DK154555B - Analogifremgangsmaade til fremstilling af carbazolyl-(4)-oxy-propanolaminderivater eller deres farmakologisk anvendelige salte - Google Patents
Analogifremgangsmaade til fremstilling af carbazolyl-(4)-oxy-propanolaminderivater eller deres farmakologisk anvendelige salte Download PDFInfo
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- DK154555B DK154555B DK141979AA DK141979A DK154555B DK 154555 B DK154555 B DK 154555B DK 141979A A DK141979A A DK 141979AA DK 141979 A DK141979 A DK 141979A DK 154555 B DK154555 B DK 154555B
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- 238000000034 method Methods 0.000 title description 9
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- 230000000144 pharmacologic effect Effects 0.000 title description 2
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- -1 methylenedioxy group Chemical group 0.000 claims description 38
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- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 12
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- 125000003118 aryl group Chemical group 0.000 description 3
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- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- LYUQWQRTDLVQGA-UHFFFAOYSA-N 3-phenylpropylamine Chemical compound NCCCC1=CC=CC=C1 LYUQWQRTDLVQGA-UHFFFAOYSA-N 0.000 description 1
- MHIAMONBYDFGFO-UHFFFAOYSA-N 4-(2-aminoethoxy)benzamide Chemical compound NCCOC1=CC=C(C(N)=O)C=C1 MHIAMONBYDFGFO-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- PPJKLEQAFZWIQY-UHFFFAOYSA-N 5-fluoro-2-methoxyphenol Chemical compound COC1=CC=C(F)C=C1O PPJKLEQAFZWIQY-UHFFFAOYSA-N 0.000 description 1
- LHSDDDNWNOTMEE-UHFFFAOYSA-N 6-[2-(benzylamino)ethoxy]pyridine-3-carboxamide Chemical compound N1=CC(C(=O)N)=CC=C1OCCNCC1=CC=CC=C1 LHSDDDNWNOTMEE-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000320529 Allobates femoralis Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 101100334117 Caenorhabditis elegans fah-1 gene Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- ZMQBBPRAZLACCW-UHFFFAOYSA-N acetic acid;dichloromethane Chemical compound ClCCl.CC(O)=O ZMQBBPRAZLACCW-UHFFFAOYSA-N 0.000 description 1
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- GFTWDQJSZPFMOZ-UHFFFAOYSA-N acetyl acetate Chemical compound CC(=O)OC(C)=O.CC(=O)OC(C)=O GFTWDQJSZPFMOZ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- ZXVOCOLRQJZVBW-UHFFFAOYSA-N azane;ethanol Chemical compound N.CCO ZXVOCOLRQJZVBW-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000006480 benzoylation reaction Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- 238000009530 blood pressure measurement Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 150000001716 carbazoles Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 210000000959 ear middle Anatomy 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 150000003944 halohydrins Chemical class 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- JWQOQWYYUBHJFI-UHFFFAOYSA-N n-[2-(2-methoxyphenoxy)ethyl]butan-1-amine Chemical compound CCCCNCCOC1=CC=CC=C1OC JWQOQWYYUBHJFI-UHFFFAOYSA-N 0.000 description 1
- SZDYRZVWNVIYGO-UHFFFAOYSA-N n-benzyl-2-(2-methoxyphenoxy)ethanamine Chemical compound COC1=CC=CC=C1OCCNCC1=CC=CC=C1 SZDYRZVWNVIYGO-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004780 naphthols Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000008775 paternal effect Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- FZJCXIDLUFPGPP-UHFFFAOYSA-N propan-2-ol;toluene Chemical compound CC(C)O.CC1=CC=CC=C1 FZJCXIDLUFPGPP-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000009960 sympathetic pathway Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles 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 to carbon atoms of the ring system
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 to atoms of the carbocyclic ring
- C07D317/64—Oxygen atoms
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
i
DK 154555 B
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte carbazolyl-(4)-oxy-pro-panolaminderivater med den almene formel I
/'"V6 0-CH2-CH-CH2-N - CH-CH-X- i ArΛ ° R2 R3 R4
ULJU R
N (I) ,
H
hvor 5 R^" er hydrogen, en alkanoylgruppe med 1-6 carbonatomer eller en benzoyl- eller naphthoylgruppe, o R er hydrogen, en alkylgruppe med 1-6 carbonatomer eller en benzyl-, phenethyl- eller phenylpropylgruppe, R er hydrogen eller en alkylgruppe med 1-6 carbonatomer, er hydrogen eller en alkylgruppe med 1-6 carbonatomer, X er en valensstreg, en -CH2-gruppe, et oxygen- eller svovlatom,
Ar er en phenyl-, naphthyl-, indanyl-, tetrahydronaphthyl- eller pyridylgruppe, og 15 R~* og , der kan være ens eller forskellige, hver er hydro gen, fluor, chlor eller brom, en alkylgruppe med 1-6 carbonatomer, en aminocarbony1gruppe, en hydroxygruppe, en alkoxygruppe med 1-6 carbonatomer, en benzyloxygruppe, en alkylmercaptogruppe med 1-6 carbonatomer, en alkyl-20 sulfinylgruppe med 1-6 carbonatomer, en alkylsulfonylgrup- pe med 1-6 carbonatomer eller også saircnen betyder en methv- lendioxygruppe, hvorhos i det tilfælde, hvor X er et oxy-4 5 genatom, R og R sammen også kan betyde gruppen -CH20-, eller deres fysiologisk anvendelige salte.
25 Alkylgrupperne indeholder 1-6, fortrinsvis 1-4, carbonatomer og kan være ligekædede eller forgrenede. Som foretrukne skal nævnes methyl-, ethyl-, isopropyl-, t.-butyl- og n-butylres-sten.
DK 154555 B
2
Alkanoylgrupper er grupper med 1-6 carbonatomer, især formyl-, acetyl-, propionyl- og pivaloylgruppen.
5
En alkoxy-, alkylmercapto-, alkylsulfinyl- eller alkylsulfony1-gruppe indeholder 1-6, fortrinsvis 1-4, carbonatomeri Foretrukne er methoxy- og ethoxygruppen, methylmercapto-, methyl-sulfinyl- og methylsulfonyIgruppen.
10 4 5
Som eksempel på en rest, hvor r og Rb sammen danner en -Cl^-O-gruppe, når X = oxygenatom, skal nævnes l,4-ben2odioxa- nyl-(2)-methylresten.
15 Forbindelserne af formlen I og deres fysiologisk anvendelige salte udviser ved den farmakologiske prøve vasodilaterende og β-receptorblokerende virkninger, og de egner sig derfor til behandling og forebyggelse af kredsløbs- og hjertesygdomme, f.eks. hypertension og angina pectoris.
20
Der kendes allerede fra tysk patentskrift 2.240.599 carbazol-derivater, som blokerer aktiviteten af β-receptorerne i sym-pathicus. Til forskel fra de fra dette patentskrift kendte forbindelser udviser de ifølge opfindelsen fremstillede for-25 bindeiser både vasodilaterende og β-receptorblokerende virkning inden for samme dosisområde.
