CA2048809A1 - Heterocyclic imidazoles, pharmaceutical compositions containing these compounds and processes for preparing them - Google Patents
Heterocyclic imidazoles, pharmaceutical compositions containing these compounds and processes for preparing themInfo
- Publication number
- CA2048809A1 CA2048809A1 CA002048809A CA2048809A CA2048809A1 CA 2048809 A1 CA2048809 A1 CA 2048809A1 CA 002048809 A CA002048809 A CA 002048809A CA 2048809 A CA2048809 A CA 2048809A CA 2048809 A1 CA2048809 A1 CA 2048809A1
- Authority
- CA
- Canada
- Prior art keywords
- group
- methyl
- butyl
- biphenyl
- pyridin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- -1 Heterocyclic imidazoles Chemical class 0.000 title claims abstract description 429
- 150000001875 compounds Chemical class 0.000 title claims description 107
- 238000000034 method Methods 0.000 title claims description 17
- 230000008569 process Effects 0.000 title claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 239000000203 mixture Substances 0.000 claims abstract description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 174
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 139
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 72
- 239000004305 biphenyl Substances 0.000 claims description 52
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 44
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 42
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 23
- 235000010290 biphenyl Nutrition 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 23
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 21
- 239000000460 chlorine Chemical group 0.000 claims description 21
- 229910052801 chlorine Inorganic materials 0.000 claims description 21
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 20
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical group ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 15
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 15
- 239000005977 Ethylene Substances 0.000 claims description 15
- 125000003277 amino group Chemical group 0.000 claims description 15
- 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 description 14
- 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 description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 206010019280 Heart failures Diseases 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 125000005544 phthalimido group Chemical group 0.000 claims description 11
- 125000005999 2-bromoethyl group Chemical group 0.000 claims description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000006289 hydroxybenzyl group Chemical group 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 7
- 150000007524 organic acids Chemical class 0.000 claims description 7
- 206010002383 Angina Pectoris Diseases 0.000 claims description 6
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 6
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 6
- 208000010412 Glaucoma Diseases 0.000 claims description 6
- 206010020772 Hypertension Diseases 0.000 claims description 6
- 150000001204 N-oxides Chemical class 0.000 claims description 6
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 6
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 6
- 230000000302 ischemic effect Effects 0.000 claims description 6
- 230000002093 peripheral effect Effects 0.000 claims description 6
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- 208000010125 myocardial infarction Diseases 0.000 claims description 5
- 208000031225 myocardial ischemia Diseases 0.000 claims description 5
- 208000026533 urinary bladder disease Diseases 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 claims description 4
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 4
- 230000000269 nucleophilic effect Effects 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 238000007056 transamidation reaction Methods 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 125000006639 cyclohexyl carbonyl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 238000001149 thermolysis Methods 0.000 claims description 3
- WIGWADCUTYRBEG-UHFFFAOYSA-N 2-[4-[(5-amino-2-butylimidazo[4,5-b]pyridin-3-yl)methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC2=CC=C(N)N=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O WIGWADCUTYRBEG-UHFFFAOYSA-N 0.000 claims description 2
- FGKNOOCGKPVVNM-UHFFFAOYSA-N 2-[4-[[2-(benzylamino)-8-butylpurin-9-yl]methyl]phenyl]benzoic acid Chemical compound N1=C2N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C(O)=O)C(CCCC)=NC2=CN=C1NCC1=CC=CC=C1 FGKNOOCGKPVVNM-UHFFFAOYSA-N 0.000 claims description 2
- ABAUHLAZIYYHNJ-UHFFFAOYSA-N 2-[4-[[2-butyl-5-[cyclohexanecarbonyl(ethyl)amino]imidazo[4,5-b]pyridin-3-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC2=CC=C(N(CC)C(=O)C3CCCCC3)N=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O ABAUHLAZIYYHNJ-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 7
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 3
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 2
- 125000006576 di-(C1-C3-alkyl)-aminocarbonyl group Chemical group 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 1
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 1
- NYNLURAUJYFWIR-UHFFFAOYSA-N 2-[4-[(2-butylimidazo[4,5-c]pyridin-1-yl)methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC2=CN=CC=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O NYNLURAUJYFWIR-UHFFFAOYSA-N 0.000 claims 1
- GBJIMJWEKOENAL-UHFFFAOYSA-N 2-[4-[[2-butyl-5-(cyclohexylamino)imidazo[4,5-b]pyridin-3-yl]methyl]phenyl]benzoic acid Chemical compound N1=C2N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C(O)=O)C(CCCC)=NC2=CC=C1NC1CCCCC1 GBJIMJWEKOENAL-UHFFFAOYSA-N 0.000 claims 1
- MOYONDKQRKUEJG-UHFFFAOYSA-N 2-[4-[[2-butyl-5-methyl-6-(pentanoylamino)imidazo[4,5-b]pyridin-3-yl]methyl]phenyl]benzoic acid Chemical compound C1=2N=C(C)C(NC(=O)CCCC)=CC=2N=C(CCCC)N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O MOYONDKQRKUEJG-UHFFFAOYSA-N 0.000 claims 1
- GTAQYUKQYRGMRC-UHFFFAOYSA-N 2-[4-[[2-butyl-5-methyl-6-(propanoylamino)imidazo[4,5-b]pyridin-3-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC2=CC(NC(=O)CC)=C(C)N=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O GTAQYUKQYRGMRC-UHFFFAOYSA-N 0.000 claims 1
- DUOIPKZLPMSRIJ-UHFFFAOYSA-N 2-[4-[[2-butyl-6-(1,3-dioxoisoindol-2-yl)-5-methylimidazo[4,5-b]pyridin-3-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC2=CC(N3C(C4=CC=CC=C4C3=O)=O)=C(C)N=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O DUOIPKZLPMSRIJ-UHFFFAOYSA-N 0.000 claims 1
- CTZIMXNPYJQWIL-UHFFFAOYSA-N 2-[4-[[5-(3-benzyl-2-oxo-1,3-diazinan-1-yl)-2-butylimidazo[4,5-b]pyridin-3-yl]methyl]phenyl]benzoic acid Chemical compound C(CCC)C1=NC=2C(=NC(=CC2)N2C(N(CCC2)CC2=CC=CC=C2)=O)N1CC1=CC=C(C=C1)C=1C(=CC=CC1)C(=O)O CTZIMXNPYJQWIL-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- LKUYAJWPPUDDBD-UHFFFAOYSA-N n-[2-ethyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazo[4,5-b]pyridin-5-yl]-2,2-dimethylpropanamide Chemical group CCC1=NC2=CC=C(NC(=O)C(C)(C)C)N=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 LKUYAJWPPUDDBD-UHFFFAOYSA-N 0.000 claims 1
- VFXZDIYJJAFIEC-UHFFFAOYSA-N n-[2-propyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazo[4,5-b]pyridin-5-yl]cyclohexanecarboxamide Chemical group N1=C2N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(CCC)=NC2=CC=C1NC(=O)C1CCCCC1 VFXZDIYJJAFIEC-UHFFFAOYSA-N 0.000 claims 1
- 125000003884 phenylalkyl group Chemical group 0.000 claims 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 5
- 230000000144 pharmacologic effect Effects 0.000 abstract description 4
- 229940123073 Angiotensin antagonist Drugs 0.000 abstract description 3
- 239000002369 angiotensin antagonist Substances 0.000 abstract description 3
- 229940123413 Angiotensin II antagonist Drugs 0.000 abstract description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 abstract description 2
- 150000002460 imidazoles Chemical class 0.000 abstract 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 183
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 141
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 126
- 230000008018 melting Effects 0.000 description 119
- 238000002844 melting Methods 0.000 description 119
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 101
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 65
- 239000000741 silica gel Substances 0.000 description 59
- 229910002027 silica gel Inorganic materials 0.000 description 59
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
- ILYSAKHOYBPSPC-UHFFFAOYSA-N 2-phenylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=CC=C1 ILYSAKHOYBPSPC-UHFFFAOYSA-N 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- 229910001868 water Inorganic materials 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000002904 solvent Substances 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000002253 acid Substances 0.000 description 27
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 25
- 239000013543 active substance Substances 0.000 description 25
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- 239000003208 petroleum Substances 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 11
- 229910021529 ammonia Inorganic materials 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 239000008096 xylene Substances 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- 230000008020 evaporation Effects 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- 229920002261 Corn starch Polymers 0.000 description 7
- 239000008120 corn starch Substances 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 7
- 229940032007 methylethyl ketone Drugs 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000001117 sulphuric acid Substances 0.000 description 6
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- 239000012024 dehydrating agents Substances 0.000 description 1
- 201000009101 diabetic angiopathy Diseases 0.000 description 1
- 201000002249 diabetic peripheral angiopathy Diseases 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 229960000192 felbinac Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical group OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- 150000007928 imidazolide derivatives Chemical class 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 125000006316 iso-butyl amino group Chemical group [H]N(*)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- JDYBYUQXCFDOOS-UHFFFAOYSA-N methyl 2-[4-[(8-butyl-2-ethoxypurin-7-yl)methyl]phenyl]benzoate Chemical compound C(CCC)C1=NC2=NC(=NC=C2N1CC1=CC=C(C=C1)C=1C(=CC=CC1)C(=O)OC)OCC JDYBYUQXCFDOOS-UHFFFAOYSA-N 0.000 description 1
- LKSLFRRSKOKCHD-UHFFFAOYSA-N methyl 2-[4-[[8-butyl-2-(butylamino)purin-9-yl]methyl]phenyl]benzoate Chemical compound C(CCC)C=1N(C2=NC(=NC=C2N1)NCCCC)CC1=CC=C(C=C1)C=1C(=CC=CC1)C(=O)OC LKSLFRRSKOKCHD-UHFFFAOYSA-N 0.000 description 1
- DUOGYBKJKHDGAC-UHFFFAOYSA-N methyl 2-[4-[[8-butyl-2-(cyclohexylamino)purin-9-yl]methyl]phenyl]benzoate Chemical compound C(CCC)C=1N(C2=NC(=NC=C2N1)NC1CCCCC1)CC1=CC=C(C=C1)C=1C(=CC=CC1)C(=O)OC DUOGYBKJKHDGAC-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- QTNMKQSDNNPZFQ-UHFFFAOYSA-N n-(2-methylpropyl)-2-propyl-3-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]imidazo[4,5-b]pyridin-5-amine Chemical group CCCC1=NC2=CC=C(NCC(C)C)N=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 QTNMKQSDNNPZFQ-UHFFFAOYSA-N 0.000 description 1
- QKRCFLRPQULVHI-UHFFFAOYSA-N n-(2-propyl-1h-imidazo[4,5-b]pyridin-5-yl)cyclohexanecarboxamide Chemical compound C=1C=C2NC(CCC)=NC2=NC=1NC(=O)C1CCCCC1 QKRCFLRPQULVHI-UHFFFAOYSA-N 0.000 description 1
- KGUBZAZZLQVSOX-UHFFFAOYSA-N n-[5-nitro-6-(pentanoylamino)pyridin-2-yl]pentanamide Chemical compound CCCCC(=O)NC1=CC=C([N+]([O-])=O)C(NC(=O)CCCC)=N1 KGUBZAZZLQVSOX-UHFFFAOYSA-N 0.000 description 1
- FRLZYIRKJGFMNP-UHFFFAOYSA-N n-benzyl-8-butyl-7h-purin-2-amine Chemical compound N=1C=C2NC(CCCC)=NC2=NC=1NCC1=CC=CC=C1 FRLZYIRKJGFMNP-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- FIKPXCOQUIZNHB-WDEREUQCSA-N repotrectinib Chemical compound C[C@H]1CNC(=O)C2=C3N=C(N[C@H](C)C4=C(O1)C=CC(F)=C4)C=CN3N=C2 FIKPXCOQUIZNHB-WDEREUQCSA-N 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
- SQMCFUSVGSBKFK-UHFFFAOYSA-M sodium;5-(cyclohexen-1-yl)-1,5-dimethylpyrimidin-3-ide-2,4,6-trione Chemical compound [Na+].O=C1N(C)C(=O)[N-]C(=O)C1(C)C1=CCCCC1 SQMCFUSVGSBKFK-UHFFFAOYSA-M 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 235000012976 tarts Nutrition 0.000 description 1
- YHXCWNQNVMAENQ-UHFFFAOYSA-N tert-butyl 2-[4-(bromomethyl)phenyl]benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=C1C1=CC=C(CBr)C=C1 YHXCWNQNVMAENQ-UHFFFAOYSA-N 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- NFRGCMIFZVPLSJ-UHFFFAOYSA-N thiazepane 1,1-dioxide Chemical compound O=S1(=O)CCCCCN1 NFRGCMIFZVPLSJ-UHFFFAOYSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LYRCQNDYYRPFMF-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C LYRCQNDYYRPFMF-UHFFFAOYSA-N 0.000 description 1
- SBXWFLISHPUINY-UHFFFAOYSA-N triphenyltin Chemical compound C1=CC=CC=C1[Sn](C=1C=CC=CC=1)C1=CC=CC=C1 SBXWFLISHPUINY-UHFFFAOYSA-N 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Ophthalmology & Optometry (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Abstract Imidazoles The invention relates to heterocyclic imidazoles of formula I
Description
20~88~9 568~5/000.533 Xmida20Ie~
The present invention relates to novel heterocyclic imidazoles, processes for their preparation and pharmaceutical compositions containing them.
We have found that certain new heterocyclic imidazoles possess interesting and valuable pharmacological activities making them particularly suitable for the treatment of hypertension and cardiac insufficiency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial in~arct and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder ~diseases.
Thus, according to one aspect the present invention provides,compounds of formula I
~=~ ~ s (wherein one or two of A1, A2~ A3 and A4 represent a nitrogen atom and the remaining two or three of A1, A2, A3 and A4 each represent a methine group;
R1 represents a fluorine, chlorine or bromine atom, a hydroxy, alkyl or alkoxy group, ~ : :, ,: -: , . .
~ , , : :
:
20~8~09 an amino group optionally mono- or disubstituted, or an N-acylamino group optionally monosubstituted, at the nitrogen atom by a C16-alkyl, phenyl, C57-cycloalkyl, phenyl(C13-alkyl)or (C57-cycloalkyl)C13-alkyl group, which substituents may be identical or different and which acyl group is a C17-alkanoyl group optionally substituted in the 3-, 4-, 5-, 6- or 7-position by a halogen atom or a hydroxy group, a (C13-alkoxy)carbonyl group, a C16-alkylsulphonyl group, a benzoyl, benzenesulphonyl, phenyl(C13-alkanesulphonyl), naphthalenesulphonyl, 2-carboxy-cyclohexylcarbonyl, 2-. aminocarbonyl-cyclohexylcarbonyl, (C57-cycloalkyl)-carbonyl, phenyl(C14-alkanoyl) or (C57-cycloalkyl)-C14-alkanoyl group, in which the above-mentioned phenyl nuclei are optionally mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group which substituents may be identical or different, ~, a C35-alkylsultam group, a pyrrolidino, piperidino or hexamethyleneimino group optionally substituted by a C13-alkyl or hydroxycarbonyl(C13-alkyl)group, a pyrrolidinone, piperidinone or hexamethyleneiminone group, an optionally totally or partially hydrogenated phthalimido or 2-oxo-isoindolin-l-yl group or a group of formula ~' - N - CO - N
\ R
. [in which R6, R7 and R8, which may be identical or different, represent hydrogen atoms, C18-alkyl groups, Cs7-cycloalkyl, phenyl, tC57-cycloalkyl)C13-alkyl or phenyl(C13-alkyl) groups, and '''~
~. : ' . ' :
, .
. , : ~ ~
0~8~0~
RA may also represent a 2-chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3-bromo-propyl group, and where R6 and R7 together represent an ethylene or propylene group, R~
may also represent a di(C13-al:kyl)aminocarbonyl group, or R6 and R7 together represent an ethylene or propylene group and in which the phenyl nucleus of the above-mentioned phenyl and phenyl(Cl3-alkyl) groups may in each case be mono- or disubstituted by hydroxy or C13-alkoxy groups which substituents may be identical or dif~erent~, and R1 may also represent a hydrogen atom, except where Rz represents a hydrogen atom, R3 represents an n-butyl group, R4 represents a carboxy group and Rs represents a hydroyen atom, and (i) one of the groups A1, A2, A3 and A4 represents a nitrogen atom and the remaining groups A1, A2, A3 or A4 each represent methine groups, or (ii) A2 and A4 or A1 and A3 each represent a nitrogen atom and the remaining groups A1 and A3 or A2 and A4 each represent a methine group, or (iii) A4 represents a nitrogen atom and A3 represents a methine group substituted by a hydroxy or methoxy : group and the remaining groups A1 and A2 each represent a methine group, or : (iv) A4 represents a nitrogen atom, A1 represents a methine group sub~tituted by a methyl group and the remaining groups A2 and A3 each represent a methine group;
, `, , ' `
' ~' `
` 2048809 R2 represents a hydrogen atom or a C13-alkyl group;
R3 represents a C16-alkyl group;
R4 represents a carboxy, cyano, lH-tetrazolyl or 1-triphenylmethyl-tetrazolyl group or a (C14-alkoxy)-carbonyl group; and R5 represents a hydrogen, fluorine, chlorine or bromine atom);
and isomers and salts, particularly the 1-, 3-isomer mixtures, tautomers, enantiomers and addition salts thereof, and more particularly for pharmaceutical use the physiologically acceptable addition salts thereof with organic or inorganic acids or bases.
Examples of heteroaromatic groups covered by the definition of the groups A1, A2, A3 and A4 hereinbefore include pyrido, pyrimido, pyrazino or pyridazino groups.
The following are examples of the definitions of the groups R1, R2, R3, R4 and Rs as mentioned hereinbefore:
R1 may represent a hydrogen, fluorine, chlorine or bromine atom, a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, formylamino, acetylamino, propionylamino, n-butanoylamino, isobutanoylamino, n-pentanoylamino, 2-methyl-n-butanoylamino, 3-methyl-n-butanoylamino, n-hexanoylamino, n-heptanoylamino, cyclopentylcarbonyl-amino, cyclohexylcarbonylamino, cycloheptylcarbonyl-amino, cyclopentylmethylcarbonylamino, cyclohexylmethyl-carbonylamino, cycloheptylmethylcarbonylamino, (2-cyclopentylethyl)-carbonylamino, (2-cyclohexylethyl)-carbonylamino, ~2-cycloheptylethyl)-carbonylamino, benzoylamino, phenylacetylamino, 2-phenylpropionylamino, ~' ' ' ~ ' 4~09 naphthyl (1)-carbonylamino, naphthyl-(2)-carbonylamino, methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, methane~;ulphonylamino, ethane-sulphonylamino, n-propanesulphonylamino, isopropane-sulphonylamino, n-butanesulphonylamino, n-pentane-sulphonylamino, n-hexanesulphonylamino, benzene-sulphonylamino, 2-methylbenzenesulphonylamino, 4-methylbenzenesulphonylamino, 2-methoxybenzenesulphonyl-amino, ~-methoxybenzenesulphonylamino, 2-fluorobenzene-sulphonylamino, 4-fl~orobenzenesulphonylamino, 2-chlorobenzenesulphonylamino, 4-chlorobenzenesulphonyl-amino, 2-bromobenzenesulphonylamino, 4-bromobenzene-sulphonylamino, 2,4-dimethoxybenzenesulphonylamino, benzylsulphonylamino, naphthalene-(1)-sulphonylamino, naphthalene-(2)-sulphonylamino, propanesultam-(l)-yl, n-butanesultam-(l)-yl, n-pentanesultam~ yl, amino, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, n-pentylamino, n-hexylamino, dimethylamino, diethylamino, di-n-propylamino, methyl-ethylamino, methyl-isopropylamino, methyl-n-butylamino, ethyl-n-propylamino, methyl-n-pentylamino, ethyl-n-hexylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclopentylmethyl-amino, cyclohexylmethylamino, cycloheptylmethylamino, (2-cyclopentylethyl)-amino, (2-cyclohexylethyl)-amino, (2-cycloheptylethyl)-amino, (3-cyclopentylpropyl)-amino, ~3-cyclohexylpropyl)-amino, (3-cycloheptylpropyl)-amino, benzylamino, Z-phenylethylamino, 3-phenylpropylamino, phenylamino, dicyclohexylamino, dicyclohexylmethylamino, dibenzylamino, N-methyl-cyclopropylamino, N-methyl-cyclopentylamino, N-ethyl-cyclohexylamino, N-(n-propyl) cycloheptylamino, N-methyl-cyclopentylmethylamino, N-ethyl-cyclohexylmethylamino, N-(n-propyl)-cycloheptyl-methylamino, N-methyl-(2-cyclopentylethyl)-amino, N-ethyl-(2-cyclohe~ylethyl~-amino, N-(n-propyl)-(2-cycloheptylethyl)-amino, N-methyl-(3-cyclopentylpropyl)-amino, N-ethyl-(3-cyclohexylpropyl~-amino, N-methyl-, .
.: ' ' :-- 2~48~09 benzylamino, N-ethyl-benzylamino, N-isopropyl-benæylamino, N-methyl-(2-phenylethyl)-amino, N-methyl-phenylamino, N-(n-propyl)-phenylamino, N-acetyl-methylamino, N-acetyl-ethylamino, N-acetyl-isopropylamino, N-acetyl-n-butylamino, N-acetyl-n-hexylamino, N-propionyl-methylamino, N-propionyl-ethylamino, N-propionyl-n-buty:lamino, N-n-butanoyl-methylamino, N-n-butanoyl-ethy:Lamino, N-n-butanoyl-n-pentylamino, N-isobutanoyl-methylamino, N-isobutanoyl-ethylamino, N-isobutanoyl-isopropylamino, N-isobutanoyl-n-butylamino, N-isobutanoyl-n-pentylamino, N-n-pentanoyl methylamino, N-n-pentanoyl-ethylamino, N-n-pentanoyl-isopropylamino, N-n-pentanoyl-n-pentylamino, N-n-hexanoyl-methylamino, N-n-hexanoyl-ethylamino, N-n-hexanoyl-isopropylamino, N-n-hexanoyl-n-pentylamino, N-cyclopentylcarbonyl-methylamino, N-cyclohexylcarbonyl-methylamino, N-cyclohexylcarbonyl-ethylamino, N-cycloheptylcarbonyl-methylamino, N-cyclopentylmethyl-carbonyl-methylamino, N-cyclohexylmethylcarbonyl-methylamino, N-cycloheptylmethylcarbonyl-methylamino, N-(2-cyclopentylethylcarbonyl)-methylamino, N-(2-cyclohexylethylcarbonyl)-methylamino, N-(2-cycloheptyl-ethylcarbonyl)-methylamino, N-henzoyl-methylamino, ~-benzoyl-ethylamino, N-benzoyl-isopropylamino, N-benzoyl-n-butylamino, N-benzoyl-n-pentylamino, N-benzoyl-n-hexylamino, N phenylacetyl-methylamino, N-naphthyl~
carbonyl-methylamino, N-naphthyl-(2)-carbonyl-methylamino, ~-methoxycarbonyl-methylamino, N-methoxycarbonyl-ethylamino, N-methoxycarbonyl-n-butylamino, N-methoxycarbonyl-isobutylamino, N-ethoxycarbonyl-methylamino, N-ethoxycarbonyl-ethylamino, N-ethoxycarbonyl-isopropylamino, N-ethoxycarbonyl-n-butylamino, N-n-propoxycarbonyl-methylamino, N-methanesulphonyl-methylamino, N-ethanesulphonyl-isopropylamino, N-(n-propanesulphonyl)-methylamino, isopropanesulphonylmethylamino, N-(n-butanesulphonyl)-methylamino, N~(n-pentanesulphonyl)-methylamino, N-(n-' ~' ~ ' .
.
, ~ ' , ' , , .
, .
` 2~8809 ~ 7 --hexanesulphonyl)-methylamino, benzenesulphonylmethylamino, N-(2-methylbenzenesulphonyl)-methylamino, N-(4-methylbenzenesulphonyl)-methylamino, N-(2-methoxy-benzenesulphonyl)-methylamino, N-(4-methoxybenzene-sulphonyl)-methylamino, N-(2-f'Luorobenzenesulphonyl)-methylamino, N-(4-fluorobenzenesulphonyl)-methylamino, N-(2-chlorobenzenesulphonyl)-methylamino, N-(4-chlorobenzene-sulphonyl)-methylamino, N-(2-bromoben~enesulphonyl)-methylamino, N-(4-bromobenzenesulphonyl)-methylamino, N (2,4-dimethoxybenzenesulphonyl)-methylamino, N-benzyl-sulphonyl-methylamino, N-(naphthalene-(1)-sulphonyl)-methylamino, N-(naphthalene-(2)-sulphonyl)-methylamino, N-benzoyl-cyclopentylamino, N-benzoyl-cyclohexylamino, N-benzoyl-cycloheptylamino, N-phenylacetyl-cyclopentyl-amino, N-phenylacetyl-cyclohexylamino, N-phenylacetyl-cycloheptylamino, N-benzoyl-cyclopentylmethylamino, N-benzoyl-cyclohexylmethylamino, N-benzoyl-cycloheptyl-methylamino, N-phenylacetyl-cyclopentylmethylamino, N-phenylacetyl-cyclohexylmethylamino, N-phenylacetyl-cycloheptylmethylamino, N-(3-phenylpropionyl)-methylamino, N-(3-phenylpropionyl)-ethylamino, N-(3-phenylpropionyl)-isopropylamino, N (3-phenylpropionyl)-isobutylamino, N-benzoyl-(2-cyclopentylethyl)-amino, N-benzoyl-(2-cyclohexylethyl)-amino, N-benzoyl-(2-cycloheptylethyl)-amino, N-phenylacetyl (2-cyclopentylethyl)-amino, N-phenylacetyl-(2-cyclohexyl-ethyl)-amino, N-phenylacekyl-(2-cycloheptylethyl)-amino, N-benzoyl-(3-cyclopentylpropyl)-amino~ N-benzoyl-(3-cyclohexylpropyl)-amino, N-benzoyl-(3-cycloheptyl-propyl)-amino, N-phenylacetyl-(3-cyclopentylpropyl)-amino, N-phenylacetyl (3-cyclohexylpropyl)-amino, N-phenylacetyl-[3-cycloheptylpropyl)-amino, N-acetyl-cyclopentylamino, N-acetyl-cyclohexylamino, N-acetyl-cycloheptylamino, N-acetyl-cyclopentylmethylamino, N-acetyl-cyclohexylmethylamino, N-acetyl-cycloheptyl methylamino, N-acetyl-(2-cyclopentylethyl)-amino, N-, .
.:
, .
The present invention relates to novel heterocyclic imidazoles, processes for their preparation and pharmaceutical compositions containing them.
We have found that certain new heterocyclic imidazoles possess interesting and valuable pharmacological activities making them particularly suitable for the treatment of hypertension and cardiac insufficiency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial in~arct and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder ~diseases.
Thus, according to one aspect the present invention provides,compounds of formula I
~=~ ~ s (wherein one or two of A1, A2~ A3 and A4 represent a nitrogen atom and the remaining two or three of A1, A2, A3 and A4 each represent a methine group;
R1 represents a fluorine, chlorine or bromine atom, a hydroxy, alkyl or alkoxy group, ~ : :, ,: -: , . .
~ , , : :
:
20~8~09 an amino group optionally mono- or disubstituted, or an N-acylamino group optionally monosubstituted, at the nitrogen atom by a C16-alkyl, phenyl, C57-cycloalkyl, phenyl(C13-alkyl)or (C57-cycloalkyl)C13-alkyl group, which substituents may be identical or different and which acyl group is a C17-alkanoyl group optionally substituted in the 3-, 4-, 5-, 6- or 7-position by a halogen atom or a hydroxy group, a (C13-alkoxy)carbonyl group, a C16-alkylsulphonyl group, a benzoyl, benzenesulphonyl, phenyl(C13-alkanesulphonyl), naphthalenesulphonyl, 2-carboxy-cyclohexylcarbonyl, 2-. aminocarbonyl-cyclohexylcarbonyl, (C57-cycloalkyl)-carbonyl, phenyl(C14-alkanoyl) or (C57-cycloalkyl)-C14-alkanoyl group, in which the above-mentioned phenyl nuclei are optionally mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group which substituents may be identical or different, ~, a C35-alkylsultam group, a pyrrolidino, piperidino or hexamethyleneimino group optionally substituted by a C13-alkyl or hydroxycarbonyl(C13-alkyl)group, a pyrrolidinone, piperidinone or hexamethyleneiminone group, an optionally totally or partially hydrogenated phthalimido or 2-oxo-isoindolin-l-yl group or a group of formula ~' - N - CO - N
\ R
. [in which R6, R7 and R8, which may be identical or different, represent hydrogen atoms, C18-alkyl groups, Cs7-cycloalkyl, phenyl, tC57-cycloalkyl)C13-alkyl or phenyl(C13-alkyl) groups, and '''~
~. : ' . ' :
, .
. , : ~ ~
0~8~0~
RA may also represent a 2-chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3-bromo-propyl group, and where R6 and R7 together represent an ethylene or propylene group, R~
may also represent a di(C13-al:kyl)aminocarbonyl group, or R6 and R7 together represent an ethylene or propylene group and in which the phenyl nucleus of the above-mentioned phenyl and phenyl(Cl3-alkyl) groups may in each case be mono- or disubstituted by hydroxy or C13-alkoxy groups which substituents may be identical or dif~erent~, and R1 may also represent a hydrogen atom, except where Rz represents a hydrogen atom, R3 represents an n-butyl group, R4 represents a carboxy group and Rs represents a hydroyen atom, and (i) one of the groups A1, A2, A3 and A4 represents a nitrogen atom and the remaining groups A1, A2, A3 or A4 each represent methine groups, or (ii) A2 and A4 or A1 and A3 each represent a nitrogen atom and the remaining groups A1 and A3 or A2 and A4 each represent a methine group, or (iii) A4 represents a nitrogen atom and A3 represents a methine group substituted by a hydroxy or methoxy : group and the remaining groups A1 and A2 each represent a methine group, or : (iv) A4 represents a nitrogen atom, A1 represents a methine group sub~tituted by a methyl group and the remaining groups A2 and A3 each represent a methine group;
, `, , ' `
' ~' `
` 2048809 R2 represents a hydrogen atom or a C13-alkyl group;
R3 represents a C16-alkyl group;
R4 represents a carboxy, cyano, lH-tetrazolyl or 1-triphenylmethyl-tetrazolyl group or a (C14-alkoxy)-carbonyl group; and R5 represents a hydrogen, fluorine, chlorine or bromine atom);
and isomers and salts, particularly the 1-, 3-isomer mixtures, tautomers, enantiomers and addition salts thereof, and more particularly for pharmaceutical use the physiologically acceptable addition salts thereof with organic or inorganic acids or bases.
Examples of heteroaromatic groups covered by the definition of the groups A1, A2, A3 and A4 hereinbefore include pyrido, pyrimido, pyrazino or pyridazino groups.
The following are examples of the definitions of the groups R1, R2, R3, R4 and Rs as mentioned hereinbefore:
R1 may represent a hydrogen, fluorine, chlorine or bromine atom, a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, formylamino, acetylamino, propionylamino, n-butanoylamino, isobutanoylamino, n-pentanoylamino, 2-methyl-n-butanoylamino, 3-methyl-n-butanoylamino, n-hexanoylamino, n-heptanoylamino, cyclopentylcarbonyl-amino, cyclohexylcarbonylamino, cycloheptylcarbonyl-amino, cyclopentylmethylcarbonylamino, cyclohexylmethyl-carbonylamino, cycloheptylmethylcarbonylamino, (2-cyclopentylethyl)-carbonylamino, (2-cyclohexylethyl)-carbonylamino, ~2-cycloheptylethyl)-carbonylamino, benzoylamino, phenylacetylamino, 2-phenylpropionylamino, ~' ' ' ~ ' 4~09 naphthyl (1)-carbonylamino, naphthyl-(2)-carbonylamino, methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, methane~;ulphonylamino, ethane-sulphonylamino, n-propanesulphonylamino, isopropane-sulphonylamino, n-butanesulphonylamino, n-pentane-sulphonylamino, n-hexanesulphonylamino, benzene-sulphonylamino, 2-methylbenzenesulphonylamino, 4-methylbenzenesulphonylamino, 2-methoxybenzenesulphonyl-amino, ~-methoxybenzenesulphonylamino, 2-fluorobenzene-sulphonylamino, 4-fl~orobenzenesulphonylamino, 2-chlorobenzenesulphonylamino, 4-chlorobenzenesulphonyl-amino, 2-bromobenzenesulphonylamino, 4-bromobenzene-sulphonylamino, 2,4-dimethoxybenzenesulphonylamino, benzylsulphonylamino, naphthalene-(1)-sulphonylamino, naphthalene-(2)-sulphonylamino, propanesultam-(l)-yl, n-butanesultam-(l)-yl, n-pentanesultam~ yl, amino, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, n-pentylamino, n-hexylamino, dimethylamino, diethylamino, di-n-propylamino, methyl-ethylamino, methyl-isopropylamino, methyl-n-butylamino, ethyl-n-propylamino, methyl-n-pentylamino, ethyl-n-hexylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclopentylmethyl-amino, cyclohexylmethylamino, cycloheptylmethylamino, (2-cyclopentylethyl)-amino, (2-cyclohexylethyl)-amino, (2-cycloheptylethyl)-amino, (3-cyclopentylpropyl)-amino, ~3-cyclohexylpropyl)-amino, (3-cycloheptylpropyl)-amino, benzylamino, Z-phenylethylamino, 3-phenylpropylamino, phenylamino, dicyclohexylamino, dicyclohexylmethylamino, dibenzylamino, N-methyl-cyclopropylamino, N-methyl-cyclopentylamino, N-ethyl-cyclohexylamino, N-(n-propyl) cycloheptylamino, N-methyl-cyclopentylmethylamino, N-ethyl-cyclohexylmethylamino, N-(n-propyl)-cycloheptyl-methylamino, N-methyl-(2-cyclopentylethyl)-amino, N-ethyl-(2-cyclohe~ylethyl~-amino, N-(n-propyl)-(2-cycloheptylethyl)-amino, N-methyl-(3-cyclopentylpropyl)-amino, N-ethyl-(3-cyclohexylpropyl~-amino, N-methyl-, .
.: ' ' :-- 2~48~09 benzylamino, N-ethyl-benzylamino, N-isopropyl-benæylamino, N-methyl-(2-phenylethyl)-amino, N-methyl-phenylamino, N-(n-propyl)-phenylamino, N-acetyl-methylamino, N-acetyl-ethylamino, N-acetyl-isopropylamino, N-acetyl-n-butylamino, N-acetyl-n-hexylamino, N-propionyl-methylamino, N-propionyl-ethylamino, N-propionyl-n-buty:lamino, N-n-butanoyl-methylamino, N-n-butanoyl-ethy:Lamino, N-n-butanoyl-n-pentylamino, N-isobutanoyl-methylamino, N-isobutanoyl-ethylamino, N-isobutanoyl-isopropylamino, N-isobutanoyl-n-butylamino, N-isobutanoyl-n-pentylamino, N-n-pentanoyl methylamino, N-n-pentanoyl-ethylamino, N-n-pentanoyl-isopropylamino, N-n-pentanoyl-n-pentylamino, N-n-hexanoyl-methylamino, N-n-hexanoyl-ethylamino, N-n-hexanoyl-isopropylamino, N-n-hexanoyl-n-pentylamino, N-cyclopentylcarbonyl-methylamino, N-cyclohexylcarbonyl-methylamino, N-cyclohexylcarbonyl-ethylamino, N-cycloheptylcarbonyl-methylamino, N-cyclopentylmethyl-carbonyl-methylamino, N-cyclohexylmethylcarbonyl-methylamino, N-cycloheptylmethylcarbonyl-methylamino, N-(2-cyclopentylethylcarbonyl)-methylamino, N-(2-cyclohexylethylcarbonyl)-methylamino, N-(2-cycloheptyl-ethylcarbonyl)-methylamino, N-henzoyl-methylamino, ~-benzoyl-ethylamino, N-benzoyl-isopropylamino, N-benzoyl-n-butylamino, N-benzoyl-n-pentylamino, N-benzoyl-n-hexylamino, N phenylacetyl-methylamino, N-naphthyl~
carbonyl-methylamino, N-naphthyl-(2)-carbonyl-methylamino, ~-methoxycarbonyl-methylamino, N-methoxycarbonyl-ethylamino, N-methoxycarbonyl-n-butylamino, N-methoxycarbonyl-isobutylamino, N-ethoxycarbonyl-methylamino, N-ethoxycarbonyl-ethylamino, N-ethoxycarbonyl-isopropylamino, N-ethoxycarbonyl-n-butylamino, N-n-propoxycarbonyl-methylamino, N-methanesulphonyl-methylamino, N-ethanesulphonyl-isopropylamino, N-(n-propanesulphonyl)-methylamino, isopropanesulphonylmethylamino, N-(n-butanesulphonyl)-methylamino, N~(n-pentanesulphonyl)-methylamino, N-(n-' ~' ~ ' .
.
, ~ ' , ' , , .
, .
` 2~8809 ~ 7 --hexanesulphonyl)-methylamino, benzenesulphonylmethylamino, N-(2-methylbenzenesulphonyl)-methylamino, N-(4-methylbenzenesulphonyl)-methylamino, N-(2-methoxy-benzenesulphonyl)-methylamino, N-(4-methoxybenzene-sulphonyl)-methylamino, N-(2-f'Luorobenzenesulphonyl)-methylamino, N-(4-fluorobenzenesulphonyl)-methylamino, N-(2-chlorobenzenesulphonyl)-methylamino, N-(4-chlorobenzene-sulphonyl)-methylamino, N-(2-bromoben~enesulphonyl)-methylamino, N-(4-bromobenzenesulphonyl)-methylamino, N (2,4-dimethoxybenzenesulphonyl)-methylamino, N-benzyl-sulphonyl-methylamino, N-(naphthalene-(1)-sulphonyl)-methylamino, N-(naphthalene-(2)-sulphonyl)-methylamino, N-benzoyl-cyclopentylamino, N-benzoyl-cyclohexylamino, N-benzoyl-cycloheptylamino, N-phenylacetyl-cyclopentyl-amino, N-phenylacetyl-cyclohexylamino, N-phenylacetyl-cycloheptylamino, N-benzoyl-cyclopentylmethylamino, N-benzoyl-cyclohexylmethylamino, N-benzoyl-cycloheptyl-methylamino, N-phenylacetyl-cyclopentylmethylamino, N-phenylacetyl-cyclohexylmethylamino, N-phenylacetyl-cycloheptylmethylamino, N-(3-phenylpropionyl)-methylamino, N-(3-phenylpropionyl)-ethylamino, N-(3-phenylpropionyl)-isopropylamino, N (3-phenylpropionyl)-isobutylamino, N-benzoyl-(2-cyclopentylethyl)-amino, N-benzoyl-(2-cyclohexylethyl)-amino, N-benzoyl-(2-cycloheptylethyl)-amino, N-phenylacetyl (2-cyclopentylethyl)-amino, N-phenylacetyl-(2-cyclohexyl-ethyl)-amino, N-phenylacekyl-(2-cycloheptylethyl)-amino, N-benzoyl-(3-cyclopentylpropyl)-amino~ N-benzoyl-(3-cyclohexylpropyl)-amino, N-benzoyl-(3-cycloheptyl-propyl)-amino, N-phenylacetyl-(3-cyclopentylpropyl)-amino, N-phenylacetyl (3-cyclohexylpropyl)-amino, N-phenylacetyl-[3-cycloheptylpropyl)-amino, N-acetyl-cyclopentylamino, N-acetyl-cyclohexylamino, N-acetyl-cycloheptylamino, N-acetyl-cyclopentylmethylamino, N-acetyl-cyclohexylmethylamino, N-acetyl-cycloheptyl methylamino, N-acetyl-(2-cyclopentylethyl)-amino, N-, .
.:
, .
