NO963411L - Endothelinreseptorantagonister - Google Patents
EndothelinreseptorantagonisterInfo
- Publication number
- NO963411L NO963411L NO963411A NO963411A NO963411L NO 963411 L NO963411 L NO 963411L NO 963411 A NO963411 A NO 963411A NO 963411 A NO963411 A NO 963411A NO 963411 L NO963411 L NO 963411L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- dihydro
- methyl
- group
- benzodioxol
- Prior art date
Links
- -1 1H-tetrazolyl-5-yl Chemical group 0.000 claims description 184
- 150000001875 compounds Chemical class 0.000 claims description 59
- 150000003839 salts Chemical class 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- JCOCJLFUXDDTAT-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)-2-(1,3-dioxoisoindol-5-yl)oxyacetic acid Chemical compound C1=C2OCOC2=CC(C(OC=2C=C3C(=O)NC(=O)C3=CC=2)C(=O)O)=C1 JCOCJLFUXDDTAT-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 238000006268 reductive amination reaction Methods 0.000 claims description 3
- XOMOCLJYOAAIRD-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)-n-(4-tert-butylphenyl)sulfonyl-2-(1,3-dioxoisoindol-5-yl)oxyacetamide Chemical compound C1=CC(C(C)(C)C)=CC=C1S(=O)(=O)NC(=O)C(C=1C=C2OCOC2=CC=1)OC1=CC=C(C(=O)NC2=O)C2=C1 XOMOCLJYOAAIRD-UHFFFAOYSA-N 0.000 claims description 2
- 229940118365 Endothelin receptor antagonist Drugs 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000002308 endothelin receptor antagonist Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 238000006467 substitution reaction Methods 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
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- IRKVJDZDWQTQCI-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)-2-(1,3-dioxoisoindol-5-yl)oxy-n-(4-propan-2-ylphenyl)sulfonylacetamide Chemical compound C1=CC(C(C)C)=CC=C1S(=O)(=O)NC(=O)C(C=1C=C2OCOC2=CC=1)OC1=CC=C(C(=O)NC2=O)C2=C1 IRKVJDZDWQTQCI-UHFFFAOYSA-N 0.000 claims 1
- JXAIAVVSWQCFFX-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)-2-(1-methyl-2-propylbenzimidazol-4-yl)oxyacetic acid Chemical compound C1=C2OCOC2=CC(C(C(O)=O)OC2=C3N=C(N(C3=CC=C2)C)CCC)=C1 JXAIAVVSWQCFFX-UHFFFAOYSA-N 0.000 claims 1
- PHESBRDFBLEIRT-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)-2-(7-propylquinolin-8-yl)oxyacetic acid Chemical compound C1=C2OCOC2=CC(C(C(O)=O)OC2=C3N=CC=CC3=CC=C2CCC)=C1 PHESBRDFBLEIRT-UHFFFAOYSA-N 0.000 claims 1
- CGMZJSADDCSVFZ-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)-2-[(6-propyl-1h-indol-7-yl)oxy]acetic acid Chemical compound C1=C2OCOC2=CC(C(C(O)=O)OC2=C3NC=CC3=CC=C2CCC)=C1 CGMZJSADDCSVFZ-UHFFFAOYSA-N 0.000 claims 1
- UQAAOKQYRQKASX-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)-n-(4-tert-butylphenyl)sulfonyl-2-(7-propylquinolin-8-yl)oxyacetamide Chemical compound CCCC1=CC=C2C=CC=NC2=C1OC(C=1C=C2OCOC2=CC=1)C(=O)NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 UQAAOKQYRQKASX-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 229940126601 medicinal product Drugs 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 235000011054 acetic acid Nutrition 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000012442 inert solvent Substances 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 150000001243 acetic acids Chemical class 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 4
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 4
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 150000001408 amides Chemical class 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
- 239000012154 double-distilled water Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection 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
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- IZFOPMSVNDORMZ-UHFFFAOYSA-N 1-benzofuran-5-ol Chemical compound OC1=CC=C2OC=CC2=C1 IZFOPMSVNDORMZ-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 2
- 125000004362 3,4,5-trichlorophenyl group Chemical group [H]C1=C(Cl)C(Cl)=C(Cl)C([H])=C1* 0.000 description 2
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 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
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- NHXFINXXELODNV-UHFFFAOYSA-N 5-hydroxyisoindole-1,3-dione Chemical compound OC1=CC=C2C(=O)NC(=O)C2=C1 NHXFINXXELODNV-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 102000002045 Endothelin Human genes 0.000 description 2
- 108050009340 Endothelin Proteins 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
- 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 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-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
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 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
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 150000003869 acetamides Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- UVSNFZAOYHOOJO-UHFFFAOYSA-N chembl1343456 Chemical compound OC1=CC=C2N=NNC2=C1 UVSNFZAOYHOOJO-UHFFFAOYSA-N 0.000 description 2
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- NPKATACLAVJRPB-UHFFFAOYSA-N methyl 2-(1,3-benzodioxol-5-yl)-2-bromoacetate Chemical compound COC(=O)C(Br)C1=CC=C2OCOC2=C1 NPKATACLAVJRPB-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- WZXIELYYIKKPGQ-UHFFFAOYSA-N methyl 2-(1,3-benzodioxol-5-yl)-2-(1,3-dioxoisoindol-5-yl)oxyacetate Chemical compound C1=C2OCOC2=CC(C(OC=2C=C3C(=O)NC(=O)C3=CC=2)C(=O)OC)=C1 WZXIELYYIKKPGQ-UHFFFAOYSA-N 0.000 description 1
- ZJXPBEXOGWFULD-UHFFFAOYSA-N methyl 2-(1,3-benzodioxol-5-yl)-2-hydroxyacetate Chemical compound COC(=O)C(O)C1=CC=C2OCOC2=C1 ZJXPBEXOGWFULD-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- CPRRHERYRRXBRZ-SRVKXCTJSA-N methyl n-[(2s)-1-[[(2s)-1-hydroxy-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CO)C[C@@H]1CCNC1=O CPRRHERYRRXBRZ-SRVKXCTJSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 208000031225 myocardial ischemia 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
- JRWDINYPHDTRJJ-UHFFFAOYSA-N n-(4-tert-butylphenyl)sulfonyl-2-(1,3-dioxoisoindol-5-yl)oxy-2-(4-nitrophenyl)acetamide Chemical compound C1=CC(C(C)(C)C)=CC=C1S(=O)(=O)NC(=O)C(C=1C=CC(=CC=1)[N+]([O-])=O)OC1=CC=C(C(=O)NC2=O)C2=C1 JRWDINYPHDTRJJ-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
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 229960003540 oxyquinoline Drugs 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 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
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-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
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 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
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 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
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time 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
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003797 solvolysis reaction Methods 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
- 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
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 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
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
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- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Oppfinnelsen vedrører forbindelser med formel I
hvor
X betyr en mettet, helt eller delvis umettet alkylen-kjede med 3-4 ledd, hvor 1-3 C-atomer kan være erstattet med N, og/eller 1-2 C-atomer kan være erstattet med 1-2 0- og/eller 1-2 S-atomer, idet imidlertid høyst inntil 3 C-atomer er erstattet, og idet det i tillegg kan opptre en en-, to- eller tre-gangers substitusjon av alkylenkjeden og/eller av et nitrogenatom som befinner seg i den, med A, R<8>
og/eller NR4R4' , og idet videre også en CH2-gruppe i
alkylenkjeden kan være erstattet med en C=0-gruppe,
A betyr alkyl med 1-6 C-atomer, hvor én eller to CH2~
grupper kan være erstattet med 0- eller S-atomer eller med -CR4=CR4' -grupper, og også 1-7 H-atomer kan
være erstattet med F,
R<1>betyr H eller A,
R<2>betyrC00R<4>, CN, lH-tetrazolyl-5-yl eller C0NHS02R<8>,
R3betyr Ar,
R<4>og R4 betyr uavhengig av hverandre H, alkyl med 1-6 C-
atomer eller benzyl,
Ar betyr usubstituert eller én, to eller tre ganger med
R<5>,R<6>ellerR<7>substituert fenyl eller naftyl, eller
en usubstituert eller i fenyldelen én eller to ganger medR<5>eller R<6>substituert
R<5>,R<6>ogR<7>betyr uavhengig av hverandre R<4>, OR<4>, Hal, CF3,
OCF3, OCHF2, OCH2F, N02, NR4R4' , NHCOR4, CN, NHS02R<4>, COOR<4>, COR<4>, CONHS02R<8>, 0(CH2)nR<2>, OPh, 0(CH2)n<O>R<4>eller
S(0)nR<4>,
R<8>betyr usubstituert eller én, to eller tre ganger med A,OR<1>, NR4R4 eller Hal substituert fenyl eller
naftyl,
E betyr CH2eller 0,
D betyr karbonyl eller [C(R<4>R<4>')]n,
Hal betyr F, Cl, Br eller I,
m betyr 0, 1 eller 2, og
n betyr 1 eller 2,
samt deres salter.
