NO170358B - BETWEEN SHAFT-GEAR - Google Patents
BETWEEN SHAFT-GEAR Download PDFInfo
- Publication number
- NO170358B NO170358B NO882323A NO882323A NO170358B NO 170358 B NO170358 B NO 170358B NO 882323 A NO882323 A NO 882323A NO 882323 A NO882323 A NO 882323A NO 170358 B NO170358 B NO 170358B
- Authority
- NO
- Norway
- Prior art keywords
- coumarin
- general formula
- methyl
- mol
- dimethoxy
- Prior art date
Links
- 238000000034 method Methods 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 6
- 150000004775 coumarins Chemical class 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- CFNMUZCFSDMZPQ-GHXNOFRVSA-N 7-[(z)-3-methyl-4-(4-methyl-5-oxo-2h-furan-2-yl)but-2-enoxy]chromen-2-one Chemical compound C=1C=C2C=CC(=O)OC2=CC=1OC/C=C(/C)CC1OC(=O)C(C)=C1 CFNMUZCFSDMZPQ-GHXNOFRVSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- -1 haloalkyl ester Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 235000011121 sodium hydroxide Nutrition 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000000052 vinegar Substances 0.000 description 8
- 235000021419 vinegar Nutrition 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000007795 chemical reaction product Substances 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 150000005690 diesters Chemical class 0.000 description 7
- 239000013067 intermediate product Substances 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- BUHYMJLFRZAFBF-UHFFFAOYSA-N 3,4,5-trimethoxybenzoyl chloride Chemical compound COC1=CC(C(Cl)=O)=CC(OC)=C1OC BUHYMJLFRZAFBF-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 229940072033 potash Drugs 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229910001873 dinitrogen Inorganic materials 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- AESFGSJWSUZRGW-UHFFFAOYSA-N (3,4-diacetyloxyphenyl) acetate Chemical compound CC(=O)OC1=CC=C(OC(C)=O)C(OC(C)=O)=C1 AESFGSJWSUZRGW-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 230000004872 arterial blood pressure Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- 238000004383 yellowing Methods 0.000 description 2
- JXGNMYHBTAZENZ-UHFFFAOYSA-N 3,4-dimethoxychromen-2-one Chemical compound C1=CC=CC2=C1OC(=O)C(OC)=C2OC JXGNMYHBTAZENZ-UHFFFAOYSA-N 0.000 description 1
- OMQHDIHZSDEIFH-UHFFFAOYSA-N 3-Acetyldihydro-2(3H)-furanone Chemical compound CC(=O)C1CCOC1=O OMQHDIHZSDEIFH-UHFFFAOYSA-N 0.000 description 1
- VCLGIEGDPDKRDU-UHFFFAOYSA-N 7,8-dimethoxy-3-methylchromen-2-one Chemical compound CC=1C(OC2=C(C(=CC=C2C1)OC)OC)=O VCLGIEGDPDKRDU-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 241001465754 Metazoa Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 229940079877 pyrogallol Drugs 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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Description
Fremgangsmåte til fremstilling av nye, Process for the production of new,
terapeutisk aktive cumarinderivater. therapeutically active coumarin derivatives.
Oppfinnelsen vedrører en fremgangsmåte til fremstilling av farmakologisk verdifulle cumarinderivater med den generelle formel The invention relates to a method for the production of pharmacologically valuable coumarin derivatives with the general formula
hvori in which
R1 betyr hydrogen, lavmolekylært alkyl eller fenyl, R1 means hydrogen, low molecular weight alkyl or phenyl,
R2 betyr lavere alkoksy i 6,7- eller 7,8-stilling, R2 means lower alkoxy in the 6,7- or 7,8-position,
Ry betyr lavere alkoksy, Ry means lower alkoxy,
m betyr tallene 1, 2 eller 3, m means the numbers 1, 2 or 3,
A, betyr en rettlinjet eller forgrenet alkylenrest med 2-3 A, means a linear or branched alkylene residue with 2-3
C-atomer, C atoms,
A2 betyr en rettlinjet eller forgrenet alkylenrest med 2-4 A2 means a linear or branched alkylene residue with 2-4
C-atomer, og C atoms, and
Y betyr hydrogen, en hydroksylgruppe eller resten, Y means hydrogen, a hydroxyl group or the residue,
idet fremgangsmåten er karakterisert ved at man på i og for seg kjent måte enten in that the method is characterized by the fact that, in a manner known per se, either
a) acylerer cumarinderivatet med den generelle formel a) acylates the coumarin derivative of the general formula
hvori X betyr hydrogen eller en hydroksylgruppe, med en alkoksybenzosyre med den generelle formel eller et funksjonelt derivat eventuelt i nærvær av et syrebindende middel eller b) at man for fremstilling av forbindelser med den generelle formel kondenserer cumarinderivatet med den generelle formel med et alkoksybenzosyre-halogenalkylester med den generelle formel in which X means hydrogen or a hydroxyl group, with an alkoxybenzoic acid of the general formula or a functional derivative optionally in the presence of an acid-binding agent or b) that to produce compounds of the general formula, the coumarin derivative of the general formula is condensed with an alkoxybenzoic acid haloalkyl ester with the general formula
hvori Hal betyr et halogenatom, eventuelt i nærvær av et syrebindende middel. wherein Hal means a halogen atom, optionally in the presence of an acid binding agent.
Som lavmolekylære alkylrester FL og som alkoksyrester As low molecular weight alkyl residues FL and as aldehyde residues
R2 i 6,7- eller 7,8-stilling resp. R^ kommer det spesielt slike i betraktning med 1- H C-atomer. Har R^ betydningen av aryl, så kommer det hertil spesielt på tale en eventuelt videresubstituert fenylrest. R2 in 6.7 or 7.8 position resp. R^ especially such come into consideration with 1- H C atoms. If R^ has the meaning of aryl, then an optionally further substituted phenyl residue is particularly relevant here.
Fremgangsmåten ifølge oppfinnelsen gir i tilfelle anvendelse av utgangsprodukter, hvori mellomleddet A-^ ikke inneholder en hydroksylgruppe, de tilsvarende monoestere og i tilfelle nærvær av en hydroksylgruppe får man mono- resp. diestere. I sistnevnte tilfelle gir fremgangsmåtevariant a) ved anvendelse av 1 mol av alkoksybenzosyren resp. dens funksjonelle derivat monoestere, ved anvendelse av 2 mol de tilsvarende diestere. Porestringen kan i tilfelle fremstilling av diestere også foretas trinnvis, idet man i de to trinn også kan anvende forskjellige alkoksybenzosyrer resp. deres funksjonelle derivater som acyleringsmiddel. På denne måte lykkes fremstillingen av blandede diestere som inneholder to forskjellige acylrester. Fremgangsmåtevariant b) fører i første rekke bare til monoestere, som imidlertid etter fremgangsmåtevariant a), hvis mellomleddet A^ dessuten inneholder en acylerbar hydroksylgruppe, med et annet mol av acyleringsmidlet likeledes kan overføres i diesteren. The method according to the invention gives, in the case of the use of starting products, in which the intermediate A-^ does not contain a hydroxyl group, the corresponding monoesters and in the case of the presence of a hydroxyl group, one obtains mono- or diesters. In the latter case, method variant a) using 1 mol of the alkoxybenzoic acid resp. its functional derivative monoesters, using 2 moles of the corresponding diesters. In the case of the production of diesters, the poreesterification can also be carried out in stages, since in the two stages different alkoxybenzoic acids or their functional derivatives as acylating agent. In this way, the preparation of mixed diesters containing two different acyl residues is successful. Process variant b) primarily leads only to monoesters, which, however, according to process variant a), if the intermediate A^ also contains an acylatable hydroxyl group, with another mole of the acylating agent can likewise be transferred into the diester.