2~!8~09 acetyl-(2-cyclohexylethyl) amino, N-acetyl-(2-cycloheptylethyl)-amino, N-acetyl-(3-cyclopentylpropyl) amino, N-acetyl-(3-cyclohexylpropyl)-amino, N-acetyl-(3-cycloheptylpropyl)-amino, N-acetyl-benzylamino, N-acetyl-(2-phenylethyl)-amino, N-acetyl-(3~phenylpropyl)-amino, N-benzoyl-benzylamino, N-benzoyl-(2-phenylethyl)-amino, N-benzoyl-(3-phenylpropyl)-amino, 2-carboxy-cyclohexylcarbonylamino, 2-ami.nocarbonyl-cyclohexyl-carbonylamino, phthalimido, tetrahydrophthalimido, hexahydrophthalimido, cis-hexahydrophthalimido, ~rans-hexahydrophthalimido, pyrroliclino, methylpyrrolidino, ethyl-pyrrolidino, isopropylpyrrolidino, piperidino, methylpiperidino, ethylpiperidino, isopropylpiperidino, hexamethyleneimino, methylhexamethyleneimino, ethyl hexamethyleneimino, isopropylhexamethyleneimino, 2-carboxymethyl-pyrrolidino, 2-oxo-pyrrolidino, 2-oxo-piperidino, 2-oxo-hexamethyleneimino, aminocarbonyl-amino, methylaminocarbonylamino, dimethylaminocarbonyl-amino, N-methylaminocarbonyl-methylamino, N-(dimethyl-aminocarbonyl~-methylamino, N-dimethylaminocarbonyl-ethylamino, N~dimethylaminocarbonyl-isopropylamino, N-(dimethylaminocarbonyl)-n-pentylamino, N-methylamino-carbonyl-ethylamino, N-methylaminocarbonyl-n-pentylamino, N-methylaminocarbonyl-n-hexylamino, N-methylaminocarbonyl-n-octylamino, N-methylamino~-carbonyl-cyclohexylamino, ethylaminocarbonylamino, N-ethylaminocarbonyl-methylamino, N-ethylaminocarbonyl-ethylamino, N-ethylaminocarbonyl-n-hexylamino, N-ethylaminocarbonyl-n-heptylamino, N-ethylaminocarbonyl-cyclohexylamino, diethylaminocarbonylamino, N-(diethylaminocarbonyl)-methylamino, N-(diethylamino-carbonyl)~ethylamino, N-(diethylaminocarbonyl)-n-butylamino, N-(diethylaminocarbonyl)-n-hexylamino, N-(diethylaminocarbonyl)-n-octylamino, isopropylamino-carbonylamino, N-isopropylaminocarbonyl-methylamino, n-butylaminocarbonylamino, N-(n-butylamino~arbonyl)-methylamino, N-(n-butylaminocarbonyl)-ethylamino, N-(n-, :: ~
, :1 , , ~
- , ' 20~8~09 g butylaminocarbonyl)-i~opropylamino, N-(n-bu~ylamino-carbonyl)-n-butylamino, N-(n-butylaminocarbonyl)-n-hexylamino, N-(n-butylaminocarbonyl)-cyclohexylamino, N-(di-(n-butyl)-aminocarbonyl)-amino, N-(di-(n-butyl)-aminocarbonyl)-methylamino, N-di-(n-butyl)-aminocarbonyl)-ethylamino, N-(di-(n-butyl) aminocarbonyl)-n-butylamino, N-(di-(n-butyl)-aminocarbonyl)-n-hexylamino, N (n-pentylaminocarbonyl)-ethylamino, N-(n-hexylaminocarbonyl)-ethylamino, n-hexylaminocarbonylamino, n heptylaminocarbonylamino, n-octylaminocarbonylamino, N-(n-hexylaminocarbonyl)-n-butylamino, N-(n hexylaminocarbonyl)-n-pentylamino, N-(n-hexylaminocarbonyl)-n-hexylamino, N-(n-hexylamino-carbonyl)-cyclohexylamino, di-(n~hexyl)-aminocarbonyl-amino, N-(di-(n-hexyl)-aminocarbonyl)-methylamino, N-((n-hexyl)-methylaminocarbonyl)-amino, cyclohexylamino-carbonylamino, N-cyclohexylaminocarbonyl-methylamino, N-cyclohexylaminocarbonyl-ethylamino, N-cyclohexylamino-carbonyl-n-butylamino, N-cyclohexylaminocarbonyl-isobutylamino, N-cyclohexylaminocarbonyl-n-pentylamino, N-cyclohexylaminocarbonyl-n-hexylamino, N-cyclohexylaminocarbonyl-cyclohexylamino, N-(ethyl-cyclohexylaminocarbonyl) methylamino, N-(propyl-cyclo-hexylaminocarbonyl)-methylamino, N-(n-butyl-cyclohexyl-aminocarbonyl)-methylamino, N-benzylaminocarbonyl-isobutylamino, 2(1H)-imidazolidinon-1-yl, 3-methyl-2(lH)-imidazolidinon-l-yl, 3-ethyl-2(lH)-imidazolidinon-l-yl, 3-n-propyl-2(1~)-imidazolidinon-1-yl, 3-isopropyl-2(lH)-imidazolidinon-1-yl, 3-n-bu~yl-2(lH)-imidazolidinon-1-yl, 3-isobutyl-2(lH)-imidazolidinon-1-yl, 3-n-pentyl-2(1H)-imidazolidinon-l-ylr 3-n-hexyl-2(lH)-imidazolidinon-l-yl, 3-cyclopentyl-2(lH)-imidazolidinon-1-yl, 3-cyclohexyl-2(lH)-imidazolidinon-1-yl, 3-cycloheptyl-2(lH)-imidazolidinon-1-yl, 3-benzyl-2~lH)-imidazolidinon-l-yl, 3-(3-hydroxybenzyl)-2(lH)-imidazolidinon-l-yl, 3-(4-hydroxybenzyl)-2(lH)-imidazolidinon-l-yl, 3-(3-methoxybenzyl)-2(lH)-~`' '~ ~ ' ' ' ,`
, ~"
20~8809 imidazolidinon l-yl, 3-(4-methoxybenzyl)-2(1H)-imidazolidinon-l-yl, 3-(3,4-dihydroxybenzyl)-2(1H)-imidazolidinon-1-yl, 3-(3,4-dimethoxybenzyl)-2(lH)-imidazolidonon-l-yl, 3-cyclopentylmethyl-2(lH)-imidazolidinon-1-yl, 3-cyclohexylmethyl-2(1~)-imidazolidinon-1-yl, 3-cycloheptylmethyl-2(lH)-imidazolidinon-l-yl, 3-(2-phellylethyl)-2(lH)-imidazolidinon-l-yl, 3-(2-cyclop~ntylethyl)-2(lH)-.~ imidazolidinon-l-yl, 3-(2-cyclohexylethyl)-2(lH)-imidazolidinon-l-yl, 3-(2-cycloheptylethyl)-2(lH)-imidazolidinon-l-yl, 3-(3-phenylpropyl)-2(lH)-imidazolidinon-~.-yl, 3-(3-cyclopentylpropyl)-2(1H)-imidazolidinon-1-yl, 3-(3-cyclohexylpropyl)-2(lH)-imidazolidinon-l-yl, 3-(3-cycloheptylpropyl)-2(lH)-imidazolidinon-l-yl, 3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-methyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-ethyl 3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-n-propyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-isopropyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl, 3-n-butyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-isobutyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-n pentyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-n-hexyl-3,4,5,6~tetrahydro-2(lH)-pyrimidon-l-yl, 3-cyclopentyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-cyclohexyl-3,4/~,6-tetrahydro-2( lH) -pyrimidon-l-yl, 3-cycloheptyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-(3-hydroxybenzyl)-3,4,5,6-tetrahydro-2(lH~-pyrimidon-1-yl, 3-(4-hydroxybenzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl, 3-(3-methoxybenzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl, 3-(4-methoxybenzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-(3,4-dihydroxybenzyl)-3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-(3,4-dimethoxy-benzyl)-3,4,5,6-tetrahydro-2(1~)-pyrimidon-1-yl, 3-cyclohexylmethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-cycloheptylmethyl 3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-(2-phenylethyl)-3,4,5,6-tetrahydro , . . .
~0488~9 ~ 1.1. --2(1H)-pyrimidon-1-yl, 3-(~-cyclopentylethyl)-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-(2-cyclohexylethyl)-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-(2-cycloheptylethyl)-3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-(3-phenylpropyl)-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-(3-cyclopentylpropyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-(3-cyclohexylpropyl)-3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-(3-cycloheptylpropyl)-3,4,5,6-tetrahydro-2(1~)-pyrimidon-1-yl, 2-chloroethylaminocarbonylamino, 3-chloropropyl-aminocarbonylamino, 2-bromoethylaminocarbonylamino, 3- -bromopropylaminocarbonylamino, (N-2-chloroethyl-methylaminocarbonyl)-amino, (N-2-bromoethyl-methylamino-carbonyl)-amino, (N-2-chloropropylmethylaminocarbonyl)-amino, tert.butylcarbonylamino, (N-2-bromopropyl-methylaminocarbonyl)-amino, 2-oxo-isoindolin-1-yl, 3-dimethylaminocarbonyl-2(1H)-imidazolidinon-l-yl, 3-diethylaminocarbonyl-2(lH)-imidazolidinon-l-yl, 3-di-n-propylaminocarbonyl-2(lH)-imidazolidinon-l-yl, 3-dimethylaminocarbonyl-3,4,5,6-tatrahydro-2(lH)-pyrimidon-l-yl, 3-diethylaminocarbonyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-diisopropylamino-carbonyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-chloro-propionylamino, ~-chloro-butanoylamino, 5-chloropentanoylamino, 6-chloro-hexanoylamino, 7-chloro-heptanoylamino, 3-hydroxy-propionylamino, 4-hydroxy-butanoylamino, 5-hydroxy-pentanoylamino, 6-hydroxy-hexanoylamino, 7-hydroxy-heptanoylamino, 2,2-dimethyl-propionylamino or tert.-butylamino group;
R2 may represent a hydrogen atom, a methyl, ethyl, n-propyl or isopropyl group;
R3 may represent a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobut:yl, tert.-butyl, n-pentyl, n-hexyl, 1-methylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-methylpentyl, 2-methylpentyl, 3-. , : .
- 20~8~09 methylpentyl, 4-methylpentyl, 1-ethylpropyl or 1,1-diethylethyl group;
R4 may represent a carboxy, cyano, lH-tetrazolyl, 1-triphenylmethyl-tetrazolyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n butoxycarbonyl, isobutoxycarbonyl or tert.-butoxycarbonyl group; and ~, may represent a hydrogen, fluorine, chlorlne or bromine atom.
Preferred compounds according to the invention include those of formula I wherein one or two o~ A1, A2, A3 and A4 represent a nitrogen atom and the remaining two or three of A1, A2, A3 and A4 each represent a methine group;
R1 represents a fluorine atom, an amino or C16-alkylamino group substituted at the nitrogen atom hy a phenyl, C57-cycloalkyl, phenyl(C13-alkyl) or (C57-cycloalkyl)C13-alkyl yroup, an amino group disubstituted by a phenyl, Cs7-cycloalkyl, phenyl(C13-alkyl) or (C57 cycloalkyl)C13-alkyl group which substituents may be identical or dif~erent, or an acylamino group optionally substituted at the nitrogen atom by a C16 alkyl group or by a phenyl, Cs7-cycloalkyl, phenyl(C13-alkyl) or (Cs7-cycloalkyl)C13-alkyl group, wher~in the acyl group is a C~7-alkanoyl group substituted in the terminal position by a chlorine atom or by a hydroxy group, a (C13-alkoxy)carbonyl group, a C16-alkylsulphonyl group, a formyl, benzoyl, benzenesulphonyl, phenyl(C13-alkanesulphonyl), naphthalenesulphonyl, 2-carboxy-cyclohexylcarbonyl, 2 aminocarbonyl-cyclohexylcarbonyl, ~C57 cycloalkyl)-:
20~8~09 carbonyl, phenylalkanoyl or (C57-cycloalkyl)C14-alkanoyl group, in which the above-mentioned phenyl nuclei is optionally mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy yroup which substituents may be identical or different, a C35-alkylsultam group, a pyrrolidino, piperidino or hexamethyleneimino group optionally substituted by a Cl3-alkyl or hydroxycarbonyl(Cl3-alkyl)group, a pyrrolidinone, piperidinone or hexamethyleneiminone group, an optionally wholly or partially hydrogenated phthalimido group or a group of formula l6 / R7 - N - CO - N
~in which R6, R7 and R8, which may be identical or different, represent hydrogen atoms, C18-alkyl groups, C~7-cycloalkyl, phenyl, (C57-cycloalkyl)C13-alkyl or phenyl(C13-alkyl) groups, and R8 may also represent a 2-chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3-bromo-propyl group, and where R6 and R7 together represent an ethylene or propylene group, R8 may also represent a di(C13-alkyl)aminocarbonyl group, or R6 and R7 together represent an ethylene or propylene group, and in which the phenyl nucleus of the above-mentioned phenyl and phenyl(C13-alkyl) groups may be mono- or disubstitutecl by hydroxy or C13-alkoxy groups which substituents may be identical or different];
, . , ~ : .: ,, .
:. . . . i ~ ~ . .:
-` 2~809 R2 represents a hydrogen atom or a C13-alkyl group;
R3 represents a C16-alkyl group;
R4 represents a carboxy, cyano, lH-tetra~olyl, l-triphenylmethyl-tetrazolyl group or a (C14-alkoxy)-carbonyl group; and R5 represents a hydrogen, fluorine, chlorine or bromine atom;
and the isomers and salts thereof especially the l-, 3-isomer mixtures, tautomers, enantiomers and addition salts thereof with organic or inorganic aaids or bases.
Particularly preferred compounds according to the invention include those of formula I wherein one or two of A1, A2, A3 and A4 represent a nitrogen atom and the remaining two or three of A1, A2, A3 and A4 each represent a methine group;
R1 represents an amino, methylamino or ethylamino group substituted by a cyclohexyl, cyclohexylmethyl, benzyl or : dimethoxybenzyl group, an amino, cyclohexylamino, cyclohexylmethyl or C14alkylamino group substituted by a C26-alkanoyl group, by a C14-alkanesulphonyl group, by a C24-alkoxycarbonyl group or by a cyclohexylcarbonyl, benzylcarbonyl, 2-aminocarbonyl-cyclohexylcarbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a C34-alkylsultam group, a pyrrolidino or piperidino group optionally substituted by a methyl or hydroxycarbonylmethyl group, a pyrrolidin-2-on-l-yl or piperidin-2-on-l-yl group, an optionally wholly hydrogenated phthalimido or 2-oxo-isoindolin-l-yl group or a group of formula \R8 . .
.
- .
. ~
2~8809 ~in which R6, R7 and R~, which may be identical or difEerent, represent hydrogen atoms, C14-alkyl groups, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, and R8 may also represent a 2 chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3-bromo-propyl group, and where R6 and R7 together represent an ekhylene or propylene group, R8 may also represent a dimethylaminocarbonyl group, or R6 and R7 together represent an ethylene or propylene group];
R2 represents a hydrogen atom or a methyl or athyl group;
R3 represents a C15-alkyl group;
R4 represents a carboxy or lH-tetrazolyl group; and Rs represents a hydrogen atom;
and the isomers and salts thereof, especially the l-, 3-isomer mixtures, tautomers, enantiomers and addition salts thereof with organic or inorganic acids or bases.
More particularly preferred compounds according to the invention include those of formula I wherein one or two of A1, A2, A3 and A4 represent a nitrogen atom and the remaining two or three of A1, A2, A3 and A4 each represent a methine group;
R1 represents an amino, methylamino or ethylamino group substituted by a cyclohexyl or cyclohexylmethyl group, a cyclohexylamino or cyclohexylmethylamino group substituted by a C26-alkanoyl group, by a C14-alkanesulphor1yl group, by a C24-alkoxycarbonyl group, by ; ~ :
2048~0g a benzylcarbonyl, 2-aminocarbonylcyclohexylcarbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a cyclohexylcarbonylamino group, a cyclohexylamino, cyclohexylmethylamino or C14alkylamino group substituted by a Cl4-alkanesulphonyl, cycl.ohexylcarbonyl, 2-aminocarbonyl-cyclohexyl-carbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a C34-alkylsultam group, a pyrrolidino or piperidino group substituted by a methyl or hydroxycarbonylmethyl group, a pyrrolidin-2-on-1-yl or piperidin-2-on-1-yl group, an optionally ~ully hydrogenated phthalimido or 2-oxo-isoindolin-l-yl group or a group of formula l6 / R7 [in which one of the groups R6, R7 or R8 represents a cyclopentyl, cyclohexyl or cyclohexylmethyl group, and the remaining groups R6, R7 or R8, which may be identical or different, represent hydrogen atoms, C14-alkyl groups, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, or R7 represents a 2 chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3-bromo-propyl group, and R6 and R8, which may be ~identical or different, represent hydrogen atoms, C14-alkyl groups, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, or R6 and R7 together represent an ethylene or propylene group, and R8 represents a hydrogen atom, a C14-alkyl group, a cyclohexyl, phenyl, cyclohexylmethyl, benzyl, : - :
:
' 2~8~9 methoxybenzyl, hydroxybenzyl, 2-ahloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl, 3-bromo-propyl or dimethylamino-carbonyl group];
R2 represents a hydrogen atom or a methyl or ethyl group;
R3 represents a C15-alkyl group;
R4 represents a carboxy or lH-tetrazolyl group; and R5 represents a hydrogen atom;
and the isomers and salts thereof, especially the 1-, 3-isomer mixtures, tautomers, enantiomers and addikion salts thereof with organic or inorganic acids or basss.
Although the present invention relates to new compounds of formula I, the corresponding cyano, alkoxycarbonyl and triphenylmethyl compounds, in particular, are valuable intermediates which can readily be converted to one of the pharmacologically active compounds and thus form further aspects of the present invention.
According to a still further aspect, the invention also provides a process for the preparation of compounds of the invention, said process comprising at least one of the following steps:
a) cyclising a compound of formula II
A 2~ ~1/
R 2~ ~ ( I I ) 3`AI Yl .
(wherein .
. - . ~.
, , .
., .
8 ~ ~
R1, R2, A1, A2l A3 and A" are as hereinbefore defined;
one of the groups X1 or Yl represents a group of formula Rg and the other group X1 or Y1 represents a group of formula Z1~ /Z2 R3 and Rs are as hereinbefore de.fined;
R~ represents a hydrogen atom or an R3CO group; and R3 is as hereinbefore defined;
Z1 and Z2~ which ~ay be identical or different, represent optionally substituted amino g:roups or hydroxy or mercapto groups optionally substituted by lower (eg. C16)alkyl groups, or Z1 and Z2 together represent an oxygen or sulphur atom, an imino group optionally substituted by a C13-alkyl group, or a C23-alkylenedioxy or C23-alkylenedithio group, with the proviso that one o~ the groups X1 or Y
must represent a group of formula R5 or \
C o R 3 - ~ ~ . f ., 20~o~
-- lg --NH - C - R~ ) or an N-oxide thereof and if necessary subsequently reducing the cyclized N-oxide;
b) reactiny a compound o~ formula III
R2_ ~ ~ ~ R3 (lll) (wherein R1, R2, R3, A1, A2, A3 and A4 are as hereinbefore defined) with a biphenyl compound of formula IV
(wherein R4 and R5 are as hereinbefore defined; and Z3 represents a nucleophilic leaving group such as a halogen atom, e~g. a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, e.g. a methanesulphonyloxy, phenylsulphonyloxy or p-toluenesulphonyloxy group);
c) (to prepare a compound of formula I wherein R4 represents a carboxy group) convarting a compound of .. : , . ~ . .
,~ , ' , ' ; '~ :
.. ~ .
20~8809 formula V
(wherein R1, R2, R3~ Rs~ A1, A2, A3 and A4 are as hereinbePore de~ined; and R4' represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound;
d) (to prepare a compound of formula I wherein R4 represents a lH-tetrazolyl group) cleaving a protecting group from a compound of formula VI
R
~ ~3 :
(wherein R1, R2, R3~ R5~ A1, A2, A3 and A4 are as hereinbefore defined; and R4" represents a lH-tetrazolyl group protected in the l-; ~ position by a protecting group);
:::
~, ~...... . . . . . .
- ;, . . . .
~, . ... , ~ .
~, . : , 2 ~
- 2.1 -e) (to prepare a compouncl o~ ~ormula I whereln R4 represents a lll-tetrazolyl group) reacting a compound of formula VII
R ,+ 3~ ~ ~, ( V I I
(wherein R1, R2, R3~ R5~ A1, A2~ A3 and A4 are as hereinbefore de~ined) with hydrazoic acid or a salt thereof;
f) (to prepare compounds of formula I wherein R1 represents an amino group optionally substituted by a (C16-alkyl) group or by a phenyl, C57-cycloalkyl, phenyl (C13-alkyl) or (Cs7-cycloalkyl)C13-alkyl group) converting a compound of formula VIII
CN ( V I I I ) ~`A
(wherein R2, R3, R4~ R5~ A1, A2, A3 and A4 are as hereinbefor~
defined; and R10 represents a group which can be converted by hydrolysis, hydrogenolysis or transamidation into an amino group optionally substituted by a Cl6-alkyl group or by a phenyl, Cs7~cycloalkyl, phenyl(C13-alkyl~ or :
.
20~88~9 (C5 7-cyClOal~yl) C13-alkyl group);
g) (to prepare compounds of formula I wherein R
represents a group of formula - N - cO - N
reacting a compound of formula IX
R s (wherein R2, R3~ R4~ R5, A1, A2, A3 and A4 are as hereinbefore defined; and ~: R11 represents an R6NH group, wherein R6 i5 as hereinbefore defined) with a compound of formula X
\ N - CO - Z4 (X) (wherein R7 and R8 are as hereinbefore defined;
Z4 represents a nucleophilic leaving group such as a : chlorine or bromine atom, or ~ Z4 together with R7 represents a nitrogen-carbon bond);
:
h) (to prepare compounds of formula I wherein R
:
::
.
:. , :
2~8~09 repre~ents an N-acylamino group optionally substituted at the nitroyen atom by a C16-alkyl, phenyl, cycloalkyl, phenylalXyl or cycloalkylalkyl group~ acylating a compound of formula XI
(wherein R2~ R3~ R4~ Rs~ A1~ A2~ A3 and A4 are as hereinbefore defined; and R12 represents an amino group optionally substituted by a C16-alkyl, phenyl, Cs7-cycloalkyl, phenyl(C13-alkyl) or (C57-cycloalkyl)C13-alkyl group) with a compound of formula XII
: R13 ~ W - OH (XII) (wherein W represents a carbonyl or sulphonyl group; and R13 represents a C16-alkyl group, a C13-alkoxy group, a phenyl(C13-alkyl), C5 7-cycloalkyl or (Cs 7-cycloalkyl)C1 3-alkyl group, a phenyl, naphthyl, 2-carboxy-cycloh~xyl or 2-aminocarbonyl-cyclohexyl group, in which the above-mentioned phenyl nuclei may be mono- or disubstitutPd by a fluorine, chlorine or bromine atom or by a methyl or methoxy group which substituents may be identical or different, o:r, if W represents a carbonyl group, R13 may also represent a hydrogen atom) or with a reactive derivative thereof, such as an acid halide, acid ester or acid anhydride;
... . .. .
- .
.
. : - . ~ .: . :
. .
, -. . , .
, . . . ~ :
20~L8~09 - 2~ -i) (to prepare a compou~d of formula I wherein ~6 and R7 together represent an ethylene or n-propylene group) cyclising a compound of formu:La XIII
, R~Z
H N~ ~R J ( X I I I ) H ~ I I C ~ 2 ) ~ \ ~ R 5 twherein 2~ 3, R4, R5, R8, A1, A2, A3 and A4 are as hereinbefore defined;
Hal represents a chlorine, bromine or iodine atom; and n represents the number 2 or 3) and if necessary subsequently reacting with a compound of formula XIV
R8 ~ Hal (~IV) (wherein R8 is as hereinbefore defined, with the exception of the hydrogen atom; and ~al represents a chlorine, bromine or iodine atom);
j) resolving a 1-, 3- isomer mixture of a compound of formula I by isomer separation into the 1- and 3-isomers thereof;
k) converting a compound of formula I into an addition salt thereof, more particularly, for pharmaceutical use into a physiologically acceptable salt thereof with an organic or inorqanic acid or base, or converting a salt of a compound of formula I into the free compound; and 1) performing a process as defined in any one of steps (a) to (k) above on a corresponding protected compound - , .
. . ~
20~8809 and subsequently removing the pro-tecting group used.
The cyclisation of step (a) may conveniently be carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycol-dimethylether, sulpholane, dimethylformamide, tetraline or in an excess of the acylating agent used to prepare the compound of formula II, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide. 1'he reaction is conveniently effected at temperatures between 0 and 250C, preferably at the boiling temperature of the reaction mixture, optionally in the presence o~ a condensing agent such as phosphorusoxychloride, thionylchloride, sulphurylchloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid/ phosphoric acid, polyphosphoric acid or acetic anhydride, or optionally in the presence of a base such as potassium ethoxide or potassium tert.-butoxide. However, cyclisation may also be carried out without a solvent and/or condensing agent.
It is particularly advantageous to carry out the reaction of step ~a) by preparing a compound of formula II in the reaction mixture by reducing a corresponding o-nitro-amino compoundt optionally in the presence of a carboxylic acid of general formula R3COOH, or by acyIating a corresponding o-diamino compound. When the reduction of the nitro group is broken off at the hydroxylamine stage, the N-oxide of a compound of formula I is obtained in the subsequent cyclisation.
The resulting N-oxide is then converted by reduction into a corresponding compound of formula I~ The subsequent reduction of the N oxide of formula I
obtained is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ,, . ~. , ~
- . .
. . . .
8 ~ 9 ethyl acetate or dimethylformamlde, with hydroyen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid such as acetic, hydrochloric or sulphuric acid, with salts such as iron(II)sulphate, tin(II)chloride or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 50C, preferably at ambient temperature.
The reaction of step (b) may conveniently be carried out in a solvent or mixture of solvents such as methylene chloride, diethylether, acetone, tetrahydrofuran, dioxane, dimethylsulphoxide, or benzene, optionally in the presence of an acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert.-butoxide, sodium hydride, triethylamine or pyridine, whilst the latter two may simultaneously also be used as solvent, conveniently at temperatures between 0 and 100C, preferably at temperatures between ambient temperature and 50C. A mixture of the 1- and 3- isomers is preferably obtained.
In step (c) functional derivatives of the carboxy group such as the optionally substituted amides, esters, thiolesters, orthoesters, iminoethers, amidines or anhydrides or the nitrile group may be converted by hydrolysis into a carboxy group, esters with tertiary alcohols, e.g. the tert.butylester, may be converted by thermolysis into a carboxy group and esters with aralkanols, e.y. the benzylester, may be converted by hydrogenolysis into a carboxy group.
The hydrolysis o~ step (cl may conveniently be carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trichloroacetic or trifluoroacetic acid or in the presence of a base such .
:: ~
.
.
.
- 27 - 2~8~09 as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10C and 120C, preferably at temperatures between ambient temperature and the boiling temperature of the reaction mixture. When the hydrolysis is carried out in the presence of an organic acid such as trichloroacetic or trifluoroacetic acid, any alcoholic hydroxy groups present may optionally simultaneously be converted into a corresponding acyloxy group such as the trifluoroacetoxy group.
If R4' in a compound of formula V represents a cyano or aminocarbonyl group, these groups may also be converted into the carboxy group with a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulphuric acid, which may simultaneously also be used as solvent, at temperatures between 0 and 50C.
If R4' in a compound of formula V represents for example a tert.-butyloxycarbonyl group, the tert.-butyl group may also be thermally cleaved, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as trifluoroacetic acid, p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, conveniently at temperatures between 40C and 100C, preferably at the boiling temperature of the solvent used.
If R4' in a compound of formula V represents for example a benzyloxycarbonyl group, the benzyl group may al~o be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, . .
:
, ~ ~ :
. ~ . .
~ :. i .
.
20~8809 - 2~ -dioxane or dimethyltormamide, preferably at temperatures between 0 and 50C, more preferably at ambient temperature, under a hydrogen pressure of 1 to 5 bar.
During hydrogenolysis, other group.s may be reduced at the same time, e.g. a nitro group may be reduced to the amino group, a benzyloxy group to the hydroxy group, a vinylidelle group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenyl-propionic acid group, or they may be replaced by hydrogen atoms, e.g. a halogen may be replaced by a hydrogen atom.
If R1 in a compound of formula V represents one of the above mentioned hydrolysable groups, it may be converted during the reaction into a corresponding amino compound.
Suitable protecting groups for use in step (d) include, for example, the triphenylmethyl, trimethyl tin, tributyl tin, triphenyl tin, propionic acid nitrile or p-nitrobenzyl groups. The cleaving of a protecting group used is preferably carried out in the presence of a hydrohalic acid, preferably in the presence of hydrochloric acid, in the presence of a base such as sodium hydroxide or alcoholic ammonia in a suitable solvent such as methylene chloride, methanol, methanol/ammonia, ethanol or isopropanol, conveniently at temperatures between 0 and 100C, preferably at ambient temperature or, if the reaction is carried out in the presence of alcoholic ammonia, at elevated temperatures, e.g. at temperatures between 100 and 150C, preferably at temperatures between 120 and 140C.
The reaction o~ step (e) is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at temperatures between 80 and 150C, preferably at 125C.
Appropriately, either the hydrazoic acid is liberated during the reaction from an alkali metal azide, e.g.
sodiu~ azide in the presence of a weak acid such as ammonium chloride, or the tetrazolide salt obtained in , , : :
: .` ~ ~ .
.
' .
20~809 - 29 ~
the reaction mixture from the reaction with a salt of hydrazoic acid, preferably with aluminium azide or tributyl tin azide, which is also preferably produced in the reaction mixture by reacting aluminium chloride or tributyl tin chloride with an alkali metal azide such as sodium azide, is subsequently liberated by acidification with a dilute acid such as 2N hydrochloric or 2N
sulphuric acid.
In the reagent of formula VIII used in step (f), acylamino groups, e.g. the val~eroylamino, benzoylamino or phthalimido group, may be converted by hydrolysis into an amino group, and imino groups, e.g. the phthalimino group, may be converted by transamidation into an amino group.
The hydrolysis of step (f) may conveniently be carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trichloroacetic or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/iso-propanol or water/dioxane conveniently at temperatures of between ~10C and 120C, preferably at temperatures between ambient temperature and the boiling temperature of the reaction mixture.
When hydrolysis is carried out in the presence of an organic acid such as trichloroacetic acid or trifluoroacetic acid, any alcoholic hydroxy groups present may simultaneously be converted into a corresponding acyloxy group such as the trifluoroacetoxy group. If R1o represents a phthalimido group, this group may, to particular advantage, be converted into an amino group in the presence of a primary organic base such as methylamine, ethylamine or propylamine or with hydrazine optionally in a suitable solvent such as methanol, ethanol, isopropanol, dimethyl~ormamide, methanol/di-' ~ ~ !. ; , , ' ~!
' - ' , ' :
' ':
.
1, , .
~, , g o 9 - 30 ~
methyl~ormamide or methanol/water by transamidation at temperatures between 0 and 50C, pre~erably at ambient temperature.
The reaction of step (g) is preferably carried out in a solvent such as tetrahydrofuran, dioxane, ethylene chloride or benzene, optional]y in the presence of an acid binding agent such as triethylamine or pyridine, conveniently at temperatures between 0 and 100C, preferably at temperatures bet:ween 20 and 80C.
Examples of reactive derivatives of a compound of formula XII in step (h) include, for example, the esters thereof such as the methyl, ethyl or benzylesters, the thioesters such as the methylthio or ethylthioesters, and the halides such as the acid chloride, the anhydrides or imidazolides thereof.
The reaction of step (h) may conveniently be carried out in a solvent or mixture of solvents such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide with a corresponding carboxylic acid in the presence of an acid-activating or dehydrating agent such as thionyl chloride, with the anhydrides thereof such as acetic acid anhydride, with the esters thereof such as ethyl acetate, with the halides thereof such as acetyl chloride or methanesulphonyl chloride, optionally in the presence of an inorganic or tertiary organic base such as sodium hydroxide, potassium carbonate, triethylamine or pyridine, whilst the latter two may simultaneously serve as solvent, conveniently at temperatures between -~5 and 100C, prefexably at temperatures between 10 and 80C.
The cyclisation of step (i) and, if necessary, the subsequent alkylation are expediently carried out in a solvent such as methanol, ethanol, benzene or , .' ' . ~
:
. :
~ ' ,' ' , 20~809 dimethylsulphoxide, optionally in the presence of a phase transfer catalyst such as benzyltriethylammonium bromide in the presence of an acid binding agent such as sodium hydroxide, sodium mekhoxide, sodium ethoxide, sodium hydride or potassium tert.-butoxide at temperatures between 20 and 100, preferably at temperatures between 30 and 70C.
The isomer separation of step (j) is preferably carried out by chromatography using a substrate such as silica gel or aluminium oxide.
The compounds of formula I obtained may, if desired, be converted into the acid addition salts thereof, more particularly ~or pharmaceutical use the physiologically acceptable salts thereof with organic or inorganic acids. Suitable acids for this purpose include hydrochloric, hydrobromic, sulphuric, phosphoric, fumaric, succinic, lactic, citric, tartaric and maleic acid.
Furthermore, the new compounds of formula I thus obtained, if they contain a carboxy or tetrazolyl group, may, if desired, subsequently be converted into the addition salts thereof with organic or inorganic bases, more particularly for pharmaceutical use into the physiologically acceptable addition salts thereof.
Suitable bases for this purpose include sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
Some of the compounds of formulae II to XIV used as starting materials are known from the literature.
Otherwise these compounds may be obtained by methods known from the literature.
Thus, for example, a compound of general formula II is :, :,, , :
. :- -.
- :
.
.
-20~8~
obtained by alkylation of a corresponding o-amino-nitro compound and subsequent reduction of the nitro group.
Compounds of formulae III, V, VI, VII, VIII, IX, XI or XIII used as starting materials are obtained by alkylation of a corresponding o-diamine or a corresponding o-amino-nitro compound, followed by reduction of the nitro group and subsequent cyclisation of an o-diamino compound thus obtained, or by NH-alkylation vf a corresponding lH-compound, whilst the isomer mixture thus obtained may subsequently be resolved by conventional methods, e.g. chromatography.
The new compounds of general formula I and the physiologically acceptable addition salts thereof have valuable pharmacological properties. They are angiotensin antagonists, in particular, angiotensin-II-antagonists. Compounds of formula I which are of particular value are those wherein R4 represents an alkoxycarbonyl, carboxy or lH-tetrazolyl group.
Thus in a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable addition salt thereof together with at least one pharmaceutical carrier or excipient.
In a still further aspect the present invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of cardiac insufficiency progression after myocardial infarct, or for the treatment of diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
.
.
. ~ ' 2~48~09 In a stil.l yet ~urther aspect the present invention provides a method of treatment of the human or non-human animal body to combat hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemi.a (angina), cardiac insufficiency progression a~ter myocardial infarction, diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering to said body a compound of formula I or a physiologically acceptable addition salt thereof.
By way of example, the following compounds:
A = 4~-[(2~n-butyl-5-methyl-6-phthalimido-3H-im.idazo-[4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylic acid;
B = 4'-[(2-n-butyl-5-amino-3H-imidaæo[4,5-b]pyridin-3-yl)mPthyl]biphenyl-2-carboxylic acid;
C = 4'-[(2-benzylamino-8-n-butyl-9H-purin-9-yl)-methyl]-biphenyl-2-carboxylia acid;
D = 4'-[[2-n-butyl-5-methyl-6-(cis-hexahydrophthal-imido)-3H-imidazo[4,5-b~pyridin-3-yl]methyl~-biphenyl-2-carboxylic acid;
E = 4'-[(2-n-butyl-5-cyclohexylamino-3H-imidazo~4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylic acid;
F = 4'-[[2-n-butyl-5-~N-cyclohexylcarbonyl-ethylamino)~
3H imidazo[4,5-b]pyridin-3-yl~methyl]biphenyl-2-carboxylic acid;
G = 4'-[(2-n-butyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2-(lH-tetrazol-5-yl)biphenyl;
, , .. ~ :
-, :~ :- , .
, 20~09 - 3~ -H = 4'-[[2-n-butyl-5-(3-benzyl-3,4,5,6-tetrahydro-2[1H)-pyrimidinon l-yl)-3H-imidazoC4,5-b]pyridin-3-yl]
methyl]-biphenyl-2-carboxylic acid;
I = 4'-[(2-n-propyl-5-cyclohexylcarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2-~lH-tetrazol-5-y])biphenyl;
J = 4'-[[~-ethyl-5-t2,2-dimethyl-propionylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; and K = 4'-[[2-n-propyl-5-t2-methyl-propylamino)-3H-imidazo-[~,5-b]pyridin-3-yl~-methyl]-2-(lH-tetrazol-5-yl)-biphenyl were tested for their biological effects as follows:
Rats (male, 180-220 g) are anaesthetised with sodium hexobarbital (150 mg/kg i.p.). After they have become unconscious, a tracheal cannula is inserted, the animals are pithed and then immediately artificially respirated with a ventilator pump. The arterial blood pressure is recorded by means of a cannula in the carotid artery using a Bell & ~owell pressure recorder. The substances are administered in the jugular vein through a cannula.
Test substances are administered in three doses (10, 20 and 30 mg/kg i.Y. ), with one dose of substance being tested on each animal. Three minutes after the intravenous administration of the test substance, angiotensin-II is administered intravenously in increasing doses and in this way a cumulative dose-activity relationship is achieved for angiotensin-II in the presence of the test substances. The increase in arterial blood pressure is measured.
.
:~ .. . l ~ . . , :
~:: . : ' : ! , 20~8809 These dose activity cuxves are compared with standard curves for angiotensin-II without the use of any test substances. Using a computer program, the shifts to the right in the dose-activity curves for angiotensin-II
as a result of the administrat:ion of the test su~stances are determined and corresponding pA2-values are calculated for the test substances.
The PA2 values of the above-mentioned test compounds A to K are between 5.1 and 7.9.
Moreover, when the above-mentioned compounds were administered in a dose of 30 mg/kg i.v. no toxic side effects, e.g. negative inotropic effects or heart rhythm diosorders, were observed. Accordingly, the compounds are well tolerated.
The new compounds and their physiologically acceptable addition salts are suitable for their treatment of hypertension and cardiac insufficiency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
The new compounds and the physiologically acceptable addition salts thereof are also suitable for treating pulmonary diseases, e.g. lung oedema and chronic bronchitis, for preventing arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy. In view of the effects of angiotensin on the release of acetyl choline and dopamine in the brain, the new angiotensin antagonists are also suitable for alleviating central nervous system disorders, e.g. depression, Alzheimer's . : , , , , ~ , ~ , .
.. . .
- .. ~ : , .
. .. . . ' i, , :
';
. .
2~L8809 disease, Parkinson syndrome, bulimia and disorders of cognitive function.
The dosage required to achieve these effects is conv~niently, when administered intravenously, 20 to 100 mg, preferably 30 to 70 my, and, when administered orally, 50 to 200 mg, preferably 75 to 150 mg, 1 to 3 times a day. For this purpose, the compounds of formula I prepared accordirg to the invention, optionally in conjunction with other active substances, may be incorporated together with one or more inert conventional carriers and/or diluents, for example with corn starch, lactose, g~ucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene-glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The following non-limiting Examples are provided to illustrate the invention. Unless otherwise specified all percentages and ratios given are by weight.
, , , ,, :
- . .
.: .
~0~809 Example A
2-n-Butyl-7-methyl-imidazo[4,5-b]pyridine .
3.Ç g (29 mMol) of 2,3-diamino-4-methyl-pyridine and 3 ml of valeric acid are refluxed for 2 hours in 30 ml of phosphorusoxytrichloride. The reaction mixture is evaporated down in vacuo and the residue is mixed with 100 ml of ice water. By adding 20% sodium hydroxide solution, the mixture is neutralised and then extracted twice with 100 ml o~ ethyl acetate. After drying over magnesium sulphate and evaporation of the solvent, an oil is obtained.
Yield: 4.8 g (87% of theory), Rf value: 0.40 tsilica gel, eluant: ethylmethylketone/
xylene - 1:1 by volume) C11H1sN3 (l89.26) Calculated: C 69.81 H 7.99 N 22.20 Found: 69.60 7.91 21.96 The following compounds are obtained analogously:
8-n-butyl-2-benzylamino-purine Oil, ~f value: 0.55 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) 8-n-butyl-2-n-butylamino~purine Melting point: 111-114C
8-n-butyl-2-cyclohexylamino-purine Oil, Rf value: 0.60 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) 8-n-butyl-2~ethoxy-purine Melting point: 181-182C
8-n-butyl-2~methoxy-purine Melting point: 166C
, `:
2~48809 8-n-butyl-purine Melting poi.nt~ 17~ 0C
2-n-butyl-5-bromo-imidazo[4,5-b]pyridine Melting point: 223-225C
Example B
2-n-Butyl-5-va.leroylamino-imidazo[4,5-b]pyridine Prepared from 2,6-bis(n-pentanoylamino)-3-nitro-pyridine analogously to Example 1.
