NO924745L - Benzofuraner - Google Patents
Benzofuraner Download PDFInfo
- Publication number
- NO924745L NO924745L NO92924745A NO924745A NO924745L NO 924745 L NO924745 L NO 924745L NO 92924745 A NO92924745 A NO 92924745A NO 924745 A NO924745 A NO 924745A NO 924745 L NO924745 L NO 924745L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- benzofuran
- imidazo
- methyl
- pyridine
- Prior art date
Links
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 58
- -1 5-tetrazolyl Chemical group 0.000 claims description 56
- 150000003839 salts Chemical class 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 9
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 150000001907 coumarones Chemical class 0.000 claims description 3
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- XFHSJWQFTBHOOS-UHFFFAOYSA-N 2-[2-butyl-4-oxo-3-[[2-[2-(2h-tetrazol-5-yl)phenyl]-1-benzofuran-5-yl]methyl]imidazo[4,5-c]pyridin-5-yl]acetic acid Chemical compound CCCCC1=NC=2C=CN(CC(O)=O)C(=O)C=2N1CC(C=C1C=2)=CC=C1OC=2C1=CC=CC=C1C=1N=NNN=1 XFHSJWQFTBHOOS-UHFFFAOYSA-N 0.000 claims description 2
- VAVOAPGEQHWNJU-UHFFFAOYSA-N 2-[[2-butyl-4-oxo-3-[[2-[2-(2h-tetrazol-5-yl)phenyl]-1-benzofuran-5-yl]methyl]imidazo[4,5-c]pyridin-5-yl]methyl]benzoic acid Chemical compound O=C1C=2N(CC=3C=C4C=C(OC4=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(CCCC)=NC=2C=CN1CC1=CC=CC=C1C(O)=O VAVOAPGEQHWNJU-UHFFFAOYSA-N 0.000 claims description 2
- IQPUBXYKGIFELA-UHFFFAOYSA-N 2-ethyl-5,7-dimethyl-3-[[2-[2-(2h-tetrazol-5-yl)phenyl]-1-benzofuran-5-yl]methyl]imidazo[4,5-b]pyridine Chemical compound CCC1=NC2=C(C)C=C(C)N=C2N1CC(C=C1C=2)=CC=C1OC=2C1=CC=CC=C1C=1N=NNN=1 IQPUBXYKGIFELA-UHFFFAOYSA-N 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 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 2
- 239000007788 liquid Substances 0.000 claims 2
- OWARPLXIJMRLPE-UHFFFAOYSA-N 2-butyl-3-[[2-[2-(2h-tetrazol-5-yl)phenyl]-1-benzofuran-5-yl]methyl]-5h-imidazo[4,5-c]pyridin-4-one Chemical compound CCCCC1=NC=2C=CNC(=O)C=2N1CC(C=C1C=2)=CC=C1OC=2C1=CC=CC=C1C=1N=NNN=1 OWARPLXIJMRLPE-UHFFFAOYSA-N 0.000 claims 1
- 229940126601 medicinal product Drugs 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 150000003222 pyridines Chemical class 0.000 description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 150000001340 alkali metals Chemical class 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 125000003831 tetrazolyl group Chemical group 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 2
- 125000006039 1-hexenyl group Chemical group 0.000 description 2
- 125000006023 1-pentenyl group Chemical group 0.000 description 2
- 125000006017 1-propenyl group Chemical group 0.000 description 2
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 2
- QGXNHCXKWFNKCG-UHFFFAOYSA-N 2-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC=C1C#N QGXNHCXKWFNKCG-UHFFFAOYSA-N 0.000 description 2
- APFGBHBYRSRYBZ-UHFFFAOYSA-N 2-[5-[(2-butyl-7-methylimidazo[4,5-b]pyridin-3-yl)methyl]-1-benzofuran-2-yl]benzonitrile Chemical compound C(CCC)C1=NC=2C(=NC=CC=2C)N1CC=1C=CC2=C(C=C(O2)C2=C(C=CC=C2)C#N)C=1 APFGBHBYRSRYBZ-UHFFFAOYSA-N 0.000 description 2
- SXAHGRWSMLJJIG-UHFFFAOYSA-N 2-[5-[(2-butylimidazo[4,5-b]pyridin-3-yl)methyl]-1-benzofuran-2-yl]aniline Chemical compound CCCCC1=NC2=CC=CN=C2N1CC(C=C1C=2)=CC=C1OC=2C1=CC=CC=C1N SXAHGRWSMLJJIG-UHFFFAOYSA-N 0.000 description 2
- RHSKKQPEBWBEBT-UHFFFAOYSA-N 2-butyl-3-[[2-(2-nitrophenyl)-1-benzofuran-5-yl]methyl]imidazo[4,5-b]pyridine Chemical compound CCCCC1=NC2=CC=CN=C2N1CC(C=C1C=2)=CC=C1OC=2C1=CC=CC=C1[N+]([O-])=O RHSKKQPEBWBEBT-UHFFFAOYSA-N 0.000 description 2
- CEOBRCUFSUIMAC-UHFFFAOYSA-N 2-butyl-3-[[2-[2-(1-trityltetrazol-5-yl)phenyl]-1-benzofuran-5-yl]methyl]-5h-imidazo[4,5-c]pyridin-4-one Chemical compound CCCCC1=NC=2C=CNC(=O)C=2N1CC(C=C1C=2)=CC=C1OC=2C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 CEOBRCUFSUIMAC-UHFFFAOYSA-N 0.000 description 2
- SCOVNNMMIJKAGJ-UHFFFAOYSA-N 2-butyl-7-methyl-3-[[2-[2-(2h-tetrazol-5-yl)phenyl]-1-benzofuran-5-yl]methyl]imidazo[4,5-b]pyridine Chemical compound CCCCC1=NC2=C(C)C=CN=C2N1CC(C=C1C=2)=CC=C1OC=2C1=CC=CC=C1C=1N=NNN=1 SCOVNNMMIJKAGJ-UHFFFAOYSA-N 0.000 description 2
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 2
- ILEIUTCVWLYZOM-UHFFFAOYSA-N 2-hydroxy-5-methylbenzaldehyde Chemical compound CC1=CC=C(O)C(C=O)=C1 ILEIUTCVWLYZOM-UHFFFAOYSA-N 0.000 description 2
- NWPNXBQSRGKSJB-UHFFFAOYSA-N 2-methylbenzonitrile Chemical compound CC1=CC=CC=C1C#N NWPNXBQSRGKSJB-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- UBOOKRVGOBKDMM-UHFFFAOYSA-N 3h-imidazo[4,5-c]pyridine Chemical compound C1=NC=C2NC=NC2=C1 UBOOKRVGOBKDMM-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 2
- 102000005862 Angiotensin II Human genes 0.000 description 2
- 101800000733 Angiotensin-2 Proteins 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 206010020571 Hyperaldosteronism Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229950006323 angiotensin ii Drugs 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 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 2
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical class N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 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 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003797 solvolysis reaction Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- YQNQXYBUAVBUDV-UHFFFAOYSA-N benzyl 2-(3-benzyl-2-butyl-4-oxoimidazo[4,5-c]pyridin-5-yl)acetate Chemical compound O=C1C=2N(CC=3C=CC=CC=3)C(CCCC)=NC=2C=CN1CC(=O)OCC1=CC=CC=C1 YQNQXYBUAVBUDV-UHFFFAOYSA-N 0.000 description 1
- UASWBODKARRWBL-UHFFFAOYSA-N benzyl 2-[(3-benzyl-2-butyl-4-oxoimidazo[4,5-c]pyridin-5-yl)methyl]benzoate Chemical compound O=C1C=2N(CC=3C=CC=CC=3)C(CCCC)=NC=2C=CN1CC1=CC=CC=C1C(=O)OCC1=CC=CC=C1 UASWBODKARRWBL-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- QGXJAWIDBPIKRO-UHFFFAOYSA-N ethyl 2-[5-(bromomethyl)-3-chloro-1-benzofuran-2-yl]benzoate Chemical compound CCOC(=O)C1=CC=CC=C1C1=C(Cl)C2=CC(CBr)=CC=C2O1 QGXJAWIDBPIKRO-UHFFFAOYSA-N 0.000 description 1
- ASKFJXKUFMCLCB-UHFFFAOYSA-N ethyl 2-[5-[(2-butylimidazo[4,5-b]pyridin-3-yl)methyl]-3-chloro-1-benzofuran-2-yl]benzoate Chemical compound CCCCC1=NC2=CC=CN=C2N1CC(C=C1C=2Cl)=CC=C1OC=2C1=CC=CC=C1C(=O)OCC ASKFJXKUFMCLCB-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 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