De ifølge oppfinnelsen fremstillbare cumarinderivater The coumarin derivatives that can be prepared according to the invention
er verdifulle legemidler, de har f.eks. en spesifikk, coronarkar-utvidende virkning og er i denne henseende overlegen kjente stoffer av denne type. are valuable medicines, they have e.g. a specific, coronary vessel dilating effect and is in this respect superior to known substances of this type.
Deres salter er fargeløse, krystallinske, i vann lett oppløselige stoffer. Their salts are colourless, crystalline substances that are easily soluble in water.
Den farmakologiske undersøkelse av den coronarkar-utvidende virkning gjennomføres ved hjelp av forandring av oksygen-trykket i coronarvenøst blod etter den av W.K.A. Schaper og med-arbeidere beskrevne metode på hund (se W.K.A. Schaper, R. Xhonneux og J.M. Bogaard "Uber die kontinuierliche Messung des Sauerstoff-drucks im venosen Coronarblut") (Naunyn-Schmiedeberg<*>s Arch. exp.Path.u.Pharmak. 245, 383-389 (1963)). De narkotiserte, spontant pustende dyr får undersøkelsespreparatene applisert intravenøst. ;Ved denne forsøksanordning fører en ved hjelp av undersøkelses-stoffet frembragt utvidelse av coronararteriene og den dermed for-bundne økning avcoronargjennomstrømningen til en økning av oksygen-trykket i coronarvenøst blod. Oksygentrykkets måling foregikk polarografisk med en platinaelektrode ifølge Gleichmann-Lubbers (se U. Gleichmann og D.W. Lubbers "Die Messung des Sauerstoffdruckes in Gasen und Fliissigkeiten mit der Platin-Elektrode unter besonderer Beriicksichtigung der Messung im Blut" Pfltigers arkiv 271, 431-455 (196b)). Hjertefrekvensen.ble bestemt kontinuerlig elektronisk fra de systoliske maksima av arterielt blodtrykk. Det arterielle blodtrykk ble på kjent måte målt med et Statham-strain-gauge-elektromano-meter i Arteria femoralis. ;I følgende tabell er det sammenfattet resultatene av ;de gjennomførte farmakologiske undersøkelsene. Preparatene ble hver gang undersøkt i form av deres dihydroklorider. ;;Ved fremstilling av dragéer og tabletter med de ifølge oppfinnelsen fremstillbare cumarin-derivater som virksomme stoff-mengder kan disse stoffer sammenblandes med de vanlige tabletterings-hjelpemidler, som stivelse, laktose, talkum og lignende. Alle i farmasien vanlige tabletterings- og drageringsmaterialer kan anvendes. For fremstillingen av injeksjonsoppløsninger er det f.eks. egnet hydrokloridene av cumarinderivatene, da disse for det meste er godt vannoppløselige. Selvsagt kan det også fremstilles injeksjonsoppløs-ninger av ikke vannoppløselige produkter under medanvendelse av kjente suspenderingsmidler, emulgatorer og/eller oppløsningsformidlere på kjent måte. ;Eksempel. 1. ;;37,6 g (0,1 mol) 3-/^-(4,-(e-hydroksyetyl)-piperazino/<->127)-etyl7-4-metyl-7,8-dimetoksy-cumarin suspenderes i 200 ml vannfri benzol og tilsettes 10,1 g (0,1 mol) trietylamin. Nå tildrypper man under omrøring ved værelsetemperatur i løpet av 30 minutter en oppløsning av 23 g (0,1 mol) 3,4,5-trimetoksybenzoylklorid i 100 ml vannfri benzol og etteromrører i 4-5 timer ved værelsetemperatur. Deretter omrører man i 2 timer under tilbakeløp og frasuger varmt fra utskilt trietylaminhydroklorid. Filtratet vaskes med vann, 5%- ig vandig natriumbikarbonatoppløsning og igjen med vann og tørkes déretter over vannfritt natriumsulfat. Nå avdestillerer man oppløsningsmidlet i vannstrålevakuum ved 50°C og oppløser residuet, en lysegul seig olje, i litt vannfri eddikester. Etter tilsetning av eterisk saltsyre inntil kongosur reaksjon får man dihydrokloridet av ~ b~ l~8-(4'-($-3 ", 4 ", 5 "-trimetoksybenzoksyetyl) -piperazino/~l_|7) -etyl7-4-metyl-7,8-dimetoksy-cumarin i fargeløse krystaller med spaltningspunkt 239-240°CV Utbytte: 53 g = 83$ av det teoretiske. ;Det som utgangsprodukt anvendte 3-/3-(4<1->(3-hydroksyetyl)-piperazino/<->1^7)-etyl7-4-metyl-7,8-dimetoksy-cumarin kan fremstilles på følgende måte: a) 13 g (0,055 mol) 3-(8-hydrok"syetyl)-4-metyl-7,8-dihydroksy-cumarin (fremstilt etter den i Chem." Abstr. 54, 24690 g (196O) angitte metode), 40 ml iseddik og 36 ml 48#-ig bromhydrogensyre omrøres i 5 timer ved 110-115°C. Etter avkjøling' heller man reaksjonsblandingen i den femdobbelte vannmengde og frasuger den utfelte utfelling. Det ennå fuktige reaksjonsprodukt lar seg omkrystallisere fra iseddik. ;Man får således 14 g (855? av det teoretiske) 3-(6-brometyl)-4-metyl-7,8-dihydroksy-cumarin med smeltepunkt 190°C. På analog måte ble det fremstilt følgende produkter: 3-(6-brometyl)-4-n-propyl-7,8-dihydroksy-cumarin, smp. 175_177°C, 3-(6-brometyl)-4-fenyl-7,8-dihydroksy-cumarin, smp. 211-213°C, b) 15 g (0,05 mol) 3-(6-brometyl)-4-metyl-7,8-dihydroksy-cumarin oppløses i 100 ml dioksan og blandes med 25 g dimetylsulfat. ;Under gjennomføring av nitrogengass tildrypper man deretter under omrøring ved 35_40°C en oppløsning av 7 g etsnatron i 20 ml vann. Reaksjonsblandingen etteromrøres ved 35_40°C så lenge til den ;alkaliske reaksjon er forsvunnet. Etter ytterligere tilsetning av 25 g dimetylsulfat inndryppes igjen en oppløsning av 7g etsnatron i 20 ml vann. Etter forsvinning av den alkaliske reaksjon inndampes reaksjonsblandingen i vakuum, og residuet fortynnes med vann. Det utfelte reaksjonsprodukt opptas i eddikester og eddikestersjiktet vaskes med fortynnet natronlut. Eddikestersjiktet tørkes og inndampes i vakuum til tørrhet. Man får således 3-( 8-brometyl)-4-metyl-7,8-dimetoksy-cumarin i fargeløse krystaller med smp. l47-l49°C. ;Utbytte: 13 g = 79,35? av det teoretiske. ;Analogt til den ovenfor omtalte fremgangsmåte lar ;det seg fremstille følgende mellomprodukter: 3-(3-brometyl)-4-n-propyl-7,8-dimetoksy-cumarin, smp. 87-90°C. 3-(g-brometyl)-4-fenyl-7,8-dimetoksy-cumarin, smp. l63-l65°C. ;c) 32,7 g (0,1 mol) 3-(e-brometyl)-4-metyl-7,8-dimetoksy-cumarin og 13 g (0,1 mol) N-(3-hydroksyetyl)-piperazin oppløses i ;100 ml klorbenzol og etter tilsetning av 10,6 g (0,1 mol) vannfri soda omrøres i 12 timer under tilbakeløpskokning. Etter avkjøling suger man fra utskilt natriumbromid og inndamper filtratet i vakuum. Det tilbakeblivende oljeaktige råprodukt bringes ved sammenrøring ;med litt eddikester til krystallisering, suges fra og