Yield: 83% o~ theory, Melting point: 148-150C
The following compounds are obtained analogously:
2-n-butyl-5-dimethylamino-imidazo[4,5-b]pyridine Melking point: 128-129C
2-n-butyl-5-methyl-6-amino-imidazo[4,5-b]pyridine Oil, Rf value: 0.23 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) 2-n-butyl-6-amino-imidazo[4,5-b]pyridine Oil, Rf value: 0~15 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90lO:1 by volume) Example C
2-n-Butyl-5-(cis-hexahydrophthalimido~-imidazor4,5-b]-pyridine Prepared by reacting 2-n-butyl-5-amino-imidazo[4,5-b]-pyridine with cis-hexahydrophthalic acid anhydride analogously to ~xample 4.
Yield: 63~ of theory, Oil, Rf value: 0.50 (silica gel; eluant: methylene , , j .
. : .
. ` ~ ' . ' , ~' .
. .
chloride/ ethanol = 9:1 by volume) The following compounds are obtained analogously:
2-n-butyl-5-methyl-6-phthalimido imidazo[4,5-b]pyridine Oil, Rf value: 0.77 tsilica ge:L; eluant: methylene chloride/ethano:L = 19:1 by volume) 2-n-butyl-6-phthalimido-imidazot4,5-b]pyridine Oil, Rf value: 0.68 (silica ge:L; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) 2-n-propyl-5-(2,2-dimethylpropionylamino)-imidazo-[4,5-b]pyridine Oil, Rf value: 0.42 (silica gel; eluant: ethyl acetate/petroleum ether = 1:1 by volume) 2-n-propyl-5-cyclohexylcarbonylamino-imidazo[4,5-b]-pyridine Oil, Rf value: 0.67 (silica gel; eluant: e~hyl ~cetate/petroleum ether = 1:1 by volume) - . - .. ..
~ . . . .
.., :: : ' :' ' - 20~8~09 ~ 40 ~
Example 1 Tert.-butyl 4'~[(2-n-butyl-5-methylamino-3H imidazo-[4,5-b]pyridin-3-yl)-methyl]b,iphenyl-2-carboxylate , . _ 1.8 g (3.5 mMol) of 2-[N-~-(2-tert.butoxycarbonyl-phenyl)benzyl-N-pentanoylamino]-3-nitro-6-methylamino-pyridine are dissolved in 200 ml of ethanol, mixed with 1.0 g of 10% palladium on activated charcoal and hydrogenated for 2 hours at ambient temperature under 5 bars of hydrogen pressure. After the uptake of hydrogen has ended the catalyst is filtered off and the residue is concentrated by evaporation. The residue is dissolved in ~0 ml of glacial acetic acid and heated for 30 minutes over a steam bath. Then the reaction mixture is evaporated down, the residue i5 dissolved in 100 ml of ethyl acetate and washed with saturated sodium hydrogen carbonate solution and with saturated sodium chloride solution. After drying over magnesium sulphate, evaporation of the solvent and column chromatography on silica gel ~particle size:
0.06-0.2 mm, eluant: petroleum ether/ethyl acetate = 1:1 by volume) a colourless oil is obtained.
Yield: 1.4 g (86~ of th~ory), Oil, hf value: 0.27 (silica gel; eluant: petroleum ether/ethyl acetate = l:l by volume) C29H34N4O2 (470.61) Calculated: C 74.01 ~ 7.28 N 11.91 Found: 73.86 7.35 12.13 The following compounds are obtained analogously:
tert.butyl 4'-[(2-n-butyl-5-cyclohexylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.45 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4l_~(2-n-butyl-5-n-butylamino-3H-imidazo-.
, .
:` :
.
,~ .
: i .
, 20~8809 ~1 --[4,5-b]pyridin~3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.43 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-~(2-n-b~tyl-5-ethylamino-3H-imidazo-t4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate Oil, Rf value: 0.3~ (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-[(2-n-butyl-5-cyclohexylmethylamino-3H~
imidazo[4,5-b]pyridin-3--yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.48 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) 4'-[[2-n-propyl-5-(2-methylpropylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl Melting point: 132-135C
tert.butyl 4'-[[2-n-butyl-5~(2,4-dimethoxybenzyl~amino-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylate Oil, Rf value: 0.40 (si~ica gel; eluant: petroleum ether/ethyl acetate - 1:1 by volume) tert.butyl 4'-[(2-n-butyl-5-benzylamino-3H-imidazo-[4,5-b~pyridin-3-yl)~methyl]biphenyl-2-carboxylate Oil, Rf value: 0.36 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-[(2-n-butyl-5-methoxy-lH-imidazo[4,5-b~-pyridin-l-yl)methyl]biphenyl-2-carboxylate Oil, Rf valueo 0.44 (silica gel; eluant: ethylmethyl-ketone/xylene = 1:2 by volume~
4'-C[2-n-butyl-5-(4-methyl-piperidino)-3H-imidaæo-[4,5-b]pyridin-3-ylJmethyl]-2-(1-triphenylmethyl-",, ~ . .
, 21~8~0g tetrazol-5-yl)-biphenyl Melting point: 147-149C
Example 2 Tert.butyl 4'-[(2-n-butyl-5-vaLeroylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylate (I) and Tert.butyl ~'-[(2-n-butyl-5-vaLeroylamino-lH-imidazo-r4 / 5-b]pyridin-1-yl)methyl]-biphenyl-2-carboxylate (II) 8.9 g (10.6 mMol) of 2-n-butyl-5-valeroylamino-3H~
imidazo[4,5-b]pyridine are dissolved in 400 ml of acetone, mixed with 7.3 g (53 mMol) of potassium carbonate and with 5.5 g (15.9 ~ol) of tert.butyl 4'-bromomethyl-biphenyl-2-carboxylate and refluxed for 6 hours with stirring. The reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is purified over a silica gel column (particle size:
0.063-0.2 mm), using a mixture of petroleum ether and ethyl acetate in the ratio 3:1 by volume as eluant. The uniform fractions are evaporated to dryness and triturated with diethylether. The solids thus crystallised are washed with ether and dried.
I: Yield: 4.2 g ~73% of theory), Melting point: 102-104C
C33H39N403 (539.70) Calculated: C 73.20 H 7.46 N 10.36 Found: 73.18 7.7210.19 II: Yield: 1.1 g (20% of theory), Melting point: 107-108C
C33H39N403 (539.70) Calculated: C 73O20 H 7.46 N 10.36 Found: 73.14 7.4410.38 The ~ollowing compounds are obtained analogously:
~ ~ .
. . .
; ~ .
.
~88~9 tart.b~tyl 4'-C(2-n~propyl-5-butanoylamino 3~1-imidazo-[4,5-b]pyridirl-3-yl)methyl~biphenyl-2--carboxylate Melting point: 157-158C
tert.butyl 4'-[(2-n-propyl-5 butanoylamino-lH-imidazo-[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylate Amorphous, Rf value: 0.38 (silica gel, eluant: ethyl acetate) tert.butyl 4'-[(2-n-propyl-5-butanoylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-4-bromo-2-carboxylate Oil, Rf value: 0.40 (silica gel; eluant: methylene chloride/ethanol = ~9:1 by volume) tert.butyl ~'-[(2-n-butyl-5-dimethylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.37 ~aluminium oxide; eluant: ethyl acetate/petroleum ether = 1:1 by volume) tert.butyl 4'-[(2-n-butyl-5-bromo-3H imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.55 (silica gel; eluant: methylethyl-ketone/xylene = 1:2 by volume) tert.butyl 4'-[(2-n-butyl-5-bromo-lH-imidazo[4,5-b]-pyridin-l-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.20 (silica gel; eluant: methylethyl-ketone/xylene = 1:2 by volume) :
tert.butyl 4'-[(2-n-butyl-5-methyl-6-phthalimido-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.52 (silica gel; eluant: methylethyl-ketone/xylene = 1:4 by volume) tert.butyl ~'-[(2-n-butyl-5-methyl-6-phthalimido-lH-imidazo[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylate - - , . .
.
: :
,. ~ , 20~0g Oil, Rf value: 0.18 (silica gel; eluant: methylethyl-ketone/xylene = ~:1 by volume) tert.butyl ~'-[(2-n-butyl-6-phthalimido-3H-imidazo-[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate Oil, Rf value: 0.62 (silica gel; eluant: methylethyl-ketone/xylene = 1:1 hy volume) terk.butyl 4'-[(2-n-butyl-6-phthalimido-lH-imidazo-t4,5-b]pyridin-1-yl)-methyl]biphenyl-2-carboxylate Oil, Rf value: 0.43 (silica ge:L; eluant: methyl~thyl-ketone/xylene = 1:1 by volume) tert.butyl 4'-~(2-n-buty]-6-hexahydrophthalimido-3H-imidazo[4,5-b~pyridin-3-yl)-methyl]biphenyl-2 carboxylate Oil, Rf value: 0.58 (silica gel; eluant: methylethyl-ketone/xylene = 1:1 by volume) tert.butyl 4'-[(2-n-butyl-6-hexahydrophthalimido-lH-imidazo[4,5-b]pyridin-1-yl)-methylJbiphenyl-2-carboxylate Oil, Rf value: 0.31 (silica gel; eluant: methylethyl-ketone/xylene = 1:1 by volume) 4'-[[2-n-butyl-5-(cis-hexahydrophthalimido)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl Oil, Rf value: 0.45 (silica gel; eluant: ethyl acetate) tert.butyl ~'-[(2-benzylamino-8-n-butyl-9H-purin-9-yl)-methyl]biphenyl-2-carboxylate Oil, Rf value: 0.45 (silica gel; eluant: ethyl acetate) mathyl 4'-[(2-n-butylamino-8-n-butyl-9H-purin-9-yl)methyl]biphenyl-2-carboxylate Melting point: 125-126C
~,, ' ....................................... . .
8 ~ 9 - ~5 -methyl 4'-C(2-cyclohexylamino-8-n-butyl 9H-purin-9-yl)-methyl]biphenyl~2-carboxylate Oil, Rf value: 0.52 (silica gel; eluant: methylene chloride/ethanol = 95:5 by volume) methyl 4'-t(2-ethoxy-8 n-butyl-9H-purin-9-yl)methyl]-biphenyl-2-carboxylate Oil, Rf value: 0.55 (silica gel; eluant: methylene chloride/ethanol - 95:5 by volume) methyl 4'-[(2-methoxy-8-n-butyl-9H-purin-9-yl)methyl]-biphenyl-2-carboxylake Oil, Rf value: 0.50 (silica gel; eluant: methylene chloride/ethanol = 95:5 by volume) 4'-[[2-n-propyl-5-(2,2-dimethylpropionylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl~-2-(lH-tetrazol-5-yl)-biphenyl Melting point: 177-178C
4'-[(2-n-propyl-5-cyclohexylcarbonylamino-3H-imidazo-~4,5-b~pyridin-3-yl)methyl]-2-tlH-tetrazol-5-yl)biphenyl Melting point: 183-184C
Example 3 Tert.butyl 4'-t(2-n-butyl-5-amino-3H-imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylate 3.4 g (6.3 mMol) of ~ert.butyl 4'-[(2-n-butyl-5-valeroylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylate are dissolved in 75 ml of ethanol, mixed with 35 ml o~ 2N sodium hydroxide solution and heated to 80C for 8 hours with stirring.
The reaction mixture is concentrated by evaporation, taken up in ethyl acetate and extracted with water. The aqueous phase is re~extracted twice with about 100 ml of ethyl acetate. The organic phases are combined, washed , . . . ~ . . ~ : , .: . .
, ~, , , : : -, : :
.
-', ~ ': ' . ' '' ;. ' '~
%~8~9 - ~6 -with saturated saline solution and dried over maynesium sulphate. After evaporation of the solvent the residue is crystallised by triturating with pet~oleum ether.
Yield: 2.1 g (73% of theory), Melting point: 112-124C
C2~H32N42 (456.59) Calculated: C 73. 66 H 7.07 N 12.21 Found: 73.72 7.20 12.12 The following compounds are obtained analoyously:
tert.butyl 4'-[(2-n-propyl-5-amino-3H-imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.50 (silica gel; eluant: ethyl acetate) tert.butyl 4'-[(2-n-butyl-5-methyl-6-amino-3H-imidazo-~4,5-b]pyridin-3-yl)methyl~biphenyl-2 carboxylate Oil, Rf value: 0.56 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) tert.butyl 4'-[(2-n-butyl-5-methyl-6-amino-lH-imidazo-[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.48 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) Example 4 4'-[[2-n-Butyl-5-(N-acetyl-cyclohexylamino~-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid . ~
0.3 g (0.62 mMol) of 4'-[~2-n-butyl-5-cyclohexylamino-3H-imidazo[4,5-b]pyxidin-3-yl)methyl]biphenyl-2-carboxylic acid are dissolved in 3.0 g (38 mMol) of acetyl chloride and refluxed for 2 hours. The reaction mixture is evaporated down, the residue is mixed with water and neutralised with aqueous ammonia solution.
The precipitate formed after acidification with glacial acetic acid is suction filtered, washed with water and . . : . . , ' .
" ''' . ' = ' ,i . ' . ' . ' . .
, ~ ' ' ~ ',' ' ~0~8809 dried.
Yield: 0.22 g (68% of theory), Melting point: 121-123C
C3zH36N4O3 (524-67) Calculated: c 73.26 H 6.92 N 10.68 Found: 72.43 6.93 10.96 The following compounds are obtained analogously:
tert. butyl 4'-[(2 n-propyl-5-]benzylcarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.36 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-[[2-n-butyl-5-(cis-hexahydrophthalimido)-3H-imidazo[4,5-b]pyridin-3-yl~methyl]biphenyl-2-carboxylate Oil, Rf value: 0.66 (silica gel; eluant: ethyl acetate) tert.butyl 4'-[[2-n-butyl-5-tN-acetyl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.21 (silica gel; eluant: petr~leum ether/ethyl acetate = 1 1 by volume) tert.butyl 4'-[[2-n-butyl-5 tN-ethoxycarbonyl ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate Oil, Rf value: 0.45 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-[[2-n-butyl-5-~N-cyclohexylcarbonyl-ethylamino~-3H~imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate Oil, Rf value: 0.34 ~silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-[[2-n-butyl-5 N-[(2-methyl-propionyl)-n-` ~ , : ' ` :
: . , ;. ::
' , .
~0~8~9 butylamino]-3H-imidaæo[4,5-b~pyridin-3-yl]methyl]-biphenyl-2-carboxylate Oil, Rf value: 0.48 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-[[2-n-butyl-5~(N-ethoxycarbonyl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2~carboxylate Oil, Rf value: 0.53 (silica gel; eluant: petroleum ether/ethyl acetate - 1:1 by volume) tert.butyl 4'-[(2-n-butyl-5-methyl-6-dimethylamino-carbonylamino-lH-imidazo[4,5-b]pyridin-1-yl)methyl]-biphenyl-2-carboxylate Amorphous, Rf value: 0.55 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:20:2 by volume) tert.butyl 4'-[(2-n-butyl-5-methyl-6-dimethylaminocarbonylamino-3H-imidazot4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate Amorphous, Rf value: 0.50 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) tert.butyl 4'-[[2-n-butyl-5-methyl-6-tN-ethyl-cyclohexylcarbonylamino)-3H-imidazo[4,5-b]pyridin 3-yl]methyl]biphenyl-2-carboxylate Oil, R~ value: 0.46 (silica gel; eluant: methylene chloride/ethanol = 19:1 by volume) tert.butyl 4l-[[2-n-butyl-5-methyl-6-(5-chloropentanoyl-amino)-lH-imidazo[4,5-b]pyridin-1-yl]methyl]biphenyl 2-carboxylate Oil, Rf value: 0.63 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) tert.butyl 4'-[~2-n~butyl-5-methyl-6-(N-acetyl-n-butylamino)-3H-imidazo[4,5~b]pyridin-3-yl]methyl]-., , ;
.
.': ; ' ,~ , . .
~8~09 biphenyl-2-carboxylate Oil, Rf value: 0.48 (silica yel; eluant: methyl ketone/ethanol = 1:2 by volume) tert.butyl 4'-[[2-n-butyl-5 (4-chlorophenylsulphonyl-amino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.39 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Exam~e 5 4'-~[2-n-Butyl-5-(N-acetyl-cyclohexylmethylamino~-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid .. _ ~ .. . . . . _ .. .
Prepared analogously to Example 4 ~rom 4'-[(2-n-butyl-5-cyclohexylmethylamino-3~-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid and acetylchloride.
Yield: 93% of theory, Melting point: 180-185C
C33H38N403 (538.20) Calculated: C 73.58 H 7 .11N 10 . 40 Found: 73.56 7.37 10.46 ~ml2~
4'-t(2-n-Butyl-5-propionylamino-3~-imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl-2~carboxylic acid . .. ..... _ _ Prepared analogously to Example 4 from 4'-[(2-n-butyl-5-amino-3H-imidazo[4,5-b]pyridin 3-yl)methyl]biphenyl-2-carboxylate and propionic acid anhydride.
Yield: 66% o~ theory, Melting point: 278-281C
C27H28N4o3 ~456.55) Calculated:C 71.03H 6.18 N 12.27 Found:70.86 6.23 12.40 , :
.. . , :
.
: ' - ~ ..
20~g809 Example 7 4'-[[2-n-Butyl-5-(2-mekhylpropionylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid .
Prepared analogously to Example 4 from 4'-t(2-n-butyl-5-amino-3H imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid and isobutyric acid chloride.
Yield: 49~ of theory, Meltiny point: 250C
c28H30Nh3 (~30.58) Calculated: C 71.47 H 6.43 N 11.91 F'ound: 71.26 6.31 11.66 Example 8 Tert.butyl 4'-[~2-n-butyl-5-(N-(3-chloropropylamino-carbonyl)-amino)-3H-imidazoC4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate 1.3 g (2.9 mMol) of tert.butyl 4'-t(2-n-butyl-5-amino-3H-imidazo~4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate are dissolved in 10 ml of dimethylformamide, mixed with 1.4 g (12 mMol) of 3-chloropropylisocyanate and stirred for 40 hours at ambient temperature. After the addition of 200 ml of ice water the mixture is extracted twice with 100 ml of ethyl acetate. After drying over magnesium sulphate the solvent is evaporated and the residue is triturated with ether. The precipitate formed is suction filtered and dried.
Yield: 1.5 g (90% of theory), Melting point: 207-209C
C32H38ClN503 (646-17) Calculated: C 66.71 H 6.65 N 12.16 Found: 66.71 6.72 12.47 The following compounds are obtained analogously:
.
: ' ` ~' 20~8~9 tert.butyl 4'-[~2-n-propyl-5- (N- ( 3 -chloropropylamino-carbonyl)-amino) 3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carbo~ylate Oil, Rf value: 0~20 (silica gel; eluant: ethyl acetate) tert.butyl 4'-[[2-n-butyl-5-(N-cyclohexylaminocarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate Oil, Rf value: 0.30 (silica gel; eluant: ethyl acetate~petroleum ether = 1:1 by volume) tert.butyl 4'-[[2-n-butyl-5-(N-cyclohexylaminocarbonyl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate Oil, Rf value: 0.55 (silica gel; eluant: ethyl acetate/petroleum ether = 1:2 by volume) tert.butyl 4'-[[2-n-butyl-5-methyl-6-[N-(3-chloro-propylaminocarbonyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.58 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) 4'-[[2-n-propyl-6-(N-benzylaminocarbonyl-isobutylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(l triphenyl-methyl-tetrazol-5-yl)biphenyl Oil, Rf value: 0.67 (silica gel; eluant: methylene chloride/ethanol = 19:1 by volume) 4'~[[2-n-propyl-5-(N-cyclohexylaminocarbonyl-isobutyl-amino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl Oil, Rf value: 0.62 (silica gel; eluant: methylene chloride/ethanol = 19:1 by volume) , .
Example 9 4'-[(2 n-Butyl-5-cyclohexylaminocarbonylamino-3~-imidazo[4~5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 8 fr~m 4'-[(2-n-butyl-5-amino-3H-imida~o[4,5-b]pyridin-3~yl)methyl]biphenyl-2-carboxylic acid and cyclohexylisocyanate.
Yield: 46% of theory, Melting point: 287-291C
C31H3sNsO3 (525.66) Calculated: C 70.83 H 6.71 N 13.32 Found: 69.01 6.66 13.18 Example 10 Tert.butyl 4'-[[2-n-butyl-5-(3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin 3-yl]methyl]-biphenyl-2-carboxylate . ~
0.26 g (5.3 mMol) of sodium hydride are dissolved in 20 ml of tert.butanol. After 5 minutes at ambient temperature, 0.58 g (1.0 mMol) of tert.-butyl 4'-[r2-n-butyl-5-(N-(3-chloropropylaminocarbonyl)-amino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate are added in batches~ The mixture is stirred for 10 hours at ambient temperature~ By adding 2N hydrochloric acid the pH is adjusted to 5 and the tert~-butanol is evaporated off in vacuo. The residue is stirred with 100 ml of ethyl acetate and 100 ml of water, the organic phase is separated off and the aqueous phase is extracted twice with 50 ml of ethyl acetate. The combined organic phases are washed with saturated saline solution and dried over magnesium sulphate. After evaporation of the solvent the residue is triturated with ether, the precipitate formed is suction filtered and dried.
, ~ ~
: . ~ ' " ' :
:.~
~0488~9 :. - 53 -Yield: 0.~ g (7~6 of theory), Rf value: 0.33 (s.ilica gel; eluant: ethyl acetate/ethanol = 9:1 by volume) C32H37Ns3 (539-~8) Calculated: c 71.22 H 6. 91 N 12.98 Found: 70.99 6 . 98 12 . 81 The following compounds are obtained analogously:
tert.butyl ~'-[[2-n-propyl-5-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate Melting point: 175C
;
tert.butyl 4'-~[2-n~butyl-5-methyl 6-(3 t 4 ~ 5, 6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo[~,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylate ~elting point: 200-202C
tert.hutyl 4'-[[2-n-butyl-5-methyl-6-(2-oxo-piperidin-1-yl)-lH-imidazo[4,5-b]pyridin-1-yl]methyl]biphenyl-2-carboxylate Rf value: 0O49 (silica gel; eluant: methylene chloride/
ethanol = 9:1 by volume) tert.butyl 4'-~2-n-butyl-5-methyl-6-(n-butanesultam-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Rf value: O.S0 (silica gel; eluant: methylene chloride/
ethanol = 19:1 by volume) tert.butyl 4'-[[2~n-butyl-5-methyl-6 (2-oxo-piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl3biphenyl-2-carboxylate Rf value: 0.60 (silica gel; eluant: methylene chloride/
ethanol = 19:1 by volume) ' ~
~ , , , .
' 20~8809 Example 11 Tert.butyl 4'-[[2-n-butyl-5~(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidin~n-1-yl)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylate 0.4 g (0.74 mMol) of tert.butyl 4'-[r2-n-butyl-5-(N-(3-chloropropylaminocarbonyl)-amino)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylate are suspended in 20 ml of dimethylformamide and mixed with 0.04 g (0.85 mMol) of sodium hydride. The mixture is stirred for 10 minutes at 60C, 0.5 ml (4.25 mMol) o~
benzylbromide are added and the resulting mixture is stirred for 3 hours at ambient temperature. The reaction mixture i~ poured onto ice and extracted twice with 100 ml of ethyl acetate. The combined organic phases are washed with saturated saline solution and ~ried over magnesium sulphate. A~ter the solvent has been evaporated, a colourless oil is obtained.
Yield: 0.35 g (75% of theory), Rf value: 0.41 (silica gel; eluant: methylene chloride/ethyl acetate = 1:1 by volume) Mass ispectrum: M~ = 629 The following compounds are obtained analogously:
tert.butyl ~'-[[2-n-butyl-5-(3-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.41 (silica gel; eluant: ethyl acetate/ethanol = 9:1 by volume) tert.butyl 4'-[[2-n-butyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.44 (silica gel; eluanto methylene chloride/ethanol = 19:1 by volume) . :: .
~;
': ~ ' ' :
.
2~488(19 Example 12 4'-[[2-n-Butyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-oiphenyl-2-carboxylic acid 0.35 g (0.55 mMol) of tert.butyl 4'-[[2-n-butyl-5-~3-benzyl-3,4,5,6-tetrahydro-2~lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl~methyl]-biphenyl-2-carboxylate are dissolved in 10 ml of methylene chloride and mixed with 5 ml of trifluoroacetic acid. The mixture is stirred for 65 hours at ambient temperature.
The solvent is evaporated off, the residue is taken up in ice water and acidified with ylacial acetic acid.
The precipitate thus formed is filtered off, washed with water and dried at 60C.
Yield: 0.26 g (82% of theory), Melting point: 168-170C
C35H3sNsO3 (573-70) Calculated: C 73.28 H 6.15 N 12.21 Found: 73.37 6.51 12.12 Example 13 4'-[[2-n-Butyl 5-(3-methyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylic acid . _ . _ Prepared analogously tn Example 12 from tert.butyl 4'-E ~ 2-n-butyl-5-(3-methyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b~pyridin-3-yl]methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 64% of theory, Melting point: 249-252C
Cz9H31NsO3 (497.60) Calculated: C 70.00 H 6.28 N 14.00 Found: 69.85 6.40 13.89 .
':
20~8809 Example 14 4'-[[2-n-Butyl-5-(3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Exampl~e 12 from tert.butyl 4'-[[2-n-butyl-5-(3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 80% of theory, Melting point: 300-302C
C28H29NsO3 (483.58) Calculated: C 68.27 H 6.14 N 14.22 Found: 68.47 6.11 14.28 ,Example 15 4'-[[2-n-Propyl-5-(3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo[4,5-b~pyridin-3-yl]methyl]biph~nyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-propyl-5-(3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 92% of theory, Melting point: 265-268~C
C27H27N503 (46g.55~
Calculated: C 69.07 H 5.80 N 14092 Found: 68.87 5.78 15.00 Example 16 4'-[(2-n-Butyl-5-cyclohexylmethylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl~2-carboxylic acid .
Prepared analogously to Example 12 ~rom tert.butyl 4'-.. . . . . . ..
. ~ : . ~ . ...
. ;~
. ~ .
... .
:: , ' :
.~ .
, 20~809 t(2-n-butyl-5-cyclohexylmethylamino-3H-imidazo[4,5-b]
pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 23.6~ of theory, Melting point: 202-205c C31H36N4O2 (496.66) Calculated: C 74.97 H 7.31N 11.2 Found: 74.~2 7.~ 10.98 Example 17 4'-[(2-n-Butyl-5-ethylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid .... _ . . _ Prepared analogously ko Example 12 from tert.butyl 4'-[(2-n-butyl~5-ethylamino-3H-imidazot4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 76% of theory, Melting point: 245-247C
C26H2~N4O2 (428.54) Calculated: C 72.87 H 6.59N 13.09 Found: 72.72 6.65 12.84 Example 18 4'-[(2-n-Butyl-5-n-butylamino-3H-imidazo[4,5-b]pyridin-3-yl)~methyl]biphenyl-2-carboxylic acid . . _ .
Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-S-n-butylamino-3H-imidazot4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 67% of theory, Melting point: 217-219C
C2~H32N4O2 (456.59) Calculated:C 73.66H 7.06 N 12.27 Found:73.46 7.03 12.17 - `
`" '; ;
: ' 204880~
_ample 19 4'~~(2-n-Butyl-5-cyclohexylamino-3H-imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl 2-carboxylic acid Prepared analogously to Examp:le 12 from tertubutyl 4'-; t(2-n-butyl-5-cyclohexylamino--3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 67% of theory, Melting point: 221-224C
C30H34N402 (482.63) Calculated: C 73.29 H 7.18 N 11.40 Found: 73.51 6.95 11.25 Example 20 ~'-[(2~n-Butyl-5-methylamino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-5-methylamino 3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 61% of theory, Melting point: 274-277C
C2sH26N402 (414.51) Calculated: C 72.44 H 6.32 N 13.52 Found: 72.26 ~.26 13.30 Example 21 4'-[(2-n-Butyl-5-amino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-~-carboxylic acid ...... _ Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-5-amino~3H-imidazo[4,5-b3pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic . . ..
: . , . ~ , , .. ..
.
~: . , , . , ~ . ~ ;
' 20~809 acid.
Yield: 35% of theory, Melting point: 238-240C
C24H24N4Oz (400.48) Calculated: C 71.98 H 6.04 N 13.99 Found: 71.90 5.96 13.86 Example 22 4'-t(2-n-Butyl-5-dimethylamino-3H-imidazo[4,5-b]pyridin-3-yl) methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl~5-dimethylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and tri~luoroacetic acid.
Yield: 81~ of theory, Melting point: 213-215C
C26H28N4O2 (428-54) Calculated: C 72.87 H 6.57 N 13.08 Found: 72.~2 6.7312.90 Example 23 4'-[(2-n-Butyl-5-benzylamino-3H-imidazo~4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid .. _ _ . . . . _ Prepared analogously to Example 12 from tert.butyl 4'-E ( 2-n-butyl-5-benzylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 67% of theory, Melting point: 224-225C
C31H30N4Oz (490.61) Calculated: C 75.89 H 6.16 N 11.42 Found: 75.70 6.24 11.37 ': ' " , . : : , , . .
:
2~8809 Example 24 4'-[[2-n-Butyl-5-(2,4-dimethoxybenzylamino)-31~~
imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(2,4-dimethoxybenzylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 73% of theory, Melting point: 223-226C
C33H34N404 (490.61) Calculated: C 71.98 H 6.22 N 10.18 Found: 71.70 6.21 10.16 Example 25 4'-~2-n-Butyl-5-(N-isobutyryl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl~-methyl]biphenyl-2-carboxylic acid r ~
Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(N-isobutyryl-n-butylamino-3H- midazo-[4,5-b]pyridin-3-yl3methyl]biphenyl-2 carboxyIate and trifluoroacetic acid.
Yield: 33% of theory;
Melting point- 186-189C
C32H38N4o3 (490-61) Calculated: C 72.98 EI 7.27 N 10.64 Found: 73.09 7.~5 10.53 . ; ....... .
, , .
: ~
' .
2~8809 Example 26 4'-[[2-n-Butyl-5-(N-acetyl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid _ _ _ Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(N-acetyl-n-butylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 36% of theory, Melting point: 173-175~C
C30H34N~,03 (498-63) Calculated: C 72.26 H 6.87 N 11.24 Found: 72.39 7.00 11.07 Example 27 4'-[[2-n-Butyl-5-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid .
Prepared analogously to Example lZ from tert.butyl 4'-[[2-n-butyl-5-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 95~ of theory, Melting point: 203-205C
C33H3aN4O3 (538.70) Calculated: C 73.58 H 7.11 N 10.40 Found: 73.66 7.19 10.35 Example 28 4'-[[2-n-Butyl-5-(N-acetyl-ethylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid . . . _ _ .
Prepared analogously to Example 12 from tert.butyl 4'-. ~ :
. .
- : ,, . ~ .
20~8go9 [t2~n--butyl-5-(N-acetyl-ethylamino)~3H-imidazo-[~,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 80% of theory, Melting point: 89-93C
C33H38N4O3 (470.58) Calculated: C 70.99 H 6.47 N 11.79 Found: ~0.79 6.47 11.52 Example 29 4'-[(2-n-Butyl-5-valeroylamino~3H-imidazo[4,5-b]-pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid _ _ _ _ Prepared analogously to Example 12 ~rom tert.butyl 4'-[(2-n-butyl-5-valeroylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 56% of theory, Melting point: 240-242C
C33H38N4O3 (484.60) Calculated: C 71.88 H 6.66 N 11.56 Found: 71.61 6.72 11.47 Example 30 4'-[(2-n-Propyl-5-butanoylamino-3H-imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-propyl-5-butanoylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 68% of theory, Melting point: 254-255~C
Cz7H2sN43 (456-55) Calculated: C 71.03 H 6.18 N 12.27 Found: 70.98 6.25 12.36 ;, : . . .. ,:
, ~ ~ : ,, . , ; :
- , . .
.
.
Example 31 4'-[(2-n-Propyl-5-butanoylamino-3H-imidazo[4,5 b]-pyridin-3-yl)methyl]biphenyl-4-bromo-2-carboxylic acid .... . .
Prepared analogous]y to Exampl,e 12 from tert.butyl 4'-[(2-n-propyl-5-butanoylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-4-bromo-2-carboxylate and trifluoroacetic acid.
Yield: 83% of theory, Melting point: 244-245C
c27H27N4O3Br (535-54) Calculated: C 60.56 H 5.08N 10.46 Br 14.92 Found: 60.42 5.07 10.41 14.82 Example 32 4'-[[2-n-Propyl-5-(2-methyl-valeroylamino)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylic acid .
Prepared analogously to Example 12 from tert.butyl 4'-[[2-n~propyl-5-(2-methyl-valeroylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 97% of theory, Melting point: 244-245C
Cz9H32N4O3 (484.61~
Cal~ulated: C 71.88 H 6.66 N 11.56 Found: 71.77 6.79 11.51 Example 33 4'~ E ( 2-n-Propyl-5-benzylcarbonylamino-3H-imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-~(2-n-propyl-5 benzylcarbonylamino-3H-imidazo-. .
.
, 20~8~309 - 6~ -[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 93% of theory, Meltinq point: 252-254C
C31HzsN403 (504-60) Calculated: C 73.79 H 5.59 N ll.lo Found: 73.85 5.78 10.93 Example 34 4'-[(2-n-Propyl-5-butanoylamino-lH-imidazo[4,5-b]-pyridin-1-yl)methyl~biphenyl-2-carboxylic acid _ _ .. ..
Prepared analogously to Example 12 ~rom tert.butyl 4'-~(2-n-propyl-5-butanoylamino-lH-imidazo-[4,5-b]pyridin-l-yl)methyl~biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 88% o~ theory, Melting point: 120C
C27H28N403 (456.55) Calculated: C 70.34H 6.23 N 12.15 Found: 70.14 6.24 12.34 Example 35 4'-[t2-n-Butyl-5-(N-ethoxycarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to ~xample 12 from tert.butyl 4'-[[2-n-butyl-5-(N-ethoxycarbonyl-ethylamino~-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 95% of theory, Melting point: 182-185C
C29H32N404 (500.61) Calculated: C 69.58 H 6~44 N 11.19 Found: 69.72 6.57 11.13 : .: , :. .
2~88~9 Exa~e 36 4'-[[~-n-Butyl~5-(N-cyclohexylaminocarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-5-(N-cyclohexylaminocarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 95% of theory, Melting point: 182-185C
C33H39NsO3 (500~61) Calculated: C 71.58 H 7.10 N 12.65 Found: 71.77 7.22 12.59 Example 37 4~-[[2-n-Butyl-5-(N-ethoxycarbonyl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid .
Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(N-ethoxycarbonyl-n-butylamino)-3H-imidazo[4,5~b~pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 37% of theory, Melting point: 154-156C
C31H36N4O4 (528.66) Calculated: C 70.43 H 6.86 N 10.60 Found:70.68 7.10 10.50 ;:
: . . .
.. ~
2~8~09 Example 3~
4'-[[2-n-Butyl-5-(N-cyclohexylaminocarbonyl-n-bu-tyl-amino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(N-cyclohexylaminocarbonyl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-Z-carboxylate and trifluoroacetic acid.
Yield: 89% of theory, Melting point: 195~198C
C35H43NsO3 (581.47) Calculated: C 72.26 ~ 7.45 N 12.04 Found: 72.29 7.66 11.81 Example 39 4l-[[2-n-Butyl-5-(n-butylaminocarbonylamino)-lH-imidazo[4,5-b]pyridin-1-yl]methyl]biphenyl-2-carboxylic acid _ _ Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl--5-(n-butylaminocarbonylamino)-lH--imidazo-[4,5-b]pyridin-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 83% of theory, Melting point: 290-295C
C2sH33NsO3 (499-62) Calculated: C 69.72 H 6.66 N 14.02 Found: 69.62 6.76 13.98 .
. , -~, . '; , , ~ . .
~: .
, 2~8809 Example 40 4'-[[2-n-Butyl-5-(cis hexahydrophthalimido)-3H-imidazo[4,5 b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(cis-hexahydrophthalimido)-3H-imidazo-[4,5-b]pyridin-3-yl~methyl~biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 84~ of theory, Melting point: 113-115C
C32H32N4o4 (536.6~) Calculated: C 62.76 H 5.11 N 8.61 Found: 62.79 5.21 8.~8 Example 41 4'~[(2-n-Butyl-5~methoxy-lH-imidazo[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylic acid-trifluoroacetate-hydra~e Prepared analogously to Example 12 from tert.butyl 4l_ [r2-n-butyl-5-methoxy-lH-imidazo[4,S-b~pyridin-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 80~ of theory, Melting point: 126-128C
C2sH2sN33 x CF3COOH x H20 (547-54) Calculated: C 59.23 H 5.15 N 7.68 Found: 59.46 4.99 7.63 Example 42 4'-[(2-n-Butyl-6-bromo-lH-imidazo[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylic acid .
Prepared analoyously to Example 12 from tert.butyl 4'-[(2-n-butyl-6-bromo~lH-imidazo[4,5-b]pyridin-1-:
20~8~09 ~ 68 ~
yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 79% of theory, Meltinq point: 239-240C
~24HzzBrN30z (464-36) Calculated: C 62.08 H 4.77N 9.05Br 17.21 Found: 61.83 4.71 8.92 17.43 Example 43 4'-[(2-n-Butyl-6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid . _ _ . . . .
Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 85% of theory, Melting point: 221-223C
Cz4HzzBrN30z (464.36) Calculated: C 62.08 H 4.77N 9.05Br 17.21 Found: 61.95 4.84 8.96 17.38 Example 44 4'-[~2-n-Butyl-5-methyl-6-phthalimido-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid _ _ ... .
Prepared analogously to Example 1? from tert.butyl 4'-[t2-n-butyl-5-methyl-6-phthalimido-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yi~ld: 75% of theory, Melting point: 336-340C
C33H28N404 (544.62) Calculated: C 72.78 H 5.18 N 10.29 Found: 72.59 5.1810.26 ,.. . .
:" . ., ~ , .. . . ..
,~ . : . . , .
.
". , ~0~8~09 Example_45 4'-[(2-n-Butyl-5-methyl-6-phthalimido-lH-imidazo-[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Exampl,e 12 from tert.butyl 4'-[(2-n-butyl-5-methyl-6-phthali~ido-lH-imidazo-[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 63% of theory, Melting point: 301-303C
C33H28N404 (544.62) Calculated: C 72.78 H 5.18 N 10.29 Found: 72.71 5.25 10.18 Example 46 4'-[(8-n-Butyl-2-methoxy-9H-purin-9-yl)-methyl]-biphenyl-2-carboxylic acid .... . _ Prepared analogously to Example 12 from tert.butyl 4'-~(8-n-butyl-2-methoxy-9H-purin-9-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 73% of theory, Melting point: 146-148~C
C24H24N4o3 (416-48) Calculated: C 69.21 H 5.81 N 13.45 Found: 68.97 5.84 13.17 Example 47 4'-[(8-n-Butyl-2-methoxy-7H-purin-7-yl)-methyl]-biphenyl-2-carboxylic acid _ _ _ Prepared analogously to Example 12 from tert.butyl 4'-~(8-n~butyl-2-methoxy-7H-purin-7-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 73~ of theory, "' ~ , . ' ~
.
2048~09 Melting point: 146-1~8C
Cz4H24N403 (416.43) Calculated: C 69.21 H 5.81 N 13.45 Found: 69.07 5.94 13.27 Example 48 4'-[(2-Benzylamino-8-n-butyl-9H-purin-9-yl)-methyl]-biphenyl-2-carboxylic acid .... ... _ .
Prepared analogously to Example 12 from tert.butyl 4'-r ( 2-benzylamino-8-n-butyl-9H-purin-9-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 13% of theory, Melting point: 232-234C
C30H29NsO2 (491.60) Calculated: C 73.20 H 5.95 N 14.25 Found: 73.16 6.05 14.44 Example 49 4'-[(2-n-~utyl-5-methyl-6-(N~acetyl n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl)-methyl3biphenyl-2-carboxylic acid _ _ Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-5-methyl-6-(N-acetyl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yi~ld: 56% of theory, Melting point: 144-146C
C3lH36N403 (512-65) Calculated, C 72.63 H 7.08 N 10.93 Found:72.39 7.15 ~ 10.79 , .
. .
