DK163996B - 1h-indol-3-yl-holdige 1,3-dimethyl-1h-purin-2,6-dioner, fremgangsmaade til fremstilling af forbindelserne samt farmaceutiske praeparater med indhold deraf - Google Patents
1h-indol-3-yl-holdige 1,3-dimethyl-1h-purin-2,6-dioner, fremgangsmaade til fremstilling af forbindelserne samt farmaceutiske praeparater med indhold deraf Download PDFInfo
- Publication number
- DK163996B DK163996B DK444085A DK444085A DK163996B DK 163996 B DK163996 B DK 163996B DK 444085 A DK444085 A DK 444085A DK 444085 A DK444085 A DK 444085A DK 163996 B DK163996 B DK 163996B
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- DK
- Denmark
- Prior art keywords
- dione
- indol
- dimethyl
- formula
- purine
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 11
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- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- 239000002253 acid Substances 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims abstract description 14
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
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- 241001465754 Metazoa Species 0.000 claims description 10
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
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- 238000002360 preparation method Methods 0.000 claims description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
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- Neurology (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Description
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I Europæisk Patentskrift nr. 71.738 beskrives et antal piperi-din- og piperazin-holdige theophyllin-derivater som forbindelser med forskellige farmakologiske aktiviteter. Endvidere beskrives et antal 4-[1H-indol-3-yl]-piperidiner i U.S. Patentskrift nr. 3.980.658 og i 05 U.S. Patentskrift nr. 3.947.578 som forbindelser, der er anvendelige som beroligende midler, henholdsvis som neuroleptica og, som beskrevet i U.S. Patentskrift nr. 4.359.468 og U.S. Patentskrift nr. 4.342.870, anti-allergiske midler og hypotensive midler, henholdsvis serotonin-antagonister. Forbindelserne ifølge den forelig-10 gende opfindelse adskiller sig hovedsageligt fra de ovenstående forbindelser ved uomgængeligt at indeholde en 1,3-dimethyl-1H--purin-2,6-dion-del, der er bundet til en 1H-indol-3~yl-substitueret piperidin eller 3,6-dihydro-1(2H)-pyridin, og ved deres specielle farmakologiske egenskaber.
15 Den foreliggende opfindelse angår hidtil ukendte 1H-indol-3-yl- holdige 1,3-dimethyl-1H-purin-2,6-dioner med den følgende strukturformel Γ3
20 ViA
CH3-N J-N-Alk-N m (I) * w
R
25 samt farmaceutisk acceptable syreadditionssalte deraf, hvori Alk repræsenterer en bivalent lavere alkyl-gruppe, R er hydrogen, lavere alkyl, halogen, lavere alkyloxy eller hydroxy, og den punkterede linie indikerer en eventuel dobbelt-30 binding mellem 3- og 4-carbonatomerne i piperidin-kernen.
I de ovenstående definitioner er “halogen" en fællesbetegnelse for fluor, chlor, brom og iod, og “lavere alkyl" omfatter ligekædede og forgrenede mættede carbonhydrid-grupper med fra 1 til 6 carbon-atomer såsom for eksempel methyl, ethyl, 1-methylethyl, 1,1-di-35 methylethyl, propyl, butyl, pentyl, hexyl og lignende.
De mest foretrukne forbindelser er udvalgt fra gruppen bestående af 7-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dihydro-1,3-
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2 -dimethyl-1H-purin-2,6-dion og de farmaceutisk acceptable syre-additionssalte deraf.
Forbindelserne med formel (l) kan generelt fremstilles ved at omsætte et mellemprodukt med formel (II) med et piperidin med 05 formel (III) i henhold til kendte alkylerings-metoder.
cn3 ch3-k jl-J-B1 + _> (I) i° T (Λ (II) (III)
R
1 (II) og (111) er og udvalgt således, at 1,3-dihydro-2,6-Ί5 dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl-gruppen under alkylerings-reaktionen bliver forbundet via -Alk- til den substituerede 1-pipe-ridinyl- eller 3,6-dihydro-1(2H)-pyridinyl-gruppe som angivet I formel (I).
Forbindelserne med formel (I) kan for eksempel generelt frem- 20 stilles ved N-alkylering af et mellemprodukt med formel (III), hvori 2 Q er hydrogen, hvilket mellemprodukt angives ved formel (IIl-a), med et reagens med formel (II), hvori Q betegner -Alk-W, hvilket reagens har formlen (Il-a).
