NO172488B - PROCEDURE FOR THE PREPARATION OF 1,5-BENZOTIAZEPINE DERIVATIVES - Google Patents
PROCEDURE FOR THE PREPARATION OF 1,5-BENZOTIAZEPINE DERIVATIVES Download PDFInfo
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- NO172488B NO172488B NO922254A NO922254A NO172488B NO 172488 B NO172488 B NO 172488B NO 922254 A NO922254 A NO 922254A NO 922254 A NO922254 A NO 922254A NO 172488 B NO172488 B NO 172488B
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- 238000000034 method Methods 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 17
- -1 alkali metal hydrogen carbonate Chemical class 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- 238000006482 condensation reaction Methods 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- KJFRSZASZNLCDF-UHFFFAOYSA-N 1,5-benzothiazepine Chemical class S1C=CC=NC2=CC=CC=C12 KJFRSZASZNLCDF-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000012024 dehydrating agents Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 4
- SDGHXWKVBZYHRR-UHFFFAOYSA-N 2-(1h-imidazol-2-ylsulfonyl)-1h-imidazole Chemical compound N=1C=CNC=1S(=O)(=O)C1=NC=CN1 SDGHXWKVBZYHRR-UHFFFAOYSA-N 0.000 claims description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical group 0.000 claims description 2
- NCBFTYFOPLPRBX-UHFFFAOYSA-N dimethyl azodicarboxylate Substances COC(=O)N=NC(=O)OC NCBFTYFOPLPRBX-UHFFFAOYSA-N 0.000 claims description 2
- NCBFTYFOPLPRBX-AATRIKPKSA-N methyl (ne)-n-methoxycarbonyliminocarbamate Chemical compound COC(=O)\N=N\C(=O)OC NCBFTYFOPLPRBX-AATRIKPKSA-N 0.000 claims description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- CRYDUXLWJITARY-UHFFFAOYSA-N dimethyl(2-methylsulfonyloxyethyl)azanium;chloride Chemical compound Cl.CN(C)CCOS(C)(=O)=O CRYDUXLWJITARY-UHFFFAOYSA-N 0.000 description 4
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 4
- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- KYWXRBNOYGGPIZ-UHFFFAOYSA-N 1-morpholin-4-ylethanone Chemical compound CC(=O)N1CCOCC1 KYWXRBNOYGGPIZ-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- IKJIITMEIPMVQE-SJORKVTESA-N [(2s,3s)-8-chloro-2-(4-methoxyphenyl)-4-oxo-3,5-dihydro-2h-1,5-benzothiazepin-3-yl] acetate Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)NC2=CC=C(Cl)C=C2S1 IKJIITMEIPMVQE-SJORKVTESA-N 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 229940113088 dimethylacetamide Drugs 0.000 description 2
- 229910010272 inorganic material Inorganic materials 0.000 description 2
- 239000011147 inorganic material Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 229940017219 methyl propionate Drugs 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-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
- 239000008096 xylene Substances 0.000 description 2
- KAANMZCKNKVSAA-CABCVRRESA-N (2s,3s)-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-3,5-dihydro-2h-1,5-benzothiazepin-4-one Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](O)C(=O)NC2=CC=C(Cl)C=C2S1 KAANMZCKNKVSAA-CABCVRRESA-N 0.000 description 1
- FTUXVMVEKYLKGE-WECFPGDBSA-N (z)-but-2-enedioic acid;[(2s,3s)-8-chloro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate Chemical compound OC(=O)\C=C/C(O)=O.C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=C(Cl)C=C2S1 FTUXVMVEKYLKGE-WECFPGDBSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- BVABFIZTUSTDDW-UHFFFAOYSA-N 5h-1,2-benzothiazepin-4-one Chemical compound S1N=CC(=O)CC2=CC=CC=C21 BVABFIZTUSTDDW-UHFFFAOYSA-N 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- BNNSIRUFFKEGQU-BHDTVMLSSA-N [(2s,3s)-8-chloro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate;hydrochloride Chemical compound Cl.C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=C(Cl)C=C2S1 BNNSIRUFFKEGQU-BHDTVMLSSA-N 0.000 description 1
- WYVFVMUROJPJSS-UHFFFAOYSA-N [2-(dimethylamino)ethoxy]sulfonic acid Chemical compound CN(C)CCOS(O)(=O)=O WYVFVMUROJPJSS-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
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- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Hydrogenated Pyridines (AREA)
Description
Den foreliggende søknaden er avdelt fra NO patentsøknad 913422. The present application is divided from NO patent application 913422.