20~8809 Example S0 4'-[(2-n-Butyl-5-methyl 6-amino-3H-imidazo[4,5-b]-pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 ~rom tert.butyl 4'-~(2~n-butyl-s-methyl-6-amino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 80% of theory, Melting point: 168-170C
C26Hz6N402 (414.57) Calculated: C 72.44 H 6.32 N 13.52 Found: 72.40 6.5013.32 Example 51 4~-[(2-n-Butyl-6-hexahydrophthalimido 3H-imidazo[4,5-b]-pyridin-3-yl)-methyl]biphenyl-Z-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-6-hexahydrophthalimido-3H-imidazo-[4,S-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 90% of theory, Melting point: 179-181C
C32H32N4O4 ~536.64) Calculated: C 71.62 H 6.01 N 10.44 Found: 71.87 6.0010.36 Example 52 4'-[(2-n-Butyl-5-methyl-6-butyrylamino-3H-imidazo-[4,5-b]pyridin-3-yl~-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-5-methyl-6-butyrylamino-3H-imidazo-[4,5-b3pyridin-3-yl)methyl]biphenyl-2-carboxylate and ., .. ~ , , - . .
, . ~ .~ .
. . . .
, ,.
20~09 tri~luoroacetic acid.
Example 53 4'-[[2-n-Butyl-5-methyl-6-(2~oxo piperidin-l-yl)-lH-imidazo[4,5-b]pyridin-1-yl]methyl]biphenyl-2-carboxylic i acid-trifluoroacetate Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-methyl-6-(2-oxo-piperidin-1-yl)-lH-imidazo[4,5-b]pyridin-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 91% of theory, Melting point: 171-173C
C30H32N403 x CF3COOH t610.65) Calculated: C 62.94 H 5.45 N 9.18 Found: 62.74 5.49 8.98 .:
Example 54 4'-[[2-n-Butyl-5-methyl-6-(2-methyl-propionylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid _ Prepared analogously to Example 12 from tert.butyl 4'-[~2-n-butyl-5-methyl-6-(2-methyl-propionylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl~biphenyl-2-carboxylate and tri~luoroacetic acid.
Example 55 4'-[[2-n-Butyl-5-methyl-6-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylic acid -Prepared analogously to Example 12 from tert~butyl 4'-E [2-n-butyl-5-methyl-6-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo[4,5-b~pyridin-3-yl]-methyl]-:
" . . . . ~ .
"
. :: : :, ,; , . , . , , ,~
: . ; , .
.
20488~9 biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 78% of theory, Melting point: 164-166C
C34H40N403 (552.72) Calculated: C 73.88 H 7.29N 10.14 Found: 73.58 7.29 10.04 Example 56 4'-[[2-n-Butyl-5-methyl-6-(cis-hexahydrophthalimido)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid . . _ . . .
Prepared analogou~ly to Example 12 from tert.butyl 4'-[[2-n-butyl-5-methyl-6-(cis-hexahydrophthalimldo)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 81% of theory, Melting point: 261-263C
C33H34N404 (550.67) Calculated: C 71.98 H 6.22N 10.18 Found: ~71.78 6.25 9.95 Example 57 4'-~(2-n-Butyl-6-(cis-hexahydrophthalimido)-lH-imidazo-~4,5-b]pyridin-1-yl~methyl]biphenyl-2-carboxylic acid-dihydrate Prepared analogously to ~xample 12 from tert.butyl 4'-[(2-n-butyl-6-(cis-hexahydrophthalimido)-lH-imidazo-[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 70% of theory, Melting point: 203-205~C
C32H32N404 x 2 H2O (572.68) Calculated:C 67.11H 6.33 N 9.78 Fou~d:67.25 6.30 9.78 .
, ~ ~
, :, . .
, 20~8~09 - 7~ -Example 58 4'-[[2-n-Butyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)~pyrimidinon-1-yl) -3H--imidazo[4,5-b~pyridin-3-yl]-methyl]biphenyl-2-ciarboxylic acid-tri~luoroacetate . . ~
Prepared analogously to Examp]e 12 from tert.butyl 4'-[[2-n-butyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3~I-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 77% of theory, Melting point: 168-170C
C36H37Ns3 x CF3COOH (701.76) Calculated: C 65.04 H 5.46 N 9.98 Found: 64.98 5.67 9.91 Exampl,e 59 4'-[[2-n-Butyl-5-[3-(4-methoxy)benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl]-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxyl;c acid _ _ .. . . .
Prepared analogously to Example 12 from tert.butyl 4'-~[2-n-butyl-5-[3-(4-methoxy)benzyl-3,4,5,6-tetrahydro-2tl~)-pyrimidinon 1-yl]-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Example ~0 4'-[[2-n-Butyl-5-[3-(4-hydroxy)benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl]-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[t2 n-butyl-5-[3-(4 hydroxy)-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl]-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and tri~luoroacetic , ,. .. . .
. . - , . . ~ .
~:
. , .
. .
2048~09 acid.
Example 61 4'-[[2-n-Butyl-5-(3-cyclohexylmethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo~4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2 n-butyl-5~(3-cyclohexylmethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Example 62 4'-[t2-n-Propyl-$-~(2-carboxymethyl)pyrrolidino]-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-propyl-5-[(2-carboxymethyl)pyrrolidino~-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 37~ of theory, Melting point: 137-13gC
C2~H30N404 (498-62) Calculated: C 69.86 H 6.06 N 11.24 Found: 69.59 6.20 11.04 Example 63 4~-[(2-n-Butyl-6-phthalimido lH-imidazo[4,5-b]pyridin-1-yl)-methyl3biphenyl-2-carboxylic acid-trifluoroacetate Prepared analogously to Example 12 from tert.butyl 4'~
[(2-n-butyl-6-phthalimido-lH-imidazot4,5-b]pyridin-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic ,~ . . . . .
: .:
-: :- . , :
. ~
, . . .
~8g~9 acid.
Yield: 74% o~ theory, Melting point: 168-170C
C32H26N4o4 x CF3COOH (644.61) Calculated: C 63.35 H 4.22 N 8.96 Found: 63.50 4.53 9.06 Example 64 4'-[t8-n-Butyl-2-(n-butylamino)-9H-purin-9-yl]methyl]-biphenyl-2-carboxylic acid 0.45 g (0.95 mMol) of methyl 4'-[[8-n-butyl-2-(n-butylamino)-9H-purin-9-yl]methyl]biphenyl-2-carboxylate are dissolved in 20 ml of methanol and 10 ml of water, mixed with 0.4 g of powdered potassium hydroxide and re~luxed for 3 hours. The reaction mixture is then concentrated by evaporation and the residue is dissolved in 30 ml of water. It is filtered over charcoal and acidified with glacial acetic acid~ The precipitate formed is suction filtered, washed with water and dried.
Yield: 0.4 g (92% of theory), Melting point: 213-~15C
C27H31~52 (457.58) Calculated: C 70.87 H 6.83 N 15.31 Found: 70.70 6.89 15.19 Example 65 4' C(8-n-Butyl-Z-cyclohexylamino-9H-purin-9-yl)methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 64 from methyl 4'-[(8-n-butyl-2-cyclohexylamino-9H-purin-9-yl)methyl]biphenyl-2-carboxylate and methanolic potassium hydroxide solution.
Yield: 55% of theory, Melting point: 213-215C
C2sH33Ns2 t483 62) - ~ ~
.
, .
.-: : . ... . .
.
i~
. .
20~88~9 Calculated: C 72.02 H 6.88 N 14.48 Found: 71. 84 6 . 98 14 . 62 xample 66 4'-[(8-n-Butyl-2-ethoxy-9H-purin-9-yl)methyl]biphenyl-2-carboxylic acid -Prepared analogously to Exampl!e 64 from methyl 4'-[(8-n-butyl-2-ethoxy-9H-purin-9-yl)m~ethyl]biphenyl-2-carboxylate and methanolic potassium hydroxide solution.
Yield: 48~ of theory, Melting point: 190-192C
C2sH26N4O3 (430.51) Calculated: C 69.75 H 6.09 N 13.01 Found: 69.75 6.13 12.83 Example 67 4'-[(~-n-Butyl-2-ethoxy-7H-purin-7-yl)methyl]biphenyl-2-carboxylic acid . ~
Prepared analogously to Example 64 from methyl 4'-[(8-n-butyl-2-ethoxy-7H-purin-7-yl)methyl]biphenyl-2-carboxylate and methanolic potassium hydroxide solution.
Yield: 10% of theory, Melting point: 155-158C
C2sH26N4O3 (430.51) Calculated: C 69.75 H 6.09 N 13.01 Found: 69.95 6.10 :L1.83 Example 68 4l-[[2-n-Propyl-5-(2-methylpropylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl~-2-(lH-tetrazol-5-yl)biphenyl 0.32 g (0.42 mMol) of 4'~[~2-n-propyl-5-(2-methylpropyl-amino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-.
.
'' ~ ' ;' :
' `
,~
~0~809 ~ 7~ -triphenylmethyl-tetrazol-5-yl)-biphenyl are dissolved in 20 ml of methanolic hydrochloric acid and stirred for 2 hours at ambient temperature. The solvent is concentrated by evaporation, the residue is triturated with 20 ml of water, suction filtered and dried. After column chromatography on silica gel (particle size:
0.06-0.2 mm, eluant: methylene chloride/ethanol 0-10%) a white solid is obtained.
Yield: 0.1 g (51% of theory), Melting point: 128-130C
C27H30N~ (466.60) Calculated: C 69.50 H 6.4~ N 24.02 Found: 69.44 6.73 24.04 Example 69 4'-[[Z-n-Butyl-5-(2-aminocarbonyl-cyclohexylcarbonyl-amino)-3H-imidazo[4,5-b]pyridin-3-yl]methylJ-2 (lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-butyl-5-(2-aminocarbonyl-cyclohexylcarbonylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl and methanolic hydrochloric acid.
Yield: 37% of theory, Melting point: 165-175C
32H35NsOz (577 70) Calculated: C 66.53 H 6.11 N 2~.82 Found: 65.73 6.13 21.84 Example 70 `:
4'-[[2-n-Butyl-5-(cis-hexahydrophthalimido)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl . . .
Prepared analogously to Example 68 from 4'-[[2-n-butyl-5-(cis-hexahydrophthalimido~-3N-imidazo~4,5-b]pyridin-3-: , ~ ~ , ~ ' ' : ' .
.
. : : ~ ' ' ' : :
~OA8~09 yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl and glacial acetic acid.
Yield: 30~ of theory, Melting point: 127C
C32H32N8O2 (560.66) Mass spectrum: M~ - 560 Example 71 4'-t[2-n-Butyl-5-t4 methyl-piperidino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl . . _ . . . _ . . . _ Pre~ared analogously to Example 68 ~rom 4'-[[2-n-butyl-5-t4-methyl-piperidino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl~biphenyl and methanolic hydrochloric acid.
Yield: 39% o~ theory, Melting point: 187-189C
C30H34N8 (506-70) Mass spectrum: M~ = 506 Example 72 4'-[[2-n-Propyl-5-[N-(3-phenylpropionyl)isobutylamino]-3H-imidazo~4,5-b]pyridin-3-yl]methyl]-2~(lH-tetrazol-5-; yl)-biphenyl Prepared analogously to Example 68 from 4'-[t2-n-propyl-5-[N-(3-phenylpropionyl)-isobutylamino]-3~-imidazo-[4,5-b]pyridin~3-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
~,,: . ,, . , , , ~ ..... .
. . .: :
:
2~88~9 Example 73 4'-[[2-n-Propyl-5-(N-benzylaminocarbonyl-iscbutylamino) 3H-imidazo[4,5-b]pyridin-3-yl]methyl]-~-(lH-tetrazol-5-yl)-biphenyl _ _ Prepared analogously to Example 68 from 4'-[[2-n-propyl-5-(N-benzylaminocarbonyl-isobu-tylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Yield: 37% of theory, Melting point: 195-196~C
C3sH37N9O (599~75) Calculated: C 70.09 H 6.22 N 21.02 Found: 69.95 6.3220.86 Example 7 4~~E[2-n-propyl-5-(N-cyclohexylaminocarbonyl-isobutylamino)-3H-imidazo[4,5-b]pyridin 3-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-propyl-5-(N-cyclohexylaminocarbonyl-isobutylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl] 2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Yield: 38% of theory, Melting point: 112-113C
C3~H41N9O (591.77) Calculated:C 69.01H 6.g8 N 21.30 Found:68.86 6.88 21.18 . .
: ' ' ' ` '~ ` .
, `
, 20~18~09 _xample 75 4'~[[2-n-Butyl-5-(3-benzyl-3,4,5,6-tetrahydro-Z(lH)-pyrimidinon-l-yl)-3~-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-butyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenyl-methyl-tetrazol-5-yl) biphenyl and methanolic hydrochloric acid.
Example 76 4'-[(2-n-Butyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid . _ Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 65% of theory, Melting point: 233-235C
C2s~2sN3o2 (399.50) Calculated: C 75.16 H 6.31 N 10.52 Found: 75.06 6.3510.46 Example 77 4'-[[2-n-Butyl-5-(2-oxo-pyrrolidino~-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[ E 2-n-butyl-5-(2-oxo-pyrrolidino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenyl-methyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
' ~ . . . .
'' ,~ :
- ~2 -Example 78 4'[[2-n-Propyl-5-(2-oxo-pyrrolidino)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl _ Prepared analogously to Example 68 from 4'-[[2-n-propyl-5-(2-oxo-pyrrolidino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(1-triphenyl-methyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Example 79 4'[[2-n-Butyl-5-(2-oxo-piperidino)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)-hiphenyl _ _ Prepared analogously to Example 68 from 4'-[[2-n-butyl-5-(2-oxo-piperidino)-3H-imidazo[~,5-b]pyridin-3-yl]-methyl]-2-(1-triphenyl-methyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Example 80 4'[[2-n-Propyl-5-(2-oxo-piperidino)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]-2~(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-propyl-5-(2-oxo-piperidino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(l-triphenyl-methyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Example 81 4'-[[2-n-Butyl-5-methyl-6 (cis-hexahydrophthalimido)-lH-imidazo[4,5~b]pyridin-l-yl]methyl]biphenyl-2-carboxylic acid-trifluoroacetate .. . . _ . _ Prepared analogously to Example 12 from tert.butyl 4'-[t2-n-butyl-5-methyl-6-(cis-hexahydrophthalimido)-lH-imidazo[4,5-b]pyridin-l-yl]methyl]biphenyl-2-carboxylate 2~)~880.9 and trifluoroacetic acid.
Yield: 79~ of theory, Melting point: 188-l90~C
C33H34N~04 x CF3COOH (664.68) Calculated: C 63.24 H 5.31 N 8.4~
Found: 63.5Z 5.65 8.69 Example 82 4'-[(2-n-Butyl-5-methyl-6-dimethylaminocarbonylamino~
imidaæo[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylic acid trifluoroacetate . . _ _ . _ . _ . . . _ Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-methyl-6 dimethylaminocarbonylamino-lH-imidazo[4~5-b~pyridin-1-yl]methyl]biphenyl 2-carboxylate and trifluoroacetic acid.
Yield: 83~ of theory, Melting point: 147-149C
c28H31N53 x CF3COOH (599.61) Calculated: C 60.09 H 5.37 N 11.6~
Found: 60.31 5.39 11.51 Example 83 4'-[(2-n-Butyl-5-methyl-lH-imidazo[4,5-b]pyridin-1-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4' E (2-n-butyl-5-methyl-lH-imidazo[4,5-b]pyridin-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 77~ of theory, Melting point: 230-232C
C25H25N302 (399 50) Calculated:C 75.16 H 6.31 N 10.52 Found:74.86 6.39 10.46 -. : : ~
, .
,.;.
. ~ .
.
20~8~9 Example 84 4'-[(2-n-~utyl-6-phthalimido-3H-imidazo[4,5-b]pyridin-3~
yl)-methyl]biphenyl-2-carboxylic acid . ~ . _ .. ~ . .
Prepared analogously to Example 12 from tert.butyl 4'-t(2-n-butyl-6-phthalimido-3H-imidazo[4,5-b~pyridin-3-yl)-methyl]biphenyl-2-carboxylalte and tri~luoroacetic acid.
Yield: 78% of theory, Melting point: 271-272C
C32H26N404 (530 59) Calculated: C 72.44 H 4.94 N 10.56 Found: 72.37 4.99 10.48 Example 85 4'-[[2-n-Butyl-5-(4-chlorophenyl)sulphonylamino-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid-hydrate Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(4-chlorophenyl)sulphonylamino-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 63% of theory, Melting point: 158-160C
C30~1z7N404ClS X H20 (593 Calculated: C 60.75 H 4.93 N 9.45 Found: 60.62 4.76 9.27 Example 86 4'-[(2-n-Butyl-5-n-butylsulphonylamino-3~-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid ... _ . .. . . _ Prepared analogously to Example 4 from 4'-~(2-n-butyl-5-amino-3H-imidazo[4,5-b]pyridin-3-yl)methyl~biphenyl-2-.: , ' . ~
.
:, -:
20~8809 carboxylic acid and butanesulphonyl chloride in pyridine.
Yield: 16% of theory, Melting point: > 250C
C28H3zN404S (520-70) Calculated: C 65.59 H 6.19 N 10.76 Found: 65.41 6.28 10.58 The following compounds are obtained analogously:
4'-[(2-n-butyl-5-n-propylsulphonylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl 2 carboxylic acid 4'-t(2-n~butyl-5-isopropylsulphonylamino-3H-imidazo-[4,5-b]pyridin-3~yl)methyl]biphenyl-2-carboxylic acid 4'-[[2-n-butyl-5-(3-chloropropylsulphonylamino)-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2~carboxylic acid [(2-n-butyl-5-n-hexylsulphonylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid 4'-[(2-n-butyl-5-benzylsulphonylamino-3H-imidazot4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Example 87 4'-[[2-n-Butyl-5-(n butanesultam-1-yl)-3H-imidazo-~4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[~2-n-butyl~
5-~n-butanesultam-1-yl)-3H-imidazot4,5-b]pyridin-3-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl and methanolic hydrochloric acid.
The following compounds are obtained analogously:
.
- . : . `
:' , .
-, .
2~g80~
- ~6 -4'-[~2~n-propyl-5-(n-butanesultam-1-yl~-3H-ilnidazo-[4,5-b]pyridi.n 3-yl]-methyl]-2-(~H-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-5-(n-propanesultam-l-yl)-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl 4'-[[2-n-propyl-5-(n-propanesultam-1-yl)-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-5-(n-butanesultam-1-yl)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid 4'-[[2-n-propyl-5-(n-butanesultam-l-yl)-3H-imidazo-~4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid 4'-[[2-n-butyl-5--(n-propanesultam-1-yl)-3H-imidazo-[~,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid 4'-[[2-n-propyl-5-(n-propanesultam-l-yl)-3H-imidazo [4,5-b]pyridin-3-yl]-methyl~biphenyl-2-carboxylic acid Example 88 ~`
4'-[(2-n-Butyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3~yl)-: methyl]-2-(lH-tetrazol-5-yl)biphenyl . . _ . .
Prepared analogously to Example 68 ~rom 4'-[(2-n-butyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2~
triphenylmethyl-tetrazol-5-yl)biphenyl and methanolic hydrochloric acid.
Yield: 43% of theory, Melting point: 206-207C
C25H25N7 (439.52) Calculated:C 68.32 H 5.73N 22.31 Found: 68.11 5.88 22.19 .. . .
;, ~ ~ , :, , : ' .
,:
20~09 Example 89 ~'-t(2-n-Butyl-3E~-imidazo[4,5-b]pyridin-5-on-3-yl)-methyl]-2-(lH-tetrazol-5-yl)biphenyl Prepared analogously to Example 68 from 4'-[(Z-n-butyl-3H-imidazo[4,5-b]pyridin-5-on 3-yl)methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl and methanolic hydrochloric acid.
Yield: 18% of theory, Melting point: amorphous C24H23N7 (425.50) Calculated: C 67.7S H 5.45 N 23.04 Found: 67.54 5.42 22.91 Example 90 4'-[[2-n-Propyl-5-(2,2-dimethylpropionylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)~
biphenyl Prepared analogously to Example 68 from 4'-[[2-n-propyl-5-(2,2-dimethylpropionylamino) 3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-~1-triphenylmethyl-tetrazol-S-yl)biphenyl and methanolic hydrochloric acid.
Yield: 81% of theory, Melting point: 217-220C
C28H30N80 (49A.60) Calculated: C 67.99 H 6.11 N 22.66 Found: 67.82 6.22 22.46 Example 91 4'-~(2-n-Propyl-5-cyclohexylcarbonylamino-3H imidazo-t4,5-b]pyridin-3-yl)methyl]-2-~lH-tetrazol-5-yl)-biphenyl _ Prepared analogously to Example 68 from 4'-[(2-n-propyl-~ ~ .
. j .
~'' .. ~
, 204880~
5-cyclohexylcarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl and methanolia hydrochloric aaid.
Yield: 89% of theory, Melting point: 229-231C
C30H32Ns (520.64) Calculated: C 69.21 H 6.20 N 21.52 Found: 69.14 6.20 21.32 Example 92 4~-[~2-n-sutyl-5-methyl-6-dimethylaminocarbonylamino-3H
imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid . _ . . . . . _ ...
Prepared analogously to Example 12 from ter-t.bu-tyl 4'-[(2-n-butyl-5-methyl-6-dimethylaminocarbonylamino 3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 74% of theory, Melting point: 220-221C
C28H31N503 (485.58~
Calculated: c 69.26 H 6.44 N 14.42 Found: 69.08 6.47 14.25 Example_93 4'-[(2-n-Butyl-4-chloro-3H-imidazo[4,5-c]pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid . .
Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-4-chloro-3H-imidazo[4,5-c]pyridin-3-yl~-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 85% of theory, Melting point: 221-222C
C24H22ClN3o2 (419.92) Calculated: C 68.65 H 5.28 N 10.00 Found: 68.66 5.15 10.19 :, ~
.
' - . ~ ~ . . - ;
.
- 20~09 Example 94 4'-[(2-n-Butyl-4-chloro-lH-imidazo[4,5-c]pyridin-1-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-4-chloro-lH-imidazo[4,5-c]pyridin-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 85~ o~ theory, Meltin~ point: 221~222C
C24H22ClN302 (419-92) Calculated: C 68.65 H 5.28 N 10.00 Found: 68.56 5.18 10.09 _xample 95 4'-[(2-Ethyl-5 propionylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2 carboxylic acid . . . _ . . . _ .
Prepared analogously to Example 12 ~rom tert.butyl 4'-[(2-ethyl-5-propionylamino-3H-imidazo[4,5-b~pyridin-3-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 99% of theory, Melting point: 283-293C
C25H24N403 (428.50) Calculated: C 70.08 H 5.65 N 13.08 Found: 69.87 5.68 13.05 Example 96 4'-[t2-n-Propyl-5-(5-hydroxy-valeroylamino)-3H-imidazo[4,5 b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid . .
Prepared analogously to Example 12 from tert.butyl 4'-t[2-n-propyl-5-(5-hydroxy n-valeroylamino~-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-. - -, . :, .
: : .
~ .
carboxylate and trifluoroacetic acid.
Yie]d: 80% o~ theory, Meltlng point: 220C
C28H30N404 (486.60) Calculated: C 69.12 H 6.22 N 11.52 Found: 68.97 6.~411.39 Exam~le 97 4'-[[2-Ethyl-5-(3-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid semihydrate Prepared analogously to Example 12 from tert.butyl 4'-[[2-ethyl-5-(3-methyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3~-imidazo~4,5-b~pyridin~3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 62% of theory, Melting point: from 250C (decomp.) C27H2~NsO3 x 1/2 HzO (478.60) Calculated: C 67.77 H 5.90 N 14.64 Found: 67.98 5.84 14.66 Example 98 4'-[[2-n-Propyl-5-(3-methyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazot4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[~2-n-propyl-5-(3-methyl-3,4,5,6-tetrahydro-2(lH~-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 74% of theory, Melting point: 202-205C
Cz8H29NsO3 (483.57) Calculated: C 69.55 H 6.04 N 14.48 Found: 69.30 5.9814.62 .~~, ... .
" . . .. .
~8809 _x mPle 99 4'-[[2~Ethyl-5 (3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl~-biphenyl-2-carboxylic acid-semihydrate Prepared analogou~ly to Example 12 from tert.butyl 4'-[[2-ethyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 66% of theory, Melting point: 137-138C
C33H31NsO3 x 1/2 H20 (545.70) Calculated: C 72.64 H 5.73 N 12.84 E'ound- 72~40 5.76 12.~8 Example 100 4'-[[2-n-Propyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-propyl-5-(3-benzyl-3,4,5,6 tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 77% of theory, Melting point: 149-152C
C34H33N503 (559.67) Calculated:C 72.97H 5.94 N 12.51 Found:73.11 5.91 12.39 , ~ .
,, - . , .
20~880~
X~,_ 101 4'-[~2-n-Propyl-5-(N-cyclohexy:Laminocarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid .
Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-propyl-5-(N-cyclohexylaminocarbonyl-ethylamino)-3H-imidazot4,5-b]pyridin-3-yl]--methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 10% of theory, Melting point: 166-167nC
C34H33Ns3 (S3g-69) Calculated: C 71.22 H 6.91 N ~2.98 Found: 71.37 6.7012.80 Example 102 4'-[[2-Ethyl-5-(N-cyclohexylaminocarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl~-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-ethyl-5-(N-cyclohexylaminocarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 25% of theory, Melting point: 95-100C (decomp.) C31H35NsO3 (525.66) Calculated: C 70.83 H 6.71 N 13.32 Found: 70.69 6.65 13.30 ' ' ,: '`
~0~8809 Example 103 4'-C[2-n-Propyl-5-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-propyl-5-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl] biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 83% of theory, Melting point: 112-115C
C32H36N403 (524.67) Calculated: C 73.26 H 6.92 N 10.6~
Found: 73.18 7.19 10.67 Exampl_ 104 4'-[[2-Ethyl-5-(N-cyclohexylcarbonyl-ethylamino)-3H-imida30[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid . . _ _ . . _ Prepared analogously to Example 12 from tert.butyl 4'-t[2-ethyl-5-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo[4,5-b] pyridin-3-yl ] -methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yieldo 91% of theory, Melting point: 223-224C
C31H34N403 (510.65) Calculated: C 72.92 H 6.71 N 10.97 Found: 72.97 6.65 10.93 Example 105 4'-[[2~(N-Isobutyryl-n-butylamino)-8-n-butyl-9H-purin-9-yl~ methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 4 from 4'-~[2-(n-.
' ~ : : ' ,, ` 204~809 ~- 94 -butylamino3-8-n-butyl-9H-purin-9-yl]-methyl]-biphenyl-2 carboxylic acid and isobutyric acid chloride.
Yield: 38% of theory, Melting point: 80OC
C31H37NsO3 (527.68) Calculated: C 70.56 H 7.07 N 13.27 Found: 70.45 7.22 13.06 Example 106 4'-[[2-n-Butyl-5-methyl-6-(2-oxo-piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid . _ . . _ . . _ . . . _ Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-methyl-6-(2-oxo-piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl] biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 77Po of theory, Melting point: 266-268c C30l~32N403 (496.62) Calculated: C 72.56 H 6.50 N 11.23 Found: 72.46 6.73 11.10 Example 107 4'-[[2-n-Butyl-5-methyl-6-(n-butanesultam-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]~methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-~[2-n-butyl-5 methyl-6-(n-butanesultam-1-yl)-3H-imidazo~4,5-b~pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 78% of theory, Melting point: 287-288C
C29H32N404S (532-67) Calculated: C 65.39 H 6.06 N 10.52 ;
. ,, ' .
- 2~8~09 Found: 65.26 6.25 10.37 Example 108 4'-[[2-n-Butyl-5-methyl-6-(N-cyclohexylaminocarbonyl-ethylamino)~lH-imidazo[4,5-b]pyridin-1-yl]-methyl]-biphenyl-2~carboxylic acid Prepared analogously to Exampl,e 12 from tert.butyl 4'-~[2-n-butyl-5-methyl-6-(N-cyclohexylaminocarbonyl-ethylamino) lH-imidazo[4,5-b]p~yridin-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 88% of theory, Melting point: 177-179C
C34H31N503 (567.74) Calculated: C 71.93 H 7.28 N 12.34 Found: 71.76 7.20 12.13 Example_109 4'-[[2,5-Dimethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b~pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 ~rom tert.butyl 4'-[t2,5-dimethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 74% of theory, Melting point: 277-280C
C33H~1Ns3 (545.65) Calculated: C 72.64 H 5.73 N 12.84 Found: 72.87 5.57 12.66 ,, . . , -.
- 20~880~
~ 96 -E mple 110 4'-~[2,5-Dimethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-lH-imidazo[4,5-b]pyridin-1-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2,5-dimethyl-6 (3-benzyl-3,4,5,6-tetrahydro 2tlH)-pyrimidinon-l-yl)-lH-imidazo[4,5-b]pyridin-1-y:L]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 77% of theory, Melting point: 142-144C
C33H31NsO3 (545.65) Calculated: C 72.64 H 5.73 N 12.84 Found: 72.59 5.51 12.60 Example 111 4'-~[2-Ethyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[~2-ethyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5~b]pyridin-3-yl~-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 73% of theory, Melting point: 272-274C
C34H33Ns3 (559-68) Calculated: C 72.97 H 5.94 N 12.51 Found: 72.87 5.97 12.37 . . .
: ' ; -:''- ' , ' ~
:, .. . .
20~88~9 Example 112 4'-[(2~n-Butyl-5-ethyl-6-dimethylaminocarbonylamino-3H-imidazo~4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylic acid-trifluoroacetate Prepared analogously to Example 12 from tert.butyl 4'-Ct2-n-butyl-5-ethyl-6-dimethylaminocarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 72% of theory, Melting point: 180-182C
C2sH33Ns3 x CF3C00~ (613.65) Calculated: C 60.67 H 5. 58 N 11.41 Found: 60.81 5.81 11.65 Example 113 4'-[(2-n-Propyl-5-methyl-6-dimethylaminocarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylic acid-trifluoroacetate _ _ . .
Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-propyl-5-methyl-6-dimethylaminocarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 81% of theory, Melting point: 243-245C
C27H29N503 x CF3COOH (585.60) Calculated:C 59.48 H 5.16 N 11.96 Found:59.68 5.26 11.99 .
" : ~ ~
, . . . .
2~809 _ 9~ _ Exam le 114 4'-[(2-n-Propyl-5~methyl-6-dimethylaminocarbonylamino-lH-imidazo[4,5-b~pyridin-1 yl)methyl]-biphenyl-2-carboxylic acid-trifluoroacetate .
Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-propyl-S-methyl-6-dimethylaminocarbonylamino-lH-imidazo[4,5-b]pyridin-1-yl)-methyl~-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 90% of theory, Melting point: 213-216C
Cz7H2sNsO3 x CF3COOH (585.60) Calculated: C 59.4~ H 5.16 N 11~96 Found: 59.61 5.13 11.77 Example ~15 4'-[(2-n-Butyl-5-methyl-6-diethylaminocarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-biphenyl-2 carboxylic acid-trifluoroacetate . . _ . _ . . . _ . . _ _ Prepared analogously to Example 12 from tert.butyl 4'-[(2~n-butyl-5-methyl-6-diethylaminocarbonylamino-3H-imidazo[4~5-b]pyridin-3-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 90% of theory, Melting point: 137-140C
C30H35N5O3 x CF3COOH (627.67) Calculated: C 61.23 H 5.78 N 11.16 Found: 60.975.33 10.9~
,, ~, . .. . ..
:: , .'' . ' ' .
:
~ ' ~0~8~0~
. 99 Example 116 4'-[t2-n-Butyl-5-ethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazot4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid . . . _ . . _ Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-ethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl~-methyl] biphenyl-2~carboxylate and trifluoroacetic acid.
Yield: 85% of theory, Melting point: 173-175C
C37H39NsO3 (601.76) Calculated: C 73.85 H 6.53 N 11.64 E'ound: 73.63 6.40 11.41 Example 117 4~-[[2-n-Propyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid . . _ . . _ ~
Prepared analogously to Example 12 from tert.butyl 4'-[~2-n-propyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 64% of theory, Melting point: 199-201C
C35H35NsO3 (573.69) Cals~ulated: C 73.27 H 6.05 N 12.21 Found: 73.20 6.19 12.08 . . . . .. .
- , . .
., , ~ -. :. . . : .
.. . . .
.
2~8~V9 Example 118 4'-[[2-n-Butyl-5-methyl-6-(3-dimethylaminocarbonyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid . _ _ Prepared analogously to Example 12 from tert.butyl 4'-[t2-n-butyl-5-methyl-6-(3-dimethylaminocarbonyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l--yl)-3H-imidazo[4,5-b]-pyr.idin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
_ample 119 4'-[[2-n-Butyl-5-methyl~6~(3-benzyl-3,4,5-trihydro-2(lH)-imidazolinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid . . . _ _ , .
Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-methyl-6-(3-benzyl-3,4,5-trihydro-2(lH)-imidazolinon-l-yl)-3H-imidazo[4,5-b]-pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield. 92% of theory, Melting point: 149-151~C
C3sH3sNsO3 (573-70) Calculated: C 73028 H 6.15 N 12.21 Found: 73.16 5.9812.07 Example 120 4'-[(2-n-Propyl-5-methyl-6-(cis-hexahydrophthalimido)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-~(2-n-propyl-5-methyl-6-(cis-hexahydrophthalimido)-3H-imidazo[4,5-b]-pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
.. . . .
.
'; ' ~ ;
2~8809 Yield: 77% of theory, Melting point: 269~270C
C32H3zN4O4 (536-64) Calculated: C 71.62 ~ 6.01 N 10.44 Found: 71.48 6.24 10.31 .
Example 121 4'-[(2-n-Propyl-5-methyl-6-(c.is-hexahydrophthalimido)-lH-imidazo[4,5-b]pyridin-1-yl)methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-propyl-5-methyl-6-(cis-hexahydrophthalimido)-lH-imidazo[4,5-b]-pyridin-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 79% of theory, Nelting point: 219-221C
C32H32N4O4 (536.64~
Calculated: C 71.62 H 6.01 N 10.44 Found: 71.45 5.86 10.21 Example 122 4'-t[2-n-Butyl-5-(N-phenylsulphonyl-methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid . _ _ .. _ ... . . _ ..
Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(N-phenylsulphonyl-methylamino)-3H-imidazo[4,5-b]-pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 83% of thaory, Melting point 226-227C
H30N4O4S (554.60) Calculated: C 67.14 H 5.45 N 10.10 S 5.79 Found: 67.00 5.51 10.25 5.78 ..:, ......
~. , ,' :, ' ~ ~
- ' '' , : , ,'. ~ ~ , ' ' . : ' -20~8~09 Example 123 4'-[[2-n-Propyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1l~)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl . _ . . _ _ . . _ , . .
Prepared analogously to Example 68 from 4'-[[2-n-propyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo~4,5-b]pyridin-3-yl]-methyl]-2-(1-triphenyl-methyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Yield: 72~ of theory, Melting point: amorphous C34H33Ns (583.70) Calculated: C 69.96 H 5.70 N 21.60 Found: 70.11 5.5721.49 Example 124 4'-~2-n-Propyl-5-(2-oxo-indolin-1-yl)-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-propyl-5-(2 oxo-indolin-1-yl)-3H-imidazo[4,5 b]pyridin~3-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Yield~ of theory, Melting point- sinters from 190C
C31H26N8 (526.51) Mass spectrum: (M-~H)+ a 527 ' ,, ~, .
., .
204~8~9 Example 125 4'-[(2-n-Butyl-5-methyl-6-dimethylaminocarbonylamino-3H-imidazo~4,5-b]pyridin-3-yl)methyl]-2-(lH-tetrazol-5-yl)-biphenyl ._ _ Prepared analogously to Example 68 from 4'-[(2-n-butyl-5-methyl-6-dimethylaminocarbonylamino-3H-imidazo[4,5-b]-pyridin-3-yl)-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl~-biphenyl and methanolic hydrochloric acid.
Example 126 4'-[[2-Ethyl-5-(2,2-dimethyl-propionylamino)-3~-imidazo-~4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl-hydrochloride Prepared analogously to Example 68 from 4'-[[2-ethyl-5-(2,2-dimethyl-propionylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Yield: 52% of theory, Melting point: sinters from 188~C
C27H2sNsO x E~Cl (517.04) Calculated: C 62.95 H 5.65 N 21.90 Cl 6.85 Found: 62.73 5.47 21.75 5067 Example 127 . .
4'-[(2-n-Butyl-5-ethyl-6-phthalimido-lH-imidazo[4,5-b]-pyridin-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example l~ from tert.butyl 4'-[(2-n-butyl-5-ethyl-6-phthalimido-lH-imidazo[4,5-b]-pyridin-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 56% o~ theory Melting point: 277-279C
.. . . . :
-, .. .
: : .
~0~809 C34H30N~04 (558.64) Calculated: C 73.10 H 5.41 ~7 10.03 Found:72.97 5.52 10.16 Example 128 4'-~(2-n-Butyl-5~methoxy-lH-imidazo[4,5-b]pyridin-1-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-E(2-n-butyl-5-methoxy-lH-imidazo[4,5-b]pyridin-1-yl)-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloxic acid.
Yield: 60% of theory, Melting point: 170-171C
C2sH2sN70 (439-53) Calculated:C 68.32H 5.73 N 22.31 Found:68.19 5.53 22.06 ....... . . .
. ~. . ; , .
, :, , 20~gO9 In the Examples of Pharmaceutical Formulations which follow, any suitable compound o~ formula I, particularly compounds A to K of the pharmacological test report, may be used as the active substance:
Exam~le I
Ampoules containing 50 mg of active substance per 5 ml _ _ Active substance 50 mg KHzPO4 2 mg NazHPO4 x 2Hzo 50 mg NaCl 12 mg Water for injections ad 5 ml Preparation:
The buffer substances and isotonic substance are dissolved in some of the water. The active substance is added and, once it has completely dissolved, water is added to make up the required volume.
Example II
Ampoules containing 100 mg of active substance per 5 ml . ~
Active substance 100 mg Methyl glucamine 35 mg Glycofurol 1000 mg Polyethyleneglycol-polypropylene-glycol block polymer 250 mg Water for injections ad 5 ml Preparation:
Methyl glucamine is dissolved in some of the water and . , ; . , :
: .
' 20~88~
the active substance i8 dissolved with stirring and heating. After the addition of solvents, water is added to make up the desired volume.
Example IIl Tablets containing 50 mg of active substance .
Active substance 50.0 mg Calcium phosphate 70.0 mg Lactose 40.0 mg Corn starch 35.0 mg Polyvinylpyrrolidone 3.5 mg Magnesium stearate __1 5_~
200.0 mg Preparation:
The active substance, CaHP04, lactose and corn starch are uniformly moistened with an aqueous PVP solution. The mass is passed through a 2 m~ screen, dried at 50C in a circulating air dryer and screened again.
After the lubricant has been added, the granules are compressed in a tablet making machine.
Example IV
Coated tablets containing 50 mg of active substance Active substance 50.0 mg Lysine 25.0 mg Lactose 60.0 mg Corn starch 34.0 mg Gelatin 10.0 mg Magnesium stearate 1.0 ma , . .
i ,.
.; ~ ' ' . ' ' :
. '' ~ ~ ~ . ' ' " .
2~809 180.0 mg Preparation:
The active substance is mixed with the excipients and moistened with an aqueous gelatin solution. After screening and drying, the granules are mixed with magnesium stearate and compressed to form tablet cores.
The cores thus produced are covered with a coating by known methods. A colouring may be added to the coatiny suspension or solution.
Example V
Coated tablets containing lO0 mg of active substance . . . _ _ Ac-tive substance 100.0 mg Lysine 50.0 mg Lactose 86.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone2.8 mg Microcrystalline cellulose 60.0 mg Magnesium stearate 1.2 mg 350.0 my Preparation:
The active substance is mixed with the excipients and moistened with an aqueous PVP solution. The moist mass is passed through a 1.5 mm screen and dried at 45C.
A~ter drying, it is filtered again and the magnesium stearate is added. This mixture is then compressed into cores.
The cores thus produced are covered with a coating by known methods. Colourings may be added to the coating "~ ' :, ~ . ` .
`
:
2048~09 suspension or solution.
Example VI
Capsules containing z50 mg of active substance . _ .
Active substance 250.0 mg Corn starch 68.5 mg Magnesium stearate 1.5 mg 320.0 mg Preparation:
The active substance and corn starch are mixed together and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The final mixture is packed into size l hard gelatin capsules.