Lignende forbindelser med indan- og indengrunn-skjelett er kjent fra W0 93/08799, slike med indolsystemer er kjent fra W0 94/14434, pyrimidinderivater er kjent fra EP
0 526 708 Al, og fenyl- og naftylforbindelser er kjent fra EP 0 617 001 Al.
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 ved god forenlighet. Særlig utviser de endotelinreseptorantagonistiske egenskaper og kan således anvendes til behandling av sykdommer som hypertoni, hjerteinsuffislens, koronar hjertesykdom, renal, cerebral og myokardial iskemi, nyreinsuffislens, hjerneinfarkt, subaraknoidal blødning, arteriosklerose, høyt pulmonalt trykk, betennelser, astma, prostatahyperplasi, endo-toksisk sjokk og ved komplikasjoner etter administreringen av stoffer som f.eks. syklosporin, samt andre sykdommer som er forbundet med endotelinaktiviteter.
Forbindelsene utviser blant annet en høy affinitet til endotelinsubreseptorene ETRog ETB. Disse virkningene kan undersøkes etter vanlige in vltro- eller in vivo-metoder, som f.eks. beskrevet av P.D. Stein et al., J. Med. Chem., 37, 1994, 329-331, og E. Ohlstein et al., Proe. Nati. Acad. Sei. USA, 91, 1994, 8052-8056.
En egnet fremgangsmåte for bestemmelse av den blod- trykkssenkende virkning beskrives f.eks. av M.K. Bazil et al., J. Cardiovasc. Pharmacol., 22, 1993, 897-905, og J. Lange et al., Lab Animal, 20, 1991, Appl. Note 1016.
Forbindelsene med formel I kan anvendes som aktive legemiddelforbindelser innen human- og veterinærmedisinen, særlig til profylakse og/eller behandling av hjerte-, krets-løps- og karsykdommer, fremfor alt av hypertoni og hjerteinsuffisiens.
Oppfinnelsens gjenstand er forbindelsene med formel I og deres salter, samt en fremgangsmåte for fremstilling av disse forbindelsene samt deres salter, kjennetegnet ved at
en forbindelse med formel II
hvor
R<1>og X har den i krav 1 angitte betydning,
omsettes direkte eller etter forutgående anionisering av hydroksygruppen med en forbindelse med formel III
hvor
Q betyr Cl, Br, I eller en fri eller reaksjonsdyktig,
funksjonelt omdannet OH-gruppe, og
R<2>ogR<3>har den i krav 1 angitte betydning,
og/eller
én eller flere resterR<1>,R<2>og/ellerR<3>i en forbindelse med formel I omdannes til én eller flere resterR<1>, R<2>og/ellerR<3>, idet man
i) reduserer en nitrogruppe til en aminogruppe, ii) hydrolyserer en estergruppe til en karboksygruppe,
iii) omdanner en aminogruppe ved reduktiv aminering
til et alkyiert amin,
iv) omdanner en karboksygruppe til en sulfonamidokarbonylgruppe,
og/eller
omdanner en base eller syre med formel I til et av dens salter.
For alle restene som opptrer flere ganger, som f.eks. R<4>og R<8>, gjelder det at deres betydninger er uavhengige av hverandre.
I formlene ovenfor har A 1-6, fortrinnsvis 1, 2, 3 eller 4, C-atomer. A betyr fortrinnsvis metyl, dessuten etyl, propyl, isopropyl, butyl, isobutyl, sek.-butyl eller tert.-butyl, videre også pentyl, 1-, 2- eller 3-metylbutyl, 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, 1-etyl-2-metylpropyl, 1,1,2- eller 1,2,2-trimetylpropyl.
E betyr fortrinnsvis 0, videre er også CH2foretrukket .
D betyr fortrinnsvis CH2, likeens er også karbonyl foretrukket.
X betyr fortrinnsvis -CO-NH-CO, -C0-NH-CH2-, -NH-CH=CH-, -0-CH=CH-, -N=CH-0-, -N=CH-NH-, -NH-NH-CO-, -NH-N=N-,
-NH-C0-CH2-, -NH-CO-0-, -N=CH-S-, -NH-CO-S-, -NH-CO-NH-, -0-NH-CO-, -NH-O-CO-, -N=CH-CH=CH-, -CH=N-CH=CH-, -N=N-CH=CH-, -N=CH-N=CH-, -N=CH-CH=N-, -N=N-N=CH-, -NH-C0-CH=CH-, -NH-CH=CH-CO-,-NH-CO-CH2-CH2-, -NH-CH2-CH2-CO-, -NH-C0-N=CH-, -N=CH-NH-C0-, -NH-CO-NH-CO-, -NH-C0-NH-CH2-, -CH=N-N=CH-,
videre -CH=N-NH-C0-, -CO-NH-NH-CO-, -N=N-NH-C0-, -0-C0-NH-CH2~eller -0-C0-NH-C0-.
m betyr særlig 0, videre foretrukket også 1 og 2.
n er fortrinnsvis 1, videre foretrukket 2.
Hal betyr fortrinnsvis F, Cl eller Br, men også I.
Ar er usubstituert, fortrinnsvis - som angitt - monosubstituert fenyl, særlig foretrukket fenyl, o-, m- eller p-tolyl, o-, m- eller p-etylfenyl, o-, m- eller p-propylfenyl, o-, m- eller p-isopropylfenyl, o-, m- eller p-tert.-butyl-fenyl, o-, m- eller p-trifluormetylfenyl, o-, m- eller p- hydroksyfenyl, o-, m- eller p-nitrofenyl, o-, m- eller p-aminofenyl, o-, m- eller p-(N-metylaminometyl)-fenyl, o-, m-eller p-acetamidofenyl, o-, m- eller p-(trifluormetoksy)-fenyl, o-, m- eller p-cyanfenyl, o-, m- eller p-metoksyfenyl, o-, m- eller p-etoksyfenyl, o-, m- eller p-karboksyfenyl, o-, m- eller p-metoksykarbonylfenyl, o-, m- eller p-etoksykarbo-nylfenyl, o-, m- eller p-benzyloksykarbonylfenyl, o-, m- eller p-(karboksymetyloksy)-fenyl, o-, m- eller p-(metoksykarbonyl-metyloksy)-fenyl, o-, m- eller p-(metoksykarbonyletyloksy)-fenyl, o-, m- eller p-(N,N-dimetylamino)-fenyl, o-, m- eller p-(N-etylamino)-fenyl, o-, m- eller p-(N,N-dietylamino)-fenyl, o-, m- eller p-fluorfenyl, o-, m- eller p-bromfenyl, o-, m-eller p-klorfenyl, o-, m- eller p-(difluormetoksy)-fenyl, o-, m- eller p-(fluormetoksy)-fenyl, o-, m- eller p-formylfenyl, o-, m- eller p-acetylfenyl, o-, m- eller p-propionylfenyl, o-, m- eller p-butyrylfenyl, o-, m- eller p-pentanoylfenyl, o-, m-eller p-(fenylsulfonamidokarbonyl)-fenyl, o-, m- eller p-fenoksyfenyl, o-, m- eller p-metyltiofenyl, o-, m- eller p-metylsulfinylfenyl, o-, m- eller p-metylsulfonylfenyl, o-, m-eller p-benzyloksyfenyl, o-, m- eller p-cyanmetyloksyfenyl, videre foretrukket 2,3-metylendioksyfenyl, 3,4-metylendioksyfenyl, 2,3-etylendioksyfenyl, 3,4-etylendioksyfenyl, 2,3-(2-oksometylendioksy)-fenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- eller 3,5-(difluormetoksy)-(karboksymetyloksy)-fenyl, 2,3-, 2,4-, 2.5- , 2,6-, 3,4- eller 3,5-metoksy-(karboksymetyloksy)-fenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- eller 3,5-hydroksy-(karboksy-metyloksy ) -f enyl .