Den foreliggende oppfinnelsen angår en framgangsmåte for framstilling av 1,5-benzontiazepinderivater angitt ved formelen: The present invention relates to a process for the production of 1,5-benzothiazepine derivatives indicated by the formula:
hvor R<1> er en lavere alkoksygruppe, R<2> er hydrogen eller en lavere alkanoylgruppe, en av R<3 >og R<*> er et halogenatom, og den andre er hydrogen, og hver av R<5> og R<6> er en lavere alkylgruppe. ;1,5-benzotiazepinderivatet (I) og et farmasøytisk akseptabelt salt derav fremstilt ved tilsats av syre er egnede farmasøytiske forbindelser med en utmerket hypotensiv aktivitet, cerebral eller koronar vasodilaterende aktivitet og/eller blodplate sammenhopningsinhiberende aktivitet er kjent fra norske utlegningsskrifter 162518 og 163488, og blant forbindelsene (I), er en forbindelse hvor R<2> er hydrogenatom også egnet som et mellomprodukt for framstilling av farmasøytiske midler. ;Beskrivelse av de foretrukne utførelsesformene ;Eksempler på forbindelsen (I) under den foreliggende oppfinnelsen kan omfatte forbindelse hvori R<1> er en lavere alkoksygruppe, R2 er hydrogen eller en lavere alkanoylgruppe, en av R<3> eller R<4 >er et halogenatom, og den andre er hydrogenatom, og hver av R5 og R<6> er en lavere alkylgruppe. ;I de ovenfor nevnte eksempler på 1,5-benzotiazepinderivatet (I), inkluderer den lavere alkylgruppen, den lavere alkoksygruppen og den lavere alkanoylgruppen en alkylgruppe med fra 1 til 6 karbonatomer, en alkoksygruppe med fra 1 til 6 karbonatomer og en alkanoylgruppe med fra 2 til 6 karbonatomer, respektive. Foretrukne eksempler på disse gruppene er en alkylgruppe med fra 1 til 4 karbonatomer, en alkoksygruppe med fra 1 til 4 karbonatomer og en alkanoylgruppe med fra 2 til 5 karbonatomer. ;I følge den foreliggende oppfinnelsen kan forbindelsen (I) fremstilles ved å la en forbindelse angitt med formelen: hvor R<1>, R<2>, R<3> og R<*> har samme betydning som definert ovenfor, reagere med en aminetanol angitt med formelen: where R<1> is a lower alkoxy group, R<2> is hydrogen or a lower alkanoyl group, one of R<3 >and R<*> is a halogen atom, and the other is hydrogen, and each of R<5> and R<6> is a lower alkyl group. ; the 1,5-benzothiazepine derivative (I) and a pharmaceutically acceptable salt thereof prepared by the addition of acid are suitable pharmaceutical compounds with an excellent hypotensive activity, cerebral or coronary vasodilatory activity and/or platelet aggregation inhibitory activity are known from Norwegian explanatory documents 162518 and 163488, and among the compounds (I), a compound in which R<2> is a hydrogen atom is also suitable as an intermediate for the production of pharmaceuticals. ;Description of the preferred embodiments ;Examples of the compound (I) under the present invention may include compound in which R<1> is a lower alkoxy group, R2 is hydrogen or a lower alkanoyl group, one of R<3> or R<4> a halogen atom, and the other is a hydrogen atom, and each of R5 and R<6> is a lower alkyl group. ;In the above-mentioned examples of the 1,5-benzothiazepine derivative (I), the lower alkyl group, the lower alkoxy group and the lower alkanoyl group include an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms and an alkanoyl group having from 2 to 6 carbon atoms, respectively. Preferred examples of these groups are an alkyl group with from 1 to 4 carbon atoms, an alkoxy group with from 1 to 4 carbon atoms and an alkanoyl group with from 2 to 5 carbon atoms. According to the present invention, the compound (I) can be prepared by allowing a compound represented by the formula: where R<1>, R<2>, R<3> and R<*> have the same meaning as defined above, to react with an amine ethanol given by the formula:
hvor R<5> og R<6> har samme betydning som angitt ovenfor, og Z er hydrogen, en lavere alkylsulfonylgruppe, en arylsulfonylgruppe eller sulfogruppe, ved en kondensasjonsreaksjon. where R<5> and R<6> have the same meaning as stated above, and Z is hydrogen, a lower alkylsulfonyl group, an arylsulfonyl group or sulfo group, by a condensation reaction.
