NO781556L - BENZIMIDAZOLE DERIVATIVES. - Google Patents
BENZIMIDAZOLE DERIVATIVES.Info
- Publication number
- NO781556L NO781556L NO781556A NO781556A NO781556L NO 781556 L NO781556 L NO 781556L NO 781556 A NO781556 A NO 781556A NO 781556 A NO781556 A NO 781556A NO 781556 L NO781556 L NO 781556L
- Authority
- NO
- Norway
- Prior art keywords
- lower alkyl
- hydrogen atom
- benzimidazolinone
- formula
- alkyl group
- Prior art date
Links
- 150000001556 benzimidazoles Chemical class 0.000 title claims description 25
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 79
- 150000001875 compounds Chemical class 0.000 claims description 69
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 63
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 46
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 31
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 18
- -1 4-[3-(cyclohexylamino)-2-hydroxypropoxy]-2-benzimidazolinone Chemical compound 0.000 claims description 15
- 239000007858 starting material Substances 0.000 claims description 14
- 150000001412 amines Chemical class 0.000 claims description 10
- 150000002118 epoxides Chemical class 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000004434 sulfur atom Chemical group 0.000 claims description 8
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 claims description 8
- 238000011065 in-situ storage Methods 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 150000003573 thiols Chemical class 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 150000004985 diamines Chemical class 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- VQRLGEWFYFOXPA-UHFFFAOYSA-N 4-[2-hydroxy-3-(propan-2-ylamino)propoxy]-1,3-dihydrobenzimidazol-2-one Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1NC(=O)N2 VQRLGEWFYFOXPA-UHFFFAOYSA-N 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- VMIJBKBEEHFLGX-UHFFFAOYSA-N 4-[2-hydroxy-3-(methylamino)propoxy]-1,3-dihydrobenzimidazol-2-one Chemical compound OC(COC1=CC=CC=2NC(NC21)=O)CNC VMIJBKBEEHFLGX-UHFFFAOYSA-N 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 238000012546 transfer Methods 0.000 claims description 3
- XWTPLMIQYPKYIO-UHFFFAOYSA-N 4-[3-(dicyclopentylamino)-2-hydroxypropoxy]-1,3-dihydrobenzimidazol-2-one Chemical compound C1(CCCC1)N(CC(COC1=CC=CC=2NC(NC21)=O)O)C2CCCC2 XWTPLMIQYPKYIO-UHFFFAOYSA-N 0.000 claims description 2
- WYIWKNNQOKPTNM-UHFFFAOYSA-N 4-[3-(diethylamino)-2-hydroxypropoxy]-1,3-dihydrobenzimidazol-2-one Chemical compound C(C)N(CC(COC1=CC=CC=2NC(NC21)=O)O)CC WYIWKNNQOKPTNM-UHFFFAOYSA-N 0.000 claims description 2
- RKJCHTLIMAXXBD-UHFFFAOYSA-N 4-[3-(diethylamino)-2-hydroxypropoxy]-1,3-dihydrobenzimidazole-2-thione Chemical compound C(C)N(CC(COC1=CC=CC=2N=C(NC21)S)O)CC RKJCHTLIMAXXBD-UHFFFAOYSA-N 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 4
- BXNJPNCQXGADIY-UHFFFAOYSA-N 4-[2-hydroxy-3-(propylamino)propoxy]-1,3-dihydrobenzimidazol-2-one Chemical compound OC(COC1=CC=CC=2NC(NC21)=O)CNCCC BXNJPNCQXGADIY-UHFFFAOYSA-N 0.000 claims 2
- VZXVEQHBGHZBNJ-UHFFFAOYSA-N 4-[3-(dicyclopentylamino)-2-hydroxypropoxy]-7-methyl-1,3-dihydrobenzimidazol-2-one Chemical compound C1(CCCC1)N(CC(COC1=CC=C(C=2NC(NC21)=O)C)O)C2CCCC2 VZXVEQHBGHZBNJ-UHFFFAOYSA-N 0.000 claims 2
- KXEZNOXGNFPRDB-UHFFFAOYSA-N 4-[3-[cyclohexyl(methyl)amino]-2-hydroxypropoxy]-1,3-dihydrobenzimidazol-2-one Chemical compound OC(COC1=CC=CC=2NC(NC21)=O)CN(C)C2CCCCC2 KXEZNOXGNFPRDB-UHFFFAOYSA-N 0.000 claims 2
- GJHQPGOUBCJWJZ-UHFFFAOYSA-N 4-[3-(tert-butylamino)-2-hydroxypropoxy]-7-methyl-1,3-dihydrobenzimidazol-2-one Chemical compound CC1=CC=C(OCC(O)CNC(C)(C)C)C2=C1NC(=O)N2 GJHQPGOUBCJWJZ-UHFFFAOYSA-N 0.000 claims 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000013543 active substance Substances 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000011593 sulfur Chemical group 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 156
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 229960004592 isopropanol Drugs 0.000 description 42
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 230000008018 melting Effects 0.000 description 26
- 238000002844 melting Methods 0.000 description 26
- 238000004458 analytical method Methods 0.000 description 21
- 239000000706 filtrate Substances 0.000 description 18
- 239000001257 hydrogen Substances 0.000 description 17
- 229910052739 hydrogen Inorganic materials 0.000 description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 16
- HKHPFDCMZHIIBQ-UHFFFAOYSA-N 2-[(2,3-dinitrophenoxy)methyl]oxirane Chemical compound [O-][N+](=O)C1=CC=CC(OCC2OC2)=C1[N+]([O-])=O HKHPFDCMZHIIBQ-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 239000003960 organic solvent Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 239000003054 catalyst Substances 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- CPBGGIHYAYWNDD-UHFFFAOYSA-N 4-hydroxy-1,3-dihydrobenzimidazol-2-one Chemical compound OC1=CC=CC2=C1NC(=O)N2 CPBGGIHYAYWNDD-UHFFFAOYSA-N 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- 238000011282 treatment Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- XQRIIZNTOKFIBU-UHFFFAOYSA-N 2-[(4-methyl-2,3-dinitrophenoxy)methyl]oxirane Chemical compound [O-][N+](=O)C1=C([N+]([O-])=O)C(C)=CC=C1OCC1OC1 XQRIIZNTOKFIBU-UHFFFAOYSA-N 0.000 description 5
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 5
- MHKBMNACOMRIAW-UHFFFAOYSA-N 2,3-dinitrophenol Chemical compound OC1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O MHKBMNACOMRIAW-UHFFFAOYSA-N 0.000 description 4
- RGAFTXCTIKLLTR-UHFFFAOYSA-N 4-methoxy-1,3-dihydrobenzimidazol-2-one Chemical compound COC1=CC=CC2=C1NC(=O)N2 RGAFTXCTIKLLTR-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 4
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 4
- 229960002508 pindolol Drugs 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- KKXAQCNTKFVOJL-UHFFFAOYSA-N 1-(dicyclopentylamino)-3-(4-methyl-2,3-dinitrophenoxy)propan-2-ol Chemical compound [O-][N+](=O)C1=C([N+]([O-])=O)C(C)=CC=C1OCC(O)CN(C1CCCC1)C1CCCC1 KKXAQCNTKFVOJL-UHFFFAOYSA-N 0.000 description 3
- NDKWDGCTUOOAPF-UHFFFAOYSA-N 2-methoxy-6-nitroaniline Chemical compound COC1=CC=CC([N+]([O-])=O)=C1N NDKWDGCTUOOAPF-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 125000006309 butyl amino group Chemical group 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000012876 carrier material Substances 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 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
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000004611 spectroscopical analysis Methods 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- OJWGZMNOJJAHTR-UHFFFAOYSA-N 4-[3-(cyclohexylamino)-2-hydroxypropoxy]-1,3-dihydrobenzimidazol-2-one hydrochloride Chemical compound Cl.C1(CCCCC1)NCC(COC1=CC=CC=2NC(NC21)=O)O OJWGZMNOJJAHTR-UHFFFAOYSA-N 0.000 description 2
- VIORRNJSVRGDCJ-UHFFFAOYSA-N 4-[3-(cyclopentylamino)-2-hydroxypropoxy]-7-methyl-1,3-dihydrobenzimidazol-2-one Chemical compound C1(CCCC1)NCC(COC1=CC=C(C=2NC(NC21)=O)C)O VIORRNJSVRGDCJ-UHFFFAOYSA-N 0.000 description 2
- ZONXEHPKQZCPNN-UHFFFAOYSA-N 4-[3-(diethylamino)-2-hydroxypropoxy]-1,3-dihydrobenzimidazol-2-one hydrochloride Chemical compound Cl.C(C)N(CC(COC1=CC=CC=2NC(NC21)=O)O)CC ZONXEHPKQZCPNN-UHFFFAOYSA-N 0.000 description 2
- PULXDWLLHIOXKI-UHFFFAOYSA-N Cl.C(C)N(CC)CC(COC1=CC=CC=2N=C(NC21)S)O Chemical compound Cl.C(C)N(CC)CC(COC1=CC=CC=2N=C(NC21)S)O PULXDWLLHIOXKI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 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
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 239000007963 capsule composition Substances 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000002026 chloroform extract Substances 0.000 description 2
- 229910017052 cobalt Inorganic materials 0.000 description 2
- 239000010941 cobalt Substances 0.000 description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- PHQRMKOKTRIKEN-UHFFFAOYSA-N n-cyclopentylcyclopentanamine;hydrochloride Chemical compound Cl.C1CCCC1NC1CCCC1 PHQRMKOKTRIKEN-UHFFFAOYSA-N 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- LWNDLCRUZVMGFG-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one;hydrochloride Chemical compound Cl.C1=CC=C2NC(=O)NC2=C1 LWNDLCRUZVMGFG-UHFFFAOYSA-N 0.000 description 1
- DERBQHFIKUMUPM-UHFFFAOYSA-N 1-(2,3-diaminophenoxy)-3-(dicyclopentylamino)propan-2-ol Chemical compound NC1=CC=CC(OCC(O)CN(C2CCCC2)C2CCCC2)=C1N DERBQHFIKUMUPM-UHFFFAOYSA-N 0.000 description 1
- JRNIQGKMYQYSGH-UHFFFAOYSA-N 1-(2,3-diaminophenoxy)-3-(diethylamino)propan-2-ol Chemical compound CCN(CC)CC(O)COC1=CC=CC(N)=C1N JRNIQGKMYQYSGH-UHFFFAOYSA-N 0.000 description 1
- RVWRKMLCKHPUBK-UHFFFAOYSA-N 1-(2,3-diaminophenoxy)-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NCC(O)COC1=CC=CC(N)=C1N RVWRKMLCKHPUBK-UHFFFAOYSA-N 0.000 description 1
- YGSXLVZEEOBCDJ-UHFFFAOYSA-N 1-(2,3-diaminophenoxy)-3-(propylamino)propan-2-ol Chemical compound CCCNCC(O)COC1=CC=CC(N)=C1N YGSXLVZEEOBCDJ-UHFFFAOYSA-N 0.000 description 1
- HBPKLTJWNQDWFT-UHFFFAOYSA-N 1-(cyclohexylamino)-3-(2,3-diaminophenoxy)propan-2-ol Chemical compound NC1=CC=CC(OCC(O)CNC2CCCCC2)=C1N HBPKLTJWNQDWFT-UHFFFAOYSA-N 0.000 description 1
- XKVZCHHXURMTDB-UHFFFAOYSA-N 1-(dicyclopentylamino)-3-(2,3-dinitrophenoxy)propan-2-ol Chemical compound C1CCCC1N(C1CCCC1)CC(O)COC1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O XKVZCHHXURMTDB-UHFFFAOYSA-N 0.000 description 1
- AJLQESNKUTZRAL-UHFFFAOYSA-N 1-(tert-butylamino)-3-(2,3-diamino-4-methylphenoxy)propan-2-ol Chemical compound CC1=CC=C(OCC(O)CNC(C)(C)C)C(N)=C1N AJLQESNKUTZRAL-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/28—Sulfur atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Benzimidazol-derivaterBenzimidazole derivatives
Foreliggende oppfinnelse vedrører benzimidazol-derivater. Nærmere bestemt vedrører oppfinnelsen benzimidazol-derivater, en fremgangsmåte for fremstilling av disse og farma-søytiske preparater som inneholder disse. The present invention relates to benzimidazole derivatives. More specifically, the invention relates to benzimidazole derivatives, a method for their production and pharmaceutical preparations containing them.
Benzimidazol-derivatene som tilveiebringes ved foreliggende oppfinnelse er forbindelser med den generelle formel The benzimidazole derivatives provided by the present invention are compounds of the general formula
Hvor R representerer et hydrogen-atom eller en lavere alkyl-aruppe, R"*" representerer et hydrogen-atom eller Where R represents a hydrogen atom or a lower alkyl group, R"*" represents a hydrogen atom or
' 2 en lavere alkyl- eller lavere cykloalkyl-g.ruppe, R representerer en lavere alkyl eller lavere cykloalkyl- ' 2 a lower alkyl or lower cycloalkyl group, R represents a lower alkyl or lower cycloalkyl
3 3
gruppe, R representerer et hydrogen-atom eller en primær eller sekundær lavere alkyl-gruppe Y representerer et oksygen eller svovel-atom, group, R represents a hydrogen atom or a primary or secondary lower alkyl group Y represents an oxygen or sulfur atom,
og farmasøytisk fordragelige syreaddisjons-salter derav. and pharmaceutically acceptable acid addition salts thereof.
Som her brukt i beskrivelsen betyr utrykket "lavere alkyl" en rettlinjet eller forgreinet alkyl-gruppe som fortrinnsvis inneholder fra 1 til 6 karbonatomer (f.eks. metyl, etyl, As used herein in the specification, the term "lower alkyl" means a straight or branched alkyl group preferably containing from 1 to 6 carbon atoms (e.g. methyl, ethyl,
n-propyl, isopropyl, n-butyl, sec.butyl, tert.butyl og lignende). Utrykket "lavere cykloalkyl" betyr en cykloalkyl- n-propyl, isopropyl, n-butyl, sec.butyl, tert.butyl and the like). The term "lower cycloalkyl" means a cycloalkyl-
gruppe som fortrinnsvis inneholder fra 3 til 8 karbon-atomer ( f.eks. cyklopropyl, cyklobutyl, cyklopentyl, cykloheksyl og lignende). group which preferably contains from 3 to 8 carbon atoms (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like).
Benzimidazol-derivatene med formel 1 forut hvor Y representerer et svovel-atom foreligger hovedsaklig i deres tauto-mere form med den generelle formel The benzimidazole derivatives with formula 1 above where Y represents a sulfur atom exist mainly in their tautomeric form with the general formula
12 3 12 3
hvori R, R , R og R har de tidligere angitte betydninger. wherein R, R , R and R have the meanings previously indicated.
Foretrukne benzimidazol-derivater som tilveiebringes ved foreliggende oppfinnelse er slike hvori R representerer en lavere alkyl-gruppe, spesielt metyl-gfuppen. Også foretrukket er slike benzimidazol-derivater hvor R"<*>" representerer et hydrogen-atom, spesielt sådanne hvor R<2>representerer en lavere alkyl-gruppe og spesielt en forgrenet-kjedet lavere alkyl-gruppe som isopropyl eller tert.butyl-gruppen. Preferred benzimidazole derivatives provided by the present invention are those in which R represents a lower alkyl group, especially the methyl group. Also preferred are such benzimidazole derivatives where R"<*>" represents a hydrogen atom, especially those where R<2>represents a lower alkyl group and especially a branched-chain lower alkyl group such as isopropyl or tert.butyl- the group.
Spesielle benzimidazol-derivater som tilveiebringes ved foreliggende oppfinnelse er sådanne hvor Y representerer et oksy-12 gen-atom, R og R representerer et hydrogen-atom og R og R har forut angitte betydning, dvs. forbindelse med den generelle formel 12 ' Hvor R og R har forut angitte betydning. Special benzimidazole derivatives which are provided by the present invention are those where Y represents an oxygen atom, R and R represent a hydrogen atom and R and R have the previously stated meaning, i.e. compound with the general formula 12 ' Where R and R has the aforesaid meaning.
Særlige benzimidazol-derivater er sådanne med formel Ia forut hvor R 1 representerer et hydrogen-atom og R 2representerer en lavere cykloalkyl-gruppe eller R 1 og R 2 hver for seg representerer en lavere alkyl- eller lavere cykloalkyl-gruppe. Particular benzimidazole derivatives are those of formula Ia where R 1 represents a hydrogen atom and R 2 represents a lower cycloalkyl group or R 1 and R 2 each separately represent a lower alkyl or lower cycloalkyl group.
