NO178189B - Tetrazolmellomprodukter - Google Patents
Tetrazolmellomprodukter Download PDFInfo
- Publication number
- NO178189B NO178189B NO882241A NO882241A NO178189B NO 178189 B NO178189 B NO 178189B NO 882241 A NO882241 A NO 882241A NO 882241 A NO882241 A NO 882241A NO 178189 B NO178189 B NO 178189B
- Authority
- NO
- Norway
- Prior art keywords
- phenyl
- alkyl
- tetrazole
- mol
- benzyl
- Prior art date
Links
- 150000003536 tetrazoles Chemical class 0.000 title claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 4
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- -1 OR or NR 10 R 7 is H Chemical group 0.000 abstract description 7
- 125000000217 alkyl group Chemical group 0.000 abstract 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 5
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 4
- 125000005010 perfluoroalkyl group Chemical group 0.000 abstract 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 abstract 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 abstract 1
- 125000002252 acyl group Chemical group 0.000 abstract 1
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- 125000000304 alkynyl group Chemical group 0.000 abstract 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 20
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical class OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 150000002825 nitriles Chemical class 0.000 description 5
- ILYSAKHOYBPSPC-UHFFFAOYSA-N 2-phenylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=CC=C1 ILYSAKHOYBPSPC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- WFPZPJSADLPSON-UHFFFAOYSA-N dinitrogen tetraoxide Chemical compound [O-][N+](=O)[N+]([O-])=O WFPZPJSADLPSON-UHFFFAOYSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- 150000001411 amidrazones Chemical class 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000012258 stirred mixture Substances 0.000 description 3
- SMIXZZMSWYOQPW-UHFFFAOYSA-N (4-nitrophenyl)methylazanium;chloride Chemical compound [Cl-].[NH3+]CC1=CC=C([N+]([O-])=O)C=C1 SMIXZZMSWYOQPW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- GUWHRJQTTVADPB-UHFFFAOYSA-N lithium azide Chemical compound [Li+].[N-]=[N+]=[N-] GUWHRJQTTVADPB-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 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 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- MIFMRFMMWFFJPO-UHFFFAOYSA-N 2-(4-methylphenyl)-n-[(4-nitrophenyl)methyl]benzamide Chemical compound C1=CC(C)=CC=C1C1=CC=CC=C1C(=O)NCC1=CC=C([N+]([O-])=O)C=C1 MIFMRFMMWFFJPO-UHFFFAOYSA-N 0.000 description 1
- ZSTUEICKYWFYIC-UHFFFAOYSA-N 2-(4-methylphenyl)benzoic acid Chemical compound C1=CC(C)=CC=C1C1=CC=CC=C1C(O)=O ZSTUEICKYWFYIC-UHFFFAOYSA-N 0.000 description 1
- CWYDJVNQLOTFNE-UHFFFAOYSA-N 2-(4-methylphenyl)benzoyl chloride Chemical compound C1=CC(C)=CC=C1C1=CC=CC=C1C(Cl)=O CWYDJVNQLOTFNE-UHFFFAOYSA-N 0.000 description 1
- FGCNIDUBRIVYBP-UHFFFAOYSA-N 2-[4-[[2-butyl-4-chloro-5-(hydroxymethyl)imidazol-1-yl]methyl]phenyl]benzonitrile Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C#N)C=C1 FGCNIDUBRIVYBP-UHFFFAOYSA-N 0.000 description 1
- JLVIHQCWASNXCK-UHFFFAOYSA-N 2-butyl-5-chloro-1h-imidazole-4-carbaldehyde Chemical compound CCCCC1=NC(C=O)=C(Cl)N1 JLVIHQCWASNXCK-UHFFFAOYSA-N 0.000 description 1
