoic acid Chemical compound N1=C(C#CCC)N=C(C#CCC)N1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 YWIJVBXQRFGCJI-UHFFFAOYSA-N 0.000 claims 1
- JJGIDRQVEZCZRW-UHFFFAOYSA-N 3-[[4-[[3,5-bis(but-2-enyl)-1,2,4-triazol-1-yl]methyl]phenyl]methyl]benzoic acid Chemical compound N1=C(CC=CC)N=C(CC=CC)N1CC(C=C1)=CC=C1CC1=CC=CC(C(O)=O)=C1 JJGIDRQVEZCZRW-UHFFFAOYSA-N 0.000 claims 1
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- PFGWGEPQIUAZME-NXSMLHPHSA-N saralasin Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CNC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)C1=CC=C(O)C=C1 PFGWGEPQIUAZME-NXSMLHPHSA-N 0.000 description 1
- 229960004785 saralasin Drugs 0.000 description 1
- UISHOHGMISMAQN-UHFFFAOYSA-M sodium;2-[2-butyl-5-chloro-3-[(2-chlorophenyl)methyl]imidazol-4-yl]acetate Chemical compound [Na+].CCCCC1=NC(Cl)=C(CC([O-])=O)N1CC1=CC=CC=C1Cl UISHOHGMISMAQN-UHFFFAOYSA-M 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- 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
-
- 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
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Definitions
- Non-peptidic 1H-substituted-1,2,4-triazole compounds are described for use in treatment of
- cardiovascular disorders such as hypertension and
- angiotensin II antagonist compounds provided by 1,2,4- triazoles having a biphenylmethyl moiety attached to the nitrogen atom at the one-position of the 1,2,4-triazole.
- the renin-angiotensin system is one of the hormonal mechanisms involved in regulation of
- angiotensin II the primary active species of this system.
- This octapeptide, angiotensin II is a potent
- vasoconstrictor agent and also produces other physiological effects such as promoting aldosterone secretion, promoting sodium and fluid retention, inhibiting renin secretion, increasing sympathetic nervous system activity, increasing vasopressin secretion, causing positive cardiac inotropic effect and modulating other hormonal systems.
- antagonizing angiotensin II at its receptors is a viable approach to inhibit the renin-angiotensin system, given the pivotal role of this octapeptide which mediates the actions of the renin-angiotensin system through interaction with various tissue receptors.
- angiotensin II antagonists most of which are peptidic in nature. Such peptidic compounds are of limited use due to their lack of oral bioavailability or their short duration of action.
- commercially-available peptidic angiotensin II antagonists e.g., Saralasin
- Non-peptidic compounds with angiotensin II antagonist properties are known.
- the sodium salt of 2-n-butyl-4-chloro-1-(2-chlorobenzyl)imidazole-5- acetic acid has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [P. C. Wong et al, J. Pharmacol. Exp. Ther., 247 (1), 1-7 (1988)].
- the sodium salt of 2-butyl-4-chloro-1-(2- nitrobenzyl)imidazole-5-acetic acid has specific
- U.S. Patent No. 4,880,804 to Carini et al describes a family of
- biphenylmethylbenzimidazole compounds as angiotensin II receptor blockers for use in treatment of hypertension and congestive heart failure.
- m is a number selected from one to four
- each of R 1 through R 11 is independently selected from hydrido, formyl, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,
- aralkoxycarbonyl alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, polycycloalkyl,
- alkoxycarbonylaminoalkyl glutamic acid alkyl ester, alkylcarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl,
- alkylcarbonylthio alkylthiocarbonyloxy
- alkylthiocarbonylthio alkylthiothiocarbonyl
- alkylsulfonyl aralkylsulfinyl, aralkylsulfonyl,
- arylsulfinyl arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula
- R 12 and R 13 taken together, R 14 and R 15 taken together and R 16 and R 17 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical and which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein each of R 1 2 and R 13 taken together and each of R 14 and R 15 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and wherein each
- n is a number selected from zero through three, inclusive, and wherein A is an acidic group selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties;
- Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms;
- B is a single bond connecting the phenyl rings to form a biphenyl moiety or B is a group selected from
- R 18 is selected from hydrido, alkyl, aryl, formyl, alkylcarbonyl, arylcarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl and
- any of the foregoing R 1 through R 18 , Y, A and B groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, alkynyl, aralkyl,
- hydroxyalkyl trifluoromethyl, halo, oxo, difluoroalkyl, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy,
- alkoxycarbonyloxy alkylcarbonyl, alkoxycarbonyl,
- aralkoxycarbonyl carboxyl, mercapto, mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl, aralkyIsulfinyl, aralkylsulfonyl,
- D is selected from oxygen atom and sulfur atom and R 24 is selected from hydrido, alkyl, cycloalkyl,
- R 20 , R 21 , R 22 , R 23 , R 25 and R 26 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl,
- alkoxycarbonyl carboxyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, haloalkylsulfinyl,
- R 20 , R 21 , R 22 , R 23 R 25 and R 26 is further independently selected from amino and amido radicals of the formula
- each of R 20 and R 21 taken together and each of R 22 and R 23 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein each of R 20 and R 21 taken together and each of R 25 and R 26 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
- Compounds of Formula I would be useful in treating a variety of circulatory disorders including cardiovascular disorders, such as hypertension, congestive heart failure and arteriosclerosis, and to treat other disorders such as glaucoma. These compounds would also be useful as adjunctive therapies.
- cardiovascular disorders such as hypertension, congestive heart failure and arteriosclerosis
- compounds of Formula I may be used in combination with other drugs, such as a diuretic, to treat hypertension.
- compounds of Formula I could be used in conjunction with certain drugs, such as a diuretic, to treat hypertension.
- Compounds of Formula I are therapeutically effective in treatment of cardiovascular disorders by acting as antagonists to, or blockers of, the angiotensin II (All) receptor. Compounds of Formula I would be therapeutically effective in
- cardiovascular disorders or would be precursors to, or prodrugs of, therapeutically-effective compounds.
- substituents are selected from the aforementioned R 1 and R 2 groups.
- R 1 and R 2 groups Compounds having alkyl groups, especially lower alkyl groups, at both of the R 1 and R 2 positions are particularly useful as angiotensin II antagonists. Also especially useful are compounds having one of the R 1 and R 2 substituents selected from
- alkylcarbonyl monoalkoxyalkyl, dialkoxyalkyl
- difluoroalkyl groups When the selected substituent for R 1 and R 2 is difluoroalkyl, then it is particularly useful for both of the fluoro atoms of the difluoroalkyl group to be substituted on the difluoroalkyl group carbon atom attached at the R 1 or R 2 positions of the triazole ring.