En ytterligere spesiell klasse benzimidazol-derivater som tilveiebringes ved foreliggende oppfinnelse er sådanne hvor Y representerer et oksygenatom, R representerer én lavere A further special class of benzimidazole derivatives provided by the present invention are those where Y represents an oxygen atom, R represents one lower
12 3 12 3
alkyl-gruppe og R , R og R har forut angitte betydning, dvs. forbindelser med den generelle formel alkyl group and R , R and R have the previously stated meaning, i.e. compounds with the general formula
1 2 hvor R1 representerer en lavere alkyl-gruppe og R , R og R 3 har tidligere angitte betydning. Enda en spesiell klasse benzimidazol-derivater som tilveiebringes ved foreliggende oppfinnelse er sådanne hvor Y representerer et svovel-atom, R"*" representerer et hydrogen-atom 2 eller en lavere alkyl-gruppe, R representerer én lavere alkyl-gruppe og R og R 3 har forut angitte betydning, dvs. forbind elser med den generelle formel 1 2 where R 1 represents a lower alkyl group and R , R and R 3 have previously indicated meanings. Another special class of benzimidazole derivatives provided by the present invention are those where Y represents a sulfur atom, R"*" represents a hydrogen atom 2 or a lower alkyl group, R represents one lower alkyl group and R and R 3 have the previously stated meaning, i.e. connect else with the general formula
Hvor R representerer et hydrogen-atom eller en lavere alkyl-gruppe, R 2' representerer en lavere alkyl-gruppe og R og R 3 har tidligere angitte betydning, og thioltautomerene derav. Where R represents a hydrogen atom or a lower alkyl group, R 2' represents a lower alkyl group and R and R 3 have previously indicated meaning, and the thiol tautomers thereof.
Eksempler på benzimidazol-derivater som tilveiebringes ved foreliggende oppfinnelse er: 4—[3-(tert.butylamino)-2-hydroksypropoksy]-7-metyl-2-benzimidazolinon, 4-[3-(cyklopentylamino)-2-hydroksypropoksy]-7-metyl-2-benzimidazolinon, 4-[3-(dicyklo<p>entylamino)-2-hydroksypropoksy]-7-metyl-2-benzimidazolinon, 7-[3-(tert-butylamino)-2-hydroksypropoksy]-1,4-dimetyl-2-benzimidazolinon, 4-[2-hydroksy-3-(metylamino)propoksy]-2-benzimidazolinon, 4-[2-hydroksy-3-(n-propylamino)<p>ropoksy]-2-benzimidazolinon, 4-[2-hydroksy-3-(isopropylamino)propoksy]-2-benzimidazolinon, 4-[3-(tert.butylamino)-2-hydroksypropoksy]-2-benzimidazolinon, 4-[3-(dietylamino)-2-hydroksypropoksy]-2-benzimidazolinon, 4-[3-(cykloheksylamino)-2-hydroksypropoksy]-2-benzimidazolinon, 4-[3-(dicyklopentylamino)-2-hydroksypropoksy]-2-benzimidazolinon, 4-[2-hydroksy-3-(N-metylcykloheksylamino)propoksy]-2^benzimidazolinon, 1-(tert.butylamino)-3-(2-merkapto-7-metyl-4-benzimidazolyloksy) -2-propanol, Examples of benzimidazole derivatives provided by the present invention are: 4-[3-(tert.butylamino)-2-hydroxypropoxy]-7-methyl-2-benzimidazolinone, 4-[3-(cyclopentylamino)-2-hydroxypropoxy]- 7-methyl-2-benzimidazolinone, 4-[3-(dicyclo<p>entylamino)-2-hydroxypropoxy]-7-methyl-2-benzimidazolinone, 7-[3-(tert-butylamino)-2-hydroxypropoxy]- 1,4-dimethyl-2-benzimidazolinone, 4-[2-hydroxy-3-(methylamino)propoxy]-2-benzimidazolinone, 4-[2-hydroxy-3-(n-propylamino)<p>propoxy]-2 -benzimidazolinone, 4-[2-hydroxy-3-(isopropylamino)propoxy]-2-benzimidazolinone, 4-[3-(tert.butylamino)-2-hydroxypropoxy]-2-benzimidazolinone, 4-[3-(diethylamino) -2-hydroxypropoxy]-2-benzimidazolinone, 4-[3-(cyclohexylamino)-2-hydroxypropoxy]-2-benzimidazolinone, 4-[3-(dicyclopentylamino)-2-hydroxypropoxy]-2-benzimidazolinone, 4-[2 -hydroxy-3-(N-methylcyclohexylamino)propoxy]-2^benzimidazolinone, 1-(tert.butylamino)-3-(2-mercapto-7-methyl-4-benzimidazolyloxy)-2-propanol,
1-(tert.butylamino)-3-(2-merkapto-4-benzimidazolyloksy)-2-propanol, 1-(tert.butylamino)-3-(2-mercapto-4-benzimidazolyloxy)-2-propanol,
1-(tert.butylamino)~3-(2-merkapto-l,4-dimetyl-7-benzimidazoly-loksy)-2-propanol og 1-(dietylamino)-3-(2-merkapto-4-benzimidazolyloksy)-2-propanol og hydrogenhalogenidene derav, spesielt hydrokloridene. 1-(tert.butylamino)~3-(2-mercapto-1,4-dimethyl-7-benzimidazolyloxy)-2-propanol and 1-(diethylamino)-3-(2-mercapto-4-benzimidazolyloxy)- 2-propanol and its hydrogen halides, especially the hydrochlorides.
I følge fremgangsmåten som tilveiebringes ved foreliggende oppfinnelse fremstilles forannevnte benziminazol-derivater (dvs. forbindelse med formel I forut og deres farmasøytisk fordragelige syreaddisjons-salter) ved en fremgangsmåte som omfatter According to the method provided by the present invention, the aforementioned benziminazole derivatives (i.e. compound of formula I above and their pharmaceutically acceptable acid addition salts) are prepared by a method comprising
a) omsettning av en forbindelse med den generelle formel a) reaction of a compound with the general formula
12 3 hvor R, R , R' og R har tidligere angitte betydning, med en forbindelse med den generelle formel 12 3 where R, R , R' and R have previously indicated meanings, with a compound of the general formula
hvor Z representerer et klor-atom eller en amino- gruppe og Y har forut angitte betydning, where Z represents a chlorine atom or an amino group and Y has the previously stated meaning,
elleror
b) Forbindelse med formel I hvori Y representerer et oksygen-12 3 b) Compound of formula I in which Y represents an oxygen-12 3
atom og R, R , R og R har tidligere angitte betydning, fremstilles ved omsetning av epoksyd med den generelle formel atom and R, R , R and R have previously indicated meaning, is produced by reaction of epoxide with the general formula
3 hvor R og R har tidligere angitte betydning, med et amin med den generelle formel 3 where R and R have previously indicated meaning, with an amine of the general formula
12 12
hvor R og R har tidligere angitte betydning,where R and R have previously stated meaning,
elleror
c) oppløsning av en racemlsk forbindelse med formel I i de optiske isomerene, og om ønsket overfor en erholdt forbindelse c) resolution of a racemic compound of formula I in the optical isomers, and if desired to a compound obtained
med formel I i et farmasøytisk fordragelig syreaddisjons-salt. of formula I in a pharmaceutically acceptable acid addition salt.
Omsetningen aven forbindelse med formel III med fosgen eller thiofosgen dvs. én forbindelse med formel IV hvor Z betyr et klor-atom, kan utføres i følge i og for seg kjente metoder. The reaction of the compound of formula III with phosgene or thiophosgene, i.e. one compound of formula IV where Z represents a chlorine atom, can be carried out according to methods known per se.
I en foretrukket ,utførelse utføres reaksjonen under sure betingelser. F.eks. kan jeg i forbindelse med formel III opp-løses en vanndig mineralsyre som vanndig hydrohalogensyre (f.eks. vanndig saltsyre) og behandles med fosgen eller thiofosgen, fortrinnsvis i overskudd, hvilket gir det tilsvarende syreaddisjons-salt av en forbindelse med formel I som kan overføres til en fri base med formel I på konvensjonell måte om ønsket. Reaksjonen utføres med fordel ved romtemperatur eller under romtemperatur og ved atmosfærisk trykk. Det foretrekkes å utføre reaksjonen med thiofosgen under en at-mosfære av en inert gass som nitrogen eller argon. In a preferred embodiment, the reaction is carried out under acidic conditions. E.g. in connection with formula III, an aqueous mineral acid such as aqueous hydrohalic acid (e.g. aqueous hydrochloric acid) can be dissolved and treated with phosgene or thiophosgene, preferably in excess, which gives the corresponding acid addition salt of a compound of formula I which can is transferred to a free base of formula I in a conventional manner if desired. The reaction is advantageously carried out at room temperature or below room temperature and at atmospheric pressure. It is preferred to carry out the reaction with thiophosgene under an atmosphere of an inert gas such as nitrogen or argon.
Omsetningen av en forbindelse med formel III med urea eller thiourea, dvs. en forbindelse med formel IV hvor Z representerer en amino-gruppe, kan utføres i nærvær eller fravær av et inert organisk løsningsmiddel. I en foretrukket utfør-élsesform utføres reaksjonen i nærvær av et inert organisk løsningsmiddel ved å smelte reaktantene sammen under en at-mosfære av en inert gass som nitrogen eller argon. Når reaksjonen utføres i nærvær av et inert organisk løsnings-middel innbefatter egnede løsningsmiddeler f.eks. hydrokarboner, spesielt aromatiske hydrokarboner som benzen, toluen og lignende, lavere alkanoler som metanol, etanol og lignende etc. Når et inert organisk løsningsmiddel brukes, utføres re-, aksjonen med fordel ved høyere temperatur og ved atmosfærisk trykk. The reaction of a compound of formula III with urea or thiourea, i.e. a compound of formula IV where Z represents an amino group, can be carried out in the presence or absence of an inert organic solvent. In a preferred embodiment, the reaction is carried out in the presence of an inert organic solvent by fusing the reactants together under an atmosphere of an inert gas such as nitrogen or argon. When the reaction is carried out in the presence of an inert organic solvent, suitable solvents include e.g. hydrocarbons, especially aromatic hydrocarbons such as benzene, toluene and the like, lower alkanols such as methanol, ethanol and the like, etc. When an inert organic solvent is used, the reaction is advantageously carried out at a higher temperature and at atmospheric pressure.
Utgangsmaterialene nted formel III er relativt ustabile og i en foretrukket utførelsesform av foreliggende oppfinnelse, omsettes de in situ (dvs. uten opparbeidelse eller rensning) med forbindelsene med formel IV. The starting materials of formula III are relatively unstable and, in a preferred embodiment of the present invention, they are reacted in situ (ie without processing or purification) with the compounds of formula IV.
Omsetningen av et epoksyd med formel V med et amin med formel VI i følge utførelse og form (b) av fremgangsmåten kan utføres The reaction of an epoxide of formula V with an amine of formula VI according to embodiment and form (b) of the method can be carried out
r nærvær eller fravær av et inert organisk løsningsmiddel.r presence or absence of an inert organic solvent.
Når et inert organisk løsningsmiddel brukes, kan dette f.eks. være en lavere alkohol som metanol, etånol eller lignende. Alternativt kan et overskudd av et amin med formel VI brukes When an inert organic solvent is used, this can e.g. be a lower alcohol such as methanol, ethanol or the like. Alternatively, an excess of an amine of formula VI may be used
og kan derved også tjene som løsningsmiddel. Reaksjonen ut-føres fortrinnsvis ved en temperatur fra ca. 0°C til romtemperatur og under atmosfærisk trykk.. Epoksyder med formel V er relativt ustabile og, i et foretrukket aspekt av denne utførelsesformen, omsettes de in situ (dvs. uten opparbeiding eller rensning) med et amin med formel VI. and can thereby also serve as a solvent. The reaction is preferably carried out at a temperature from approx. 0°C to room temperature and under atmospheric pressure. Epoxides of formula V are relatively unstable and, in a preferred aspect of this embodiment, are reacted in situ (ie without workup or purification) with an amine of formula VI.
Det vil være klart at forbindelse med formel I forut inneholder et assymetrisk karbon-atom og kan foreligge i racemiske eller optiske aktive former. Foreliggende oppfinnelse innbefatter racematene så vel som de optiske aktive former. Et racemat kan om ønsket oppløses i de optiske isomerer i' følge i og for seg kjente metoder, f.eks. ved fraksjonert krystallisering av dannede salter med optiske aktive syrer. It will be clear that compound of formula I above contains an asymmetric carbon atom and may exist in racemic or optically active forms. The present invention includes the racemates as well as the optically active forms. A racemate can, if desired, be dissolved into the optical isomers according to methods known per se, e.g. by fractional crystallization of formed salts with optically active acids.
Forbindelsene med formel I kan overføres i farmasøytisk fordragelige syreaddisjons-salter og behandling med farmasøytisk fordragelige organiske syrer (f.eks. saltsyre, hydrogenbromidsyre, svovelsyre, fosforsyre etc.) og med farmasøytisk fordragelige organiske syrer (f.eks. eddiksyre, vinsyre, sitronsyre, fumarsyre, maleinsyre, malinsyre, metansylfonsyre, paratoluensulfonsyre etc.). The compounds of formula I can be transferred into pharmaceutically acceptable acid addition salts and treatment with pharmaceutically acceptable organic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid etc.) and with pharmaceutically acceptable organic acids (e.g. acetic acid, tartaric acid, citric acid) , fumaric acid, maleic acid, malic acid, methanesulfonic acid, paratoluenesulfonic acid, etc.).
Utgangsmaterialene med formel III forut kan fremstilles, f.eks. The starting materials of formula III above can be prepared, e.g.
2 3 2 3
i følge det følgende formelskjerna A hvor R, R , R og R har de tidligere angitte betydninger, R representerer et hydrogen-atom eller bensyl-gruppen og en lavere alkyl eller lavere cykloalkyl-gruppe og R 30 representerer en primær eller sekundær lavere alkyl-gruppe: according to the following formula nucleus A where R, R , R and R have the previously indicated meanings, R represents a hydrogen atom or the benzyl group and a lower alkyl or lower cycloalkyl group and R 30 represents a primary or secondary lower alkyl- group:
I trinn (i) i det foregående formelskjerna A overføres en forbindelse med formel VII i et epoksyd med formel VIII ved omsettning med epihalogen-hydrin, fortrinnsvis épiklor-hydrin. Reaksjonen utføres fortrinnsvis i nærvær av piperidin ved høyere temperatur (f.eks. ca. 80°C) og det erholdte produkt behandles deretter med et alkalimetall-hydroksyd som natriumhydroksyd eller kaliumhydroksyd, fortrinnsvis natriumhydroksyd. Denne behandlingen utføres fortrinnsvis i et vannblandbart inert organisk løsningsmiddel som dioksan. Alternativt kan en forbindelse med formel VII omsettes med:et epihalogen-hydrin i nærvær av et alkalimetall-hydroksyd som natriumhydroksyd eller kaliumhydroksyd, fortrinnsvis natriumhydroksyd. Reaksjonen utføres hensiktsmessig i nærvær av et vannblandbart inert organisk løsningsmiddel som en lavere alkanol (f.eks. metanol, etanol eller lignende) ved en temperatur fra ca. 0°C til romtemperatur, fortrinnsvis rundt romtemperatur. In step (i) in the preceding formula core A, a compound of formula VII is transferred into an epoxide of formula VIII by reaction with epihalohydrin, preferably epichlorohydrin. The reaction is preferably carried out in the presence of piperidine at a higher temperature (eg approx. 80°C) and the product obtained is then treated with an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. This treatment is preferably carried out in a water-miscible inert organic solvent such as dioxane. Alternatively, a compound of formula VII can be reacted with: an epihalohydrin in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. The reaction is suitably carried out in the presence of a water-miscible inert organic solvent such as a lower alkanol (e.g. methanol, ethanol or the like) at a temperature from approx. 0°C to room temperature, preferably around room temperature.
I trinn (ii) i formelskjema A omsettes et epoksyd med formel VIII med et amin med den generelle formel In step (ii) in formula scheme A, an epoxide of formula VIII is reacted with an amine of the general formula
2 10 2 10
hvor R og R har de tidligere angitte betydninger • where R and R have the previously stated meanings •
for å gi en forbindelse med formel IX. Denne reaksjonen ut-føres i nærvær av et inert organisk løsningsmiddel, fortrinnsvis en lavere alkanol som metanol, etanol eller lignende. Reaksjonen kan utføres ved romtemperatur eller ved en høyere temperatur (f.eks. en temperatur opptil reaksjonsblanding- to give a compound of formula IX. This reaction is carried out in the presence of an inert organic solvent, preferably a lower alkanol such as methanol, ethanol or the like. The reaction can be carried out at room temperature or at a higher temperature (e.g. a temperature up to reaction mix-
ens kokepunkt). Under visse omstendigheter kan det være en fordel å bruke et syreaddisjons-salt av et aminsalt med formel XI ( f.eks. et hydrogenhalogenid som hydrokloridet) i dette trinnet og utføre reaksjonen i nærvær av en egnet uorganisk base (f.eks. et alkalimetall-karbonat som kaliumkarbonat). same boiling point). In certain circumstances, it may be advantageous to use an acid addition salt of an amine salt of formula XI (eg a hydrogen halide such as the hydrochloride) in this step and carry out the reaction in the presence of a suitable inorganic base (eg an alkali metal -carbonate such as potassium carbonate).