Kondensasjonsreaksjonen ovenfor, når utgangsforbindelsen (TH) hvor Z er hydrogen benyttes, kan utføres i nærvær av et dehydreringsmiddel. Som dehydreringsmiddel kan det f.eks. brukes en blanding av trifenylfosfin og dietylazodikarboksylat, en blanding a trifenylfosfm og dimetylazodikarboksylat, en blanding av sulfuryldiimidazol og natriumhydrid. Denne kondensasjonsreksjonen kan fortrinnsvis utføres i et egnet løsningsmiddel, (f.eks., kloroform, dikloroetan, diklorometan, aceton, dietylketon, metyletylketon, etylacetat, metylacetat, etylpropionat, metylpropionat, dimetylformamid, dietylformat, dimetylacetamid, N-formylmorfolin, N-acetylmorfolin, dioxan, tetrahydrofuran, eter, dimetoksyetan, diglym, toluen, benzen, xylen, etc.) ved 0 til 150°C. The above condensation reaction, when the starting compound (TH) where Z is hydrogen is used, can be carried out in the presence of a dehydrating agent. As a dehydrating agent, it can e.g. a mixture of triphenylphosphine and diethylazodicarboxylate, a mixture of triphenylphosphine and dimethylazodicarboxylate, a mixture of sulphuryldiimidazole and sodium hydride are used. This condensation reaction can preferably be carried out in a suitable solvent, (eg, chloroform, dichloroethane, dichloromethane, acetone, diethyl ketone, methyl ethyl ketone, ethyl acetate, methyl acetate, ethyl propionate, methyl propionate, dimethylformamide, diethyl formate, dimethylacetamide, N-formylmorpholine, N-acetylmorpholine, dioxane, tetrahydrofuran, ether, dimethoxyethane, diglyme, toluene, benzene, xylene, etc.) at 0 to 150°C.