- difluoroalkyl group may be characterized as an "alpha- carbon difluoro-substituted difluoroalkyl group", or as an "alpha,alpha-difluoro-substituted alkyl group".
- R 1 or R 2 When the selected substituent for R 1 or R 2 is monoalkoxyalkyl or dialkoxyalkyl, then it is particularly useful for the single alkoxy group or the two alkoxy groups, respectively, to be substituted on the carbon atom of the selected substituent which is attached at the R 1 or R 2 positions of the triazole ring.
- alkoxyalkyl groups may be
- alkylcarbonyl When the selected substituent is alkylcarbonyl, then it is particularly useful for the carbonyl group to be attached at the R 1 or R 2 positions of the triazole ring.
- alkylcarbonyl group may be characterized as an "alpha-oxo-s ⁇ bstituted alkyl group", and may be exemplified by the substituents 1-oxoethyl, 1- oxopropyl and 1-oxobutyl.
- compounds of Formula I contain any of these above-mentioned particularly-useful alpha-carbon substituted R 1 or R 2 groups at the triazole ring three- or five-position, it is preferred that such particularly-useful group be attached at the three- position, that is, as an R 1 substituent.
- the phrase "acidic group selected to contain at least one acidic hydrogen atom”, as used to define the -Y n A moiety, is intended to embrace chemical groups which, when attached to any of the R 3 through R 11 positions of Formula I, confers acidic character to the compound of Formula I.
- “Acidic character” means proton-donor capability, that is, the capacity of the compound of Formula I to be a proton donor in the presence of a proton-receiving substance such as water.
- the acidic group should be selected to have proton-donor capability such that the product compound of Formula I has a pK a in a range from about one to about twelve. More typically, the Formula I compound would have a pK a in a range from about two to about seven.
- an acidic group containing at least one acidic hydrogen atom is carboxyl group (-COOH). Where n is zero and A is -COOH, in the -Y n A moiety, such carboxyl group would be attached directly to one of the R 3 through R 11 positions.
- the Formula I compound may have one -Y n A moiety attached at one of the R 3 through R 11 positions, or may have a plurality of such -Y n A moieties attached at more than one of the R 3 through R 11 positions, up to a maximum of nine such -Y n A moieties.
- acidic groups other than carboxyl group selectable to contain at least one acidic hydrogen atom. Such other acidic groups may be collectively referred to as
- bioisosteres of carboxylic acid or referred to as “acidic bioisosteres”. Specific examples of such acidic
- Formula I having the -Y n A moiety attached at one of positions R 5 , R 6 , R 8 and R 9 would be expected to have preferred properties, while attachment at R 5 or R 9 would be more preferred.
- a preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein each of R 1 through R 11 is independently selected from hydrido, formyl, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, polycycloalkyl,
- alkoxycarbonylaminoalkyl glutamic acid alkyl ester, alkylcarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl,
- alkylcarbonylthio alkylcarbonylthio, alkylthiocarbonyloxy, alkylthio- arbonylthio, alkylthiothiocarbonyl, alkylthiothio- carbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio,
- aralkylthio aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio,
- aralkylthiocarbonyl aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl,
- aralkylsulfonyl arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms and amino and amido radicals of the formula
- R 3 through R 11 may be further selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R 3 through R 11 may be further
- n is a number selected from zero through three, inclusive; wherein A is an acidic group selected from acids containing one or more atoms selected from oxygen, sulfur, phosphorus and nitrogen atoms, and wherein said acidic group is selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl,
- cycloalkylalkyl alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; wherein B is a single bond or is a group selected from
- R 18 is selected from hydrido, alkyl, aryl, formyl, alkylcarbonyl, arylcarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl and aralkoxycarbonyl; and wherein any of the foregoing R 1 through R 18 , Y, A and B groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, aralkyl, hydroxyalkyl, trifluoromethyl, difluoroalkyl, oxo, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercaptocarbonyl, alkylthio, alkylthiocarbonyl, and amino and amido radicals of the formula
- X is selected from oxygen atom and sulfur atom; wherein R 19 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, and DR 24 and
- R 24 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 20 , R 21 , R 22 , R 23 , R 25 and R 26 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl.
- R 20 , R 21 , R 22 , R 23 , R 25 , and R 26 is further independently selected from amino and amido radicals of the formula
- haloalkylsulfonyl aralkyl and aryl; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
- a more preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein each of R 1 through R 11 is independently selected from hydrido, hydroxy, formyl, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl,
- alkoxycarbonyl alkenyl, cycloalkenyl, alkynyl
- cycloalkynyl cyano, nitro, carboxyl, carboxyalkyl, polycycloalkyl, polycycloalkylalkyl, haloalkyl,
- thienylalkyl phenylacyl, phenylhaloalkyl, aminoalkyl, acylaminoalkyl, alkoxycarbonylaminoalkyl, glutamic acid alkyl ester, alkylcarbonyloxy, mercaptocarbonyl,
- alkylsulfonyl aralkylsulfinyl, aralkylsulfonyl,
- arylsulfinyl arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; and amino and amido radicals of the formula
- each of R 3 through R 11 may be an acidic moiety further independently selected from hydrido and haloalkyl, and from acidic moieties of the formula
- n is a number selected from zero through three, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from
- each W is independently selected from oxygen atom, sulfur atom and NR 37 ; wherein each of R 33 , R 34 , R 35 , R 36 and R 37 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl,
- each of R 33 , R 34 , R 35 and R 36 may be further independently selected from amino radical of the formula wherein each of R 38 and R 39 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
- R 38 and R 39 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein R 38 and R 39 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; wherein each of R 34 and R 35 may be further independently selected from hydroxy, alkoxy, alkylthio, aryloxy, arylthio, aralkylthio and aralkoxy; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of carboxylic acid may
- heterocyclic ring unsaturated, and which heterocyclic ring may be attached at a single position selected from R 3 through R 11 or may be attached at any two adjacent positions selected from R 3 through R 11 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups;
- Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl;
- B is a single bond or is a group selected from
- R 18 is selected from hydrido, alkyl, aryl, formyl, alkylcarbonyl, arylcarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl and
- R 1 through R 18 , Y, A and B groups having a substitutable position may be substituted by one or more groups selected from alkyl, alkenyl, aralkyl, hydroxyalkyl, trifluoromethyl,
- X is selected from oxygen atom and sulfur atom
- R 19 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl and DR 24 and wherein D is selected from oxygen atom and sulfur atom, wherein R 24 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 20 , R 21 , R 22 , R 23 , R 25 and R 26 is
- alkyl independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
- An even more preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein each of R 1 and R 2 is independently selected from hydrido, hydroxy, formyl, alkyl, carboxyalkyl, phenyl, phenylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl,
- each of R 3 through R 11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylthio, aralkylthi
- n is a number selected from zero through three, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from