Ar betyr videre foretrukket 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oksofuranyl, videre foretrukket 2,3-, 2,4-, 2,5-,
2.6- , 3,4- eller 3,5-difluorfenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-eller 3,5-diklorfenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- eller 3,5-dibromfenyl, 2-klor-3-metyl-, 2-klor-4-metyl-, 2-klor-5-metyl-, 2-klor-6-metyl-, 2-metyl-3-klor-, 2-metyl-4-klor-, 2-metyl-5-klor-, 2-metyl-6-klor-, 3-klor-4-metyl-, 3-klor-5-metyl- eller 3-metyl-4-klorfenyl, 2-brom-3-metyl-, 2-brom-4-metyl-, 2-brom-5-metyl-, 2-brom-6-metyl-, 2-metyl-3-brom-, 2-metyl-4-brom-, 2-metyl-5-brom-, 2-metyl-6-brom-, 3-brom-4-metyl-, 3-brom-5-metyl- eller 3-metyl-4-bromfenyl, 2,4- eller 2,5-dinitrofenyl, 2,5- eller 3,4-dimetoksyfenyl, 3-nitro-4-
klorfenyl, 2-amino-3-klor-, 2-amino-4-klor-, 2-amino-5-klor-eller 2-amino-6-klorfenyl, 2-nitro-4-N,N-dimetylamino- eller 3-nitro-4-N,N-dimetylaminofenyl, 3-karboksy-2-metoksy-, 3-karboksy-4-metoksy- eller 3-karboksy-5-metoksyfenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- eller 3,4,5-triklorfenyl, 2,4,6-tri-tert.-butylfenyl, videre foretrukket 2-nitro-4-(trifluor-metyl)-fenyl, 3,5-di-(trifluormetyl)-fenyl, 2,5-dimetylfenyl, 2-hydroksy-3,5-diklorfenyl, 2-fluor-5- eller 4-fluor-3-(tri-fluormetyl)-fenyl, 4-klor-2- eller 4-klor-3-(trifluormetyl)-, 2-klor-4- eller 2-klor-5-(trifluormetyl)-fenyl, 4-brom-2-eller 4-brom-3-(trifluormetyl)-fenyl, p-jodfenyl, 2-nitro-4-metoksyfenyl, 2,5-dimetoksy-4-nitrofenyl, 3,5-dikarboksyfenyl, 2-klor-3-nitro-5-karboksyfenyl, 4-klor-3-karboksyfenyl, 2-metyl-5-nitrofenyl, 2,4-dimetyl-3-nitrofenyl, 3,6-diklor-4-aminofenyl, 4-fluor-3-klorfenyl, 4-fluor-3,5-dimetylfenyl, 2-fluor-4-bromfenyl, 2,5-difluor-4-bromfenyl, 2,4-diklor-5-metylfenyl, 3-brom-6-metoksyfenyl, 3-klor-6-metoksyfenyl, 3-klor-4-acetamidofenyl, 4-hydroksy-3-karboksyfenyl, 2-metoksy-5-metylfenyl eller 2,4,6-triisopropylfenyl eller naftyl.
Resten R<2>betyr fortrinnsvis karbometoksy, karbo-etoksy, karbopropoksy, karbobutoksy, karbobenzyloksy, videre cyan, lH-tetrazol-5-yl eller karboksy, særlig foretrukket er imidlertid fenylsulfonylamidokarbonyl eller 4-alkylfenyl-sulfonamidokarbonyl.
Resten R<8>betyr usubstituert, fortrinnsvis - som angitt - monosubstituert fenyl, særlig foretrukket fenyl, o-, m- eller p-tolyl, o-, m- eller p-etylfenyl, o-, m- eller p-propylfenyl, o-, m- eller p-isopropylfenyl, o-, m- eller p-tert.-butylfenyl, o-, m- eller p-hydroksyfenyl, o-, m- eller p-aminofenyl, o-, m- eller p-(N-metylamino)-fenyl, o-, m-eller p-metoksyfenyl, o-, m- eller p-etoksyfenyl, o-, m- eller p-(N,N-dimetylamino)-fenyl, o-, m- eller p-(N-et.ylamino)-fenyl, o-, m- eller p-(N,N-dietylamino)-fenyl, o-, m- eller p-fluorfenyl, o-, m- eller p-bromfenyl, o-, m- eller p-klorfenyl, videre foretrukket 2,3-, 2,4-, 2,5-, 2,6-, 3,4- eller 3,5-difluorfenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- eller 3,5-diklorfenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- eller 3,5-dibromfenyl, 2-klor-3-metyl-, 2-klor-4-metyl-, 2-klor-5-metyl-, 2-klor-6-metyl-, 2-metyl-3-klor-, 2-metyl-4-klor-, 2-metyl-5-klor-, 2- metyl-6-klor-, 3-klor-4-metyl-, 3-klor-5-metyl- eller 3-metyl-4-klorfenyl, 2-brom-3-metyl-, 2-brom-4-metyl-, 2-brom-5-metyl-, 2-brom-6-metyl-, 2-metyl-3-brom-, 2-metyl-4-brom-, 2-metyl-5-brom-, 2-metyl-6-brom-, 3-brom-4-metyl-, 3-brom-5-metyl- eller 3-metyl-4-bromfenyl, 2-amino-3-klor-, 2-amino-4-klor-, 2-amino-5-klor- eller 2-amino-6-klorfenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- eller 3,4,5-triklorfenyl, 2,4,6-tri-tert.-butylfenyl, 2,5-dimetylfenyl, 2-hydroksy-3,5-diklorfenyl, 3,6-diklor-4-aminofenyl, 4-fluor-3-klorfenyl, 4-fluor-3,5-dimetylfenyl, 2-fluor-4-bromfenyl, 2,5-difluor-4-bromfenyl, 2,4-diklor-5-metylfenyl, 2,4,6-triisopropylfenyl, videre også naftyl eller 5-dimetylamino-l-naftyl (dansyl).
Forbindelsene med formel I kan ha ett eller flere kirale sentre og således forekomme i forskjellige stereoiso-mere former. Formel I omfatter alle disse formene.