På den andre side, når forbindelsen (III) hvor Z er en lavere alkylsulfonylgruppe (f.eks. metylsulfonylgruppe, etylsulfonylgruppe) en arylsulfonylgruppe, (f.eks. benzensulfonylgruppe, tosylgruppe) eller sulfogruppe, kan kondensasjonsreaksjonen for nevnte forbindelse og forbindelsen (2) fortrinnsvis utføres i nærvær av et alkalisk reagens. Eksempler på det alkaliske reagens kan omfatte alkalimetallhydroksider (f.eks. kaliumhydroksid, etc), alkalimetall karbonater (f.eks. kaliumkarbonat, etc), alkalimetall hydrogenkarbonater (f.eks. kaliumhydrogenkarbonat, etc), alkalimetall hydrider (f.eks. natriumhydrid, etc). Denne kondensasjonsreaksjonen bør fortrinnsvis utføres i et egnet løsningsmiddel (f.eks. metyletylketon, dietylketon, aceton, dimetylsulfoksid, dimetylformamid, etylacetat, metylpropionat, etylpropionat, tetrahydrofuran, dioxan, eter, dimetoksyetan, diglym, toluen, benzen, xylen, acetonitril, dimetylacetamid, dietylformamid, N-formylmorfolin, N-acetylmorfolin, etc.) ved 0 til 150°C. On the other hand, when the compound (III) where Z is a lower alkylsulfonyl group (e.g., methylsulfonyl group, ethylsulfonyl group), an arylsulfonyl group, (e.g., benzenesulfonyl group, tosyl group) or sulfo group, the condensation reaction of said compound and the compound (2) preferably carried out in the presence of an alkaline reagent. Examples of the alkaline reagent may include alkali metal hydroxides (e.g. potassium hydroxide, etc), alkali metal carbonates (e.g. potassium carbonate, etc), alkali metal hydrogen carbonates (e.g. potassium hydrogen carbonate, etc), alkali metal hydrides (e.g. sodium hydride , etc). This condensation reaction should preferably be carried out in a suitable solvent (e.g. methyl ethyl ketone, diethyl ketone, acetone, dimethyl sulfoxide, dimethyl formamide, ethyl acetate, methyl propionate, ethyl propionate, tetrahydrofuran, dioxane, ether, dimethoxyethane, diglyme, toluene, benzene, xylene, acetonitrile, dimethyl acetamide, diethylformamide, N-formylmorpholine, N-acetylmorpholine, etc.) at 0 to 150°C.
Da reaksjonen under den foreliggende oppfinnelsen som nevnt ovenfor går uten medfølgende racemisering, kan forbindelsen (I) fremstilles som en optisk aktiv forbindelse ved bruk av en optisk aktiv forbindelse (II) som utgangsmateriale. Også, blant forbindelsene (I), er forbindelsen hvor R2 er hydrogen også nyttig som et syntetisk mellomprodukt, siden denne forbindelsen kan konverteres ved acylering til en forbindelse (I) hvor R<2> er en lavere alkanoylgruppe. Since the reaction under the present invention as mentioned above proceeds without accompanying racemization, the compound (I) can be prepared as an optically active compound using an optically active compound (II) as starting material. Also, among the compounds (I), the compound wherein R 2 is hydrogen is also useful as a synthetic intermediate, since this compound can be converted by acylation to a compound (I) wherein R< 2 > is a lower alkanoyl group.
Utgangsforbindelsen (II) for bruk under den foreliggende oppfinnelsen kan framstilles ifølge framgangsmåtene beskrevet i japansk patentskrift nr. 225174/1984, (som tilsvarer U.S. Patentskrift nr. 4 567 175). The starting compound (II) for use in the present invention can be prepared according to the methods described in Japanese Patent No. 225174/1984, (corresponding to U.S. Patent No. 4,567,175).
Forbindelsen (I) og forbindelsen (II) omfatter også enten to slag stereoisomerer (det vil si, cis og trans-siomerer) eller 4 slag optiske isomerer (det vil si, (+) -cis, (-)-cis, (+)-trans og (-)-trans isomerer) og blandinger derav basert på asymetriske karbonatomer (2) i molekylet. The compound (I) and the compound (II) also include either two kinds of stereoisomers (that is, cis and trans isomers) or 4 kinds of optical isomers (that is, (+)-cis, (-)-cis, (+ )-trans and (-)-trans isomers) and mixtures thereof based on asymmetric carbon atoms (2) in the molecule.