I trinn (iii) i formelskjema A hydrogeneres en forbindelseIn step (iii) of formula A, a compound is hydrogenated
med formel IX for å gi et utgangsmateriale med formel III hvor R"^ representerer et hydrogen-atom og hvor, nårR"<*>"^ i forbindelsen med formel IX representerer bensy1-gruppen, representerer R"*" et hydrogen-atom. Hydrogeneringen kan utføres i nærvær av en edelmetall—katalysator (f.eks. en palladium- eller platinakatalysator som palladium-på-kull eller platinaoksyd), skjønt andre konvensjonelle hydrogeneringskatalysatorer som Raney-nikkel, Raney-kobolt og lignende også kan.brukes. Denne katalytiske hydrogeneringen kan utføres på en konvensjonell måte, f.eks. i et inert organisk løsningsmiddel som en lavere alkanol (f.eks. metanol, etanol eller lignende) og ved romtemperatur og atmosfærisk trykk. I følge en foretrukket fremgangsmåte utføres trinn (iii) in situ, dvs. uten å isolere en forbindelse formel IX fra mediet hvori det fremstilles. of formula IX to give a starting material of formula III wherein R"^ represents a hydrogen atom and where, when R"<*>"^ in the compound of formula IX represents the benzyl group, R"*" represents a hydrogen atom. The hydrogenation can be carried out in the presence of a noble metal catalyst (eg a palladium or platinum catalyst such as palladium-on-charcoal or platinum oxide), although other conventional hydrogenation catalysts such as Raney nickel, Raney cobalt and the like can also be used. the catalytic hydrogenation can be carried out in a conventional manner, for example in an inert organic solvent such as a lower alkanol (e.g. methanol, ethanol or the like) and at room temperature and atmospheric pressure. According to a preferred method step (iii) is carried out in situ, i.e. without isolating a compound of formula IX from the medium in which it is produced.
Trinn (iv) i formelskjemaet A omfatter omsetningen av én forbindelse med formel IX med et primært eller sekundært lavere alkylamin (f.eks. metylamin, etylamin, isopropylamin eller lignende) hvilket gir en forbindelse med formel X. Denne reaksjonen utføres gjerne i nærvær av et inert organisk løs-ningsmiddel, fortrinnsvis en lavere alkanol som metanol, etanol eller lignende. Det foretrekkes å utføre denne reaksjonen ved høyere temperatur og atmosfærisk trykk. Step (iv) of formula A comprises the reaction of one compound of formula IX with a primary or secondary lower alkylamine (e.g. methylamine, ethylamine, isopropylamine or the like) which gives a compound of formula X. This reaction is preferably carried out in the presence of an inert organic solvent, preferably a lower alkanol such as methanol, ethanol or the like. It is preferred to carry out this reaction at higher temperature and atmospheric pressure.
I forbindelse med formel Xhydrogeneres så i trinn (v) i formelskjema A hvilket gir et utgangsmateriale med formel (III hvor R 3 representerer en primær eller sekundær lavere alkyl-gruppe og hvor, når R i forbindelsen med formel X representerer bensy 1-gruppen, representerer R"^ et hydrogen-atom. Hydrogeneringen kan utføres hovedsaklig på samme måte som beskrevet tidligere i forbindelse med hydrogeneringen av en forbindelse med formel IX. In connection with formula X is then hydrogenated in step (v) in formula scheme A which gives a starting material of formula (III where R 3 represents a primary or secondary lower alkyl group and where, when R in the connection with formula X represents the benzyl 1 group, represents R"^ a hydrogen atom. The hydrogenation can be carried out essentially in the same way as described earlier in connection with the hydrogenation of a compound of formula IX.
Når det er ønskelig å fremstille utgangsmateriale med formel III When it is desired to produce starting material with formula III
1 2 1 2
hvor R representerer et hydrogen-atom og R representerer en primær eller sekundær lavere alkyl-gruppe, foretrekkes det å gå frem via en tilsvarende forbindelse med formel IX hvor representerer bénsy1-gruppen. where R represents a hydrogen atom and R represents a primary or secondary lower alkyl group, it is preferred to proceed via a corresponding compound of formula IX where represents the bensy1 group.
Fore-trukne utgangsmaterialer av formel III er sådanne hvor R representerer en lavere alkyl-gruppe, spesielt mety1-gruppen. Videre foretrukket er slike utgangsmaterialer med formel III hvor R 1 representerer et hydrogen-atom, særlig slike hvor R<2>representerer en lavere alkyl-gruppe og spesielt en forgrenet-kjedet lavere alkyl-gruppe som isopropyl eller tert.butyl-gruppen. Preferred starting materials of formula III are those where R represents a lower alkyl group, especially the methyl group. Further preferred are such starting materials with formula III where R 1 represents a hydrogen atom, especially those where R<2> represents a lower alkyl group and especially a branched-chain lower alkyl group such as the isopropyl or tert-butyl group.
Spesielle utgangsmaterialer med formel III er sådanne hvor R^ representerer et hydrogen-atom og R<2>representerer en lavere 1 2 cykloalkyl-gruppe eller R og R hver for seg representerer en lavere alkyl eller lavere cykloalkyl-gruppe. Special starting materials of formula III are those where R^ represents a hydrogen atom and R<2> represents a lower 1 2 cycloalkyl group or R and R each represent a lower alkyl or lower cycloalkyl group.
Epoksyd-utgangsmaterialene med formel V forut, kan fremstilles f.eks. ifølge formelskjema B i det etterfølgende hvor R og R<3>har de tidligere angitte betydninger.: The epoxy starting materials with formula V above can be prepared, e.g. according to formula form B in the following where R and R<3> have the previously stated meanings.:
I formelskjema B i trinn (i) reduseres et 2-metoksy-6-nitro-anilin med formel XI til et o-diamin med formel XII. Reduk- In formula B in step (i), a 2-methoxy-6-nitroaniline of formula XI is reduced to an o-diamine of formula XII. Reduce-
sjonen utføres gjerne ved å bruke hydrogen i nærvær av en edelmetall-katalysator (f.eks. en palladium, platina eller rhodiumkatalysator som palladium-på-tjærekull, platinaoksyd, rhodium-på-karbon eller rhodium-alluminiumoksyd) selv om andre konvensjonelle hydrogeneringskatalysatorer som Raney-nikkel, Raney-kobolt og lignende også kan brukes . En palla-diumkatalysator, spesielt palladium-på-kull, brukes fortrinnsvis. Denne katalytiske hydrogeneringen utføres gjerne i nærvær av et inert organisk løsningsmiddel (f.eks. en lavere alkanol som metanol etanol etc). Det foretrekkes å utføre den katalytiske hydrogeneringen ved romtemperatur og atmosfærisk trykk. tion is often carried out using hydrogen in the presence of a noble metal catalyst (e.g. a palladium, platinum or rhodium catalyst such as palladium-on-tar coal, platinum oxide, rhodium-on-carbon or rhodium-alumina) although other conventional hydrogenation catalysts such as Raney nickel, Raney cobalt and the like can also be used. A palladium catalyst, especially palladium-on-charcoal, is preferably used. This catalytic hydrogenation is preferably carried out in the presence of an inert organic solvent (e.g. a lower alkanol such as methanol ethanol etc). It is preferred to carry out the catalytic hydrogenation at room temperature and atmospheric pressure.
I trinn (ii) i formelskjema B omsettes o-diamin med formelIn step (ii) in formula B, o-diamine is reacted with formula
XII med fosgen hvilket gir et 4-metoksy-2-benzimidazolinonXII with phosgene giving a 4-methoxy-2-benzimidazolinone
med formel XIII og reaksjonen utføres hovedsaklig under samme betingelser som beskrevet forut i forbindelse med omsetningen av et diamin med formel II med fosgen. Da o-diaminer med formel XII er relativt ustabile omsettes de fortrinnsvis in situ (dvs. uten opparbeiding eller rensning) med fosgen. with formula XIII and the reaction is essentially carried out under the same conditions as described above in connection with the reaction of a diamine of formula II with phosgene. As o-diamines of formula XII are relatively unstable, they are preferably reacted in situ (ie without work-up or purification) with phosgene.
Trinn (iii) i formelskjema B' innbefatter overføringen av metoksy-gruppen i et 4-metoksy-2-benzimidazolinon med formel XIII til en hydroksy-gruppe hvorved oppnås et tilsvarende 4-hydroksy-2-benzimidazolinon med formel XIV hvor R 3representerer et hydrogen-atom. Denne overføringen.utføres ifølge i og for seg kjente metoder, f.eks. ved behandling med hydrogenbromid i eddiksyre ved en høyere temperatur (f.eks. 80°C). Step (iii) in formula scheme B' includes the transfer of the methoxy group in a 4-methoxy-2-benzimidazolinone of formula XIII to a hydroxy group whereby a corresponding 4-hydroxy-2-benzimidazolinone of formula XIV is obtained where R 3 represents a hydrogen -atom. This transfer is carried out according to methods known per se, e.g. by treatment with hydrogen bromide in acetic acid at a higher temperature (e.g. 80°C).
En alternativ vei til 4-hydroksy-2-benzimidazolinon med formel XIV består av trinnene (iv), (v), (vi), (vii) og (viii) i formelskjema B. An alternative route to 4-hydroxy-2-benzimidazolinone of formula XIV consists of steps (iv), (v), (vi), (vii) and (viii) of Formula Scheme B.
I trinn(iv) nitreres et 3-nitrofenol med formel XV på i og for seg kjent måte som ved behandling med salpetersyre i nærvær In step (iv) a 3-nitrophenol of formula XV is nitrated in a manner known per se as by treatment with nitric acid in the presence
av svovelsyre hvilket gir det tilsvarende 2,3-dinitrofenol med formel XVI. of sulfuric acid which gives the corresponding 2,3-dinitrophenol of formula XVI.
Et 2,3-dinitrofenol med formel XVI reduseres så i trinn (v) hvilket gir det tilsvarende o-diamin med formel XVII hvor A 2,3-dinitrophenol of formula XVI is then reduced in step (v) which gives the corresponding o-diamine of formula XVII where
representerer et hydrogen-atom. Denne reduksjonen utføres hovedsaklig på samme måten som tidligere beskrevet i forbindelse med reduksjonen-av et.2-metoksy-6-nitroanilin med formel represents a hydrogen atom. This reduction is mainly carried out in the same way as previously described in connection with the reduction of et.2-methoxy-6-nitroaniline with the formula
XI. XI.
Trinn (vi) i formelskjema B omfatter reaksjonen av et 2,3-dinitrofenol med formel XVI med et primært eller sekundært lavere alkylamin (f.eks. metylamin, etylamin, isopropylamin . eller lignende) hvilket gir en forbindelse med formel XVIII. Denne reaksjonen utføres gjerne i nærvær av et inert organisk løsningsmiddel, fortrinnsvis en lavere alkanol som metanol, etanol el. Det foretrekkes å utføre denne reaksjonen ved en høyere temperatur og atmosfærisk trykk. Step (vi) in formula scheme B comprises the reaction of a 2,3-dinitrophenol of formula XVI with a primary or secondary lower alkylamine (eg methylamine, ethylamine, isopropylamine or the like) which gives a compound of formula XVIII. This reaction is usually carried out in the presence of an inert organic solvent, preferably a lower alkanol such as methanol, ethanol or the like. It is preferred to carry out this reaction at a higher temperature and atmospheric pressure.
En forbindelse med formel XVIII hydrogeneres så i trinn (vii) i formelskjema B hvilket gir et o-diamin med formel XIV hvor R representerer en primær eller sekundær lavere alkyl-gruppe. Hydrogeneringen kan utføres på hovedsaklig samme måte som tidligere beskrevet i forbindelse med hydrogeneringen av en forbindelse med formel IX. A compound of formula XVIII is then hydrogenated in step (vii) of formula B which gives an o-diamine of formula XIV where R represents a primary or secondary lower alkyl group. The hydrogenation can be carried out in essentially the same way as previously described in connection with the hydrogenation of a compound of formula IX.
I trinn (viii) omsettes et o-diamin med formel XVII med fosgen hvilket gir det tilsvarende 4-hydroksy-2-benzimidazolinon med formel XIV. Denne reaksjonen utføres under hovedsaklig de samme betingelser som tidligere beskrevet i. forbindelse med reaksjonen av et diamin med formel II med fosgen. Videre er o-diaminer med formel XVII relativt ustabile og omsettes fortrinnsvis in situ (dvs. uten opparbeidelse eller rensning) med fosgen. In step (viii), an o-diamine of formula XVII is reacted with phosgene, which gives the corresponding 4-hydroxy-2-benzimidazolinone of formula XIV. This reaction is carried out under essentially the same conditions as previously described in connection with the reaction of a diamine of formula II with phosgene. Furthermore, o-diamines of formula XVII are relatively unstable and are preferably reacted in situ (ie without work-up or purification) with phosgene.
Et 4-hydroksy-2-benzimidazolinon med formel XIV er nå som erholdes ifølge hver av de forannevnte ruter overføres i trinn (ix) i formelskjema B i det ønskede epoksyd-utgangsmaterialet med formel V med omsetning med et epihalogenhydrid, fortrinnsvis épiklorhydriri i nærvær av et alkalimetall-hydroksyd som natriumhydroksyd eller kaliumhydroksyd, fortrinnsvis natriumhydroksyd. Reakajonen utføres gjerne i nærvær av et vann- A 4-hydroxy-2-benzimidazolinone of formula XIV which is obtained according to each of the aforementioned routes is transferred in step (ix) of formula scheme B into the desired epoxide starting material of formula V by reaction with an epihalohydride, preferably epichlorohydrin, in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. The reaction is preferably carried out in the presence of a water
blandbart inert organisk løsningsmiddel som en lavere alkanol miscible inert organic solvent such as a lower alkanol
(f.eks. metanol, etanol el.) ved en temperatur fra ca 0 C til romtemperatur, fortrinnsvis ved ca.romtemperatur. (e.g. methanol, ethanol etc.) at a temperature from about 0 C to room temperature, preferably at about room temperature.
Amin-utgangsmaterialet med formel IV forut er kjent. Fore-trukne amin-utgangsmaterialer med formel IV er sådanne hvor R representerer et hydrogenatom, spesielt sådanne hvor R 3 representerer en lavere alkyl-gruppe og spesielt en forgrenet lavere alkyl-gruppe som isopropyl eller tert.buty1-gruppen. Videre foretrukne er sådanne amin-utgangsmaterialer hvor R"^ The amine starting material of formula IV above is known. Preferred amine starting materials of formula IV are those where R represents a hydrogen atom, especially those where R 3 represents a lower alkyl group and especially a branched lower alkyl group such as the isopropyl or tert.butyl group. Further preferred are such amine starting materials where R"^
2 2
representerer et hydrogen-atom, R representerer en lavere represents a hydrogen atom, R represents a lower
12 12
cyklo-alkyl-gruppe eller R og R hver for seg representerer en lavere alkyl- eller lavere cykloalkyl-gruppe: Forbindelsene med formelene V, VIII, IX, X, XIII og XIV forut og forbindelsene med formel III i'det foregående hvor R rep-12 3 cycloalkyl group or R and R each represent a lower alkyl or lower cycloalkyl group: The compounds of formulas V, VIII, IX, X, XIII and XIV above and the compounds of formula III above where R represents -12 3
resenterer en lavere alkyl-gruppe og R , R og R har tidligere angitte betydning eller R representerer et hydrogen-atom og R representerer en lavere alkyl-gruppe eller lavere cyklo-2 3 represents a lower alkyl group and R , R and R have previously indicated meaning or R represents a hydrogen atom and R represents a lower alkyl group or lower cyclo-2 3
alkyl-gruppe og R og R har tidligere angitte betydning, er nye og disse forbindelser danner også en bestanddel av foreliggende oppfinnelse. alkyl group and R and R have previously indicated meaning, are new and these compounds also form a component of the present invention.