- KYSNYDMRSMPPTF-UHFFFAOYSA-N 5-[2-(4-methylphenyl)phenyl]-1-[(4-nitrophenyl)methyl]tetrazole Chemical compound C1=CC(C)=CC=C1C1=CC=CC=C1C1=NN=NN1CC1=CC=C([N+]([O-])=O)C=C1 KYSNYDMRSMPPTF-UHFFFAOYSA-N 0.000 description 1
- USPYDUPOCUYHQL-VEVMSBRDSA-N 5beta-dihydrodeoxycorticosterone Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CC[C@@H]21 USPYDUPOCUYHQL-VEVMSBRDSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- ZKJNVODQIYQUNQ-UHFFFAOYSA-N [2-butyl-5-chloro-3-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2N(N=NN=2)C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)C=C1 ZKJNVODQIYQUNQ-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- BJUSKQNPSWYMEI-UHFFFAOYSA-N azido(triphenyl)stannane Chemical class C=1C=CC=CC=1[Sn](C=1C=CC=CC=1)(N=[N+]=[N-])C1=CC=CC=C1 BJUSKQNPSWYMEI-UHFFFAOYSA-N 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000002465 imidoyl halides Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical group CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- PCTNAMGLSYHIPL-UHFFFAOYSA-N tin(4+) tetraazide Chemical class [Sn+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] PCTNAMGLSYHIPL-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/22—Tin compounds
- C07F7/2284—Compounds with one or more Sn-N linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Surface Acoustic Wave Elements And Circuit Networks Thereof (AREA)
Abstract
Totrazolderivater av formelen:. hvori Xer H, Sn(R), -C(fenyl), p-nitrobenzyl eller (3-propionitril,er H, Cl, Br, I, O-tosyl, OH, O-mesyl ellerR er alkyl, fenyl eller cyclohexyl;er alkyl, alkenyl, alkynyl og substituert benzyl; Rer fenylalkenyl, -(CH)-imidazoyl-l-yl, -(CH)-l,2,3-triazolyl, (CH_) -tetrazolyl,R er H, F, Cl, Br, I, N02, CF3 eller CN; R4 er H, alkyl, cycloalkyl, fenyl eller benzyl; R5 er H, alkyl eller perfluoralkyl, cycloalkyl, fenyl eller benzyl; R6 er H, alkyl, OReller NR10R7 er H, alkyl, cycloalkyl, fenyl,p benzyl, acyl, fenacyl; R er alkyl eller perfluoralkyl, 1-adamantyl, 1-nafthyl, 1-(1-nafthyl)-ethyl eller (CH.) Cj-H,; R9 er H, alkyl, cycloalkylp 10 11 eller fenyl; Rxu og R er H, alkyl, fenyl, benzyl ellerQ er NR, 0 eller CH; Rer H, alkyl eller fenyl; m er 1 til 5;n er 1 til 10; s er 0 til 5; p er 0 til 3; t er 0 eller 1,forutsatt at når X= H, kan XikkeværeRJ R
Description
Foreliggende oppfinnelse angår substituerte tetrazoler som er anvendbare som mellomprodukter ved fremstilling av antihypertensive forbindelser beskrevet i US patentsøknad 884.920 innlevert 11. juli 1986.
S. Kozima et al., J. Organometallic Chem., 3_3, 337
(1971) og ibid, 92., 303 (1975) beskriver substituerte tetrazoler av formelen:
hvori
Ri er lavere alkyl, benzyl, lavere alkenyl eller fenyl eventuelt substituert med nitro, lavere alkyl, lavere alkoxy eller halogen; og
R<2> er SnR3.
R. Lofquist et al., J. Amer. Chem. Soc, 80, 3909
(1958) beskriver substituerte tetrazoler av formelen:
hvori R er lavere alkyl, benzyl, cycloalkyl med 4 carbon-atomer, n-heptylperfluor, -SR<1> hvori R<1> er lavere alkyl, benzyl; -(CH2)nR<2> hvori R<2> er OH, CX^R<1>, OR<1>, S03Na og n er 1 eller 2; eller fenyl eventuelt substituert med amino, lavere alkoxy, lavere alkyl, nitro eller cyano.
W. Beck et al., Chem. Ber., 116, 2691 (1983)
beskriver fremstilling av 2-trityl-5-fenyltetrazol.