Eksempel 1: Example 1:
Til 80 ml diklorometanoppløsning av 3 g av (+)-cis-2-(4- metoksyfenyl)-3-acetoksy-8-cloro-2,3-dihydro-l,5-benzotiazepin- 4(5H)-on og 2,3 g trifenylfosfin ble det tilsatt 15 ml diklorometanoppløsning av 779 mg 2- (dimetylamino)etanol i løpet av 20 minutter, deretter 15 ml diklorometanoppløsning av 1,52 g dietylazodikarboksylat ved romtemperatur i løpet av 20 minutter. Blandingen ble omrørt i 20 timer ved romtemperatur, etterfulgt av inndampning under redusert trykk. Residuet ble oppløst i etylacetat og uoppløselige stoffer ble fjernet ved filterering. Filtratet ble ekstrahert med en 10% saltsyre, og den vanndige fasen ble gjort alkalisk ved hjelp av kaliumkarbonat og ekstrahert med kloroform. Ekstraktet ble vasket med vann, tørket og fordampet under redusert trykk. Residuet ble konvertert til maleat og rekrystallisering fra etanol gav 3,55 g (+)-cis-2(4-metoksyfenyl)-3-acetoksy-5-[2-(dimetylamino)etyl]-8-cloro-2,3-dihydro-l,5-benzotiazepin-4(5H)-on.maleat.Utbytte: 79.2 %. To 80 ml dichloromethane solution of 3 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 2 .3 g of triphenylphosphine, 15 ml of a dichloromethane solution of 779 mg of 2-(dimethylamino)ethanol was added over the course of 20 minutes, then 15 ml of a dichloromethane solution of 1.52 g of diethyl azodicarboxylate at room temperature over the course of 20 minutes. The mixture was stirred for 20 hours at room temperature, followed by evaporation under reduced pressure. The residue was dissolved in ethyl acetate and insoluble substances were removed by filtration. The filtrate was extracted with a 10% hydrochloric acid, and the aqueous phase was made alkaline with potassium carbonate and extracted with chloroform. The extract was washed with water, dried and evaporated under reduced pressure. The residue was converted to maleate and recrystallization from ethanol gave 3.55 g of (+)-cis-2(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3- dihydro-1,5-benzothiazepin-4(5H)-one maleate. Yield: 79.2%.
Smeltepunkt 158 til 160 °C. Melting point 158 to 160 °C.
Eksempel 2: Example 2:
Etter omrøring av en blanding av 354 mg 2-(dimetylamino)- etanol og 159 mg av 60% natriumhydrid i 14 ml dimetylformamid ved romtemperatur i 20 minutter, ble det tilsatt 787 mg sulfuryldiimidazol ved -40 °C til bladningen og blandingen ble omrørt ved samme temperaturen i en time. Deretter ble det tilsatt 5 ml dimetylsulfoksid-oppløsning av en 1.0 g av (+)-cis-2-(4-metoksyfenyl)-3-acetoksy-8-kloro-2,3-dihydro-l ,5-benzotiazepin^(5H)-on ved - 40°C og etter gradvis oppvarming, ble reaksjonsblandingen omrørt ved romtemperatur i 20 timer. Etter at reaksjonen hadde gått til endes ble det tilsatt metanol og kloroform. Blandingen ble vasket med vann og tørket, etterfulgt av fjerning av løsningsmiddelet, og residuet ble separert i en kromatografisk kolonne. Etter fjerning av utgangslaktamet ved elusjon med kloroform-etanol (20:1), ble det deretter eluerte oljeaktige produktet konvertert til mal eat og rekrystallisert fra etanol for å gi 777 mg (+)-cis-2-(4-metoksyfenyl)-3-acetoksy-5-[2-dimetylamino)-etyl]-8-klor-2,3-dihydro-l,5-benzotiazepin-4(5H)-on.maleat. After stirring a mixture of 354 mg of 2-(dimethylamino)-ethanol and 159 mg of 60% sodium hydride in 14 ml of dimethylformamide at room temperature for 20 minutes, 787 mg of sulfuryldiimidazole was added at -40 °C until the leafing and the mixture was stirred at same temperature for one hour. Then 5 ml of dimethylsulfoxide solution of a 1.0 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepine (5H )-on at -40°C and after gradual heating, the reaction mixture was stirred at room temperature for 20 hours. After the reaction had gone to completion, methanol and chloroform were added. The mixture was washed with water and dried, followed by removal of the solvent, and the residue was separated on a chromatographic column. After removal of the starting lactam by elution with chloroform-ethanol (20:1), the subsequently eluted oily product was converted to malt and recrystallized from ethanol to give 777 mg of (+)-cis-2-(4-methoxyphenyl)-3 -acetoxy-5-[2-dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one maleate.