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 125000003564 m-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(C#N)=C1[H])C([H])([H])* 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- QANFJNZGZJOHAG-UHFFFAOYSA-N methyl 2-[5-(bromomethyl)-1-benzofuran-2-yl]benzoate Chemical compound COC(=O)C1=CC=CC=C1C1=CC2=CC(CBr)=CC=C2O1 QANFJNZGZJOHAG-UHFFFAOYSA-N 0.000 description 1
- UYRUTNPDSMEBBR-UHFFFAOYSA-N methyl 2-[5-[(2-butylimidazo[4,5-b]pyridin-3-yl)methyl]-1-benzofuran-2-yl]benzoate Chemical compound CCCCC1=NC2=CC=CN=C2N1CC(C=C1C=2)=CC=C1OC=2C1=CC=CC=C1C(=O)OC UYRUTNPDSMEBBR-UHFFFAOYSA-N 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- VHGGMTGQFNCDBO-UHFFFAOYSA-N n-[2-[5-(bromomethyl)-1-benzofuran-2-yl]phenyl]-2,2,2-trifluoroacetamide Chemical compound FC(F)(F)C(=O)NC1=CC=CC=C1C1=CC2=CC(CBr)=CC=C2O1 VHGGMTGQFNCDBO-UHFFFAOYSA-N 0.000 description 1
- NUROIPAIBBQWOJ-UHFFFAOYSA-N n-[2-[5-[(2-butylimidazo[4,5-b]pyridin-3-yl)methyl]-1-benzofuran-2-yl]phenyl]-2,2,2-trifluoroacetamide Chemical compound CCCCC1=NC2=CC=CN=C2N1CC(C=C1C=2)=CC=C1OC=2C1=CC=CC=C1NC(=O)C(F)(F)F NUROIPAIBBQWOJ-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000006504 o-cyanobenzyl group Chemical group [H]C1=C([H])C(C#N)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229940045681 other alkylating agent in atc Drugs 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 1
- KGCNHWXDPDPSBV-UHFFFAOYSA-N p-nitrobenzyl chloride Chemical compound [O-][N+](=O)C1=CC=C(CCl)C=C1 KGCNHWXDPDPSBV-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 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
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 208000007442 rickets Diseases 0.000 description 1
- 230000007017 scission Effects 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RKSOPLXZQNSWAS-UHFFFAOYSA-N tert-butyl bromide Chemical compound CC(C)(C)Br RKSOPLXZQNSWAS-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
-
- 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
Landscapes
- 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)
- Diabetes (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Oppfinnelsen vedrører nye benzofuraner med formel I
hvor
R er resten
R<1>er H, Hal, COOH, CONH2, CHO, CN, NH2eller 5-tetrazolyl,
R<2>er H, COOH, COOR<3>, CN, N02, NH2, NHCOCF3, NHS02CF3
eller 5-tétrazolyl,
R<3>er H, alkyl, alkenyl eller alkynyl, hver med inntil
6 C-atomer,
R<4>er H, alkyl med 1-6 C-atomer, cyanalkyl, R<3>OOC-alkyl,
5-tetrazolylalkyl eller aralkyl, hver med 1-6 C-
atomer i "alkyl"-delen,
-A-B-C-D- er en av gruppene -CH=CH-CH=N-, -CH=CH-N=CH-, -CH=N-CH=CH-, -N=CH-CH=CH-, -CH=CH-CO-NR<4->, -CH=CH-NR4-CO-, -CO-NR4-CH=CH- eller -NR<4>-CO-CH=CH-, hvor H-atomet i -CH-gruppene kan være substituert med alkyl med 1-6 C-atomer, Hal, COOR<3>, CN og/eller 5-tetra-
zolyl,
Ar er usubstituert eller én eller to ganger med Hal, R<3>,
C<F>3, COOR<3>, CN, OR<3>, N02, NH2, NHCOCF3, NHS02CF3eller
5-tetrazolyl substituert fenyl, og
Hal er F, Cl, Br eller I,
samt salter derav.
Lignende forbindelser er kjent fra EP-A2-0430 709, de inneholder imidlertid en benzotiofenring i stedet for benzo-furanringen og en eventuelt substituert imidazolylgruppe i stedet for resten R.
Til grunn for oppfinnelsen lå den oppgave å finne
frem til nye forbindelser med verdifulle egenskaper, særlig slike som kan anvendes til fremstilling av legemidler.
Det ble funnet at forbindelsene med formel I og deres salter har svært verdifulle farmakologiske egenskaper med god forenlighet. Særlig oppviser de angiotensin Il-antagonistiske egenskaper og kan således anvendes til behandling av angiotensin II-avhengig hypertensjon, aldosteronisme og hjerteinsuffisiens, samt av forstyrrelser i sentralnervesystemet. Disse virkningene kan undersøkes ifølge vanlige metoder in vitro eller in vivo, som f.eks. beskrevet i US patentskrift nr. 4.880.804 og i W0 91/14367, videre av A.T. Chiu et al., J. Pharmacol. Exp. Therap., 250, s. 867-874 (1989), og av P.C. Wong et al., ibid., 252, s. 719-725 (1990; in vivo, på rotter).
Forbindelsene med formel I kan anvendes som aktive legemiddelforbindelser innen human- og veterinærmedisinen, særlig til profylakse og/eller terapi av hjerte-, kretsløps-og karsykdommer, fremfor alt av hypertoni, hjerteinsuffisiens og hyperaldosteronisme, videre av hypertrofi og hyperplasi i blodårene og i hjertet, angina pectoris, hjerteinfarkt, slag-anfall, ristenoser etter angioplasti eller bypass-operasjoner, arteriosklerose, forhøyetøyetrykk, glaukomer, makular degene-rasjon, hyperurikemi, nyrefunksjonsforstyrrelser som f.eks. nyresvikt, diabetisk nefropati, diabetisk retinopati, psori-asis, angiotensin II-medierte forstyrrelser i kvinnelige for-plantningsorganer, sanseforstyrrelser som f.eks. demens, amnesi, hukommelsesforstyrrelser, angsttilstander, depresjon og/eller epilepsi.
Oppfinnelsens gjenstand er forbindelsene med formel I og salter derav, samt en fremgangsmåte for fremstilling av disse forbindelsene samt salter derav, som er kjennetegnet ved at en forbindelse med formel II
hvor
E er Cl, Br, I eller en fri eller reaksjonsdyktig.
funksjonelt omdannet OH-gruppe, og
R<1>ogR<2>har den i krav 1 angitte betydning,
omsettes méd en forbindelse med formel III
hvor
R har den i krav 1 angitte betydning,
eller at en forbindelse med formel I frisettes fra et av dens funksjonelle derivater ved behandling med et solvolyserende eller hydrogenolyserende middel,
og/eller at én eller flere rest(er) R<1>, R<2>og/eller R i en forbindelse med formel I omdannes til én eller flere andre rester R<1>, R2 og/eller R, og/eller en base eller syre med formel I overføres til et salt derav.
Ovenfor og nedenunder har restene eller parametrene R, Rx-R4, -A-B-C-D-, Ar,Hal og E de for formlene I og II angitte betydninger dersom ikke noe annet er uttrykkelig angitt.
I formlene ovenfor har "alkyl" 1-6, fortrinnsvis 1, 2, 3 eller 4, C-atomer. "Alkyl" betyr fortrinnsvis metyl, dessuten etyl, propyl, isopropyl, butyl, isobutyl, sek.-butyl eller tert.-butyl, videre også pentyl, 1-, 2- eller 3-metyl-butyl, 1,1-, 1,2- eller 2,2-dimetylpropyl, 1-etylpropyl, heksyl, 1-, 2-, 3- eller 4-metylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- eller 3,3-dimetylbutyl, 1- eller 2-etylbutyl, 1-etyl-l-metylpropyl, l-etyl-2-metylpropyl, 1,1,2- eller 1,2,2-tri-metylpropyl. Alkenyl står fortrinnsvis for vinyl, 1- eller 2-propenyl, 1-butenyl, videre 1-pentenyl eller 1-heksenyl. Alkynyl står fortrinnsvis for etynyl, 1- eller 2-propynyl, videre 1-butynyl, 1-pentynyl eller 1-heksynyl.
Hal betyr fortrinnsvis F, Cl eller Br, men også J.