Ifølge oppfinnelsen er det tilveiebrakt nye forbindelser av formel I som er tetrazolmellomprodukter som er anvendbare for fremstilling av antihypertensive forbindelser. Disse tetrazoler ér kjennetegnet ved at de har formelen
hvori
X<1> er H, -Sn(R)3, -C( fenyl )3 eller p>-nitrobenzyl, X<2> er H, Br eller
R er methyl eller fenyl; forutsatt at når X<1> er H kan X<2> ikke være
Spesielt foretrukne forbindelser er de av formel (I)
hvori:
(1) X<1> er H, -Sn(R)3 eller -C( fenyl )3,
(2) X<1> er H, -Sn(R)3 eller -C( fenyl)3 og X<2> er H, i (3) X<1> er -C( fenyl )3 og X<2> er Br og (4) X1 er -Sn(CH3)3 eller -C( fenyl )3 og X<2> er
De nye forbindelser av formel (I) kan fremstilles under anvendelse av de reaksjoner og teknikker som er beskrevet i dette avsnitt. Reaksjonene utføres i et løsningsmiddel som er egnet for de reagenser og materialer som anvendes og som er egnet for denne omdannelse som utføres. Det vil forstås av fagmannen at funksjonaliteten tilstedeværende på imidazolen og andre deler av molekylet, må være i overensstemmelse med den foreslåtte kjemiske omdannelse. Dette vil hyppig nødvendiggjøre bedømmelse med hensyn til rekkefølgen av syntesetrinn, de nødvendige beskyttende grupper, avbeskyttelsesbetingelser, og aktivering av en benzylisk posisjon for å muliggjøre binding til nitrogenet på imidazolkjernen. I det etter-følgende avsnitt kan ikke alle forbindelser av formel (I) som faller inn under en gitt klasse, nødvendigvis fremstilles ved alle metoder beskrevet for denne klasse. Substituenter på utgangsmaterialene kan være uforenlige med enkelte av de reaksjonsbetingelser som kreves i enkelte av de beskrevne metoder. Slike begrensninger med hensyn til substituentene som er forenlige med reaksjonsbetingelsene, vil lett fremgå for fagmannen, og alternative metoder må da anvendes.
Forbindelser av formel (I) hvori X<1> er Sn(R)3 og R er methyl og X<2> er substituert imidazolyl som ovenfor angitt, kan fremstilles ved 1,3-dipolar cycloaddi-
sjon av trialkyltinn eller trifenyltinnazider til det egnede, substituerte nitril (II) (reaksjonsskjema I). Et eksempel på denne teknikk er beskrevet av S. Kozima et al., J. Organometallic Chemistry, 33_, 337 (1971). Nitrilet (II) er beskrevet i US patentsøknad 884.920 innlevert 11. juli
1986. Andre nødvendige nitriler og trialkyl- eller triaryltinnazider er enten tilgjengelige kommersielt, eller kan fremstilles under anvendelse av teknikker og metoder beskrevet i litteraturen, J. Luijten et al., Ree. Trav. Chem., 81, 202 (1962).
Reaksjonsskjerna I
Forbindelser av formel (I) hvori X<1> og X<2> er H, kan fremstilles ved fjerning av en egnet beskyttende gruppe på tetrazolkjernen. Egnede beskyttende grupper for tetrazoldelen innbefatter p-nitrobenzyl, £-propionitril, trifenylmethyl og trialkyltinn, som fremstilles via de etterfølgende metoder. Nitrobenzylbeskyttelsesgruppen bindes som vist i reaksjonsskjerna II. Syren (IV) omdannes til syreklorid-mellomproduktet med oxalylklorid under standardbetingelser. Syrekloridet omdannes til amidet (V) ved kondensasjon med 4-nitrobenzylamin-hydroklorid i pyridin i nærvær av en katalytisk mengde 4-dimethylaminopyridin (DMAP). Amidet (V) omdannes til iminoylklorid-mellomproduktet via omsetning med fosforpentaklorid i carbontetraklorid. Ett eksempel på denne metode er beskrevet av H. Ulrich, The Chemistry of Imidoyl Halides, Plenum Press, N.Y., N.Y. (1968). Iminoylklorid-mellomproduktet omdannes til tetrazol (VI) med lithiumazid i dimethylformamid (DMF). Et eksempel på denne metode er beskrevet av Elderfield, Heterocyclic Compounds, John Wiley and Sons, (1967). Den beskyttede tetrazol (VI) hydrogeneres deretter ved 3,5 kg/cm<2> i nærvær av en katalytisk mengde av W6 Raney-nikkel i ethanol under dannelse av (I). Den nødvendige syre (IV) er tilgjengelig kommersielt eller kan fremstilles under anvendelse av teknikker og metoder beskrevet i den kjemiske litteratur.
Trifenylmethylgruppen bindes som vist i reaksjonsskjerna III. Tetrazolen (I) reagerer med trifenylmethylklorid i methylenklorid inneholdende triethylamin som base under standardbetingelser under dannelse av den beskyttede tetrazol (VII).