omkrystalliseres for ytterligere rensning fra eddikester. Man får således 3-/—3-(4'-hydroksyetyl-piperazino/<->l_y-etyl7-4-metyl-7,8-dimetoksy-cumarin med smp. 210-212°C. ;Utbytte: 34 g = 905? av det teoretiske. ;På analog måte lar det seg også fremstille de følgende mellomprodukter som tilsvarer den generelle formel: ;Generell formel ;;På analog måte som beskrevet i dette eksempel, første avsnitt, kan det av forannevnte mellomprodukter ifølge oppfinnelsen fremstilles følgende forbindelser: ;. Generell formel ;;Eksempel 2. ;40,6 g (0,1 mol) 3-/y-(4 '-(B-hydroksyetyl)-piperazinq/^lV)~$-hydroksypropy l7-4-metyl-7,8-dimetoksy-cumarin oppløses i 350 ml vannfri kloroform og blandes med 10,1 g (0,1 mol) trietylamin. Nå tildrypper man under omrøring 23 g (0,1 mol) 3,4,5-trimetoksybenzoylklorid, oppløst i 100 ml vannfri kloroform i løpet av 1 time. Etter den eksoterme reaksjons avslutning omrører man ytterligere i 2 timer ved 40-50°C. Etter avkjøling blander man med vann, adskiller kloroformfasen og vasker denne gjentatt med vann, 5%- i- g, natriumbi-karbonatoppløsning og igjen med vann. Etter kloroformoppløsningens tørkning over glødet natriumsulfat avdestillerer man oppløsningsmidlet i vakuum ved 50°C. Residuet oppløses i fortynnet vandig saltsyre og den vandige saltsure oppløsning ekstraheres for rensing med eddikester. Den vandige saltsure oppløsning gjør man med pottaske alkalisk (pH 9) og ekstraherer det som olje utskilte reaksjonsprodukt med eddikester. Eddikesteroppløsningen tørkes over glødet natriumsulfat, befris i vakuum for oppløsningsmidlet og residuet oppløses i ca. ;100 ml vannfri metanol. Ved tilsetning av metanolisk saltsyre får man således dihydrokloridet av 3-/—Y-(4*-(B-3",4",5"-trimetoksy-benzoksyetyl)-piperazino/~1^7)-$-oksypropyl7-4-metyl-7,8-dimetoksy- The pharmacological examination of the coronary vasodilating effect is carried out by means of changes in the oxygen pressure in coronary venous blood following that of W.K.A. Schaper and co-workers described method on dogs (see W.K.A. Schaper, R. Xhonneux and J.M. Bogaard "Uber die continuous Messung des Sauerstoff-drucks im venosen Coronarblut") (Naunyn-Schmiedeberg<*>s Arch. exp.Path.u. Pharm. 245, 383-389 (1963)). The anesthetized, spontaneously breathing animals are given the test preparations intravenously. With this test device, an expansion of the coronary arteries produced by the test substance and the associated increase in coronary flow leads to an increase in the oxygen pressure in coronary venous blood. The oxygen pressure was measured polarographically with a platinum electrode according to Gleichmann-Lubbers (see U. Gleichmann and D.W. Lubbers "Die Messung des Sauerstoffdruckes in Gasen und Fliissigkeiten mit der Platin-Elektrode unter besonderer Beriicksichtigung der Messung im Blut" Pfltiger's archive 271, 431-455 (196b )). The heart rate was determined continuously electronically from the systolic maxima of arterial blood pressure. The arterial blood pressure was measured in a known manner with a Statham strain gauge electromanometer in the Arteria femoralis. The following table summarizes the results of the conducted pharmacological investigations. The preparations were each time examined in the form of their dihydrochlorides. ;;When producing dragees and tablets with the coumarin derivatives that can be prepared according to the invention as active substance quantities, these substances can be mixed with the usual tableting aids, such as starch, lactose, talc and the like. All tableting and coating materials common in pharmacy can be used. For the production of injection solutions, there is e.g. the hydrochlorides of the coumarin derivatives are suitable, as these are mostly well water-soluble. Of course, injection solutions of non-water-soluble products can also be prepared using known suspending agents, emulsifiers and/or dissolution agents in a known manner. ;Example. 1. ;;37.6 g (0.1 mol) 3-/^-(4,-(e-hydroxyethyl)-piperazino/<->127)-ethyl7-4-methyl-7,8-dimethoxy-coumarin is suspended in 200 ml of anhydrous benzene and 10.1 g (0.1 mol) of triethylamine is added. A solution of 23 g (0.1 mol) of 3,4,5-trimethoxybenzoyl chloride in 100 ml of anhydrous benzene is now added dropwise while stirring at room temperature over the course of 30 minutes and the mixture is stirred for 4-5 hours at room temperature. The mixture is then stirred for 2 hours under reflux and the separated triethylamine hydrochloride is extracted with suction. The filtrate is washed with water, 5% aqueous sodium bicarbonate solution and again with water and then dried over anhydrous sodium sulfate. The solvent is now distilled off in a water jet vacuum at 50°C and the residue, a light yellow tough oil, is dissolved in a little anhydrous vinegar. After addition of ethereal hydrochloric acid until Congo acid reaction, the dihydrochloride of ~ b~ l~8-(4'-($-3 ", 4 ", 5 "-trimethoxybenzoxyethyl)-piperazino/~l_|7)-ethyl7-4- is obtained methyl-7,8-dimethoxy-coumarin in colorless crystals with cleavage point 239-240°CV Yield: 53 g = 83$ of the theoretical. ;The starting product used 3-/3-(4<1->(3-hydroxyethyl )-piperazino(<->1^7)-ethyl7-4-methyl-7,8-dimethoxy-coumarin can be prepared as follows: a) 13 g (0.055 mol) 3-(8-hydroxyethyl)-4 -methyl-7,8-dihydroxy-coumarin (prepared according to the method given in Chem." Abstr. 54, 24690 g (196O)), 40 ml of glacial acetic acid and 36 ml of 48#-ig hydrobromic acid are stirred for 5 hours at 110-115 °C. After cooling, the reaction mixture is poured into five times the amount of water and the precipitate that has formed is filtered off with suction. The still moist reaction product can be recrystallized from glacial acetic acid. Thus, 14 g (855% of the theoretical) of 3-(6-bromomethyl)- 4-methyl-7,8-dihydroxy-coumarin with a melting point of 190° C. In an analogous manner, the following products: 3-(6-bromomethyl)-4-n-propyl-7,8-dihydroxy-coumarin, m.p. 175-177°C, 3-(6-bromomethyl)-4-phenyl-7,8-dihydroxycoumarin, m.p. 211-213°C, b) 15 g (0.05 mol) of 3-(6-bromomethyl)-4-methyl-7,8-dihydroxy-coumarin are dissolved in 100 ml of dioxane and mixed with 25 g of dimethyl sulphate. A solution of 7 g of caustic soda in 20 ml of water is then added dropwise while stirring at 35-40°C while passing through nitrogen gas. The reaction mixture is stirred at 35-40°C until the alkaline reaction has disappeared. After further addition of 25 g of dimethylsulphate, a solution of 7 g of caustic soda in 20 ml of water is dripped in again. After the alkaline reaction has disappeared, the reaction mixture is evaporated in vacuo, and the residue is diluted with water. The precipitated reaction product is taken up in vinegar and the vinegar layer is washed with diluted caustic soda. The acetic ester layer is dried and evaporated in vacuo to dryness. 