Example VII
Oral suspension containing 50 mg of active substance per 5 ml Active substance 50.0 mg Hydroxyethylcellulose50.0 mg Sorbic acid 5.0 mg 70% sorbitol 600.0 mg Glycerol 200.0 mg Flavouring 15.0 mg Water ad 5.0 ml Preparation:
Distilled water is heated to 70C. Hydroxyethyl-cellulose is dissolved therein with stirring. By the ,, .
, . ., ~ .
! .
~8~0~
addition of sorbitol solution and glycerol the mixture is cooled to ambient temperature. At ambient temperature, sorbic acid, flavouring and active substance are added. The suspension is evacuated with stirring to remove any air. One dose of 50 mg is contained in 5.0 ml.
Example VIII
Suppositories containing 100 mg of active substance . .
Active substance 100.0 my Solid fat 1600.0 mq 1700.0 mg Pre~aration:
The hard fat is melted. At 40C the ground active substance is homogeneously dispersed in the melt. It is cooled to 38C and poured into slightly chilled suppository moulds.
. . , -.
-
, :1 , , ~
- , ' 20~8~09 g butylaminocarbonyl)-i~opropylamino, N-(n-bu~ylamino-carbonyl)-n-butylamino, N-(n-butylaminocarbonyl)-n-hexylamino, N-(n-butylaminocarbonyl)-cyclohexylamino, N-(di-(n-butyl)-aminocarbonyl)-amino, N-(di-(n-butyl)-aminocarbonyl)-methylamino, N-di-(n-butyl)-aminocarbonyl)-ethylamino, N-(di-(n-butyl) aminocarbonyl)-n-butylamino, N-(di-(n-butyl)-aminocarbonyl)-n-hexylamino, N (n-pentylaminocarbonyl)-ethylamino, N-(n-hexylaminocarbonyl)-ethylamino, n-hexylaminocarbonylamino, n heptylaminocarbonylamino, n-octylaminocarbonylamino, N-(n-hexylaminocarbonyl)-n-butylamino, N-(n hexylaminocarbonyl)-n-pentylamino, N-(n-hexylaminocarbonyl)-n-hexylamino, N-(n-hexylamino-carbonyl)-cyclohexylamino, di-(n~hexyl)-aminocarbonyl-amino, N-(di-(n-hexyl)-aminocarbonyl)-methylamino, N-((n-hexyl)-methylaminocarbonyl)-amino, cyclohexylamino-carbonylamino, N-cyclohexylaminocarbonyl-methylamino, N-cyclohexylaminocarbonyl-ethylamino, N-cyclohexylamino-carbonyl-n-butylamino, N-cyclohexylaminocarbonyl-isobutylamino, N-cyclohexylaminocarbonyl-n-pentylamino, N-cyclohexylaminocarbonyl-n-hexylamino, N-cyclohexylaminocarbonyl-cyclohexylamino, N-(ethyl-cyclohexylaminocarbonyl) methylamino, N-(propyl-cyclo-hexylaminocarbonyl)-methylamino, N-(n-butyl-cyclohexyl-aminocarbonyl)-methylamino, N-benzylaminocarbonyl-isobutylamino, 2(1H)-imidazolidinon-1-yl, 3-methyl-2(lH)-imidazolidinon-l-yl, 3-ethyl-2(lH)-imidazolidinon-l-yl, 3-n-propyl-2(1~)-imidazolidinon-1-yl, 3-isopropyl-2(lH)-imidazolidinon-1-yl, 3-n-bu~yl-2(lH)-imidazolidinon-1-yl, 3-isobutyl-2(lH)-imidazolidinon-1-yl, 3-n-pentyl-2(1H)-imidazolidinon-l-ylr 3-n-hexyl-2(lH)-imidazolidinon-l-yl, 3-cyclopentyl-2(lH)-imidazolidinon-1-yl, 3-cyclohexyl-2(lH)-imidazolidinon-1-yl, 3-cycloheptyl-2(lH)-imidazolidinon-1-yl, 3-benzyl-2~lH)-imidazolidinon-l-yl, 3-(3-hydroxybenzyl)-2(lH)-imidazolidinon-l-yl, 3-(4-hydroxybenzyl)-2(lH)-imidazolidinon-l-yl, 3-(3-methoxybenzyl)-2(lH)-~`' '~ ~ ' ' ' ,`
, ~"
20~8809 imidazolidinon l-yl, 3-(4-methoxybenzyl)-2(1H)-imidazolidinon-l-yl, 3-(3,4-dihydroxybenzyl)-2(1H)-imidazolidinon-1-yl, 3-(3,4-dimethoxybenzyl)-2(lH)-imidazolidonon-l-yl, 3-cyclopentylmethyl-2(lH)-imidazolidinon-1-yl, 3-cyclohexylmethyl-2(1~)-imidazolidinon-1-yl, 3-cycloheptylmethyl-2(lH)-imidazolidinon-l-yl, 3-(2-phellylethyl)-2(lH)-imidazolidinon-l-yl, 3-(2-cyclop~ntylethyl)-2(lH)-.~ imidazolidinon-l-yl, 3-(2-cyclohexylethyl)-2(lH)-imidazolidinon-l-yl, 3-(2-cycloheptylethyl)-2(lH)-imidazolidinon-l-yl, 3-(3-phenylpropyl)-2(lH)-imidazolidinon-~.-yl, 3-(3-cyclopentylpropyl)-2(1H)-imidazolidinon-1-yl, 3-(3-cyclohexylpropyl)-2(lH)-imidazolidinon-l-yl, 3-(3-cycloheptylpropyl)-2(lH)-imidazolidinon-l-yl, 3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-methyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-ethyl 3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-n-propyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-isopropyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl, 3-n-butyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-isobutyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-n pentyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-n-hexyl-3,4,5,6~tetrahydro-2(lH)-pyrimidon-l-yl, 3-cyclopentyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-cyclohexyl-3,4/~,6-tetrahydro-2( lH) -pyrimidon-l-yl, 3-cycloheptyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-(3-hydroxybenzyl)-3,4,5,6-tetrahydro-2(lH~-pyrimidon-1-yl, 3-(4-hydroxybenzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl, 3-(3-methoxybenzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl, 3-(4-methoxybenzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-(3,4-dihydroxybenzyl)-3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-(3,4-dimethoxy-benzyl)-3,4,5,6-tetrahydro-2(1~)-pyrimidon-1-yl, 3-cyclohexylmethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-cycloheptylmethyl 3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-(2-phenylethyl)-3,4,5,6-tetrahydro , . . .
~0488~9 ~ 1.1. --2(1H)-pyrimidon-1-yl, 3-(~-cyclopentylethyl)-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-(2-cyclohexylethyl)-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-(2-cycloheptylethyl)-3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-(3-phenylpropyl)-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-(3-cyclopentylpropyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-(3-cyclohexylpropyl)-3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-(3-cycloheptylpropyl)-3,4,5,6-tetrahydro-2(1~)-pyrimidon-1-yl, 2-chloroethylaminocarbonylamino, 3-chloropropyl-aminocarbonylamino, 2-bromoethylaminocarbonylamino, 3- -bromopropylaminocarbonylamino, (N-2-chloroethyl-methylaminocarbonyl)-amino, (N-2-bromoethyl-methylamino-carbonyl)-amino, (N-2-chloropropylmethylaminocarbonyl)-amino, tert.butylcarbonylamino, (N-2-bromopropyl-methylaminocarbonyl)-amino, 2-oxo-isoindolin-1-yl, 3-dimethylaminocarbonyl-2(1H)-imidazolidinon-l-yl, 3-diethylaminocarbonyl-2(lH)-imidazolidinon-l-yl, 3-di-n-propylaminocarbonyl-2(lH)-imidazolidinon-l-yl, 3-dimethylaminocarbonyl-3,4,5,6-tatrahydro-2(lH)-pyrimidon-l-yl, 3-diethylaminocarbonyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-diisopropylamino-carbonyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-chloro-propionylamino, ~-chloro-butanoylamino, 5-chloropentanoylamino, 6-chloro-hexanoylamino, 7-chloro-heptanoylamino, 3-hydroxy-propionylamino, 4-hydroxy-butanoylamino, 5-hydroxy-pentanoylamino, 6-hydroxy-hexanoylamino, 7-hydroxy-heptanoylamino, 2,2-dimethyl-propionylamino or tert.-butylamino group;
R2 may represent a hydrogen atom, a methyl, ethyl, n-propyl or isopropyl group;
R3 may represent a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobut:yl, tert.-butyl, n-pentyl, n-hexyl, 1-methylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-methylpentyl, 2-methylpentyl, 3-. , : .
- 20~8~09 methylpentyl, 4-methylpentyl, 1-ethylpropyl or 1,1-diethylethyl group;
R4 may represent a carboxy, cyano, lH-tetrazolyl, 1-triphenylmethyl-tetrazolyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n butoxycarbonyl, isobutoxycarbonyl or tert.-butoxycarbonyl group; and ~, may represent a hydrogen, fluorine, chlorlne or bromine atom.
Preferred compounds according to the invention include those of formula I wherein one or two o~ A1, A2, A3 and A4 represent a nitrogen atom and the remaining two or three of A1, A2, A3 and A4 each represent a methine group;
R1 represents a fluorine atom, an amino or C16-alkylamino group substituted at the nitrogen atom hy a phenyl, C57-cycloalkyl, phenyl(C13-alkyl) or (C57-cycloalkyl)C13-alkyl yroup, an amino group disubstituted by a phenyl, Cs7-cycloalkyl, phenyl(C13-alkyl) or (C57 cycloalkyl)C13-alkyl group which substituents may be identical or dif~erent, or an acylamino group optionally substituted at the nitrogen atom by a C16 alkyl group or by a phenyl, Cs7-cycloalkyl, phenyl(C13-alkyl) or (Cs7-cycloalkyl)C13-alkyl group, wher~in the acyl group is a C~7-alkanoyl group substituted in the terminal position by a chlorine atom or by a hydroxy group, a (C13-alkoxy)carbonyl group, a C16-alkylsulphonyl group, a formyl, benzoyl, benzenesulphonyl, phenyl(C13-alkanesulphonyl), naphthalenesulphonyl, 2-carboxy-cyclohexylcarbonyl, 2 aminocarbonyl-cyclohexylcarbonyl, ~C57 cycloalkyl)-:
20~8~09 carbonyl, phenylalkanoyl or (C57-cycloalkyl)C14-alkanoyl group, in which the above-mentioned phenyl nuclei is optionally mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy yroup which substituents may be identical or different, a C35-alkylsultam group, a pyrrolidino, piperidino or hexamethyleneimino group optionally substituted by a Cl3-alkyl or hydroxycarbonyl(Cl3-alkyl)group, a pyrrolidinone, piperidinone or hexamethyleneiminone group, an optionally wholly or partially hydrogenated phthalimido group or a group of formula l6 / R7 - N - CO - N
~in which R6, R7 and R8, which may be identical or different, represent hydrogen atoms, C18-alkyl groups, C~7-cycloalkyl, phenyl, (C57-cycloalkyl)C13-alkyl or phenyl(C13-alkyl) groups, and R8 may also represent a 2-chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3-bromo-propyl group, and where R6 and R7 together represent an ethylene or propylene group, R8 may also represent a di(C13-alkyl)aminocarbonyl group, or R6 and R7 together represent an ethylene or propylene group, and in which the phenyl nucleus of the above-mentioned phenyl and phenyl(C13-alkyl) groups may be mono- or disubstitutecl by hydroxy or C13-alkoxy groups which substituents may be identical or different];
, . , ~ : .: ,, .
:. . . . i ~ ~ . .:
-` 2~809 R2 represents a hydrogen atom or a C13-alkyl group;
R3 represents a C16-alkyl group;
R4 represents a carboxy, cyano, lH-tetra~olyl, l-triphenylmethyl-tetrazolyl group or a (C14-alkoxy)-carbonyl group; and R5 represents a hydrogen, fluorine, chlorine or bromine atom;
and the isomers and salts thereof especially the l-, 3-isomer mixtures, tautomers, enantiomers and addition salts thereof with organic or inorganic aaids or bases.
Particularly preferred compounds according to the invention include those of formula I wherein one or two of A1, A2, A3 and A4 represent a nitrogen atom and the remaining two or three of A1, A2, A3 and A4 each represent a methine group;
R1 represents an amino, methylamino or ethylamino group substituted by a cyclohexyl, cyclohexylmethyl, benzyl or : dimethoxybenzyl group, an amino, cyclohexylamino, cyclohexylmethyl or C14alkylamino group substituted by a C26-alkanoyl group, by a C14-alkanesulphonyl group, by a C24-alkoxycarbonyl group or by a cyclohexylcarbonyl, benzylcarbonyl, 2-aminocarbonyl-cyclohexylcarbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a C34-alkylsultam group, a pyrrolidino or piperidino group optionally substituted by a methyl or hydroxycarbonylmethyl group, a pyrrolidin-2-on-l-yl or piperidin-2-on-l-yl group, an optionally wholly hydrogenated phthalimido or 2-oxo-isoindolin-l-yl group or a group of formula \R8 . .
.
- .
. ~
2~8809 ~in which R6, R7 and R~, which may be identical or difEerent, represent hydrogen atoms, C14-alkyl groups, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, and R8 may also represent a 2 chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3-bromo-propyl group, and where R6 and R7 together represent an ekhylene or propylene group, R8 may also represent a dimethylaminocarbonyl group, or R6 and R7 together represent an ethylene or propylene group];
R2 represents a hydrogen atom or a methyl or athyl group;
R3 represents a C15-alkyl group;
R4 represents a carboxy or lH-tetrazolyl group; and Rs represents a hydrogen atom;
and the isomers and salts thereof, especially the l-, 3-isomer mixtures, tautomers, enantiomers and addition salts thereof with organic or inorganic acids or bases.
More particularly preferred compounds according to the invention include those of formula I wherein one or two of A1, A2, A3 and A4 represent a nitrogen atom and the remaining two or three of A1, A2, A3 and A4 each represent a methine group;
R1 represents an amino, methylamino or ethylamino group substituted by a cyclohexyl or cyclohexylmethyl group, a cyclohexylamino or cyclohexylmethylamino group substituted by a C26-alkanoyl group, by a C14-alkanesulphor1yl group, by a C24-alkoxycarbonyl group, by ; ~ :
2048~0g a benzylcarbonyl, 2-aminocarbonylcyclohexylcarbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a cyclohexylcarbonylamino group, a cyclohexylamino, cyclohexylmethylamino or C14alkylamino group substituted by a Cl4-alkanesulphonyl, cycl.ohexylcarbonyl, 2-aminocarbonyl-cyclohexyl-carbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a C34-alkylsultam group, a pyrrolidino or piperidino group substituted by a methyl or hydroxycarbonylmethyl group, a pyrrolidin-2-on-1-yl or piperidin-2-on-1-yl group, an optionally ~ully hydrogenated phthalimido or 2-oxo-isoindolin-l-yl group or a group of formula l6 / R7 [in which one of the groups R6, R7 or R8 represents a cyclopentyl, cyclohexyl or cyclohexylmethyl group, and the remaining groups R6, R7 or R8, which may be identical or different, represent hydrogen atoms, C14-alkyl groups, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, or R7 represents a 2 chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3-bromo-propyl group, and R6 and R8, which may be ~identical or different, represent hydrogen atoms, C14-alkyl groups, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, or R6 and R7 together represent an ethylene or propylene group, and R8 represents a hydrogen atom, a C14-alkyl group, a cyclohexyl, phenyl, cyclohexylmethyl, benzyl, : - :
:
' 2~8~9 methoxybenzyl, hydroxybenzyl, 2-ahloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl, 3-bromo-propyl or dimethylamino-carbonyl group];
R2 represents a hydrogen atom or a methyl or ethyl group;
R3 represents a C15-alkyl group;
R4 represents a carboxy or lH-tetrazolyl group; and R5 represents a hydrogen atom;
and the isomers and salts thereof, especially the 1-, 3-isomer mixtures, tautomers, enantiomers and addikion salts thereof with organic or inorganic acids or basss.
Although the present invention relates to new compounds of formula I, the corresponding cyano, alkoxycarbonyl and triphenylmethyl compounds, in particular, are valuable intermediates which can readily be converted to one of the pharmacologically active compounds and thus form further aspects of the present invention.
According to a still further aspect, the invention also provides a process for the preparation of compounds of the invention, said process comprising at least one of the following steps:
a) cyclising a compound of formula II
A 2~ ~1/
R 2~ ~ ( I I ) 3`AI Yl .
(wherein .
. - . ~.
, , .
., .
8 ~ ~
R1, R2, A1, A2l A3 and A" are as hereinbefore defined;
one of the groups X1 or Yl represents a group of formula Rg and the other group X1 or Y1 represents a group of formula Z1~ /Z2 R3 and Rs are as hereinbefore de.fined;
R~ represents a hydrogen atom or an R3CO group; and R3 is as hereinbefore defined;
Z1 and Z2~ which ~ay be identical or different, represent optionally substituted amino g:roups or hydroxy or mercapto groups optionally substituted by lower (eg. C16)alkyl groups, or Z1 and Z2 together represent an oxygen or sulphur atom, an imino group optionally substituted by a C13-alkyl group, or a C23-alkylenedioxy or C23-alkylenedithio group, with the proviso that one o~ the groups X1 or Y
must represent a group of formula R5 or \
C o R 3 - ~ ~ . f ., 20~o~
-- lg --NH - C - R~ ) or an N-oxide thereof and if necessary subsequently reducing the cyclized N-oxide;
b) reactiny a compound o~ formula III
R2_ ~ ~ ~ R3 (lll) (wherein R1, R2, R3, A1, A2, A3 and A4 are as hereinbefore defined) with a biphenyl compound of formula IV
(wherein R4 and R5 are as hereinbefore defined; and Z3 represents a nucleophilic leaving group such as a halogen atom, e~g. a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, e.g. a methanesulphonyloxy, phenylsulphonyloxy or p-toluenesulphonyloxy group);
c) (to prepare a compound of formula I wherein R4 represents a carboxy group) convarting a compound of .. : , . ~ . .
,~ , ' , ' ; '~ :
.. ~ .
20~8809 formula V
(wherein R1, R2, R3~ Rs~ A1, A2, A3 and A4 are as hereinbePore de~ined; and R4' represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound;
d) (to prepare a compound of formula I wherein R4 represents a lH-tetrazolyl group) cleaving a protecting group from a compound of formula VI
R
~ ~3 :
(wherein R1, R2, R3~ R5~ A1, A2, A3 and A4 are as hereinbefore defined; and R4" represents a lH-tetrazolyl group protected in the l-; ~ position by a protecting group);
:::
~, ~...... . . . . . .
- ;, . . . .
~, . ... , ~ .
~, . : , 2 ~
- 2.1 -e) (to prepare a compouncl o~ ~ormula I whereln R4 represents a lll-tetrazolyl group) reacting a compound of formula VII
R ,+ 3~ ~ ~, ( V I I
(wherein R1, R2, R3~ R5~ A1, A2~ A3 and A4 are as hereinbefore de~ined) with hydrazoic acid or a salt thereof;
f) (to prepare compounds of formula I wherein R1 represents an amino group optionally substituted by a (C16-alkyl) group or by a phenyl, C57-cycloalkyl, phenyl (C13-alkyl) or (Cs7-cycloalkyl)C13-alkyl group) converting a compound of formula VIII
CN ( V I I I ) ~`A
(wherein R2, R3, R4~ R5~ A1, A2, A3 and A4 are as hereinbefor~
defined; and R10 represents a group which can be converted by hydrolysis, hydrogenolysis or transamidation into an amino group optionally substituted by a Cl6-alkyl group or by a phenyl, Cs7~cycloalkyl, phenyl(C13-alkyl~ or :
.
20~88~9 (C5 7-cyClOal~yl) C13-alkyl group);
g) (to prepare compounds of formula I wherein R
represents a group of formula - N - cO - N
reacting a compound of formula IX
R s (wherein R2, R3~ R4~ R5, A1, A2, A3 and A4 are as hereinbefore defined; and ~: R11 represents an R6NH group, wherein R6 i5 as hereinbefore defined) with a compound of formula X
\ N - CO - Z4 (X) (wherein R7 and R8 are as hereinbefore defined;
Z4 represents a nucleophilic leaving group such as a : chlorine or bromine atom, or ~ Z4 together with R7 represents a nitrogen-carbon bond);
:
h) (to prepare compounds of formula I wherein R
:
::
.
:. , :
2~8~09 repre~ents an N-acylamino group optionally substituted at the nitroyen atom by a C16-alkyl, phenyl, cycloalkyl, phenylalXyl or cycloalkylalkyl group~ acylating a compound of formula XI
(wherein R2~ R3~ R4~ Rs~ A1~ A2~ A3 and A4 are as hereinbefore defined; and R12 represents an amino group optionally substituted by a C16-alkyl, phenyl, Cs7-cycloalkyl, phenyl(C13-alkyl) or (C57-cycloalkyl)C13-alkyl group) with a compound of formula XII
: R13 ~ W - OH (XII) (wherein W represents a carbonyl or sulphonyl group; and R13 represents a C16-alkyl group, a C13-alkoxy group, a phenyl(C13-alkyl), C5 7-cycloalkyl or (Cs 7-cycloalkyl)C1 3-alkyl group, a phenyl, naphthyl, 2-carboxy-cycloh~xyl or 2-aminocarbonyl-cyclohexyl group, in which the above-mentioned phenyl nuclei may be mono- or disubstitutPd by a fluorine, chlorine or bromine atom or by a methyl or methoxy group which substituents may be identical or different, o:r, if W represents a carbonyl group, R13 may also represent a hydrogen atom) or with a reactive derivative thereof, such as an acid halide, acid ester or acid anhydride;
... . .. .
- .
.
. : - . ~ .: . :
. .
, -. . , .
, . . . ~ :
20~L8~09 - 2~ -i) (to prepare a compou~d of formula I wherein ~6 and R7 together represent an ethylene or n-propylene group) cyclising a compound of formu:La XIII
, R~Z
H N~ ~R J ( X I I I ) H ~ I I C ~ 2 ) ~ \ ~ R 5 twherein 2~ 3, R4, R5, R8, A1, A2, A3 and A4 are as hereinbefore defined;
Hal represents a chlorine, bromine or iodine atom; and n represents the number 2 or 3) and if necessary subsequently reacting with a compound of formula XIV
R8 ~ Hal (~IV) (wherein R8 is as hereinbefore defined, with the exception of the hydrogen atom; and ~al represents a chlorine, bromine or iodine atom);
j) resolving a 1-, 3- isomer mixture of a compound of formula I by isomer separation into the 1- and 3-isomers thereof;
k) converting a compound of formula I into an addition salt thereof, more particularly, for pharmaceutical use into a physiologically acceptable salt thereof with an organic or inorqanic acid or base, or converting a salt of a compound of formula I into the free compound; and 1) performing a process as defined in any one of steps (a) to (k) above on a corresponding protected compound - , .
. . ~
20~8809 and subsequently removing the pro-tecting group used.
The cyclisation of step (a) may conveniently be carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycol-dimethylether, sulpholane, dimethylformamide, tetraline or in an excess of the acylating agent used to prepare the compound of formula II, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide. 1'he reaction is conveniently effected at temperatures between 0 and 250C, preferably at the boiling temperature of the reaction mixture, optionally in the presence o~ a condensing agent such as phosphorusoxychloride, thionylchloride, sulphurylchloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid/ phosphoric acid, polyphosphoric acid or acetic anhydride, or optionally in the presence of a base such as potassium ethoxide or potassium tert.-butoxide. However, cyclisation may also be carried out without a solvent and/or condensing agent.
It is particularly advantageous to carry out the reaction of step ~a) by preparing a compound of formula II in the reaction mixture by reducing a corresponding o-nitro-amino compoundt optionally in the presence of a carboxylic acid of general formula R3COOH, or by acyIating a corresponding o-diamino compound. When the reduction of the nitro group is broken off at the hydroxylamine stage, the N-oxide of a compound of formula I is obtained in the subsequent cyclisation.
The resulting N-oxide is then converted by reduction into a corresponding compound of formula I~ The subsequent reduction of the N oxide of formula I
obtained is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ,, . ~. , ~
- . .
. . . .
8 ~ 9 ethyl acetate or dimethylformamlde, with hydroyen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid such as acetic, hydrochloric or sulphuric acid, with salts such as iron(II)sulphate, tin(II)chloride or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 50C, preferably at ambient temperature.
The reaction of step (b) may conveniently be carried out in a solvent or mixture of solvents such as methylene chloride, diethylether, acetone, tetrahydrofuran, dioxane, dimethylsulphoxide, or benzene, optionally in the presence of an acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert.-butoxide, sodium hydride, triethylamine or pyridine, whilst the latter two may simultaneously also be used as solvent, conveniently at temperatures between 0 and 100C, preferably at temperatures between ambient temperature and 50C. A mixture of the 1- and 3- isomers is preferably obtained.
In step (c) functional derivatives of the carboxy group such as the optionally substituted amides, esters, thiolesters, orthoesters, iminoethers, amidines or anhydrides or the nitrile group may be converted by hydrolysis into a carboxy group, esters with tertiary alcohols, e.g. the tert.butylester, may be converted by thermolysis into a carboxy group and esters with aralkanols, e.y. the benzylester, may be converted by hydrogenolysis into a carboxy group.
The hydrolysis o~ step (cl may conveniently be carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trichloroacetic or trifluoroacetic acid or in the presence of a base such .
:: ~
.
.
.
- 27 - 2~8~09 as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10C and 120C, preferably at temperatures between ambient temperature and the boiling temperature of the reaction mixture. When the hydrolysis is carried out in the presence of an organic acid such as trichloroacetic or trifluoroacetic acid, any alcoholic hydroxy groups present may optionally simultaneously be converted into a corresponding acyloxy group such as the trifluoroacetoxy group.
If R4' in a compound of formula V represents a cyano or aminocarbonyl group, these groups may also be converted into the carboxy group with a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulphuric acid, which may simultaneously also be used as solvent, at temperatures between 0 and 50C.
If R4' in a compound of formula V represents for example a tert.-butyloxycarbonyl group, the tert.-butyl group may also be thermally cleaved, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as trifluoroacetic acid, p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, conveniently at temperatures between 40C and 100C, preferably at the boiling temperature of the solvent used.
If R4' in a compound of formula V represents for example a benzyloxycarbonyl group, the benzyl group may al~o be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, . .
:
, ~ ~ :
. ~ . .
~ :. i .
.
20~8809 - 2~ -dioxane or dimethyltormamide, preferably at temperatures between 0 and 50C, more preferably at ambient temperature, under a hydrogen pressure of 1 to 5 bar.
During hydrogenolysis, other group.s may be reduced at the same time, e.g. a nitro group may be reduced to the amino group, a benzyloxy group to the hydroxy group, a vinylidelle group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenyl-propionic acid group, or they may be replaced by hydrogen atoms, e.g. a halogen may be replaced by a hydrogen atom.
If R1 in a compound of formula V represents one of the above mentioned hydrolysable groups, it may be converted during the reaction into a corresponding amino compound.
Suitable protecting groups for use in step (d) include, for example, the triphenylmethyl, trimethyl tin, tributyl tin, triphenyl tin, propionic acid nitrile or p-nitrobenzyl groups. The cleaving of a protecting group used is preferably carried out in the presence of a hydrohalic acid, preferably in the presence of hydrochloric acid, in the presence of a base such as sodium hydroxide or alcoholic ammonia in a suitable solvent such as methylene chloride, methanol, methanol/ammonia, ethanol or isopropanol, conveniently at temperatures between 0 and 100C, preferably at ambient temperature or, if the reaction is carried out in the presence of alcoholic ammonia, at elevated temperatures, e.g. at temperatures between 100 and 150C, preferably at temperatures between 120 and 140C.
The reaction o~ step (e) is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at temperatures between 80 and 150C, preferably at 125C.
Appropriately, either the hydrazoic acid is liberated during the reaction from an alkali metal azide, e.g.
sodiu~ azide in the presence of a weak acid such as ammonium chloride, or the tetrazolide salt obtained in , , : :
: .` ~ ~ .
.
' .
20~809 - 29 ~
the reaction mixture from the reaction with a salt of hydrazoic acid, preferably with aluminium azide or tributyl tin azide, which is also preferably produced in the reaction mixture by reacting aluminium chloride or tributyl tin chloride with an alkali metal azide such as sodium azide, is subsequently liberated by acidification with a dilute acid such as 2N hydrochloric or 2N
sulphuric acid.
In the reagent of formula VIII used in step (f), acylamino groups, e.g. the val~eroylamino, benzoylamino or phthalimido group, may be converted by hydrolysis into an amino group, and imino groups, e.g. the phthalimino group, may be converted by transamidation into an amino group.
The hydrolysis of step (f) may conveniently be carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trichloroacetic or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/iso-propanol or water/dioxane conveniently at temperatures of between ~10C and 120C, preferably at temperatures between ambient temperature and the boiling temperature of the reaction mixture.
When hydrolysis is carried out in the presence of an organic acid such as trichloroacetic acid or trifluoroacetic acid, any alcoholic hydroxy groups present may simultaneously be converted into a corresponding acyloxy group such as the trifluoroacetoxy group. If R1o represents a phthalimido group, this group may, to particular advantage, be converted into an amino group in the presence of a primary organic base such as methylamine, ethylamine or propylamine or with hydrazine optionally in a suitable solvent such as methanol, ethanol, isopropanol, dimethyl~ormamide, methanol/di-' ~ ~ !. ; , , ' ~!
' - ' , ' :
' ':
.
1, , .
~, , g o 9 - 30 ~
methyl~ormamide or methanol/water by transamidation at temperatures between 0 and 50C, pre~erably at ambient temperature.
The reaction of step (g) is preferably carried out in a solvent such as tetrahydrofuran, dioxane, ethylene chloride or benzene, optional]y in the presence of an acid binding agent such as triethylamine or pyridine, conveniently at temperatures between 0 and 100C, preferably at temperatures bet:ween 20 and 80C.
Examples of reactive derivatives of a compound of formula XII in step (h) include, for example, the esters thereof such as the methyl, ethyl or benzylesters, the thioesters such as the methylthio or ethylthioesters, and the halides such as the acid chloride, the anhydrides or imidazolides thereof.
The reaction of step (h) may conveniently be carried out in a solvent or mixture of solvents such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide with a corresponding carboxylic acid in the presence of an acid-activating or dehydrating agent such as thionyl chloride, with the anhydrides thereof such as acetic acid anhydride, with the esters thereof such as ethyl acetate, with the halides thereof such as acetyl chloride or methanesulphonyl chloride, optionally in the presence of an inorganic or tertiary organic base such as sodium hydroxide, potassium carbonate, triethylamine or pyridine, whilst the latter two may simultaneously serve as solvent, conveniently at temperatures between -~5 and 100C, prefexably at temperatures between 10 and 80C.
The cyclisation of step (i) and, if necessary, the subsequent alkylation are expediently carried out in a solvent such as methanol, ethanol, benzene or , .' ' . ~
:
. :
~ ' ,' ' , 20~809 dimethylsulphoxide, optionally in the presence of a phase transfer catalyst such as benzyltriethylammonium bromide in the presence of an acid binding agent such as sodium hydroxide, sodium mekhoxide, sodium ethoxide, sodium hydride or potassium tert.-butoxide at temperatures between 20 and 100, preferably at temperatures between 30 and 70C.
The isomer separation of step (j) is preferably carried out by chromatography using a substrate such as silica gel or aluminium oxide.
The compounds of formula I obtained may, if desired, be converted into the acid addition salts thereof, more particularly ~or pharmaceutical use the physiologically acceptable salts thereof with organic or inorganic acids. Suitable acids for this purpose include hydrochloric, hydrobromic, sulphuric, phosphoric, fumaric, succinic, lactic, citric, tartaric and maleic acid.
Furthermore, the new compounds of formula I thus obtained, if they contain a carboxy or tetrazolyl group, may, if desired, subsequently be converted into the addition salts thereof with organic or inorganic bases, more particularly for pharmaceutical use into the physiologically acceptable addition salts thereof.
Suitable bases for this purpose include sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
Some of the compounds of formulae II to XIV used as starting materials are known from the literature.
Otherwise these compounds may be obtained by methods known from the literature.
Thus, for example, a compound of general formula II is :, :,, , :
. :- -.
- :
.
.
-20~8~
obtained by alkylation of a corresponding o-amino-nitro compound and subsequent reduction of the nitro group.
Compounds of formulae III, V, VI, VII, VIII, IX, XI or XIII used as starting materials are obtained by alkylation of a corresponding o-diamine or a corresponding o-amino-nitro compound, followed by reduction of the nitro group and subsequent cyclisation of an o-diamino compound thus obtained, or by NH-alkylation vf a corresponding lH-compound, whilst the isomer mixture thus obtained may subsequently be resolved by conventional methods, e.g. chromatography.
The new compounds of general formula I and the physiologically acceptable addition salts thereof have valuable pharmacological properties. They are angiotensin antagonists, in particular, angiotensin-II-antagonists. Compounds of formula I which are of particular value are those wherein R4 represents an alkoxycarbonyl, carboxy or lH-tetrazolyl group.
Thus in a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable addition salt thereof together with at least one pharmaceutical carrier or excipient.
In a still further aspect the present invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of cardiac insufficiency progression after myocardial infarct, or for the treatment of diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
.
.
. ~ ' 2~48~09 In a stil.l yet ~urther aspect the present invention provides a method of treatment of the human or non-human animal body to combat hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemi.a (angina), cardiac insufficiency progression a~ter myocardial infarction, diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering to said body a compound of formula I or a physiologically acceptable addition salt thereof.
By way of example, the following compounds:
A = 4~-[(2~n-butyl-5-methyl-6-phthalimido-3H-im.idazo-[4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylic acid;
B = 4'-[(2-n-butyl-5-amino-3H-imidaæo[4,5-b]pyridin-3-yl)mPthyl]biphenyl-2-carboxylic acid;
C = 4'-[(2-benzylamino-8-n-butyl-9H-purin-9-yl)-methyl]-biphenyl-2-carboxylia acid;
D = 4'-[[2-n-butyl-5-methyl-6-(cis-hexahydrophthal-imido)-3H-imidazo[4,5-b~pyridin-3-yl]methyl~-biphenyl-2-carboxylic acid;
E = 4'-[(2-n-butyl-5-cyclohexylamino-3H-imidazo~4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylic acid;
F = 4'-[[2-n-butyl-5-~N-cyclohexylcarbonyl-ethylamino)~
3H imidazo[4,5-b]pyridin-3-yl~methyl]biphenyl-2-carboxylic acid;
G = 4'-[(2-n-butyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2-(lH-tetrazol-5-yl)biphenyl;
, , .. ~ :
-, :~ :- , .
, 20~09 - 3~ -H = 4'-[[2-n-butyl-5-(3-benzyl-3,4,5,6-tetrahydro-2[1H)-pyrimidinon l-yl)-3H-imidazoC4,5-b]pyridin-3-yl]
methyl]-biphenyl-2-carboxylic acid;
I = 4'-[(2-n-propyl-5-cyclohexylcarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2-~lH-tetrazol-5-y])biphenyl;
J = 4'-[[~-ethyl-5-t2,2-dimethyl-propionylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; and K = 4'-[[2-n-propyl-5-t2-methyl-propylamino)-3H-imidazo-[~,5-b]pyridin-3-yl~-methyl]-2-(lH-tetrazol-5-yl)-biphenyl were tested for their biological effects as follows:
Rats (male, 180-220 g) are anaesthetised with sodium hexobarbital (150 mg/kg i.p.). After they have become unconscious, a tracheal cannula is inserted, the animals are pithed and then immediately artificially respirated with a ventilator pump. The arterial blood pressure is recorded by means of a cannula in the carotid artery using a Bell & ~owell pressure recorder. The substances are administered in the jugular vein through a cannula.
Test substances are administered in three doses (10, 20 and 30 mg/kg i.Y. ), with one dose of substance being tested on each animal. Three minutes after the intravenous administration of the test substance, angiotensin-II is administered intravenously in increasing doses and in this way a cumulative dose-activity relationship is achieved for angiotensin-II in the presence of the test substances. The increase in arterial blood pressure is measured.
.
:~ .. . l ~ . . , :
~:: . : ' : ! , 20~8809 These dose activity cuxves are compared with standard curves for angiotensin-II without the use of any test substances. Using a computer program, the shifts to the right in the dose-activity curves for angiotensin-II
as a result of the administrat:ion of the test su~stances are determined and corresponding pA2-values are calculated for the test substances.
The PA2 values of the above-mentioned test compounds A to K are between 5.1 and 7.9.
Moreover, when the above-mentioned compounds were administered in a dose of 30 mg/kg i.v. no toxic side effects, e.g. negative inotropic effects or heart rhythm diosorders, were observed. Accordingly, the compounds are well tolerated.
The new compounds and their physiologically acceptable addition salts are suitable for their treatment of hypertension and cardiac insufficiency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
The new compounds and the physiologically acceptable addition salts thereof are also suitable for treating pulmonary diseases, e.g. lung oedema and chronic bronchitis, for preventing arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy. In view of the effects of angiotensin on the release of acetyl choline and dopamine in the brain, the new angiotensin antagonists are also suitable for alleviating central nervous system disorders, e.g. depression, Alzheimer's . : , , , , ~ , ~ , .
.. . .
- .. ~ : , .
. .. . . ' i, , :
';
. .
2~L8809 disease, Parkinson syndrome, bulimia and disorders of cognitive function.
The dosage required to achieve these effects is conv~niently, when administered intravenously, 20 to 100 mg, preferably 30 to 70 my, and, when administered orally, 50 to 200 mg, preferably 75 to 150 mg, 1 to 3 times a day. For this purpose, the compounds of formula I prepared accordirg to the invention, optionally in conjunction with other active substances, may be incorporated together with one or more inert conventional carriers and/or diluents, for example with corn starch, lactose, g~ucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene-glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The following non-limiting Examples are provided to illustrate the invention. Unless otherwise specified all percentages and ratios given are by weight.
, , , ,, :
- . .
.: .
~0~809 Example A
2-n-Butyl-7-methyl-imidazo[4,5-b]pyridine .
3.Ç g (29 mMol) of 2,3-diamino-4-methyl-pyridine and 3 ml of valeric acid are refluxed for 2 hours in 30 ml of phosphorusoxytrichloride. The reaction mixture is evaporated down in vacuo and the residue is mixed with 100 ml of ice water. By adding 20% sodium hydroxide solution, the mixture is neutralised and then extracted twice with 100 ml o~ ethyl acetate. After drying over magnesium sulphate and evaporation of the solvent, an oil is obtained.
Yield: 4.8 g (87% of theory), Rf value: 0.40 tsilica gel, eluant: ethylmethylketone/
xylene - 1:1 by volume) C11H1sN3 (l89.26) Calculated: C 69.81 H 7.99 N 22.20 Found: 69.60 7.91 21.96 The following compounds are obtained analogously:
8-n-butyl-2-benzylamino-purine Oil, ~f value: 0.55 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) 8-n-butyl-2-n-butylamino~purine Melting point: 111-114C
8-n-butyl-2-cyclohexylamino-purine Oil, Rf value: 0.60 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) 8-n-butyl-2~ethoxy-purine Melting point: 181-182C
8-n-butyl-2~methoxy-purine Melting point: 166C
, `:
2~48809 8-n-butyl-purine Melting poi.nt~ 17~ 0C
2-n-butyl-5-bromo-imidazo[4,5-b]pyridine Melting point: 223-225C
Example B
2-n-Butyl-5-va.leroylamino-imidazo[4,5-b]pyridine Prepared from 2,6-bis(n-pentanoylamino)-3-nitro-pyridine analogously to Example 1.
Yield: 83% o~ theory, Melting point: 148-150C
The following compounds are obtained analogously:
2-n-butyl-5-dimethylamino-imidazo[4,5-b]pyridine Melking point: 128-129C
2-n-butyl-5-methyl-6-amino-imidazo[4,5-b]pyridine Oil, Rf value: 0.23 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) 2-n-butyl-6-amino-imidazo[4,5-b]pyridine Oil, Rf value: 0~15 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90lO:1 by volume) Example C
2-n-Butyl-5-(cis-hexahydrophthalimido~-imidazor4,5-b]-pyridine Prepared by reacting 2-n-butyl-5-amino-imidazo[4,5-b]-pyridine with cis-hexahydrophthalic acid anhydride analogously to ~xample 4.
Yield: 63~ of theory, Oil, Rf value: 0.50 (silica gel; eluant: methylene , , j .
. : .
. ` ~ ' . ' , ~' .