Propionitrilbeskyttelsesgruppen bindes som vist i reaksjonsskjema IV. Bifenylcarboxylsyren (IV) kan omdannes til syrekloridet med et utall av reagenser velkjente for fagmannen. Syreklorid-mellomproduktet reagerer med p-aminopropionitril i nærvær av en syreutvasker slik som vandig natriumhydroxyd under dannelse av amidet (VIII). Amidet (VIII) reagerer med fosforpentaklorid eller fosgen under dannelse av iminoylklorid-mellomproduktet (IX) som ved omsetning med hydrazin gir amidrazonet (X). Amidrazonet (X) reagerer lett med dinitrogentetroxyd (N2O4) som hensiktsmessig kan håndteres som en løsning i carbontetraklorid under dannelse av tetrazol (XI). Hydraziner og hydrazider er blitt vist å gjennomgå en lett omdannelse til deres tilsvarende azider med ^ 2°4 som beskrevet av Y. H. Kim et al., Tetrahedron Letters, 2_7, 4749 (1986). Den beskyttede tetrazol (XI) avbeskyttes med vandig base slik som IN NaOH, med eller uten et ytterligere organisk løs-ningsmiddel som tetrahydrofuran, under dannelse av tetrazol (I). Amidrazonet (X) kan også omdannes til tetrazolen (XI) under anvendelse av salpetersyrling eller dens ekvivalenter som beskrevet av D. G. Neilson et al., Chem. Rev., 70, 151
(1970).
Foretrukne beskyttende grupper er de hvori X<1> er Sn(R)3 og C(fenyl)3 og R er som tidligere beskrevet (reaksjonsskjema V). De ovenfor angitte grupper kan eventuelt fjernes via sur eller basisk hydrolyse, katalytisk hydro-genering og bestråling som beskrevet av Greene, Protective Groups in Organic Synthesis, Wiley-Interscience (1980).
Forbindelser av formel (I) hvori X<1> er C(fenyl)3 og X^ er Br, kan fremstilles via radikal bromering av (VII) med N-bromsuccinimid (NBS) og dibenzoylperoxyd (Bz202) under dannelse av (XII) som vist i reaksjonsskjema VI. Et eksempel på denne omdannelse er beskrevet av L. Horner et al., Angew. Chem., 71, 349 (1959.
j
Forbindelser av formel (I) hvori X<1> er C(fenyl)3 og X er I, kan fremstilles via fortrengning av bromdelen i (XII) med natriumjodid i aceton under standardbetingelser,
under dannelse av (XIII). Fortrengning av det ovenfor
i angitte bromid (XII) med hydroxydion gir den substituerte benzylalkohol (XIV). Benzylalkoholen (XIV) kan omdannes til kloridet (XV) via omsetning med carbontetraklorid og trifenylfosfin. Benzylalkoholen (XIV) kan omdannes til
tosylatet eller mesylatet (XVI) via omsetning med
) p-toluensulfonylklorid eller methansulfonylklorid i pyridin under standardbetingelser (reaksjonsskjerna VII).
Forbindelser av formel (I) hvori X<1> er C(fenyl)3 og X<2> er imidazoyl hvori R<1> er n-butyl, R<3> er Cl og R<2> er hydroxymethyl, kan fremstilles via alkylering av imidazol (XVII) med det egnede substituerte benzylhalogenid under anvendelse av natriumethoxyd som base, etterfulgt av reduksjon av formaldehyddelen på imidazolen (XVII) til hydroxymethyl med natriumborhydrid som gir (XVIII). Fremstilling av imidazolen (XVII) i reaksjonsskjerna VIII er beskrevet av Furukawa et al., i US 4.355.040.
Forbindelsene ifølge oppfinnelsen og deres fremstilling forstås ytterligere av de etterfølgende
eksempler, men skal ikke begrenses til disse. I disse eksempler er alle temperaturer i grader Celsius, og deres og prosenter er på vektbasis med mindre annet er angitt.
Eksempel 1
Del A: 4'-methylbifenyl-2-carbonylklorid
En løsning av 31,84 g (0,15 mol) 4'-methyl-bifenyl-2-carboxylsyre i 200 ml kloroform ble tilsatt dråpevis til en omrørt blanding av 25 ml kloroform, 25 ml oxalylklorid og 1,0 ml dimethylformamid ved romtemperatur. Etter at blandingen var omrørt i 24 timer ved romtemperatur, ble løsningen fordampet i vakuum under dannelse av 36,4 g av det urene syreklorid. IR: 1784,0 cm-<1> (C0C1).