Således er oppfinnelsens gjenstand særlig slike forbindelser med formel I hvor minst én av de nevnte rester har en av de ovenfor angitte, foretrukne betydninger. Noen foretrukne grupper av forbindelser kan uttrykkes gjennom de følgende delformlene Ia-Ig, som tilsvarer formel I, og hvor de ikke nærmere angitte rester har den for formel I angitte betydning, hvor imidlertid
i Ia X betyr -CO-NH-CO-;
i Ib X betyr -0-CH=N-;
i Ic X betyr -N=CH-CH=CH-;
i Id X betyr -NH-CO-S-, og
i le X betyr -N=C(A)-N(R<4>)-; i If X betyr -N=C(A)-N(R<4>)-, og i lg X betyr -CO-NH-CO-, og
Forbindelsene med formel I og også utgangsforbindelsene for deres fremstilling fremstilles for øvrig etter i og for seg kjente fremgangsmåter, slik som de er beskrevet i litteraturen (f.eks. i standardverkene som Houben-Weyl,
Methoden der organischenChemie, Georg-Thieme-Verlag, Stutt-gart; imidlertid særlig i EP-0 617 001 Al), og da under reaksjonsbetingelser som er kjent og egnet for de nevnte om-setninger. Derved kan man gjøre bruk av i og for seg kjente,
her ikke nærmere belyste varianter.
Utgangsforbindelsene kan om ønsket også dannes in
situ, slik at man ikke isolerer dem fra reaksjonsblandingen,
men straks omsetter videre til forbindelsene med formel I.
Forbindelser med formel I kan fortrinnsvis fås ved at man omsetter forbindelser med formel II med forbindelser med formel III.
I forbindelsene med formel III betyr Q fortrinnsvis
Cl, Br, I eller en reaksjonsdyktig, omdannet OH-gruppe som alkylsulfonyloksy med 1-6 C-atomer (foretrukket metylsulfonyl-oksy) eller arylsulfonyloksy med 6-10 C-atomer (foretrukket fenyl- eller p-tolylsulfonyloksy).
Omsetningen skjer som regel i et inert oppløsnings-middel i nærvær av et syrebindende middel, fortrinnsvis et alkal:
eller jordalkalimetallhydroksid, -karbonat eller
-bikarbonat, eller et annet salt av en svak syre med alkali-eller jordalkalimetall, fortrinnsvis kalium, natrium, kalsium eller cesium. Også tilsetningen av en organisk base som trietylamin, dimetylanilin, pyridin eller kinolin, eller et over-skudd av fenolkomponenten med formel II henholdsvis alkyler-ingsderivatet med formel III, kan være gunstig. Reaksjonstiden ligger alt etter de anvendte betingelser mellom noen minutter og 14 dager, reaksjonstemperaturen mellom ca. 0 og 150 °C, normalt mellom 20 og 130 °C.
Som inert oppløsningsmiddel egner seg f.eks. hydrokarboner som heksan, petroleter, benzen, toluen eller xylen; klorerte hydrokarboner som trikloretylen, 1,2-dikloretan, karbontetraklorid, kloroform eller diklormetan; alkoholer som metanol, etanol, isopropanol, n-propanol, n-butanol eller tert.-butanol; etere som dietyleter, diisopropyleter, tetra-hydrofuran (THF) eller dioksan; glykoletere som etylenglykol-monometyl- eller -monoetyleter (metylglykol eller etylglykol), etylenglykoldimetyleter (diglym); ketoner som aceton eller butanon; amider som acetamid, dimetylacetamid eller dimetyl-formamid (DMF); nitriler som acetonitril; sulfoksider som dimetylsulfoksid (DMSO); karbondisulfid; karboksylsyrer som maursyre eller eddiksyre; nitroforbindelser som nitrometan eller nitrobenzen; estere som etylacetat; eller blandinger av de nevnte oppløsningsmidler.
Utgangsforbindelsene med formel II er som regel kjente, mens de med formel III som regel er nye. Disse kan imidlertid fremstilles etter i og for seg kjente fremgangsmåter. Således kan f.eks. benzo[1,3]dioksol-5-ylbromeddiksyre-metylester fås ved omsetning av benzo[1,3]dioksol-5-ylhydrok-syeddiksyremetylester med fosfortribromid. Dette skjer hensiktsmessig ved temperaturer mellom 0 og ca. 200 °C; fortrinnsvis arbeider man mellom 30 og 80 °C. Som inert oppløs-ningsmiddel egner seg de allerede nevnte.
Det er videre mulig å omdanne en forbindelse med formel I til en annen forbindelse med formel I, idet man omdanner én eller flere rester R<1>, R<2>og/eller R<3>til én eller flere andre resterR<1>,R<2>og/ellerR<3>, f.eks. idet man reduserer nitrogrupper (f.eks. ved hydrogenering på Raney-nikkel eller Pd-karbon i et inert oppløsningsmiddel som metanol eller etanol) til aminogrupper, og/eller hydrolyserer en estergruppe til en karboksygruppe, og/eller omdanner en aminogruppe ved reduktiv aminering til et alkylert amin, og/eller omdanner en karboksygruppe til en sulfonamidokarbonylgruppe.
Videre kan man acylere frie aminogrupper på vanlig måte med et syreklorid eller -anhydrid, eller alkylere med et usubstituert eller substituert alkylhalogenid, 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.
Om ønsket kan en funksjonelt omdannet amino- og/eller hydroksygruppe i en forbindelse med formel I frisettes ved solvolyse eller hydrogenolyse etter vanlige fremgangsmåter. Således kan f.eks. en forbindelse med formel I som inneholder enNHCOR<4->eller en COOR<4->gruppe, omdannes til den tilsvarende forbindelse med formel I som i stedet inneholder en NH2- eller en HOOC-gruppe. COOR<4->grupper kan f.eks. forsåpes med NaOH eller KOH i vann, vann-THF eller vann-dioksan ved temperaturer mellom 0 og 100 °C.
En base med formel I kan overføres med en syre til det tilhørende syreaddisjonssalt, f.eks. ved omsetning av ekvivalente mengder av basen og syren i et inert oppløsnings-middel som etanol, og med påfølgende inndamping. For denne omsetningen kommer det særlig på tale med syrer som gir fysiologisk akseptable salter. Således kan det anvendes uorganiske syrer, f.eks. svovelsyre, salpetersyre, hydrogenhalogensyrer som saltsyre eller hydrogenbromsyre, fosforsyrer som orto-fosforsyre, sulfaminsyre, videre organiske syrer, særlig ali-fatiske, alisykliske, aralifatiske, aromatiske eller hetero-sykliske en- eller flerbasiske karboksyl-, sulfon- eller svovelsyrer, f.eks. maursyre, eddiksyre, propionsyre, pivalin-syre, dietyleddiksyre, malonsyre, ravsyre, pimelinsyre, fumar-syre, maleinsyre, melkesyre, vinsyre, eplesyre, sitronsyre, glukonsyre, askorbinsyre, nikotinsyre, isonikotinsyre, metan-eller etansulfonsyre, etandisulfonsyre, 2-hydroksyetansulfon-syre, benzensulfonsyre, p-toluensulfonsyre, naftalenmono- og
-disulfonsyrer, og laurylsvovelsyre. Salter med fysiologisk ikke akseptable syrer, f.eks. pikrater, kan anvendes til isolering og/eller rensing av forbindelsene med formel I. På den annen side kan forbindelser med formel I omdannes med baser (f.eks. natrium- eller kaliumhydroksid eller -karbonat) til de tilsvarende metall-, særlig alkalimetall-eller jordalkalimetallsalter, eller de tilsvarende ammonium-salter.
Gjenstand for oppfinnelsen er videre anvendelsen av forbindelsene med formel I og/eller deres fysiologisk akseptable salter til fremstilling av farmasøytiske preparater, særlig på ikke-kjemisk måte. Herved kan de bringes sammen med minst ett fast, flytende og/eller halvflytende bærer- eller hjelpestoff, og eventuelt i kombinasjon med én eller flere ytterligere aktive forbindelser i en egnet doseringsform.
Gjenstand for oppfinnelsen er videre farmasøytiske preparater som inneholder minst én forbindelse med formel I og/eller et av dens fysiologisk akseptable salter.