3-(8-bromomethyl)-4-methyl-7,8-dimethoxy-coumarin is thus obtained in colorless crystals with m.p. 147-149°C. ;Yield: 13 g = 79.35? of the theoretical. Analogous to the method mentioned above, the following intermediate products can be prepared: 3-(3-bromomethyl)-4-n-propyl-7,8-dimethoxy-coumarin, m.p. 87-90°C. 3-(g-bromomethyl)-4-phenyl-7,8-dimethoxy-coumarin, m.p. 163-165°C. ;c) 32.7 g (0.1 mol) 3-(e-bromomethyl)-4-methyl-7,8-dimethoxy-coumarin and 13 g (0.1 mol) N-(3-hydroxyethyl)-piperazine dissolve in ;100 ml of chlorobenzene and, after adding 10.6 g (0.1 mol) of anhydrous soda, stir for 12 hours under reflux. After cooling, the separated sodium bromide is sucked off and the filtrate evaporated in a vacuum. The remaining oily crude product is brought to crystallization by mixing with a little acetic acid, sucked off and recrystallized for further purification from acetic acid. 3-(4'-Hydroxyethyl-piperazino/<->l_y-ethyl7-4-methyl-7,8-dimethoxy-coumarin is thus obtained with m.p. 210-212°C. Yield: 34 g = 905? of the theoretical. ;In an analogous way, the following intermediate products corresponding to the general formula can also be prepared: ;General formula ;;In an analogous way as described in this example, first paragraph, the following can be prepared from the aforementioned intermediate products according to the invention compounds: ;.General formula ;;Example 2. ;40.6 g (0.1 mol) 3-/y-(4 '-(B-hydroxyethyl)-piperazinq/^lV)~$-hydroxypropyl l7-4- methyl-7,8-dimethoxy-coumarin is dissolved in 350 ml of anhydrous chloroform and mixed with 10.1 g (0.1 mol) of triethylamine. Now 23 g (0.1 mol) of 3,4,5-trimethoxybenzoyl chloride is added dropwise while stirring , dissolved in 100 ml of anhydrous chloroform over the course of 1 hour. After the end of the exothermic reaction, stirring is continued for 2 hours at 40-50° C. After cooling, the mixture is mixed with water, the chloroform phase is separated and this is washed repeatedly with water, 5%- i- g, sodium bi -carbonate solution and again with water. After drying the chloroform solution over heated sodium sulphate, the solvent is distilled off in a vacuum at 50°C. The residue is dissolved in dilute aqueous hydrochloric acid and the aqueous hydrochloric acid solution is extracted for purification with vinegar. The aqueous hydrochloric acid solution is made alkaline with pot ash (pH 9) and the reaction product separated as oil is extracted with vinegar. The acetic ester solution is dried over heated sodium sulphate, freed from the solvent in a vacuum and the residue is dissolved in approx. ;100 ml anhydrous methanol. By adding methanolic hydrochloric acid, one thus obtains the dihydrochloride of 3-/—Y-(4*-(B-3",4",5"-trimethoxy-benzoxyethyl)-piperazino/~1^7)-$-oxypropyl7-4 -methyl-7,8-dimethoxy-
cumarin i form av fargeløse krystaller med spaltningspunkt 231-233°C (etter omkrystallisering fra metanol - vann i forholdet 20:1). coumarin in the form of colorless crystals with a melting point of 231-233°C (after recrystallization from methanol - water in a ratio of 20:1).
Utbytte: 59 g = 8755 av det teoretiske. Yield: 59 g = 8755 of the theoretical.
Det som utgangsprodukt nødvendige 3-/y"-(4'-(3-hydroksy-etyl)-piperazino/~l_|_7)-3-hydroksypropyl7-4-met yl-7,8-dimetoksy-cumarin kan fremstilles på følgende måte: 28,4 g (0,1 mol) 3-/Y-klor-3-hydroksy-propyl7-4-metyl-7,8-dihydroksy-cumarin (fremstilt ved kondensering av a-acetyl-Y-klormetyl-butyrolakton med pyrogallol etter den i britisk patent nr. 1.044.608 angitte metode) oppløses i 20.0 ml dioksan under oppvarmning. Etter avkjøling til ca. 40°C tilsetter man 40 g dimetylsulfat og lar da under omrøring i nitrogengassatmosfære en oppløsning av 42 g pottaske i 80 ml tildryppe. Reaksjonsblandingen etteromrøres ved 40°C så lenge til en prøve ved sammenblanding med fortynnet natronlut ikke mer viser gulfargning, hvilket er tilfelle etter ca. The starting product required 3-[y"-(4'-(3-hydroxy-ethyl)-piperazino]-3-hydroxypropyl-7-4-methyl-7,8-dimethoxy-coumarin can be prepared as follows method: 28.4 g (0.1 mol) 3-[Y-chloro-3-hydroxy-propyl7-4-methyl-7,8-dihydroxy-coumarin (prepared by condensation of α-acetyl-Y-chloromethyl-butyrolactone with pyrogallol according to the method specified in British patent no. 1,044,608) is dissolved in 20.0 ml of dioxane while heating. After cooling to approx. 40°C, 40 g of dimethyl sulfate is added and then, with stirring in a nitrogen gas atmosphere, a solution of 42 g of pot ash in Add 80 ml drop by drop.The reaction mixture is stirred at 40°C until a sample when mixed with diluted caustic soda no longer shows yellowing, which is the case after approx.
2- 3 timer. Ved fortynning med vann utskiller reaksjonsproduktet seg i form av fargeløse nåler. Til rensning oppløses det frasugde råprodukt i kloroform, oppløsningen vaskes med fortynnet natronlut og tørkes. Etter kloroformoppløsningens inndampning får man således 3- /Y-klor-.3-hydroksypropyl7-4-metyl-7,8-dimetoksy-cumarin i form av fargeløse nåler med smp. l42-l44°C. 2-3 hours. When diluted with water, the reaction product separates in the form of colorless needles. For purification, the aspirated crude product is dissolved in chloroform, the solution is washed with diluted caustic soda and dried. After evaporation of the chloroform solution, 3- /Y-chloro-.3-hydroxypropyl7-4-methyl-7,8-dimethoxy-coumarin is thus obtained in the form of colorless needles with m.p. 142-144°C.
Utbytte: 27 g hvilket tilsvarer 86,5$ av det teoretiske. Yield: 27 g which corresponds to 86.5$ of the theoretical.