30 35
DK 154555 B
3
Fremgangsmåden, ifølge opfindelsen er ejendommelig ved, at man på i og for sig kendt måde
a) omsætter en forbindelse af formlen II
0-CH2-CH-CH2-Y
R1’ (II),
H
1 i
hvor Y er en snlfonsyrerest eller et halogenatom, og R
1 i«
5 har den for R anførte betydning, eller Y og R tilsammen betyder en valensstreg, méd en forbindelse med formlen III
k~vr6 HN - CH-CH-X- ( ArT r . , , (III), 2 3 4
R R R
2 3 4 5 6 hvor R , R , R , X, Ar, R3 og R° har den anførte betydning, eller
b) omsætter en forbindelse med formlen IV
o-ch2-ch-ch2-nh [tS ? r pi (IV),
^ N v R
H
1 2
10 hvor R og R har den anførte betydning, med en forbindelse af formlen V
DK 154555 B
4 o^6 Y-CH-CH-X- Ar-T (V) , '3 hvor Y, R3, R1, X, Ar, R3 og R^ har den anførte betydning, eller
c) reducerer en blanding af en forbindelse af formlen IV og en forbindelsen af formlen VI
0=C - CH-X- i Ar*) (VI), i* i« r2 3 4 5 6 5 hvor R , R , X, Ar, R og R har den anførte betydning, eller
d) omsætter en forbindelse af formlen IV med en forbindel= sen af formlen VII
°s rv r6 X C-CH-X- ( Ar *Ί ,TTTT, Y/ ;4 (VII)' 5 6 hvor Y, R , X, Ar, R og R har den anførte betydning, og 10 reducerer det fremkomne amid, hvorpå man om ønsket omdanner en alkylmercaptogruppe i en forbindelse af den almene formel I til en alkylsulfinyl- eller alkylsulfonylgruppe ved oxidation og/eller på kendt måde forethrer en forbindelse, hvori 2 6 R eller R er en hydroxygruppe, og/eller forestrer en for-15 bindelse, hvori R3- er hydrogen, og/eller hydrolyserer en forbindelse, hvori R3 er alkanoyl, til den tilsvarende forbindelse». VlTTHri R ~ or nn /all ar nmrlarinor on forivr nrlal co
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5 5 6 hvori R eller R er alkoxy eller benzyloxy, til den tilsva-rende forbindelse, hvori R eller R er hydroxy, samt om ønsket omdanner den fremkomne forbindelse af den almene formel I til et farmakologisk anvendeligt salt deraf.
5 Fremgangsmåderne a) og b) ifølge opfindelsen udføres hen= sigtsmæssigt i et under reaktionsbetingelserne indifferent organisk opløsningsmiddel, f.eks. toluol, dioxan, ethylen= glycoldimethylether, isopropanol eller dimethylformamid, eventuelt i nærværelse af et syrebindende middel. Omsætnin= 1 · 10 gen af epoxiderne af formlen II (Y og R tilsammen en va= lensstreg) med aminerne af formlen III kan også bevirkes efter blanding af reaktionskomponenterne ved henstilling ved stuetemperatur eller ved opvarmning. Ifølge fremgangs= måde c) hydreres en blanding af amin af formlen IV med en 15 carbonylforbindelse af formlen VI i et egnet opløsningsmiddel (f.eks. methanol) i nærværelse af en katalysator (f.eks. Raneynikkel).
Reduktionen af de ved fremgangsmåde d) fremstillede amider sker ved hjælp af komplekse metalhydrider, f.eks. lithium-20 aluminiumhydrid.
De ved fremgangsmåden ifølge opfindelsen anvendte udgangs= forbindelser er i reglen forbindelser kendt fra litteratu= ren. Hidtil ukendte forbindelser fremstilles i almindelig= hed analogt med de til fremstilling af disse kendte beskrev= 25 ne fremgangsmåder. Således kan aminerne af den almene for= mel III fortrinsvis fremstilles ved omsætning af halogen-alkyl-nitriler med tilsvarende phenoler, naphtholer eller arylforbindelser (f.eks. chloracetonitril og phenol) og
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påfølgende hydrering i nærværelse af ammoniak.
Aminerne af den almene formel IV kan fås af den kendte 4-(2,3-epoxypropoxy)-carbazol (jf. tysk patentskrift nr.2.240.599) ved omsætning med flydende ammoniak.
5 Reaktionsdygtige forbindelser af den almene formel V, f.
eks. p-toluolsulfonsyreestere fremstilles i reglen af de tilsvarende phenoler, naphtholer eller arylforbindelser ved omsætning med halogenalkoholer og påfølgende forestring med p-toluolsulfonsyre.
10 Carbonylforbindelserne med den almene formel VI og syre= chlorider med den almene formel VII fås af tilsvarende phenoler, naphtholer og arylforbindelser via omsætninger med egnede halogenalkylforbindelser.
En påfølgende omdannelse af en alkylmercaptogruppe i en 15 forbindelse med den almene formel I til en alkylsulfinyl- eller alkylsulfonylgruppe, sker ved oxidation. Endvidere kan hydroxygrupper forethres eller forestres på kendte måder eller omvendt ester- og ethergrupper omdannes til hydroxygrupper .
20
Med henblik på omdannelse af forbindelserne af formlen I til deres farmakologisk uskadelige salte omsætter man dis= se fortrinsvis i et organisk opløsningsmiddel med den ækvivalente mængde af en uorganisk eller organisk syre, f.
25 eks. saltsyre, brombrintesyre, phosphorsyre, svovlsyre, eddikesyre, citronsyre, maleinsyre, benzoesyre.
Forbindelserne af formlen I kan af deres racemiske blandinger opdeles i de optisk aktive former på i og for kendte måder via de diastereomere salte. Til racematspaltningen 30 kan f.eks. anvendes vinsyre, æblesyre, camphersyre, campher-sulfonsyre.
*
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7
Til fremstilling af lægemidler blandes stofferne I på i og for sig kendt måde med egnede farmaceutiske bærestoffer, aromastoffer, smagsstoffer og farvestoffer og udformes f. eks. som tabletter eller drageer eller bliver under tilsæt= 5 ning af passende hjælpestoffer suspenderet eller opløst i vand eller olie, f.eks. olivenolie.