Smeltepunkt 158 til 160 °C. Melting point 158 to 160 °C.
Eksempel 3: Example 3:
Til 30 ml acetonoppløsning av 1,86 g (+)-cis-2-(4-metoksyfenyl)-3-acetoksy-8-kloro-2,3-dihydro-l,5-benzotiazepin-4(5H)-on ble det tilsatt 2.4 g pulverformet kaliumkarbonat og 1,1 g av 2-(metylamino)etyl metan-sulfonat.hydroklorid, og blandingen ble kokt med tilbakeløp under omrøring i 10 timer. Etter at reaksjonen hadde gått til endes, ble uorganiske materialer fjernet ved filtrering, til residuet ble det tilsatt 10% saltsyre og etylacetat, og ekstrahert med 10% saltsyre. Ekstraktet ble vasket med vann, tørket og inndampet under redusert trykk. Residuet ble konvertert til hydroklorid og rekrystallisert fra en blanding av aceton-etanol for å gi 2,10 g (+)-cis-2-(4-metoksyfenyl)-3-acetoksy-5-[2Klimetylamino)etyl]-8-klor-2,3-dmydro-l,5-berizotiazepin-4(5H)-on.hydroklorid. To 30 ml acetone solution of 1.86 g (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was 2.4 g of powdered potassium carbonate and 1.1 g of 2-(methylamino)ethyl methanesulfonate hydrochloride were added, and the mixture was refluxed with stirring for 10 hours. After the reaction had gone to completion, inorganic materials were removed by filtration, 10% hydrochloric acid and ethyl acetate were added to the residue, and extracted with 10% hydrochloric acid. The extract was washed with water, dried and evaporated under reduced pressure. The residue was converted to the hydrochloride and recrystallized from an acetone-ethanol mixture to give 2.10 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2Clmethylamino)ethyl]-8-chloro -2,3-dihydro-1,5-berisothiazepin-4(5H)-one hydrochloride.
Utbytte: 86,5%. Yield: 86.5%.
Smeltepunkt 127 til 131 °C (dekomponerte). Melting point 127 to 131 °C (decomposed).
Eksempel 4: Example 4:
Til 50 ml dimetylsulfoksid oppløsning av 3.36 g av (+)-cis-2-(4-metoksyfenyl)-3-hydroksy-8-kloro-2,3-dihydro-l,5-benzotiazepin-4(5H)-on ble det tilsatt 1,35 g kaliumhydroksid under iskjøling og, etter omrøring ved romtemeratur, ble det tilsatt 244 mg 2-(dimetyIamino)etyl metansulfonat hydroklorid, etterfulgt av omrøring ved romtemperatur i 16 timer. Etter at reaksjonen hadde gått til endes, ble blandingen helt over i isvann og blandingen ble ekstrahert med en 1:1 blanding av kloroform og etanol. Ekstraktet ble vasket med vann, tørket og fordampet under redusert trykk. Rekrystallisering av 3,48 g av residuet fra en løsningsmiddelblanding av etylacetat og heksan ga 3,06 g (+)-cis-2-(4-metoksyfenyl)-3-hydroksy-5-[2-(dimetylamino)etyl]-8-klor-2,3-dihydro-l,5- To 50 ml of dimethyl sulfoxide solution of 3.36 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was to it was added 1.35 g of potassium hydroxide under ice-cooling and, after stirring at room temperature, 244 mg of 2-(dimethylamino)ethyl methanesulfonate hydrochloride was added, followed by stirring at room temperature for 16 hours. After the reaction had gone to completion, the mixture was poured into ice water and the mixture was extracted with a 1:1 mixture of chloroform and ethanol. The extract was washed with water, dried and evaporated under reduced pressure. Recrystallization of 3.48 g of the residue from a solvent mixture of ethyl acetate and hexane gave 3.06 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8 -chloro-2,3-dihydro-1,5-
benzotiazepin-4(5H)-on. benzothiazepin-4(5H)-one.