. .
chloride/ ethanol = 9:1 by volume) The following compounds are obtained analogously:
2-n-butyl-5-methyl-6-phthalimido imidazo[4,5-b]pyridine Oil, Rf value: 0.77 tsilica ge:L; eluant: methylene chloride/ethano:L = 19:1 by volume) 2-n-butyl-6-phthalimido-imidazot4,5-b]pyridine Oil, Rf value: 0.68 (silica ge:L; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) 2-n-propyl-5-(2,2-dimethylpropionylamino)-imidazo-[4,5-b]pyridine Oil, Rf value: 0.42 (silica gel; eluant: ethyl acetate/petroleum ether = 1:1 by volume) 2-n-propyl-5-cyclohexylcarbonylamino-imidazo[4,5-b]-pyridine Oil, Rf value: 0.67 (silica gel; eluant: e~hyl ~cetate/petroleum ether = 1:1 by volume) - . - .. ..
~ . . . .
.., :: : ' :' ' - 20~8~09 ~ 40 ~
Example 1 Tert.-butyl 4'~[(2-n-butyl-5-methylamino-3H imidazo-[4,5-b]pyridin-3-yl)-methyl]b,iphenyl-2-carboxylate , . _ 1.8 g (3.5 mMol) of 2-[N-~-(2-tert.butoxycarbonyl-phenyl)benzyl-N-pentanoylamino]-3-nitro-6-methylamino-pyridine are dissolved in 200 ml of ethanol, mixed with 1.0 g of 10% palladium on activated charcoal and hydrogenated for 2 hours at ambient temperature under 5 bars of hydrogen pressure. After the uptake of hydrogen has ended the catalyst is filtered off and the residue is concentrated by evaporation. The residue is dissolved in ~0 ml of glacial acetic acid and heated for 30 minutes over a steam bath. Then the reaction mixture is evaporated down, the residue i5 dissolved in 100 ml of ethyl acetate and washed with saturated sodium hydrogen carbonate solution and with saturated sodium chloride solution. After drying over magnesium sulphate, evaporation of the solvent and column chromatography on silica gel ~particle size:
0.06-0.2 mm, eluant: petroleum ether/ethyl acetate = 1:1 by volume) a colourless oil is obtained.
Yield: 1.4 g (86~ of th~ory), Oil, hf value: 0.27 (silica gel; eluant: petroleum ether/ethyl acetate = l:l by volume) C29H34N4O2 (470.61) Calculated: C 74.01 ~ 7.28 N 11.91 Found: 73.86 7.35 12.13 The following compounds are obtained analogously:
tert.butyl 4'-[(2-n-butyl-5-cyclohexylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.45 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4l_~(2-n-butyl-5-n-butylamino-3H-imidazo-.
, .
:` :
.
,~ .
: i .
, 20~8809 ~1 --[4,5-b]pyridin~3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.43 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-~(2-n-b~tyl-5-ethylamino-3H-imidazo-t4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate Oil, Rf value: 0.3~ (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-[(2-n-butyl-5-cyclohexylmethylamino-3H~
imidazo[4,5-b]pyridin-3--yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.48 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) 4'-[[2-n-propyl-5-(2-methylpropylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl Melting point: 132-135C
tert.butyl 4'-[[2-n-butyl-5~(2,4-dimethoxybenzyl~amino-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylate Oil, Rf value: 0.40 (si~ica gel; eluant: petroleum ether/ethyl acetate - 1:1 by volume) tert.butyl 4'-[(2-n-butyl-5-benzylamino-3H-imidazo-[4,5-b~pyridin-3-yl)~methyl]biphenyl-2-carboxylate Oil, Rf value: 0.36 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-[(2-n-butyl-5-methoxy-lH-imidazo[4,5-b~-pyridin-l-yl)methyl]biphenyl-2-carboxylate Oil, Rf valueo 0.44 (silica gel; eluant: ethylmethyl-ketone/xylene = 1:2 by volume~
4'-C[2-n-butyl-5-(4-methyl-piperidino)-3H-imidaæo-[4,5-b]pyridin-3-ylJmethyl]-2-(1-triphenylmethyl-",, ~ . .
, 21~8~0g tetrazol-5-yl)-biphenyl Melting point: 147-149C
Example 2 Tert.butyl 4'-[(2-n-butyl-5-vaLeroylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylate (I) and Tert.butyl ~'-[(2-n-butyl-5-vaLeroylamino-lH-imidazo-r4 / 5-b]pyridin-1-yl)methyl]-biphenyl-2-carboxylate (II) 8.9 g (10.6 mMol) of 2-n-butyl-5-valeroylamino-3H~
imidazo[4,5-b]pyridine are dissolved in 400 ml of acetone, mixed with 7.3 g (53 mMol) of potassium carbonate and with 5.5 g (15.9 ~ol) of tert.butyl 4'-bromomethyl-biphenyl-2-carboxylate and refluxed for 6 hours with stirring. The reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is purified over a silica gel column (particle size:
0.063-0.2 mm), using a mixture of petroleum ether and ethyl acetate in the ratio 3:1 by volume as eluant. The uniform fractions are evaporated to dryness and triturated with diethylether. The solids thus crystallised are washed with ether and dried.
I: Yield: 4.2 g ~73% of theory), Melting point: 102-104C
C33H39N403 (539.70) Calculated: C 73.20 H 7.46 N 10.36 Found: 73.18 7.7210.19 II: Yield: 1.1 g (20% of theory), Melting point: 107-108C
C33H39N403 (539.70) Calculated: C 73O20 H 7.46 N 10.36 Found: 73.14 7.4410.38 The ~ollowing compounds are obtained analogously:
~ ~ .
. . .
; ~ .
.
~88~9 tart.b~tyl 4'-C(2-n~propyl-5-butanoylamino 3~1-imidazo-[4,5-b]pyridirl-3-yl)methyl~biphenyl-2--carboxylate Melting point: 157-158C
tert.butyl 4'-[(2-n-propyl-5 butanoylamino-lH-imidazo-[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylate Amorphous, Rf value: 0.38 (silica gel, eluant: ethyl acetate) tert.butyl 4'-[(2-n-propyl-5-butanoylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-4-bromo-2-carboxylate Oil, Rf value: 0.40 (silica gel; eluant: methylene chloride/ethanol = ~9:1 by volume) tert.butyl ~'-[(2-n-butyl-5-dimethylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.37 ~aluminium oxide; eluant: ethyl acetate/petroleum ether = 1:1 by volume) tert.butyl 4'-[(2-n-butyl-5-bromo-3H imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.55 (silica gel; eluant: methylethyl-ketone/xylene = 1:2 by volume) tert.butyl 4'-[(2-n-butyl-5-bromo-lH-imidazo[4,5-b]-pyridin-l-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.20 (silica gel; eluant: methylethyl-ketone/xylene = 1:2 by volume) :
tert.butyl 4'-[(2-n-butyl-5-methyl-6-phthalimido-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.52 (silica gel; eluant: methylethyl-ketone/xylene = 1:4 by volume) tert.butyl ~'-[(2-n-butyl-5-methyl-6-phthalimido-lH-imidazo[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylate - - , . .
.
: :
,. ~ , 20~0g Oil, Rf value: 0.18 (silica gel; eluant: methylethyl-ketone/xylene = ~:1 by volume) tert.butyl ~'-[(2-n-butyl-6-phthalimido-3H-imidazo-[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate Oil, Rf value: 0.62 (silica gel; eluant: methylethyl-ketone/xylene = 1:1 hy volume) terk.butyl 4'-[(2-n-butyl-6-phthalimido-lH-imidazo-t4,5-b]pyridin-1-yl)-methyl]biphenyl-2-carboxylate Oil, Rf value: 0.43 (silica ge:L; eluant: methyl~thyl-ketone/xylene = 1:1 by volume) tert.butyl 4'-~(2-n-buty]-6-hexahydrophthalimido-3H-imidazo[4,5-b~pyridin-3-yl)-methyl]biphenyl-2 carboxylate Oil, Rf value: 0.58 (silica gel; eluant: methylethyl-ketone/xylene = 1:1 by volume) tert.butyl 4'-[(2-n-butyl-6-hexahydrophthalimido-lH-imidazo[4,5-b]pyridin-1-yl)-methylJbiphenyl-2-carboxylate Oil, Rf value: 0.31 (silica gel; eluant: methylethyl-ketone/xylene = 1:1 by volume) 4'-[[2-n-butyl-5-(cis-hexahydrophthalimido)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl Oil, Rf value: 0.45 (silica gel; eluant: ethyl acetate) tert.butyl ~'-[(2-benzylamino-8-n-butyl-9H-purin-9-yl)-methyl]biphenyl-2-carboxylate Oil, Rf value: 0.45 (silica gel; eluant: ethyl acetate) mathyl 4'-[(2-n-butylamino-8-n-butyl-9H-purin-9-yl)methyl]biphenyl-2-carboxylate Melting point: 125-126C
~,, ' ....................................... . .
8 ~ 9 - ~5 -methyl 4'-C(2-cyclohexylamino-8-n-butyl 9H-purin-9-yl)-methyl]biphenyl~2-carboxylate Oil, Rf value: 0.52 (silica gel; eluant: methylene chloride/ethanol = 95:5 by volume) methyl 4'-t(2-ethoxy-8 n-butyl-9H-purin-9-yl)methyl]-biphenyl-2-carboxylate Oil, Rf value: 0.55 (silica gel; eluant: methylene chloride/ethanol - 95:5 by volume) methyl 4'-[(2-methoxy-8-n-butyl-9H-purin-9-yl)methyl]-biphenyl-2-carboxylake Oil, Rf value: 0.50 (silica gel; eluant: methylene chloride/ethanol = 95:5 by volume) 4'-[[2-n-propyl-5-(2,2-dimethylpropionylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl~-2-(lH-tetrazol-5-yl)-biphenyl Melting point: 177-178C
4'-[(2-n-propyl-5-cyclohexylcarbonylamino-3H-imidazo-~4,5-b~pyridin-3-yl)methyl]-2-tlH-tetrazol-5-yl)biphenyl Melting point: 183-184C
Example 3 Tert.butyl 4'-t(2-n-butyl-5-amino-3H-imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylate 3.4 g (6.3 mMol) of ~ert.butyl 4'-[(2-n-butyl-5-valeroylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylate are dissolved in 75 ml of ethanol, mixed with 35 ml o~ 2N sodium hydroxide solution and heated to 80C for 8 hours with stirring.
The reaction mixture is concentrated by evaporation, taken up in ethyl acetate and extracted with water. The aqueous phase is re~extracted twice with about 100 ml of ethyl acetate. The organic phases are combined, washed , . . . ~ . . ~ : , .: . .
, ~, , , : : -, : :
.
-', ~ ': ' . ' '' ;. ' '~
%~8~9 - ~6 -with saturated saline solution and dried over maynesium sulphate. After evaporation of the solvent the residue is crystallised by triturating with pet~oleum ether.
Yield: 2.1 g (73% of theory), Melting point: 112-124C
C2~H32N42 (456.59) Calculated: C 73. 66 H 7.07 N 12.21 Found: 73.72 7.20 12.12 The following compounds are obtained analoyously:
tert.butyl 4'-[(2-n-propyl-5-amino-3H-imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.50 (silica gel; eluant: ethyl acetate) tert.butyl 4'-[(2-n-butyl-5-methyl-6-amino-3H-imidazo-~4,5-b]pyridin-3-yl)methyl~biphenyl-2 carboxylate Oil, Rf value: 0.56 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) tert.butyl 4'-[(2-n-butyl-5-methyl-6-amino-lH-imidazo-[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.48 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) Example 4 4'-[[2-n-Butyl-5-(N-acetyl-cyclohexylamino~-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid . ~
0.3 g (0.62 mMol) of 4'-[~2-n-butyl-5-cyclohexylamino-3H-imidazo[4,5-b]pyxidin-3-yl)methyl]biphenyl-2-carboxylic acid are dissolved in 3.0 g (38 mMol) of acetyl chloride and refluxed for 2 hours. The reaction mixture is evaporated down, the residue is mixed with water and neutralised with aqueous ammonia solution.
The precipitate formed after acidification with glacial acetic acid is suction filtered, washed with water and . . : . . , ' .
" ''' . ' = ' ,i . ' . ' . ' . .
, ~ ' ' ~ ',' ' ~0~8809 dried.
Yield: 0.22 g (68% of theory), Melting point: 121-123C
C3zH36N4O3 (524-67) Calculated: c 73.26 H 6.92 N 10.68 Found: 72.43 6.93 10.96 The following compounds are obtained analogously:
tert. butyl 4'-[(2 n-propyl-5-]benzylcarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.36 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-[[2-n-butyl-5-(cis-hexahydrophthalimido)-3H-imidazo[4,5-b]pyridin-3-yl~methyl]biphenyl-2-carboxylate Oil, Rf value: 0.66 (silica gel; eluant: ethyl acetate) tert.butyl 4'-[[2-n-butyl-5-tN-acetyl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.21 (silica gel; eluant: petr~leum ether/ethyl acetate = 1 1 by volume) tert.butyl 4'-[[2-n-butyl-5 tN-ethoxycarbonyl ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate Oil, Rf value: 0.45 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-[[2-n-butyl-5-~N-cyclohexylcarbonyl-ethylamino~-3H~imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate Oil, Rf value: 0.34 ~silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-[[2-n-butyl-5 N-[(2-methyl-propionyl)-n-` ~ , : ' ` :
: . , ;. ::
' , .
~0~8~9 butylamino]-3H-imidaæo[4,5-b~pyridin-3-yl]methyl]-biphenyl-2-carboxylate Oil, Rf value: 0.48 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-[[2-n-butyl-5~(N-ethoxycarbonyl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2~carboxylate Oil, Rf value: 0.53 (silica gel; eluant: petroleum ether/ethyl acetate - 1:1 by volume) tert.butyl 4'-[(2-n-butyl-5-methyl-6-dimethylamino-carbonylamino-lH-imidazo[4,5-b]pyridin-1-yl)methyl]-biphenyl-2-carboxylate Amorphous, Rf value: 0.55 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:20:2 by volume) tert.butyl 4'-[(2-n-butyl-5-methyl-6-dimethylaminocarbonylamino-3H-imidazot4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate Amorphous, Rf value: 0.50 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) tert.butyl 4'-[[2-n-butyl-5-methyl-6-tN-ethyl-cyclohexylcarbonylamino)-3H-imidazo[4,5-b]pyridin 3-yl]methyl]biphenyl-2-carboxylate Oil, R~ value: 0.46 (silica gel; eluant: methylene chloride/ethanol = 19:1 by volume) tert.butyl 4l-[[2-n-butyl-5-methyl-6-(5-chloropentanoyl-amino)-lH-imidazo[4,5-b]pyridin-1-yl]methyl]biphenyl 2-carboxylate Oil, Rf value: 0.63 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) tert.butyl 4'-[~2-n~butyl-5-methyl-6-(N-acetyl-n-butylamino)-3H-imidazo[4,5~b]pyridin-3-yl]methyl]-., , ;
.
.': ; ' ,~ , . .
~8~09 biphenyl-2-carboxylate Oil, Rf value: 0.48 (silica yel; eluant: methyl ketone/ethanol = 1:2 by volume) tert.butyl 4'-[[2-n-butyl-5 (4-chlorophenylsulphonyl-amino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.39 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Exam~e 5 4'-~[2-n-Butyl-5-(N-acetyl-cyclohexylmethylamino~-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid .. _ ~ .. . . . . _ .. .
Prepared analogously to Example 4 ~rom 4'-[(2-n-butyl-5-cyclohexylmethylamino-3~-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid and acetylchloride.
Yield: 93% of theory, Melting point: 180-185C
C33H38N403 (538.20) Calculated: C 73.58 H 7 .11N 10 . 40 Found: 73.56 7.37 10.46 ~ml2~
4'-t(2-n-Butyl-5-propionylamino-3~-imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl-2~carboxylic acid . .. ..... _ _ Prepared analogously to Example 4 from 4'-[(2-n-butyl-5-amino-3H-imidazo[4,5-b]pyridin 3-yl)methyl]biphenyl-2-carboxylate and propionic acid anhydride.
Yield: 66% o~ theory, Melting point: 278-281C
C27H28N4o3 ~456.55) Calculated:C 71.03H 6.18 N 12.27 Found:70.86 6.23 12.40 , :
.. . , :
.
: ' - ~ ..
20~g809 Example 7 4'-[[2-n-Butyl-5-(2-mekhylpropionylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid .
Prepared analogously to Example 4 from 4'-t(2-n-butyl-5-amino-3H imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid and isobutyric acid chloride.
Yield: 49~ of theory, Meltiny point: 250C
c28H30Nh3 (~30.58) Calculated: C 71.47 H 6.43 N 11.91 F'ound: 71.26 6.31 11.66 Example 8 Tert.butyl 4'-[~2-n-butyl-5-(N-(3-chloropropylamino-carbonyl)-amino)-3H-imidazoC4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate 1.3 g (2.9 mMol) of tert.butyl 4'-t(2-n-butyl-5-amino-3H-imidazo~4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate are dissolved in 10 ml of dimethylformamide, mixed with 1.4 g (12 mMol) of 3-chloropropylisocyanate and stirred for 40 hours at ambient temperature. After the addition of 200 ml of ice water the mixture is extracted twice with 100 ml of ethyl acetate. After drying over magnesium sulphate the solvent is evaporated and the residue is triturated with ether. The precipitate formed is suction filtered and dried.
Yield: 1.5 g (90% of theory), Melting point: 207-209C
C32H38ClN503 (646-17) Calculated: C 66.71 H 6.65 N 12.16 Found: 66.71 6.72 12.47 The following compounds are obtained analogously:
.
: ' ` ~' 20~8~9 tert.butyl 4'-[~2-n-propyl-5- (N- ( 3 -chloropropylamino-carbonyl)-amino) 3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carbo~ylate Oil, Rf value: 0~20 (silica gel; eluant: ethyl acetate) tert.butyl 4'-[[2-n-butyl-5-(N-cyclohexylaminocarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate Oil, Rf value: 0.30 (silica gel; eluant: ethyl acetate~petroleum ether = 1:1 by volume) tert.butyl 4'-[[2-n-butyl-5-(N-cyclohexylaminocarbonyl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate Oil, Rf value: 0.55 (silica gel; eluant: ethyl acetate/petroleum ether = 1:2 by volume) tert.butyl 4'-[[2-n-butyl-5-methyl-6-[N-(3-chloro-propylaminocarbonyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.58 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) 4'-[[2-n-propyl-6-(N-benzylaminocarbonyl-isobutylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(l triphenyl-methyl-tetrazol-5-yl)biphenyl Oil, Rf value: 0.67 (silica gel; eluant: methylene chloride/ethanol = 19:1 by volume) 4'~[[2-n-propyl-5-(N-cyclohexylaminocarbonyl-isobutyl-amino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl Oil, Rf value: 0.62 (silica gel; eluant: methylene chloride/ethanol = 19:1 by volume) , .
Example 9 4'-[(2 n-Butyl-5-cyclohexylaminocarbonylamino-3~-imidazo[4~5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 8 fr~m 4'-[(2-n-butyl-5-amino-3H-imida~o[4,5-b]pyridin-3~yl)methyl]biphenyl-2-carboxylic acid and cyclohexylisocyanate.
Yield: 46% of theory, Melting point: 287-291C
C31H3sNsO3 (525.66) Calculated: C 70.83 H 6.71 N 13.32 Found: 69.01 6.66 13.18 Example 10 Tert.butyl 4'-[[2-n-butyl-5-(3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin 3-yl]methyl]-biphenyl-2-carboxylate . ~
0.26 g (5.3 mMol) of sodium hydride are dissolved in 20 ml of tert.butanol. After 5 minutes at ambient temperature, 0.58 g (1.0 mMol) of tert.-butyl 4'-[r2-n-butyl-5-(N-(3-chloropropylaminocarbonyl)-amino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate are added in batches~ The mixture is stirred for 10 hours at ambient temperature~ By adding 2N hydrochloric acid the pH is adjusted to 5 and the tert~-butanol is evaporated off in vacuo. The residue is stirred with 100 ml of ethyl acetate and 100 ml of water, the organic phase is separated off and the aqueous phase is extracted twice with 50 ml of ethyl acetate. The combined organic phases are washed with saturated saline solution and dried over magnesium sulphate. After evaporation of the solvent the residue is triturated with ether, the precipitate formed is suction filtered and dried.
, ~ ~
: . ~ ' " ' :
:.~
~0488~9 :. - 53 -Yield: 0.~ g (7~6 of theory), Rf value: 0.33 (s.ilica gel; eluant: ethyl acetate/ethanol = 9:1 by volume) C32H37Ns3 (539-~8) Calculated: c 71.22 H 6. 91 N 12.98 Found: 70.99 6 . 98 12 . 81 The following compounds are obtained analogously:
tert.butyl ~'-[[2-n-propyl-5-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate Melting point: 175C
;
tert.butyl 4'-~[2-n~butyl-5-methyl 6-(3 t 4 ~ 5, 6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo[~,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylate ~elting point: 200-202C
tert.hutyl 4'-[[2-n-butyl-5-methyl-6-(2-oxo-piperidin-1-yl)-lH-imidazo[4,5-b]pyridin-1-yl]methyl]biphenyl-2-carboxylate Rf value: 0O49 (silica gel; eluant: methylene chloride/
ethanol = 9:1 by volume) tert.butyl 4'-~2-n-butyl-5-methyl-6-(n-butanesultam-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Rf value: O.S0 (silica gel; eluant: methylene chloride/
ethanol = 19:1 by volume) tert.butyl 4'-[[2~n-butyl-5-methyl-6 (2-oxo-piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl3biphenyl-2-carboxylate Rf value: 0.60 (silica gel; eluant: methylene chloride/
ethanol = 19:1 by volume) ' ~
~ , , , .
' 20~8809 Example 11 Tert.butyl 4'-[[2-n-butyl-5~(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidin~n-1-yl)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylate 0.4 g (0.74 mMol) of tert.butyl 4'-[r2-n-butyl-5-(N-(3-chloropropylaminocarbonyl)-amino)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylate are suspended in 20 ml of dimethylformamide and mixed with 0.04 g (0.85 mMol) of sodium hydride. The mixture is stirred for 10 minutes at 60C, 0.5 ml (4.25 mMol) o~
benzylbromide are added and the resulting mixture is stirred for 3 hours at ambient temperature. The reaction mixture i~ poured onto ice and extracted twice with 100 ml of ethyl acetate. The combined organic phases are washed with saturated saline solution and ~ried over magnesium sulphate. A~ter the solvent has been evaporated, a colourless oil is obtained.
Yield: 0.35 g (75% of theory), Rf value: 0.41 (silica gel; eluant: methylene chloride/ethyl acetate = 1:1 by volume) Mass ispectrum: M~ = 629 The following compounds are obtained analogously:
tert.butyl ~'-[[2-n-butyl-5-(3-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.41 (silica gel; eluant: ethyl acetate/ethanol = 9:1 by volume) tert.butyl 4'-[[2-n-butyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.44 (silica gel; eluanto methylene chloride/ethanol = 19:1 by volume) . :: .
~;
': ~ ' ' :
.
2~488(19 Example 12 4'-[[2-n-Butyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-oiphenyl-2-carboxylic acid 0.35 g (0.55 mMol) of tert.butyl 4'-[[2-n-butyl-5-~3-benzyl-3,4,5,6-tetrahydro-2~lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl~methyl]-biphenyl-2-carboxylate are dissolved in 10 ml of methylene chloride and mixed with 5 ml of trifluoroacetic acid. The mixture is stirred for 65 hours at ambient temperature.
The solvent is evaporated off, the residue is taken up in ice water and acidified with ylacial acetic acid.
The precipitate thus formed is filtered off, washed with water and dried at 60C.
Yield: 0.26 g (82% of theory), Melting point: 168-170C
C35H3sNsO3 (573-70) Calculated: C 73.28 H 6.15 N 12.21 Found: 73.37 6.51 12.12 Example 13 4'-[[2-n-Butyl 5-(3-methyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylic acid . _ . _ Prepared analogously tn Example 12 from tert.butyl 4'-E ~ 2-n-butyl-5-(3-methyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b~pyridin-3-yl]methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 64% of theory, Melting point: 249-252C
Cz9H31NsO3 (497.60) Calculated: C 70.00 H 6.28 N 14.00 Found: 69.85 6.40 13.89 .
':
20~8809 Example 14 4'-[[2-n-Butyl-5-(3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Exampl~e 12 from tert.butyl 4'-[[2-n-butyl-5-(3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 80% of theory, Melting point: 300-302C
C28H29NsO3 (483.58) Calculated: C 68.27 H 6.14 N 14.22 Found: 68.47 6.11 14.28 ,Example 15 4'-[[2-n-Propyl-5-(3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo[4,5-b~pyridin-3-yl]methyl]biph~nyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-propyl-5-(3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 92% of theory, Melting point: 265-268~C
C27H27N503 (46g.55~
Calculated: C 69.07 H 5.80 N 14092 Found: 68.87 5.78 15.00 Example 16 4'-[(2-n-Butyl-5-cyclohexylmethylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl~2-carboxylic acid .
Prepared analogously to Example 12 ~rom tert.butyl 4'-.. . . . . . ..
. ~ : . ~ . ...
. ;~
. ~ .
... .
:: , ' :
.~ .
, 20~809 t(2-n-butyl-5-cyclohexylmethylamino-3H-imidazo[4,5-b]
pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 23.6~ of theory, Melting point: 202-205c C31H36N4O2 (496.66) Calculated: C 74.97 H 7.31N 11.2 Found: 74.~2 7.~ 10.98 Example 17 4'-[(2-n-Butyl-5-ethylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid .... _ . . _ Prepared analogously ko Example 12 from tert.butyl 4'-[(2-n-butyl~5-ethylamino-3H-imidazot4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 76% of theory, Melting point: 245-247C
C26H2~N4O2 (428.54) Calculated: C 72.87 H 6.59N 13.09 Found: 72.72 6.65 12.84 Example 18 4'-[(2-n-Butyl-5-n-butylamino-3H-imidazo[4,5-b]pyridin-3-yl)~methyl]biphenyl-2-carboxylic acid . . _ .
Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-S-n-butylamino-3H-imidazot4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 67% of theory, Melting point: 217-219C
C2~H32N4O2 (456.59) Calculated:C 73.66H 7.06 N 12.27 Found:73.46 7.03 12.17 - `
`" '; ;
: ' 204880~
_ample 19 4'~~(2-n-Butyl-5-cyclohexylamino-3H-imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl 2-carboxylic acid Prepared analogously to Examp:le 12 from tertubutyl 4'-; t(2-n-butyl-5-cyclohexylamino--3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 67% of theory, Melting point: 221-224C
C30H34N402 (482.63) Calculated: C 73.29 H 7.18 N 11.40 Found: 73.51 6.95 11.25 Example 20 ~'-[(2~n-Butyl-5-methylamino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-5-methylamino 3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 61% of theory, Melting point: 274-277C
C2sH26N402 (414.51) Calculated: C 72.44 H 6.32 N 13.52 Found: 72.26 ~.26 13.30 Example 21 4'-[(2-n-Butyl-5-amino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-~-carboxylic acid ...... _ Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-5-amino~3H-imidazo[4,5-b3pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic . . ..
: . , . ~ , , .. ..
.
~: . , , . , ~ . ~ ;
' 20~809 acid.
Yield: 35% of theory, Melting point: 238-240C
C24H24N4Oz (400.48) Calculated: C 71.98 H 6.04 N 13.99 Found: 71.90 5.96 13.86 Example 22 4'-t(2-n-Butyl-5-dimethylamino-3H-imidazo[4,5-b]pyridin-3-yl) methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl~5-dimethylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and tri~luoroacetic acid.
Yield: 81~ of theory, Melting point: 213-215C
C26H28N4O2 (428-54) Calculated: C 72.87 H 6.57 N 13.08 Found: 72.~2 6.7312.90 Example 23 4'-[(2-n-Butyl-5-benzylamino-3H-imidazo~4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid .. _ _ . . . . _ Prepared analogously to Example 12 from tert.butyl 4'-E ( 2-n-butyl-5-benzylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 67% of theory, Melting point: 224-225C
C31H30N4Oz (490.61) Calculated: C 75.89 H 6.16 N 11.42 Found: 75.70 6.24 11.37 ': ' " , . : : , , . .
:
2~8809 Example 24 4'-[[2-n-Butyl-5-(2,4-dimethoxybenzylamino)-31~~
imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(2,4-dimethoxybenzylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 73% of theory, Melting point: 223-226C
C33H34N404 (490.61) Calculated: C 71.98 H 6.22 N 10.18 Found: 71.70 6.21 10.16 Example 25 4'-~2-n-Butyl-5-(N-isobutyryl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl~-methyl]biphenyl-2-carboxylic acid r ~
Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(N-isobutyryl-n-butylamino-3H- midazo-[4,5-b]pyridin-3-yl3methyl]biphenyl-2 carboxyIate and trifluoroacetic acid.
Yield: 33% of theory;
Melting point- 186-189C
C32H38N4o3 (490-61) Calculated: C 72.98 EI 7.27 N 10.64 Found: 73.09 7.~5 10.53 . ; ....... .
, , .
: ~
' .
2~8809 Example 26 4'-[[2-n-Butyl-5-(N-acetyl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid _ _ _ Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(N-acetyl-n-butylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 36% of theory, Melting point: 173-175~C
C30H34N~,03 (498-63) Calculated: C 72.26 H 6.87 N 11.24 Found: 72.39 7.00 11.07 Example 27 4'-[[2-n-Butyl-5-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid .
Prepared analogously to Example lZ from tert.butyl 4'-[[2-n-butyl-5-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 95~ of theory, Melting point: 203-205C
C33H3aN4O3 (538.70) Calculated: C 73.58 H 7.11 N 10.40 Found: 73.66 7.19 10.35 Example 28 4'-[[2-n-Butyl-5-(N-acetyl-ethylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid . . . _ _ .
Prepared analogously to Example 12 from tert.butyl 4'-. ~ :
. .
- : ,, . ~ .
20~8go9 [t2~n--butyl-5-(N-acetyl-ethylamino)~3H-imidazo-[~,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 80% of theory, Melting point: 89-93C
C33H38N4O3 (470.58) Calculated: C 70.99 H 6.47 N 11.79 Found: ~0.79 6.47 11.52 Example 29 4'-[(2-n-Butyl-5-valeroylamino~3H-imidazo[4,5-b]-pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid _ _ _ _ Prepared analogously to Example 12 ~rom tert.butyl 4'-[(2-n-butyl-5-valeroylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 56% of theory, Melting point: 240-242C
C33H38N4O3 (484.60) Calculated: C 71.88 H 6.66 N 11.56 Found: 71.61 6.72 11.47 Example 30 4'-[(2-n-Propyl-5-butanoylamino-3H-imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-propyl-5-butanoylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 68% of theory, Melting point: 254-255~C
Cz7H2sN43 (456-55) Calculated: C 71.03 H 6.18 N 12.27 Found: 70.98 6.25 12.36 ;, : . . .. ,:
, ~ ~ : ,, . , ; :
- , . .
.
.
Example 31 4'-[(2-n-Propyl-5-butanoylamino-3H-imidazo[4,5 b]-pyridin-3-yl)methyl]biphenyl-4-bromo-2-carboxylic acid .... . .
Prepared analogous]y to Exampl,e 12 from tert.butyl 4'-[(2-n-propyl-5-butanoylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-4-bromo-2-carboxylate and trifluoroacetic acid.
Yield: 83% of theory, Melting point: 244-245C
c27H27N4O3Br (535-54) Calculated: C 60.56 H 5.08N 10.46 Br 14.92 Found: 60.42 5.07 10.41 14.82 Example 32 4'-[[2-n-Propyl-5-(2-methyl-valeroylamino)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylic acid .
Prepared analogously to Example 12 from tert.butyl 4'-[[2-n~propyl-5-(2-methyl-valeroylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 97% of theory, Melting point: 244-245C
Cz9H32N4O3 (484.61~
Cal~ulated: C 71.88 H 6.66 N 11.56 Found: 71.77 6.79 11.51 Example 33 4'~ E ( 2-n-Propyl-5-benzylcarbonylamino-3H-imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-~(2-n-propyl-5 benzylcarbonylamino-3H-imidazo-. .
.
, 20~8~309 - 6~ -[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 93% of theory, Meltinq point: 252-254C
C31HzsN403 (504-60) Calculated: C 73.79 H 5.59 N ll.lo Found: 73.85 5.78 10.93 Example 34 4'-[(2-n-Propyl-5-butanoylamino-lH-imidazo[4,5-b]-pyridin-1-yl)methyl~biphenyl-2-carboxylic acid _ _ .. ..
Prepared analogously to Example 12 ~rom tert.butyl 4'-~(2-n-propyl-5-butanoylamino-lH-imidazo-[4,5-b]pyridin-l-yl)methyl~biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 88% o~ theory, Melting point: 120C
C27H28N403 (456.55) Calculated: C 70.34H 6.23 N 12.15 Found: 70.14 6.24 12.34 Example 35 4'-[t2-n-Butyl-5-(N-ethoxycarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to ~xample 12 from tert.butyl 4'-[[2-n-butyl-5-(N-ethoxycarbonyl-ethylamino~-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 95% of theory, Melting point: 182-185C
C29H32N404 (500.61) Calculated: C 69.58 H 6~44 N 11.19 Found: 69.72 6.57 11.13 : .: , :. .
2~88~9 Exa~e 36 4'-[[~-n-Butyl~5-(N-cyclohexylaminocarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-5-(N-cyclohexylaminocarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 95% of theory, Melting point: 182-185C
C33H39NsO3 (500~61) Calculated: C 71.58 H 7.10 N 12.65 Found: 71.77 7.22 12.59 Example 37 4~-[[2-n-Butyl-5-(N-ethoxycarbonyl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid .
Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(N-ethoxycarbonyl-n-butylamino)-3H-imidazo[4,5~b~pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 37% of theory, Melting point: 154-156C
C31H36N4O4 (528.66) Calculated: C 70.43 H 6.86 N 10.60 Found:70.68 7.10 10.50 ;:
: . . .
.. ~
2~8~09 Example 3~
4'-[[2-n-Butyl-5-(N-cyclohexylaminocarbonyl-n-bu-tyl-amino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(N-cyclohexylaminocarbonyl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-Z-carboxylate and trifluoroacetic acid.
Yield: 89% of theory, Melting point: 195~198C
C35H43NsO3 (581.47) Calculated: C 72.26 ~ 7.45 N 12.04 Found: 72.29 7.66 11.81 Example 39 4l-[[2-n-Butyl-5-(n-butylaminocarbonylamino)-lH-imidazo[4,5-b]pyridin-1-yl]methyl]biphenyl-2-carboxylic acid _ _ Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl--5-(n-butylaminocarbonylamino)-lH--imidazo-[4,5-b]pyridin-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 83% of theory, Melting point: 290-295C
C2sH33NsO3 (499-62) Calculated: C 69.72 H 6.66 N 14.02 Found: 69.62 6.76 13.98 .
. , -~, . '; , , ~ . .
~: .
, 2~8809 Example 40 4'-[[2-n-Butyl-5-(cis hexahydrophthalimido)-3H-imidazo[4,5 b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(cis-hexahydrophthalimido)-3H-imidazo-[4,5-b]pyridin-3-yl~methyl~biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 84~ of theory, Melting point: 113-115C
C32H32N4o4 (536.6~) Calculated: C 62.76 H 5.11 N 8.61 Found: 62.79 5.21 8.~8 Example 41 4'~[(2-n-Butyl-5~methoxy-lH-imidazo[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylic acid-trifluoroacetate-hydra~e Prepared analogously to Example 12 from tert.butyl 4l_ [r2-n-butyl-5-methoxy-lH-imidazo[4,S-b~pyridin-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 80~ of theory, Melting point: 126-128C
C2sH2sN33 x CF3COOH x H20 (547-54) Calculated: C 59.23 H 5.15 N 7.68 Found: 59.46 4.99 7.63 Example 42 4'-[(2-n-Butyl-6-bromo-lH-imidazo[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylic acid .
Prepared analoyously to Example 12 from tert.butyl 4'-[(2-n-butyl-6-bromo~lH-imidazo[4,5-b]pyridin-1-:
20~8~09 ~ 68 ~
yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 79% of theory, Meltinq point: 239-240C
~24HzzBrN30z (464-36) Calculated: C 62.08 H 4.77N 9.05Br 17.21 Found: 61.83 4.71 8.92 17.43 Example 43 4'-[(2-n-Butyl-6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid . _ _ . . . .
Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 85% of theory, Melting point: 221-223C
Cz4HzzBrN30z (464.36) Calculated: C 62.08 H 4.77N 9.05Br 17.21 Found: 61.95 4.84 8.96 17.38 Example 44 4'-[~2-n-Butyl-5-methyl-6-phthalimido-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid _ _ ... .
Prepared analogously to Example 1? from tert.butyl 4'-[t2-n-butyl-5-methyl-6-phthalimido-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yi~ld: 75% of theory, Melting point: 336-340C
C33H28N404 (544.62) Calculated: C 72.78 H 5.18 N 10.29 Found: 72.59 5.1810.26 ,.. . .
:" . ., ~ , .. . . ..
,~ . : . . , .
.
". , ~0~8~09 Example_45 4'-[(2-n-Butyl-5-methyl-6-phthalimido-lH-imidazo-[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Exampl,e 12 from tert.butyl 4'-[(2-n-butyl-5-methyl-6-phthali~ido-lH-imidazo-[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 63% of theory, Melting point: 301-303C
C33H28N404 (544.62) Calculated: C 72.78 H 5.18 N 10.29 Found: 72.71 5.25 10.18 Example 46 4'-[(8-n-Butyl-2-methoxy-9H-purin-9-yl)-methyl]-biphenyl-2-carboxylic acid .... . _ Prepared analogously to Example 12 from tert.butyl 4'-~(8-n-butyl-2-methoxy-9H-purin-9-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 73% of theory, Melting point: 146-148~C
C24H24N4o3 (416-48) Calculated: C 69.21 H 5.81 N 13.45 Found: 68.97 5.84 13.17 Example 47 4'-[(8-n-Butyl-2-methoxy-7H-purin-7-yl)-methyl]-biphenyl-2-carboxylic acid _ _ _ Prepared analogously to Example 12 from tert.butyl 4'-~(8-n~butyl-2-methoxy-7H-purin-7-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 73~ of theory, "' ~ , . ' ~
.
2048~09 Melting point: 146-1~8C
Cz4H24N403 (416.43) Calculated: C 69.21 H 5.81 N 13.45 Found: 69.07 5.94 13.27 Example 48 4'-[(2-Benzylamino-8-n-butyl-9H-purin-9-yl)-methyl]-biphenyl-2-carboxylic acid .... ... _ .
Prepared analogously to Example 12 from tert.butyl 4'-r ( 2-benzylamino-8-n-butyl-9H-purin-9-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 13% of theory, Melting point: 232-234C
C30H29NsO2 (491.60) Calculated: C 73.20 H 5.95 N 14.25 Found: 73.16 6.05 14.44 Example 49 4'-[(2-n-~utyl-5-methyl-6-(N~acetyl n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl)-methyl3biphenyl-2-carboxylic acid _ _ Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-5-methyl-6-(N-acetyl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yi~ld: 56% of theory, Melting point: 144-146C
C3lH36N403 (512-65) Calculated, C 72.63 H 7.08 N 10.93 Found:72.39 7.15 ~ 10.79 , .
. .
20~8809 Example S0 4'-[(2-n-Butyl-5-methyl 6-amino-3H-imidazo[4,5-b]-pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 ~rom tert.butyl 4'-~(2~n-butyl-s-methyl-6-amino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 80% of theory, Melting point: 168-170C
C26Hz6N402 (414.57) Calculated: C 72.44 H 6.32 N 13.52 Found: 72.40 6.5013.32 Example 51 4~-[(2-n-Butyl-6-hexahydrophthalimido 3H-imidazo[4,5-b]-pyridin-3-yl)-methyl]biphenyl-Z-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-6-hexahydrophthalimido-3H-imidazo-[4,S-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 90% of theory, Melting point: 179-181C
C32H32N4O4 ~536.64) Calculated: C 71.62 H 6.01 N 10.44 Found: 71.87 6.0010.36 Example 52 4'-[(2-n-Butyl-5-methyl-6-butyrylamino-3H-imidazo-[4,5-b]pyridin-3-yl~-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-5-methyl-6-butyrylamino-3H-imidazo-[4,5-b3pyridin-3-yl)methyl]biphenyl-2-carboxylate and ., .. ~ , , - . .
, . ~ .~ .
. . . .
, ,.
20~09 tri~luoroacetic acid.