R er en rest som er avledet fra 1H- eller 3H-imidazo-[4,5-b]pyridin eller fra 1H- eller 3H-imidazo[4,5-c]pyridin, nærmere bestemt: (a) 2-R<3->3H-imidazo[4,5-b]pyridin-3-yl (dersom -A-B-C-D- = -CH=CH-CH=N-), (b) 2-R<3->3H-imidazo[4,5-c]pyridin-3-yl (dersom -A-B-C-D- = -CH=CH-N=CH-), (c) 2-R<3->lH-imidazo[4,5-c]pyridin-l-yl (dersom -A-B-C-D- = -CH=N-CH=CH-), (d) 2-R<3->lH-imidazo[4,5-b]pyridin-l-yl (dersom -A-B-C-D- = -N=CH-CH=CH-), (e) 2-R<3->4-R<4->4,5-dihydro-5-okso-3H-imidazo[4,5-b]-pyridin-3-yl (dersom -A-B-C-D- = -CH=CH-CO-NR<4->), (f) 2-R<3->5-R<4->4,5-dihydro-4-okso-3H-imidazo[4,5-c]-pyridin-3-yl (dersom -A-B-C-D- = -CH=CH-NR<4->C0-), (g) 2-R<3->5-R<4->4,5-dihydro-4-okso-lH-imidazo[4,5-c]-pyridin-3-yl (dersom -A-B-C-D- = -CO-NR<4->CH=
CH-),
(h) 2-R<3->4-R<4->4,5-dihydro-5-okso-lH-imidazo[4,5-b]-pyridin-3-yl (dersom -A-B-C-D- = -NR<4>-CO-CH=
CH-) .
Således kan H-atomene som befinner seg på C-atomene i restene -A-B-C-D- være substituert med alkyl (fortrinnsvis metyl), Hal (fortrinnsvis F eller Cl), COOR<3>(fortrinnsvis COOH, COOCH3eller COOC2H5), CN og/eller 5-tetrazolyl. Som substituenter er det foretrukket med CH3og COOH. Fortrinnsvis er bare én eller to av disse H-atomene substituert med en av de angitte substituenter.
Tilsvarende omfatter forbindelsene med formel I slike med formlene Ia-Ih, hvor R har de under henholdsvis (a)-(h) angitte betydninger. Forbindelsene med formlene Ia og If er foretrukket.
Resten R<1>er fortrinnsvis H eller Br.
Resten R2 er fortrinnsvis CN, videre foretrukket 5-tetrazolyl, COOH, COOCH3, COOC2H5eller NHS02CF3.
Resten R3 (såfremt den ikke betyr H) er fortrinnsvis rettkjedet og står fortrinnsvis for alkyl eller alkenyl, hver med 2-6 C-atomer, særlig butyl, videre etyl eller propyl, dessuten pentyl, heksyl, allyl eller 1-propenyl, videre 1-"butenyl, 1-pentenyl, 1-heksenyl, etynyl, 1-propynyl, 1-butynyl, 1-pentynyl eller 1-heksynyl.
Resten R4 er fortrinnsvis H, videre foretrukket alkyl (særlig CH3), cyanalkyl (særlig cyanmetyl, 2-cyanetyl, 3-cyan-propyl, AOOC-alkyl (særlig metoksykarbonylmetyl, etoksykarbo-nylmetyl, 2-metoksykarbonyletyl, 2-etoksykarbonyletyl), kar-boksyalkyl (særlig karboksymetyl, 2-karboksyetyl, 3-karboksy- propyl), 5-tetrazolylalkyl [særlig 5-tetrazolylmetyl, 2-(5-tetrazolyl)-etyl, 3-(5-tetrazolyl)-propyl], idet alle disse restene fortrinnsvis hver totalt kan inneholde inntil 6 C-atomer. Dessuten er resten R<4>fortrinnsvis aralkyl med 7-11 C-atomer, særlig benzyl, 1- eller 2-fenyletyl, 1-, 2- eller 3-fenylpropyl, 1-, 2-, 3- eller 4-fenylbutyl, o-, m- eller p-fluorbenzyl, (foretrukket) o-, m- eller p-klorbenzyl, o-, m-eller p-brombenzyl, o-, m- eller p-metylbenzyl, o-, m- eller p-trifluormetylbenzyl, o-, m- eller p-metoksykarbonylbenzyl, o-, m- eller p-etoksykarbonylbenzyl, (foretrukket) o-, m-eller p-cyanbenzyl, o-, m- eller p-karboksybenzyl, o-, m-eller p-nitrobenzyl, (foretrukket) o-, m- eller p-aminobenzyl, (foretrukket o-, m- eller p-(5-tetrazolyl)-benzyl.
Forbindelsene med formel I kan ha ett eller flere kirale sentre og således forekomme i forskjellige optisk aktive eller optisk inaktive former. Formel I omfatter alle disse formene.
Tilsvarende er særlig de forbindelsene med formel I hvor minst én av de nevnte rester har en av de ovenfor angitte, foretrukne betydninger gjenstand for oppfinnelsen. Noen foretrukne grupper av forbindelser kan uttrykkes ved de føl-gende delformlene li, Ij, Iai-Ihi og Iaj-Ihj, som tilsvarer formlene I samt Ia-Ih, og hvor de ikke nærmere angitte rester har de for formlene I samt Ia-Ih angitte betydninger: Forbindelser med formel li samt lai, Ibi, Ici, Idi, lei, Ifi, Igi og Ihi: disse tilsvarer formlene I samt Ia-Ih, i tillegg betyr i hver av dem R<1>imidlertid H.
Forbindelser med formlene Ij samt Iaj, Ibj, Icj, Idj, Iej, Ifj, Igj, Ihj, Iij, laij, Ibij, Icij, Idij, leij, Ifij, Igij og Ihij: disse tilsvarer formlene I samt Ia-Ii og Iai-Ihi, i tillegg betyr i hver av dem R2 imidlertid CN eller (foretrukket) 5-tetrazolyl.
En ytterligere utvalgt gruppe foretrukne forbindelser tilsvarer formel I, hvor R<1>er H, R2 er 5-tetrazolyl, R<3>er alkyl med 2-4 C-atomer og -A-B-C-D- -C(CH3)=CH-CH=N-, -C(CH3)-=CH-C(CH3)=N-, -CH=CH-N(o-HOOC-C6H„-CH2)-CO-, -CH=CH-NH-CO-eller -CH=CH-N(CH2COOH)-CO-.
Forbindelsene med formel I og også utgangsforbindelsene for fremstilling derav fremstilles for øvrig etter i og for seg kjente fremgangsmåter, slik de er kjent fra litte-raturen (f.eks. i standardverker som Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart; særlig imidlertid i EP-A2-0 430 709 og i US patentskrift nr. 4.880.804), og da under reaksjonsbetingelser som er kjent og egnet for de nevnte omsetninger.• Således kan man også gjøre bruk av i og for seg kjente, her ikke nærmere belyste vari-anter.
Utgangsforbindelsene kan om ønsket også dannes in situ, slik at man ikke isolerer dem fra reaksjonsblandingen, men omsetter dem øyeblikkelig videre til forbindelsene med formel I.
Forbindelsene med formel I kan fortrinnsvis fås ved at man omsetter forbindelser med formel II med forbindelser med formel III.
I forbindelsene med formel II betyr E fortrinnsvis Cl, Br, I eller en reaksjonsdyktig, funksjonelt omdannet 0H-gruppe som alkylsulfonyloksy med 1-6 C-atomer (fortrinnsvis metylsulfonyloksy) eller arylsulfonyloksy med 6-10 C-atomer (fortrinnsvis fenyl- eller p-tolylsulfonyloksy).
Omsetningen av II med III skjer hensiktsmessig ved at man først omdanner III ved behandling med en base til et salt, fortrinnsvis med et alkalimetallalkoholat som CH30Na eller Il-tert.-butylat, i en alkohol som CH30H eller med et alkali-metallhydrid som NaH eller et alkalimetallalkoholat i dimetyl-formamid (DMF), og så omsetter dette i et inert oppløsnings-middel, f.eks. et amid som DMF eller dimetylacetamid, eller et sulfoksid som dimetylsulfoksid (DMSO), med II, hensiktsmessig ved temperaturer mellom -20 og 100 °C, fortrinnsvis mellom 10 og 30 °C. Som baser egner seg også alkalimetallkarbonater som Na2C03eller K2C03, eller alkalimetallhydrogenkarbonater som NaHC03eller KHC03.
Utgangsforbindelsene, særlig de med formel III, er delvis kjent. Dersom de ikke er kjent, kan de fremstilles etter i og for seg kjente fremgangsmåter analogt med de kjente forbindelser.
Forbindelser med formel II er nye. Slike med formel II (E = Br) lar seg f.eks. erholde ved omsetning av 5-metyl salisylaldehyd med et a-R<1->2-R<2->benzylbromid med formel IV til en a-R<1->2-R<2->benzyleter med formel V,
ringslutning under vannavspalting (f.eks. med NaH/DMF) til tilsvarende 3-R1-2-( 2-R2-fenyl)-5-metylbenzofuran (formel II, men H i stedet for E) og bromering (f.eks. med N-bromsuccinimid).