Sådanne præparater kan anvendes enteralt eller paren-teralt. Som injektionsmedium anvendes fortrinsvis vand, som indeholder de til injektionsopløsninger sæd-10 vanlige tilsætninger såsom stabiliseringsmidler, opløs= • ningsformidlere eller stødpuder. Sådanne tilsætninger er f.eks. tartrat- og citratstødpude, ethanol, kompleksdanne= re (såsom ethylendiamintetraeddikesyre og deres ugiftige salte), højmolekulære polymere (såsom flydende polyethylen= 15 oxid) til viskositetsregulering. Faste bærestoffer er f. eks. stivelse, lactose, mannit, methylcellulose, talkum, højdisper kieselsyre, højmolekulære fedtsyrer (såsom stea= rinsyre) gelatine, agar-agar, calciumphosphat, magniumstea= rat, dyriske og vegetabilske fedtstoffer og faste højmoleku= 20 lære polymere (såsom polyethylenglycoler) og præparater egnede til oral applikation kan om ønsket indeholde smags= stoffer og sødestoffer.
Fremgangsmåden ifølge opfindelsen belyses nærmere af følgende eksempler. Eksempel 1 25 i-[carbazolyl-(4)-oxy]-3-[2-(2-methoxyphenyl)-ethylamino]- propanol-(2).__ 6,0 g 4-(2,3-epoxypropoxy)-carbazol og 7,6 g 2-(2-methoxy= phenyl)-ethylamin omrøres i 20 timer ved 70°C. Man udriver med ether, frasuger og omkrystalliserer af eddikeester under 30 anvendelse af aktive kul og blegejord.
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8
Udbytte: 6,0 g (61% af det teoretiske) farveløse krystaller, smeltepunkt 135-136°C.
På analog måde får man: a) 1-[carbazolyl-(4)-oxy]—3—[2—(3,4-dimethoxyphenyl)-ethyl= 5 amino] -propanol- (2)_ : ' : - _' ~ : ~ 42% af det teoretiske, smeltepunkt 129-130°C, eddikesurt salt, smeltepunkt 180-183°C, af 4-(2,3-epoxypropoxy)-car= bazol og 2-(3,4-dimethoxyphenyl)-ethylamin.
b) 1-[carbazolyl-(4)-oxy]-3-[2-(2-pyridyl)-ethylamino]-pro= 10 panol-(2)_ ) .
32% af det teoretiske, smeltepunkt 105-107°C, af 4-(2,3-epoxypropoxy)-carbazol og 2-(2-pyridyl)-ethylamin.
c) 1-[carbazolyl-(4)-oxy]-3-[2-(4-pyridyl)-ethylamino]-pro= panol-(2)_ 15 24% af det teoretiske, smeltepunkt 86-88°C, af 4-(2,3-epo= xypropoxy)-carbazol og 2-(4-pyridyl)-ethylamin.
d) 1-[carbazolyl-(4)-oxy]-3-(3-phenylpropylamino)-propanol- (2) ____________ 30% af det teoretiske, ravsurt salt, smeltepunkt 98-99°C, 20 af 4-(2,3-epoxypropoxy)-carbazol og 3-phenylpropylamin.
e) 1-[carbazolyl-(4)-oxy]-3-[4-phenylbutyl-(2)-amino]-pro= panol-(2)_ 13% af det teoretiske, smeltepunkt 124-125°C af 4-(2,3-epoxypropoxy)-carbazol og 4-phenylbutyl-(2)-amin.
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Eksempel 2 1-[carbazolyl-(4)-oxy]-3-[2-(2-methoxyphenoxy)-ethylamino]-propanol-(2)_ 22,6 g 4-(2,3-epoxypropoxy)-carbazol og 17,4 g 2-(2-meth= 5 oxyphenoxy)-ethylamin i 75 ml ethylenglycoldimethylether omrøres i 25 timer ved 50°C. Blandingen bringes til tørhed på roterende fordamper, udrives med ether og omkrystallise= res af eddikester under anvendelse af aktive kul.
. Udbytte: 15,1 g (39% af det teoretiske) farveløse krystal= 10 ler, smeltepunkt 114-115°C.
På analog måde får man: a) 1-[carbazolyl-(4)-oxy]-3-(2-phenoxy-ethylamino)-propa= nol- (2)__;__ 32% af det teoretiske, smeltepunkt 105-107°C, af 4-(2,3-15 epoxypropoxy)-carbazol og 2-phenoxyethylamin.
b) 1-[carbazolyl-(4)-oxy]-3-[1-phenoxypropyl-(2)-amino]- propanol- (2).......- _ 31% af det teoretiske. Hydrochlorid smeltepunkt 116-119°C, af 4-(2,3-epoxypropoxy)-carbazol og 1-phenoxypropyl-(2)-20 amin.
c) 1-[carbazolyl-(4)-oxy]-3-[l,4-benzodioxanyl-(2)-methyl= amino] -propanol- ('2)_ - ' ~ ~_' : _ 28% af det teoretiske, smeltepunkt 129-131°C, af 4-(2,3-epoxypropoxy)-carbazol og 2-(aminomethyl)-1,4-benzodioxan.
25 d) l-[carbazolyl-(4)-oxy]-3-[2-(4-carbamoylphenoxy)-ethyl= amino ] -propanol- (2) _' ' ' ' :_' _
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10 13% af det teoretiske, smeltepunkt 120-122°C, af 4-(2,3-epo= xypropoxy)-carbazol og 2-(4-carbamoylphenoxy)-ethylamin.
Eksempel 3 1-[carbazolyl-(4)-oxy]-3-[2-(2-ethoxyphenoxy)-ethylamino]-5 propanol- (2)_' __ 6,0 g 4-(2,3-epoxypropoxy)-carbazol og 9,1 g 2-(2-ethoxy= phenoxy)-ethylamin omrøres i 20 timer ved 70°C. Efter af= køling omrører man med ether, frasuger og omkrystalliserer remanensen af eddikeester under anvendelse af aktive kul 10 og blegejord.
Udbytte 4,4 g (42% af det teoretiske) farveløse krystaller, smeltepunkt 127,5-128,5°C.
På analog måde får man: a) 1-[carbazolyl-(4)-oxy]-3-[2-(4-fluorphenoxy)-ethylamino]- 15 propanol-(2)_- - ' __ 56% af det teoretiske, smeltepunkt 145-146°C, af 4-(2,3-epoxypropoxy)-carbazol og 2-(4-fluorphenoxy)-ethylamin.
b) 1-[carbazolyl-(4)-oxy]-3-[2-(4-tert-butylphenoxy)-ethyl= amino ] -propanol- (2)_-- :_____ 20 51% af det teoretiske, smeltepunkt 127-128°C, af 4-(2,3- epoxypropoxy)-carbazol og 2-(4-tert-butylphenoxy)-ethyl= amin.
c) 1-[carbazolyl-(4)-oxy]-3-[2-(2,3-dimethylphenoxy)-ethyl= amino]-propanol-(2)____ 25 51% af det teoretiske, smeltepunkt 128-129°C, af 4-(2,3- epoxypropoxy)-carbazol og 2-(2,3-dimethylphenoxy)-ethylamin.
d) 1-[carbazolyl(4)-oxy]-3- 2-[indanyl-(5)-oxy]-ethylamino - propanol- (2)_________
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11 54% af det teoretiske, smeltepunkt 143-145°C, af 4-(2,3-epoxypropoxy)-carbazol og 2-[indanyl-(5)-oxy]-ethylamin.