- each W is independently selected from oxygen atom, sulfur atom and NR 37 ; wherein each of R 33 , R 36 and R 37 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl,
- each of R 33 and R 36 may be further independently selected from amino radical of the formula wherein each of R 38 and R 39 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
- R 38 and R 39 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms, and which heterocyclic group may be saturated or partially unsaturated; wherein R 38 and R 39 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and the amide, ester and salt derivatives of said acidic groups;
- bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R 3 through R 11 or may be attached at any two adjacent positions selected from R 3 through R 11 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; wherein B is a single bond or is a group selected from
- R 1 through R 11 , Y, A and B independently may be substituted at any substitutable position with one or more groups selected from alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, oxo, trifluoromethyl, difluoroalkyl, alkoxycarbonyl, cyano, nitro, alkylsulfonyl,
- haloalkylsulfonyl aryl, aralkyl, alkoxy, aryloxy and
- a highly preferred class of compounds consists of those compounds wherein m is one; wherein each of R 1 and R 2 is independently selected from hydrido, hydroxy, formyl, alkyl, carboxyalkyl, phenyl, phenylalkyl, cycloalkyl,
- each of R 3 through R 11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio, mercapto and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms
- n is a number selected from zero through two
- A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from
- each W is independently selected from oxygen atom, sulfur atom and NR 37 ; wherein each of R 33 , R 36 and R 37 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, phenyl and benzyl; wherein each of R 33 and R 36 may be further
- each of R 38 and R 39 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
- bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R 3 through R 11 or may be attached at any two adjacent positions selected from R 3 through R 11 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl, phenalkyl and aral
- R 1 through R 18 , Y, A and B and independently may be substituted at any substitutable position with one or more groups selected from alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, oxo, trifluoromethyl, alkoxycarbonyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
- An even more highly preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein each of R 1 and R 2 is independently selected from hydrido, hydroxy, formyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 4-methylbutyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, carboxyethyl, phenyl, benzyl, phenethyl, cyclopentyl,
- cyclohexylethyl cyclohexylpropyl, adamantyl, adamantyImethyl, 1-oxoethyl, oxobutyl, 1-oxopentyl, dimethoxymethyl,
- each of R 3 through R 11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, acetyl,
- each of R 3 through R 11 may be an acidic moiety further independently selected from acidic moieties consisting of CO 2 H, CO 2 CH 3 , SH, CH 2 SH, C 2 H 4 SH, PO 3 H 2 , NHSO 2 CF 3 ,
- heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R 3 through R 11 or may be attached at any two adjacent positions selected from R 3 through R 11 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein B is a single bond or is one or more groups selected from
- aralkoxycarbonyl or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
- a class of compounds of particular interest consists of those compounds of Formula I wherein m is one; wherein R 1 is selected from hydrido, hydroxy, formyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 4-methylbutyl, n-pentyl, neopentyl, n-hexyl, n- heptyl, n-octyl, n-nonyl, carboxyethyl, phenyl, benzyl, phenethyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl,
- adamantyl adamantylmethyl, 1-oxoethyl, 1-oxopropyl, 1- oxobutyl, 1-oxopentyl, dimethoxymethyl, diethoxymethyl, 1,1- dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxypropyl, halo, monofluoromethyl, difluoromethyl,
- R 2 is selected from hydrido, carboxyethyl, cyclohexyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,
- R 1 and R 2 cannot be hydrido simultaneously; wherein each of R 3 , R 4 , R 7 , R 9 , R 10 and R 11 is hydrido; wherein at least one of R 5 , R 6 , R 8 and R 9 is an acidic moiety selected from CO 2 H, SH, PO 3 H 2 , SO 3 H, CONHNH 2, CONHNHSO 2 CF 3 , OH,
- each of R 40 and R 41 is independently selected from Cl, CN, NO 2 , CF 3 , CO 2 CH 3 and SO 2 CF 3 ; and the amide, ester and salt derivatives of said acidic moieties; wherein B is a single bond or is a group selected from
- R 18 is selected from hydrido, alkyl, aryl, formyl, alkylcarbonyl, arylcarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl and
- aralkoxycarbonyl or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
- a class of compounds of more particular interest consists of those compounds of Formula I wherein m is one;
- R 1 is selected from hydroxy, formyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 4-methylbutyl, n-pentyl, neopentyl, n-hexyl, n-heptyl,
- n-octyl n-nonyl, carboxyethyl, phenyl, benzyl, phenethyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, adamantyl, adamantylmethyl, 1-oxoethyl, 1 -oxopropyl, 1-oxobutyl, 1-oxopentyl,
- R 2 is selected from carboxyethyl, cyclohexyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl and neopentyl; wherein each of R 3 , R 4 , R 7 , R 9 , R 10 and R 11 is hydrido; wherein at least one of R 5 , R 6 , R 8 and R 9 is an acidic moiety selected from CO 2 H, SH, PO 3 H 2 SO 3 H, CONHNH 2, CONHNHSO 2 CF 3 , OH, wherein
- R 5 and R 9 are compounds wherein at least one of R 5 and R 9 is selected from the acidic groups specified for this class of compounds of more
- a sub-class of compounds within Formula I, consisting of biphenylmethyl 1H-substituted-1,2,4-triazole compounds useful in treating circulatory and cardiovascular disorders, is defined by Formula II:
- m is a number selected from one to four, inclusive; wherein each of R 1 through R 11 is independently selected from hydrido, formyl, hydroxy, alkyl, hydroxyalkyl, halo,
- haloalkyl cycloalkyl, cycloalkylalkyl, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl,
- alkylcarbonyl alkylcarbonylalkyl, alkoxycarbonyl
- aralkoxycarbonyl alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, polycycloalkyl,
- alkoxycarbonylaminoalkyl glutamic acid alkyl ester
- alkylcarbonyloxy mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl,
- alkylcarbonylthio alkylthiocarbonyloxy
- alkylthiocarbonylthio alkylthiothiocarbonyl
- alkylthiocarbonyl aralkylthiocarbonylthio, mercapto
- alkylsulfinyl alkylsulfonyl, aralkylsulfinyl
- R 12 and R 13 taken together, R 16 and R 16 taken together and R 16 and R 17 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical and which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein each of R 12 and R 13 taken together and each of R 14 and R 15 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and wherein each of R 3 through R 11 may be further
- n is a number selected from zero through three, inclusive, and wherein A is an acidic group selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties;
- Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; and wherein any of the foregoing R 1 through R 17 , Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, halo, haloalkyl, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyal
- aralkylsulfonyl arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula
- X is selected from oxygen atom and sulfur atom
- R 19 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR 24 and wherein D is selected from oxygen atom and sulfur atom and R 24 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 20 , R 21 , R 22 , R 23 , R 25 and R 26 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, haloalkylsulfinyl,
- each of R 20 and R 21 taken together and each of R 22 and R 23 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein each of R 20 and R 21 taken together and each of R 25 and R 26 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; or a tautomer thereof or a pharmaceutically- acceptable salt thereof.