Videre kan man frisette en forbindelse med formel I fra et av dens funksjonelle derivater ved behandling med et solvolyserende (f.eks. hydrolyserende) eller hydrogenolyserende middel.
Det er således mulig å fremstille en forbindelse som tilsvarer formel I etter en av de angitte fremgangsmåter, men som i stedet for en 5-tetrazolylgruppe inneholder en i 1-stil-ling funksjonelt omdannet (beskyttet med en beskyttelses-gruppe) 5-tetrazolylgruppe. Som beskyttelsesgrupper egner seg f.eks.: trifenylmetyl, avspaltbar med HC1 eller maursyre i et inert oppløsningsmiddel eller en inert oppløsningsmiddelblan-ding, f.eks. eter/diklormetan/metanol; 2-cyanetyl, avspaltbar med NaOH i vann/THF; p-nitrobenzyl, avspaltbar med H2/Raney-nikkel i etanol (jf. EP-A2-0 291 969).
Det er videre mulig å omdanne en forbindelse med formel I til en annen forbindelse med formel I, idet man omdanner én eller flere av restene R<1>, R<2>og/eller R til andre rester, R<1>, R<2>og/eller R, f.eks. idet man reduserer nitro-grupper (f.eks. ved hydrogenering på Raney-nikkel i et inert oppløsningsmiddel som metanol eller etanol). til aminogrupper, og/eller omdanner frie amino- og/eller hydroksygrupper funksjonelt, og/eller frisetter funksjonelt omdannede amino-og/eller hydroksygrupper ved solvolyse eller hydrogenolyse, og/eller erstatter halogenatomer (f.eks. ved reaksjon med kobber(I)cyanid) med CN-grupper, og/eller hydrolyserer nitril-grupper til COOH-grupper, eller omsetter med derivater av hydrogenazidsyre, f.eks. natriumazid i N-metylpyrrolidon, eller trimetyltinnazid i toluen, til tetrazolylgrupper.
Således kan f.eks. frie aminogrupper på vanlig måte acyleres med et syreklorid eller -anhydrid, eller frie hyd-roksy- og/eller NH-grupper alkyleres med et usubstituert eller substituert alkyl- eller aralkylhalogenid, hensiktsmessig i et inert oppløsningsmiddel som diklormetan eller THF, og/eller i nærvær av en base som trietylamin eller pyridin, ved temperaturer mellom 60 og +30 °C. Av betydning er omdannelsen av en rest R hvor R<4>= H til en annen rest R hvor R4 er forskjellig fra H. Her arbeides det fortrinnsvis i et syreamid som DMF, N-metylpyrrolidon, 1,3-dimetyl-2-oksoheksahydropyrimidin eller fosforsyreheksametyltriamid, en alkohol som metanol eller tert.-butanol, en eter som THF, eller et halogenert hydrokarbon som diklormetan, eller blandinger derav som oppløs-ningsmiddel, og/eller i nærvær av et alkalimetallalkoholat som natriummetylat eller kalium-tert.-butylat, et alkalimetall-hydrid som natrium- eller kaliumhydrid, et alkalimetallkarbo-nat som natrium- eller kaliumkarbonat, et alkalimetallbikarbo-nat som natrium- eller kaliumbikarbonat, eller et tertiært amin som trietylamin eller etyldiisopropylamin, ved temperaturer mellom ca. -30 og 200 °C, fortrinnsvis mellom 20 og 60 °C.
Om ønsket kan en funksjonelt omdannet amino- og/eller hydroksygruppe i en forbindelse med formel I frisettes ved solvolyse eller hydrogenolyse etter vanlige metoder. Således kan f.eks. en forbindelse med formel I som inneholder en NHCOCF3- eller en C00R<3->gruppe (hvor R3 er forskjellig fra H) omdannes til den tilsvarende forbindelse med formel I, som i stedet for denne inneholder en NH2- eller en HOOC-gruppe. Estergrupper kan f.eks. forsåpes med NaOH eller KOH i vann, vann-THF eller vann-dioksan ved temperaturer mellom 0 og 100 °C.
Omsetning av nitriler med formel I (R<1>og/eller R<2>= CN) med derivater av hydrogenazidsyre fører til tetrazoler med formel I (R<1>og/eller R<2>= 5-tetrazolyl). Det er foretrukket å anvende trialkyltinnazid som trimetyltinnazid i et inert opp-løsningsmiddel, f.eks. et aromatisk hydrokarbon som toluen, ved temperaturer mellom 20 og 150 °C, fortrinnsvis mellom 80 og 140 °C, eller natriumazid i N-metylpyrrolidon ved temperaturer mellom ca. 100 og 200 °C.
En base med formel I kan overføres med en syre til det tilhørende syreaddisjonssalt. For denne omsetningen kommer det særlig på tale med syrer som gir fysiologisk akseptable salter. Således kan det anvendes uorganiske syrer som f.eks. svovelsyre, salpetersyre, hydrogenhalogensyrer som saltsyre eller hydrogenbromsyre, fosforsyrer som ortofosforsyre, sulfaminsyre, videre organiske syrer, særlig alifatiske, ali-sykliske, aralifatiske, aromatiske eller heterosykliske én-eller flerbasiske karboksyl-, sulfon- eller svovelsyrer, f.eks. maursyre, eddiksyre, propionsyre, pivalinsyre, dietyl-eddiksyre, malonsyre, ravsyre, pimelinsyre, fumarsyre, malein-syre, melkesyre, vinsyre, eplesyre, sitronsyre, glukonsyre, askorbinsyre, nikotinsyre, isonikotinsyre, metan- eller etan-sulfonsyre, etandisulfonsyre, 2-hydroksyetansulfonsyre, benzensulfonsyre, p-toluensulfonsyre, naftalinmono- og nafta-lindisulfonsyre og laurylsvovelsyre. Salter med fysiologisk ikke-akseptable syrer, f.eks. pikrater, kan anvendes for isolering og/eller rensing av forbindelsene med formel I.
På den annen side kan forbindelser med formel I som inneholder COOH- eller tetrazolylgrupper, omdannes med baser (f.eks. natrium- eller kaliumhydroksid eller -karbonat) til de tilsvarende metallsalter, særlig alkalimetall- eller jord-alkalimetallsalter, eller til de tilsvarende ammoniumsalter. Kaliumsaltet av tetrazolylderivatet er særlig foretrukket.
De nye forbindelsene med formel I og deres fysiologisk akseptable salter kan anvendes til fremstilling av farma-søytiske preparater idet man bringer dem sammen med minst ett bærer- eller hjelpestoff, og om ønsket sammen med ett eller flere ytterligere aktive stoffer i en egnet doseringsform. De således erholdte preparater kan anvendes som legemiddel innen human- eller veterinærmedisinen. Som bærerstoffer kommer det på tale med organiske eller uorganiske stoffer som egner seg for enteral (f.eks. oral eller rektal) eller parenteral applikasjon, eller for en applikasjon i form av en inhalasjonsspray, og som ikke reagerer med de nye forbindelsene, f.eks. vann, planteolje, benzylalkohol, polyetylenglykol, glyserol-triacetat og andre fettsyreglyserider, gelatin, soyalecitin, karbonhydrater som laktose eller stivelse, magnesiumstearat, talkum og cellulose. For oral anvendelse tjener særlig tabletter, drasjeer, kapsler, siruper, safter eller dråper; av inte-resse er spesielt lakktabletter og kapsler med magesaftresi-stente overtrekk eller kapselhylser. For rektal anvendelse tjener suppositorier, for parenteral applikasjon oppløsninger, fortrinnsvis olje- eller vannoppløsninger, videre suspen-sjoner, emulsjoner eller implantater. For applikasjonen som inhalasjonsspray kan det anvendes sprayer som enten inneholder den aktive forbindelse oppløst eller oppslemmet i en drivgass-blanding (f.eks. fluorklorhydrokarboner). Hensiktsmessig anvendes den aktive forbindelse da i mikronisert form, idet ett eller flere ytterligere fysiologisk forenlige oppløsningsmid-ler kan være tilsatt, f.eks. etanol. Inhalasjonsoppløsninger kan administreres ved hjelp av vanlige inhalatorer. De nye forbindelsene kan også lyofiliseres og de erholdte lyofili-sater anvendes f.eks. til fremstilling av injeksjonsprepa-rater. De angitte preparater kan være sterilisert og/eller inneholde hjelpestoffer som konserverings-, stabiliserings-og/eller fuktemidler, emulgatorer, salter for påvirkning av det osmotiske trykk, bufferstoffer, farge- og/eller aromastof-fer. De kan om ønsket også inneholde ett eller flere ytterligere aktive stoffer, f.eks. ett eller flere vitaminer, diu-retika eller antiflogistika.