Example 53 4'-[[2-n-Butyl-5-methyl-6-(2~oxo piperidin-l-yl)-lH-imidazo[4,5-b]pyridin-1-yl]methyl]biphenyl-2-carboxylic i acid-trifluoroacetate Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-methyl-6-(2-oxo-piperidin-1-yl)-lH-imidazo[4,5-b]pyridin-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 91% of theory, Melting point: 171-173C
C30H32N403 x CF3COOH t610.65) Calculated: C 62.94 H 5.45 N 9.18 Found: 62.74 5.49 8.98 .:
Example 54 4'-[[2-n-Butyl-5-methyl-6-(2-methyl-propionylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid _ Prepared analogously to Example 12 from tert.butyl 4'-[~2-n-butyl-5-methyl-6-(2-methyl-propionylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl~biphenyl-2-carboxylate and tri~luoroacetic acid.
Example 55 4'-[[2-n-Butyl-5-methyl-6-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylic acid -Prepared analogously to Example 12 from tert~butyl 4'-E [2-n-butyl-5-methyl-6-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo[4,5-b~pyridin-3-yl]-methyl]-:
" . . . . ~ .
"
. :: : :, ,; , . , . , , ,~
: . ; , .
.
20488~9 biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 78% of theory, Melting point: 164-166C
C34H40N403 (552.72) Calculated: C 73.88 H 7.29N 10.14 Found: 73.58 7.29 10.04 Example 56 4'-[[2-n-Butyl-5-methyl-6-(cis-hexahydrophthalimido)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid . . _ . . .
Prepared analogou~ly to Example 12 from tert.butyl 4'-[[2-n-butyl-5-methyl-6-(cis-hexahydrophthalimldo)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 81% of theory, Melting point: 261-263C
C33H34N404 (550.67) Calculated: C 71.98 H 6.22N 10.18 Found: ~71.78 6.25 9.95 Example 57 4'-~(2-n-Butyl-6-(cis-hexahydrophthalimido)-lH-imidazo-~4,5-b]pyridin-1-yl~methyl]biphenyl-2-carboxylic acid-dihydrate Prepared analogously to ~xample 12 from tert.butyl 4'-[(2-n-butyl-6-(cis-hexahydrophthalimido)-lH-imidazo-[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 70% of theory, Melting point: 203-205~C
C32H32N404 x 2 H2O (572.68) Calculated:C 67.11H 6.33 N 9.78 Fou~d:67.25 6.30 9.78 .
, ~ ~
, :, . .
, 20~8~09 - 7~ -Example 58 4'-[[2-n-Butyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)~pyrimidinon-1-yl) -3H--imidazo[4,5-b~pyridin-3-yl]-methyl]biphenyl-2-ciarboxylic acid-tri~luoroacetate . . ~
Prepared analogously to Examp]e 12 from tert.butyl 4'-[[2-n-butyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3~I-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 77% of theory, Melting point: 168-170C
C36H37Ns3 x CF3COOH (701.76) Calculated: C 65.04 H 5.46 N 9.98 Found: 64.98 5.67 9.91 Exampl,e 59 4'-[[2-n-Butyl-5-[3-(4-methoxy)benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl]-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxyl;c acid _ _ .. . . .
Prepared analogously to Example 12 from tert.butyl 4'-~[2-n-butyl-5-[3-(4-methoxy)benzyl-3,4,5,6-tetrahydro-2tl~)-pyrimidinon 1-yl]-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Example ~0 4'-[[2-n-Butyl-5-[3-(4-hydroxy)benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl]-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[t2 n-butyl-5-[3-(4 hydroxy)-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl]-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and tri~luoroacetic , ,. .. . .
. . - , . . ~ .
~:
. , .
. .
2048~09 acid.
Example 61 4'-[[2-n-Butyl-5-(3-cyclohexylmethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo~4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2 n-butyl-5~(3-cyclohexylmethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Example 62 4'-[t2-n-Propyl-$-~(2-carboxymethyl)pyrrolidino]-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-propyl-5-[(2-carboxymethyl)pyrrolidino~-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 37~ of theory, Melting point: 137-13gC
C2~H30N404 (498-62) Calculated: C 69.86 H 6.06 N 11.24 Found: 69.59 6.20 11.04 Example 63 4~-[(2-n-Butyl-6-phthalimido lH-imidazo[4,5-b]pyridin-1-yl)-methyl3biphenyl-2-carboxylic acid-trifluoroacetate Prepared analogously to Example 12 from tert.butyl 4'~
[(2-n-butyl-6-phthalimido-lH-imidazot4,5-b]pyridin-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic ,~ . . . . .
: .:
-: :- . , :
. ~
, . . .
~8g~9 acid.
Yield: 74% o~ theory, Melting point: 168-170C
C32H26N4o4 x CF3COOH (644.61) Calculated: C 63.35 H 4.22 N 8.96 Found: 63.50 4.53 9.06 Example 64 4'-[t8-n-Butyl-2-(n-butylamino)-9H-purin-9-yl]methyl]-biphenyl-2-carboxylic acid 0.45 g (0.95 mMol) of methyl 4'-[[8-n-butyl-2-(n-butylamino)-9H-purin-9-yl]methyl]biphenyl-2-carboxylate are dissolved in 20 ml of methanol and 10 ml of water, mixed with 0.4 g of powdered potassium hydroxide and re~luxed for 3 hours. The reaction mixture is then concentrated by evaporation and the residue is dissolved in 30 ml of water. It is filtered over charcoal and acidified with glacial acetic acid~ The precipitate formed is suction filtered, washed with water and dried.
Yield: 0.4 g (92% of theory), Melting point: 213-~15C
C27H31~52 (457.58) Calculated: C 70.87 H 6.83 N 15.31 Found: 70.70 6.89 15.19 Example 65 4' C(8-n-Butyl-Z-cyclohexylamino-9H-purin-9-yl)methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 64 from methyl 4'-[(8-n-butyl-2-cyclohexylamino-9H-purin-9-yl)methyl]biphenyl-2-carboxylate and methanolic potassium hydroxide solution.
Yield: 55% of theory, Melting point: 213-215C
C2sH33Ns2 t483 62) - ~ ~
.
, .
.-: : . ... . .
.
i~
. .
20~88~9 Calculated: C 72.02 H 6.88 N 14.48 Found: 71. 84 6 . 98 14 . 62 xample 66 4'-[(8-n-Butyl-2-ethoxy-9H-purin-9-yl)methyl]biphenyl-2-carboxylic acid -Prepared analogously to Exampl!e 64 from methyl 4'-[(8-n-butyl-2-ethoxy-9H-purin-9-yl)m~ethyl]biphenyl-2-carboxylate and methanolic potassium hydroxide solution.
Yield: 48~ of theory, Melting point: 190-192C
C2sH26N4O3 (430.51) Calculated: C 69.75 H 6.09 N 13.01 Found: 69.75 6.13 12.83 Example 67 4'-[(~-n-Butyl-2-ethoxy-7H-purin-7-yl)methyl]biphenyl-2-carboxylic acid . ~
Prepared analogously to Example 64 from methyl 4'-[(8-n-butyl-2-ethoxy-7H-purin-7-yl)methyl]biphenyl-2-carboxylate and methanolic potassium hydroxide solution.
Yield: 10% of theory, Melting point: 155-158C
C2sH26N4O3 (430.51) Calculated: C 69.75 H 6.09 N 13.01 Found: 69.95 6.10 :L1.83 Example 68 4l-[[2-n-Propyl-5-(2-methylpropylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl~-2-(lH-tetrazol-5-yl)biphenyl 0.32 g (0.42 mMol) of 4'~[~2-n-propyl-5-(2-methylpropyl-amino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-.
.
'' ~ ' ;' :
' `
,~
~0~809 ~ 7~ -triphenylmethyl-tetrazol-5-yl)-biphenyl are dissolved in 20 ml of methanolic hydrochloric acid and stirred for 2 hours at ambient temperature. The solvent is concentrated by evaporation, the residue is triturated with 20 ml of water, suction filtered and dried. After column chromatography on silica gel (particle size:
0.06-0.2 mm, eluant: methylene chloride/ethanol 0-10%) a white solid is obtained.
Yield: 0.1 g (51% of theory), Melting point: 128-130C
C27H30N~ (466.60) Calculated: C 69.50 H 6.4~ N 24.02 Found: 69.44 6.73 24.04 Example 69 4'-[[Z-n-Butyl-5-(2-aminocarbonyl-cyclohexylcarbonyl-amino)-3H-imidazo[4,5-b]pyridin-3-yl]methylJ-2 (lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-butyl-5-(2-aminocarbonyl-cyclohexylcarbonylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl and methanolic hydrochloric acid.
Yield: 37% of theory, Melting point: 165-175C
32H35NsOz (577 70) Calculated: C 66.53 H 6.11 N 2~.82 Found: 65.73 6.13 21.84 Example 70 `:
4'-[[2-n-Butyl-5-(cis-hexahydrophthalimido)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl . . .
Prepared analogously to Example 68 from 4'-[[2-n-butyl-5-(cis-hexahydrophthalimido~-3N-imidazo~4,5-b]pyridin-3-: , ~ ~ , ~ ' ' : ' .
.
. : : ~ ' ' ' : :
~OA8~09 yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl and glacial acetic acid.
Yield: 30~ of theory, Melting point: 127C
C32H32N8O2 (560.66) Mass spectrum: M~ - 560 Example 71 4'-t[2-n-Butyl-5-t4 methyl-piperidino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl . . _ . . . _ . . . _ Pre~ared analogously to Example 68 ~rom 4'-[[2-n-butyl-5-t4-methyl-piperidino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl~biphenyl and methanolic hydrochloric acid.
Yield: 39% o~ theory, Melting point: 187-189C
C30H34N8 (506-70) Mass spectrum: M~ = 506 Example 72 4'-[[2-n-Propyl-5-[N-(3-phenylpropionyl)isobutylamino]-3H-imidazo~4,5-b]pyridin-3-yl]methyl]-2~(lH-tetrazol-5-; yl)-biphenyl Prepared analogously to Example 68 from 4'-[t2-n-propyl-5-[N-(3-phenylpropionyl)-isobutylamino]-3~-imidazo-[4,5-b]pyridin~3-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
~,,: . ,, . , , , ~ ..... .
. . .: :
:
2~88~9 Example 73 4'-[[2-n-Propyl-5-(N-benzylaminocarbonyl-iscbutylamino) 3H-imidazo[4,5-b]pyridin-3-yl]methyl]-~-(lH-tetrazol-5-yl)-biphenyl _ _ Prepared analogously to Example 68 from 4'-[[2-n-propyl-5-(N-benzylaminocarbonyl-isobu-tylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Yield: 37% of theory, Melting point: 195-196~C
C3sH37N9O (599~75) Calculated: C 70.09 H 6.22 N 21.02 Found: 69.95 6.3220.86 Example 7 4~~E[2-n-propyl-5-(N-cyclohexylaminocarbonyl-isobutylamino)-3H-imidazo[4,5-b]pyridin 3-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-propyl-5-(N-cyclohexylaminocarbonyl-isobutylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl] 2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Yield: 38% of theory, Melting point: 112-113C
C3~H41N9O (591.77) Calculated:C 69.01H 6.g8 N 21.30 Found:68.86 6.88 21.18 . .
: ' ' ' ` '~ ` .
, `
, 20~18~09 _xample 75 4'~[[2-n-Butyl-5-(3-benzyl-3,4,5,6-tetrahydro-Z(lH)-pyrimidinon-l-yl)-3~-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-butyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenyl-methyl-tetrazol-5-yl) biphenyl and methanolic hydrochloric acid.
Example 76 4'-[(2-n-Butyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid . _ Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 65% of theory, Melting point: 233-235C
C2s~2sN3o2 (399.50) Calculated: C 75.16 H 6.31 N 10.52 Found: 75.06 6.3510.46 Example 77 4'-[[2-n-Butyl-5-(2-oxo-pyrrolidino~-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[ E 2-n-butyl-5-(2-oxo-pyrrolidino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenyl-methyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
' ~ . . . .
'' ,~ :
- ~2 -Example 78 4'[[2-n-Propyl-5-(2-oxo-pyrrolidino)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl _ Prepared analogously to Example 68 from 4'-[[2-n-propyl-5-(2-oxo-pyrrolidino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(1-triphenyl-methyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Example 79 4'[[2-n-Butyl-5-(2-oxo-piperidino)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)-hiphenyl _ _ Prepared analogously to Example 68 from 4'-[[2-n-butyl-5-(2-oxo-piperidino)-3H-imidazo[~,5-b]pyridin-3-yl]-methyl]-2-(1-triphenyl-methyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Example 80 4'[[2-n-Propyl-5-(2-oxo-piperidino)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]-2~(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-propyl-5-(2-oxo-piperidino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(l-triphenyl-methyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Example 81 4'-[[2-n-Butyl-5-methyl-6 (cis-hexahydrophthalimido)-lH-imidazo[4,5~b]pyridin-l-yl]methyl]biphenyl-2-carboxylic acid-trifluoroacetate .. . . _ . _ Prepared analogously to Example 12 from tert.butyl 4'-[t2-n-butyl-5-methyl-6-(cis-hexahydrophthalimido)-lH-imidazo[4,5-b]pyridin-l-yl]methyl]biphenyl-2-carboxylate 2~)~880.9 and trifluoroacetic acid.
Yield: 79~ of theory, Melting point: 188-l90~C
C33H34N~04 x CF3COOH (664.68) Calculated: C 63.24 H 5.31 N 8.4~
Found: 63.5Z 5.65 8.69 Example 82 4'-[(2-n-Butyl-5-methyl-6-dimethylaminocarbonylamino~
imidaæo[4,5-b]pyridin-1-yl)methyl]biphenyl-2-carboxylic acid trifluoroacetate . . _ _ . _ . _ . . . _ Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-methyl-6 dimethylaminocarbonylamino-lH-imidazo[4~5-b~pyridin-1-yl]methyl]biphenyl 2-carboxylate and trifluoroacetic acid.
Yield: 83~ of theory, Melting point: 147-149C
c28H31N53 x CF3COOH (599.61) Calculated: C 60.09 H 5.37 N 11.6~
Found: 60.31 5.39 11.51 Example 83 4'-[(2-n-Butyl-5-methyl-lH-imidazo[4,5-b]pyridin-1-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4' E (2-n-butyl-5-methyl-lH-imidazo[4,5-b]pyridin-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 77~ of theory, Melting point: 230-232C
C25H25N302 (399 50) Calculated:C 75.16 H 6.31 N 10.52 Found:74.86 6.39 10.46 -. : : ~
, .
,.;.
. ~ .
.
20~8~9 Example 84 4'-[(2-n-~utyl-6-phthalimido-3H-imidazo[4,5-b]pyridin-3~
yl)-methyl]biphenyl-2-carboxylic acid . ~ . _ .. ~ . .
Prepared analogously to Example 12 from tert.butyl 4'-t(2-n-butyl-6-phthalimido-3H-imidazo[4,5-b~pyridin-3-yl)-methyl]biphenyl-2-carboxylalte and tri~luoroacetic acid.
Yield: 78% of theory, Melting point: 271-272C
C32H26N404 (530 59) Calculated: C 72.44 H 4.94 N 10.56 Found: 72.37 4.99 10.48 Example 85 4'-[[2-n-Butyl-5-(4-chlorophenyl)sulphonylamino-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid-hydrate Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(4-chlorophenyl)sulphonylamino-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 63% of theory, Melting point: 158-160C
C30~1z7N404ClS X H20 (593 Calculated: C 60.75 H 4.93 N 9.45 Found: 60.62 4.76 9.27 Example 86 4'-[(2-n-Butyl-5-n-butylsulphonylamino-3~-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid ... _ . .. . . _ Prepared analogously to Example 4 from 4'-~(2-n-butyl-5-amino-3H-imidazo[4,5-b]pyridin-3-yl)methyl~biphenyl-2-.: , ' . ~
.
:, -:
20~8809 carboxylic acid and butanesulphonyl chloride in pyridine.
Yield: 16% of theory, Melting point: > 250C
C28H3zN404S (520-70) Calculated: C 65.59 H 6.19 N 10.76 Found: 65.41 6.28 10.58 The following compounds are obtained analogously:
4'-[(2-n-butyl-5-n-propylsulphonylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl 2 carboxylic acid 4'-t(2-n~butyl-5-isopropylsulphonylamino-3H-imidazo-[4,5-b]pyridin-3~yl)methyl]biphenyl-2-carboxylic acid 4'-[[2-n-butyl-5-(3-chloropropylsulphonylamino)-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2~carboxylic acid [(2-n-butyl-5-n-hexylsulphonylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid 4'-[(2-n-butyl-5-benzylsulphonylamino-3H-imidazot4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Example 87 4'-[[2-n-Butyl-5-(n butanesultam-1-yl)-3H-imidazo-~4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[~2-n-butyl~
5-~n-butanesultam-1-yl)-3H-imidazot4,5-b]pyridin-3-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl and methanolic hydrochloric acid.
The following compounds are obtained analogously:
.
- . : . `
:' , .
-, .
2~g80~
- ~6 -4'-[~2~n-propyl-5-(n-butanesultam-1-yl~-3H-ilnidazo-[4,5-b]pyridi.n 3-yl]-methyl]-2-(~H-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-5-(n-propanesultam-l-yl)-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl 4'-[[2-n-propyl-5-(n-propanesultam-1-yl)-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-5-(n-butanesultam-1-yl)-3H-imidazo-[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid 4'-[[2-n-propyl-5-(n-butanesultam-l-yl)-3H-imidazo-~4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid 4'-[[2-n-butyl-5--(n-propanesultam-1-yl)-3H-imidazo-[~,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid 4'-[[2-n-propyl-5-(n-propanesultam-l-yl)-3H-imidazo [4,5-b]pyridin-3-yl]-methyl~biphenyl-2-carboxylic acid Example 88 ~`
4'-[(2-n-Butyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3~yl)-: methyl]-2-(lH-tetrazol-5-yl)biphenyl . . _ . .
Prepared analogously to Example 68 ~rom 4'-[(2-n-butyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2~
triphenylmethyl-tetrazol-5-yl)biphenyl and methanolic hydrochloric acid.
Yield: 43% of theory, Melting point: 206-207C
C25H25N7 (439.52) Calculated:C 68.32 H 5.73N 22.31 Found: 68.11 5.88 22.19 .. . .
;, ~ ~ , :, , : ' .
,:
20~09 Example 89 ~'-t(2-n-Butyl-3E~-imidazo[4,5-b]pyridin-5-on-3-yl)-methyl]-2-(lH-tetrazol-5-yl)biphenyl Prepared analogously to Example 68 from 4'-[(Z-n-butyl-3H-imidazo[4,5-b]pyridin-5-on 3-yl)methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl and methanolic hydrochloric acid.
Yield: 18% of theory, Melting point: amorphous C24H23N7 (425.50) Calculated: C 67.7S H 5.45 N 23.04 Found: 67.54 5.42 22.91 Example 90 4'-[[2-n-Propyl-5-(2,2-dimethylpropionylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)~
biphenyl Prepared analogously to Example 68 from 4'-[[2-n-propyl-5-(2,2-dimethylpropionylamino) 3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-~1-triphenylmethyl-tetrazol-S-yl)biphenyl and methanolic hydrochloric acid.
Yield: 81% of theory, Melting point: 217-220C
C28H30N80 (49A.60) Calculated: C 67.99 H 6.11 N 22.66 Found: 67.82 6.22 22.46 Example 91 4'-~(2-n-Propyl-5-cyclohexylcarbonylamino-3H imidazo-t4,5-b]pyridin-3-yl)methyl]-2-~lH-tetrazol-5-yl)-biphenyl _ Prepared analogously to Example 68 from 4'-[(2-n-propyl-~ ~ .
. j .
~'' .. ~
, 204880~
5-cyclohexylcarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl and methanolia hydrochloric aaid.
Yield: 89% of theory, Melting point: 229-231C
C30H32Ns (520.64) Calculated: C 69.21 H 6.20 N 21.52 Found: 69.14 6.20 21.32 Example 92 4~-[~2-n-sutyl-5-methyl-6-dimethylaminocarbonylamino-3H
imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid . _ . . . . . _ ...
Prepared analogously to Example 12 from ter-t.bu-tyl 4'-[(2-n-butyl-5-methyl-6-dimethylaminocarbonylamino 3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 74% of theory, Melting point: 220-221C
C28H31N503 (485.58~
Calculated: c 69.26 H 6.44 N 14.42 Found: 69.08 6.47 14.25 Example_93 4'-[(2-n-Butyl-4-chloro-3H-imidazo[4,5-c]pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid . .
Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-4-chloro-3H-imidazo[4,5-c]pyridin-3-yl~-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 85% of theory, Melting point: 221-222C
C24H22ClN3o2 (419.92) Calculated: C 68.65 H 5.28 N 10.00 Found: 68.66 5.15 10.19 :, ~
.
' - . ~ ~ . . - ;
.
- 20~09 Example 94 4'-[(2-n-Butyl-4-chloro-lH-imidazo[4,5-c]pyridin-1-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-butyl-4-chloro-lH-imidazo[4,5-c]pyridin-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 85~ o~ theory, Meltin~ point: 221~222C
C24H22ClN302 (419-92) Calculated: C 68.65 H 5.28 N 10.00 Found: 68.56 5.18 10.09 _xample 95 4'-[(2-Ethyl-5 propionylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2 carboxylic acid . . . _ . . . _ .
Prepared analogously to Example 12 ~rom tert.butyl 4'-[(2-ethyl-5-propionylamino-3H-imidazo[4,5-b~pyridin-3-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 99% of theory, Melting point: 283-293C
C25H24N403 (428.50) Calculated: C 70.08 H 5.65 N 13.08 Found: 69.87 5.68 13.05 Example 96 4'-[t2-n-Propyl-5-(5-hydroxy-valeroylamino)-3H-imidazo[4,5 b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid . .
Prepared analogously to Example 12 from tert.butyl 4'-t[2-n-propyl-5-(5-hydroxy n-valeroylamino~-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-. - -, . :, .
: : .
~ .
carboxylate and trifluoroacetic acid.
Yie]d: 80% o~ theory, Meltlng point: 220C
C28H30N404 (486.60) Calculated: C 69.12 H 6.22 N 11.52 Found: 68.97 6.~411.39 Exam~le 97 4'-[[2-Ethyl-5-(3-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid semihydrate Prepared analogously to Example 12 from tert.butyl 4'-[[2-ethyl-5-(3-methyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3~-imidazo~4,5-b~pyridin~3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 62% of theory, Melting point: from 250C (decomp.) C27H2~NsO3 x 1/2 HzO (478.60) Calculated: C 67.77 H 5.90 N 14.64 Found: 67.98 5.84 14.66 Example 98 4'-[[2-n-Propyl-5-(3-methyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazot4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[~2-n-propyl-5-(3-methyl-3,4,5,6-tetrahydro-2(lH~-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 74% of theory, Melting point: 202-205C
Cz8H29NsO3 (483.57) Calculated: C 69.55 H 6.04 N 14.48 Found: 69.30 5.9814.62 .~~, ... .
" . . .. .
~8809 _x mPle 99 4'-[[2~Ethyl-5 (3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl~-biphenyl-2-carboxylic acid-semihydrate Prepared analogou~ly to Example 12 from tert.butyl 4'-[[2-ethyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 66% of theory, Melting point: 137-138C
C33H31NsO3 x 1/2 H20 (545.70) Calculated: C 72.64 H 5.73 N 12.84 E'ound- 72~40 5.76 12.~8 Example 100 4'-[[2-n-Propyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-propyl-5-(3-benzyl-3,4,5,6 tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 77% of theory, Melting point: 149-152C
C34H33N503 (559.67) Calculated:C 72.97H 5.94 N 12.51 Found:73.11 5.91 12.39 , ~ .
,, - . , .
20~880~
X~,_ 101 4'-[~2-n-Propyl-5-(N-cyclohexy:Laminocarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid .
Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-propyl-5-(N-cyclohexylaminocarbonyl-ethylamino)-3H-imidazot4,5-b]pyridin-3-yl]--methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 10% of theory, Melting point: 166-167nC
C34H33Ns3 (S3g-69) Calculated: C 71.22 H 6.91 N ~2.98 Found: 71.37 6.7012.80 Example 102 4'-[[2-Ethyl-5-(N-cyclohexylaminocarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl~-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-ethyl-5-(N-cyclohexylaminocarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 25% of theory, Melting point: 95-100C (decomp.) C31H35NsO3 (525.66) Calculated: C 70.83 H 6.71 N 13.32 Found: 70.69 6.65 13.30 ' ' ,: '`
~0~8809 Example 103 4'-C[2-n-Propyl-5-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-propyl-5-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl] biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 83% of theory, Melting point: 112-115C
C32H36N403 (524.67) Calculated: C 73.26 H 6.92 N 10.6~
Found: 73.18 7.19 10.67 Exampl_ 104 4'-[[2-Ethyl-5-(N-cyclohexylcarbonyl-ethylamino)-3H-imida30[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid . . _ _ . . _ Prepared analogously to Example 12 from tert.butyl 4'-t[2-ethyl-5-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo[4,5-b] pyridin-3-yl ] -methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yieldo 91% of theory, Melting point: 223-224C
C31H34N403 (510.65) Calculated: C 72.92 H 6.71 N 10.97 Found: 72.97 6.65 10.93 Example 105 4'-[[2~(N-Isobutyryl-n-butylamino)-8-n-butyl-9H-purin-9-yl~ methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 4 from 4'-~[2-(n-.
' ~ : : ' ,, ` 204~809 ~- 94 -butylamino3-8-n-butyl-9H-purin-9-yl]-methyl]-biphenyl-2 carboxylic acid and isobutyric acid chloride.
Yield: 38% of theory, Melting point: 80OC
C31H37NsO3 (527.68) Calculated: C 70.56 H 7.07 N 13.27 Found: 70.45 7.22 13.06 Example 106 4'-[[2-n-Butyl-5-methyl-6-(2-oxo-piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid . _ . . _ . . _ . . . _ Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-methyl-6-(2-oxo-piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl] biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 77Po of theory, Melting point: 266-268c C30l~32N403 (496.62) Calculated: C 72.56 H 6.50 N 11.23 Found: 72.46 6.73 11.10 Example 107 4'-[[2-n-Butyl-5-methyl-6-(n-butanesultam-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]~methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-~[2-n-butyl-5 methyl-6-(n-butanesultam-1-yl)-3H-imidazo~4,5-b~pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 78% of theory, Melting point: 287-288C
C29H32N404S (532-67) Calculated: C 65.39 H 6.06 N 10.52 ;
. ,, ' .
- 2~8~09 Found: 65.26 6.25 10.37 Example 108 4'-[[2-n-Butyl-5-methyl-6-(N-cyclohexylaminocarbonyl-ethylamino)~lH-imidazo[4,5-b]pyridin-1-yl]-methyl]-biphenyl-2~carboxylic acid Prepared analogously to Exampl,e 12 from tert.butyl 4'-~[2-n-butyl-5-methyl-6-(N-cyclohexylaminocarbonyl-ethylamino) lH-imidazo[4,5-b]p~yridin-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 88% of theory, Melting point: 177-179C
C34H31N503 (567.74) Calculated: C 71.93 H 7.28 N 12.34 Found: 71.76 7.20 12.13 Example_109 4'-[[2,5-Dimethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b~pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 ~rom tert.butyl 4'-[t2,5-dimethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 74% of theory, Melting point: 277-280C
C33H~1Ns3 (545.65) Calculated: C 72.64 H 5.73 N 12.84 Found: 72.87 5.57 12.66 ,, . . , -.
- 20~880~
~ 96 -E mple 110 4'-~[2,5-Dimethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-lH-imidazo[4,5-b]pyridin-1-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[[2,5-dimethyl-6 (3-benzyl-3,4,5,6-tetrahydro 2tlH)-pyrimidinon-l-yl)-lH-imidazo[4,5-b]pyridin-1-y:L]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 77% of theory, Melting point: 142-144C
C33H31NsO3 (545.65) Calculated: C 72.64 H 5.73 N 12.84 Found: 72.59 5.51 12.60 Example 111 4'-~[2-Ethyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[~2-ethyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5~b]pyridin-3-yl~-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 73% of theory, Melting point: 272-274C
C34H33Ns3 (559-68) Calculated: C 72.97 H 5.94 N 12.51 Found: 72.87 5.97 12.37 . . .
: ' ; -:''- ' , ' ~
:, .. . .
20~88~9 Example 112 4'-[(2~n-Butyl-5-ethyl-6-dimethylaminocarbonylamino-3H-imidazo~4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylic acid-trifluoroacetate Prepared analogously to Example 12 from tert.butyl 4'-Ct2-n-butyl-5-ethyl-6-dimethylaminocarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 72% of theory, Melting point: 180-182C
C2sH33Ns3 x CF3C00~ (613.65) Calculated: C 60.67 H 5. 58 N 11.41 Found: 60.81 5.81 11.65 Example 113 4'-[(2-n-Propyl-5-methyl-6-dimethylaminocarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylic acid-trifluoroacetate _ _ . .
Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-propyl-5-methyl-6-dimethylaminocarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 81% of theory, Melting point: 243-245C
C27H29N503 x CF3COOH (585.60) Calculated:C 59.48 H 5.16 N 11.96 Found:59.68 5.26 11.99 .
" : ~ ~
, . . . .
2~809 _ 9~ _ Exam le 114 4'-[(2-n-Propyl-5~methyl-6-dimethylaminocarbonylamino-lH-imidazo[4,5-b~pyridin-1 yl)methyl]-biphenyl-2-carboxylic acid-trifluoroacetate .
Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-propyl-S-methyl-6-dimethylaminocarbonylamino-lH-imidazo[4,5-b]pyridin-1-yl)-methyl~-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 90% of theory, Melting point: 213-216C
Cz7H2sNsO3 x CF3COOH (585.60) Calculated: C 59.4~ H 5.16 N 11~96 Found: 59.61 5.13 11.77 Example ~15 4'-[(2-n-Butyl-5-methyl-6-diethylaminocarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-biphenyl-2 carboxylic acid-trifluoroacetate . . _ . _ . . . _ . . _ _ Prepared analogously to Example 12 from tert.butyl 4'-[(2~n-butyl-5-methyl-6-diethylaminocarbonylamino-3H-imidazo[4~5-b]pyridin-3-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 90% of theory, Melting point: 137-140C
C30H35N5O3 x CF3COOH (627.67) Calculated: C 61.23 H 5.78 N 11.16 Found: 60.975.33 10.9~
,, ~, . .. . ..
:: , .'' . ' ' .
:
~ ' ~0~8~0~
. 99 Example 116 4'-[t2-n-Butyl-5-ethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazot4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid . . . _ . . _ Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-ethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl~-methyl] biphenyl-2~carboxylate and trifluoroacetic acid.
Yield: 85% of theory, Melting point: 173-175C
C37H39NsO3 (601.76) Calculated: C 73.85 H 6.53 N 11.64 E'ound: 73.63 6.40 11.41 Example 117 4~-[[2-n-Propyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid . . _ . . _ ~
Prepared analogously to Example 12 from tert.butyl 4'-[~2-n-propyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 64% of theory, Melting point: 199-201C
C35H35NsO3 (573.69) Cals~ulated: C 73.27 H 6.05 N 12.21 Found: 73.20 6.19 12.08 . . . . .. .
- , . .
., , ~ -. :. . . : .
.. . . .
.
2~8~V9 Example 118 4'-[[2-n-Butyl-5-methyl-6-(3-dimethylaminocarbonyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid . _ _ Prepared analogously to Example 12 from tert.butyl 4'-[t2-n-butyl-5-methyl-6-(3-dimethylaminocarbonyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l--yl)-3H-imidazo[4,5-b]-pyr.idin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
_ample 119 4'-[[2-n-Butyl-5-methyl~6~(3-benzyl-3,4,5-trihydro-2(lH)-imidazolinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid . . . _ _ , .
Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-methyl-6-(3-benzyl-3,4,5-trihydro-2(lH)-imidazolinon-l-yl)-3H-imidazo[4,5-b]-pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield. 92% of theory, Melting point: 149-151~C
C3sH3sNsO3 (573-70) Calculated: C 73028 H 6.15 N 12.21 Found: 73.16 5.9812.07 Example 120 4'-[(2-n-Propyl-5-methyl-6-(cis-hexahydrophthalimido)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-~(2-n-propyl-5-methyl-6-(cis-hexahydrophthalimido)-3H-imidazo[4,5-b]-pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
.. . . .
.
'; ' ~ ;
2~8809 Yield: 77% of theory, Melting point: 269~270C
C32H3zN4O4 (536-64) Calculated: C 71.62 ~ 6.01 N 10.44 Found: 71.48 6.24 10.31 .
Example 121 4'-[(2-n-Propyl-5-methyl-6-(c.is-hexahydrophthalimido)-lH-imidazo[4,5-b]pyridin-1-yl)methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'-[(2-n-propyl-5-methyl-6-(cis-hexahydrophthalimido)-lH-imidazo[4,5-b]-pyridin-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 79% of theory, Nelting point: 219-221C
C32H32N4O4 (536.64~
Calculated: C 71.62 H 6.01 N 10.44 Found: 71.45 5.86 10.21 Example 122 4'-t[2-n-Butyl-5-(N-phenylsulphonyl-methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxylic acid . _ _ .. _ ... . . _ ..
Prepared analogously to Example 12 from tert.butyl 4'-[[2-n-butyl-5-(N-phenylsulphonyl-methylamino)-3H-imidazo[4,5-b]-pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 83% of thaory, Melting point 226-227C
H30N4O4S (554.60) Calculated: C 67.14 H 5.45 N 10.10 S 5.79 Found: 67.00 5.51 10.25 5.78 ..:, ......
~. , ,' :, ' ~ ~
- ' '' , : , ,'. ~ ~ , ' ' . : ' -20~8~09 Example 123 4'-[[2-n-Propyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1l~)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl . _ . . _ _ . . _ , . .
Prepared analogously to Example 68 from 4'-[[2-n-propyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3H-imidazo~4,5-b]pyridin-3-yl]-methyl]-2-(1-triphenyl-methyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Yield: 72~ of theory, Melting point: amorphous C34H33Ns (583.70) Calculated: C 69.96 H 5.70 N 21.60 Found: 70.11 5.5721.49 Example 124 4'-~2-n-Propyl-5-(2-oxo-indolin-1-yl)-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-propyl-5-(2 oxo-indolin-1-yl)-3H-imidazo[4,5 b]pyridin~3-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Yield~ of theory, Melting point- sinters from 190C
C31H26N8 (526.51) Mass spectrum: (M-~H)+ a 527 ' ,, ~, .
., .
204~8~9 Example 125 4'-[(2-n-Butyl-5-methyl-6-dimethylaminocarbonylamino-3H-imidazo~4,5-b]pyridin-3-yl)methyl]-2-(lH-tetrazol-5-yl)-biphenyl ._ _ Prepared analogously to Example 68 from 4'-[(2-n-butyl-5-methyl-6-dimethylaminocarbonylamino-3H-imidazo[4,5-b]-pyridin-3-yl)-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl~-biphenyl and methanolic hydrochloric acid.
Example 126 4'-[[2-Ethyl-5-(2,2-dimethyl-propionylamino)-3~-imidazo-~4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl-hydrochloride Prepared analogously to Example 68 from 4'-[[2-ethyl-5-(2,2-dimethyl-propionylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Yield: 52% of theory, Melting point: sinters from 188~C
C27H2sNsO x E~Cl (517.04) Calculated: C 62.95 H 5.65 N 21.90 Cl 6.85 Found: 62.73 5.47 21.75 5067 Example 127 . .
4'-[(2-n-Butyl-5-ethyl-6-phthalimido-lH-imidazo[4,5-b]-pyridin-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example l~ from tert.butyl 4'-[(2-n-butyl-5-ethyl-6-phthalimido-lH-imidazo[4,5-b]-pyridin-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 56% o~ theory Melting point: 277-279C
.. . . . :
-, .. .
: : .
~0~809 C34H30N~04 (558.64) Calculated: C 73.10 H 5.41 ~7 10.03 Found:72.97 5.52 10.16 Example 128 4'-~(2-n-Butyl-5~methoxy-lH-imidazo[4,5-b]pyridin-1-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-E(2-n-butyl-5-methoxy-lH-imidazo[4,5-b]pyridin-1-yl)-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloxic acid.
Yield: 60% of theory, Melting point: 170-171C
C2sH2sN70 (439-53) Calculated:C 68.32H 5.73 N 22.31 Found:68.19 5.53 22.06 ....... . . .
. ~. . ; , .
, :, , 20~gO9 In the Examples of Pharmaceutical Formulations which follow, any suitable compound o~ formula I, particularly compounds A to K of the pharmacological test report, may be used as the active substance:
Exam~le I
Ampoules containing 50 mg of active substance per 5 ml _ _ Active substance 50 mg KHzPO4 2 mg NazHPO4 x 2Hzo 50 mg NaCl 12 mg Water for injections ad 5 ml Preparation:
The buffer substances and isotonic substance are dissolved in some of the water. The active substance is added and, once it has completely dissolved, water is added to make up the required volume.
Example II
Ampoules containing 100 mg of active substance per 5 ml . ~
Active substance 100 mg Methyl glucamine 35 mg Glycofurol 1000 mg Polyethyleneglycol-polypropylene-glycol block polymer 250 mg Water for injections ad 5 ml Preparation:
Methyl glucamine is dissolved in some of the water and . , ; . , :
: .
' 20~88~
the active substance i8 dissolved with stirring and heating. After the addition of solvents, water is added to make up the desired volume.
Example IIl Tablets containing 50 mg of active substance .
Active substance 50.0 mg Calcium phosphate 70.0 mg Lactose 40.0 mg Corn starch 35.0 mg Polyvinylpyrrolidone 3.5 mg Magnesium stearate __1 5_~
200.0 mg Preparation:
The active substance, CaHP04, lactose and corn starch are uniformly moistened with an aqueous PVP solution. The mass is passed through a 2 m~ screen, dried at 50C in a circulating air dryer and screened again.
After the lubricant has been added, the granules are compressed in a tablet making machine.
Example IV
Coated tablets containing 50 mg of active substance Active substance 50.0 mg Lysine 25.0 mg Lactose 60.0 mg Corn starch 34.0 mg Gelatin 10.0 mg Magnesium stearate 1.0 ma , . .
i ,.
.; ~ ' ' . ' ' :
. '' ~ ~ ~ . ' ' " .
2~809 180.0 mg Preparation:
The active substance is mixed with the excipients and moistened with an aqueous gelatin solution. After screening and drying, the granules are mixed with magnesium stearate and compressed to form tablet cores.
The cores thus produced are covered with a coating by known methods. A colouring may be added to the coatiny suspension or solution.
Example V
Coated tablets containing lO0 mg of active substance . . . _ _ Ac-tive substance 100.0 mg Lysine 50.0 mg Lactose 86.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone2.8 mg Microcrystalline cellulose 60.0 mg Magnesium stearate 1.2 mg 350.0 my Preparation:
The active substance is mixed with the excipients and moistened with an aqueous PVP solution. The moist mass is passed through a 1.5 mm screen and dried at 45C.
A~ter drying, it is filtered again and the magnesium stearate is added. This mixture is then compressed into cores.
The cores thus produced are covered with a coating by known methods. Colourings may be added to the coating "~ ' :, ~ . ` .
`
:
2048~09 suspension or solution.
Example VI
Capsules containing z50 mg of active substance . _ .
Active substance 250.0 mg Corn starch 68.5 mg Magnesium stearate 1.5 mg 320.0 mg Preparation:
The active substance and corn starch are mixed together and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The final mixture is packed into size l hard gelatin capsules.
Example VII
Oral suspension containing 50 mg of active substance per 5 ml Active substance 50.0 mg Hydroxyethylcellulose50.0 mg Sorbic acid 5.0 mg 70% sorbitol 600.0 mg Glycerol 200.0 mg Flavouring 15.0 mg Water ad 5.0 ml Preparation:
Distilled water is heated to 70C. Hydroxyethyl-cellulose is dissolved therein with stirring. By the ,, .
, . ., ~ .
! .
~8~0~
addition of sorbitol solution and glycerol the mixture is cooled to ambient temperature. At ambient temperature, sorbic acid, flavouring and active substance are added. The suspension is evacuated with stirring to remove any air. One dose of 50 mg is contained in 5.0 ml.
Example VIII
Suppositories containing 100 mg of active substance . .
Active substance 100.0 my Solid fat 1600.0 mq 1700.0 mg Pre~aration:
The hard fat is melted. At 40C the ground active substance is homogeneously dispersed in the melt. It is cooled to 38C and poured into slightly chilled suppository moulds.
. . , -.