25 CH3 yy*i /-λ ^ -n—Alk—w + hn ^ (i)
® O
30 (Il-a) (III-a) I (Il-a) betegner W en passende reaktiv fraspaltelig gruppe såsom for eksempel halogen, f.eks. chlor, brom eller iod, eller en sulfo-nyloxy-gruppe, f.eks. methylsulfonyloxy eller 4-methylphenyl-35 sulfonyloxy.
Endvidere kan forbindelserne med formel (I) også fremstilles ved N-alkylering af et mellemprodukt med formel (II), hvori Q er
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3 hydrogen, hvilket mellemprodukt angives ved formel (ll-b), med et p mellemprodukt med formel (III), hvori Q er -Alk-W, (lll-b).
Γ3 05 V ^ - CU-Vl.J NH + W- Alk -N γζ' ^NH _^ (I) * · w/~i (II—b) (Ill-b) 10 I (lll-b) har W den førnævnte betydning.
Alkyleringsreaktionerne udføres passende i et inert organisk opløsningsmiddel såsom for eksempel et aromatisk carbonhydrid, f.eks. benzen, methylbenzen, dimethylbenzen og lignende, en lavere 15 alkanol, f.eks. methanol, ethanol, 1-butanol og lignende, en keton, f.eks. 2-propanon, 4-methyl-2-pentanon og lignende, en ether, f.eks. 1,4-dioxan, 1,1'-oxybisethan, tetrahydrofuran og lignende; Ν,Ν-dimethylformamid (DMF), Ν,Ν-dimethylacetamid (DMA), nitrobenzen, 1-methyl-2-pyrrolidinon, og lignende. Tilsætning af en pas-20 sende base såsom for eksempel et alkalimetalcarbonat eller -hydro-gencarbonat, natriumhydrid eller en organisk base såsom f.eks. Ν,Ν-diethylethanamin eller N-(1-methylethyl)-2-propanamin kan anvendes til at opfange den syre, der frigives i løbet af reaktionen.
I nogle tilfælde er det hensigtsmæssigt at tilsætte iodid, fortrinsvis 25 et alkalimetaliodid. En noget forhøjet temperatur kan forøge reaktionshastigheden.
Ved alle oven- og nedennævnte reaktioner kan reaktionsprodukterne isoleres fra reaktionsblandingen og, om nødvendigt, renses yderligere i henhold til kendte metoder.
30 Forbindelserne med formel (I) har basiske egenskaber og kan følgelig omdannes til terapeutisk aktive, non-toxiske syreadditions-salte deraf ved behandling med passende syrer som for eksempel uorganiske syrer såsom halogenbrintesyre, f.eks. saltsyre, brom-brintesyre og lignende, svovlsyre, salpetersyre, phosphorsyre og 35 lignende, eller organiske syrer som f.eks. eddikesyre, propansyre, hydroxyeddikesyre, 2-hydroxy-propansyre, 2-oxopropansyre, ethan-disyre, propandisyre, butandisyre, (Z)-2-butendisyre, (E)-2-buten-
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4 disyre, 2-hydroxybutandisyre, 2,3-dihydroxybutandisyre, 2--hydroxy-1,2,3-propantricarboxylsyre, methansulfonsyre, ethan-sulfonsyre, benzensulfonsyre, 4-methylbenzensulfonsyre, cyklo-hexaminosvovlsyre, 2-hydroxybenzoesyre, 4-amino-2-hydroxybenzoe-05 syre og lignende syrer. Omvendt kan saltformen omdannes ved behandling med alkali til den frie base-form.
Mellemprodukterne og udgangsmaterialerne ved ovennævnte reaktioner kan fremstilles i henhold til kendte metoder, der for eksempel er beskrevet i U.S. Patentskrift nr. 4.064.255, nr.
10 4.196.209 og i de i første afsnit af denne beskrivelse nævnte referencer.
Forbindelserne med formel (I) og de farmaceutisk acceptable syreadditionssalte deraf er kraftigt virkende antagonister til en række neurotransmittorer og har derfor nyttige farmakologiske egen-15 skaber. For eksempel besidder forbindelserne med formel (I) og deres farmaceutisk acceptable syreadditionssalte apomorphin-, tryptamin- og norepinephrin-antagonistisk aktivitet. Disse aktiviteter belyses i forbindelse med nedenstående testmetoder, og opnåede testresultater fremgår af eksempel 1.