5 e) 1-[carbazolyl-(4)-oxy]-3-{2-[naphthyl-(1)-oxy]-ethyla= mino j-propanol- (2)_______ 64% af det teoretiske, smeltepunkt 116-119°C, af 4— (2,3— epoxypropoxy)-carbazol of 2-[naphthyl-(1)-oxy]-ethylamin.
f) 1-[carbazolyl-(4)-oxy]-3-[2-(3,4-methylendioxyphenoxy)- 10 ethylamino]-propanol-(2)_ 32% af det teoretiske, smeltepunkt 142-143°C, af 4-(2,3-epoxypropoxy)-carbazol og 2-(3,4-methylendioxyphenoxy)-ethylamin.
g) 1-[carbazoyl-(4)-oxy]-3-12-(2,6-dimethoxyphenoxy}-ethyl- 15 amino]-propanol-(2) _ : : _ 65% af det teoretiske, smeltepunkt 136-138°C, af 4-(2,3-epoxypropoxy)-carbazol og 2-(2,6-dimethoxyphenoxy)-ethyl= amin.
h) 1-[carbazoyl-(4)-oxy]-3-[2-(2-methoxyphenoxy)-propyl= 20 amino]-propanol-(2)_ 83% af det teoretiske, smeltepunkt 137-157°C (rå blanding af diastereomere) og deraf ved 2 ganges omkrystallisation af eddikeestere: 22% af det teoretiske, smeltepunkt 173-175°C, af 4-(2,3-epoxypropoxy)-carbazol og 2-(2-methoxy= 2 5 phenoxy)-propylamin.
i) 1-[carbazolyl-(4)-oxy]-3-[2-(2-methylmercaptophenoxy)- ethylamino]-propanol-(2) '_
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12 40% af det teoretiske, smeltepunkt 83-85°C, af 4-(2,3-epoxy= propoxy)-carbazol og 2-(2-methylmercaptophenoxy)-ethylamin.
k) 1-[carbazolyl-(4)-oxy]-3-[2-(2-benzyloxyphenoxy)-ethyl= amino]-propanol-(2)_: _ 5 56% af det teoretiske, smeltepunkt 138-139°C, af 4-(2,3- epoxypropoxy)-carbazol og 2-(2-benzyloxyphenoxy)-ethylamin.
De i eksemplerne 3c, 3d, 3f, 3g og 3i anvendte udgangsami= ner kan fremstilles ved litteraturanaloge omsætninger via de tilsvarende nitriler.
10 2,3-dimethylphenoxy-acetonitril.
100 g 2,3-dimethylphenol, 57 ml chloracetonitril, 110 g kaliumcarbonat og 2,0 g kaliumjodid omrøres i 300 ml me= thylethylketon i 5 timer under tilbagesvaling. Man frasuger, inddamper, destillerer remanensen og får 88,0 g farveløs 15 olie, kogepunkt13 137-142°C.
Analogt får man ved omsætninger af 5-indanol, 3,4-methylen= dioxyphenol eller 2-(methylmercapto)-phenol med chloraceto= nitril:
Indanyl-(5)-oxy-acetonitril, kogepunkt^ 162-165°C 20 3,4-methylendioxyphenoxy-acetonitril, kogepunkt^ 170-175°C
2-methylmercaptophenoxy-acetonitril, smeltepunkt 56-58°C, kogepunkt^2 173-176°C.
2-[Indanyl-(5)-oxy]-ethylamin 109 g Indanyl-(5)-oxy-acetonitril bliver i nærværelse af 25 Raneynikkel hydreret i 700 ml ethanol og 180 ml flydende ammoniak ved 110 atmosfærer og 90°C. Efter destillation får man 86 g farveløs olie, kogepunkt^ 154-156°C.
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Analogt får man af 2,3-dimethylphenoxy-acetonitril, hen= holdsvis 3,4-methylendioxyphenoxy-acetonitril ved hydre= ring:
5 2-(2,3-dimethylphenoxy)-ethylamin, kogepunkt^ 129-132°C
2-(3,4-methylendioxyphenoxy)-ethylamin, kogepunkt.^ 162-164° C.
2-(2-methylmercaptophenoxyj-ethylamin 26,7 g (2-methylmercaptophenoxy)-acetonitril reduceres med 10 8,5 g lithiumaluminiumhydrid i 1,3 liter ether (4 timer under tilbagesvaling). Efter sædvanlig oparbejdning og de= stillation fås 21,0 g farveløs olie, kogepunktQ ^ 117-120° C.
Analogt ved reduktion af 2,6-dimethoxyphenoxy-acetonitril:
15 2-(2,6-dimethoxyphenoxy)-ethylamin, kogepunkt^ 160-162°C
Eksempel 4 1-[carbazolyl-(4)-oxy]-3-[2-(2-methylphenoxy)-ethylamino]-propanol- (2) _' _' _' _ 6,0 g 4-(2,3-epoxypropoxy)-carbazol og 7,6 g 2-(2-methyl= 20 phenoxy)-ethylamin omrøres i 20 timer ved 70°C. Man oplø= ser i methylenchlorid og adskiller blandingen ved kromato= grafi på en kieselgelsøjle (500 ml) med løbemidlerne me= thylenchlorid, methylenchlorid-eddikeester (9:1 og 7:3), eddikeester og eddikeester-methanol (9:1). Rækkefølge i 25 elueringen: tertiær amin, sekundær amin, primær udgangs= amin. Efter udrivning med ether og omkrystallisation af ed= dikeester under anvendelse af aktive kul og blegejord fås tepunkt 125-126°C.
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14 På analog måde får man: a) 1-[carbazolyl-(4)-oxy]-3-[2-(3-methylphenoxy)-ethylami= no] -propanol- (2)_;_ : : : ' 5 43% af det teoretiske, smeltepunkt 129-130°C, af 4-(2,3- epoxypropoxy)-carbazol og 2-(3-methylphenoxy)-ethylamin.
b) 1-[carbazolyl-(4)-oxy]-3-[2-(2-chlorphenoxy)-ethylamino]- propanol-(2)_ 26% af det teoretiske, smeltepunkt lll-112°Cf af 4-(2,3-10 epoxypropoxy)-carbazol og 2-(2-chlorphenoxy)-ethylamin.
c) 1-[carbazolyl-(4)-oxy]-3-[2-(3-methoxyphenoxy)-ethylami= no]-propanol-(2)_ 22% af det teoretiske, smeltepunkt 111-113°C, af 4-(2,3-epoxypropoxy)-carbazol og 2-(3-methoxyphenoxy)-ethylamin.