På analog måte får man: Analogously, you get:
3-/Y-klor-3-hydroksypropyl7-4-n-propyl-7,8-dimetoksy-cumarin, 3-[Y-chloro-3-hydroxypropyl-7-4-n-propyl-7,8-dimethoxy-coumarin,
smp. 136-137°C m.p. 136-137°C
3-/Y-klor-3-hydroksypropyl7-4-feny1-7,8-dimetoksy-cumarin, 3-[Y-chloro-3-hydroxypropyl-7-4-phenyl-7,8-dimethoxy-coumarin,
smp. 142°C. m.p. 142°C.
3-/Y-klor-3-hydroksypropyl7-4-metyl-7,8-dietoksy-cumarin, 3-[Y-chloro-3-hydroxypropyl-7-4-methyl-7,8-diethoxy-coumarin,
smp. 136-138°C. m.p. 136-138°C.
31,2 g (0,1 mol) 3-(Y-klor-3-hydroksypropyl)-4-metyl-7,8-dimetoksy-cumarin og 13 g N-(8-hydroksyetyl)-piperazin oppløses i 150 ml klorbenzol og omrøres etter tilsetning av 11 g vannfri soda i 7 timer ved 120°C. Etter avkjøling frasuger man utskilt koksalt og inndampér filtratet i vakuum. Det etter inndampningen utkrystalliserte råprodukt utrøres for ytterligere rensning med 100 ml eddikester, frasuges og tørkes i vakuum. Man får således 3-/Y~(4'.-($-hydroksyet yl )-piperazino/~l_[7)-3-hydroksypropyl7_jj_metyl-7,8-dimetoksy-cumarin med smp. l42-l45°C. 31.2 g (0.1 mol) of 3-(Y-chloro-3-hydroxypropyl)-4-methyl-7,8-dimethoxy-coumarin and 13 g of N-(8-hydroxyethyl)-piperazine are dissolved in 150 ml of chlorobenzene and stirred after adding 11 g of anhydrous soda for 7 hours at 120°C. After cooling, the secreted sodium chloride is sucked off and the filtrate is evaporated in a vacuum. The crude product crystallized after evaporation is stirred for further purification with 100 ml of acetic acid, sucked off and dried in a vacuum. One thus obtains 3-[Y~(4'.-($-hydroxyethyl)-piperazino/~1_[7)-3-hydroxypropyl-7-jj_methyl-7,8-dimethoxy-coumarin with m.p. 142-145°C.
Utbytte: 31a3 g hvilket tilsvarer 11% av det teoretiske. Yield: 31a3 g which corresponds to 11% of the theoretical.
På analog måte lar det seg fremstille følgende mellomprodukter : In an analogous way, the following intermediate products can be produced:
Generell formel: General formula:
Eksempel 3. Example 3.
40,6 g (0,1 mol) 3-/.Y "(4 '-(S-hydroksyetyl)-piperazino-r~l_|7)-$-hydroksypropyl7-4-metyl-7,8-dimetoksycumarin oppløses i 350 ml vannfri kloroform og tilsettes 20,2 g (0,2 mol) trietylamin. Nå tildrypper man under omrøring 46 g (0,2 mol) 3,4,5-trimetoksybenzoylklorid, oppløst i 200 ml vannfri kloroform i løpet av 2 timer. Den indre temperatur øker da til ca. 50°C. Etter den eksoterme reaksjons avkjøling omrører man ytterligere i 2 timer ved 40-50°C og opparbeider deretter som angitt i eksempel 2. 40.6 g (0.1 mol) of 3-[Y(4'-(S-hydroxyethyl)-piperazino-r~l_|7)-$-hydroxypropyl7-4-methyl-7,8-dimethoxycoumarin is dissolved in 350 ml of anhydrous chloroform and 20.2 g (0.2 mol) of triethylamine are added. Now, while stirring, 46 g (0.2 mol) of 3,4,5-trimethoxybenzoyl chloride, dissolved in 200 ml of anhydrous chloroform, are added dropwise over the course of 2 hours The internal temperature then increases to approximately 50° C. After the exothermic reaction cools down, stirring is continued for 2 hours at 40-50° C and then processed as indicated in example 2.
Man får således dihydrokloridet av diesteren med den ovenfor angitte generelle formel i fargeløse krystaller med spaltningspunkt 158°C etter omkrystallisering fra metanol. The dihydrochloride of the diester with the general formula given above is thus obtained in colorless crystals with a cleavage point of 158°C after recrystallization from methanol.
Utbytte: 70 g hvilket tilsvarer 82$ av det teoretiske. Yield: 70 g which corresponds to 82$ of the theoretical amount.
Den ovenfor omtalte diester får man også når man om-setter den ifølge eksempel 2 dannede monoester i kloroform med 3,4,5-trimetoksybenzoylklorid under tilsetning av trietylamin. Eksempel 4. The above-mentioned diester is also obtained when the monoester formed according to example 2 is reacted in chloroform with 3,4,5-trimethoxybenzoyl chloride while adding triethylamine. Example 4.
36,2 g (0,1 mol) 3-/Y-piperazino/—l_|7-p-oksypropyl7-4-metyl-7,8-dimetoksy-cumarin oppløses i 100 ml klorbenzol og etter tilsetning av 13,8 g (0,1 mol) pottaske tildryppes ved 50-60°C 36.2 g (0.1 mol) of 3-[Y-piperazino]-1_|7-p-oxypropyl7-4-methyl-7,8-dimethoxy-coumarin is dissolved in 100 ml of chlorobenzene and after the addition of 13.8 g (0.1 mol) pot ash is added dropwise at 50-60°C
under omrøring en oppløsning av 29 g (0,1 mol) 3>4,5-trimetoksybenzo-syre-Y-klorpropylester i 50 ml klorbenzol i løpet av 1 time. Deretter, omrører man i 12 timer under oppvarmning og tilbakeløp. Deretter fra-filtreres ennå varmt fra uoppløst, og filtratet befris i vannstrålevakuum for oppløsningsmiddel. Etter ytterligere opparbeidelse, som angitt i eksempel 2, får man dihydrokloridet av 3-/—Y_(4'-(y-3",4",5"-trimet oksybenzoksypropy 1) -piperazino/-1_|7) - Ø-oksypr opyl7-4 -metyl - 7,8-dimetoksy-cumarin. Man får det således i form av fargeløse krystaller med spaltningspunkt 225°C. with stirring a solution of 29 g (0.1 mol) of 3>4,5-trimethoxybenzoic acid Y-chloropropyl ester in 50 ml of chlorobenzene over the course of 1 hour. Then, it is stirred for 12 hours while heating and refluxing. The still hot undissolved is then filtered off, and the filtrate is freed of solvent in a water jet vacuum. After further work-up, as indicated in example 2, one obtains the dihydrochloride of 3-/—Y_(4'-(y-3",4",5"-trimet oxybenzoxypropyl 1)-piperazino/-1_|7) - Ø- oxypropyl7-4-methyl-7,8-dimethoxy-coumarin It is thus obtained in the form of colorless crystals with a cleavage point of 225°C.
Utbytte: 50 g hvilket tilsvarer 73$ av det teoretiske. Yield: 50 g which corresponds to 73$ of the theoretical.