Benzimidazol-derivatene iølge den foreliggende oppfinnelsen har (3-adrenoceptor-blokkerende aktivitet som ved slike derivater hvor R representerer en lavere alkyl-gruppe generelt følges av lav indre stimulerende aktivitet (ISA). De foreliggende benzimidazol-derivater kan følgelig brukes for pro-fylaks og behandling av sykdommer i hjerte som f.eks. angina pectoris og kardial arrytmi. Den kan også brukes som anti-hypertensive midler. The benzimidazole derivatives according to the present invention have (3-adrenoceptor blocking activity which, in such derivatives where R represents a lower alkyl group, is generally followed by low internal stimulating activity (ISA). The present benzimidazole derivatives can therefore be used for prophylaxis and treatment of diseases of the heart such as angina pectoris and cardiac arrhythmia.It can also be used as anti-hypertensive agents.
Den 3~adrenoceptor-blokkerende virkning til de foreliggende benzimidazolderivater kan demonstreres ved hjelp av standard-metoder. Den 3-adrenoceptor-blokkerende aktivitet in vitro demonstreres ved å bruke reserpiniserte kattungehjerter ifølge den metode som er beskrevet av Kaumann og Birnbaumer, J. Biol. Chem., 249 7874-7885, 1974. Resultatene er uttrykt som I5Q-verdier, nemlig konsentrasjonen i mol av substans som testes The 3-adrenoceptor blocking action of the present benzimidazole derivatives can be demonstrated by standard methods. The 3-adrenoceptor blocking activity in vitro is demonstrated using reserpinized kitten hearts according to the method described by Kaumann and Birnbaumer, J. Biol. Chem., 249 7874-7885, 1974. The results are expressed as I5Q values, namely the concentration in moles of substance being tested
nødvendig for å inhibiere med 50 % den isoprenalin-stimulerte required to inhibit by 50% the isoprenaline-stimulated
økning i adenylyl-cyklase-aktivitet i hjertet. Den 3-adreno- increase in adenylyl cyclase activity in the heart. The 3-adreno-
ceptor-blokkerende aktivitet in vitro demonstreres hos mus ved å bestemme doseringen i mg/kg i.p. av substans som testes ceptor-blocking activity in vitro is demonstrated in mice by determining the dosage in mg/kg i.p. of substance being tested
som er nødvendig for å gi en 50 % reduksjon i isoprenalin-in-dosert tachycardin, hvor denne dosering uttrukkes som ED^q. which is necessary to give a 50% reduction in isoprenaline-dosed tachycardin, where this dosage is extracted as ED^q.
Prøven for ISA utføres ved å bruke hannrotter som har fått deplert perifere katekolamin-lagringer ved behandling med res-erpin (5 mg/kg i.p.) ifølge metoden som er beskrevet av Barrett and Carter, Br. J. Pharmac., 1970, 4_0, 373-381. Resultatene er uttrykt som ED^g, nemlig doseringen av substans som prøves i mg/kg i.v. som gir en økning i hjertehastigheten på 30 slag pr. min. The test for ISA is performed using male rats that have had peripheral catecholamine stores depleted by treatment with res-erpine (5 mg/kg i.p.) according to the method described by Barrett and Carter, Br. J.Pharmac., 1970, 4_0, 373-381. The results are expressed as ED^g, namely the dosage of substance tested in mg/kg i.v. which gives an increase in the heart rate of 30 beats per my.
De erholdte resultater i den foregående prøven ved benyttelse av representative benzimidazol-derivater som tilveiebringes ved foreliggende oppfinnelse og propanolol og pindolol, to velkjente 3_adreOceptor-blokkerende midler, er oppført i de følgende tabeller: The results obtained in the preceding test using representative benzimidazole derivatives provided by the present invention and propanolol and pindolol, two well-known 3-adreOceptor blocking agents, are listed in the following tables:
Tabell II Table II
ISA ISA
Forsøkssubstans - 3-blokkerende aktivitet Test substance - 3-blocking activity
T50( mol) ED- 50 ( mg/ kg i. p.) mg^ gi. v.) T50 ( mol) ED- 50 ( mg/ kg i. p.) mg^ gi. v.)
4-[3-(tert.butyl-4-[3-(tert.butyl-
amino) -2-hydroksy-amino) -2-hydroxy-
propoksy ]-7-metyl-2-benzimidazolinon- propoxy ]-7-methyl-2-benzimidazolinone-
hydroklorid 3,4 x 10~9 0,06 >10 hydrochloride 3.4 x 10~9 0.06 >10
propanolol 36 x 10~<9>0,29 >10 propanolol 36 x 10~<9>0.29 >10
pindolol 5, 2 x 10~ 9 0, 01 0, 005 pindolol 5.2 x 10~ 9 0.01 0.005
Tabell IIITable III
Forsøkssubstans 3-blokkerende aktivitet ISATest substance 3-blocking activity ISA
I5Q( mol) ED5Q( mg/ kg i. p. ) ^ 30,^ . >v>) I5Q( mol) ED5Q( mg/ kg i. p. ) ^ 30,^ . >v>)
1-(tert.butylamino)-1-(tert.butylamino)-
3-(2-merkapt.o-7-3-(2-mercapt.o-7-
metyl-4-benzimi-methyl-4-benzimi-
dazolyloksy)-2-pro-dazolyloxy)-2-pro-
panol-hydroklorid 1,8 x 10~<9>.0,01 >1,Q panol hydrochloride 1.8 x 10~<9>.0.01 >1.Q
propanolol 36 x 10~9 0 ,29 -> 1,0 propanolol 36 x 10~9 0 .29 -> 1.0
pindolol 5, 2' x 10~ 9 0, 01 0, 005 pindolol 5.2' x 10~ 9 0.01 0.005
Det fremgår også at.de farmakologiske data for propanolol og pindolol ikke er identiske i alle tre ovenstående tabeller. Dette forårsakes av det faktum at eksperementene ble. utført i forskjellige serier. It also appears that the pharmacological data for propanolol and pindolol are not identical in all three tables above. This is caused by the fact that the experiments were performed in different series.
Toksisiteten til de foreliggende benzimidazol-derivater er lav, og LDj-q overstiger generelt ikke mer enn 200 mg/kg ved oral-administréring til mus. The toxicity of the present benzimidazole derivatives is low, and the LDj-q generally does not exceed more than 200 mg/kg when administered orally to mice.
Benzimidazol-derivatene som tilveiebringes ved foreliggende oppfinnelse kan brukes som medikamenter, f.eks. i form av The benzimidazole derivatives provided by the present invention can be used as drugs, e.g. in the form of
farmasøytiske preparater som inneholder dem sammen med et fordragelig farmasøytisk bæremateriale. Dette bærematerialet kan være et inert organisk eller uorganisk bæremateriale som er egnet for enteral (f.eks oral) eller parenteral admini-strering. Eksempler på slike bærematerialer er vann, gelatin, talkum, stivelse, magnesiumstearat, gummi arabicum, vegetabile oljer, polyalkylenglykoler, petroleum "jelly" o.l. De farma-søytiske preparatene kan fremstilles på en konvensjonell måte og endelig doseringsformer kan være faste doseringsformer (f.eks. tabletter, drageer, suppositorer,, kapsler etc.) eller flytende doseringsformer (f.eks. løsninger, suspensjoner, emulsjoner etc). De farmasøytiske preparatene kan utsettes for konvensjonelle farmasøytiske operasjoner som sterilisering og/ eller kan inneholde konvensjonelle hjelpestoffer som preserva-tiver, stabilisatorer , fuktemidler, puffere,salter for varia-sjon av osmotisk trykk etc. pharmaceutical preparations containing them together with a tolerable pharmaceutical carrier. This carrier material can be an inert organic or inorganic carrier material which is suitable for enteral (eg oral) or parenteral administration. Examples of such carrier materials are water, gelatin, talc, starch, magnesium stearate, gum arabic, vegetable oils, polyalkylene glycols, petroleum "jelly" and the like. The pharmaceutical preparations can be prepared in a conventional manner and final dosage forms can be solid dosage forms (e.g. tablets, dragees, suppositories, capsules, etc.) or liquid dosage forms (e.g. solutions, suspensions, emulsions, etc.). The pharmaceutical preparations may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional auxiliary substances such as preservatives, stabilisers, wetting agents, buffers, salts for variation of osmotic pressure etc.
Benzimidazol-derivatene som tilveiebringes ved foreliggende oppfinnelse gis gjerne til voksne i en mengde på ca. 5 - 100 mg pr. dag. Det vil være klart at dette doseringsområdet er angitt som eksempel og at det kan varieres oppad eller nedad avhengig av faktorer som det spesielle benzimidazol-derivat som administreres, administreringsruten og pasientens behov slik legen har fastslått det. The benzimidazole derivatives provided by the present invention are preferably given to adults in an amount of approx. 5 - 100 mg per day. It will be clear that this dosage range is given as an example and that it may be varied upwards or downwards depending on factors such as the particular benzimidazole derivative being administered, the route of administration and the patient's needs as determined by the physician.
De følgende eksempler illustrerer fremgangsmåten som tilveiebringes ved foreliggende oppfinnelse. Uttrykket "(DSC)" som brukes i eksemplene i forbindelse med smeltepunkter betyr at smeltepunktene ble bestemt ved "Differential Scanning Calori-metry". The following examples illustrate the method provided by the present invention. The term "(DSC)" used in the examples in connection with melting points means that the melting points were determined by "Differential Scanning Calorimetry".
Eksempel 1 Example 1
(A) 4- hydroksy- 2- benzimidazolinon(A) 4- hydroxy- 2- benzimidazolinone
(i) 10 g 2-metoksy-6-nitroanilin i 160 ml etanol ble hydrogenert ved romtemperatur og atmosfæretrykk over 2,5 g 10 % palladium-på-karbon inntil hydrogenopptaket stoppet. Blandingen ble så filtrert og filtratet inndampet i våkum hvilket ga det ustabile o-diamin, 2,3-diåminoanisol som umiddelbart ble opp-løst i 50 ml 2-N saltsyre og kjølt til 0°C. En langsom fosgen-strøm ble ført gjennom løsningen 2 timer, overskudd fosgen ble. fjernet ved hjelp av en rask nitrogenstrøm og presibytatet ble oppsamlet, vasket med vann og krystallisert fra etanol hvilket ga 7,7 g (79 %) 4-metoksy-2-benzimidazolinon med smeltepunkt 257°-259°C. Analyse for CgHg02N2Beregnet: C: 58.5; H: 4.9; N: 17.0 %; Funnet: C: 58.4; H: 5.2; N: 17.2 %; 20 g 4-metoksy-2-benzimidazolinon i 40 % hydrogenbromid/eddiksyre (200ml) ble oppvarmet ved 80°C i et forseglet rør i 20 timer. Den erholdte løsning ble inndampet til tørrhet i våkum og resten omkrystallisert fra etanol/kloroform hvilket ga 10,95 g (60 %).4-hydroksy-2-benzimidazolinon méd smeltepunkt 285°-287°C. (i) 10 g of 2-methoxy-6-nitroaniline in 160 ml of ethanol was hydrogenated at room temperature and atmospheric pressure over 2.5 g of 10% palladium-on-carbon until hydrogen uptake stopped. The mixture was then filtered and the filtrate evaporated in vacuo to give the unstable o-diamine, 2,3-diaminoanisole which was immediately dissolved in 50 ml of 2-N hydrochloric acid and cooled to 0°C. A slow stream of phosgene was passed through the solution for 2 hours, excess phosgene remaining. removed by a rapid stream of nitrogen and the precipitate collected, washed with water and crystallized from ethanol to give 7.7 g (79%) of 4-methoxy-2-benzimidazolinone mp 257°-259°C. Analysis for CgHgO2N2Calculated: C: 58.5; H: 4.9; N: 17.0%; Found: C: 58.4; H: 5.2; N: 17.2%; 20 g of 4-methoxy-2-benzimidazolinone in 40% hydrogen bromide/acetic acid (200 ml) was heated at 80°C in a sealed tube for 20 hours. The resulting solution was evaporated to dryness in vacuo and the residue recrystallized from ethanol/chloroform which gave 10.95 g (60%). 4-hydroxy-2-benzimidazolinone with melting point 285°-287°C.
Analyse for C^HgC^^Analysis for C^HgC^^
Beregnet: C: 56.0; H: 4.0; N: 18.7 %.Calculated: C: 56.0; H: 4.0; N: 18.7%.
Funnet: C: 55.6; H: 3.9; N: 18.4 %..Found: C: 55.6; H: 3.9; N: 18.4%..
(ii) 10 g 2 ,.3-dinitrof enol i 50 ml etanol ble hydrogenert ved romtemperatur og atmosfærisk trykk over 4 g 10 % palladium-på karbon inntil hydrogenopptaket sluttet. Løsningen ble filtrert og filtratet konsentrert i våkum hvilket ga det ustabile o-diamin, 2,3-diaminofenol, som ble oppløst i 30 ml 2-N saltsyre. (ii) 10 g of 2,.3-dinitroph enol in 50 ml of ethanol was hydrogenated at room temperature and atmospheric pressure over 4 g of 10% palladium-on-carbon until hydrogen uptake ceased. The solution was filtered and the filtrate concentrated in vacuo to give the unstable o-diamine, 2,3-diaminophenol, which was dissolved in 30 ml of 2-N hydrochloric acid.
En langsom fosgenstrøm ble ført gjennom løsningen i 40 min. Det dannede presipitatet ble filtrert fra og rekrystallisért fra etanol/kloroform hvilket ga 4,8 g 4-hydroksy-2-benzimidazolinon som, ifølge infrarødt, kjernemagnetisk resonnans og masse-spéktrdskopisk analyse var identisk med den forbindelse som ble erholdt som beskrevet i del (i) forut. A slow stream of phosgene was passed through the solution for 40 min. The precipitate formed was filtered off and recrystallized from ethanol/chloroform to give 4.8 g of 4-hydroxy-2-benzimidazolinone which, according to infrared, nuclear magnetic resonance and mass spectroscopic analysis, was identical to the compound obtained as described in part ( i) before.
(B) 4-[ 2- hydroksy- 3-( isopropylamino) propoksy]- 2- benzimidazolinon (B) 4-[ 2- hydroxy- 3-( isopropylamino) propoxy]- 2- benzimidazolinone
En løsning av 1,175 g '(0, 0294 mol) natriumhydroksyd in 16 ml vann ble satt til en løsning av 4 g (0,0265 mol) 4-hydroksy-2-benzimidazolinon i 24 ml metanol. 4.16 g (0,045 mol) epy-klorhydrin ble så tilsatt og den resulterende, løsning fikk stå ved romtemperatur i 17 timer. Hovedmengden av metanolen ble fjernet ved inndampning i våkum og resten ble ekstrahert med etylasetat. De organiske ekstrakter ble vasket med vann og inndampet til tørrhet i våkum ved romtemperatur hvilket ga 2,5 g av epoksydet, 4-(2,3-epoksypropoksy)-2-benzimidazolinon, som øyeblikkelig ble behandlet med et overskudd isopropylamin (25 ml). Blandingen fikk stå ved romtemperatur i 48 timer. Løsningen ble inndampet til tørrhet i våkum og resten kromatografert på 250 g kisel-gel i etanol/trietylamin/isopropylamin/kloroform (100:40:1:259) hvilket ga 0,19 g (2,7 %) 4- [-hydroksy-3-(isopropylamino)propoksy]-2-benzimidazolinon i form av en olje. Behandling av denne ol jen.med etanolisk saltsyre ga 4-/2-hydroksy-3-(isopropylamino)propoksy]-2-benzimidazolinon-hydroklorid som ble omkrystallisert fra isopropanol/dietyleter og som ifølge infrarød og massespektroskopisk analyse var identisk med det erholdte produkt ifølge eksempel 2 (B) i det følgende. A solution of 1.175 g (0.0294 mol) of sodium hydroxide in 16 ml of water was added to a solution of 4 g (0.0265 mol) of 4-hydroxy-2-benzimidazolinone in 24 ml of methanol. 4.16 g (0.045 mol) of epichlorohydrin was then added and the resulting solution was allowed to stand at room temperature for 17 hours. The bulk of the methanol was removed by evaporation in vacuo and the residue was extracted with ethyl acetate. The organic extracts were washed with water and evaporated to dryness in vacuo at room temperature to give 2.5 g of the epoxide, 4-(2,3-epoxypropoxy)-2-benzimidazolinone, which was immediately treated with an excess of isopropylamine (25 mL) . The mixture was allowed to stand at room temperature for 48 hours. The solution was evaporated to dryness in vacuo and the residue chromatographed on 250 g of silica gel in ethanol/triethylamine/isopropylamine/chloroform (100:40:1:259) which gave 0.19 g (2.7%) of 4-[-hydroxy -3-(isopropylamino)propoxy]-2-benzimidazolinone in the form of an oil. Treatment of this oil with ethanolic hydrochloric acid gave 4-(2-hydroxy-3-(isopropylamino)propoxy)-2-benzimidazolinone hydrochloride which was recrystallized from isopropanol/diethyl ether and which, according to infrared and mass spectroscopic analysis, was identical to the product obtained according to example 2 (B) below.
eksempel 2example 2
( A) 2, 3- dinitrofenyl 2, 3- epoksypropyl- eter(A) 2,3-dinitrophenyl 2,3-epoxypropyl ether
30 g 2,3-dinitrofenol, 90 g epiklorhydrin og 2,5 ml piperidin ble oppvarmet ved 80°C i 17,5 timer. Løsningen ble inndampet til tørrhet i våkum inntil oljen størknet. 90 ml 2-N natriumhydroksyd-løsning ble så tilsatt til en kraftig rørt oppløsning av det faste stoffet i 60 ml dioksan og den resulterende løs-ning ble rørt ved romtemperatur i en time. Presipitatet ble oppsamlet, vasket godt med vann og tørket i våkum, i 6 0°G. 30 g of 2,3-dinitrophenol, 90 g of epichlorohydrin and 2.5 ml of piperidine were heated at 80°C for 17.5 hours. The solution was evaporated to dryness in vacuo until the oil solidified. 90 ml of 2-N sodium hydroxide solution was then added to a vigorously stirred solution of the solid in 60 ml of dioxane and the resulting solution was stirred at room temperature for one hour. The precipitate was collected, washed well with water and dried in vacuum at 60°C.