15 d) 1-[carbazolyl-(4)-oxy]-3-[2-(4-methoxyphenoxy)-ethylami= no ] -propanol- (2)_' __ 48% af det teoretiske, smeltepunkt 106-108°C, af 4-(2,3-epoxypropoxy)-carbazol og 2-(4-methoxyphenoxy)-ethylamin.
e) 1-[carbazolyl-(4)-oxy]-3-[2-(2-methoxyphenylmercapto)- 20 ethylamino] -propanol- (2)__' __ 15% af det teoretiske, smeltepunkt 108-109°C, af 4-(2,3-epoxypropoxy)-carbazol og 2-(2-methoxyphenylmercapto)-ethylamin.
f) 1-[carbazolyl-(4)-oxy]-3-[1-(2-methoxyphenoxy)-propyl- 25 (2)-amino]-propanol-(2)__;_ ' '
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15 85% af det teoretiske, smeltepunkt 112-125°C (rå blanding af diastereomere) og deraf ved omkrystallisation af ethanol eddikeester og toluol—isopropanol, farveløse krystaller, smeltepunkt 140-141°C og af moderluden et yderligere pro= 5 dukt, smeltepunkt 121,5-122,5°C, af 4-(2,3-epoxyprqpoxy)-carbazol og 1-(2-methøxyphenoxy)-propyl-(2)-amin.
g) 1-[carbazolyl-(4)-oxy]-3-[2-(2-methylsulfinylphenoxy)-ethylamino 3-propanol-(2)_ 25% af det teoretiske,, oxalat smelter fra 126°C under de= 10 komponering, af 4-(2,3-epoxypropoxy)-carbazol og 2—(2-me= thylsulfinylphenoxy)-ethylamin.
Forbindelsen fås også ved oxidation af 1-[carbazolyl-(4)-oxy]-3-[2-(2-methylmercaptophenoxy)-ethylamino]—propanol- (2), jf. eksempel 3i, med den ækvivalente mængde hydrogen= 15 peroxid i eddikesyre ved stuetemperatur.
Udgangsaminerne til eksemplerne 4e, 4f og 4g kan fremstil= les ved litteraturanaloge omsætninger som følger: 2- (2 -methoxyphenyIntercapto) -ethylamin
Ved omsætning af o-(2—chlorethylmercapto)-anisol i flyden= 20 de ammoniak (8 timer 120°C), olie med kogepunkt0 118-122°C, smeltepunkt af hydrochlorid 163-167°C.
1- (2-methoxyphenoxy)-propyl-(2)-amin
Ved hydrering af 2-methoxyphenoxy-acetone i ammoniak-etha= nol (120 atmosfærer, 90°C), olie, kogepunkt.^ 144-M6°C, 25 oxalat smeltepunkt 199-200°C under dekomponering.
2- (2-methylsulf inylphenoxy)-ethylamin
Ved oxidation af 2-(2-methylmercapto)-ethylamin med 1 ækvi=
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16 valent perhydrol (30%) i eddikesyre ved stuetemperatur, olie, oxalat smeltepunkt 174-175°C.
Eksempel 5 1-[carbazolyl-(4)-oxy]-3-[N-benzyl-2-(2-methoxyphenoxy)-5 ethylamino]-propanol-(2)_ 15,1 g 4-(2,3-epoxypropoxy)-carbazol og 16,2 g N-[2-(2-methoxyphenoxy)-ethyl]-benzylamin i 50 ml ethylenglycol= dimethylether opvarmes under tilbagesvaling i 24 timer.
Man bringer til tørhed, renser over en kieselgelsøjle med 10 løbemidlerne methylenchlorid, methylenchlorid-eddikeester (9:1 og 7:3) eddikeester og udriver remanensen af hoved= fraktionen med ether. Udbytte 25,0 g (80% af det teoreti= ske) farveløse krystaller, smeltepunkt 97-99°C.
På analog måde får man: 15 a) 1-[carbazolyl-(4)-oxy3-3-[N-methyl-2-(2-methoxyphenoxy)-ethylamino]-propanol-(2)' ' · 22% af det teoretiske, farveløs olie, hydrochlorid smelte= punkt 109°C (let gasudvikling), af 4-(2,3-epoxypropoxy)-carbazol og N-methyl-2-(2-methoxyphenoxy)-ethylamin.
20 b) 1-[carbazolyl-(4)-oxy]-3-[N-buty1-2-(2-methophenoxy)- ehtylamino 3 -propanol- (2)...... ' : : 84% af det teoretiske, farveløse olie, hydrochlorid smelte= punkt 169-170°C, af 4-(2,3-epoxypropoxy)-carbazol og N-[2-(2-methoxyphenoxy)-ethyl]-butylamin.
25 c) 1-[carbazolyl-(4)-oxy]-3-[N-benzyl-2-(5-carbamoyl-2-py= ridyloxy)-ethylamino]-propanol-(2) _____ 80% af det teoretiske, smeltepunkt 165-167°C.
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17 af 4-(2,3-epoxypropoxy)-carbazol og N-[2-(5-carbamqyl-2-pyridyloxy)-ethyl]-benzylamin.
Eksempel 6 5 1-[carbazolyl-(4)-oxy]-2-formyloxy-3-[N-benzyl-2-(2-metho= xyphenoxy)-ethylamino]-propanhydrochlorid_
Man lader en af 3 ml myresyre og 6 ml eddikesyreanhydrid fremstillet myresyre—eddikesyre-anhydridblanding indvirke på 7,9 g 1-[carbazolyl-(4)-oxy]-3-[N-benzyl-2-(2-methoxy= 10 phenoxy)-ethylamino]-propanol-(2) i 2 1/2 dag ved stuetem= peratur, hælder i isvand neutraliserer, med natriumbicarbonat= opløsning, ekstraherer med methylenchlorid og udfælder hy= drochloridet af en etherisk opløsning af ekstraktremanensen. Udbytte 8,1 g (91% af det teoretiske) farveløse krystaller, 15 der sintrer fra 85°C og danner blærer fra 120°C.
Eksempel 7 1-[carbazolyl-(4)-oxy]-2-pivaloyloxy-3-[N-benzyl-2-(2-meth= oxyphenoxy)-ethylamino]-propanhydrochlorid._ I en opløsning af 7,0 g 1-[carbazolyl-(4)-oxy]-3-[N-benzyl-20 2-(2-methoxyphenoxy)—ethylamino]-propanol-(2) i 35 ml py= ridin indføres 1,9 ml pivalinsyrechlorid. Efter henstand natten over hælder man i vand, optager i methylenchlorid, renser kromatografisk over en kieselgelsøjle og udfælder hydrochloridet af en etherisk opløsning af basen.
25 Udbytte 6,6 g (77% af det teoretiske) farveløse krystaller, der sintrer fra 102°C, og som har smeltepunkt 120°C under let gasudvikling.
På analog måde får man ved benzoylering:
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18 1-[carbazolyl-(4)-oxy]-2-benzoyloxy-3-[N-benzyl-2-(2-meth= oxyphenoxy)-ethylamino]-propanhydrochlorid_ 70% af det teoretiske, smeltepunkt 113°C (let gasudvikling).