20
Den kombinerede apomorphin (APO)-, tryptamin (TRY)- og norepinephrin (NOR)-test på rotter
De forsøgsdyr, der anvendtes ved denne test, var voksne 25 Wistar-rotter af hankøn (vægt 240 ± 10 g). Efter faste natten over behandledes dyrene subkutant (1 ml/100 g) med en vandig opløsning af den forbindelse, der skulle undersøges (tid = nul) og anbragtes i isolerede observationsbure. Tredive minutter derefter (tid = 30 minutter) injiceredes 1,25 mg/kg apomorphin,hydrochlorid 30 (APO) intravenøst, og rotterne observeredes i 1 time for tilstedeværelse eller fravær af følgende apomorphin-inducerede fænomen: uro og stereotyp tyggen. Ved udløbet af denne 1 times periode (tid - 90 minutter) injiceredes de samme dyr intravenøst med 40 mg/kg tryptamin (TRY), og tilstedeværelse af de typiske tryptamin-induce-35 rede, dobbeltsidige toniske anfald noteredes. To timer efter forbehandling (tid = 120 minutter) injiceredes dyrene sluttelig intravenøst med 1,25 mg/kg norepinephrin (NOR), og mulige dødsfald op til 60 minutter senere registreredes.
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5 I tabel 1 anføres ED^-værdier af et antal af de forbindelser, der er undersøgt. I det foreliggende angiver EDgQ-værdien den dosis, der beskytter 50% af dyrene mod det apomorphin-, tryptamin-eller norepinephrin-inducerede fænomen.
05 Forbindelserne anført i tabel 1 skal blot eksemplificere de nyttige farmakologiske egenskaber af alle forbindelserne med formel (I).
Tabel 1 10 ch3 °m rvs ενγ— «-(CH2> r'v_yy_/
15 \ V
R
Forb. r C-C R APO TRY NOR
20 Nr.
1 2 C-C H 0,39 0,78 1,2 21 2 C=C H - 1,25 2,5 3 2 C-C 7‘CH3 “ 5 1,25 25 5 2 C-C 5-F 2,5 5 2,5 13* 3 C-C H - 2,5 0,31 7 2 C-C 5-CI 1,25 1,25 17 3 C=C H 5 - 1,25 18 4 C=C H - - 0,10 30 10* 3 C-C 7"CH3 - “ 0/50 12 2 C=C 6-F 1,25 0,63 1,25 14 3 C-C 6-F 5 5 0,12 15** 4 C-C H - - 0,08 16 4 C-C 6-F - - 0,04 35 ...................
* : (E)-2-butendisyresalt (1:1) ** : (E)-2-butendisyresalt (2:1)
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6
Pi grund af den farmakologiske aktivitet kan forbindelserne med formel (I) og farmaceutisk acceptable syreadditionssalte deraf anvendes ved behandlingen af varmblodede dyr, der lider af psycho-trope sygdomme. De omhandlede forbindelser har også nyttige egen-05 skaber som sedativer, anxiolytika, anti-aggressionsmidler og anti-stressmidler og er derfor nyttige til beskyttelse af ikke-humane, varmblodede dyr, f.eks. i stress-situationer såsom under transport og i lignende situationer. Mere specielt er de omhandlede forbindelser nyttige ved manipulationer, mindre og større kirurgiske indgreb, 10 transport og sammenstuvning af kvæg.
I betragtning af de omhandlede forbindelsers nyttige egenskaber ved behandlingen af phychotrope sygdomme og deres virkning som sedativer, anxiolytika, anti-aggressionsmidler og anti-stress-midler kan de pågældende forbindelser formuleres på mange forskel-15 lige farmaceutiske måder.til administreringsformål.
Til fremstilling af de farmaceutiske forbindelser ifølge opfindelsen forenes en effektiv mængde af den specielle forbindelse, i form af base eller syreadditionssalt, som aktive bestanddel i intim blanding med en farmaceutisk acceptabel bærer, hvilken bærer kan 20 antage mange forskellige former afhængigt af præparatet, der ønskes til administrering. Det foretrækkes, at disse farmaceutiske forbindelser er pi enhedsdosisform, fortrinsvis til administrering ad oral, rektal eller parenteral vej. For eksempel kan der ved fremstilling af forbindelserne pi oral dosisform anvendes ethvert af de sædvanlige 25 farmaceutiske medier såsom f.eks. vand, glycoler, olier, alkoholer og lignende, når det drejer sig om flydende orale præparater såsom suspensioner, sirupper, eliksirer og opløsninger, eller faste bærere såsom stivelser, sukkerarter, kaolin, smøremidler, bindemidler, disintegreringsmidler og lignende, når det drejer sig om pulvere, 30 piller, kapsler og tabletter. Da tabletter og kapsler er lette at administrere, repræsenterer de den mest fordelagtige orale dosisenhedsform, i hvilket tilfælde faste farmaceutiske bærere naturligvis anvendes. Til parenterale præparater omfatter bæreren sædvanligvis sterilt vand, i det mindste som en større bestanddel, selv om andre 35 ingredienser for eksempel kan tilsættes for at lette opløseligheden.