Forbindelsene ifølge oppfinnelsen administreres som regel analogt med andre kjente preparater som finnes i han-delen, særlig imidlertid analogt med de forbindelser som er beskrevet i US patentskrift nr. 4.880.804, fortrinnsvis i doseringer mellom ca. 1 mg og 1 g, særlig mellom 50 og 500 mg pr. doseringsenhet. Daglig dosering ligger fortrinnsvis mellom ca. 0,1 og 50 mg/kg, særlig 1 og 100 mg/kg, kroppsvekt. Den spesielle dose for hver bestemt pasient avhenger imidlertid av de forskjelligste faktorer, f.eks. av aktiviteten til den an-vendte spesielle forbindelse, av alderen, kroppsvekten, den generelle helsetilstand, arv, av kosten, av administrasjons-tidspunktet og -veien, av utskillelseshastigheten, legemiddel-kombinasjonen og alvorligheten av den enkelte sykdom som be-handlingen gjelder. Den orale applikasjon er foretrukket. Ovenfor og nedenunder er alle temperaturer angitt i °C. I de etterfølgende eksempler betyr "vanlig opparbeidelse": om ønsket tilsettes vann, alt etter sluttproduktets konsti-tusjon innstilles om ønsket pH-verdien mellom 2 og 10, det ekstraheres med etylacetat eller diklormetan, den organiske fase fraskilles, tørkes over natriumsulfat, inndampes og renses ved kromatografi på silikagel og/eller ved krystallisa-sjon. MS (FAB) = massespektrum (erholdt etter "fast atom bombardment"-metoden.
Eksempel 1
En oppløsning av 0,23 g Na i 20 ml metanol ble dryppet i løpet av 15 minutter til en oppløsning av 3,2 g 2-butyl-l(eller 3)H-imidazo[4,5-b]pyridin i 75 ml metanol. Det ble om-rørt i ytterligere 30 minutter ved 20 °C, inndampet, resten ble oppløst i 20 ml DMF, og ved 0 °C ble det under omrøring tildryppet en oppløsning av 3,45 g 5-brommetyl-2-(2-metoksy-karbonylfenyl)-benzofuran i 10 ml DMF. Det ble omrørt i 16 timer ved 20 °C, inndampet, opparbeidet som vanlig, kro-matografert på silikagel og erholdt 2-butyl-3-(2-(2-metoksy-karbonylfenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-b]pyridin.
Eksempel 2
(a) 1,89 g 2-butyl-7-metyl-3H-imidazo[4,5-b]pyridin (sm.p. 75-76 °C) ble oppløst i 60 ml DMF, det ble tilsatt 1,44 g kaliumkarbonat ved -10 til -14 °C, omrørt i 40 minutter ved -14 °C og tildryppet en oppløsning av 5,97 g 5-brommetyl-2- ( 2- (1-trifenylmetyl-lH-tetrazol-5-yl)-fenylbenzofuran ("A" ) i 120 ml DMF. Blandingen ble så omrørt i ytterligere 2 timer ved -14 °C og i 16 timer ved 20 °C, inndampet og opparbeidet med vann og etylacetat. Etter kromatografi, først med diklormetan og metanol i forholdet 98:2 og så med toluen og etylacetat i forholdet 8:2, fikk man 2-butyl-7-metyl-3-(2-(2-(1-trifenylmetyl-lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-b]pyridin, Rf 0,61 (diklormetan/metanol 97:3); MS (FAB) 706.
Utgangsmaterialet "A" ble erholdt på følgende måte: Bromering av o-tolunitril i tetraklormetan (UV-be-stråling) gav o-brommetylbenzonitril (sm.p. 69 °C). Dette ble omsatt med 5-metylsalisylaldehyd i aceton i nærvær av kaliumkarbonat til 2-(o-cyanbenzyloksy)-5-metylbenzaldehyd (sm.p. 99 °C). Ringslutning med NaH i DMF under argon ved 20 °C gav 2-o-cyanfenyl-5-metylbenzofuran (sm.p. 112-113 °C), som ble overført med trimetyltinnazid til 2-o-(1-trimetylstannyl-lH-tetrazol-5-yl)-fenyl-5-metylbenzofuran [sm.p. 289 °C (dek.)]. Avspalting av beskyttelsesgruppen med HC1 i metanol og eter førte til 2-[2-(lH-tetrazol-5-yl)-fenyl]-5-metylbenzofuran, som i urenset tilstand ble omdannet med trifenylklormetan i diklormetan i nærvær av trietylamin til 2-[2-(1-trifenylmetyl-lH-tetrazol-5-yl)-fenyl]-5-metylbenzofuran (sm.p. 167 °C). Bromering med N-bromsuccinimid gav "A" (sm.p. 169 °C). (b) Det ifølge (a) erholdte produkt (Rf 0,61, lg) ble oppløst i 60 ml 4 N HC1 i dioksan og omrørt ved 20 °C i 16 timer. Etter inndamping og vanlig opparbeidelse fikk man 2-butyl-7-metyl-3-(2-(2-(lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-b]pyridin, sm.p. 250 °C (dek.); MS (FAB) 464.
Analogt fikk man:
av 2-etyl-5,7-dimetyl-3H-imidazo[4,5-b]pyridin og "A": 2-etyl-5,7-dimetyl-3-(2-(2-(1-trifenylmetyl-lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-b]pyridin, og av dette 2-etyl-5,7-dimetyl-3-(2-(2-(lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-b]pyridin, sm.p. 256 °C med HC1 og dioksan;
av 2-butyl-5-(2-karboksybenzyl)-4, 5-dihydro-4-okso-3H-imidazo[4,5-c]pyridin ("C", som lar seg erholde ved hydrogenolyse av 3-benzyl-5-(2-benzyloksykarbonylbenzyl)-2-butyl-4,5-dihydro-4-okso-3H-imidazo[4,5-c]pyridin) og "A": 2-butyl-5-(2-karboksybenzyl)-4,5-dihydro-4-okso-3-(2-(2-(1-trifenylmetyl-lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-c]pyridin, og av dette 2-butyl-5-(2-karboksybenzyl )-4,5-dihydro-4-okso-3-(2-( 2-(lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-c]pyridin med HC1 og dioksan;
fra 2-butyl-4,5-dihydro-4-okso-3H-imidazo[4,5-c]-pyridin og "A": 2-butyl-4,5-dihydro-4-okso-3-(2-(2-(1-trifenylmetyl-lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-c]pyridin, og av dette 2-butyl-4,5-dihydro-4-okso-
3-( 2-(2-(1H-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-c]pyridin med HC1 og dioksan;
av 2-butyl-5-karboksymetyl-4,5-dihydro-4-okso-3H-imidazo[4,5-c]pyridin (som lar seg erholde ved hydrogenolyse av 3-benzyl-5-benzyloksykarbonylmetyl-2-butyl-4,5-dihydro-4-okso-3H-imidazo[4,5-c]pyridin) og "A": 2-butyl-5-karboksymetyl-4,5-dihydro-4-okso-3-(2-(2-(1-trifenylmetyl-lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-c]pyridin, og av dette 2-butyl-5-karboksymetyl-4,5-dihydro-4-okso-3-(2-(2-(lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-c]pyridin med HC1 og dioksan.
Eksempel 3
Analogt med eksempel 2(a) fikk man med 5-brommetyl-2-(2-cyanfenyl)-benzofuran: 2- butyl-3-(2-(2-cyanfenyl)-benzofuran-5-yl-metyl)-7-metyl-3H-imidazo[4,5-b]pyridin,
3- (2-(2-cyanfenyl)-benzofuran-5-yl-metyl)-2-etyl-5,7-dimetyl-3H-imidazo[4,5-b]pyridin,
2-butyl-5-(2-karboksybenzyl)-3-(2-(2-cyanfenyl)-benzofuran-5-yl-metyl-4,5-dihydro-4-okso-3H-imidazo[4,5-c]-pyridin,
2-butyl-3-(2-(2-cyanfenyl)-benzofuran-5-yl-metyl)-4,5-dihydro-4-okso-3H-imidazo[4,5-c]pyridin og
2- butyl-5-karboksymetyl-3-(2-(2-cyanfenyl)-benzofuran-5-yl)-metyl-4,5-dihydro-4-okso-3H-imidazo[4,5-c]pyridin.