Det i dette eksempel som utgangsprodukt benyttede 3-/—Y_piperazino/—l_y-$-oksypropyl7-4-metyl-7,8-dimetoksycumarin ble fremstilt på følgende måte: The 3-/—Y_piperazino/—1_y-$-oxypropyl7-4-methyl-7,8-dimethoxycoumarin used as starting product in this example was prepared in the following way:
86 g (1 mol) vannfritt, destillert piperazin oppløses 86 g (1 mol) of anhydrous, distilled piperazine are dissolved
i 150 ml klorbenzol og oppvarmes etter tilsetning av 11 g soda til 120°C. I denne blanding tildryppes langsomt under opprøring en oppløsning av 31 g (0,1 mol) 3-(Y-klor-$-hydroksypropyl)-4-metyl-7,8-dimetoksy-cumarin i 150 ml klorbenzol. Deretter etteromrøres i 12 timer ved 120°C. Etter frasugning inndampes filtratet og deretter avdestilleres i vakuum den største del av piperazinet som foreligger i overskudd. Residuet blandes med vann og ekstraheres etter tilsetning av pottaske med metylenklorid. Etter tørkning inndampes metylen-kloridsjiktet i vakuum. Etter noen henstand krystalliseres 3-(y-piperazino/<->lj_7-$-oksypropyl)-4-metyl-7,8-dimetoksy-cumarin i form av fargeløse nåler med smp. 124-126°C. in 150 ml of chlorobenzene and heated after adding 11 g of soda ash to 120°C. A solution of 31 g (0.1 mol) of 3-(Y-chloro-$-hydroxypropyl)-4-methyl-7,8-dimethoxy-coumarin in 150 ml of chlorobenzene is slowly added dropwise to this mixture while stirring. The mixture is then stirred for 12 hours at 120°C. After extraction, the filtrate is evaporated and then the largest part of the excess piperazine is distilled off in a vacuum. The residue is mixed with water and extracted after adding pot ash with methylene chloride. After drying, the methylene chloride layer is evaporated in vacuo. After some delay, 3-(γ-piperazino[<->lj_7-$-oxypropyl)-4-methyl-7,8-dimethoxy-coumarin crystallizes in the form of colorless needles with m.p. 124-126°C.
Utbytte: 19 g hvilket tilsvarer 52, 5% av det teoretiske. Yield: 19 g which corresponds to 52.5% of the theoretical.
På analog måte, som beskrevet i eksemplene 2, 3 og 4, kan det ved fremgangsmåten ifølge oppfinnelsen fremstilles følgende forbindelser: In an analogous manner, as described in examples 2, 3 and 4, the following compounds can be produced by the method according to the invention:
Eksempel 5 - 37,6 g (0,1 mol) 3-/ B-(4'-(B-hydroksyetyl)-piperazino/ l_^7)-etyl7-4-metyl-6,7-dimetoksy-cumarin suspenderes i 200 ml vannfri benzol og tilsettes 10,1 g (0,1 mol) trietylamin. Nå tildrypper man under omrøring ved værelsetemperatur i løpet av 30 min. en oppløsning av 23 g (0,1 mol) 3,4,5-trimetoksybenzoylklorid i 100 ml vannfri benzol og omrører i 4-5 timer ved værelsetemperatur. Deretter omrører man i 2 timer under tilbakeløp og frasuger varmt fra adskilt trietylaminhydroklorid. Filtratet vaskes med vann, 5%~ is vandig nafcrium-bikarbonat-oppløsning og igjen med vann og tørkes over vannfri natriumsulfat. Nå avdestillerer man oppløsningsmidlet i vannstrålevakuum ved 50°C og oppløser residuet, en lysegul seig olje i fortynnet, vandig saltsyre. For rensning ekstraherer man den saltsure, vandige oppløsning med eddikester. Den klare, vandige fase gjøres alkalisk med kaliumkarbonat og ekstraheres igjen med eddikester. Den således dannede eddikesteroppløsning vasker man igjen med vann, tørker den over vannfri natriumsulfat og inndamper den da til et volum på ca. 50 ml og blander residuet med eterisk saltsyre til kongosur reaksjon. Det utskilte dihydrokloridet av 3-/B.-(4 '-( $-3",4",5"-trimetoksybenz-oksyetyl)-piperazino/—1^7)-etyl7-4-metyl-6,7-dimetoksy-cumarin har etter omkrystallisering fra vannfri metanol et spaltningspunkt på 224°C.. ' Example 5 - 37.6 g (0.1 mol) of 3-[B-(4'-(B-hydroxyethyl)-piperazino]-ethyl7-4-methyl-6,7-dimethoxy-coumarin is suspended in 200 ml of anhydrous benzene and 10.1 g (0.1 mol) of triethylamine are added. Now add in drops while stirring at room temperature over the course of 30 minutes. a solution of 23 g (0.1 mol) of 3,4,5-trimethoxybenzoyl chloride in 100 ml of anhydrous benzene and stir for 4-5 hours at room temperature. The mixture is then stirred for 2 hours under reflux and heated with suction from separated triethylamine hydrochloride. The filtrate is washed with water, 5% aqueous sodium bicarbonate solution and again with water and dried over anhydrous sodium sulfate. The solvent is now distilled off in a water jet vacuum at 50°C and the residue, a pale yellow viscous oil, is dissolved in dilute, aqueous hydrochloric acid. For purification, the hydrochloric acid aqueous solution is extracted with vinegar. The clear, aqueous phase is made alkaline with potassium carbonate and extracted again with acetic acid. The acetic ester solution thus formed is washed again with water, dried over anhydrous sodium sulphate and then evaporated to a volume of approx. 50 ml and mixes the residue with ethereal hydrochloric acid for a congo acid reaction. The precipitated dihydrochloride of 3-[B.-(4'-( $-3",4",5"-trimethoxybenzo-oxyethyl)-piperazino/-1^7)-ethyl7-4-methyl-6,7-dimethoxy -coumarin has, after recrystallization from anhydrous methanol, a decomposition point of 224°C..
Utbytte: 47 g tilsvarende 73% av det teoretiske. Yield: 47 g corresponding to 73% of the theoretical.