Disse preparatene kan anvendes som legemidler innen human- eller veterinærmedisinen. Som bærerstoffer kommer det på tale med organiske eller uorganiske stoffer som egner seg for enteral (f.eks. oral), parenteral eller topisk applika-sjon, og som ikke reagerer med de nye forbindelsene, f.eks. vann, planteoljer, benzylalkoholer, alkylenglykoler, poly-etylenglykoler, glyseroltriacetat, gelatin, karbohydrater som laktose eller stivelse, magnesiumstearat, talkum og vaselin. For oral anvendelse tjener særlig tabletter, piller, drasjeer, kapsler, pulver, granulater, siruper, safter eller dråper, for rektal anvendelse suppositorier, for parenteral anvendelse oppløsninger, fortrinnsvis olje- eller vannoppløsninger, videre suspensjoner, emulsjoner eller implantater, for topisk anvendelse salver, kremer eller pudder. De nye forbindelsene kan også lyofiliseres og de erholdte lyofilisater anvendes f.eks. til fremstilling av injeksjonspreparater. De angitte preparater kan være sterilisert og/eller inneholde hjelpe-stoffer som glide-, konserverings-, stabiliserings- og/eller fuktemidler, emulgatorer, salter for påvirkning av det osmotiske trykk, bufferstoffer, farge-, smaks- og/eller flere ytterligere aktive forbindelser, f.eks. ett eller flere vita-miner .
Forbindelsene med formel I og deres fysiologisk akseptable salter kan anvendes ved bekjempelse av sykdommer, særlig av hypertoni og hjerteinsuffisiens.
Derved administreres forbindelsene ifølge oppfinnelsen som regel fortrinnsvis ved doseringer mellom ca. 1 og 500 mg, særlig mellom 5 og 100 mg pr. doseringsenhet. Den daglige dosering ligger fortrinnsvis mellom ca. 0,02 og 10 mg/kg kroppsvekt. Den spesielle dose for hver pasient av-henger imidlertid av de forskjelligste faktorer, f.eks. av aktiviteten til den spesielle forbindelse som anvendes, av alderen, kroppsvekten, den generelle helsetilstand, arv, av kosten, av administreringstidspunkt og -vei, av utskillings-hastigheten, legemiddelkombinasjonen og alvorligheten av den enkelte sykdom som behandlingen gjelder for. Den orale appli-
kas jon er foretrukket.
Ovenfor og nedenunder er alle temperaturer angitt i °C. I de etterfølgende eksempler betyr "vanlig opparbeidelse": Om nødvendig tilsettes vann, om nødvendig innstilles, alt etter sluttproduktets konstitusjon, på pH-verdi mellom 2 og 10, det ekstraheres med etylacetat eller diklormetan, sepa-reres, den organiske fase tørkes over natriumsulfat, inndampes og renses ved kromatografi på silikagel og/eller ved krystal-lisasjon. Rf-verdi på silikagel; løpemiddel: etylacetat:metanol 9:1.
Massespektrometri (MS): EI (elektronstøtionisering) M<+>
FAB (hurtig atombombardement) (M+H)<+>.
Eksempel 1
Til en oppløsning av 1,7 g 5-hydroksy-l,3-dihydroiso-indol-1,3-dion og 4,52 g 2-(l,3-benzodioksol-5-yl)-2-brom-N-(4-tert.-butylfenylsulfonyl)acetamid i 100 ml DMF tilsettes 3,3 g cesiumkarbonat. Det omrøres i 2 timer ved romtemperatur, opparbeides på vanlig måte og fås 2-(1,3-benzodioksol-5-yl)-2-(1,3-dihydro-l,3-dioksoindol-5-yloksy)-N-(4-tert.-butylfenyl-sulfonyl )acetamid, smp. 215 °C; kaliumsalt av den nevnte forbindelse FAB 575, smp. 171 °C.
Analogt får man ved omsetning av benzo[1,3]dioksol-5-ylbromeddiksyremetylester med
5-hydroksy-l,3-dihydroisoindol-l,3-dion, 5-hydroksy-N-mety1-1,3-dihydroisoindol-l,3-dion, 5-hydroksy-N-amino-l,3-dihydroisoindol-l,3-dion, 5-hydroksy-6-propyl-l,3-dihydroisoindol-l,3-dion, 5-hydroksy-l,3-dihydro-l-isoindolon, 5- hydroksyindol,
6- hydroksy-2-mety1-benzoksazol,
6-hydroksybenzimidazol,
6-hydroksy-2,3-dihydro-lH-indazol-3-on, 6- hydroksy-lH-benzotriazol,
5-hydroksy-l-mety1-2-propylbenzimidazo1, 7- hydroksy-6-propylindol,
8- hydroksykinolin,
8-hydroksy-7-metylkinolin,
8-hydroksy-7-propylkinolin,
5-hydroksybenzofuran,
4- hydroksy-2-metylindol og
5- hydroksy-l,3-benzodioksol
de følgende 2-(1,3-benzodioksol-5-yl)-2-(T-yloksy)eddiksyre-metylestere, hvor T betyr
1,3-dihydro-l,3-dioksoisoindol-5, EI 355, N-metyl-1,3-dihydro-l,3-dioksoisoindol-5, N-amino-1,3-dihydro-l,3-dioksoisoindol-5, 6- propyl-l,3-dihydro-l,3-dioksoisoindol-5, 1,3-dihydro-l-isoindolon-5,
indol-5, EI 325,
2-metylbenzoksazol-6, EI 342,
benzimidazol-6,
2,3-dihydro-lH-indazol-3-on-6,
6-hydroksy-lH-benzotriazol,
lH-benzotriazol-6,
1- metyl-2-propylbenzimidazol-5,
6- propylindol-7,
kinolin-8, EI 337,
7- metylkinolin-8,
7-propylkinolin-8,
benzofuran-5,
2- metylindol-4 og
1,3-benzodioksol-5.
Eksempel 2
En oppløsning av 1 g 2-(4-nitrofenyl)-2-(1,3-dihydro-1,3-dioksoisoindol-5-yloksy)-N-(4-tert.-butylfenylsulfonyl)-acetamid i 25 ml metanol hydrogeneres ved normaltrykk og 20 °C inntil stillstand på 1 g Raney-nikkel. Det filtreres, oppløs-ningsmidlet fjernes, og det fås 2-(4-aminofenyl)-2-(1,3-dihydro-l ,3-dioksoisoindol-5-yloksy)-N-(4-tert.-butylfenylsulfo-nyl)acetamid.
Eksempel 3
En oppløsning av 10 g 2-(1,3-benzodioksol-5-yl)-2-(1,3-dihydro-l,3-dioksoisoindol-5-yloksy)eddiksyremetylester i 300 ml metanol tilsettes 30 ml 5 N natronlut, og det omrøres i 3 timer ved romtemperatur. Det opparbeides på vanlig måte og fås 2-(1,3-benzodioksol-5-yl)-2-(1,3-dihydro-l,3-dioksoiso-indol-5-yloksy)eddiksyre, amorft (mykningspunkt 87 °C), FAB 342.