Eksempel 4
Analogt med eksempel 2 fikk man av de der angitte utgangsforbindelser med formel III med 3-brom-5-brommetyl-2-( 2-( 1-trifenylmetyl-lH-tetrazol-5-yl)-fenyl)-benzofuran: 3- (3-brom-2-(2-(1-trifenylmetyl-lH-tetrazol-5-yl )-fenyl)-benzofuran-5-yl-metyl)-2-butyl-7-metyl-3H-imidazo-[4,5-b]pyridin, og av dette 3-(3-brom-2-( 2-(lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-2-butyl-7-metyl-3H-imidazo-[4,5-b]pyridin;
3-(3-brom-2-(2-(1-trifenylmetyl-lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-2-etyl-5, 7-dimetyl-3H-imidazo-[4,5-b]pyridin, og av dette 3-(3-brom-2-(2-(lH-tetrazol-5-yl)-
fenyl)-benzofuran-5-yl-metyl)-2-etyl-5,7-dimetyl-3H-imidazo-[4,5-b]pyridin;
3-(3-brom-2-(2-(1-trifenylmetyl-lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-2-butyl-5-(2-karboksybenzyl )-4,5-dihydro-4-okso-3H-imidazo[4,5-c]pyridin, og av dette 3-(3-brom-2-(2-(lH-tetrazdl-5-yl)-fenyl)-benzofuran-5-yl-metyl) -2-butyl-5-(2-karboksybenzyl)-4,5-dihydro-4-okso-3H-imidazo-[4,5-c]pyridin;
3-(3-brom-2-(2-(l-trifenylmetyl-lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-2-butyl-4, 5-dihydro-4-okso-3H-iraidazo[4,5-c]pyridin, og av dette 3-(3-brom-2-(2-(lH-tetra-zol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-2-butyl-4,5-dihydro-4-okso-3H-imidazo[4,5-c]pyridin;
3-(3-brom-2-(2-(1-trifenylmetyl-lH-tetrazol-5-yl) -
fenyl)-benzofuran-5-yl-metyl)-2-butyl-5-karboksymetyl)-4,5-di-hydro-4-okso-3H-imidazo[4,5-c]pyridin, og av dette 3-(3-brom-2- ( 2-(lH-tetrazol-^S-yl) -fenyl) -benzofuran-5-yl-metyl) -2-metyl-5-karboksymetyl-4,5-dihydro-4-okso-3H-imidazo[4, 5-c]pyridin.
Eksempel 5
Analogt med eksempel 2(a) fikk man av 2-butyl-l(eller 3)H-imidazo[4,5-b]pyridin: med 5-brommetyl-2-(2-nitrofenyl)-benzofuran: 2-butyl-3- (2-(2-nitrofenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-b]-pyridin;
med 5-brommetyl-2-(2-trifluoracetamidofenyl)-benzofuran: 2-butyl-3-(2-(2-trifluoracetamidofenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-b]pyridin;
med 5-brommetyl-2-(2-cyanfenyl)-3-fluor-benzofuran: 2-butyl-3-(2-(2-cyanfenyl)-3-fluorbehzofuran-5-yl-metyl)-3H-imidazo[4,5-b]pyridin;
med 5-brommetyl-3-klor-2-(2-etoksykarbonyl-fenyl )-benzofuran: 2-butyl-3-(3-klor-2-(2-etoksykarbonylfenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-b]pyridin.
Eksempel 6
En blanding av 1 g 2-butyl-3-(2-(2-metoksykarbonyl-fenyl:)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-b]pyridin, 12 ml vandig 2 N NaOH-oppløsning og 48 ml etanol ble kokt i 2 timer og så inndampet. Etter surgjøring med HC1 til pH 3 fikk man 2-butyl-3-(2-(2-karboksyfenyl)-benzofuran-5-yl-metyl)-3H-imid-azo[4,5-b]pyridin, som ble frafiltrert, vasket med vann og tørket.
Eksempel 7
En blanding av 420 mg 2-butyl-3-( 2-(2-cyanfenyl) - benzofuran-5-yl-metyl)-7-metyl-3H-imidazo[4,5-b]pyridin,
206 mg trimetyltinnazid og 15 ml xylen ble kokt i 96 timer. Etter 48 timer ble det tilsatt ytterligere 0,2 g trimetyltinnazid. Det ble avkjølt, tilsatt eterisk saltsyre og inndampet. Etter vanlig opparbeidelse fikk man 2-butyl-7-metyl-3-(2-(2-(lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo-[4,5-b]pyridin, sm.p. 250 °C (dek.).
På vanlig måte ble K-saltet fremstilt fra dette.
Eksempel 8
En oppløsning av 1 g 2-butyl-3-(2-( 2-nitrofenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-b]pyridin i 30 ml etanol ble hydrogenert på 1 g Raney-Ni ved 20 "C og normaltrykk inntil H2-opptaket stanset. Det ble filtrert, inndampet og erholdt 3-( 2-( 2-aminofenyl)-benzofuran-5-yl-metyl)-2-butyl-3H-imidazo-[4,5-b]pyridin.
Eksempel 9
En oppløsning av 2,82 g trifluormetansulfonsyre-anhydrid i 10 ml diklormetan ble dryppet ved -50 til -60 °C til en oppløsning av 3,96 g 3-(2-(2-aminofenyl)-benzofuran-5-yl-metyl)-2-butyl-3H-imidazo[4,5-b]pyridin og 1,01 g trietylamin i 30 ml diklormetan. Blandingen fikk varmes opp til 20 °C, fortynnet eddiksyre ble tilsatt, og etter vanlig opparbeidelse ble det erholdt 2-butyl-3-(2-( 2-trifluormetan-sulf onamidof enyl )-benzofuran-5-yl-metyl)-3H-imidazo[4,5-b]-pyridin.
Eksempel 10
En oppløsning av 7,07 g 2-butyl-3-(2-(2-(1-trifenylmetyl-lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-4,5-di-hydro-4-okso-3H-imidazo[4,5-c]pyridin og 1,17 g K-tert.- butylat i 25 ml DMF ved 20 °C ble under omrøring dråpevis tilsatt en oppløsning av 0,79 g kloracetonitril i 5 mlDMF. Det ble omrørt i ytterligere 30 minutter ved 20 °C, helt over på is, tilsatt saltsyre inntil pH 6, opparbeidet på vanlig måte og erholdt 2-butyl-5-cyanmetyl-3-(2-(2-( 1-trifenylmetyl-lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-4,5-dihydro-4-okso-3H-imidazo[4,5-c]pyridin.