Eksempel 8 5 1-[carbazolyl-(4)-oxy]-2-formyloxy-3-[2-(2-methoxyphenoxy)- ethylamino]-propanhydrochlorid ♦_ 2,2 g 1-[carbazolyl-(4)-oxy]-2-formyloxy-3-[N-benzyl-2-(2-methoxyphenoxy)-ethylamino]-propanhydrochlorid hydreres i 40 ml absolut tetrahydrofuran i nærværelse af 0,3 g 10% 1° palladium på kulstof ved normalt tryk. Remanensen, der fås efter frasugning og inddampning, bliver krystallinsk ved gennemarbejdning med ether. Udbytte 1,3 g (70% af det teo= retiske) farveløse krystaller, smeltepunkt 62°C (under blæ= redannelse).
15 på analog måde får man: a) 1-[carbazolyl-(4)-oxy]-2-pivaloyloxy-3-[2-(2-methoxy= phenoxy)-ethylamino]-propanhydrochlorid_ 85% af det teoretiske, smeltepunkt 199-201°C (let gasud= vikling), ved hydrogenolyse af 1-[carbazolyl-(4)-oxy]-2-20 pivaloyloxy-3-[N-benzyl-2-(2-methoxyphenoxy)-ethylamino]- propanhydrochlorid.
b) 1-[carbazolyl-(4)-oxy]-2-benzoyloxy-3-[2-(2-methoxy= phenoxy)-ethylamino]-propanhydrochlorid_ 84% af det teoretiske, smeltepunkt 102°C (under gasudvik= 25 ling), ved hydrogenolyse af 1-[carbazolyl-(4)-oxy]-2-ben= zoyloxy-3-[N-benzyl-2-(2-methoxyphenoxy)-ethylamino]-pro= panhydrochlorid.
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c) 1-[carbazoyl-(4)-oxy]-3-[2-(5-carbamoyl-2-pyridyloxy)- ethylamino]-propanol- (2) _
Smeltepunkt 176-178°C, ved hydrogenolyse af 1-[carbazolyl- (4)-oxy]-3-[N-benzyl~2-(5-carbamoyl-2-pyridyloxy)-ethyl= 5 amino]-propanol-(2).
d) 1-[carbazolyl-(4)-oxy]-3-[2-(2-hydroxyphenoxy)-ethyl= amino ] -propanol- (2)________ 77% af det teoretiske, hydrochlorid, smeltepunkt 214-215° C, ved hydrogenolyse af 1-[carbazolyl-(4)-oxy]-3-[2-10 benzyloxyphenoxy)-ethylamino]-propanol-(2).
Eksempel 9 1-[-carbazolyl-(4)-oxy]-3-[2-(5-fluor-2-methoxyphenoxy)-ethylamino] -propanol-;(2)_ 7,0 g l-amino-3-[carbazolyl-(4)-oxy]-propanol-(2), 9,2 g 15 p-toluolsulfonsyre-[2—(5-fluor-2-methoxyphenoxy)-ethyl= ester] og 3,8 ml triethylamin omrøres i 20 ml dimethyl= formamid i 20 timer vad 70° C. Man hælder i fortyndet na= tronlud, ekstraherer med methylenchlorid, tørrer og renser kromatografisk som anført i eksempel 4. Efter omkrystalli= 20 sation af eddikester under anvendelse af aktive kul og ble= gejord fås 2,7 g (23% af det teoretiske) farveløse krystal= ler, smeltepunkt 146-147°C.
Udgangsforbindelserne kan fremstilles som følger: l-amino-3-[carbazolyl-(4)-oxy]-propanol-(2) 25 40 g 4-(2,3-epoxypropoxy)-carbazol omrøres med 500 :ml fly= dende ammoniak i 2 liter methanol i 24 timer ved 50°C (autoklav). Efter inddampning og omkrystallisation af etha= nol:31 g farveløse krystaller, smeltepunkt 141-143°C.
DK 154555 B
20 p-toluolsulfonsyre-[2-(5-fluor-2-methoxyphenoxy)-ethylesterj 40,4 g 5-fluor-2-methoxyphenol, 24,6 ml 2-chlorethanol og 20,7 g kaliumhydroxid omrøres i 100 ml DMF i 2 timer ved 70°C. Man hælder i vand, ekstraherer med methylenchlorid, 5 destillerer ekstraktremanensen i finvakuum og får 11,3 g 2-(5-fluor-2-methoxyphenoxy)-ethanol som en farveløs olie, der størkner ved henstand. Smeltepunkt 43-45°C. Den videre omsætning med p-toluolsulfonsyrechlorid giver tosylatet, smeltepunkt 66-68°C (af ethanol).
10 Eksempel 10 1-[carbazolyl-(4)-oxy]-3-[1-(2-methoxyphenoxy)-propyl-(2)-amino]-propanol-(2)_
Man hydrerer en blanding af 8,1 g l-amino-3-[carbazolyl- (4)-oxy]-propanol-(2) og 6,0 (2-methoxyphenoxy)-acetone i 15 250 ml methanol i nærværelse af 1,0 g 10% palladium på kulstof (5 atmosfærer,38°C) og renser det fremkomne råpro= dukt kromatografisk som anført i eksempel 4. Efter udriv= ning af hovedfraktionens remanens fås 5,5 g (41% af det teoretiske) farveløse krystaller, smeltepunkt 113-117°C, 20 rå diastereomerblanding. Ved omkrystallisation af eddike= ester og af ethanol fås deraf et produkt med konstant smel= tepunkt 140-141°C.
Eksempel 11 1-[carbazolyl-(4)-oxy]-3-[3-(2-methoxyphenyl)-propylamino] -25 propanol-(2) _ ~ ~ ' _______' '
Til en opløsning af 6,0 g l-amino-3-[carbazolyl-(4)-oxy]-propanol-(2) og 3,3 ml triethylamin i 50 ml methylenchlorid dryppes ved stuetemperatur en opløsning af 4,4 g 3-(2-meth= oxyphenyl)-propionsyrechlorid i 50 ml methylenchlorid under 30 omrøring. Efter henstand natten over udryster man med vand.
21
DK 154555B
tørrerden organiske fase, inddamper, omrører remanensen med ether og får 8,2 g (84% af det teoretiske) l-[carbazolyl-(4) -oxy]-3-[3-(2-methoxyphenyl)-propionylamino]-propanol-(2), smeltepunkt 142-144°C. 7,7 g af dette mellemprodukt reduce= 5 res med 1,5 g lithiumaluminiurahydrid i 100 ml absolut tetra= hydrofuran (20 timer under tilbagesvaling). Olien, der fås efter sædvanlig oparbejdning, renses kromatografisk over en kieselgelsøjle (jf. eksempel 4). Ved omkrystallisation af toluol under anvendelse af aktive kul og blegejord fås 2,1 g 10 (28% af det teoretiske) farveløse krystaller, smeltepunkt 102-104°C.