Analogt får man ved hydrolyse av de følgende 2-(l,3-benzodioksol-5-yl)-2-(T-yloksy)eddiksyremetylestere, hvor T betyr
N-metyl-1,3-dihydro-l,3-dioksoisoindol-5, N-amino-1,3-dihydro-l,3-dioksoisoindol-5, 6-propyl-l,3-dihydro-l,3-dioksoisoindol-5, 1,3-dihydro-l-isoindolon-5,
indol-5,
2-metylbenzoksazol-6,
benzimidazol-6,
2,3-dihydro-lH-indazol-3-on-6, lH-benzotriazol-6,
1- metyl-2-propylbenzimidazol-5, 6- propylindol-7,
kinolin-8,
7- metylkinolin-8,
7-propylkinolin-8,
benzofuran-5,
2- metylindol-4 og
1,3-benzodioksol-5,
de følgende 2-(1,3-benzodioksol-5-yl)-2-(T-yloksy)eddiksyrer, hvor T betyr
N-metyl-1,3-dihydro-l,3-dioksoisoindol-5,
N-amino-1,3-dihydro-l,3-dioksoisoindol-5, FAB 357 °C, smp. 148 °C,
6-propyl-l,3-dihydro-l,3-dioksoisoindol-5, 1,3-dihydro-l-isoindolon-5, smp. 201 °C, indol-5, amorf, FAB 312, smp. 120 °C, 2-metylbenzoksazol-6, smp. 174 °C, benzimidazol-6,
2,3-dihydro-lH-indazol-3-on-6, lH-benzotriazol-6,
l-metyl-2-propylbenzimidazol-5, 6- propylindol-7,
kinolin-8, natriumsalt, smp. > 300 °C, FAB 346, 7- metylkinolin-8,
7-propylkinolin-8, natriumsalt, smp. > 300 °C, benzofuran-5,
2-metylindol-4, smp. 193 °C, og
1,3-benzodioksol-5, FAB 317, smp. 184 °C.
Eksempel 4
En oppløsning av 6 g 2-(4-aminofenyl)-2-(1,3-dihydro-1,3-dioksoisoindol-5-yloksy)-N-(4-tert.-butylfenylsulfonyl)-acetamid og 0,5 g titantetraklorid i 100 ml metanol tilsettes 1 ml nydestillert acetaldehyd. Deretter tilsetter man 4 g natriumcyanborhydrid og omrører i 30 timer. Det tilsettes halvkonsentrert saltsyre, opparbeides på vanlig måte og fås 2-(4-etylaminofenyl)-2-(1,3-dihydro-l,3-dioksoisoindol-5-yl-oksy)-N-(4-tert.-butylfenylsulfonyl)acetamid.
Eksempel 5
En oppløsning av 1 g 2-(1,3-benzodioksol-5-yl)-2-(1,3-dihydro-l,3-dioksoisoindol-5-yloksy)eddiksyre og 0,71 g karbonyldiimidazol i 100 ml THF varmes opp ved 60 °C i 2 timer. Deretter tilsettes 0,93 g 4-tert.-butylbenzensulfon-syreamid og 0,67 g 1,8-diazabisyklo[5.4.0]undek-7-en, og det omrøres i ytterligere 1 time ved denne temperaturen. Etter vanlig opparbeidelse får man 2-(1,3-benzodioksol-5-yl)-2-(1,3-dihydro-1,3-dioksoisoindol-5-yloksy)-N-(4-tert.-butylfenyl-sulf onyl)acetamid, smp. 215 °C.
Analogt får man ved omsetning av 4-tert.-butylbenzen-sulf onsyreamid med de følgende 2-(1,3-benzodioksol-5-yl)-2-(T-yloksy)eddiksyrer, hvor T betyr N-metyl-1,3-dihydro-l,3-dioksoisoindol-5, N-amino-1,3-dihydro-l,3-dioksoisoindol-5, 6-propyl-l,3-dihydro-l,3-dioksoisoindol-5, 1,3-dihydro-l-isoindolon-5,
indol-5,
2-metylbenzoksazol-6,
benzimidazol-6,
2,3-dihydro-lH-indazol-3-on-6,
lH-benzotriazol-6,
l-metyl-2-propylbenzimidazol-5,
6-propylindol-7,
kinolin-8,
7-metylkinolin-8,
7-propylkinolin-8 og
benzofuran-5,
de følgende 2-(1,3-benzodioksol-5-yl)-2-(T-yloksy)-N-(4-tert.-butylfenylsulfonyl)acetamider, hvor T betyr N-metyl-1,3-dihydro-l,3-dioksoisoindol-5, N-amino-1,3-dihydro-l,3-dioksoisoindol-5, 6-propyl-l,3-dihydro-l,3-dioksoisoindol-5, 1,3-dihydro-l-isoindolon-5,
indol-5,
2-metylbenzoksazol-6,
benzimidazol-6,
2,3-dihydro-lH-indazol-3-on-6, lH-benzotriazol-6,
1- metyl-2-propylbenzimidazol-5, 6- propylindol-7,
kinolin-8,
7- metylkinolin-8,
7-propylkinolin-8 og
benzofuran-5.
Analogt får man ved omsetning av 4-isopropylbenzen-sulfonsyreamid med de følgende 2-(l,3-benzodioksol-5-yl)-2-(T-yloksy)eddiksyrer, hvor T betyr
1,3-dihydro-l,3-dioksoisoindol-5, N-metyl-1,3-dihydro-l,3-dioksoisoindol-5, N-amino-1,3-dihydro-l,3-dioksoisoindol-5, 6-propyl-l,3-dihydro-l,3-dioksoisoindol-5, 1,3-dihydro-l-isoindolon-5,
indol-5,
2- metylbenzoksazol-6,
benzimidazol-6,
2,3-dihydro-lH-indazol-3-on-6, lH-benzotriazol-6,
l-metyl-2-propylbenzimidazol-5, 6- propylindol-7,
kinolin-8,
7- metylkinolin-8,
7-propylkinolin-8,
benzofuran-5 og
1,3-benzodioksol-5,
de følgende 2-(1,3-benzodioksol-5-yl)-2-(T-yloksy)-N-(4-iso-propylfenylsulfonyl)acetamider, hvor T betyr 1,3-dihydro-l,3-dioksoisoindol-5, smp. 159 °C, N-metyl-1,3-dihydro-l,3-dioksoisoindol-5, N-amino-1,3-dihydro-l,3-dioksoisoindol-5, 6-propyl-l,3-dihydro-l,3-dioksoisoindol-5, 1,3-dihydro-l-isoindolon-5, FAB 509, smp. > 300 °C, indol-5,
2-metylbenzoksazol-6, FAB 509, benzimidazol-6,
2,3-dihydro-lH-indazol-3-on-6, lH-benzotriazol-6,
1- metyl-2-propylbenzimidazol-5, 6- propylindol-7,
kinolin-8,
7- metylkinolin-8,
7-propylkinolin-8,
benzofuran-5 og
1.3- benzodioksol-5, FAB 520.
Eksempel 6
Analogt med eksempel 1 får man ved omsetning av 5-hydroksy-1,3-dihydroisoindol-l,3-dion med de følgende M-brom-eddiksyremetylestere, hvor M betyr
fenyl,
1.4- benzodioksan-5-yl,
1,3-benzodioksol-4-yl,
2- metoksyfenyl,
3- metoksyfenyl,
4- metoksyfenyl,
2.3- dimetoksyfenyl,
2.4- dimetoksyfeny1,
2.5- dimetoksyfeny1,
3.4- dimetoksyfenyl,
3.5- dimetoksyfenyl,
2- karboksymetyloksyfenyl, 3- karboksymetyloksyfenyl,
4-karboksymetyloksyfenyl, 2- difluormetoksyfenyl, 3- difluormetoksyfenyl, 4- difluormetoksyfenyl, 2-metoksy-3-karboksymetyloksyfenyl, 2-metoksy-4-karboksymetyloksyfenyl, 2-karboksymetyloksy-3-metoksyfenyl, 2-karboksymetyloksy-4-metoksyfenyl, 2-difluormetoksy-3-karboksymetyloksyfenyl, 2-difluormetoksy-4-karboksymetyloksyfenyl, 2-karboksymetyloksy-3-difluormetoksyfenyl og
2-karboksymetyloksy-4-difluormetoksyfenyl, de følgende 2-(M)-2-(1,3-dihydro-l,3-dioksoisoindol-5-yloksy)-eddiksyremetylestere, hvor M betyr
fenyl,
1,4-benzodioksan-5-yl, 1,3-benzodioksol-4-yl, 2- metoksyfenyl,
3- metoksyfenyl,
4- metoksyfenyl, FAB 342, 2.3- dimetoksyfenyl, 2.4- dimetoksyfenyl, 2.5- dimetoksyfenyl, 3.4- dimetoksyfenyl, 3.5- dimetoksyfenyl, 2- karboksymetyloksyfenyl, 3- karboksymetyloksyfenyl, 4- karboksymetyloksyfenyl, 2- difluormetoksyfenyl, 3- difluormetoksyfenyl, 4- difluormetoksyfenyl, 2-metoksy-3-karboksymetyloksyfenyl, 2-metoksy-4-karboksymetyloksyfenyl, 2-karboksymetyloksy-3-metoksyfenyl, 2-karboksymetyloksy-4-metoksyfenyl, 2-difluormetoksy-3-karboksymetyloksyfenyl, 2-difluormetoksy-4-karboksymetyloksyfenyl, 2-karboksymetyloksy-3-difluormetoksyfenyl og 2-karboksymetyloksy-4-difluormetoksyfenyl.