Det som utgangsprodukt anvendte 3-/3-(4'-(g-hydroksy-etyl)-piperazino/—l_|_7)-etyl7-4-metyl-6,7-dimetoksycumarin kan fremstilles på følgende måte: a) 13 g (0,055 mol) 3~($-hydroksyetyl)-4-metyl-6,7-dihydroksy-cumarin (fremstilt ved kondensasjon av 1,2,4-triacetoksybenzol med a-acetylbutyrolakton analog den i Chem.Abstr. 54, 24690 g The starting product 3-(4'-(g-hydroxy-ethyl)-piperazino/-1_|_7)-ethyl7-4-methyl-6,7-dimethoxycoumarin can be prepared in the following way: a) 13 g (0.055 mol) 3~($-hydroxyethyl)-4-methyl-6,7-dihydroxy-coumarin (prepared by condensation of 1,2,4-triacetoxybenzene with α-acetylbutyrolactone analogous to that in Chem.Abstr. 54, 24690 g
(1960) angitte metode), 40 ml iseddik og 36 ml 48#-ig bromhydrogensyre omrøres i 5 timer ved 110-115°C. Etter avkjøling heller man reak-sj onsblandingen i den femdobbelte mengde vann og frasuger den utfelte utfelling. Den ennå fuktige reaksjonsprodukt lar seg omkrystallisere fra iseddik. Man får således 12 g (73$ av det teoretiske) 3-($-brom-etyl)-4-metyl-6,7_dihydroksy-cumarin med smp. 262°C. På analog måte ble det fremstilt følgende produkter: 3-(Ø-brometyl)-4-n-propyl-6,7_dihydroksy-cumarin, smp. 250-252°C, 3-(3-brometyl)-4-.fenyl-6,7-dihydroksy-cumarin, smp. 255°C. b) 15 g (0,05 mol) 3-(B-brometyl)-4-metyl-6,7-dihydroksy-cumarin oppløses i 100 ml dioksan og blandes med 25 g dimetylsulfat. Under gjennomføring av nitrogengass tildrypper man deretter under omrøring ved 35-40°C en oppløsning av 7 g etsnatron i 20 ml vann. Reaksjonsblandingen etterrøres ved 35-40°C så lenge til den (1960) stated method), 40 ml of glacial acetic acid and 36 ml of 48% hydrobromic acid are stirred for 5 hours at 110-115°C. After cooling, the reaction mixture is poured into five times the amount of water and the precipitate formed is sucked off. The still moist reaction product can be recrystallized from glacial acetic acid. One thus obtains 12 g (73$ of the theoretical) 3-($-bromo-ethyl)-4-methyl-6,7-dihydroxy-coumarin with m.p. 262°C. In an analogous manner, the following products were prepared: 3-(O-bromomethyl)-4-n-propyl-6,7_dihydroxy-coumarin, m.p. 250-252°C, 3-(3-bromomethyl)-4-phenyl-6,7-dihydroxy-coumarin, m.p. 255°C. b) 15 g (0.05 mol) of 3-(B-bromomethyl)-4-methyl-6,7-dihydroxy-coumarin are dissolved in 100 ml of dioxane and mixed with 25 g of dimethylsulphate. Under nitrogen gas, a solution of 7 g of caustic soda in 20 ml of water is then added dropwise while stirring at 35-40°C. The reaction mixture is then stirred at 35-40°C until it
alkaliske reaksjon er forsvunnet. Etter ytterligere tilsetning av alkaline reaction has disappeared. After further addition of
25 g dimetylsulfat inndryppes igjen en oppløsning av 7 g etsnatron i 20 ml vann. Etter forsvinning av den alkaliske reaksjon inndampes reaksjonsblandingen i vakuum, og residuet fortynnes med vann. Det utfelte reaksjonsprodukt opptas i eddikester og eddikestersjiktet vaskes med fortynnet natronlut. Eddikestersjiktet tørkes og inndampes i vakuum til tørrhet. Man får således 3-(B-brometyl)-4-metyl-6,7-dimetoksy-cumarin i fargeløse krystaller med smp. 215-2l6°C. 25 g of dimethylsulphate is again dripped into a solution of 7 g of caustic soda in 20 ml of water. After the alkaline reaction has disappeared, the reaction mixture is evaporated in vacuo, and the residue is diluted with water. The precipitated reaction product is taken up in vinegar and the vinegar layer is washed with diluted caustic soda. The acetic ester layer is dried and evaporated in vacuo to dryness. 3-(B-bromomethyl)-4-methyl-6,7-dimethoxy-coumarin is thus obtained in colorless crystals with m.p. 215-216°C.
Utbytte: 10 g tilsvarende 6l% av det teoretiske. Yield: 10 g corresponding to 6l% of the theoretical.
Analogt til den ovenfor omtalte fremgangsmåte lar det seg fremstille følgende mellomprodukter: •3-($-brometyl)-<1>l-n-propyl-6,7-dimetoksy-cumarin, smp. 115-H7°C. 3-( B-brometyl)-J4-fenyl-6,7-dimetoksy-cumarin, smp. 190-191°C. Analogously to the method mentioned above, the following intermediate products can be prepared: •3-($-bromomethyl)-<1>1-n-propyl-6,7-dimethoxy-coumarin, m.p. 115-H7°C. 3-(B-bromomethyl)-N4-phenyl-6,7-dimethoxy-coumarin, m.p. 190-191°C.
c) 32,7 g (0,1 mol) 3-($-brometyl)-4-metyl-6,7-dimetoksy-cumarin og 13 g (0,1 mol) N-(0-hydroksyetyl)-piperazin oppløses i c) 32.7 g (0.1 mol) 3-($-bromomethyl)-4-methyl-6,7-dimethoxy-coumarin and 13 g (0.1 mol) N-(0-hydroxyethyl)-piperazine are dissolved in
100 ml klorbenzol og omrøres under tilbakeløpskokning etter tilsetning av 10,6 g (0,1 mol) vannfri soda i 12 timer. Etter avkjøling frasuger man det utskilte natriumbromid og inndamper filtratet i vakuum. Det gjenblivende oljeaktige råprodukt bringes ved utrøring med litt eddikester til krystallisering, suges fra og omkrystalliseres for ytterligere rensning fra eddikester. Man får således 3-/~~B_(4'-hydroksyetyl-piperazino/-l_^7)-etyl7-4-metyl-6,7-dimetoksy-cumarin med smp. 128-130°C. 100 ml of chlorobenzene and stirred under reflux after adding 10.6 g (0.1 mol) of anhydrous soda for 12 hours. After cooling, the separated sodium bromide is sucked off and the filtrate is evaporated in a vacuum. The remaining oily crude product is brought to crystallization by stirring with a little acetic acid, sucked off and recrystallized for further purification from acetic acid. One thus obtains 3-[~B_(4'-hydroxyethyl-piperazino/-1_^7)-ethyl7-4-methyl-6,7-dimethoxy-coumarin with m.p. 128-130°C.
Utbytte: 32 g tilsvarende 85% av det teoretiske. Yield: 32 g corresponding to 85% of the theoretical.
På analog måte lar det seg også fremstille følgende mellomprodukter som tilsvarer den generelle formel: In an analogous way, it is also possible to prepare the following intermediate products which correspond to the general formula:
På analog måte som i eksempel 1, første avsnitt, kan det av ovennevnte mellomprodukter ifølge oppfinnelsen fremstilles følgende forbindelser: In an analogous way as in example 1, first paragraph, the following compounds can be prepared from the above-mentioned intermediates according to the invention:
Generell formel: General formula:
Eksempel 6. Example 6.
42,0 g (0,1 mol) 3_/.Y~(4'-(Y-hydroksypropyl)-piperazino-/ l_|_/)-B-hydroksypropyl7-4-metyl-6,7-dimetoksycumarin oppløses i 300 ml vannfri kloroform og tilsettes 20,2 g (0,2 mol) trietylamin. Nå tildrypper man-under omrøring i løpet av 2 timer en oppløsning av 46 g (0,2 mol) 3,4,5-trimetoksybenzoylklorid i 100 ml tørr kloroform. Den indre temperatur øker da til ca. 45°C. Etter den eksoterme reaksjons avslutning omrører man ennå i 2 timer ved 40-50°C. Man vasker reaksjonsoppløsningen først med vann, deretter med fortynnet vandig natriumbikarbonatoppløsning og tilslutt igjen med vann og opparbeider deretter som angitt i eksempel 5. 42.0 g (0.1 mol) of 3_/.Y~(4'-(Y-hydroxypropyl)-piperazino-/1_|_/)-B-hydroxypropyl7-4-methyl-6,7-dimethoxycoumarin is dissolved in 300 ml of anhydrous chloroform and 20.2 g (0.2 mol) of triethylamine are added. A solution of 46 g (0.2 mol) of 3,4,5-trimethoxybenzoyl chloride in 100 ml of dry chloroform is now added dropwise with stirring over the course of 2 hours. The internal temperature then increases to approx. 45°C. After the end of the exothermic reaction, stirring is continued for 2 hours at 40-50°C. The reaction solution is washed first with water, then with diluted aqueous sodium bicarbonate solution and finally again with water and then worked up as indicated in example 5.