Sammenligningsforsøg A. Vasodilatorforsøg
Kaniner blev bedøvet med urethan, og et kateter .blev indsat 15 i midterste ørearterie (A. femoralis) til kontinuerlig måling af deres arterieblodtryk. Blodtryksmålingerne blev udført under anvendelse af en elektromekanisk transducer (Statham P 23Db) og blev optegnet på en direkte printer og benyttet efter kalibrering med et kviksølvmanometer.
2o Efter bestemmelse af udgangsværdien blev begge halsarterier (A. coratis) lukket i to min., og blodtrykket blev derved midlertidigt forøget (CSE-refleks). Forsøgsforbindelsen blev så injiceret i den laveste forsøgsdosis (0,125 mg/kg) intravenøst,og otte min. senere blev CSE-refleksen igen induceret.. Med 25 intervaller på 15 min. blev farsøgsforbindelsen igen injiceret i logaritmisk forøget dosis (faktor 2), og CSE-refleksen igen induceret.
Forsøgsforbindelser, som under disse betingelser modererede den CSE-inducerede blodtryksstigning, blev påvist at være 30 vasodilatorer, og den dosis, som nedsatte CSE-refleksen med 30 mm Hg, blev bestemt (betegnet DE_^q ^ ^ i nedenstående tabel).
DK 154555 B
22 B. Forsøg med beta receptor blokerende virkning Hjertefrekvensen hos kaniner blev overvåget via implantede elektrodet og optegnet på en frekvenstæller med en massetid på 15 sek. Isoprenalin blev så injiceret intravenøst via 5 en ørevene og inducerede en stigning i hjertefrekvensen fra ca. 200 slag/min. til 330 slag/min. Derefter blev forsøgsforbindelsen administreret i stigende dosis (som i forsøg A) intravenøst, og stigningen i hjertefrekvens efter iso-prenalinbehandling blev igen optegnet. Hæmningen af isoprena-10 lin-tachycardia blev.taget som et mål for beta-blokerende virkning af forsøgsforbindelserne. Dosen, som begrænsede den af isoprenalin inducerede stigning i hjertefrekvensen til 250 slag/min. blev bestemt for hver forsøgsforbindelse og er i det følgende betegnet DE25Q.
15 Resultaterne af ovennævnte forsøg A og B er vist i nedenstående tabel. Bestemmelsen af lige effektive doser, dvs. DE „ J -30 mm Hg og DE25q/ blev foretaget på logaritmisk basis ud fra fire til seks individuelle forsøg, og derefter beregnedes kvotienten vasodilaterende dosis (DE „ )/beta-blokerende -3U mm Hg 20 dosis (DE2i-q). En høj kvotient anses for at vise forsøgsforbindelser, der udviser i hovedsagen beta-blokerende virkning, hvorimod forsøgsforbindelserne med en kvotient på ca.
1 blev betragtet som udvisende både beta-blokerende og vasodilaterende virkning i sammenlignelig grad.
23 DK 154555 B
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Claims (2)
- 0-CH9-CH-CH0-N - CH-CH-X-f Ar^] Λ, ° r2 p i* V 5 Cw;1 - H hvor R"*· er hydrogen, en alkanoylgruppe med 1-6 carbonatomer eller en benzoyl- eller naphthoylgruppe, 2 5. er hydrogen, en alkylgruppe med 1-6 carbonatomer eller en benzyl-, phenethyl- eller phenylpropylgruppe, 3 R er hydrogen eller en alkylgruppe med 1-6 carbonatomer, 4 R er hydrogen eller en alkylgruppe med 1-6 carbonatomer, X er en valensstreg, en -Cl^-gruppe, et oxygen- eller svovl-10 atom, Ar er en phenyl-, naphthyl-, indanyl-, tetrahydronaphthyl- eller pyridylgruppe, og 5 6 R og R , der kan være ens eller forskellige, hver er hydrogen, fluor, chlor eller brom, en alkylgruppe med 1-6 carbonatomer, 15 en aminocarbonylgruppe, en hydroxygruppe, en alkoxygruppe med 1-6 carbonatomer, en benzyloxygruppe, en alkylmercaptogruppe med 1-6 carbonatomer, en alkylsulfinylgruppe med 1-6 carbonatomer, en alkylsulfonylgruppe med 1-6 carbonatomer eller også sammen betyder en methylendioxygruppe, hvorhos i det tilfælde, hvor 4. o 20. er et oxygenatom, R og R sammen også kan betyde gruppen —CH20-, eller deres fysiologisk anvendelige salte, kendetegnet ved, at man på i og for sig kendt måde enten DK 154555 B a) omsætter en forbindelse af formlen II0-CHo-CH-CHo-Y Dόί , Δ o (II) i1' H i» hvor Y er en sulfonsyrerest eller et halogenatom, og R har 1 1' den for R anførte betydning, eller Y og R sammen betyder en valensstreg, med en forbindelse af formlen III HN-CH-CH-X-f Ar^} iii V ς U-J--LJ 2 3 4 V /R r r r x—y 2 3 4 5 6 5 hvor R,R,R,X, Ar, R og R har den ovennævnte betydning, eller b) omsætter en forbindelse af formlen IV o-ch~-ch-ch9-nh /vA 6 k2 <IV> QmQ ^ H 1 2 hvor R og R har den ovennævnte betydning, med en forbindelse af formlen V /Or'1'6 Y-CH-CH-X-f Ar ) (V) '3 '4 V c R R R5 t DK 154555 B 3 4 5 6 hvor Y,R,R,X, Ar,R og R har den ovennævnte betydning, eller c) reducerer en blanding af en forbindelse af formlen IV og en forbindelse af formlen VI A'·' 0=C - CH-XH Ar (VI) i3 k* \jy~~-r1 3 4 5 6 5 hvor R , R , X, Ar, R og R har den ovennævnte betydning, eller d) omsætter en forbindelse af formlen IV med en forbindelse af formlen VII °N pr r6 ^c-ch-xH Ar (VII) γ/ έ2 6 rende forbindelse, hvori R eller R er hydroxy, samt om ønsket 20 omdanner den fremkomne forbindelse af den almene formel I til et farmakologisk anvendeligt salt deraf.