- Compounds of Formula II are all characterized in having a substituent, other than hydrido, at each of the three- and five-positions of the triazo
- substituents are selected from the aforementioned R 1 and R 2 groups.
- Compounds having alkyl groups, especially lower alkyl groups, at both of the R 1 and R 2 positions are particularly useful as angiotensin II antagonists. Also especially useful are compounds having one of the R 1 and R 2 substituents
- R 1 and R 2 are selected from alkylcarbonyl, monoalkoxyalkyl, dialkoxyalkyl and difluoroalkyl groups.
- R 1 and R 2 are difluoroalkyl, then it is particularly useful for both of the fluoro atoms of the difluoroalkyl group to be substituted on the difluoroalkyl group carbon atom attached at the R 1 or R 2 positions of the triazole ring.
- difluoroalkyl group may be characterized as an "alpha-carbon difluoro-substituted difluoroalkyl group", or as an
- alpha, alpha-difluoro-substituted alkyl group When the selected substituent for R 1 or R 2 is monoalkoxyalkyl or dialkoxyalkyl, then it is particularly useful for the single alkoxy group or the two alkoxy groups, respectively, to be substituted on the carbon atom of the selected substituent which is attached at the R 1 or R 2 positions of the triazole ring.
- alkoxyalkyl groups may be characterized as "alpha- carbon monoalkoxy- or dialkoxy-substituted alkoxyalkyl groups", respectively, or “alpha-monoalkoxy-substituted or alpha, alpha-dialkoxy-substituted alkyl groups", respectively.
- the selected substituent is alkylcarbonyl, then it is particularly useful for the carbonyl group to be attached at the R 1 or R 2 positions of the triazole ring.
- alkylcarbonyl group may be characterized as an "alpha-oxo- substituted alkyl group", and may be exemplified by the substituents 1-oxoethyl, 1-oxopropyl and 1-oxobutyl.
- compounds of Formula II contain any of these above-mentioned particularly-useful alpha-carbon substituted R 1 or R 2 groups at the triazole ring three- or five-position, it is preferred that such particularly-useful group be attached at the three- position, that is, as an R 1 substituent.
- Formula II compounds may have one -Y n A moiety attached at one of the R 3 through R 11 positions of the biphenyl moiety, or may have a plurality of such -Y n A moieties attached at more than one of the R 3 through R 11 positions, up to a maximum of nine such -Y n A moieties.
- Compounds of Formula II having the -Y n A. moiety attached at one of positions R 5 , R 6 , R 8 and R 9 of the biphenyl moiety of Formula II would be expected to have preferred properties, while attachment at R 5 or R 9 would be more preferred.
- a preferred class of compounds within the sub-class defined by Formula II consists of those compounds wherein m is one; wherein each of R 1 through R 11 is independently selected from hydrido, formyl, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl,
- alkoxycarbonyl alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, polycycloalkyl,
- alkoxycarbonylaminoalkyl glutamic acid alkyl ester
- alkylcarbonyloxy mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl,
- alkylcarbonylthio alkylcarbonylthio, alkylthiocarbonyloxy, alkylthioarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl,
- arylthiothiocarbonylthio aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl,
- alkylsulfinyl alkylsulfonyl, aralkylsulfinyl
- aralkyIsulfonyl arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms and amino and amido radicals of the formula
- R 3 through R 11 may be further
- n is a number selected from zero through three, inclusive; wherein A is an acidic group selected from acids containing one or more atoms selected from oxygen, sulfur, phosphorus and nitrogen atoms, and wherein said acidic group is selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; and wherein any of the foregoing R 1 through R 17 , Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, aralkyl, hydroxyalkyl, haloalkyl, oxo, alkoxy,
- X is selected from oxygen atom and sulfur atom
- R 19 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, and DR 24 and wherein D is selected from oxygen atom and sulfur atom, and R 24 is selected from hydrido, alkyl, cycloalkyl,
- each of R 20 , R 21 , R 22 , R 23 , R 25 and R 26 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl,
- R 20 , R 21 , R 22 , R 23 , R 25 , and R 26 is further independently selected from amino and amido radicals of the formula
- haloalkylsulfonyl aralkyl and aryl; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
- a more preferred class of compounds within the subclass defined by Formula II consists of those compounds wherein m is one; wherein each of R 1 through R 11 is
- hydrido hydroxy, formyl, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl,
- polycycloalkyl polycycloalkylalkyl, haloalkyl, thienylalkyl, phenylacyl, phenylhaloalkyl, aminoalkyl, acylaminoalkyl, alkoxycarbonylaminoalkyl, glutamic acid alkyl ester,
- each of R 3 through R 11 may be an acidic moiety further independently selected from hydrido and haloalkyl, and from acidic moieties of the formula
- n is a number selected from zero through three, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from
- each W is independently selected from oxygen atom, sulfur atom and NR 37 ; wherein each of R 33 , R 34 , R 35 , R 36 and R 37 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl,
- each of R 33 , R 34 , R 35 and R 36 may be further independently selected from amino radical of the formula wherein each of R 38 and R 39 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
- R 38 and R 39 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein R 38 and R 39 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; wherein each of R 34 and R 35 may be further independently selected from hydroxy, alkoxy, alkylthio, aryloxy, arylthio, aralkylthio and aralkoxy; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of carboxylic acid may
- heterocyclic ring may be attached at a single position selected from R 3 through R 11 or may be attached at any two adjacent positions selected from R 3 through R 11 so as to form a fused-ring system with one of the phenyl rings of the biphenyl moiety of Formula II; and the amide, ester and salt derivatives of said heterocyclic acidic groups;
- Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; and wherein any of the foregoing R 1 through R 17 , Y and A groups having a substitutable position may be substituted by one or more groups selected from alkyl, alkenyl, aralkyl, hydroxyalkyl, haloalkyl, alkoxy, aryloxy, aralkoxy,
- alkoxyalkyl alkylcarbonyl, alkoxycarbonyl, carboxyl
- X is selected from oxygen atom and sulfur atom