Utbytte: 75,2 % Yield: 75.2%
Smeltepunkt: 122 til 124 °C. Melting point: 122 to 124 °C.
Eksempel 5: Example 5:
Til 30 ml aceton-0.5 ml vann oppløsning av 1,68 g (+)-cis-2-(4-metoksyfenyl)-3-hydroksy-8-kloro-2,3-dihydro-l,5-benzotiazepin-4(5H)-on ble det tilsatt 2,40 g kaliumkarbonat og 1.09 g av 2-(dimetylamino)etyl metansulfonat.hydroklorid, etterfulgt av koking med tilbakeløp i 20 timer. Etter at reaksjonen hadde gått til endes, ble uorganiske materialer fjernet ved filtrering, til residuet ble det tilsatt 10% saltsyre og etylacetat og den organiske fasen ble ekstrahert med 10 % saltsyre. Saltsyrefasene ble slått sammen og gjort alkalisk med kaliumkarbonat og så ekstrahert med etylacetat. Ekstraktet ble vasket med vann, tørket, og fordampet under redusert trykk. Rekrystallisering av residuet fra en blanding av etylacetat-n- hexan ga 1.40 g (+)-cis-2-(4-metoksyfenyl)-3-hydroksy-5-[2-dimetylamino)etyl]-8-klor-2,3-dihydro-l ,5-benzotiazepin-4(5H)-on. To 30 ml acetone-0.5 ml water solution of 1.68 g (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepine-4( 5H)-one, 2.40 g of potassium carbonate and 1.09 g of 2-(dimethylamino)ethyl methanesulfonate hydrochloride were added, followed by refluxing for 20 hours. After the reaction had gone to completion, inorganic materials were removed by filtration, 10% hydrochloric acid and ethyl acetate were added to the residue and the organic phase was extracted with 10% hydrochloric acid. The hydrochloric acid phases were combined and made alkaline with potassium carbonate and then extracted with ethyl acetate. The extract was washed with water, dried, and evaporated under reduced pressure. Recrystallization of the residue from a mixture of ethyl acetate-n-hexane gave 1.40 g (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-dimethylamino)ethyl]-8-chloro-2,3 -dihydro-1,5-benzothiazepin-4(5H)-one.
Utbytte: 68.8 %. Yield: 68.8%.
Smeltepunkt: 123 til 125 °C. Melting point: 123 to 125 °C.
Eksempel 6: Example 6:
I eksempel 3, ved bruk av 2-(dimetylamino)etylbenzen-sulfonat.hydroklorid i stedet for 2-(dimetylamino)etyl metansulfonat-hydroklorid, ble det dannet (+)-cis-2-(4-metoksyfenyl)-3-acetoksy-5-[2-(dimetylamino)etyl]-8-klor-2,3-dihydro-l,5-benzotiazepin-4(5H)-on.hydroklorid. In Example 3, using 2-(dimethylamino)ethylbenzenesulfonate hydrochloride instead of 2-(dimethylamino)ethyl methanesulfonate hydrochloride, (+)-cis-2-(4-methoxyphenyl)-3-acetoxy was formed -5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride.
Dette produktet hadde de samme fysikalske data som produktet i eksempel 3. This product had the same physical data as the product in example 3.