- 2 5 6 hvor Y, R , X, Ar, R og R har den ovennævnte betydning, og 10 reducerer det fremkomne amid, hvorpå man om ønsket omdanner en alkylmercaptogruppe i en forbindelse af den almene formel I til en alkylsulfinyl- eller alkylsulfonylgruppe ved oxidation og/eller på kendt måde forethrer en forbindelse, hvori R~* eller R^ er en hydroxygruppe, og/eller forestrer en for-15 bindelse, hvori R^ er hydrogen, og/eller hydrolyserer en forbindelse, hvori R^* er alkanoyl, til den tilsvarende forbindelse, hvori R1 er hydrogen, og/eller omdanner en forbindelse, hvori R eller R° er alkoxy eller benzyloxy, til den tilsva-
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2815926 | 1978-04-13 | ||
| DE19782815926 DE2815926A1 (de) | 1978-04-13 | 1978-04-13 | Neue carbazolyl-(4)-oxy-propanolamin-derivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK141979A DK141979A (da) | 1979-10-14 |
| DK154555B true DK154555B (da) | 1988-11-28 |
| DK154555C DK154555C (da) | 1989-06-19 |
Family
ID=6036838
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK141979A DK154555C (da) | 1978-04-13 | 1979-04-06 | Analogifremgangsmaade til fremstilling af carbazolyl-(4)-oxy-propanolaminderivater eller deres farmakologisk anvendelige salte |
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| Country | Link |
|---|---|
| US (1) | US4503067A (da) |
| EP (1) | EP0004920B1 (da) |
| JP (2) | JPS54157558A (da) |
| AT (1) | AT375639B (da) |
| AU (1) | AU522975B2 (da) |
| BG (1) | BG61419B2 (da) |
| CA (1) | CA1129416A (da) |
| CS (2) | CS227007B2 (da) |
| DD (1) | DD143607A5 (da) |
| DE (2) | DE2815926A1 (da) |
| DK (1) | DK154555C (da) |
| ES (1) | ES479396A1 (da) |
| FI (1) | FI70406C (da) |
| HK (1) | HK2385A (da) |
| HU (1) | HU179433B (da) |
| IL (1) | IL57020A (da) |
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| LU (1) | LU88320I2 (da) |
| MX (1) | MX9203380A (da) |
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| SG (1) | SG52284G (da) |
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| DE2240599A1 (de) * | 1972-08-18 | 1974-02-28 | Boehringer Mannheim Gmbh | Tricyclische diphenylamin-derivate und verfahren zur herstellung derselben |
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| AT336176B (de) * | 1971-12-10 | 1977-04-25 | Sandoz Ag | Verfahren zur herstellung eines pharmazeutischen praparates |
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| GB1508208A (en) * | 1975-12-05 | 1978-04-19 | Ici Ltd | Amide derivatives |
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1978
- 1978-04-13 DE DE19782815926 patent/DE2815926A1/de not_active Withdrawn
-
1979
- 1979-04-02 CA CA324,667A patent/CA1129416A/en not_active Expired
- 1979-04-06 SU SU792745301A patent/SU810079A3/ru active
- 1979-04-06 AU AU45820/79A patent/AU522975B2/en not_active Expired
- 1979-04-06 FI FI791142A patent/FI70406C/fi not_active IP Right Cessation
- 1979-04-06 ES ES479396A patent/ES479396A1/es not_active Expired
- 1979-04-06 DK DK141979A patent/DK154555C/da not_active IP Right Cessation
- 1979-04-07 DE DE7979101063T patent/DE2960553D1/de not_active Expired
- 1979-04-07 EP EP79101063A patent/EP0004920B1/de not_active Expired
- 1979-04-08 IL IL57020A patent/IL57020A/xx unknown
- 1979-04-09 DD DD79212096A patent/DD143607A5/de not_active IP Right Cessation
- 1979-04-10 CS CS792434A patent/CS227007B2/cs unknown
- 1979-04-11 JP JP4311979A patent/JPS54157558A/ja active Granted
- 1979-04-11 ZA ZA791732A patent/ZA791732B/xx unknown
- 1979-04-12 AT AT0276279A patent/AT375639B/de not_active IP Right Cessation
- 1979-04-12 HU HU79BO1774A patent/HU179433B/hu unknown
-
1983
- 1983-04-04 US US06/479,921 patent/US4503067A/en not_active Expired - Lifetime
-
1984
- 1984-07-20 SG SG52284A patent/SG52284G/en unknown
-
1985
- 1985-01-10 HK HK23/85A patent/HK2385A/xx not_active IP Right Cessation
-
1987
- 1987-03-31 JP JP62076548A patent/JPS63258416A/ja active Pending
-
1991
- 1991-12-31 CS CS914200A patent/CS420091A3/cs unknown
-
1992
- 1992-06-25 MX MX9203380A patent/MX9203380A/es unknown
-
1993
- 1993-06-22 LU LU88320C patent/LU88320I2/de unknown
- 1993-06-29 NL NL930110C patent/NL930110I2/nl unknown
- 1993-09-27 LT LTRP1124A patent/LT2628B/xx unknown
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1994
- 1994-02-28 BG BG098612A patent/BG61419B2/bg unknown
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2240599A1 (de) * | 1972-08-18 | 1974-02-28 | Boehringer Mannheim Gmbh | Tricyclische diphenylamin-derivate und verfahren zur herstellung derselben |
| DE2424523A1 (de) * | 1974-05-21 | 1975-12-11 | Boehringer Mannheim Gmbh | Neue 1,2,3,4-tetrahydrocarbazol-derivate und verfahren zu deren herstellung |
Also Published As
| Publication number | Publication date |
|---|---|
| ATA276279A (de) | 1984-01-15 |
| DK154555C (da) | 1989-06-19 |
| JPS63258416A (ja) | 1988-10-25 |
| EP0004920A1 (de) | 1979-10-31 |
| LU88320I2 (de) | 1994-05-04 |
| AT375639B (de) | 1984-08-27 |
| ZA791732B (en) | 1980-05-28 |
| IL57020A0 (en) | 1979-07-25 |
| SU810079A3 (ru) | 1981-02-28 |
| DD143607A5 (de) | 1980-09-03 |
| FI70406C (fi) | 1986-09-19 |
| HK2385A (en) | 1985-01-18 |
| NL930110I1 (nl) | 1993-10-18 |
| LT2628B (lt) | 1994-04-25 |
| AU522975B2 (en) | 1982-07-08 |
| FI70406B (fi) | 1986-03-27 |
| JPH0123462B2 (da) | 1989-05-02 |
| CA1129416A (en) | 1982-08-10 |
| IL57020A (en) | 1982-07-30 |
| EP0004920B1 (de) | 1981-08-05 |
| CS227007B2 (en) | 1984-04-16 |
| AU4582079A (en) | 1979-10-18 |
| US4503067A (en) | 1985-03-05 |
| NL930110I2 (nl) | 1994-12-01 |
| BG61419B2 (bg) | 1997-07-31 |
| DE2960553D1 (en) | 1981-11-05 |
| ES479396A1 (es) | 1980-04-16 |
| CS420091A3 (en) | 1992-04-15 |
| HU179433B (en) | 1982-10-28 |
| DE2815926A1 (de) | 1979-10-18 |
| FI791142A7 (fi) | 1979-10-14 |
| DK141979A (da) | 1979-10-14 |
| MX9203380A (es) | 1992-09-01 |
| SG52284G (en) | 1985-03-29 |
| JPS54157558A (en) | 1979-12-12 |
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