Man får dihydrokloridet av 3-/~Y-(4'-(y-3",4",5m<->trimetoksybenzoksypropyl)-piperazino/<->1_^7)-3-3",4",5"-trimetoksybenz-oksypropyl7-4-metyl-6,7~dimetoksy-cumarin i fargeløse krystaller med spaltningspunkt l88°C. The dihydrochloride of 3-/~Y-(4'-(y-3",4",5m<->trimethoxybenzoxypropyl)-piperazino/<->1_^7)-3-3",4",5" is obtained -trimethoxybenzo-oxypropyl7-4-methyl-6,7-dimethoxy-coumarin in colorless crystals with a melting point of 188°C.
Utbytte: 69 g tilsvarende 78, 5% av det teoretiske. Yield: 69 g corresponding to 78.5% of the theoretical.
Det som utgangsprodukt nødvendige 3-/_Y_(4 '-(Y_hydroksy-propyl)-piperazino-/_lj_7)-3-hydroksypropyl7-4-metyl-6,7-dimetoksy-cumarin kan fremstilles på følgende måte: 28,4 g (0,1 mol) 3-ZY~klor-3-hydroksypropyl7-4-metyl-6,7-dihydroksy-cumarin (fremstilt ved kondensasjon av a-acetyl-Y-klormetyl-butyrolakton med 1,2,4-triacetoksybenzol analogt den i britisk patent nr. 1.044.608 angitte metode) oppløses i 200 ml dioksan under oppvarmning. Etter avkjøling til ca. 40°C tilsetter man 40 g dimetylsulfat og lar deretter under omrøring i nitrogengassatmosfære en oppløsning av 42 g pottaske i 80 ml vann tildryppe. Reaksjonsblandingen etteromrøres ved 40°C så lenge til en prøve ved blanding med fortynnet natronlut ikke mer viser gulfargning, hvilket er tilfelle etter ca. 2-3 timer. Ved fortynning med vann utskiller reaksjonsproduktet seg i form av fargeløse nåler. For rensning opp-løses det frasugde råprodukt i kloroform, oppløsningen vaskes med fortynnet natronlut og tørkes. Etter kloroformoppløsningens inndampning får man således 3-/<.>Y_klor-8-hydroksypropyl7-4-metyl-6,7-dimetoksy-cumarin i form av fargeløse nåler med smp. l84-l85°C. Utbytte: 24,8 g tilsvarende 79% av det teoretiske. The starting product 3-[Y_(4'-(Y_hydroxy-propyl)-piperazino-/_lj_7)-3-hydroxypropyl7-4-methyl-6,7-dimethoxy-coumarin can be prepared in the following way: 28.4 g ( 0.1 mol) 3-ZY~chloro-3-hydroxypropyl7-4-methyl-6,7-dihydroxy-coumarin (prepared by condensation of α-acetyl-Y-chloromethyl-butyrolactone with 1,2,4-triacetoxybenzene analogously to method specified in British patent no. 1,044,608) is dissolved in 200 ml of dioxane while heating. After cooling to approx. At 40°C, 40 g of dimethylsulphate is added and then, with stirring in a nitrogen gas atmosphere, a solution of 42 g of pot ash in 80 ml of water is allowed to drip in. The reaction mixture is stirred again at 40°C until a sample when mixed with diluted caustic soda no longer shows yellowing, which is the case after approx. 2-3 hours. When diluted with water, the reaction product separates in the form of colorless needles. For purification, the aspirated crude product is dissolved in chloroform, the solution is washed with diluted caustic soda and dried. After evaporation of the chloroform solution, 3-/<.>Y_chloro-8-hydroxypropyl7-4-methyl-6,7-dimethoxy-coumarin is thus obtained in the form of colorless needles with m.p. 184-185°C. Yield: 24.8 g corresponding to 79% of the theoretical.
På analog måte får man: Analogously, you get:
3-/_Y-klor-3-hydr6ksypro'pyl7-4-n-propyl-6,7-dimetoksy-cumarin, 3-[Y-chloro-3-hydroxypropyl]-4-n-propyl-6,7-dimethoxy-coumarin,
smp. 132°C, 3-/Y-klor-8-hydroksypropyl7-4-fenyl-6,7-dimetoksy-cumarin, m.p. 132°C, 3-[Y-chloro-8-hydroxypropyl-7-4-phenyl-6,7-dimethoxy-coumarin,
smp. 100°C. m.p. 100°C.
31,2 g (0,1 mol) 3-(Y-klor-0-hydroksypropyl)-4-metyl-6,7-dimetoksy-cumarin og 14,4 g N-(Y-hydroksypropyl)-piperazin oppløses i 150 ml klorbenzol og omrøres etter tiDsetning av 11 g vannfri soda i 7 timer ved 120°C. Etter avkjøling frasuger man utskilt koksalt og inndamper filtratet i vakuum. Det etter inndampningen utkrystalliserte råprodukt utrøres for ytterligere rensning med 100 ml eddikester, frasuges og tørkes i vakuum. Man får således 3- fy-(4<1> -(Y-h<y>droksy<p>rop<y>l)-<p>i<p>erazino</>~1^7)-g-hydroksypropyl7-4-metyl-6,7~dimetoksy-cumarin med smp. l48-151°C. 31.2 g (0.1 mol) of 3-(Y-chloro-0-hydroxypropyl)-4-methyl-6,7-dimethoxy-coumarin and 14.4 g of N-(Y-hydroxypropyl)-piperazine are dissolved in 150 ml of chlorobenzene and stirred after adding 11 g of anhydrous soda for 7 hours at 120°C. After cooling, the secreted sodium chloride is sucked off and the filtrate is evaporated in a vacuum. The crude product crystallized after evaporation is stirred for further purification with 100 ml of acetic acid, sucked off and dried in a vacuum. One thus obtains 3- phy-(4<1> -(Y-h<y>hydroxy<p>rop<y>l)-<p>i<p>erazino</>~1^7)-g-hydroxypropyl7- 4-methyl-6,7~dimethoxy-coumarin with m.p. l48-151°C.
Utbytte: 30 g tilsvarende 71,5$ av det teoretiske. Yield: 30 g corresponding to 71.5$ of the theoretical.
På analog måte lar det seg fremstille følgende mellomprodukter: In an analogous way, the following intermediate products can be produced:
Generell formel General formula
På analog måte som i første avsnitt i dette eksempel kan det ifølge oppfinnelsen fremstilles følgende forbindelser: Generell formel In an analogous way as in the first paragraph of this example, the following compounds can be prepared according to the invention: General formula
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/914,100 US4726246A (en) | 1986-10-01 | 1986-10-01 | Countershaft transmission having two forward and two reverse speeds |
| PCT/US1986/002722 WO1988002452A1 (en) | 1986-10-01 | 1986-12-19 | Countershaft transmission |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO882323L NO882323L (en) | 1988-05-26 |
| NO882323D0 NO882323D0 (en) | 1988-05-26 |
| NO170358B true NO170358B (en) | 1992-06-29 |
| NO170358C NO170358C (en) | 1992-10-07 |
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| Application Number | Title | Priority Date | Filing Date |
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| NO882323A NO170358C (en) | 1986-10-01 | 1988-05-26 | BETWEEN SHAFT-GEAR |
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1988
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| NO882323L (en) | 1988-05-26 |
| NO882323D0 (en) | 1988-05-26 |
| NO170358C (en) | 1992-10-07 |
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