Eksempel 7: Example 7:
I eksempel 3, ved bruk av 2-(dimetylamino)etyl toluensulfonat.hydroklorid i stedet for 2-(dimetylamino)etylmetamulfonat-hydroklorid,bledetdarmet(+)-cis-2-(4-metoksyfenyl)-3-acetoksy-5-[2-(dimetylamino)etyl]-8-klor-2,3-dihydro-l,5-benzotiazepin-4(5H)-on.hydroklorid. In Example 3, using 2-(dimethylamino)ethyl toluenesulfonate hydrochloride instead of 2-(dimethylamino)ethyl metasulfonate hydrochloride, the resulting (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[ 2-(Dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride.
Dette produktet hadde de samme fysikalske data som produktet i eksempel 3. This product had the same physical data as the product in Example 3.
Eksempel 8: Example 8:
I eksempel 3, ved bruk av 2-(dimetylamino)etyl sulfat i stedet for 2-(dimetylamino)etyl metansulfonat.hydroklorid, ble det dannet (+)-cis-2-(4-metoksyfenyl)-3-acetoksy-5-[2-(dimetylamino)etyl]-8-Mor-2,3-dmydro-l,5-benzotiazepin-4(5H^ In Example 3, using 2-(dimethylamino)ethyl sulfate instead of 2-(dimethylamino)ethyl methanesulfonate hydrochloride, (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5- [2-(Dimethylamino)ethyl]-8-Mor-2,3-dihydro-1,5-benzothiazepine-4(5H
Dette produktet hadde de samme fysikalske data som produktet i eksempel 3. This product had the same physical data as the product in example 3.
Eksemplene 9 og 10 Examples 9 and 10
Ved å behandle tilsvrende utgangsmateriale på samme måte som i eksemplene 1 til 5, kan følgende forbindelser fremstilles. (9) (+)-cis-2-(4-metoksyfenyl)-3-hydroksy-5-[2-(dimetylamino)etyl]-9-klor-2,3-dihydro-l,5-benzotiazepin-4(5H)-on.perklorat. 1/4 hydrat. By treating the corresponding starting material in the same way as in Examples 1 to 5, the following compounds can be prepared. (9) (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepine-4( 5H)-one.perchlorate. 1/4 hydrate.
Smeltepunkt 190 til 192°C. Melting point 190 to 192°C.
(10) (+)-cis-2-(4-metoksyfenyl-3-acetoksy-5-[2-(dimetylamino)etyl]-9-klor-2,3-dihydro-l,5-benzotiazepin-4(5H)-on.hydroklorid.monohydrat. (10) (+)-cis-2-(4-methoxyphenyl-3-acetoxy-5-[2-(dimethylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepine-4(5H )-on.hydrochloride.monohydrate.
Smeltepunkt 140 til 143°C. Melting point 140 to 143°C.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO922254A NO172488C (en) | 1987-08-21 | 1992-06-09 | PROCEDURE FOR THE PREPARATION OF 1,5-BENZOTIAZEPINE DERIVATIVES |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62208482A JPS6450872A (en) | 1987-08-21 | 1987-08-21 | Production of 1,5-benzothiazepine derivative |
| NO883526A NO170541C (en) | 1987-08-21 | 1988-08-09 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1,5-BENZOTIAZEPINE DERIVATIVES |
| NO922254A NO172488C (en) | 1987-08-21 | 1992-06-09 | PROCEDURE FOR THE PREPARATION OF 1,5-BENZOTIAZEPINE DERIVATIVES |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO922254L NO922254L (en) | 1989-02-22 |
| NO922254D0 NO922254D0 (en) | 1992-06-09 |
| NO172488B true NO172488B (en) | 1993-04-19 |
| NO172488C NO172488C (en) | 1993-07-28 |
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| Application Number | Title | Priority Date | Filing Date |
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| NO922254A NO172488C (en) | 1987-08-21 | 1992-06-09 | PROCEDURE FOR THE PREPARATION OF 1,5-BENZOTIAZEPINE DERIVATIVES |
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| Country | Link |
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1992
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| Publication number | Publication date |
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| NO172488C (en) | 1993-07-28 |
| NO922254L (en) | 1989-02-22 |
| NO922254D0 (en) | 1992-06-09 |
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