Det ble oppnådd 35,0 g (89 %) rått 2,3-dinitrofenyl 2,3-epoksyprdpyl-eter med smeltepunkt 86°-89°C som var tilstrekke-lig rent for bruk i det neste trinnet. En prøve . ble omkrystallisert fra kloroform/dietyl-eter og ga 2,3-dinitrofenyl 2,3-epoksypropy1-eter med smeltepunkt 95°-97°C. 35.0 g (89%) of crude 2,3-dinitrophenyl 2,3-epoxypropyl ether with melting point 86°-89°C was obtained which was sufficiently pure for use in the next step. A sample . was recrystallized from chloroform/diethyl ether to give 2,3-dinitrophenyl 2,3-epoxypropyl ether m.p. 95°-97°C.
Analyse for CgHg06N2Analysis for CgHg06N2
Beregnet: C: 4 5.0; H:3.4; N: 11.7 %. Calculated: C: 4 5.0; H: 3.4; N: 11.7%.
Funnet: C: 44.6; H:3.3; N: 11.4 %.Found: C: 44.6; H: 3.3; N: 11.4%.
(B 4- [ 2- hydroksy- 3- (- isopropylamino) propoksy] - 2- benzimidazolinon hydroklorid 20 g (0 . 083 mol) 2 ,3-dinitrofenyl 2 , 3-epoksypropyl-eter ble oppløst i 500 ml varm etanol og løsningen ble dekantert fra en liten mengde uløselig rest. 18,4 g (0,123 mol) N-isopropylben-zylamin ble tilsatt og løsningen ble oppvarmet ved 50°C i 16 timer. Den avkjølte løsningen ble hydrogenert ved romtemperatur og atmosfærisk trykk over 7 g 10 % palladium-på-karbon-katalysator inntil opptaket av hydrogen opphørte. Løsningen ble filtrert og filtratet inndampet til tørrhet i våkum hvilket ga diaminét, 3-(2,3-diaminofenoksy)-1-(isopropylamino)-2-propanol, funnet m/e 239,<c>i2H21°2<N>3 kreverM'239^ som øyeblikkelig ble oppløst i 100 ml 2-N saltsyre. Løsningen ble kjølt til 0°C og rørt mens en strøm fosgen ble blåst igjennom i 45 min. Fosgenoverskuddet ble fjernet ved å blåse gjennom en kraftig nitrogenstrøm i løsningen som deretter ble fordampet til tørrhet i våkum. Resten ble omkrystallisert fra isopropanol/dietyleter hvilket ga 11,27 g (45 %) 4-[2-hydroksy-3-(isopropylamino)propoksy] -2-benz imidazolinon-hydroklorid med smeltepunkt (DSC) 232°C. (B 4-[2-hydroxy-3-(-isopropylamino)propoxy]-2-benzimidazolinone hydrochloride 20 g (0.083 mol) of 2,3-dinitrophenyl 2,3-epoxypropyl ether was dissolved in 500 ml of hot ethanol and the solution was decanted from a small amount of insoluble residue. 18.4 g (0.123 mol) N-isopropylbenzylamine was added and the solution was heated at 50° C. for 16 hours. The cooled solution was hydrogenated at room temperature and atmospheric pressure above 7 g 10% palladium-on-carbon catalyst until hydrogen uptake ceased.The solution was filtered and the filtrate evaporated to dryness in vacuo to give the diamine, 3-(2,3-diaminophenoxy)-1-(isopropylamino)-2-propanol, found m/e 239,<c>i2H21°2<N>3 requires M'239^ which was immediately dissolved in 100 ml of 2-N hydrochloric acid.The solution was cooled to 0°C and stirred while a stream of phosgene was blown through for 45 min .The excess phosgene was removed by blowing through a strong stream of nitrogen into the solution which was then evaporated to dryness in vacuo.The residue was recrystallized from isopr opanol/diethyl ether yielding 11.27 g (45%) of 4-[2-hydroxy-3-(isopropylamino)propoxy]-2-benz imidazolinone hydrochloride with melting point (DSC) 232°C.
Analyse for C]_3Hi9°3N3-HC1Analysis for C]_3Hi9°3N3-HCl
Beregnet: C: 51,8; H: 6,7; N: 13,9; Cl: 11,8 %. Calculated: C: 51.8; H: 6.7; N: 13.9; Cl: 11.8%.
Funnet: C: 51,9; H: 6,9; N: 13,6; Cl: 12,2 %. Found: C: 51.9; H: 6.9; N: 13.6; Cl: 12.2%.
Eksempel 3 Example 3
4- [ 3- ( tert . butylamino) - 2- hydroksypropoksy] - 2- be. nzimidazolinon-hydroklorid 4- [ 3- ( tert . butylamino) - 2- hydroxypropoxy] - 2- be. nzimidazolinone hydrochloride
20 g 2,3-dinitrofenyl 2,3-epoksypropyl-eter ble oppløst i 400 ul etanol slik det er beskrevet i eksempel 2(B). 100 ml tert. butylamin ble tilsatt og løsningen fikk stå ved romtemperatur i 18 timer. Inndampning.av løsningen i. våkum og krystallisasjon av resten fra isopropanol ga 17,2 g (66 %) 1-(tert.butylamino)-3-(2,3-dinitrofenoksy)-2-propanol med smeltepunkt. 120°-122°C. | 20 g of 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 400 ul of ethanol as described in example 2(B). 100 ml tart. butylamine was added and the solution was allowed to stand at room temperature for 18 hours. Evaporation of the solution in vacuo and crystallization of the residue from isopropanol gave 17.2 g (66%) of 1-(tert.butylamino)-3-(2,3-dinitrophenoxy)-2-propanol with melting point. 120°-122°C. |
t t
Analyse for C]_3Hi9°gN3Analysis for C]_3Hi9°gN3
Beregnet: C: 49,8; H: 6,1; N: 13,4 %. Calculated: C: 49.8; H: 6.1; N: 13.4%.
Funnet: C: 49/9; H: 6,0; N: 13,5Found: C: 49/9; H: 6.0; N: 13.5
5,1 g 1-(tert.butylamino)-3-(2,3-dinitrofenoksy)-2-propanol i 100 ml etanol ble hydrogenert ved romtemperatur og atmosfæretrykk over 2,5 g 10 % palladium-på-karbon-katalysator inntil hydrogenopptaket sluttet. Løsningen ble filtrert, og filtratet inndampet i våkum og resten, 1-(tert.butylamino)-3-(2,3-diamino-fenoksy)-2-propanol umiddelbart oppløst i 50 ml 2-N saltsyre. Løsningen ble kjølt til 0°C og en langsom fosgenstrøm ble blåst igjennom i 45 min. Fosgenoverskuddet ble fjernet ved hjelp av en nitrogenstrøm. Løsningen ble inndampet til tørrhet i våkum og resten omkrystallisert fra isopropanol/diety1-eter hvilket ga 2,9 g (56,3 %) 4-^3-(tert.butylamino)-2-hydroksypropoksy]-2-benzimidazolinon-hydroklorid med smeltepunkt (DSC) 263°C. 5.1 g of 1-(tert.butylamino)-3-(2,3-dinitrophenoxy)-2-propanol in 100 ml of ethanol was hydrogenated at room temperature and atmospheric pressure over 2.5 g of 10% palladium-on-carbon catalyst until hydrogen uptake ceased. The solution was filtered, and the filtrate evaporated in vacuo and the residue, 1-(tert.butylamino)-3-(2,3-diamino-phenoxy)-2-propanol immediately dissolved in 50 ml of 2-N hydrochloric acid. The solution was cooled to 0°C and a slow stream of phosgene was blown through for 45 min. The excess phosgene was removed using a stream of nitrogen. The solution was evaporated to dryness in vacuo and the residue recrystallized from isopropanol/diethyl ether yielding 2.9 g (56.3%) of 4-[3-(tert.butylamino)-2-hydroxypropoxy]-2-benzimidazolinone hydrochloride with melting point (DSC) 263°C.
Analyse for C]_4H2i°3N3-HC1Analysis for C]_4H2i°3N3-HC1
Beregnet: C: 53,3; H: 7,0; N: 13,3; Cl: 11., 2 %. Calculated: C: 53.3; H: 7.0; N: 13.3; Cl: 11., 2%.
Funnet: C: 53,1; H: 7,3; N:13,4; Cl: 11,6%. Found: C: 53.1; H: 7.3; N: 13.4; Cl: 11.6%.
Eksempel 4Example 4
4- [ 2- hydroksy- 3- ( métylamino) propoksy] - 2- benzimida. zolinon- hydroklorid 10 g (0,042 mol) 2,3-dinitrofenyl 2 , 3-epoksypropyl-eter,ble oppløst i 250 ml varm etanol som beskrevet i eksempel 2 (B). 7,56 g (0,0625 mol) N-metylbenzylamin ble tilsatt og løsningen fikk stå ved romtemperatur i 70 timer. Løsningen ble så hydrogenert over lO % palladium-på-karbon som beskrevet i eksempel 2 (B) og det resulterende diamin, 3-(.2 , 3-diaminof enoksy)--1-(métylamino)-2-propanol ble umiddelbart.omsatt, i 100 ml 2-N saltsyre med fosgen likeledes på samme måte som beskrevet i eksempel 2 (B). - Produktet ble omkrystallisert fra etanol/diet-yl-eter hvilket ga 5,36 g (47 %) 4-[2-hydroksy-3-(métylamino)-propoksy]-2-benzimidazolinon-hydroklorid med smeltepunkt 218°-220°C. 4-[2-hydroxy-3-(methylamino)propoxy]-2- benzimide. zolinone hydrochloride 10 g (0.042 mol) of 2,3-dinitrophenyl 2,3-epoxypropyl ether was dissolved in 250 ml of hot ethanol as described in example 2 (B). 7.56 g (0.0625 mol) of N-methylbenzylamine was added and the solution was allowed to stand at room temperature for 70 hours. The solution was then hydrogenated over 10% palladium-on-carbon as described in Example 2 (B) and the resulting diamine, 3-(.2,3-diaminophenoxy)--1-(methylamino)-2-propanol was immediately. reacted, in 100 ml of 2-N hydrochloric acid with phosgene likewise in the same way as described in example 2 (B). - The product was recrystallized from ethanol/diethyl ether which gave 5.36 g (47%) of 4-[2-hydroxy-3-(methylamino)-propoxy]-2-benzimidazolinone hydrochloride with melting point 218°-220° C.
Analyse for ci_]_<H>]_5°3<N>3-<H>C1Analysis for ci_]_<H>]_5°3<N>3-<H>C1
Beregnet: C:48,3; H:5,9; N:15,4%.Calculated: C:48.3; H: 5.9; N: 15.4%.
Funnet: C: 48,2; H: 5,9; N: 15,3 %. | Found: C: 48.2; H: 5.9; N: 15.3%. |
Eksempel 5 Example 5
4- [ 2- hydroksy- 3- ( N- metylcykloheksylamino) propoksy] -, 2- benzimidazolinon- hydroklorid- hemihydrat 10 g (0,042 mol) 2,3-dinitrofenyl 2,3-epoksypropyl-eter ble oppløst i 250 ml varm etanol, som beskrevet i eksempel 2(B). 4- [ 2- hydroxy- 3-( N- methylcyclohexylamino) propoxy] -, 2- benzimidazolinone hydrochloride hemihydrate 10 g (0.042 mol) of 2,3-dinitrophenyl 2,3-epoxypropyl ether was dissolved in 250 ml of hot ethanol , as described in Example 2(B).
5,18 g (0,046 mol) N-metylcykloheksylamin ble tilsatt og løsningen fikk stå ved romtemperatur 36 timer. Løsningen ble så hydrogenert over 10 % palladium-på-karbon som beskrevet i eksempel 2(B) hvilket ga 3-(2,3-diaminofenoksy)-1-(N-metyleyklo-heksylamino)-2-propanol som umiddelbart ble omsatt i 100 ml.2-N saltsyre med fosgen, også på samme måte som beskrevet i eksempel 2(B). Omkrystallisasjon av resten fra isopropanol/diety1-2ter ga .7,44 g (49 %) 4-[2-hydroksy-3-'(N-metylcykloheksylamino) propoksy]-2-benzimidazolinon-hydroklorid-hemihydrat med smeltepunkt (DSC) høyere enn 288°C (dekomponeringspunkt). 5.18 g (0.046 mol) of N-methylcyclohexylamine was added and the solution was allowed to stand at room temperature for 36 hours. The solution was then hydrogenated over 10% palladium-on-carbon as described in Example 2(B) giving 3-(2,3-diaminophenoxy)-1-(N-methylcyclohexylamino)-2-propanol which was immediately reacted in 100 ml. 2-N hydrochloric acid with phosgene, also in the same way as described in example 2(B). Recrystallization of the residue from isopropanol/diethyl ether gave 7.44 g (49%) of 4-[2-hydroxy-3-(N-methylcyclohexylamino)propoxy]-2-benzimidazolinone hydrochloride hemihydrate with melting point (DSC) higher than 288°C (decomposition point).
Analyse for<c>i7<H>25°3<N>3-<H>C1-°"5H2°Analysis for<c>i7<H>25°3<N>3-<H>C1-°"5H2°
Beregnet: C: 55,9; H: 7,5; N: 11,5 %.Calculated: C: 55.9; H: 7.5; N: 11.5%.
Funnet: C: 55,9; H: 7,3; N: 11,3 %.Found: C: 55.9; H: 7.3; N: 11.3%.
Eksempel 6 Example 6
4-[ 3-( dicyklopentylamino)- 2- hydroksypropoksy]- 2- benzimidazolinon- hydroklorid- hemihydrat 4-[ 3-(dicyclopentylamino)- 2- hydroxypropoxy]- 2- benzimidazolinone- hydrochloride- hemihydrate
8,5 g 2,3-dinitrofenyl 2,3-epoksypropyl-eter ble oppløst i 250 ml varm etanol som beskrevet i eksempel 2(B). 15 g kaliumkarbonat og 7,5 g dicyklopentylamin-hydroklorid ble tilsatt og løsningen blé oppvarmet ved 60°C i 18 timer. Løsningen ble filtrert, filtratet inndampet til tørrhet i våkum og resten ekstrahert med kloroform. Kloroformekstraktet ble vasket med vann, tørket og inndampet til tørrhet i våkum. Resten ble krystallisert fra kloroform/n-heksan hvilket ga 6,2 g 1-(dicyklopentylamino) -3-(2,3-dinitrofenoksy)-2-propanol med smeltepunkt 130°-133°C. 8.5 g of 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 250 ml of hot ethanol as described in example 2(B). 15 g of potassium carbonate and 7.5 g of dicyclopentylamine hydrochloride were added and the solution was heated at 60°C for 18 hours. The solution was filtered, the filtrate evaporated to dryness in vacuo and the residue extracted with chloroform. The chloroform extract was washed with water, dried and evaporated to dryness in vacuo. The residue was crystallized from chloroform/n-hexane which gave 6.2 g of 1-(dicyclopentylamino)-3-(2,3-dinitrophenoxy)-2-propanol with melting point 130°-133°C.