Del B: N-(4-nitrobenzyl)-4'-methylbifenyl-2-carboxamid
En løsning av materialet fra del A (36,4 g) i tørt acetonitril ble dråpevis tilsatt til en avkjølt (isbad), omrørt blanding av 23,45 g (0,12 mol) 4-nitrobenzylamin-hydroklorid, 0,5 g (0,0041 mol) 4-dimethylaminopyridin og 150,0 ml tørt pyridin. Etter 30 minutter fikk reaksjonsblandingen anta romtemperatur og ble omrørt i 16 timer ved romtemperatur. Blandingen ble helt over i en omrørt blanding av 800 ml 3N HC1, 400,0 g is og 400 ml diklormethan. ' Det organiske lag ble vasket med 2 x 200 ml 2N NaOH, 100 ml saltvann, ble tørket (MgS04) og fordampet i vakuum under dannelse av 61,9 -g urent produkt. Omkrystallisering fra ethylacetat ga 31,3 g (73%) produkt, smp. 153-154°. <1>H NMR (CDC13) S: 8,03 (d, 2H, .aromatisk) ; 7,65-7,69 (m, 1H, aromatisk); 7,12-7,48 (m, 7H, aromatisk); 7,04 (d, 2H, aromatisk); 5,77-5,79 (m, 1H, NH); 4,41 (d, 2H, J = 6,0 Hz, CH2); 2,39 (s, 3H, CH3). Massespektr. m/z = 347 (M + 1).
Del C: N-(4-nitrobenzyl)-4'-methylbifen-2-yl-carbo-iminoylklorid
I tre porsjoner og en totalmengde på 20,78 g (0,060 mol) ble produktet fra del B tilsatt til en avkjølt (isbad), omrørt løsning av 12,49 g (0,066 mol) fosforpentaklorid i 200 ml carbontetraklorid. Blandingen ble omrørt i 30 minutter ved 0°, fikk oppvarmes til romtemperatur og ble omrørt i 16 timer. Blandingen ble fordampet i vakuum under dannelse av 21,3 g urent produkt.
IR: 1691 cm-<1> (C=N). <1>H NMR (CDCI3) S: 4,79 (s, 2H, CH2).
Del D: 1-(4-Nitrobenzyl)-5-(4'-methylbifen-2-yl)-tetrazol
3,67 g, (0,75 mol) lithiumazid ble tilsatt porsjonsvis til en avkjølt løsning (isbad) av 21,3 g av produktet fra del C i dimethylformamid (200,0 ml). Blandingen fikk anta romtemperatur i løpet av 16 timer. Reaksjonsblandingen ble fordampet i vakuum. Residuet ble fordelt mellom vann og 100 ml ethylacetat. Det organiske lag ble vasket med 100 ml vann, ble tørket (MgS04) og fordampet i vakuum under dannelse av 19,5 g av et mørkt residum. Kromatografi på silica (CHCI3) etterfulgt av omkrystallisering (methanol) ga 5,37 g,
(24,1%), smp. 95,0-96,0°. <1>H NMR (CDCI3)
S : 7,98-8,02 (m, 2H, aromatisk); 7,55-7,70 (m, 2H, aromatisk); 7,37-7,49 (m, 2H, aromatisk); 6,99-7,10 (m, 2H, aromatisk); 4,87 (d, J = 8,7 Hz, aromatisk); 4,88
(s, 2H, CH2); 2,33 (s, 3H, CH3). Massespektr. m/z =
372 (M + 1).
Eksempel 2
N-trifenylmethyl-5-[2-(4<1->methylbifenylyl)]-tetrazol
Til en løsning av 17,0 g (0,072 mol) 5-[2-(4'-methylbifenyl) ]J-tetrazol i 260 ml methylenklorid ble tilsatt 21,20 g (0,076 mol) trifenylmethylklorid ved romtemperatur. 12,0 ml (0,086 mol) triethylamin ble tilsatt ved romtemperatur, og løsningen ble kokt under tilbakeløpskjøling i 2,5 time. Løsningen ble avkjølt til romtemperatur, ble vasket med 2 x 50 ml vann, ble tørket (M<g>S04) og fordampet i vakuum. Residuet ble krystallisert fra 80 ml toluen under dannelse av N-trifenylmethyl-5-[2-(4<1->methylbifenylyl)]-tetrazol (31,2 g, 90%), smp. 163-166°; <1>H NMR (CDCI3) 8: 8,10-6,80 (kompleks, 23H); 2,28 (s, 3H).