- R 19 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl and DR 24 and wherein D is selected from oxygen atom and sulfur atom, wherein R 24 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 20 , R 21 , R 22 , R 23 , R 25 and R 26 is
- alkyl independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl,
- alkanoyl alkoxycarbonyl, carboxyl, haloalkylsulfinyl
- haloalkylsulfonyl aralkyl and aryl; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
- each of R 1 and R 2 is independently selected from hydrido, hydroxy, formyl, alkyl, carboxyalkyl, phenyl, phenylalkyl, cycloalkyl,
- each of R 3 through R 11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylthio, aralkylthi
- n is a number selected from zero through three, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from
- each W is independently selected from oxygen atom, sulfur atom and NR 37 ; wherein each of R 33 , R 36 and R 37 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl,
- each of R 33 and R 36 may be further independently selected from amino radical of the formula wherein each of R 38 and R 39 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
- R 38 and R 39 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms, and which heterocyclic group may be saturated or partially unsaturated; wherein R 38 and R 39 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and the amide, ester and salt derivatives of said acidic groups;
- said bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R 3 through R 11 or may be attached at any two adjacent positions selected from R 3 through R 11 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; wherein each of R 1 through R 11 , Y and A independently may be substituted at any substitutable position with one or more groups selected from alkyl, cycl
- a highly preferred class of compounds within the sub-class defined by Formula II consists of those compounds wherein m is one; wherein each of R 1 and R 2 is independently selected from hydrido, hydroxy, formyl, alkyl, carboxyalkyl, phenyl, phenylalkyl, cycloalkyl, cycloalkylalkyl,
- each of R 3 through R 11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio, mercapto and heteroaryl having one
- n is a number selected from zero through two
- A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from
- each W is independently selected from oxygen atom, sulfur atom and NR 37 ; wherein each of R 33 , R 36 and R 37 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, phenyl and benzyl; wherein each of R 33 and R 36 may be further
- each of R 38 and R 39 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
- bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of
- heterocyclic rings of four to about nine ring members which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R 3 through R 11 or may be attached at any two adjacent positions selected from R 3 through R 11 so as to form a fused-ring system with one of the phenyl rings of the biphenyl moiety of Formula II; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl, phenalkyl and aralkyl; wherein each of R 1 through R 11 , Y and A and independently may be substituted at any substitutable position with one or more groups selected from alkyl, cycloalkyl, cycloalkyl
- An even more highly preferred class of compounds within the sub-class defined by Formula II consists of those compounds wherein m is one; wherein each of R 1 and R 2 is independently selected from hydrido, hydroxy, formyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 4-methylbutyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, carboxyethyl, phenyl, benzyl, phenethyl, cyclopentyl,
- cyclohexylethyl cyclohexylpropyl, adamantyl, adamantylmethyl, 1-oxoethyl, oxobutyl, 1-oxopentyl, dimethoxymethyl,
- each of R 3 through R 11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, acetyl,
- each of R 3 through R 11 may be an acidic moiety further independently selected from acidic moieties consisting of CO 2 H, CO 2 CH 3, SH, CH 2 SH, C 2 H 4 SH, PO 3 H 2, NHSO 2 CF 3 ,
- each of R 40 , R 41 and R 42 is independently selected from H, Cl, CN, NO 2 , CF 3, C 2 F 5 , C 3 F 7 , CHF 2 , CH 2 F, CO 2 CH 3 , CO 2 C 2 H 5 , SO 2 CH 3, SO 2 CF 3 and SO 2 C 6 F 5 ;
- Z is selected from O, S, NR 43 and CH 2;
- R 43 is selected from hydrido, CH 3 and CH 2 C 6 H 5; and wherein said acidic moiety may be a heterocyclic acidic group attached at any two adjacent positions of R 3 through R 11 so as to form a fused ring system with one of the biphenyl rings of the biphenyl moiety of Formula II, said fused ring system selected from
- a class of compounds of particular interest within the sub-class defined by Formula II consists of those
- R 1 is selected from hydrido, hydroxy, formyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 4-methylbutyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, carboxyethyl, phenyl, benzyl, phenethyl, cyclopentyl,
- cyclohexylethyl cyclohexylpropyl, adamantyl, adamantylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl,
- R 2 is selected from hydrido, carboxyethyl, cyclohexyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n- pentyl and neopentyl; with the proviso that both R 1 and R 2 cannot be hydrido simultaneously; wherein each of R 3 through R 11 is hydrido with the proviso that at least one of R 5 and R 9 must be selected from COOH, SH, PO- 3 H 2, SO 3 H, CONHNH 2,
- each of R 40 and R 41 is independently selected from chloro, cyano, nitro, trifluoromethyl, methoxycarbonyl and trifluoromethyIsulfonyl; wherein at least one of R 5 , R 6 , R 8 and R 9 is an acidic group selected from CO 2 H, SH, PO 3 H 2 SO 3 H, CONHNH 2 , CONHNHSO 2 CF 3 , OH,
- each of R 40 and R 41 is independently selected from Cl, CN, NO 2 , CF 3 , CO 2 CH 3 and SO 2 CF 3 .
- a class of compounds of more particular interest within the sub-class defined by Formula II consists of those compounds wherein m is one; wherein R 1 is selected from hydroxy, formyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 4-methylbutyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, carboxyethyl, phenyl, benzyl, phenethyl, cyclopentyl, cyclohexyl,
- cyclohexylpropyl adamantyl, adamantylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, dimethoxymethyl, diethoxymethyl, 1,1-dimethoxypropyl, 1,1-dimethoxybutyl,
- 1,1-dimethoxypentyl 1,1-dimethoxypentyl, hydroxypropyl, halo, monofluoromethyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl, 1,1-difluoropentyl, pentafluoroethyl, heptafluoropropyl, phenylacetyl, phenyldifluoroethyl,
- R 2 is selected from carboxyethyl, cyclohexyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl and neopentyl; wherein at least one of R 5 , R 6 , R 8 and R 9 is an acidic group selected from CO 2 H, SH, PO 3 H 2, SO 3 H, CONHNH 2, CONHNHSO 2 CF 3 , OH,
- each of R 40 and R 41 is independently selected from Cl, CN, NO 2 , CF 3 , CO 2 CH 3 and SO 2 CF 3 .