Analogt med eksempel 3 fås ved hydrolyse av de sist nevnte forbindelser de følgende 2-(M)-2-(1,3-dihydro-l,3-di-oksoisoindol-5-yloksy)eddiksyrer, hvor M betyr
fenyl,
1,4-benzodioksan-5-yl,
1,3-benzodioksol-4-yl,
2- metoksyfenyl,
3- metoksyfenyl,
4- metoksyfenyl,
2.3- dimetoksyfenyl,
2.4- dimetoksyfenyl,
2.5- dimetoksyfenyl,
3.4- dimetoksyfeny1,
3.5- dimetoksyfenyl,
2- karboksymetyloksyfenyl,
3- karboksymetyloksyfenyl,
4- karboksymetyloksyfenyl,
2- difluormetoksyfenyl,
3- difluormetoksyfenyl,
4- difluormetoksyfenyl,
2-metoksy-3-karboksymetyloksyfenyl, 2-metoksy-4-karboksymetyloksyfenyl, 2-karboksymetyloksy-3-metoksyfenyl, 2-karboksymetyloksy-4-metoksyfenyl, 2-difluormetoksy-3-karboksymetyloksyfenyl, 2-difluormetoksy-4-karboksymetyloksyfenyl, 2-karboksymetyloksy-3-difluormetoksyfenyl og 2-karboksymetyloksy-4-difluormetoksyfenyl.
Ved omsetning av de sist nevnte eddiksyrer med 4-tert.-butylbenzensulfonsyreamid analogt med eksempel 5 får man de følgende 2-(M)-2-(1,3-dihydro-l,3-dioksoisoindol-5-yloksy)-N-(4-tert.-butylfenylsulfonyl)acetamider, hvor M T betyr fenyl,
1,4-benzodioksan-5-yl,
1,3-benzodioksol-4-yl,
2- metoksyfenyl,
3- metoksyfenyl,
4- metoksyfenyl, smp. 154 °C,
2,3-dimetoksyfenyl,
2.4- dimetoksyfeny1,
2.5- dimetoksyfenyl,
3.4- dimetoksyfenyl,
3.5- dimetoksyfeny1,
2- karboksymetyloksyfenyl,
3- karboksymetyloksyfenyl,
4- karboksymetyloksyfenyl,
2- difluormetoksyfenyl,
3- difluormetoksyfenyl,
4- difluormetoksyfenyl,
2-metoksy-3-karboksymetyloksyfenyl,
2-metoksy-4-karboksymetyloksyfenyl,
2-karboksymetyloksy-3-metoksyfenyl,
2-karboksymetyloksy-4-metoksyfenyl,
2-difluormetoksy-3-karboksymetyloksyfenyl, 2-difluormetoksy-4-karboksymetyloksyfenyl, 2-karboksymetyloksy-3-difluormetoksyfenyl og 2-karboksymetyloksy-4-difluormetoksyfenyl.
De følgende eksempler vedrører farmasøytiske preparater :
Eksempel A
Inieksjonsglass
En oppløsning av 100 g av en aktiv forbindelse med formel I og 5 g dinatriumhydrogenfosfat i 3 1 dobbeltdestillert vann med 2 N saltsyre på pH 6,5, det sterilfiltreres, fylles i injeksjonsglass, lyofiliseres under sterile betingelser og lukkes sterilt. Hvert injeksjonsglass inneholder 5 mg aktiv forbindelse.
Eksempel B
Suppositorier
Man smelter en blanding av 20 g aktiv forbindelse med formel I med 100 g soyalecitin og 1400 g kakaosmør, heller i former og lar det avkjøles. Hvert suppositorium inneholder 20 mg aktiv forbindelse.
Eksempel C
Oppløsning
Det lages en oppløsning av 1 g av en aktiv forbindelse med formel I, 9,38 g NaH2P04«2 H20, 28,48 g Na2HP04«12 H20 og 0,1 g benzalkoniumklorid i 940 ml dobbeltdestillert vann. Det innstilles på pH 6,8, fylles opp til 1 1 og steriliseres ved bestråling. Denne oppløsningen kan anvendes i form av øye-dråper .
Eksempel D
Salve
Man blander 500 mg av en aktiv forbindelse med formel I blandes med 99,5 g vaselin under aseptiske betingelser.
Eksempel E
Tabletter
En blanding av 1 kg aktiv forbindelse med formel I,
4 kg laktose, 1,2 kg potetstivelse, 0,2 kg talkum og 0,1 kg magnesiumstearat presses på vanlig måte til tabletter, slik at hver tablett inneholder 10 mg aktiv forbindelse.
Eksempel F
Drasjeer
Analogt med eksempel E presses tabletter som deretter belegges på vanlig måte med et belegg av sakkarose, potetstivelse, talkum, tragant og fargestoff.
Eksempel G
Kapsler
2 kg aktiv forbindelse med formel I fylles på vanlig måte i hardgelatinkapsler, slik at hver kapsel inneholder
20 mg av den aktive forbindelse.
Eksempel H
Ampuller
En oppløsning av 1 kg aktiv forbindelse med formel I i 60 1 dobbeltdestillert vann sterilfiltreres, fylles i ampuller, lyofiliseres under sterile betingelser og lukkes sterilt. Hver ampulle inneholder 10 mg aktiv forbindelse.
Claims (9)
1. Forbindelser,
karakterisert ved at de har formel I
hvor
X betyr en mettet, helt eller delvis umettet alkylen-
kjede med 3-4 ledd, hvor 1-3 C-atomer kan være erstattet med N, og/eller 1-2 C-atomer kan være erstattet med 1-2 0- og/eller 1-2 S-atomer, idet imidlertid høyst inntil 3 C-atomer er erstattet, og idet det i tillegg kan opptre en en-, to- eller tre-gangers substitusjon av alkylenkjeden og/eller av et nitrogenatom som befinner seg i den, med A, R <8> og/eller NR4R4' , og idet videre også en CH2 -gruppe i alkylenkjeden kan være erstattet med en C=0-gruppe, A betyr alkyl med 1-6 C-atomer, hvor én eller to CH2 -
grupper kan være erstattet med 0- eller S-atomer eller med -CR4=CR4' -grupper, og også 1-7 H-atomer kan
være erstattet med F,
R<1> betyr H eller A,
R<2> betyr COOR<4> , CN , lH-tetrazolyl-5-yl eller CONHS02 R <8> ,R 3 betyr Ar,
R<4> ogR<4> ' betyr uavhengig av hverandre H, alkyl med 1-6 C-
atomer eller benzyl,
Ar betyr usubstituert eller én, to eller tre ganger med
R <5> ,R<6> eller R <7> substituert fenyl eller naftyl, eller en usubstituert eller i fenyldelen én eller to ganger medR<5> eller R <6> substituert
R<5> ,R<6> og R <7> betyr uavhengig av hverandreR<4> ,OR<4> ,H al, CF3 ,
OCF3 , OCHF2 , OCH2 F, N02 , NR4R4' , NHCOR <4> , CN, NHS02 R <4> , COOR<4> , COR <4> , CONHS02 R <8> , 0(CH2 )n<R2,> OPh, 0(CH2 )n<O> R <4> eller S(0)oR4,
R <8> betyr usubstituert eller én, to eller tre ganger med
A, OR<1> , NR4R4 eller Hal substituert fenyl eller naftyl,
E betyr CH2 eller 0,
D betyr karbonyl eller [C(R<4> R <4> ')]n ,
Hal betyr F, Cl, Br eller I,
m betyr 0, 1 eller 2, og
n betyr 1 eller 2,
samt deres salter.