Analogt fikk man de følgende 2-butyl-3-(2-(2-(1-trifenylmetyl-lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-4, 5-dihydro-4-okso-5-R4-3H-imidazo[4, 5-c]pyridiner:
med metyljodid: 5-metyl-
med etyljodid: 5-etyl-
med isopropyljodid: 5-isopropyl-
med butylbromid: 5-butyl-
med tert.-butylbromid: 5-tert.-butyl-
med 3-brompropionitril: 5-(2-cyanetyl)-
med 4-brombutyronitril: 5-(3-cyanpropyl)-
med bromeddiksyremetylester: 5-metoksykarbonylmetyl-med 3-brompropionsyre-
etylester: 5- ( 2-etoksykarbony1-etyl)-
med benzylbromid: 5-benzyl-
med o-fluorbenzylbromid: 5-(o-fluorbenzyl)-
med m-fluorbenzylbromid: 5-(m-fluorbenzyl)-
med p-fluorbenzylbromid: 5-(p-fluorbenzyl)-
med o-klorbenzylbromid: 5-(o-klorbenzyl)-
med m-klorbenzylbromid: 5-(m-klorbenzyl)-
med p-klorbenzylbromid: 5-(p-klorbenzyl)-
med o-brombenzylbromid: 5-(o-brombenzyl)-
med m-brombenzylbromid: 5-(m-brombenzyl)-
med p-brombenzylbromid: 5-(p-brombenzyl)-
med p-metylbenzylbromid: 5-(p-metylbenzyl)-
med o-trifluormetyl-
benzylbromid: 5-(o-trifluormetylbenzyl)-
med m-trifluormetyl-
benzylbromid: 5- (m-trifluormetylbenzyl)-
med p-trifluormetyl-
benzylbromid: 5-(p-trifluormetylbenzyl)-
med o-metoksykarbonyl-
benzylbromid: 5-(o-metoksykarbonylbenzyl)-
med m-metoksykarbonyl-
benzylbromid: 5-(m-metoksykarbonylbenzyl)-
med p-metoksykarbonyl-
benzylbromid: 5- (p-metoksykarbonylbenzyl)-
med o-cyanbenzylbromid: 5-(o-cyanbenzyl)-
med m-cyanbenzylbromid: 5-(m-cyanbenzyl)-
med p-cyanbenzylbromid: 5-( p-cyanbenzyl)-
med o-nitrobenzylklorid: 5-(o-nitrobenzyl)-
med m-nitrobenzylklorid: 5-(m-nitrobenzyl)-
med p-nitrobenzylklorid: 5-(p-nitrobenzyl)-
med o-trifluoracetamido-
benzylbromid: 5-(o-trifluoracetamido-benzyl)-
med m-trifluoracetamido-
benzylbromid: 5-(m-trifluoracetamido-benzyl)-
med p-trifluoracetamido-
benzylbromid: 5- (p-trifluoracetamido-benzyl)-
med o-trifluormetyl-
sulfonamidobenzylbromid: 5-(o-trifluormetyl-sulfonamidobenzyl)-med m-trifluormetyl-
sulfonamidobenzylbromid: 5-(m-trifluormetyl-sulfonamidobenzyl)-med p-trifluormetyl-
sulfonamidobenzylbromid: 5- (p-trifluormetyl-sulfonamidobenzyl)-
Eksempel 11
Av de i eksempel 10 beskrevne forbindelser fikk man analogt med eksempel 2(b) de følgende 2-butyl-4,5-dihydro-4-okso-3-(2-(2-(lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl) - ; 5-R<*->3H-imidazo[4,5-c]pyridiner:
5-cyanmetyl-
5-metyl-
5-etyl-
5-isopropyl-
5-butyl-
5-tert.-butyl-
5-(2-cyanetyl)-
5-(3-cyanpropyl)-5-metoksykarbonylmetyl- (ved siden av 5-karboksy-> metyl-)
5-(2-etoksykarbonyletyl)- [ved siden av 5-(2-karboksyetyl)-]
5-benzyl-
5-(o-fluorbenzyl)-
35-(m-fluorbenzyl)-
5-(p-fluorbenzyl)-
5-(o-klorbenzyl)-
5-(m-klorbenzyl)-
5-(p-klorbenzyl)-
» 5-(o-brombenzy1)-
5-(m-brombenzyl)-
5-(p-brombenzy1)-
5-(p-metylbenzyl)-5-(o-trifluormetylbenzyl)-
> 5-(m-trifluormetylbenzyl)-5-(p-trifluormetylbenzyl)-5-(o-metoksykarbonylbenzyl)- [ved siden av 5-(o-karboksybenzyl)-]
5-(m-metoksykarbonylbenzyl)- [ved siden av 5-(m-> karboksybenzy1)-]
5-(p-metoksykarbonylbenzyl)- [ved siden av 5-(p-karboksybenzyl)-]
5-(o-cyanbenzyl)-
5-(m-cyanbenzyl)-
5-(p-cyanbenzyl)-
5-(o-nitrobenzyl)-
5-(m-nitrobenzyl)-
5-(p-nitrobenzyl)-5-(o-trifluoracetamidobenzyl)-5-(m-trifluoracetamidobenzyl)-5-(p-trifluoracetamidobenzyl)-5-(o-trifluormetylsulfonamidobenzyl) - 5-(m-trifluormetylsulfonamidobenzyl)-5-(p-trifluormetylsulfonamidobenzyl)-.
Eksempel 12
Analogt med eksempel 10 fikk man ved omsetning av 3-(3-brom-2-(2-(1-trifenylmetyl-lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-2-butyl-4,5-dihydro-4-okso-3H-imidazo-[4,5-c]pyridin med kloracetonitril, eller med de andre der angitte alkyleringsmidler, de følgende 3-(3-brom-2-(2-(1-trifenylmetyl-lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-2-butyl-4, 5-dihydro-4-okso-5-R4-3H-imidazo[4, 5-c]pyridiner:
5-cyanmetyl-
5-metyl-
5-etyl-
5-isopropyl-
5-tert.-butyl-
5-(2-cyanetyl)-
5-(3-cyanpropyl)-
5-metoksykarbonylmetyl-5-(2-etoksykarbonyletyl)-
5-benzyl-
5-(o-fluorbenzyl)-
5-(m-fluorbenzyl)-
5-(p-fluorbenzyl)-
5-(o-klorbenzyl)-
5-(m-klorbenzyl)-
5-(p-klorbenzyl)-
5-(o-brombenzyl)-
5-(m-brombenzyl)-
5-(p-brombenzyl)-
5-(p-metylbenzyl)-
5-(o-trifluormetylbenzyl)-5-(m-trifluormetylbenzyl)-5-(p-trifluormetylbenzyl)-5-(o-metoksykarbonylbenzyl)-5-(m-metoksykarbonylbenzyl)-5-(p-metoksykarbonylbenzyl)-5-(o-cyanbenzyl)-
5-(m-cyanbenzyl)-
5-(p-cyanbenzyl)-
5-(o-nitrobenzyl)-
5-(m-nitrobenzyl)-
5-( p-nitrobenzyl ) -
5-(o-trifluoracetamidobenzyl)-5-(m-trifluoracetamidobenzyl)-5-(p-trifluoracetamidobenzyl)-5-(o-trifluormetylsulfonamidobenzyl)-5-(m-trifluormetylsulfonamidobenzyl)-5-(p-trifluormetylsulfonamidobenzyl)-.
Eksempel 13
Analogt med eksempel 2(b) fikk man av de i eksempel 12 beskrevne forbindelser de følgende 3-(3-brom-2-(2-(1H-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-2-butyl-4,5-di-hydro-4-okso-5-R4-3H-imidazo[4, 5-c]pyridiner:
5-cyanmetyl-
5-metyl-
5-etyl-
5-isopropyl-
5-tert.-butyl-
5-(2-cyanetyl)-
5-(3-cyanpropyl)-5-metoksykarbonylmetyl- (ved siden av 5-karboksymetyl-)
5-(2-etoksykarbonyletyl)- [ved siden av 5-(2-karboksyetyl)-]
5-benzyl-
5-(o-fluorbenzyl)-
5-(m-fluorbenzyl)-
5-(p-fluorbenzyl)-
5-(o-klorbenzyl)-
5-(m-klorbenzyl)-
5-(p-klorbenzyl)-
5-(o-brombenzyl)-
5-(m-brombenzyl)-
5-(p-brombenzyl)-
5-(p-metylbenzyl)-
5-(o-trifluormetylbenzyl)-5-(m-trifluormetylbenzyl)-5-(p-trifluormetylbenzyl)-5-(o-metoksykarbonylbenzyl)- [ved siden av 5-(o-karboksybenzyl)-]
5-(m-metoksykarbonylbenzyl)- [ved siden av 5-(m-karboksybenzyl)-]
5-(p-metoksykarbonylbenzyl)- [ved siden av 5-(p-karboksybenzyl)-]
5-(o-cyanbenzyl)-
5-(m-cyanbenzyl)-
5-(p-cyanbenzyl)-
5-(o-nitrobenzyl)-
5-(m-nitrobenzyl)-
5-(p-nitrobenzyl)-
5-(o-trifluoracetamidobenzyl)-5-(m-trifluoracetamidobenzyl)-5-(p-trifluoracetamidobenzyl)-5-(o-trifluormetylsulfonamidobenzyl)-5-(m-trifluormetylsulfonamidobenzyl)-5-(p-trifluormetylsulfonamidobenzyl)-.
Eksempel 14
En oppløsning av 1 g 2-butyl-4,5-dihydro-5-(o-nitrobenzyl )-4-okso-3-(2-(2-(lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-c]pyridin i 20 ml metanol ble hydrogenert på 0,3 g 5 %-ig Pd-karbon ved 20 °C og normaltrykk inntil opptak av den beregnede H2-mengde. Katalysatoren ble frafiltrert, det ble inndampet og erholdt 5-(o-aminobenzyl)-2-butyl-4,5-dihydro-4-okso-3-(2-(2-(lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-c]pyridin.
Analogt fikk man ved hydrogenering av de tilsvarende i eksempel 11 eller 13 nevnte nitroforbindelser de følgende 2-butyl-4,5-dihydro-4-okso-3-(2-(2-(lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-c]pyridiner:
5-(m-aminobenzyl)-
5-(p-aminobenzyl)-
eller de følgende 3-(3-brom-2-(2-(lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-2-butyl-4,5-dihydro-4-okso-4H-imidazo-[4,5-c]pyridiner:
5-(o-aminobenzyl)-
5-(m-aminobenzyl)-
5-(p-aminobenzyl)-.
De følgende eksempler vedrører farmasøytiske preparater som inneholder de aktive forbindelser med formel I eller salter derav.
Eksempel A
Tabletter og drasjeer
På vanlig måte ble det presset tabletter med den følgende sammensetning, som etter behov ble belagt med et vanlig drasjébelegg på sukrosebasis:
Eksempel B
Hardgelatinkapsler
Vanlige todelte hardgelatinkapsler ble hver fylt med:
Eksempel C
Mykqelatinkapsler
Vanlige mykgelatinkapsler ble hver fylt med en blanding av 50 mg aktiv forbindelse og 250 mg olivenolje.