- Formula II consists of those compounds wherein at least one of R 5 and R 9 is selected from the acidic groups selectable for the compounds of more particular interest.
- hydro denotes a single hydrogen atom (H) .
- This hydrido group may be attached, for example, to an oxygen atom to form a hydroxyl group; or, as another example, one hydrido group may be attached to a carbon atom to form a group; or, as another example, two hydrido groups may be attached to a carbon atom to form a -CH 2 - group.
- alkyl is used, either alone or within other terms such as “haloalkyl” and "hydroxyalkyl”
- alkyl embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms.
- alkyl radicals are "lower alkyl” radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about five carbon atoms.
- cycloalkyl embraces mono-carbocyclic saturated radicals having three to about ten ring carbon atoms, preferably three to about six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- cycloalkylalkyl denotes a cycloalkyl radical attached to an alkyl radical which is attachable to a substitutable position of Formula I or II. Examples of “cycloalkylalkyl” radicals are
- polycycloalkyl denotes a ring system radical formed by two, or by three, or by more, cycloalkyl radicals joined together through one common carbon atom, or through two common adjacent carbon atoms to form a two-ring fused ring system, or formed by an alkylene bridge across a cycloalkyl ring.
- Such ring systems may contain from four to about twenty carbon atoms, and more preferably from eight to about ten carbon atoms.
- An example of a "polycycloalkyl” radical is adamantyl, also known as tricyclodecyl radical.
- polycycloalkylalkyl denotes a polycycloalkyl radical attached to an alkyl radical which is attachable to a substitutable position of Formula I or II.
- Examples of “polycycloalkylalkyl” radicals are adamantylmethyl and adamantylethyl.
- haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with one or more halo groups, preferably selected from bromo, chloro and fluoro.
- haloalkyl are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups.
- a monohaloalkyl group for example, may have either a bromo, a chloro, or a fluoro atom within the group, such as monofluoromethyl.
- polyhaloalkyl groups may be substituted with two or more of the same halo groups, or may have a combination of different halo groups.
- a dihaloalkyl group for example, may have two fluoro atoms, such as difluoromethyl and difluorobutyl groups, or two chloro atoms, such as a dichloromethyl group, or one fluoro atom and one chloro atom, such as a fluoro-chloromethyl group.
- Examples of a polyhaloalkyl are trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,3,3-tetrafluoropropyl and perfluoropropyl groups.
- difluoroalkyl embraces alkyl groups having two fluoro atoms substituted on any one or two of the alkyl group carbon atoms.
- alkylol and “hydroxyalkyl” embrace linear or branched alkyl groups having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl groups.
- alkenyl embraces linear or branched radicals having two to about twenty carbon atoms, preferably three to about ten carbon atoms, and containing at least one carbon-carbon double bond, which carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety.
- alkynyl embraces linear or branched radicals having two to about twenty carbon atoms, preferably two to about ten carbon atoms, and containing at least one carbon-carbon triple bond.
- cycloalkenyl embraces cyclic radicals having three to about ten ring carbon atoms including one or more double bonds involving adjacent ring carbons.
- alkoxy and alkoxyalkyl embrace linear or branched oxy- containing radicals each having alkyl portions of one to about ten carbon atoms.
- An example of alkoxy is methoxy group.
- alkoxyalkyl also embraces alkyl radicals having two or more alkoxy groups attached to an alkyl radical.
- dialkoxyalkyl is exemplified by dimethoxymethyl and
- alkoxy or alkoxyalkyl radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy or
- alkylthio embraces radicals containing a linear or branched alkyl group, of one to about ten carbon atoms attached to a divalent sulfur atom, such as a methythio group. Preferred aryl groups are those consisting of one, two, or three benzene rings.
- aryl embraces aromatic radicals such as phenyl, naphthyl and biphenyl.
- aralkyl embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, phenylbutyl and diphenylethyl.
- benzyl and "phenylmethyl” are interchangeable.
- aryloxy and “arylthio” denote radical respectively, aryl groups having an oxygen or sulfur atom through which the radical is attached 'to a nucleus, examples of which are phenoxy and phenylthio.
- sulfinyl and “sulfonyl”, whether used alone or linked to other terms, denotes
- acyl whether used alone, or within terms such as acyloxy and acylaminoalkyl, denotes a radical provided by the residue after removal of hydroxyl from an organic acid, examples of such radical being acetyl and benzoyl.
- “Lower alkanoyl” is an example of a more prefered sub-class of acyl.
- amido denotes a radical consisting of nitrogen atom attached to a carbonyl group, which radical may be further substituted in the manner described herein.
- amido radical can be attached to the nucleus of a compound of the invention through the carbonyl moiety or through the nitrogen atom of the amido radical.
- alkenylalkyl denotes a radical having a double-bond unsaturation site between two carbons, and which radical may consist of only two carbons or may be further substituted with alkyl groups which may optionally contain additional double- bond unsaturation.
- heteroaryl embraces aromatic ring systems containing one or two hetero atoms selected from oxygen, nitrogen and sulfur in a ring system having five or six ring members, examples of which are thienyl, furanyl, pyridinyl, thiazolyl, pyrimidyl and isoxazolyl.
- heteroaryl may be attached as a substituent through a carbon atom of the heteroaryl ring system, or may be attached through a carbon atom of a moiety substituted on a heteroaryl ring- member carbon atom, for example, through the methylene substituent of imidazolemethyl moiety. Also, such heteroaryl may be attached through a ring nitrogen atom as long as aromaticity of the heteroaryl moiety is preserved after attachment.
- preferred radicals are those containing from one to about ten carbon atoms.
- alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, methylbutyl, dimethylbutyl and neopentyl.
- Typical alkenyl and alkynyl groups may have one unsaturated bond, such as an allyl group, or may have a plurality of unsaturated bonds, with such plurality of bonds either adjacent, such as allene-type structures, or in conjugation, or separated by several saturated carbons.
- angiotensin II is a potent vasoconstrictor and participates in the formation of aldosterone which regulates sodium and water balance in mammals.