Analyse for<C>]_9<H>27<N>3°6Analysis for<C>]_9<H>27<N>3°6
Beregnet: C: 58,0; H: 6,9; N:10,7 %J M<+>393. j Funnet: , C: 57,9; H: 7,0; N:10,6 %; m/3 393. Calculated: C: 58.0; H: 6.9; N: 10.7%J M<+>393. j Found: , C: 57.9; H: 7.0; N: 10.6%; w/3 393.
5,05 g 1-(dicyklo<p>entylamino)-3-(2,3-dinitropfenoksy)-2-propanol i 100 ml etanol ble hydrogenert ved romtemperatur og 5.05 g of 1-(dicyclo<p>entylamino)-3-(2,3-dinitropephenoxy)-2-propanol in 100 ml of ethanol were hydrogenated at room temperature and
atmosf æretrykk over 2,0 g 10 % palladium-på-ka.rbon inntil . hydrogenopptaket opphørte. Blandingen ble filtrert og filtratet inndampet i våkum hvilket ga 3-(2,3-diaminofenoksy)—1-(dicyklopentylamino) -2-propanol som umiddelbart ble oppløst i. 50 ml 2-N saltsyre og avkjølt til 0°C. En langsom fosgenstrøm ble ført gjennom løsningen i 45 min., fosgenoverskuddet ble fjernet ved hjelp av en nitrogenstrøm. Løsningen ble inndampet til tørrhet i våkum og resten krystallisert fra isopropanol/diety 1-eter hvorved man oppnådde 4,25 g (69,5 %) 4-[3-(diclyklopentylamino)-2-hydroksypropoksyJ-2-benzimidazolinon-hydroklorid-hemihydrat med smeltepunkt (DSC) høyere enn.308°C (dekomponeringspunkt). atmospheric pressure above 2.0 g 10% palladium-on-carbon up to . hydrogen uptake ceased. The mixture was filtered and the filtrate evaporated in vacuo to give 3-(2,3-diaminophenoxy)-1-(dicyclopentylamino)-2-propanol which was immediately dissolved in 50 ml of 2-N hydrochloric acid and cooled to 0°C. A slow stream of phosgene was passed through the solution for 45 min., the excess phosgene was removed by means of a stream of nitrogen. The solution was evaporated to dryness in vacuo and the residue crystallized from isopropanol/diethyl ether, whereby 4.25 g (69.5%) of 4-[3-(diclyclopentylamino)-2-hydroxypropoxyJ-2-benzimidazolinone hydrochloride hemihydrate was obtained with melting point (DSC) higher than 308°C (decomposition point).
Analyse for C2QH2gN303.HC1.O5H20Analysis for C2QH2gN3O3.HC1.O5H20
Beregnet: C: 5 9,3; H: 7,7; N: 10,4; Cl: 8,8%.Calculated: C: 5 9.3; H: 7.7; N: 10.4; Cl: 8.8%.
Funnet: C: 59,5; H: 7,8; N: 10,4; Cl: 9,5 %.Found: C: 59.5; H: 7.8; N: 10.4; Cl: 9.5%.
Eksempel 7 Example 7
4-[ 3-( dietylamino)- 2- hydroksypropoksy]- 2- benzimidazolinon-hydroklorid 4-[ 3-(diethylamino)- 2- hydroxypropoxy]- 2- benzimidazolinone hydrochloride
4,0 g 2,3-dinitrofenyl 2,3-epoksypropyl-éter ble oppløst i 100 ml varm etamol som beskrevet i eksempel 2(B). Løsningen ble behandlet med 6,1 g dietylamin og den resulterende løsning fikk stå ved romtemperatur i 24 timer. Løsningen ble så inndampet til tørrhet i våkum og resten ble hydrogenert i 50 ml etanol ved romtemperatur og atmosfæretrykk over 1 g 10 % palladium-på -karbon inntil hydrogenopptaket opphørte. Blandingen ble filtrert og filtratet inndampet i våkum hvilket ga 3-(2,3-diamino-fenoksy)-1-(dietylamino)-2-pro<p>anol som umiddelbart ble. opp-løst i 30 ml 2-N saltsyre, avkjølt til 0°C og benhandlet med en langsom fosgenstrøm i 40 min, fosgenoverskuddet' ble fjernet ved hjelp av en nitrogenstrøm. Filtrering av løsningen, inndamping av filtratet til tørrhet i våkum<p>g omkrystallisas jon av resten fra etanol/dietyl-eter ga 2,6 g (49 4-[3-(dietyl-amino) -2-hydroksypropoksy]-2-benzimidazolinon-hydroklorid med 4.0 g of 2,3-dinitrophenyl 2,3-epoxypropyl ether was dissolved in 100 ml of hot ethanol as described in example 2(B). The solution was treated with 6.1 g of diethylamine and the resulting solution was allowed to stand at room temperature for 24 hours. The solution was then evaporated to dryness in vacuo and the residue was hydrogenated in 50 ml of ethanol at room temperature and atmospheric pressure over 1 g of 10% palladium-on-carbon until hydrogen absorption ceased. The mixture was filtered and the filtrate evaporated in vacuo to give 3-(2,3-diamino-phenoxy)-1-(diethylamino)-2-pro<p>anol which immediately became. dissolved in 30 ml of 2-N hydrochloric acid, cooled to 0°C and treated with a slow stream of phosgene for 40 min, the excess phosgene was removed by means of a stream of nitrogen. Filtration of the solution, evaporation of the filtrate to dryness in vacuo<p>g recrystallization of the residue from ethanol/diethyl ether gave 2.6 g (49 4-[3-(diethyl-amino)-2-hydroxypropoxy]-2- benzimidazolinone hydrochloride with
'smeltepunkt (DSC) 247°C. melting point (DSC) 247°C.
Analyse for<c>i4<H>2i°3N3•HC1Analysis for<c>i4<H>2i°3N3•HC1
Beregnet: C: 53,2; H: 7,0; N:'13,3.%. Calculated: C: 53.2; H: 7.0; N:'13.3.%.
Funnet: C: 53,5; H: 6,9; N: 13,5 %.. Found: C: 53.5; H: 6.9; N: 13.5%..
Eksempel 8 Example 8
4-[ 3-( cykloheksylamino)- 2- hydroksypropoksy3- 2- benzimidazolinon-hydroklorid 5 g (0,021 mol) 2,3-dinitrofenyl 2,3-epoksypropyl-éter ble opp-løst i 100 ml varm etanol som beskrevet i eksempel 2(B). Løs-ningen ble kjølt, behandlet med 12,25 g (0,124 mol) cykloheksyl-amino og fikk stå ved romtemperatur i 2 4 timer. Løsningen ble inndampet til tørrhet i våkum og resten hydrogenert i 100 ml etanol.ved romtemperatur og atmosfæretrykk over 3,5 g 10 %palladium-på-karbon inntil hydrogenopptaket opphørte. Blandingen ble filtrert og filtratet inndampet til tørrhet i våkum hvilket ga 1-(cykloheksylamino)-3-(2,3-diaminofenoksy)-2-propanol som umiddelbart ble oppløst i 50 ml 2-N saltsyre, kjølt til 0°C og behandlet med en langsom fosgenstrøm i 45 min. idet fosgenoverskuddet ble fjernet ved hjelp av en nitrogenstrøm. Filtrering, inndamping av filtratet til tørrhet i våkum og om-krystallisasjon av resten fra etanol/dietyl-eter ga 1,7 g (23,9 %) 4-[3-(cykloheksylamino)-2-hydroksypropoksy]-2-benzimidazolinon-hydroklorid med smeltepunkt (DSC) 224°C. 4-[3-(cyclohexylamino)-2-hydroxypropoxy3-2-benzimidazolinone hydrochloride 5 g (0.021 mol) 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 100 ml of hot ethanol as described in example 2 (B). The solution was cooled, treated with 12.25 g (0.124 mol) cyclohexylamino and allowed to stand at room temperature for 24 hours. The solution was evaporated to dryness in vacuo and the residue hydrogenated in 100 ml of ethanol at room temperature and atmospheric pressure over 3.5 g of 10% palladium-on-carbon until hydrogen absorption ceased. The mixture was filtered and the filtrate evaporated to dryness in vacuo to give 1-(cyclohexylamino)-3-(2,3-diaminophenoxy)-2-propanol which was immediately dissolved in 50 ml of 2-N hydrochloric acid, cooled to 0°C and treated with a slow stream of phosgene for 45 min. as the excess phosgene was removed by means of a stream of nitrogen. Filtration, evaporation of the filtrate to dryness in vacuo and recrystallization of the residue from ethanol/diethyl ether gave 1.7 g (23.9%) of 4-[3-(cyclohexylamino)-2-hydroxypropoxy]-2-benzimidazolinone- hydrochloride with melting point (DSC) 224°C.
Analyse for C,,H0,0oNo.HC1Analysis for C,,H0,0oNo.HC1
16 2 3 3 3 16 2 3 3 3
Beregnet: C: 56,2; H: 7,1; N: 12,3; Cl: 10,4 %. Calculated: C: 56.2; H: 7.1; N: 12.3; Cl: 10.4%.
Funnet: C: 55,9; H: 7,2; N: 11,9; Cl: 10,2 %. Found: C: 55.9; H: 7.2; N: 11.9; Cl: 10.2%.
Eksempel 9 Example 9
4-[ 3-( cykloheksylamino)- 2- hydroksypropoksy]- 2- benzimidazolinon-hydroklorid 4-[ 3-( cyclohexylamino)- 2- hydroxypropoxy]- 2- benzimidazolinone hydrochloride
5 g 2,3-dinitrofenyl 2,3-epoksypropyl-eter i etanol ble behandlet med 4,3 g N^benzylcykloheksylamin og løsningen ble oppvarmet ved 80°C i 48 timer. Løsningen ble så hydrogenert som beskrevet i eksempel 8 og hydrogeneringsproduktet ble omsatt med fosgen og opparbeidet liksom beskrevet i eksempel 8. Krystallisajonen avj d4e-t [3-rceyskullotheerkensyde lampriondou)k-2t -hfyrda roektasynoplro/dpoiketsyy]1--e2t-beer ngza im2id,a7 zog li(n3o7n,-5<%>) 5 g of 2,3-dinitrophenyl 2,3-epoxypropyl ether in ethanol was treated with 4.3 g of N-benzylcyclohexylamine and the solution was heated at 80°C for 48 hours. The solution was then hydrogenated as described in example 8 and the hydrogenation product was reacted with phosgene and worked up as described in example 8. im2id,a7 zog li(n3o7n,-5<%>)
hydroklorid som ble vist ved massespektroskopisk analyse som er identisk med det produkt som er fremstilt som beskrevet i eksempel 8 . hydrochloride which was shown by mass spectroscopic analysis to be identical to the product prepared as described in example 8.
Eksempel 10 Example 10
4- l 2- hydroksy- 3-( n- propylamino) propoksy]- 2- benzimidazolinon- hydroklorid 4- 1 2- hydroxy- 3-( n- propylamino) propoxy]- 2- benzimidazolinone hydrochloride
4,2 g (0,0175 mol) 2,3-dinitrofenyl 2,3-epoksypropyl-eter og 4,1 g (0,0275 mol) n-propylbenzylamin ble oppløst i 100 ml etanol og blandingen fikk stå ved romtemperatur i 90 timer. Blandingen ble så hydrogenert som beskrevet i eksempel 2(B) og produktet , 3-(2,3-diaminofenoksy)-1-(n-propylamino)-2-propanol, umiddelbart omsatt med fosgen også som beskrevet i eksempel 2(B). Det erholdte produkt ble omkrystallisert fra etanol/isopropanol hvilket ga 3,4 g (64,5 %) 4-[2-hydroksy-3-(n-propylamino)pro-poksyj-2-benzimidazolinon-hydroklorid med smeltepunkt 264°-267°C. 4.2 g (0.0175 mol) of 2,3-dinitrophenyl 2,3-epoxypropyl ether and 4.1 g (0.0275 mol) of n-propylbenzylamine were dissolved in 100 ml of ethanol and the mixture was allowed to stand at room temperature for 90 hours. The mixture was then hydrogenated as described in example 2(B) and the product, 3-(2,3-diaminophenoxy)-1-(n-propylamino)-2-propanol, immediately reacted with phosgene also as described in example 2(B) . The product obtained was recrystallized from ethanol/isopropanol which gave 3.4 g (64.5%) of 4-[2-hydroxy-3-(n-propylamino)propoxyj-2-benzimidazolinone hydrochloride with melting point 264°-267 °C.
Analyse for ci3Hi9°3<N>3-<H>ClAnalysis for ci3Hi9°3<N>3-<H>Cl
Beregnet: C: 51,8; H: 6,6; N: 13,9 %. Calculated: C: 51.8; H: 6.6; N: 13.9%.
Funnet: C: 51 , 5 ; H : 6 , 7 ; N:13,5%.Found: C: 51 , 5 ; H: 6, 7; N: 13.5%.
Eksempel 11Example 11
( A) 4-( 2, 3- epoksypropoksy)- 2, 3- dinitrotoluen( A) 4-( 2, 3- epoxypropoxy)- 2, 3- dinitrotoluene
34,8 g 2,3-dinitro-p-cresol i 100 g epiklorohydrin og 3 ml piperid'in ble oppvarmet ved 80°C i 20 timer. Løsningen ble inndampet til tørrhet i våkum og resten oppløst i 60 ml dioksan. Den kraftig rørte løsningen ble tilsatt 90 ml 2-N natriumhydroksyd og den resulterende løsning ble rørt i 1 time ytterligere. Produktet ble oppsamlet, vasket godt med vann og lufttørket hvorved man fikk 40,2 g 4-(2,3-epoksypropoksy)-2,3-dinitrotoluen med smeltepunkt 118°-120°C. En omkrystallisert prøve fra etanol smeltet ved 123°-125°C. 34.8 g of 2,3-dinitro-p-cresol in 100 g of epichlorohydrin and 3 ml of piperidine were heated at 80°C for 20 hours. The solution was evaporated to dryness in vacuo and the residue dissolved in 60 ml of dioxane. To the vigorously stirred solution was added 90 ml of 2-N sodium hydroxide and the resulting solution was stirred for an additional 1 hour. The product was collected, washed well with water and air dried, whereby 40.2 g of 4-(2,3-epoxypropoxy)-2,3-dinitrotoluene with a melting point of 118°-120°C was obtained. A recrystallized sample from ethanol melted at 123°-125°C.
Analyse for c^oH10°6N2 Analysis for c^oH10°6N2
Beregnet: C: 47,25; H: 3,95; N: 11,0 %.Calculated: C: 47.25; H: 3.95; N: 11.0%.
Funnet: C:47,l; H:3,95; N: 10,9 %.Found: C:47,1; H: 3.95; N: 10.9%.
( B) 1-( tert. butylamino)- 3-( 2, 3- dinitro- p- tolyloksy)- 2- propanol 20 g 4-(2,3-epoksypropoksy)-2,3-dinitrotoluen . i 750 ml etanol ble omsatt med 100 ml. tert.butylamin ved romtemperatur i 48 timer. Løsningen ble inndampet til tørrhet i våkum og det erholdte krystallinske produkt ble omkrystallisert fra isopropanol hvilket ga 22,6 g 1-(tert.butylamino)-3-(2,3-dinitro-p-tolyloksy ) -2-propanol med smeltepunkt 117°-119°C. (B) 1-(tert.butylamino)-3-(2,3-dinitro-p-tolyloxy)-2-propanol 20 g 4-(2,3-epoxypropoxy)-2,3-dinitrotoluene. in 750 ml of ethanol was reacted with 100 ml. tert.butylamine at room temperature for 48 hours. The solution was evaporated to dryness in vacuo and the crystalline product obtained was recrystallized from isopropanol, which gave 22.6 g of 1-(tert.butylamino)-3-(2,3-dinitro-p-tolyloxy)-2-propanol with a melting point of 117 °-119°C.
Analyse for C]_4H21^6<N>3Analysis for C]_4H21^6<N>3
Beregnet: C: 51,4; H: 6,45; N: 12,85 %.Calculated: C: 51.4; H: 6.45; N: 12.85%.
Funnet: C:.51,l;. H: 6,45; N: 12,8 %.Found: C:.51,l;. H: 6.45; N: 12.8%.