2. Forbindelser med formel I ifølge krav 1, karakterisert ved at de er
a) 2-(1,3-benzodioksol-5-yl)-2-(1,3-dihydro-l,3-di-oksoisoindol-5-yloksy)eddiksyre,
b) 2-(1,3-benzodioksol-5-yl)-2-(1,3-dihydro-l,3-di-oksoisoindol-5-yloksy)-N-(4-tert.-butylfenyl-sulf onyl)acetamid,
c) 2-(1,3-benzodioksol-5-yl)-2-(1,3-dihydro-l,3-di-oksoisoindol-5-yloksy)-N-(4-isopropylfenylsulfo-nyl)acetamid,
d) 2-(1,3-benzodioksol-5-yl)-2- (7-propylkinolin-8-yloksy)eddiksyre,
e) 2-(1,3-benzodioksol-5-yl)-2-(7-propylkinolin-8-yloksy)-N-(4-tert.-butylfenylsulfonyl)acetamid,
f) 2-(1,3-benzodioksol-5-yl)-2-(6-propylindol-7-yl-oksy)eddiksyre eller
g) 2-(l,3-benzodioksol-5-yl)-2-(l-metyl-2-propyl-benzimidazol-4-yloksy)eddiksyre.
3. Fremgangsmåte for fremstilling av forbindelser med formel I ifølge krav 1 samt deres salter,
karakterisert ved at
en forbindelse med formel II
hvor
R<1> og X har den i krav 1 angitte betydning,
omsettes direkte eller etter forutgående anionisering av hydroksygruppen med en forbindelse med formel III
hvor
Q betyr Cl, Br, I eller en fri eller reaksjonsdyktig,
funksjonelt omdannet OH-gruppe, ogR<2> ogR<3> har den i krav 1 angitte betydning,
og/eller
én eller flere rester R <1> ,R<2> og/ellerR<3> i en forbindelse med formel I omdannes til én eller flere resterR<1> ,R<2> og/eller R <3> , idet man f.eks.
i) reduserer en nitrogruppe til en aminogruppe,
ii) hydrolyserer en estergruppe til en karboksygruppe ,
iii) omdanner en aminogruppe ved reduktiv aminering til et alkylert amin, eller
iv) omdanner en karboksygruppe til en sulfonamido
karbonylgruppe,
og/eller
omdanner en base eller syre med formel I til et av dens salter.
4. Fremgangsmåte for fremstilling av farmasøytiske preparater,
karakterisert ved at en forbindelse med formel I ifølge krav 1 og/eller et av dens fysiologisk akseptable salter bringes sammen med minst et fast, flytende eller halvflytende bærer- eller hjelpestoff i en egnet doseringsform.
5. Farmasøytisk preparat,
karakterisert ved et innhold av minst en forbindelse med formel I ifølge krav 1, og/eller et av dens fysiologisk akseptable salter.
6. Forbindelser med formel I ifølge krav 1 og deres fysiologisk akseptable salter for bekjempelse av sykdommer.
7. Legemiddel med formel I ifølge krav I og deres fysiologisk akseptable salter som endotelinreseptorantagonis-ter.
8. Anvendelse av forbindelser med formel I ifølge krav 1 og/eller deres fysiologisk akseptable salter til fremstilling av et legemiddel.
9. Anvendelse av forbindelser med formel I ifølge krav 1 og/eller deres fysiologisk akseptable salter ved bekjempelse av sykdommer.
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|---|---|---|---|
| DE19530032A DE19530032A1 (de) | 1995-08-16 | 1995-08-16 | Endothelin-Rezeptor-Antagonisten |
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| NO963411L true NO963411L (no) | 1997-02-17 |
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| US (1) | US5821256A (no) |
| EP (1) | EP0758650A1 (no) |
| JP (1) | JPH0959273A (no) |
| KR (1) | KR970010756A (no) |
| CN (1) | CN1149583A (no) |
| AR (1) | AR003286A1 (no) |
| AU (1) | AU6200296A (no) |
| BR (1) | BR9603432A (no) |
| CA (1) | CA2183307A1 (no) |
| CZ (1) | CZ240096A3 (no) |
| DE (1) | DE19530032A1 (no) |
| HU (1) | HUP9602253A3 (no) |
| MX (1) | MX9603343A (no) |
| NO (1) | NO963411L (no) |
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| DE19710831A1 (de) * | 1997-03-15 | 1998-09-17 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
| WO2002064094A2 (en) * | 2001-02-09 | 2002-08-22 | Merck & Co., Inc. | 2-aryloxy-2-arylalkanoic acids for diabetes and lipid disorders |
| DE10155076A1 (de) * | 2001-11-09 | 2003-05-22 | Merck Patent Gmbh | Verwendung von Endothelin-Rezeptor-Antagonisten zur Behandlung von Tumorerkrankungen |
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| JPH07110833B2 (ja) * | 1986-12-02 | 1995-11-29 | 株式会社トクヤマ | α−置換フエニル酢酸誘導体 |
| RU2086544C1 (ru) * | 1991-06-13 | 1997-08-10 | Хоффманн-Ля Рош АГ | Бензолсульфонамидные производные пиримидина или их соли, фармацевтическая композиция для лечения заболеваний, связанных с активностью эндотелина |
| GB9115153D0 (en) * | 1991-07-12 | 1991-08-28 | Patel Bipin C M | Sol-gel composition for producing glassy coatings |
| DK0612244T3 (da) * | 1991-11-05 | 2002-01-14 | Smithkline Beecham Corp | Endothelinreceptorantagonister |
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| DE69422742T2 (de) * | 1993-03-19 | 2000-08-17 | Merck & Co., Inc. | Phenoxyphenylessigsäurederivate |
| AU3642795A (en) * | 1994-09-27 | 1996-04-19 | Merck & Co., Inc. | Endothelin receptor antagonists for the treatment of emesis |
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- 1996-07-31 SK SK1000-96A patent/SK100096A3/sk unknown
- 1996-08-06 EP EP96112667A patent/EP0758650A1/de not_active Withdrawn
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Also Published As
| Publication number | Publication date |
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| BR9603432A (pt) | 1998-05-12 |
| HUP9602253A3 (en) | 1999-06-28 |
| DE19530032A1 (de) | 1997-02-20 |
| PL315707A1 (en) | 1997-02-17 |
| CA2183307A1 (en) | 1997-02-17 |
| KR970010756A (ko) | 1997-03-27 |
| CZ240096A3 (en) | 1997-03-12 |
| HUP9602253A2 (en) | 1997-12-29 |
| JPH0959273A (ja) | 1997-03-04 |
| CN1149583A (zh) | 1997-05-14 |
| NO963411D0 (no) | 1996-08-15 |
| SK100096A3 (en) | 1997-03-05 |
| HU9602253D0 (en) | 1996-10-28 |
| AR003286A1 (es) | 1998-07-08 |
| EP0758650A1 (de) | 1997-02-19 |
| ZA966933B (en) | 1997-02-19 |
| MX9603343A (es) | 1997-03-29 |
| US5821256A (en) | 1998-10-13 |
| AU6200296A (en) | 1997-02-20 |
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