- compounds of Formula I are therapeutically useful in methods for treating hypertension by administering to a hypertensive subject or patient a therapeutically- effective amount of a compound of Formula I.
- hypertensive subject or patient means, in this context, a mammalian subject suffering from or afflicted by the effects of hypertension or susceptible to a hypertensive condition if not treated to prevent or control such hypertension.
- compositions of Formula I include the tautomeric forms of the described compounds, as well as the stereoisomers and pharmaceutically-acceptable salts thereof.
- pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is
- Suitable pharmaceutically-acceptable may be prepared from an inorganic acid or from an organic acid.
- examples of such inorganic acids are hydrochloric,
- organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methansulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic,
- Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylenediamine,
- chloroprocaine choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP03508882A JP3098772B2 (en) | 1990-05-04 | 1991-05-06 | 1H-substituted-1,2,4-triazole compounds for treating cardiovascular disorders |
DE69130671T DE69130671T2 (en) | 1990-05-04 | 1991-05-06 | 1H-SUBSTITUTED-1,2,4-TRIAZOLE COMPOUNDS FOR THE TREATMENT OF HEART DISEASES |
CA002082074A CA2082074C (en) | 1990-05-04 | 1991-05-06 | 1h-substituted-1,2,4-triazole compounds for treatment of cardiovascular disorders |
EP91909072A EP0527851B1 (en) | 1990-05-04 | 1991-05-06 | 1h-substituted-1,2,4-triazole compounds for treatment of cardiovascular disorders |
DK91909072T DK0527851T3 (en) | 1990-05-04 | 1991-05-06 | 1H-Substituted 1,2,4-Triazole Compounds for the Treatment of Cardiovascular Disorders |
PT97581A PT97581B (en) | 1990-05-04 | 1991-05-06 | PROCESS FOR THE PREPARATION OF 1H-SUBSTUIDO-1,2,4-TRIAZOLE, UTEIS DERIVATIVES FOR THE TREATMENT OF CARDIOVASCULAR DISTURBACLES |
GR990400859T GR3029772T3 (en) | 1990-05-04 | 1999-03-23 | 1h-substituted-1,2,4-triazole compounds for treatment of cardiovascular disorders |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/519,380 US5098920A (en) | 1990-05-04 | 1990-05-04 | 1h-substituted-1,2,4-triazole compounds and methods of use thereof for treatment of cardiovascular disorders |
US519,380 | 1990-05-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1991017148A1 true WO1991017148A1 (en) | 1991-11-14 |
Family
ID=24068062
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1991/002926 WO1991017148A1 (en) | 1990-05-04 | 1991-05-06 | 1h-substituted-1,2,4-triazole compounds for treatment of cardiovascular disorders |
Country Status (13)
Country | Link |
---|---|
US (1) | US5098920A (en) |
EP (1) | EP0527851B1 (en) |
JP (1) | JP3098772B2 (en) |
AT (1) | ATE174910T1 (en) |
AU (1) | AU7792491A (en) |
CA (1) | CA2082074C (en) |
DE (1) | DE69130671T2 (en) |
DK (1) | DK0527851T3 (en) |
ES (1) | ES2125868T3 (en) |
GR (1) | GR3029772T3 (en) |
IE (1) | IE62867B1 (en) |
PT (1) | PT97581B (en) |
WO (1) | WO1991017148A1 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1992004335A2 (en) * | 1990-08-28 | 1992-03-19 | G.D. Searle & Co. | Renal-selective biphenylalkyl 1h-substituted-1,2,4-triazole angiotensin ii antagonists for treatment of hypertension |
EP0936221A1 (en) * | 1996-09-18 | 1999-08-18 | Lead Chemical Company Ltd. | Novel 2,4-dioxopyrrolidine and 2,4-dioxotetrahydrofuran derivatives and medicines containing the same as the active ingredient |
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 |
US7507729B2 (en) | 2005-10-11 | 2009-03-24 | Hoffmann-La Roche Inc. | Substituted imidazo-[1,5-a][1,2,4]triazolo[1,5-d][1,4] benzodiazepine derivatives |
WO2011069038A2 (en) | 2009-12-03 | 2011-06-09 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
WO2013138352A1 (en) | 2012-03-15 | 2013-09-19 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
WO2014151200A2 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
WO2014151206A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
EP2810951A2 (en) | 2008-06-04 | 2014-12-10 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
WO2014197720A2 (en) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
EP2998314A1 (en) | 2007-06-04 | 2016-03-23 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
EP3241839A1 (en) | 2008-07-16 | 2017-11-08 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
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EP0409332A3 (en) * | 1989-07-19 | 1991-08-07 | Merck & Co. Inc. | Substituted triazoles as angiotensin ii antagonists |
US20040121989A1 (en) * | 1990-08-28 | 2004-06-24 | G.D. Searle & Co. | Renal-selective biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonists for treatment of hypertension |
EP1051169A4 (en) * | 1998-01-29 | 2002-05-29 | Viropharma Inc | Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases |
US6495580B1 (en) | 1998-01-29 | 2002-12-17 | Viropharma Incorporated | Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases |
US6908948B1 (en) * | 1998-07-16 | 2005-06-21 | Research Development Foundation | DNA-cleaving antitumor agents |
US6362342B1 (en) | 1999-06-29 | 2002-03-26 | Lion Bioscience Ag | Triazole compounds and methods of making same |
CA2495245A1 (en) | 2002-08-09 | 2004-02-19 | Viropharma Incorporated | Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases |
WO2004014316A2 (en) | 2002-08-09 | 2004-02-19 | Viropharma Incorporated | Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases |
JP6905585B2 (en) | 2017-04-07 | 2021-07-21 | 四国化成工業株式会社 | Triazole silane compound, method of synthesizing the compound and its use |
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EP0253310A2 (en) * | 1986-07-11 | 1988-01-20 | E.I. Du Pont De Nemours And Company | Angiotensin II receptor blocking imidazoles |
EP0289919A2 (en) * | 1987-05-02 | 1988-11-09 | BASF Aktiengesellschaft | N-Substituted azoles |