Eksempel 3
N-trifenylmethyl-5- [2-(41-brommethyl-bifenylyl)] -
tetrazol
Til en løsning av 31,0 g (0,065 mol) N-trifenylmethyl-5-[2-(4<1->methylbifenylyl)]-tetrazol i 390,0 ml carbontetraklorid ble tilsatt 11,50 g (0,065 mol) N-bromsuccinimid og 1,10 g (0,0045 mol) dibenzoylperoxyd ved romtemperatur. Reaksjonsblandingen ble kokt under tilbakeløpskjøling i 3 timer, ble avkjølt til 40° og filtrert. Fordampning av filtratet i vakuum etterfulgt av triturering av residuet med 100,0 ml isopropylether ga N-trifenylmethyl-5-[ 2-(41-brommethyl-bifenylyl)}-tetrazol (33,10 g, 92%), smp. 135-138°. <1>H NMR (CDCI3) 5: 8,20-6,70 (kompleks, 23H); 4,33 (s, 2H).
Eksempel 4
1- {[2 '-(N-trifenylmethyl-tetrazol-5-yl)-bifenyl-4-yl]-methyl}-2-butyl-4-klor-5-hydroxymethyl-imidazol
Til en løsning av 1,24 g (0,007 mol) 2- butyl-4-klor-5-formylimidazol oppløst i 10,0 ml dimethylformamid, ble tilsatt 0,45 g (0,0066 mol) natriumethoxyd, og reaksjonsblandingen ble avkjølt til 5°. 3,70 g (0,0066 mol) N-trifenylmethyl-5-[2-(4<1->brommethyl-bif enylyl)]-tetrazol ble tilsatt, og reaksjonsblandingen fikk oppvarmes til romtemperatur. Etter 72 timer ble reaksjonsblandingen fortynnet med 25,0 ml vann og ble ekstrahert med 3 x 25 ml ethylacetat. Den organiske fase ble vasket med 2 x 25 ml vann og 3 x 25 ml saltvann, ble tørket (MgSO^) og fordampet i vakuum til en olje. Den urene olje ble oppløst i 20,0 ml methanol, og 0,24 g (0,0063 mol) natriumborhydrid ble tilsatt ved romtemperatur. Reaksjonsblandingen ble omrørt i 1,5 time, ble fortynnet med 40,0 ml vann og ble ekstrahert med 2 x 50 ml ethylacetat. Det organiske lag ble vasket med 1 x 25 ml vann, ble tørket (MgS04) og fordampet i vakuum. Residuet ble omkrystallisert en gang fra toluen/heptan, en gang fra toluen og til slutt fra methanol under dannelse av 1-{[2<1->(N-trifenylmethyl-tetrazol-5-yl)-bifenyl-4-yl]-methyl}-2-butyl-4-klor-5-hydroxymethyl-imdidazol (0,98 g, 21%), smp. 95-95°' 1H NMR (CDCI3) $: 8,20-6,60 (kompleks, 23H); 5,16 (s, 3H); 4,40 (s, 3H); 2,85 (brs, 1H); 2,54 (t, 3H); 1,9-1,1 (m, 4H); 0,88 (t, 3H).
Eksempel 5
1-£[2'-(N-trimethylstannyl-tetrazol-5-yl)-bifenyl-4-yl] - methyl}-2-buty1-4-klor-5-hydroxymethyl-imidazol
Til en løsning av 4,40 g (0,011 mol) l-[(2'-cyano-bifenyl-4-yl)-methyl]-2-butyl-4-klor-5-hydroxymethyl-imidazol i 40,0 ml xylen ble tilsatt 2,80 g (0,014 mol) trimethyltinnazid, og reaksjonsblandingen ble oppvarmet til 115-120° i 40 timer. Blandingen ble avkjølt til 50° og ble filtrert under dannelse av
1-£[2'-(N-trimethylstannyl-tetrazol-5-yl)-bifenyl-4-yl} -methyl}-2-butyl-4-klor-5-hydroxymethyl-
imidazol (6,55 g, 99%), smp. 154-160°; <1>H NMR (CDCl3/DMSO-d6) & : 7,80-7,30 (m, 4H), 7,03 (q,
4H), 5,23 (s, 3H), 4,43 (s, 3H), 2,54 (t, 3H); 2,00
(s, 1H), 1,80-1,10 (m, 4H); 0,85 (t, 3H); 0,40
(s, 9H).
Forbindelsene fremstilt ifølge eksempel 1, 2, 3, 4 og 5, er vist i tabell I.