-
Claims (12)
1. A compound of formula I
(wherein one or two of A1, A2, A3 and A4 represent a nitrogen atom and the remaining two or three of A1, A2, A3 and A4 each represent a methine group;
R1 represents a fluorine, chlorine or bromine atom, a hydroxy, alkyl or alkoxy group, an amino group optionally mono- or disubstituted, or an N-acylamino group optionally monosubstituted, at the nitrogen atom by a C16-alkyl, phenyl, C5-7-cycloalkyl, phenyl(C1-3-alkyl) or (C5-7-cycloalkyl)C1-3-alkyl group, which substituents may be identical or different and which acyl group is a C1-7-alkanoyl group optionally substituted in the 3-, 4-, 5-, 6- or 7-position by a halogen atom or a hydroxy group, a (C1-3-alkoxy)carbonyl group, a C1-6-alkylsulphonyl group, a benzoyl, benzenesulphonyl, phenyl(C1-3-alkanesulphonyl), naphthalenesulphonyl, 2-carboxy-cyclohexylcarbonyl, 2-aminocarbonyl-cyclohexylcarbonyl, (C5-7-cycloalkyl)-carbonyl, phenyl(C1-4-alkanoyl) or (C5-7-cycloalkyl)C1-4-alkanoyl group, in which the above-mentioned phenyl nuclei are optionally mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group which substituents may be identical or different a C3-5-alkylsllltam group, a pyrrolidino, piperidino or hexamethyleneimino group optionally substituted by a C1-3-alkyl or hydroxycarbonyl(C1-3-alkyl) group, a pyrrolidinone, piperidinone or hexamethyleneiminone group, an optionally totally or partially hydrogenated phthalimido or 2-oxo-isoindolin-1-yl group or a group of formula - ? - CO - [in which R6, R7 and R8, which may be identical or different, represent hydrogen atoms, C1-8-alkyl groups, C5-7-cycloalkyl, phenyl, (C5-7-cycloalkyl)C1-3-alkyl or phenyl-(C13-alkyl) groups, and R8 may also represent a 2-chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3-bromo-propyl group, and where R6 and R7 together represent an ethylene or propylene group, R8 may also represent a di(C1-3-alkyl)aminocarbonyl group, or R6 and R7 together represent an ethylene or propylene group, and in which the phenyl nucleus of the above mentioned phenyl and phenyl(C1-3-alkyl) groups may in each case be mono- or disubstituted by hydroxy or C13-alkoxy groups which substituents may be identical or different], and R1 may also represent a hydrogen atom, except where R2 represents a hydrogen atom, R3 represents an n-butyl group, R4 represents a carboxy group and R5 represents a hydrogen atom, and (i) one of the groups A1, A2, A3 and A4 represents a nitrogen atom and the remaining groups A1, A2, A3 or A4 each represent methine groups, or (ii) A2 and A4 or A1 and A3 each represent a nitrogen atom and the remaining groups A1 and A3 or A2 and A4 each represent a methine group, or (iii) A4 represents a nitrogen atom and A3 represents a methine group substituted by a hydroxy or methoxy group and the remaining groups A1 and A2 each represent a methine group, or (iv) A4 represents a nitrogen atom, A1 represents a methine group substituted by a methyl group and the remaining groups A2 and A3 each represent a methine group;
R2 represents a hydrogen atom or a C1-3-alkyl group;
R3 represents a C1-6-alkyl group;
R4 represents a carboxy, cyano, 1H-tetrazolyl or 1-triphenylmethyl-tetrazolyl group or a (C1-4-alkoxy)-carbonyl group; and R5 represents a hydrogen, fluorine, chlorine or bromine atom);
and the isomers and addition salts thereof.
(wherein one or two of A1, A2, A3 and A4 represent a nitrogen atom and the remaining two or three of A1, A2, A3 and A4 each represent a methine group;
R1 represents a fluorine, chlorine or bromine atom, a hydroxy, alkyl or alkoxy group, an amino group optionally mono- or disubstituted, or an N-acylamino group optionally monosubstituted, at the nitrogen atom by a C16-alkyl, phenyl, C5-7-cycloalkyl, phenyl(C1-3-alkyl) or (C5-7-cycloalkyl)C1-3-alkyl group, which substituents may be identical or different and which acyl group is a C1-7-alkanoyl group optionally substituted in the 3-, 4-, 5-, 6- or 7-position by a halogen atom or a hydroxy group, a (C1-3-alkoxy)carbonyl group, a C1-6-alkylsulphonyl group, a benzoyl, benzenesulphonyl, phenyl(C1-3-alkanesulphonyl), naphthalenesulphonyl, 2-carboxy-cyclohexylcarbonyl, 2-aminocarbonyl-cyclohexylcarbonyl, (C5-7-cycloalkyl)-carbonyl, phenyl(C1-4-alkanoyl) or (C5-7-cycloalkyl)C1-4-alkanoyl group, in which the above-mentioned phenyl nuclei are optionally mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group which substituents may be identical or different a C3-5-alkylsllltam group, a pyrrolidino, piperidino or hexamethyleneimino group optionally substituted by a C1-3-alkyl or hydroxycarbonyl(C1-3-alkyl) group, a pyrrolidinone, piperidinone or hexamethyleneiminone group, an optionally totally or partially hydrogenated phthalimido or 2-oxo-isoindolin-1-yl group or a group of formula - ? - CO - [in which R6, R7 and R8, which may be identical or different, represent hydrogen atoms, C1-8-alkyl groups, C5-7-cycloalkyl, phenyl, (C5-7-cycloalkyl)C1-3-alkyl or phenyl-(C13-alkyl) groups, and R8 may also represent a 2-chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3-bromo-propyl group, and where R6 and R7 together represent an ethylene or propylene group, R8 may also represent a di(C1-3-alkyl)aminocarbonyl group, or R6 and R7 together represent an ethylene or propylene group, and in which the phenyl nucleus of the above mentioned phenyl and phenyl(C1-3-alkyl) groups may in each case be mono- or disubstituted by hydroxy or C13-alkoxy groups which substituents may be identical or different], and R1 may also represent a hydrogen atom, except where R2 represents a hydrogen atom, R3 represents an n-butyl group, R4 represents a carboxy group and R5 represents a hydrogen atom, and (i) one of the groups A1, A2, A3 and A4 represents a nitrogen atom and the remaining groups A1, A2, A3 or A4 each represent methine groups, or (ii) A2 and A4 or A1 and A3 each represent a nitrogen atom and the remaining groups A1 and A3 or A2 and A4 each represent a methine group, or (iii) A4 represents a nitrogen atom and A3 represents a methine group substituted by a hydroxy or methoxy group and the remaining groups A1 and A2 each represent a methine group, or (iv) A4 represents a nitrogen atom, A1 represents a methine group substituted by a methyl group and the remaining groups A2 and A3 each represent a methine group;
R2 represents a hydrogen atom or a C1-3-alkyl group;
R3 represents a C1-6-alkyl group;
R4 represents a carboxy, cyano, 1H-tetrazolyl or 1-triphenylmethyl-tetrazolyl group or a (C1-4-alkoxy)-carbonyl group; and R5 represents a hydrogen, fluorine, chlorine or bromine atom);
and the isomers and addition salts thereof.
2. A compound of formula I as claimed in claim 1, wherein one or two of A1, A2, A3 and A4 represent a nitrogen atom and the remaining two or three of A1, A2, A3 and A4 each represent a methine group;
R1 represents a fluorine atom, an amino or C1-6-alkylamino group substituted at the nitrogen atom by a phenyl, C5-7-cycloalkyl, phenyl(C1-3-alkyl) or (C5-7-cycloalkyl)C1-3-alkyl group, an amino group disubstituted by a phenyl, C5-7-cycloalkyl, phenyl(C1-3-alkyl) or (C5-7-cycloalkyl)C1-3-alkyl group which substituents may be identical or different, or an acylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl, phenyl, C5-7-cycloalkyl, phenyl (C1-3-alkyl) or (C5-7 cycloalkyl)C1-3-alkyl group and in which the acyl group is a C2-7-alkanoyl group substituted in the terminal position by a chlorine atom or by a hydroxy group, a (C1-3-alkoxy)carbonyl group, a C1-6-alkylsulphonyl group, a formyl, benzoyl, benzenesulphonyl, phenyl (C1-3-alkanesulphonyl), naphthalenesulphonyl, 2-carboxy-cyclohexylcarbonyl, 2-aminocarbonyl-cyclohexylcarbonyl, (C5-7cycloalkyl)carbonyl, phenylalkanoyl or (C5-7-cycloalkyl)C1-4-alkanoyl group, in which the above-mentioned phenyl nuclei is optionally mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group which substituents may be identical or different, a C3-5-alkylsultam group, a pyrrolidino, piperidino or hexamethyleneimino group optionally substituted by a C13-alkyl or hydroxycarbonyl(C1-3-alkyl) group, a pyrrolidinone, piperidinone or hexamethyleneiminone group, an optionally wholly or partially hydrogenated phthalimido group or a group of formula - ? - CO - [in which R6, R7 and R8, which may be identical or different, represent hydrogen atoms, C1-8-alkyl groups, Cs7-cycloalkyl, phenyl, (C5-7-cycloalkyl)C1-3-alkyl or phenyl(C1-3-alkyl) groups, and R8 may also represent a 2-chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3-bromo-propyl group, and where R6 and R7 together represent an ethylene or propylene group, R8 may also represent a di(C1-3-alkyl)aminocarbonyl group, or R6 and R7 together represent an ethylene or propylene group), and in which the phenyl nucleus of the above-mentioned phenyl and phenyl(C1-3 alkyl) groups may be. mono or disubstituted by hydroxy or C1-3-alkoxy groups which substituents may ba identical or different], and R2 represents a hydrogen atom or a C1-3 alkyl group;
R3 represents a Cl-6-alkyl group;
R4 represents a carboxy, cyano, lH-tetrazolyl, 1-triphenylmethyl-tetrazolyl group or a (C1-4-alkoxy)-carbonyl group; and Rs represents a hydrogen, fluorine, chlorine or bromine atom;
and the isomars and addition salts thereof.
R1 represents a fluorine atom, an amino or C1-6-alkylamino group substituted at the nitrogen atom by a phenyl, C5-7-cycloalkyl, phenyl(C1-3-alkyl) or (C5-7-cycloalkyl)C1-3-alkyl group, an amino group disubstituted by a phenyl, C5-7-cycloalkyl, phenyl(C1-3-alkyl) or (C5-7-cycloalkyl)C1-3-alkyl group which substituents may be identical or different, or an acylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl, phenyl, C5-7-cycloalkyl, phenyl (C1-3-alkyl) or (C5-7 cycloalkyl)C1-3-alkyl group and in which the acyl group is a C2-7-alkanoyl group substituted in the terminal position by a chlorine atom or by a hydroxy group, a (C1-3-alkoxy)carbonyl group, a C1-6-alkylsulphonyl group, a formyl, benzoyl, benzenesulphonyl, phenyl (C1-3-alkanesulphonyl), naphthalenesulphonyl, 2-carboxy-cyclohexylcarbonyl, 2-aminocarbonyl-cyclohexylcarbonyl, (C5-7cycloalkyl)carbonyl, phenylalkanoyl or (C5-7-cycloalkyl)C1-4-alkanoyl group, in which the above-mentioned phenyl nuclei is optionally mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group which substituents may be identical or different, a C3-5-alkylsultam group, a pyrrolidino, piperidino or hexamethyleneimino group optionally substituted by a C13-alkyl or hydroxycarbonyl(C1-3-alkyl) group, a pyrrolidinone, piperidinone or hexamethyleneiminone group, an optionally wholly or partially hydrogenated phthalimido group or a group of formula - ? - CO - [in which R6, R7 and R8, which may be identical or different, represent hydrogen atoms, C1-8-alkyl groups, Cs7-cycloalkyl, phenyl, (C5-7-cycloalkyl)C1-3-alkyl or phenyl(C1-3-alkyl) groups, and R8 may also represent a 2-chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3-bromo-propyl group, and where R6 and R7 together represent an ethylene or propylene group, R8 may also represent a di(C1-3-alkyl)aminocarbonyl group, or R6 and R7 together represent an ethylene or propylene group), and in which the phenyl nucleus of the above-mentioned phenyl and phenyl(C1-3 alkyl) groups may be. mono or disubstituted by hydroxy or C1-3-alkoxy groups which substituents may ba identical or different], and R2 represents a hydrogen atom or a C1-3 alkyl group;
R3 represents a Cl-6-alkyl group;
R4 represents a carboxy, cyano, lH-tetrazolyl, 1-triphenylmethyl-tetrazolyl group or a (C1-4-alkoxy)-carbonyl group; and Rs represents a hydrogen, fluorine, chlorine or bromine atom;
and the isomars and addition salts thereof.
3. A compound of formula I as claimed in claim 1 or claim 2, wherein one or two of A1, A2, A3 and A4 represent a nitrogen atom and the remaining two or three of A1, A2, A3 and A4 each represent a methine group;
R1 represents an amino, methylamino or ethylamino group substituted by a cyclohexyl, cyclohexylmethyl, benzyl or dimethoxybenzyl group, an amino, cyclohexylamino, cyclohexylmethyl or C14-alkylamino group substituted by a C2-6-alkanoyl, C1-4,-alkanesulphonyl, C2-4-alkoxycarbonyl, cyclohexylcarbonyl, benzylcarbonyl, 2-aminocarbonyl-cyclohexylcarbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a C3-4-alkylsultam group a pyrrolidino or piperidino group optionally substituted by a methyl or hydroxycarbonylmethyl group, a pyrrolidin-2-on-1-yl or piperidin-2-on-1-yl group, an optionally fully hydrogenated phthalimido or 2-oxo-isoindolin-1-yl group or a group of formula - ? - CO - [in which R6, R7 and R8, which may be identical or different, represent hydrogen atoms, C1-4-alkyl groups, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, and R8 may also represent a 2-chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3 bromo-propyl group, and where R6 and R7 together represent an ethylene or propylene group, R8 may also represent a dimethylaminocarbonyl group, or R6 and R7 together represent an ethylene or propylene group];
R2 represents a hydrogen atom or a methyl or ethyl group;
R3 represents a C1-5-alkyl group;
R4 represents a carboxy or lH-tetrazolyl group; and R5 represents a hydrogen atom;
and the isomers and salts thereof.
R1 represents an amino, methylamino or ethylamino group substituted by a cyclohexyl, cyclohexylmethyl, benzyl or dimethoxybenzyl group, an amino, cyclohexylamino, cyclohexylmethyl or C14-alkylamino group substituted by a C2-6-alkanoyl, C1-4,-alkanesulphonyl, C2-4-alkoxycarbonyl, cyclohexylcarbonyl, benzylcarbonyl, 2-aminocarbonyl-cyclohexylcarbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a C3-4-alkylsultam group a pyrrolidino or piperidino group optionally substituted by a methyl or hydroxycarbonylmethyl group, a pyrrolidin-2-on-1-yl or piperidin-2-on-1-yl group, an optionally fully hydrogenated phthalimido or 2-oxo-isoindolin-1-yl group or a group of formula - ? - CO - [in which R6, R7 and R8, which may be identical or different, represent hydrogen atoms, C1-4-alkyl groups, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, and R8 may also represent a 2-chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3 bromo-propyl group, and where R6 and R7 together represent an ethylene or propylene group, R8 may also represent a dimethylaminocarbonyl group, or R6 and R7 together represent an ethylene or propylene group];
R2 represents a hydrogen atom or a methyl or ethyl group;
R3 represents a C1-5-alkyl group;
R4 represents a carboxy or lH-tetrazolyl group; and R5 represents a hydrogen atom;
and the isomers and salts thereof.
4. A compound as claimed in any one of claims 1 to 3 wherein one or two of Al, A2, A3 and A4 represent a nitrogen atom and the remaining two or three of A1, A2, A3 and A4 each represent a methine group;
R1 represents an amino, methylamino or ethylamino group substituted by a cyclohexyl or cyclohexylmethyl group, a cyclohexylamino or cyclohexylmethylamino group substituted by a C2-6-alkanoyl, C1-4-alkanesulphonyl, C2-4-alkoxycarbonyl, benzylcarbonyl, 2-aminocarbonylcyclohexylcarbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a cyclohexylcarbonylamino group, a cyclohexylamino, cyclohexylmethylamino or C1-4-alkylamino group substituted by a C1-4-alkanesulphonyl, cyclohexylcarbonyl, 2-aminocarbonyl-cyclohexyl-carbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a C3-4- alkylsultam group, a pyrrolidino or piperidino group substituted by a methyl or hydroxycarbonylmethyl group, a pyrrolidin-2-on-1-yl or piperidin-2-on-1-yl group, an optionally fully hydrogenated phthalimido or 2-oxo-isoindolin-1-yl group or a group of formula - ? - CO - [in which one of the groups R6, R7 or R8 represents a cyclopentyl, cyclohexyl or cyclohexylmethyl group, and the remaining groups R6, R7 or R8, which may be identical or different, represent hydrogen atoms or C14-alkyl, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, or R7 represents a 2-chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3-bromo-propyl group, and R6 and R8, which may be identical or different, represent hydrogen atoms or C14-alkyl, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, or R6 and R7 together represent an ethylene or propylene group, and R8 represents a hydrogen atom, a C14-alkyl group, a cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl, hydroxybenzyl, 2-chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl, 3-bromo-propyl or dimethylamino-carbonyl group];
R2 represents a hydrogen atom or a methyl or ethyl group;
R3 represents a C15-alkyl group;
R4 represents a carboxy or 1H-tetrazoyl group; and R5 represents a hydrogen atom;
and the isomers and addition salts thereof.
R1 represents an amino, methylamino or ethylamino group substituted by a cyclohexyl or cyclohexylmethyl group, a cyclohexylamino or cyclohexylmethylamino group substituted by a C2-6-alkanoyl, C1-4-alkanesulphonyl, C2-4-alkoxycarbonyl, benzylcarbonyl, 2-aminocarbonylcyclohexylcarbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a cyclohexylcarbonylamino group, a cyclohexylamino, cyclohexylmethylamino or C1-4-alkylamino group substituted by a C1-4-alkanesulphonyl, cyclohexylcarbonyl, 2-aminocarbonyl-cyclohexyl-carbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a C3-4- alkylsultam group, a pyrrolidino or piperidino group substituted by a methyl or hydroxycarbonylmethyl group, a pyrrolidin-2-on-1-yl or piperidin-2-on-1-yl group, an optionally fully hydrogenated phthalimido or 2-oxo-isoindolin-1-yl group or a group of formula - ? - CO - [in which one of the groups R6, R7 or R8 represents a cyclopentyl, cyclohexyl or cyclohexylmethyl group, and the remaining groups R6, R7 or R8, which may be identical or different, represent hydrogen atoms or C14-alkyl, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, or R7 represents a 2-chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl or 3-bromo-propyl group, and R6 and R8, which may be identical or different, represent hydrogen atoms or C14-alkyl, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, or R6 and R7 together represent an ethylene or propylene group, and R8 represents a hydrogen atom, a C14-alkyl group, a cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl, hydroxybenzyl, 2-chloro-ethyl, 2-bromo-ethyl, 3-chloro-propyl, 3-bromo-propyl or dimethylamino-carbonyl group];
R2 represents a hydrogen atom or a methyl or ethyl group;
R3 represents a C15-alkyl group;
R4 represents a carboxy or 1H-tetrazoyl group; and R5 represents a hydrogen atom;
and the isomers and addition salts thereof.
5. A compound as claimed in any one of claims 1 to 4 being 4'-[(2-n-butyl-3H-imidazo[4,5 b]pyridin-3-yl)methyl]-biphenyl-2-carboxylic acid;
4'-[(2-n-butyl-5-methyl-6-phthalimido-3H-imidazo[4,5-b]-pyridin-3-yl)methyl]-biphenyl-2-carboxylic acid;
4'-[(2-n-butyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-biphenyl-2-carboxylic acid;
4'-[(2-n-butyl-5-amino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]-biphenyl-2 carboxylic acid;
4'-[(2-benzylamino-8-n-butyl-9H-purin-9-yl)-methyl]-biphenyl-2-carboxylic acid;
4'-[(2-n-butyl-5-methyl-6-propionylamino-3H-imidazo-[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid;
4'-[(2-n-butyl-5-cyclohexylamino-3H-imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylic acid;
4'-[(2-n-butyl-5-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid;
4'-[(2-n-butyl-5-methyl-6-valeroylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid;
4'-[(2-n-butyl-5-[3-benzyl-3,4, 5,6-tetrahydro-2(1H)-pyrimidinon-l-yl]-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylic acid;
4'-[(2-n-propyl-5-cyclohexylcarbonylamino-3H-imidazo[4,5-b]pyridin 3-yl)methyl]-2-(1H-tetrazol-5-yl)biphenyl;
4'-[[2-ethyl-5-(2,2-dimethyl-propionylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl; or 4'-[(2-n-propyl-5-(2-methyl-propionylamino)-3H-imidazo-r4,5-b]pyridin-3-yl)-methyl]-2-(lH-tetrazol-5-yl)biphanyl;
or an addition salt thereof.
4'-[(2-n-butyl-5-methyl-6-phthalimido-3H-imidazo[4,5-b]-pyridin-3-yl)methyl]-biphenyl-2-carboxylic acid;
4'-[(2-n-butyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-biphenyl-2-carboxylic acid;
4'-[(2-n-butyl-5-amino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]-biphenyl-2 carboxylic acid;
4'-[(2-benzylamino-8-n-butyl-9H-purin-9-yl)-methyl]-biphenyl-2-carboxylic acid;
4'-[(2-n-butyl-5-methyl-6-propionylamino-3H-imidazo-[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid;
4'-[(2-n-butyl-5-cyclohexylamino-3H-imidazo[4,5-b]-pyridin-3-yl)methyl]biphenyl-2-carboxylic acid;
4'-[(2-n-butyl-5-(N-cyclohexylcarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid;
4'-[(2-n-butyl-5-methyl-6-valeroylamino-3H-imidazo-[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid;
4'-[(2-n-butyl-5-[3-benzyl-3,4, 5,6-tetrahydro-2(1H)-pyrimidinon-l-yl]-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylic acid;
4'-[(2-n-propyl-5-cyclohexylcarbonylamino-3H-imidazo[4,5-b]pyridin 3-yl)methyl]-2-(1H-tetrazol-5-yl)biphenyl;
4'-[[2-ethyl-5-(2,2-dimethyl-propionylamino)-3H-imidazo-[4,5-b]pyridin-3-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl; or 4'-[(2-n-propyl-5-(2-methyl-propionylamino)-3H-imidazo-r4,5-b]pyridin-3-yl)-methyl]-2-(lH-tetrazol-5-yl)biphanyl;
or an addition salt thereof.
6. A compound as claimed in any one of claims l to 5 being a physiologically acceptable addition salt of a compound of formula I.
7. A process for the praparation of compounds as claimed in claim l, said process comprising at least one of the following stepsO
a) cyclising a compound of formula II
(wherein R1, R2, A1, A2, A3 and A4 are as defined in claims l to 5;
one of the groups X1 or Y1 represents a group of formula and the other group X1 or Y1 represents a group of formula R3 and R5 are as defined in claims 1 to 5;
R9 represents a hydrogen atom or an R3CO group; and R3 is as hereinbefore defined;
Z1 and Z2, which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl groups, or Z1 and Z2 together represent an oxygen or sulphur atom, an imino group optionally substituted by a C13-alkyl group, or a C2-3-alkylenedioxy or C2-3-alkylenedithio group, with the proviso that one of the groups X1 or Y
must represent a group of formula or - NH - ? - R3 ) or an N-oxide thereof and if necessary subsequently reducing the cyclised N-oxide;
b) reacting a compound of formula III
(III) (wherein R1, R2, R3, A1, A2, A3 and A4 are as defined in claims 1 to 5) with a biphenyl compound of formula IV
(IV) (wherein R4 and R5 are as defined in claims 1 to 5; and Z3 represents a nucleophilic leaving group), c) (to prepare a compound of formula I wherein R4 represents a carboxy group) converting a compound of formula V
(V) (wherein R1, R2, R3, R5, A1, A2, A3 and A4 are as defined in claims 1 to 5; and R4' represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound:
d) (to prepare a compound of formula I wherein R4 represents a lH-tetrazolyl group) cleaving a protecting group from a compound of formula VI
(wherein R1, R2, R3, R5, A1, A2, A3 and A4 are as defined in claims 1 to 5; and R4" represents a 1H-tetrazolyl group protected in the 1 position by a protecting group);
e) (to prepare a compound of formula I wherein R4 represents a lH-tetrazolyl group) reacting a compound of formula VII
(wherein R1, R2, R3, R5, A1, A2, A3 and A4 are as defined in claims 1 to 5) with hydrazoic acid or the salts thereof;
f) to prepare compounds of formula I wherein R1 represents an amino group optionally substituted by a C1-6-alkyl, phenyl, C5-7-cycloalkyl, phenyl(C1-3-alkyl) or (C5-7-cycloalkyl)C1-3-alkyl group) converting a compound of formula VIII
(VIII) (wherein R2, R3, R4, R5, A1, A2, A3 and A4 are as defined in claims 1 to 5; and R10 represents a group which can be converted by hydrolysis, hydrogenolysis or transamidation into an amino group optionally substituted by a C1-6-alkyl, phenyl, C5-7-cycloalkyl, phenyl(C1-3-alkyl) or (C5-7-cycloalkyl)C1-3-alkyl group) into a corresponding compound;
g) (to prepare compounds of formula I wherein R
represents a group of formula reacting a compound of formula IX
(IX) (wherein R2, R3, R4, R5, A1, A2, A3 and A4 are as defined in claims 1 to 5; and R11 represents an R6NH group, wherein R6 is as defined in claims 1 to 5) with a compound of formula X
(X) (wherein R7 and R8 are as defined in claims 1 to 5;
Z4 represents a nucleophilic leaving group, or Z4 together with R7 represents a nitrogen-carbon bond);
h) (to prepare compounds of formula I wherein R1 represents an N-acylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl, phenyl, cycloalkyl, phenylalkyl or cycloalkylalkyl group) acylating a compound of formula XI
(XI) (wherein R2, R3, R4, R5, A1, A2, A3 and A4 are as defined in claims l. to 5; and R12 represents an amino group optionally substituted by a C1-6-alkyl, phenyl, C5-7-cycloalkyl, phenyl(C1-3-alkyl) or (Cs7-cycloalkyl)C13-alkyl group) with a compound of formula XII
R13 - W - OH (XII) (wherein W represents a carbonyl or sulphonyl group; and R13 represents a C1-6-alkyl group, a C13-alkoxy group, a phenyl(C1-3-alkyl), C5-7-cycloalkyl or (C5-7-cycloalkyl)C1-3-alkyl group, a phenyl, naphthyl, 2-carboxy-cyclohexyl or 2-aminocarbonyl-cyclohexyl group, in which the above-mentioned phenyl nuclei may be mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group which substituents may be identical or d.ifferent, or, if W represents a carbonyl group, R13 may also represent a hydrogen atom) or with a reactive derivative thereof;
i) (to prepare a compound of formula I wherein R6 and R7 together represent an ethylene or n-propylene group) cyclising a compound of formula XIII
(XIII) (wherein R2, R3, R4, R5, R8, A1, A2, A3 and A4 are as defined in claims 1 to 5;
Ha1 represents a chlorine, bromine or iodine atom; and n represents the number 2 or 3) and if necessary subsequently reacting with a compound of formula XIV
R8 - Hal (XIV) (wherein R8 is as defined in claims 1 to 5, with the exception of the hydrogen atom; and Hal represents a chlorine, brornine or iodine atom);
j) resolving a 1-, 3-isomer mixture of a compound of formula I by isomer separation into the 1- and 3-isomers thereof;
k) converting a compound of formula I into an addition salt thereof, more particularly for pharmaceutical use into a physiologically acceptable salt thereof with an inorganic or organic acid or base or converting a salt of a compound of formula I into the free compound; and 1) performing a process as defined in any one of steps (a) to (k) above on a corresponding protected compound and subsequently removing the protecting group used.
a) cyclising a compound of formula II
(wherein R1, R2, A1, A2, A3 and A4 are as defined in claims l to 5;
one of the groups X1 or Y1 represents a group of formula and the other group X1 or Y1 represents a group of formula R3 and R5 are as defined in claims 1 to 5;
R9 represents a hydrogen atom or an R3CO group; and R3 is as hereinbefore defined;
Z1 and Z2, which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl groups, or Z1 and Z2 together represent an oxygen or sulphur atom, an imino group optionally substituted by a C13-alkyl group, or a C2-3-alkylenedioxy or C2-3-alkylenedithio group, with the proviso that one of the groups X1 or Y
must represent a group of formula or - NH - ? - R3 ) or an N-oxide thereof and if necessary subsequently reducing the cyclised N-oxide;
b) reacting a compound of formula III
(III) (wherein R1, R2, R3, A1, A2, A3 and A4 are as defined in claims 1 to 5) with a biphenyl compound of formula IV
(IV) (wherein R4 and R5 are as defined in claims 1 to 5; and Z3 represents a nucleophilic leaving group), c) (to prepare a compound of formula I wherein R4 represents a carboxy group) converting a compound of formula V
(V) (wherein R1, R2, R3, R5, A1, A2, A3 and A4 are as defined in claims 1 to 5; and R4' represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound:
d) (to prepare a compound of formula I wherein R4 represents a lH-tetrazolyl group) cleaving a protecting group from a compound of formula VI
(wherein R1, R2, R3, R5, A1, A2, A3 and A4 are as defined in claims 1 to 5; and R4" represents a 1H-tetrazolyl group protected in the 1 position by a protecting group);
e) (to prepare a compound of formula I wherein R4 represents a lH-tetrazolyl group) reacting a compound of formula VII
(wherein R1, R2, R3, R5, A1, A2, A3 and A4 are as defined in claims 1 to 5) with hydrazoic acid or the salts thereof;
f) to prepare compounds of formula I wherein R1 represents an amino group optionally substituted by a C1-6-alkyl, phenyl, C5-7-cycloalkyl, phenyl(C1-3-alkyl) or (C5-7-cycloalkyl)C1-3-alkyl group) converting a compound of formula VIII
(VIII) (wherein R2, R3, R4, R5, A1, A2, A3 and A4 are as defined in claims 1 to 5; and R10 represents a group which can be converted by hydrolysis, hydrogenolysis or transamidation into an amino group optionally substituted by a C1-6-alkyl, phenyl, C5-7-cycloalkyl, phenyl(C1-3-alkyl) or (C5-7-cycloalkyl)C1-3-alkyl group) into a corresponding compound;
g) (to prepare compounds of formula I wherein R
represents a group of formula reacting a compound of formula IX
(IX) (wherein R2, R3, R4, R5, A1, A2, A3 and A4 are as defined in claims 1 to 5; and R11 represents an R6NH group, wherein R6 is as defined in claims 1 to 5) with a compound of formula X
(X) (wherein R7 and R8 are as defined in claims 1 to 5;
Z4 represents a nucleophilic leaving group, or Z4 together with R7 represents a nitrogen-carbon bond);
h) (to prepare compounds of formula I wherein R1 represents an N-acylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl, phenyl, cycloalkyl, phenylalkyl or cycloalkylalkyl group) acylating a compound of formula XI
(XI) (wherein R2, R3, R4, R5, A1, A2, A3 and A4 are as defined in claims l. to 5; and R12 represents an amino group optionally substituted by a C1-6-alkyl, phenyl, C5-7-cycloalkyl, phenyl(C1-3-alkyl) or (Cs7-cycloalkyl)C13-alkyl group) with a compound of formula XII
R13 - W - OH (XII) (wherein W represents a carbonyl or sulphonyl group; and R13 represents a C1-6-alkyl group, a C13-alkoxy group, a phenyl(C1-3-alkyl), C5-7-cycloalkyl or (C5-7-cycloalkyl)C1-3-alkyl group, a phenyl, naphthyl, 2-carboxy-cyclohexyl or 2-aminocarbonyl-cyclohexyl group, in which the above-mentioned phenyl nuclei may be mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group which substituents may be identical or d.ifferent, or, if W represents a carbonyl group, R13 may also represent a hydrogen atom) or with a reactive derivative thereof;
i) (to prepare a compound of formula I wherein R6 and R7 together represent an ethylene or n-propylene group) cyclising a compound of formula XIII
(XIII) (wherein R2, R3, R4, R5, R8, A1, A2, A3 and A4 are as defined in claims 1 to 5;
Ha1 represents a chlorine, bromine or iodine atom; and n represents the number 2 or 3) and if necessary subsequently reacting with a compound of formula XIV
R8 - Hal (XIV) (wherein R8 is as defined in claims 1 to 5, with the exception of the hydrogen atom; and Hal represents a chlorine, brornine or iodine atom);
j) resolving a 1-, 3-isomer mixture of a compound of formula I by isomer separation into the 1- and 3-isomers thereof;
k) converting a compound of formula I into an addition salt thereof, more particularly for pharmaceutical use into a physiologically acceptable salt thereof with an inorganic or organic acid or base or converting a salt of a compound of formula I into the free compound; and 1) performing a process as defined in any one of steps (a) to (k) above on a corresponding protected compound and subsequently removing the protecting group used.
8. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable addition salt thereof together with at least one pharmaceutical carrier or excipient.
9. Use of a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of cardiac insufficiency progression after myocardial infarct, or for the treatment of diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
10. A method of treatment of the human or non-human animal body to combat hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), cardiac insufficiency progression after myocardial infarction, diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering to said body a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable addition salt thereof.
11. A compound of formula I as claimed in claim 1 or a pharmaceutical composition thereof substantially as herein disclosed in any one of the Examples.
12. Each and every novel compound, composition, process, use and method as herein disclosed.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4025358.9 | 1990-08-10 | ||
| DE19904025358 DE4025358A1 (en) | 1990-08-10 | 1990-08-10 | HETEROCYCLIC IMIDAZOLE, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| DEP4031601.7 | 1990-10-05 | ||
| DE19904031601 DE4031601A1 (en) | 1990-08-10 | 1990-10-05 | HETEROCYCLIC IMIDAZOLE, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| DEP4105827.5 | 1991-02-25 | ||
| DE19914105827 DE4105827A1 (en) | 1990-08-10 | 1991-02-25 | New bi:phenyl:methyl-substd. imidazole derivs. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2048809A1 true CA2048809A1 (en) | 1992-02-11 |
Family
ID=27201550
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002048809A Abandoned CA2048809A1 (en) | 1990-08-10 | 1991-08-08 | Heterocyclic imidazoles, pharmaceutical compositions containing these compounds and processes for preparing them |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0470543A1 (en) |
| JP (1) | JPH06340665A (en) |
| AU (1) | AU650278B2 (en) |
| CA (1) | CA2048809A1 (en) |
| HU (1) | HUT59140A (en) |
| IE (1) | IE912822A1 (en) |
| PT (1) | PT98635A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10087182B2 (en) | 2010-05-17 | 2018-10-02 | Incozen Therapeutics Pvt. Ltd. | 3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of protein kinases |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5223499A (en) * | 1989-05-30 | 1993-06-29 | Merck & Co., Inc. | 6-amino substituted imidazo[4,5-bipyridines as angiotensin II antagonists |
| US5332744A (en) * | 1989-05-30 | 1994-07-26 | Merck & Co., Inc. | Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists |
| IE70593B1 (en) * | 1989-09-29 | 1996-12-11 | Eisai Co Ltd | Biphenylmethane derivative the use of it and pharmacological compositions containing same |
| DE4224752A1 (en) * | 1992-04-11 | 1994-02-03 | Thomae Gmbh Dr K | Benzimidazoles, medicaments containing these compounds and process for their preparation |
| TW274551B (en) * | 1991-04-16 | 1996-04-21 | Takeda Pharm Industry Co Ltd | |
| AU2338992A (en) * | 1991-07-26 | 1993-03-02 | G.D. Searle & Co. | Carbonate-substituted imidazo(4,5-d) pyridazine compounds for treatment of cardiovascular disorders |
| DE4129603A1 (en) * | 1991-09-06 | 1993-03-11 | Thomae Gmbh Dr K | CONDENSED 5-LOW HETEROCYCLES, METHOD FOR THE PRODUCTION THEREOF, AND MEDICAMENTS CONTAINING THESE COMPOUNDS |
| CA2077419C (en) * | 1991-09-10 | 1998-08-25 | Yasushi Honma | Imidazopyridine derivatives and process for preparation thereof |
| TW300219B (en) * | 1991-09-14 | 1997-03-11 | Hoechst Ag | |
| DE69321471T2 (en) * | 1992-07-10 | 1999-03-04 | Knoll AG, 67061 Ludwigshafen | DIOXCYCLOBUTEN DERIVATIVES AS ANGIOTENSIN II ANTAGONISTS |
| GB9218449D0 (en) | 1992-08-29 | 1992-10-14 | Boots Co Plc | Therapeutic agents |
| GB9217820D0 (en) * | 1992-08-21 | 1992-10-07 | Fujisawa Pharmaceutical Co | New use |
| DE4304455A1 (en) * | 1993-02-15 | 1994-08-18 | Bayer Ag | Heterocyclic substituted phenyl-cyclohexane-carboxylic acid derivatives |
| KR0151819B1 (en) * | 1994-06-11 | 1998-10-15 | 강박광 | Novel pyridylimidazole derivatives substituted with pyridyl n-oxide and process for the preparation thereof |
| SE9903028D0 (en) | 1999-08-27 | 1999-08-27 | Astra Ab | New use |
| BRPI0412003A (en) | 2003-07-02 | 2006-08-15 | Sugen Inc | arylmethyl triazole and imidazopyrazines as c-met inhibitors |
| MX2009004154A (en) * | 2006-10-20 | 2009-09-09 | Organon Nv | Purines as pkc-theta inhibitors. |
| EP2998314B1 (en) | 2007-06-04 | 2020-01-22 | Bausch Health Ireland Limited | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| WO2009099853A2 (en) * | 2008-02-08 | 2009-08-13 | Merck & Co., Inc. | Angiotensin ii receptor antagonists |
| EP2328910B1 (en) | 2008-06-04 | 2014-08-06 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| CA2730603C (en) | 2008-07-16 | 2019-09-24 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| DK2669270T3 (en) * | 2011-01-28 | 2018-02-26 | Sato Pharma | Indole-related compounds such as URAT1 inhibitors |
| EP2968439A2 (en) | 2013-03-15 | 2016-01-20 | 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 |
| RS65632B1 (en) | 2013-06-05 | 2024-07-31 | Bausch Health Ireland Ltd | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
| GB201321741D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4804658A (en) * | 1986-09-15 | 1989-02-14 | G. D. Searle & Co. | Imidazopyridine derivatives and pharmaceutical compositions |
| IE64514B1 (en) * | 1989-05-23 | 1995-08-09 | Zeneca Ltd | Azaindenes |
| IL94390A (en) * | 1989-05-30 | 1996-03-31 | Merck & Co Inc | Di-substituted imidazo fused 6-membered nitrogen-containing heterocycles and pharmaceutical compositions containing them |
| EP0415886A3 (en) * | 1989-08-30 | 1991-10-23 | Ciba-Geigy Ag | Aza compounds |
| IE70593B1 (en) * | 1989-09-29 | 1996-12-11 | Eisai Co Ltd | Biphenylmethane derivative the use of it and pharmacological compositions containing same |
| IL96019A0 (en) * | 1989-10-31 | 1991-07-18 | Fujisawa Pharmaceutical Co | Imidazole derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same |
-
1991
- 1991-08-05 EP EP91113121A patent/EP0470543A1/en not_active Withdrawn
- 1991-08-08 CA CA002048809A patent/CA2048809A1/en not_active Abandoned
- 1991-08-09 IE IE282291A patent/IE912822A1/en unknown
- 1991-08-09 HU HU912665A patent/HUT59140A/en unknown
- 1991-08-09 JP JP3199654A patent/JPH06340665A/en active Pending
- 1991-08-09 AU AU81717/91A patent/AU650278B2/en not_active Expired - Fee Related
- 1991-08-09 PT PT98635A patent/PT98635A/en not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10087182B2 (en) | 2010-05-17 | 2018-10-02 | Incozen Therapeutics Pvt. Ltd. | 3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of protein kinases |
| US10590129B2 (en) | 2010-05-17 | 2020-03-17 | Rhizen Pharmaceuticals Sa | 3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of protein kinases |
Also Published As
| Publication number | Publication date |
|---|---|
| HUT59140A (en) | 1992-04-28 |
| PT98635A (en) | 1992-06-30 |
| HU912665D0 (en) | 1992-01-28 |
| EP0470543A1 (en) | 1992-02-12 |
| JPH06340665A (en) | 1994-12-13 |
| AU8171791A (en) | 1992-02-13 |
| AU650278B2 (en) | 1994-06-16 |
| IE912822A1 (en) | 1992-02-12 |
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