Eksempel D
Ampuller
En oppløsning av 200 g aktiv forbindelse i 2 kg 1,2-propandiol ble tilsatt vann inntil 10 1 og fylt i ampuller, slik at hver ampulle inneholdt 20 mg aktiv forbindelse.
Eksempel E
Vandig suspensjon for oral applikasjon
En vandig suspensjon ble fremstilt på vanlig måte. Enhetsdosen (5 ml) inneholdt 100 mg aktiv forbindelse, 100 mg Na-karboksymetylcellulose, 5 ml Na-benzoat og 100 mg sorbitol.
Claims (8)
1. Benzofuraner,
karakterisert ved at de har formel I
hvor
R er resten
R <1> er H, Hal, COOH, CONH2 , CHO, CN, NH2 eller 5-tetra
zolyl,
R<2> er H, COOH, COOR <3> , CN, N02 , NH2 , NHCOCF3 , NHS02 CF3
eller 5-tetrazolyl,
R <3> er H, alkyl, alkenyl eller alkynyl, hver med inntil 6 C-atomer,
R <*> er H, alkyl med 1-6 C-atomer, cyanalkyl, R <3> OOC-alkyl, 5-tetrazolylalkyl eller aralkyl, hver med 1-6 C-atomer i "alkyl"-delen,
-A-B-C-D- er en av gruppene -CH=CH -CH =N -, -CH=CH -N =CH -,
-CH=N-CH=CH-, -N=CH-CH=CH-, -CH=CH -CO-NR<4-> , -CH=CH -NR4-CO-, -CO-NR4-CH=CH- eller -NR<4> -CO-CH=CH-, hvor H-atomet i -CH-gruppene kan være substituert med alkyl med 1-6 C-atomer, Hal, COOR <3> , CN og/eller 5-tetrazolyl,
Ar er fenyl som er usubstituert eller substituert én
eller to ganger med Hal, R <3> , CF3 , COOR <3> , CN,OR<3> ,N 02 , NH2 , NHCOCF3 , NHS02 CF3 eller 5-tetrazolyl, og Hal er F, Cl, Br eller I,
samt salter derav.
2. Benzofuran ifølge krav 1, karakterisert ved at det er a) 2-butyl-7-metyl-3-(2-(2-(lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-raetyl)-3H-imidazo[4,5-b]pyridin,
b) 2-etyl-5,7-dimetyl-3-(2-(2-(lH-tetrazol-5-yl) - fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4, 5-b]pyridin,
c) 2-butyl-5-(2-karboksybenzyl)-4,5-dihydro-4-okso-3-(2-(2-(lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-c]pyridin,
d) 2-butyl-4,5-dihydro-4-okso-3-(2-(2-(lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-c]pyridin eller
e) 2-butyl-5-karboksymetyl-4,5-dihydro-4-okso-3-
( 2-(2-(lH-tetrazol-5-yl)-fenyl)-benzofuran-5-yl-metyl)-3H-imidazo[4,5-c]pyridin.
3. Fremgangsmåte for fremstilling av benzofuraner med formel I ifølge krav 1, samt salter derav, karakterisert ved at
en forbindelse med formel II
hvor
E er Cl, Br, I eller en fri eller reaksjonsdyktig,
funksjonelt omdannet OH-gruppe, ogR<1> og R <2> har den i krav 1 angitte betydning,
omsettes med en forbindelse med formel III
hvor
R har den i krav 1 angitte betydning,
eller en forbindelse med formel I frisettes fra et av dens funksjonelle derivater ved behandling med et solvolyserende eller hydrogenolyserende middel,
og/eller én eller flere rester R <1> , R <2> og/eller R i en forbindelse med formel I omdannes til én eller flere andre rester R <1> , R2 og/eller R, og/eller en base eller syre med for mel I overføres til et salt derav.
4. Fremgangsmåte for fremstilling av farmasø ytiske preparater,
karakterisert ved at en forbindelse med formel I ifølge krav 1 og/eller et fysiologisk akseptabelt syreaddisjonssalt derav bringes sammen med minst ett fast, flytende eller halvflytende bærer- eller hjelpestoff i en egnet doseringsform.
5. Farmasøytisk preparat,
karakterisert ved at det har et innhold av minst én forbindelse med formel I ifølge krav 1 og/eller et fysiologisk akseptabelt syreaddisjonssalt derav.
6. Forbindelser med formel I ifølge krav 1 og fysiologisk akseptable syreaddisjonssalter derav for bekjempelse av sykdommer.
7. Anvendelse av forbindelser med formel I ifølge krav 1 og/eller fysiologisk akseptable syreaddisjonssalter derav for fremstilling av et legemiddel.
8. Anvendelse av forbindelser med formel I ifølge krav 1 og/eller fysiologisk akseptable syreaddisjonssalter derav ved bekjempelse av sykdommer.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4140519A DE4140519A1 (de) | 1991-12-09 | 1991-12-09 | Benzofurane |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO924745D0 NO924745D0 (no) | 1992-12-08 |
| NO924745L true NO924745L (no) | 1993-06-10 |
Family
ID=6446602
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO92924745A NO924745L (no) | 1991-12-09 | 1992-12-08 | Benzofuraner |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0546449A3 (no) |
| JP (1) | JPH05262768A (no) |
| AU (1) | AU2993792A (no) |
| CA (1) | CA2084736A1 (no) |
| DE (1) | DE4140519A1 (no) |
| HU (1) | HU9203893D0 (no) |
| MX (1) | MX9207070A (no) |
| NO (1) | NO924745L (no) |
| PL (1) | PL296865A2 (no) |
| ZA (1) | ZA929513B (no) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9110636D0 (en) * | 1991-05-16 | 1991-07-03 | Glaxo Group Ltd | Chemical compounds |
| MX9202300A (es) * | 1991-05-16 | 1992-11-01 | Glaxo Group Ltd | Derivados de benzofurano, procedimiento para su preparacion y composicion farmaceutica que los contiene. |
| DE4324580A1 (de) * | 1993-07-22 | 1995-01-26 | Thomae Gmbh Dr K | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
| DE19845153A1 (de) | 1998-10-01 | 2000-04-06 | Merck Patent Gmbh | Imidazo[4,5]-pyridin-4-on-derivate |
| EP1724271A4 (en) | 2004-02-26 | 2013-01-23 | Kyowa Hakko Kirin Co Ltd | PREVENTIVE AND / OR THERAPEUTIC AGENT AGAINST NEUTROPHIC INFLAMMATORY DISEASE |
| WO2023210623A1 (ja) * | 2022-04-28 | 2023-11-02 | 株式会社エス・ディー・エス バイオテック | ハロアルキルスルホンアニリド化合物及びそれらを含有する除草剤 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL94390A (en) * | 1989-05-30 | 1996-03-31 | Merck & Co Inc | The 6-membered trans-nitrogen-containing heterocycles are compressed with imidazo and pharmaceutical preparations containing them |
| GB8927277D0 (en) * | 1989-12-01 | 1990-01-31 | Glaxo Group Ltd | Chemical compounds |
| MX9202300A (es) * | 1991-05-16 | 1992-11-01 | Glaxo Group Ltd | Derivados de benzofurano, procedimiento para su preparacion y composicion farmaceutica que los contiene. |
-
1991
- 1991-12-09 DE DE4140519A patent/DE4140519A1/de not_active Withdrawn
-
1992
- 1992-12-03 EP EP19920120651 patent/EP0546449A3/de not_active Withdrawn
- 1992-12-07 CA CA002084736A patent/CA2084736A1/en not_active Abandoned
- 1992-12-07 AU AU29937/92A patent/AU2993792A/en not_active Abandoned
- 1992-12-07 PL PL29686592A patent/PL296865A2/xx unknown
- 1992-12-07 MX MX9207070A patent/MX9207070A/es unknown
- 1992-12-08 ZA ZA929513A patent/ZA929513B/xx unknown
- 1992-12-08 NO NO92924745A patent/NO924745L/no unknown
- 1992-12-08 JP JP4328030A patent/JPH05262768A/ja active Pending
- 1992-12-09 HU HU9203893A patent/HU9203893D0/hu unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPH05262768A (ja) | 1993-10-12 |
| NO924745D0 (no) | 1992-12-08 |
| CA2084736A1 (en) | 1993-06-10 |
| ZA929513B (en) | 1993-06-15 |
| EP0546449A3 (en) | 1993-07-14 |
| HU9203893D0 (en) | 1993-03-29 |
| PL296865A2 (en) | 1993-06-14 |
| EP0546449A2 (de) | 1993-06-16 |
| AU2993792A (en) | 1993-06-10 |
| DE4140519A1 (de) | 1993-06-17 |
| MX9207070A (es) | 1993-06-01 |
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