Claims (5)
1. Tetrazol,
karakterisert ved at den har formelen
hvori
X<1> er H, -Sn(R)3, -C( fenyl )3 eller p_-nitrobenzyl, X<2> er H, Br eller
R er methyl eller fenyl; forutsatt at når X<1> er H kan X<2> ikke være
2. Tetrazol ifølge krav 1,
karakterisert ved at X<1> er H, -Sn(R)3 eller -C( fenyl )3.
3. Tetrazol ifølge krav 1, karakterisert ved at X<1> er H, -Sn(R)3 eller -C( fenyl )3 og X<2> er H.
4. Tetrazol ifølge krav 1,
karakterisert ved at X<1> er -C( fenyl )3 og X<2 >er Br.
5. Tetrazol ifølge krav 1,
karakterisert ved at X<1> er -Sn(CH3)3 eller -C( fenyl) 3 og X<2> er
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|---|---|---|---|
| US07/053,198 US4820843A (en) | 1987-05-22 | 1987-05-22 | Tetrazole intermediates to antihypertensive compounds |
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| NO178189B true NO178189B (no) | 1995-10-30 |
| NO178189C NO178189C (no) | 1996-02-07 |
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| NO882241A NO178189C (no) | 1987-05-22 | 1988-05-20 | Tetrazolmellomprodukter |
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| CA1338238C (en) | 1988-01-07 | 1996-04-09 | David John Carini | Angiotensin ii receptor blocking imidazoles and combinations thereof with diuretics and nsaids |
| EP0733366B1 (en) * | 1988-01-07 | 1998-04-01 | E.I. Du Pont De Nemours And Company | Pharmaceutical compositions comprising angiotensin II receptor blocking imidazoles and diuretics |
| DE3928177A1 (de) * | 1989-04-08 | 1991-02-28 | Thomae Gmbh Dr K | Benzimidazole, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
| CA2016710A1 (en) * | 1989-05-15 | 1990-11-15 | Prasun K. Chakravarty | Substituted benzimidazoles as angiotensin ii antagonists |
| GB8911854D0 (en) * | 1989-05-23 | 1989-07-12 | Ici Plc | Heterocyclic compounds |
| US5064825A (en) * | 1989-06-01 | 1991-11-12 | Merck & Co., Inc. | Angiotensin ii antagonists |
| JP2568315B2 (ja) | 1989-06-30 | 1997-01-08 | イー・アイ・デュポン・ドゥ・ヌムール・アンド・カンパニー | 縮合環アリール置換イミダゾール |
| CA2020073A1 (en) * | 1989-07-03 | 1991-01-04 | Eric E. Allen | Substituted quinazolinones as angiotensin ii antagonists |
| EP0411507B1 (en) * | 1989-08-02 | 1994-10-26 | Takeda Chemical Industries, Ltd. | Pyrazole derivatives, their production and use |
| IE902909A1 (en) * | 1989-08-11 | 1991-02-27 | Ici Plc | Nitrogen compounds |
| IE70593B1 (en) * | 1989-09-29 | 1996-12-11 | Eisai Co Ltd | Biphenylmethane derivative the use of it and pharmacological compositions containing same |
| US5298518A (en) * | 1989-09-29 | 1994-03-29 | Eisai Co., Ltd. | Biphenylmethane derivative and pharmacological use |
| IL95975A (en) * | 1989-10-24 | 1997-06-10 | Takeda Chemical Industries Ltd | N-benzyl- 2-alkylbenzimidazole derivatives, their production and pharmaceutical compositions containing them |
| US5250554A (en) * | 1989-10-24 | 1993-10-05 | Takeda Chemical Industries, Ltd. | Benzimidazole derivatives useful as angiotensin II inhibitors |
| IL96019A0 (en) * | 1989-10-31 | 1991-07-18 | Fujisawa Pharmaceutical Co | Imidazole derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same |
| IE903911A1 (en) * | 1989-11-20 | 1991-05-22 | Ici Plc | Diazine derivatives |
| ATE169915T1 (de) * | 1990-02-15 | 1998-09-15 | Takeda Chemical Industries Ltd | Pyrimidindionderivate, deren herstellung und verwendung |
| ATE134624T1 (de) * | 1990-02-19 | 1996-03-15 | Ciba Geigy Ag | Acylverbindungen |
| US5284661A (en) * | 1990-02-22 | 1994-02-08 | Takeda Chemical Industries, Ltd. | Fused thiophene derivatives, their production and use |
| CA2037630C (en) * | 1990-03-07 | 2001-07-03 | Akira Morimoto | Nitrogen-containing heterocylic compounds, their production and use |