( C) 4-[ 3-( tert. butylamino)- 2- hydroksypropoksy]- 7- metyl- 2- benzimidazolinon- hydroklorid ( C) 4-[ 3-( tert. butylamino)- 2- hydroxypropoxy]- 7- methyl- 2- benzimidazolinone hydrochloride
(a) 4,7 g 1-(tert.butylamino)-3-(2,3-dinitro-p-tolyloksy)-2-propanol i 75 ml etanol ble hydrogenert ved romtemperatur og (a) 4.7 g of 1-(tert.butylamino)-3-(2,3-dinitro-p-tolyloxy)-2-propanol in 75 ml of ethanol was hydrogenated at room temperature and
atmosfæretrykk over 1,5 g 10 % palladiuro-på-karbon inntil hydrogenopptaket opphørte. Blandingen ble filtrert og filtratet inndampet til tørrhet hvilket ga det ustabile o-diaminet, l-(tert-butylamino)-3-(2,3-diamino-p-tolyloksy^-2-propanol som umiddelbart ble oppløst i 50 ml 2-N saltsyre ved romtemperatur. En langsom fosgenstrøm'ble ført gjennom løsningen i 1 time og fos-genet ble så erstattet med nitrogen og løsningen ble endelig inndampet til tørrhet i våkum. Den faste resten ble-omkrystallisert fra metanol/isopropanol hvilket ga 2,9 g 4-[3-(tert.butylamino) -2-hydroksypropoksy]-7-metyl-2-benzimidazolinon-hydroklorid med smeltepunkt 310°-312°C. atmospheric pressure above 1.5 g 10% palladiuro-on-carbon until hydrogen uptake ceased. The mixture was filtered and the filtrate evaporated to dryness yielding the unstable o-diamine, l-(tert-butylamino)-3-(2,3-diamino-p-tolyloxy^-2-propanol) which was immediately dissolved in 50 ml of 2- N hydrochloric acid at room temperature. A slow stream of phosgene was passed through the solution for 1 hour and the phosgene was then replaced with nitrogen and the solution was finally evaporated to dryness in vacuo. The solid residue was recrystallized from methanol/isopropanol to give 2.9 g 4-[3-(tert.butylamino)-2-hydroxypropoxy]-7-methyl-2-benzimidazolinone hydrochloride with melting point 310°-312°C.
Analyse for ci5H23°3N3 ,H(~1Analysis for ci5H23°3N3 ,H(~1
Beregnet: C: 54,6; H: 7,35; N: 12,75; Cl: 10,75 %. Calculated: C: 54.6; H: 7.35; N: 12.75; Cl: 10.75%.
Funnet: C: 54,5; H: 7,25; N: 12,9; Dl: 10,6 %'. Found: C: 54.5; H: 7.25; N: 12.9; D1: 10.6%'.
(b) 4,0 g 1-(tert.butylamino)-3-(2,3-diamino-p-tolyloksy)-2-propanol ble oppvarmet med 20 g urea ved 140°C i 5 timer under nitrogen. Det avkjølte produktet ble oppløst i 100 ml vann og (b) 4.0 g of 1-(tert.butylamino)-3-(2,3-diamino-p-tolyloxy)-2-propanol was heated with 20 g of urea at 140°C for 5 hours under nitrogen. The cooled product was dissolved in 100 ml of water and
ekstrahert med tre 50 ml-porsoner etyl-acetat. De kombinerte extracted with three 50 ml portions of ethyl acetate. They combined
etyl-acetatet-ekstraktene ble vasket med 50 ml vann, tørket over kaliumkarbonat og inndampet til tørrhet. Resten ble behandlet med et overskudd etanolisk hydrogenklorid og det resulterende hydrokloridet ble omkrystallisert fra metanol/isopropanol hvor ved man fikk 1,4 g 4-[3-(tert .butylamino)-2-hydroksypropoksyj- the ethyl acetate extracts were washed with 50 ml of water, dried over potassium carbonate and evaporated to dryness. The residue was treated with an excess of ethanolic hydrogen chloride and the resulting hydrochloride was recrystallized from methanol/isopropanol to give 1.4 g of 4-[3-(tert.butylamino)-2-hydroxypropoxyj-
7- metyl-2-benzimidazolinon-hydroklorid med smeltepunkt 303°-305°C. 7-methyl-2-benzimidazolinone hydrochloride with melting point 303°-305°C.
Eksempel 12 Example 12
4-[ 3-( cyklopentylamino)- 2- hydroksypropoksyj- 7- mety1- 2- benzimidazolinon 6 g 4-(2,3-epoksypropoksy)-2,3-dinitrotoluen i 200 ml etanol ble behandlet med 4,55 g N-benzylcyklopentylamin og løsningen ble oppvarmet ved 6 0°C i 2 4 timer. Løsningen ble inndampet til tørrhet i våkum hvilket ga 1-(N-benzylcyklopentylamino)-3-(2 , 3-dinitro-p-tolyloksy)-2-propanol som ble oppløst i 150 ml etanol og hydrogenert i nærvær av 1,5 g 10 % palladium-på-karbon ved romtemperatur og atmosfæretrykk inntil hydrogenopptaket. opp-hørte. Filtrering og inndamping av filtratet under redusert trykk ga en I-(cyklopentylamino)-3-(2,3-diamino-p-tolyloksy)-2-propanol som ble behandlet med fosgen som beskrevet i eksempel 11(C) (a) hvilket ga etter krystallisering fra etanol som inneholdt et spormetanol 4,8 g 4-[3-(cyklopentylamino)-2-hydroksypropoksy] -7-metyl-2-benzimidazolinon med smeltepunkt 265°-266°C. 4-[3-(cyclopentylamino)-2-hydroxypropoxy-7-methyl-2-benzimidazolinone 6 g of 4-(2,3-epoxypropoxy)-2,3-dinitrotoluene in 200 ml of ethanol was treated with 4.55 g of N- benzylcyclopentylamine and the solution was heated at 60°C for 24 hours. The solution was evaporated to dryness in vacuo to give 1-(N-benzylcyclopentylamino)-3-(2,3-dinitro-p-tolyloxy)-2-propanol which was dissolved in 150 ml of ethanol and hydrogenated in the presence of 1.5 g 10% palladium-on-carbon at room temperature and atmospheric pressure until hydrogen absorption. up-heard. Filtration and evaporation of the filtrate under reduced pressure gave a I-(cyclopentylamino)-3-(2,3-diamino-p-tolyloxy)-2-propanol which was treated with phosgene as described in Example 11(C) (a) which gave, after crystallization from ethanol containing a trace methanol, 4.8 g of 4-[3-(cyclopentylamino)-2-hydroxypropoxy]-7-methyl-2-benzimidazolinone, m.p. 265°-266°C.
Eksempel 13Example 13
(A) 1-( dicyklopentylamino)- 3-( 2, 3- dinitro- p- tolyloksy)- 2- propanol (A) 1-(dicyclopentylamino)-3-(2,3-dinitro-p-tolyloxy)-2-propanol
10 g 4-(2 , 3-epoksypropoksy)-2 , 3-dinitrotoluen. i 150 ml etanol ble behandlet med 9,05 g dicyklopentylamin-hydroklorid og 18 g vannfritt kaliumkarbonat og blandingen ble oppvarmet ved 60°C 10 g of 4-(2,3-epoxypropoxy)-2,3-dinitrotoluene. in 150 ml of ethanol was treated with 9.05 g of dicyclopentylamine hydrochloride and 18 g of anhydrous potassium carbonate and the mixture was heated at 60°C
i 30 timer. Blandingen ble så inndampet til tørrhet.i våkum 50 ml vann ble tilsatt og den resulterende løsning ble ekstrahert med to 50 ml-porsjoner kloroform. De kombinerte kloroform-ekstraktene ble vasket med vann, tørket over kaliumkarbo-; for 30 hours. The mixture was then evaporated to dryness. In vacuo 50 ml of water was added and the resulting solution was extracted with two 50 ml portions of chloroform. The combined chloroform extracts were washed with water, dried over potassium carbonate;
nat og inndampet til tørrhet i våkum. Restem ble omkrystalli- night and evaporated to dryness in vacuo. Restem was recrystallized
sert fra etyl-acetat og ga 5,9 g 1-(dicyklopentylamino)-3-(2,3 -dinitro-p-tolyloksy)-2-propanol med smeltepunkt 119°-122°C. separated from ethyl acetate and gave 5.9 g of 1-(dicyclopentylamino)-3-(2,3-dinitro-p-tolyloxy)-2-propanol with melting point 119°-122°C.
Analyse for C2oH29°6N3Analysis for C2oH29°6N3
Beregnet: C: 58,95; H: 7,2; N: 10,3 %.Calculated: C: 58.95; H: 7.2; N: 10.3%.
Funnet: C: 59,0; H: 7,3; N: 10,25 %-Found: C: 59.0; H: 7.3; N: 10.25%-
( B) 4 — 3— ( dicyklopentylamino) - 2- hydroksypropoksy] - 7- metyl- 2-benz imidazolinon- hydroklorid (B) 4 — 3— ( dicyclopentylamino) - 2- hydroxypropoxy] - 7- methyl- 2-benz imidazolinone hydrochloride
5 , 4 g l-(dicyklopentylamino) -3- (2 , 3-dinitro-p-tolyloksy) -2-propanol i 200 ml etanol ble hydrogenert i nærvær av 1,0 g palladium-på-karbon ved romtempertaur og atmosfæretrykk.inntil hydrogenopptaket hadde opphørt. Løsningen ble filtrert og filtratet inndampet til tørrhet.i våkum hvilket ga det ustabile o-diaminet 1- (dicyklopentylamino)-3-(2,3-diamino-p-tolyloksy)-2-propanol 5.4 g of 1-(dicyclopentylamino)-3-(2,3-dinitro-p-tolyloxy)-2-propanol in 200 ml of ethanol was hydrogenated in the presence of 1.0 g of palladium-on-carbon at room temperature and atmospheric pressure. until hydrogen absorption had ceased. The solution was filtered and the filtrate evaporated to dryness in vacuo to give the unstable o-diamine 1-(dicyclopentylamino)-3-(2,3-diamino-p-tolyloxy)-2-propanol
som øyeblikkelig ble opptatt i 2-N saltsyre og omsatt med fosgen som beskrevet i eksempel 1(C) (a). Produktet ble omkrystallisert fra isopropanol hvilket ga 1,8 g 4-[3-(dicyklopentylamino)-2- hydroksypropoksy] -7-metyl-2-benzimidazolinon-hydroklorid med smeltepunkt 274°-276°C. which was immediately taken up in 2-N hydrochloric acid and reacted with phosgene as described in example 1(C) (a). The product was recrystallized from isopropanol which gave 1.8 g of 4-[3-(dicyclopentylamino)-2-hydroxypropoxy]-7-methyl-2-benzimidazolinone hydrochloride with melting point 274°-276°C.
Eksempel 14 Example 14
7-[ 3-( tert. butylamino)- 2- hydroksypropoksy]- 1, 4- dimetyl- 2- benzimidazolinon- hydroklorid 7-[ 3-( tert. butylamino)- 2- hydroxypropoxy]- 1, 4- dimethyl- 2- benzimidazolinone hydrochloride
5,3 g 1-(tert.butylamino)-3-(2,3-dinitro-p-tolyloksy)-2-propanol i 100 ml etanol ble behandlet med 30 ml av en 33 %-løs-ning metylamin i etanol og den resulterende løsning ble oppvarmet ved 50°C i 48 timer. Løsningen ble så fordampet til tørrhet i våkum hvilket ga 1-(tert.butylamino)-3-(2-metylamino 5.3 g of 1-(tert.butylamino)-3-(2,3-dinitro-p-tolyloxy)-2-propanol in 100 ml of ethanol was treated with 30 ml of a 33% solution of methylamine in ethanol and the resulting solution was heated at 50°C for 48 hours. The solution was then evaporated to dryness in vacuo to give 1-(tert.butylamino)-3-(2-methylamino)
-3-nitro-p-tolyloksy)-2-propanol i form av en orange olje som ble oppløst i 100 ml etanol og hydrogenert i nærvær av 1 -3-nitro-p-tolyloxy)-2-propanol in the form of an orange oil which was dissolved in 100 ml of ethanol and hydrogenated in the presence of 1
10 % palladium-på-karbon ved romtemperatur og atmosfærisk trykk inntil hydrogenopptaket hadde opphørt. Blandingen ble filtrert og filtratet ble inndampet til tørrhet i våkum hvilket ga det ustabile 1-(tert.butylamino)-3-(3-amino-2-metylamino- 10% palladium-on-carbon at room temperature and atmospheric pressure until hydrogen uptake had ceased. The mixture was filtered and the filtrate was evaporated to dryness in vacuo to give the unstable 1-(tert.butylamino)-3-(3-amino-2-methylamino-
i p-tolyloksy)-2-propanol som ble tatt opp i 50 ml 2-N saltsyre j in p-tolyloxy)-2-propanol which was taken up in 50 ml of 2-N hydrochloric acid j
og omsatt med fosgen i 8 timer som beskrevet i.eksempel 11(C) (a). Etter omkrystallisasjonen fra etanol som inneholdt spor av metanol fikk man 1,8 g 7-[3-(tert.butylamino)-2-hydroksypropoksy] -1,4-dimétyl-2-benzimidazolinon-hydroklorid med-smeltepunkt 290°-291°C. Eksempel 15 1-( tert. butylamino)- 3-( 2- merkapto- 7- metyl- benzimidazolyloksy)-- 2- propanol- hydroklorid 5 g 1-(tert.butylamino)-3-(2,3-dinitro-p-tolyloksy)-2-propanol i 100 ml etanol ble hydrogenert ved romtemperatur og atmosfæretrykk over 1,5 g 10 % palladium-på-karbon inntil hydrogenopptaket hadde opphørt. Blandingen ble filtrert og filtratet inndampet til tørrhet hvilket ga det ustabile o-diaminet, 1--(tert.butylamino)-3-(2,3-diamino-p-tolyloksy)-2-propanol,. som umiddelbart ble oppløst i 50 ml 2-N saltsyre ved romtemperatur. 5 ml thiofosgen ble satt til løsningen og den resulterende blanding rørt kraftig under nitrogen ved romtemperatur i 4 timer. Blandingen ble inndampet til tørrhet i våkum og resten ble omkrystallisert fra isopropanol hvilket ga 3,05 g 1-(tert.butylamino)-3- (2-merkapto-7-metyl-benzimidazolyloksy) -2-propanol-hydroklorid i form av blek-gule krystaller med smeltepunkt 203°-205°C (dekomponering). and reacted with phosgene for 8 hours as described in example 11(C) (a). After recrystallization from ethanol containing traces of methanol, 1.8 g of 7-[3-(tert.butylamino)-2-hydroxypropoxy]-1,4-dimethyl-2-benzimidazolinone hydrochloride with melting point 290°-291° was obtained C. Example 15 1-(tert.butylamino)-3-(2-mercapto-7-methylbenzimidazolyloxy)-2-propanol hydrochloride 5 g 1-(tert.butylamino)-3-(2,3-dinitro-p -tolyloxy)-2-propanol in 100 ml of ethanol was hydrogenated at room temperature and atmospheric pressure over 1.5 g of 10% palladium-on-carbon until hydrogen uptake had ceased. The mixture was filtered and the filtrate evaporated to dryness to give the unstable o-diamine, 1-(tert-butylamino)-3-(2,3-diamino-p-tolyloxy)-2-propanol. which was immediately dissolved in 50 ml of 2-N hydrochloric acid at room temperature. 5 ml of thiophosgene was added to the solution and the resulting mixture stirred vigorously under nitrogen at room temperature for 4 hours. The mixture was evaporated to dryness in vacuo and the residue was recrystallized from isopropanol to give 3.05 g of 1-(tert.butylamino)-3-(2-mercapto-7-methyl-benzimidazolyloxy)-2-propanol hydrochloride as pale -yellow crystals with melting point 203°-205°C (decomposition).
Analyse for C-^302N3S . 1.33HC1Analysis for C-^302N3S . 1.33HC1
Beregnet: -C: 50,5; H: 6,6; N: 11,75 %.Calculated: -C: 50.5; H: 6.6; N: 11.75%.
Funnet: C: 50,25;.H: 6,8; N: 11,35 %. Found: C: 50.25; .H: 6.8; N: 11.35%.
Eksempel 16 Example 16
1-( tert- butylamino)- 3-( 2- merkapto- 4- benzimidazolyloksy)- 2- propanol- hydroklorid 1-( tert-butylamino)- 3-( 2- mercapto- 4- benzimidazolyloxy)- 2- propanol- hydrochloride
20 g of 2,3-dinitrofenyl 2,3-epoksypropyl-eter ble oppløst i 400 ml varm etanol og løsningen ble dekantert fra en liten mengde uoppløselig rest. 100 ml tert.butylamin ble tilsatt og løsningen fikk stå ved romtemperatur i 18 timer. Inn- 20 g of 2,3-dinitrophenyl 2,3-epoxypropyl ether was dissolved in 400 ml of hot ethanol and the solution was decanted from a small amount of insoluble residue. 100 ml of tert-butylamine was added and the solution was allowed to stand at room temperature for 18 hours. In-
dampning av løsningen i våkum og krystallisasjon av resten evaporation of the solution in vacuo and crystallization of the residue
fra isopropanol ga 17,2 g (66 %) 1-(tert.butylamino)-3-(2,3-dinitrofenoksy)-2-propanol med smeltepunkt 120O<->122°C. from isopropanol gave 17.2 g (66%) of 1-(tert.butylamino)-3-(2,3-dinitrophenoxy)-2-propanol with melting point 120O<->122°C.