EP0323841A2 (en) * | 1988-01-07 | 1989-07-12 | E.I. Du Pont De Nemours And Company | Substituted pyrrole, pyrazole and triazole angiotensin II antagonists |
EP0409332A2 (en) * | 1989-07-19 | 1991-01-23 | Merck & Co. Inc. | Substituted triazoles as angiotensin II antagonists |
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DE2461406C2 (en) * | 1974-12-24 | 1984-06-14 | Bayer Ag, 5090 Leverkusen | Azolyl- (1) -methanes and their salts, processes for their preparation and medicaments containing them |
DE2851086A1 (en) * | 1978-11-25 | 1980-06-04 | Bayer Ag | HYDROXYPROPYL-TRIAZOLES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
DE2912288A1 (en) * | 1979-03-28 | 1980-10-09 | Bayer Ag | METHOD FOR PRODUCING HYDROXYETHYL AZOLES |
US4816463A (en) * | 1986-04-01 | 1989-03-28 | Warner-Lambert Company | Substituted diimidazo [1,5-a: 4',5'-d]pyridines having antihypertensive activity |
US4880804A (en) * | 1988-01-07 | 1989-11-14 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking benzimidazoles |
-
1990
- 1990-05-04 US US07/519,380 patent/US5098920A/en not_active Expired - Lifetime
-
1991
- 1991-05-06 AT AT91909072T patent/ATE174910T1/en not_active IP Right Cessation
- 1991-05-06 WO PCT/US1991/002926 patent/WO1991017148A1/en active IP Right Grant
- 1991-05-06 PT PT97581A patent/PT97581B/en not_active IP Right Cessation
- 1991-05-06 ES ES91909072T patent/ES2125868T3/en not_active Expired - Lifetime
- 1991-05-06 JP JP03508882A patent/JP3098772B2/en not_active Expired - Fee Related
- 1991-05-06 AU AU77924/91A patent/AU7792491A/en not_active Abandoned
- 1991-05-06 CA CA002082074A patent/CA2082074C/en not_active Expired - Fee Related
- 1991-05-06 IE IE153391A patent/IE62867B1/en not_active IP Right Cessation
- 1991-05-06 DK DK91909072T patent/DK0527851T3/en active
- 1991-05-06 EP EP91909072A patent/EP0527851B1/en not_active Expired - Lifetime
- 1991-05-06 DE DE69130671T patent/DE69130671T2/en not_active Expired - Fee Related
-
1999
- 1999-03-23 GR GR990400859T patent/GR3029772T3/en unknown
Patent Citations (4)
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EP0253310A2 (en) * | 1986-07-11 | 1988-01-20 | E.I. Du Pont De Nemours And Company | Angiotensin II receptor blocking imidazoles |
EP0289919A2 (en) * | 1987-05-02 | 1988-11-09 | BASF Aktiengesellschaft | N-Substituted azoles |
EP0323841A2 (en) * | 1988-01-07 | 1989-07-12 | E.I. Du Pont De Nemours And Company | Substituted pyrrole, pyrazole and triazole angiotensin II antagonists |
EP0409332A2 (en) * | 1989-07-19 | 1991-01-23 | Merck & Co. Inc. | Substituted triazoles as angiotensin II antagonists |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992004335A3 (en) * | 1990-08-28 | 1992-04-16 | Searle & Co | Renal-selective biphenylalkyl 1h-substituted-1,2,4-triazole angiotensin ii antagonists for treatment of hypertension |
WO1992004335A2 (en) * | 1990-08-28 | 1992-03-19 | G.D. Searle & Co. | Renal-selective biphenylalkyl 1h-substituted-1,2,4-triazole angiotensin ii antagonists for treatment of hypertension |
EP0936221A1 (en) * | 1996-09-18 | 1999-08-18 | Lead Chemical Company Ltd. | Novel 2,4-dioxopyrrolidine and 2,4-dioxotetrahydrofuran derivatives and medicines containing the same as the active ingredient |
US6232335B1 (en) | 1996-09-18 | 2001-05-15 | Lead Chemical Co., Ltd. | 2,4-Dioxopyrrolidine and 2,4-dioxotetrahydrofan derivatives and medicines containing the same at the active ingredient |
EP0936221A4 (en) * | 1996-09-18 | 2001-12-19 | Lead Chem Co Ltd | Novel 2,4-dioxopyrrolidine and 2,4-dioxotetrahydrofuran derivatives and medicines containing the same as the active ingredient |
US6358984B1 (en) | 1996-09-18 | 2002-03-19 | Lead Chemical Co., Ltd. | 2,4-dioxopyrrolidine and 2,4-dioxotetrahydrofuran derivatives and medicines containing the same as the active ingredient |
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 |
US7507729B2 (en) | 2005-10-11 | 2009-03-24 | Hoffmann-La Roche Inc. | Substituted imidazo-[1,5-a][1,2,4]triazolo[1,5-d][1,4] benzodiazepine derivatives |
EP2998314A1 (en) | 2007-06-04 | 2016-03-23 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
EP2810951A2 (en) | 2008-06-04 | 2014-12-10 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
EP3241839A1 (en) | 2008-07-16 | 2017-11-08 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
EP2923706A1 (en) | 2009-12-03 | 2015-09-30 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia |
WO2011069038A2 (en) | 2009-12-03 | 2011-06-09 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
WO2013138352A1 (en) | 2012-03-15 | 2013-09-19 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
EP3708179A1 (en) | 2012-03-15 | 2020-09-16 | Bausch Health Ireland Limited | Formulations of guanylate cyclase c agonists and methods of use |
EP4309673A2 (en) | 2012-03-15 | 2024-01-24 | Bausch Health Ireland Limited | Formulations of guanylate cyclase c agonists and methods of use |
WO2014151206A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
WO2014151200A2 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
WO2014197720A2 (en) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
EP4424697A2 (en) | 2013-06-05 | 2024-09-04 | Bausch Health Ireland Limited | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
Also Published As
Publication number | Publication date |
---|---|
EP0527851A1 (en) | 1993-02-24 |
IE911533A1 (en) | 1991-11-06 |
DE69130671D1 (en) | 1999-02-04 |
JPH05507079A (en) | 1993-10-14 |
ATE174910T1 (en) | 1999-01-15 |
GR3029772T3 (en) | 1999-06-30 |
CA2082074A1 (en) | 1991-11-05 |
PT97581B (en) | 1998-08-31 |
AU7792491A (en) | 1991-11-27 |
DK0527851T3 (en) | 1999-08-23 |
EP0527851B1 (en) | 1998-12-23 |
JP3098772B2 (en) | 2000-10-16 |
US5098920A (en) | 1992-03-24 |
IE62867B1 (en) | 1995-03-08 |
ES2125868T3 (en) | 1999-03-16 |
PT97581A (en) | 1992-01-31 |
CA2082074C (en) | 2002-02-05 |
DE69130671T2 (en) | 1999-05-27 |
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