| FR2665702B1 (fr) * | 1990-08-08 | 1994-02-25 | Sanofi | Derives heterocycliques n-substitues, leur preparation, les compositions pharmaceutiques en contenant. |
| TW201738B (no) * | 1990-03-20 | 1993-03-11 | Sanofi Co | |
| FR2659967B1 (fr) * | 1990-03-20 | 1992-07-24 | Sanofi Sa | Derives d'imidazolinone n-substitues, leur preparation, les compositions pharmaceutiques en contenant. |
| US5270317A (en) * | 1990-03-20 | 1993-12-14 | Elf Sanofi | N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present |
| EP0453210A3 (en) * | 1990-04-19 | 1993-01-13 | Imperial Chemical Industries Plc | Pyridine derivatives |
| US5196444A (en) * | 1990-04-27 | 1993-03-23 | Takeda Chemical Industries, Ltd. | 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof |
| US5198439A (en) * | 1990-04-19 | 1993-03-30 | Imperial Chemical Industries Plc | Angiotension II antagonizing pyridine derivatives |
| ZA912983B (en) | 1990-04-27 | 1992-01-29 | Takeda Chemical Industries Ltd | Benzimidazole derivatives,their production and use |
| US6004989A (en) * | 1990-04-27 | 1999-12-21 | Takeda Chemical Industries, Ltd. | Benzimidazole derivatives, their production and use |
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| FR2673943B1 (fr) * | 1991-03-13 | 1994-02-18 | Roussel Uclaf | Nouveaux derives de l'imidazole, leur procede de preparation, les nouveaux intermediaires obtenus, leur application a titre de medicaments et les compositions pharmaceutiques les renfermant. |
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| JPS5671074A (en) * | 1979-11-12 | 1981-06-13 | Takeda Chem Ind Ltd | 1,2-disubstituted-4-halogenoimidazole-5-acetic acid derivative |
| JPS5967246A (ja) * | 1982-09-10 | 1984-04-16 | ザ・ウエルカム・フアウンデ−シヨン・リミテツド | 置換ビフエニル化合物 |
| JPS6323868A (ja) * | 1986-07-11 | 1988-02-01 | イー・アイ・デュポン・ドゥ・ヌムール・アンド・カンパニー | アンギオテンシン２受容体遮断性イミダゾ−ル |
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| CA1338238C (en) * | 1988-01-07 | 1996-04-09 | David John Carini | Angiotensin ii receptor blocking imidazoles and combinations thereof with diuretics and nsaids |
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1987
- 1987-05-22 US US07/053,198 patent/US4820843A/en not_active Expired - Lifetime
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1988
- 1988-04-19 CA CA000564538A patent/CA1340325C/en not_active Expired - Lifetime
- 1988-05-18 ZA ZA883528A patent/ZA883528B/xx unknown
- 1988-05-19 EP EP88108005A patent/EP0291969B1/en not_active Expired - Lifetime
- 1988-05-19 DE DE3887772T patent/DE3887772T2/de not_active Expired - Lifetime
- 1988-05-19 DK DK274788A patent/DK274788A/da not_active Application Discontinuation
- 1988-05-19 AT AT88108005T patent/ATE101603T1/de not_active IP Right Cessation
- 1988-05-19 ES ES88108005T patent/ES2061552T3/es not_active Expired - Lifetime
- 1988-05-20 JP JP63122216A patent/JPH0774207B2/ja not_active Expired - Lifetime
- 1988-05-20 NZ NZ224741A patent/NZ224741A/en unknown
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- 1988-05-20 NO NO882241A patent/NO178189C/no not_active IP Right Cessation
- 1988-05-20 PT PT87552A patent/PT87552B/pt not_active IP Right Cessation
- 1988-05-20 HU HU882601A patent/HU198698B/hu unknown
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- 1988-05-20 IE IE151588A patent/IE63204B1/en not_active IP Right Cessation
- 1988-05-20 IL IL86456A patent/IL86456A/xx not_active IP Right Cessation
- 1988-05-21 KR KR1019880006012A patent/KR960009571B1/ko not_active Expired - Lifetime
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1992
- 1992-05-18 RU SU925011512A patent/RU2091376C1/ru active
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