Analyse for ci3H^9°6N3Analysis for ci3H^9°6N3
Beregnet: C: 49,8; H: 6,1; N: 13,4 %.Calculated: C: 49.8; H: 6.1; N: 13.4%.
Funnet: C: 49 ,9; H: 6,0; N: 13,5 %.Found: C: 49.9; H: 6.0; N: 13.5%.
10 g 1-(tert.butylamino)-3-(2,3-dinitrofenoksy)-2-propanol i 150 ml etanol ble hydrogenert ved romtemperatur og atmosfæretrykk over 4 g 10 % palladium-på-karbon-katalysator inntil hydrogenopptaket opphørte. Oppløsningen ble filtrert filtratet ble inndampet i våkum og resten, 1-(tert.butylamino) 10 g of 1-(tert.butylamino)-3-(2,3-dinitrophenoxy)-2-propanol in 150 ml of ethanol was hydrogenated at room temperature and atmospheric pressure over 4 g of 10% palladium-on-carbon catalyst until hydrogen absorption ceased. The solution was filtered, the filtrate was evaporated in vacuo and the residue, 1-(tert.butylamino)
-3- (2 , 3-diaminof enoksy) - r2-propanol ble øyeblikkelig oppløst-3-(2,3-diaminophenoxy)-r2-propanol was instantly dissolved
i 50 ml 2-N saltsyre. 10 ml thiofosgen ble satt til.løs-ningen og den resulterende blanding ble rørt kraftig under nitrogen ved romtemperatur i 3 timer. Blandingen ble inndampet til tørrhet i våkum og resten ble omkrystallisert fra isopropanol hvilket ga 3,8 g 1-(tert.butylamino)-3-(2-merkapto-4-benzimidazolyloksy)-2-propanol-hydroklorid i form av. blek-gule krystaller med smeltepunkt 145°-150°C (dekomponering) . in 50 ml of 2-N hydrochloric acid. 10 ml of thiophosgene was added to the solution and the resulting mixture was stirred vigorously under nitrogen at room temperature for 3 hours. The mixture was evaporated to dryness in vacuo and the residue was recrystallized from isopropanol to give 3.8 g of 1-(tert.butylamino)-3-(2-mercapto-4-benzimidazolyloxy)-2-propanol hydrochloride in the form of pale yellow crystals with melting point 145°-150°C (decomposition).
Analyse for c14<H>2i<0>2<N>3<S>'<1,>33HC1Analysis for c14<H>2i<0>2<N>3<S>'<1,>33HC1
Beregnet: C: 48,9;. H: 6,55; N: 12,2; S: 9,35 %. Calculated: C: 48.9;. H: 6.55; N: 12.2; S: 9.35%.
Funnet: C: 48,75; II: 6,5; N: 11,7; S: 9,85 %. Found: C: 48.75; II: 6.5; N: 11.7; S: 9.85%.
Eksempel 17 Example 17
1-( tert. butylamino)- 3-( 2- merkapto- l, 4- dimetyl- 7- benzimida-zolyloksy)- 2- propanol- hydroklorid 1-( tert. butylamino)- 3-( 2- mercaptol- 4- dimethyl- 7- benzimidazolyloxy)- 2- propanol- hydrochloride
4,75 g 1-(tert.butylamino)-3-(2,3-dinitro-p-tolyloksy)-2--propanol i 100 ml etanol ble behandlet med 25 ml av en 33 % oppløsning av metylamin i etanol og den resulterende løs- 4.75 g of 1-(tert.butylamino)-3-(2,3-dinitro-p-tolyloxy)-2--propanol in 100 ml of ethanol was treated with 25 ml of a 33% solution of methylamine in ethanol and the resulting solution
ning ble oppvarmet ved 50°C i 14 timer. Løsningen ble så inndampet til tørrhet i våkum hvilket ga 1-(tert.butylamino)--3-(2-metylamino-3-nitro-p-tolyloksy)-2-propanol i form av en orange olje som ble oppløst i 100 ml etanol og hydrogenert ning was heated at 50°C for 14 hours. The solution was then evaporated to dryness in vacuo giving 1-(tert.butylamino)-3-(2-methylamino-3-nitro-p-tolyloxy)-2-propanol in the form of an orange oil which was dissolved in 100 ml ethanol and hydrogenated
i nærvær av et 10 % palladium-på-karbon ved romtemperaturin the presence of a 10% palladium-on-carbon at room temp
og atmosfærisk trykk inntil hydrogenopptaket opphørte. Blahd-j and atmospheric pressure until hydrogen absorption ceased. Blahd-j
ingen ble filtrert og filtratet ble inndampet til tørrhet i none was filtered and the filtrate was evaporated to dryness i
våkum hvilket ga det ustabile l-(tert. butylamino)-3-(3-amino--2-metylamino-p-tolyloksy)-2-propanol som ble opptatt i 50 ml 2-N saltsyre og behandlet med 5 ml thiofosgen. Blandingen ble kraftig rørt under nitrogen ved romtemperatur i 2 timer og så inndampet til tørrhet i våkum. Resten ble omkrystallisert fra isopropanol hvilket ga 3,29 g 1-(tert.butylamino)--3-(2-merkapto-l,4-dimetyl-7-benzimidazolyloksy)-2-propanol-hydroklorid i form av orange krystaller med smeltepunkt 184°-185°C (dekomponering). vacuum which gave the unstable 1-(tert.butylamino)-3-(3-amino-2-methylamino-p-tolyloxy)-2-propanol which was taken up in 50 ml of 2-N hydrochloric acid and treated with 5 ml of thiophosgene. The mixture was vigorously stirred under nitrogen at room temperature for 2 hours and then evaporated to dryness in vacuo. The residue was recrystallized from isopropanol which gave 3.29 g of 1-(tert.butylamino)-3-(2-mercapto-1,4-dimethyl-7-benzimidazolyloxy)-2-propanol hydrochloride in the form of orange crystals with melting point 184°-185°C (decomposition).
Eksempel 18 Example 18
1-( dietylamino)- 3-( 2- merkapto- 4- benzimidazolyloksy)- 2- propanol-hydroklorid 1-(diethylamino)- 3-( 2- mercapto- 4- benzimidazolyloxy)- 2- propanol hydrochloride
7 g 2,3-dinitrofenyl 2,3-epoksypropyl-eter ble oppløst i 200 7 g of 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 200
ml varm etanol og løsningen ble dekantert fra en liten mengde uoppløselig.rest. Løsningen ble behandlet med 11,2 g dietylamin. og' den resulterende løsning fikk stå ved romtemperatur i 48 timer. Løsningen ble så inndampet til tørrhet i våkum og ml of hot ethanol and the solution was decanted from a small amount of insoluble residue. The solution was treated with 11.2 g of diethylamine. and the resulting solution was allowed to stand at room temperature for 48 hours. The solution was then evaporated to dryness in vacuo and
resten ble hydrogenert i 10 0 ml etanol ved romtemperatur og atmosfæretrykk over 3,5 g 10 % palladium-på-karbon inntil hydrogenopptaket opphørte. Blandingen ble filtrert og filtratet ble inndampet i våkum hvilket ga 3-(2,3-diaminofenoksy) -1-(dietylamino)-2-propanol som øyeblikkelig ble oppløst i 50 ml 2-N saltsyre og behandlet med 5 ml thiofosgen. Blandingen ble rørt kraftig under nitrogen ved romtemperatur i 3 timer. Løsningen ble inndampet i våkum og resten ble omkrystallisert fra etanol/isopropanol hvilket ga 1,8 g 1-(diet-ylamino) -3-(2-merkapto-4-benzimidazolyloksy)-2-propanol-hydroklorid i form av blek-gule krystaller med smeltepunkt 249°-250°C (dekomponering). the residue was hydrogenated in 100 ml of ethanol at room temperature and atmospheric pressure over 3.5 g of 10% palladium-on-carbon until hydrogen uptake ceased. The mixture was filtered and the filtrate was evaporated in vacuo to give 3-(2,3-diaminophenoxy)-1-(diethylamino)-2-propanol which was immediately dissolved in 50 ml of 2-N hydrochloric acid and treated with 5 ml of thiophosgene. The mixture was stirred vigorously under nitrogen at room temperature for 3 hours. The solution was evaporated in vacuo and the residue was recrystallized from ethanol/isopropanol to give 1.8 g of 1-(diethylamino)-3-(2-mercapto-4-benzimidazolyloxy)-2-propanol hydrochloride as pale yellow crystals with melting point 249°-250°C (decomposition).
Analyse for<c>14<H>2i<0>2<N>3<S>- 1,33HC1Analysis for<c>14<H>2i<0>2<N>3<S>- 1,33HC1
Beregnet: C: 48,9; H: 6,55; N: 12,2; S: 9,3 Calculated: C: 48.9; H: 6.55; N: 12.2; S: 9.3
Funnet: C: 49,0;. H: 6,5; N: 12,3; S: 9,8 %.Found: C: 49.0;. H: 6.5; N: 12.3; S: 9.8%.
De følgende eksempler illustrerer typiske farmasøytiske pre parater som inneholder benzimidazol-derivatene som tilveiebringes ved foreliggende oppfinnelse: The following examples illustrate typical pharmaceutical preparations containing the benzimidazole derivatives provided by the present invention:
Eksempel AExample A
En tablettformulering som inneholder de følgende bestanddeler kan fremstilles på konvensjonell måte: A tablet formulation containing the following ingredients can be prepared in a conventional manner:
Eksempel B Example B
En kapselformulering som inneholder de følgende bestanddeler kan fremstilles på konvensjonell måte: A capsule formulation containing the following ingredients can be prepared in a conventional manner:
Denne kapselformuleringen fylles i nr. 4 harde gelatinkapseler. This capsule formulation is filled in No. 4 hard gelatin capsules.
Claims (9)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB18438/77A GB1595316A (en) | 1977-05-03 | 1977-05-03 | 4-(3-amino-2-hydroxy-propoxy)-benzimidazole derivatives and pharmaceutical compositions containing them |
| GB4915677 | 1977-11-25 | ||
| GB220878 | 1978-01-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO781556L true NO781556L (en) | 1978-11-06 |
Family
ID=27254036
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO781556A NO781556L (en) | 1977-05-03 | 1978-05-02 | BENZIMIDAZOLE DERIVATIVES. |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS53135979A (en) |
| AR (2) | AR220335A1 (en) |
| AU (1) | AU3569678A (en) |
| DE (1) | DE2819458A1 (en) |
| DK (1) | DK190378A (en) |
| ES (1) | ES469353A1 (en) |
| FI (1) | FI781349A (en) |
| FR (1) | FR2399414A1 (en) |
| GR (1) | GR73669B (en) |
| IL (1) | IL54591A0 (en) |
| IT (1) | IT1096276B (en) |
| LU (1) | LU79591A1 (en) |
| MC (1) | MC1192A1 (en) |
| NL (1) | NL7804794A (en) |
| NO (1) | NO781556L (en) |
| NZ (1) | NZ187066A (en) |
| PT (1) | PT67980A (en) |
| SE (1) | SE7805140L (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2801980A1 (en) | 1978-01-18 | 1979-07-19 | Boehringer Mannheim Gmbh | 4-HYDROXY-2-BENZIMIDAZOLINE-THIONE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| EP0003758A1 (en) * | 1978-02-09 | 1979-09-05 | Ciba-Geigy Ag | Etherified hydroxy-benzodiheterocycles and their acid addition salts, process for their preparation and pharmaceutical compositions containing them |
| DE2905877A1 (en) * | 1979-02-16 | 1980-08-28 | Boehringer Mannheim Gmbh | NEW AMINOPROPANOL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| CH661501A5 (en) * | 1982-01-26 | 1987-07-31 | Oreal | COMPOUNDS DERIVATIVE FROM AMINO-3 PROPANOL-2 FOR USE IN DYEING HAIR, PREPARATION METHOD THEREOF, DYE COMPOSITION CONTAINING THE SAME, AND HAIR DYEING METHOD THEREOF. |
| DE3839743A1 (en) * | 1988-11-25 | 1990-05-31 | Hoechst Ag | METHOD FOR PRODUCING BENZIMIDAZOLONES |
| US9784726B2 (en) | 2013-01-08 | 2017-10-10 | Atrogi Ab | Screening method, a kit, a method of treatment and a compound for use in a method of treatment |
| GB201714736D0 (en) | 2017-09-13 | 2017-10-25 | Atrogi Ab | New compounds and uses |
| GB201714734D0 (en) | 2017-09-13 | 2017-10-25 | Atrogi Ab | New compounds and uses |
| GB201714740D0 (en) | 2017-09-13 | 2017-10-25 | Atrogi Ab | New compounds and uses |
| GB201714745D0 (en) | 2017-09-13 | 2017-10-25 | Atrogi Ab | New compounds and uses |
| GB202205895D0 (en) | 2022-04-22 | 2022-06-08 | Atrogi Ab | New medical uses |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1058822A (en) * | 1963-07-30 | 1967-02-15 | Ici Ltd | 3-amino-2-hydroxypropoxy heterocyclic derivatives |
| CH559729A5 (en) * | 1970-10-23 | 1975-03-14 | Hoechst Ag | |
| US4081447A (en) * | 1975-04-09 | 1978-03-28 | Abbott Laboratories | 5-[2-Hydroxy-3-(3,4-dimethoxy phenethylamino)]-propoxy-3,4-dihydro carbostyril and pharmaceutically acceptable salts thereof |
| CH624395A5 (en) * | 1976-01-08 | 1981-07-31 | Ciba Geigy Ag |
-
1978
- 1978-04-26 NZ NZ187066A patent/NZ187066A/en unknown
- 1978-04-27 FR FR7812492A patent/FR2399414A1/en active Pending
- 1978-04-27 IL IL54591A patent/IL54591A0/en unknown
- 1978-05-02 PT PT67980A patent/PT67980A/en unknown
- 1978-05-02 FI FI781349A patent/FI781349A/en not_active Application Discontinuation
- 1978-05-02 JP JP5241778A patent/JPS53135979A/en active Pending
- 1978-05-02 ES ES469353A patent/ES469353A1/en not_active Expired
- 1978-05-02 MC MC781299A patent/MC1192A1/en unknown
- 1978-05-02 DK DK190378A patent/DK190378A/en not_active Application Discontinuation
- 1978-05-02 NO NO781556A patent/NO781556L/en unknown
- 1978-05-03 AU AU35696/78A patent/AU3569678A/en active Pending
- 1978-05-03 IT IT23000/78A patent/IT1096276B/en active
- 1978-05-03 SE SE7805140A patent/SE7805140L/en unknown
- 1978-05-03 LU LU79591A patent/LU79591A1/en unknown
- 1978-05-03 DE DE19782819458 patent/DE2819458A1/en not_active Withdrawn
- 1978-05-03 NL NL7804794A patent/NL7804794A/en not_active Application Discontinuation
- 1978-05-31 AR AR272019A patent/AR220335A1/en active
-
1979
- 1979-01-24 GR GR56130A patent/GR73669B/el unknown
- 1979-07-06 AR AR277226A patent/AR219173A1/en active
Also Published As
| Publication number | Publication date |
|---|---|
| IL54591A0 (en) | 1978-07-31 |
| AR219173A1 (en) | 1980-07-31 |
| FI781349A (en) | 1978-11-04 |
| LU79591A1 (en) | 1979-06-13 |
| PT67980B (en) | 1980-05-05 |
| GR73669B (en) | 1984-03-28 |
| AU3569678A (en) | 1979-11-08 |
| IT7823000A0 (en) | 1978-05-03 |
| NL7804794A (en) | 1978-11-07 |
| JPS53135979A (en) | 1978-11-28 |
| NZ187066A (en) | 1981-02-11 |
| DK190378A (en) | 1978-11-04 |
| IT1096276B (en) | 1985-08-26 |
| AR220335A1 (en) | 1980-10-31 |
| SE7805140L (en) | 1978-11-04 |
| DE2819458A1 (en) | 1978-11-16 |
| FR2399414A1 (en) | 1979-03-02 |
| ES469353A1 (en) | 1980-01-01 |
| MC1192A1 (en) | 1979-02-23 |
| PT67980A (en) | 1978-06-01 |
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