Der kan for eksempel fremstilles injicerbare opløsninger, hvor bæreren omfatter en saltvandsopløsning, glucoseopløsning eller en
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7 blanding af saltvands- og glucoseopløsning. Injicerbare suspensioner kan også fremstilles, i hvilket tilfælde egnede flydende bærere, suspensionsmidler og lignende kan anvendes. Syreadditionssalte af forbindelserne med formel (I) er pi grund af deres øgede vand-05 opløselighed i forhold til den tilsvarende basisform tydeligvis mere egnede til fremstilling af vandige præparater.
Det er specielt fordelagtigt at formulere de ovenfor nævnte farmaceutiske præparater pi dosisenhedsform for at lette administrering og dosisensartethed. Den i det foreliggende anvendte TO dosisenhedsform henfører til fysisk diskrete enheder, der er egnede som enhedsdoser, hvor hver enhed indeholder en forud bestemt mængde aktiv bestanddel, der er beregnet til frembringelse af den ønskede terapeutiske virkning, sammen med den krævede farmaceutiske bærer. Eksempler på sådanne dosisenhedsformer er tabletter 15 (herunder tabletter med delekærv eller overtrukne tabletter), kapsler, piller, pulverpakker, oblater, injicerbare opløsninger eller suspensioner, theskefulde, spiseskefulde og lignende, samt adskilte multipler deraf.
Det er indlysende, at den foreliggende opfindelse kan anven-20 des en fremgangsmåde til behandling af varmblodede dyr, der lider af de nævnte psychotrope sygdomme, eller en fremgangsmåde til behandling af varmblodede dyr ved udøvelse af sedativ, anxiolytisk, anti-aggressiv og anti-stress-påvirkning. Den nævnte fremgangsmåde omfatter systemisk administrering af en psychotropt effektiv 25 mængde af en forbindelse med formel (I) eller et farmaceutisk acceptabelt syreadditionssalt deraf i blanding med en farmaceutisk bærer.
Passende doser til administrering til individer varierer fra 0,001 mg/kg til 10 mg/kg legemsvægt, mere foretrukket fra 0,05 30 mg/kg til 0,5 mg/kg legemsvægt.
De følgende eksempler har til formål at belyse opfindelsen.
Med mindre andet er angivet, er alle dele vægtdele.
35
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8
Eksempel 1
En blanding af 5 dele 7-(2-chlorethyl)-3,7-dihydro-1,3-di-methyl-1H-purin-2,6-dion, 4 dele 3-(4-piperidinyl)-1H-indol, 8 dele 05 natriumcarbonat, 1 del kaliumiodid og 120 dele 4-methyl-2-pentanon omrørtes og tilbagesvaledes natten over. Reaktionsblandingen afkøledes, vand tilsattes og lagene separeredes. Den organiske fase tørredes, filtreredes og inddampedes. Remanensen rensedes ved søjlekromatografi over silikagel under anvendelse af en blanding af 10 trichlormethan og methanol (95:5 vol/vol) som elueringsmiddel. De rene fraktioner opsamledes, og elueringsmidlet afdampedes. Remanensen udkrystalliseredes fra 4-methy!-2-pentanon, hvilket gav 4 dele (50%) 7-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dihydro-*-1,3-dimethyl-1H-purin-2,6-dion, smp. 201,2°C (forbindelse 1).
15
Eksempel 2
En blanding af 3,65 dele 7-(2-chlorethyl)-3,7-dihydro-1,3-di-methyl-1H-purin-2,6-dion, 3 dele 3-(4-piperidinyl)-1H-indol-5-ol, 20 4,25 dele natriumcarbonat, 0,1 del kaliumiodid og 200 dele 4-methyl- 2-pentanon omrørtes og tilbagesvaledes natten over. Det hele filtreredes varmt, og filtratet inddampedes. Remanensen suspenderedes i 45 dele trichlormethan og 2,4 dele methanol. Produktet frafiltrere-des, vaskedes med 16 dele methanol og tørredes, hvilket gav 2,5 25 dele (43%) 3,7-dihydro-7-[2-[4-(5-hydroxy-1H-tndol-3-yI)-1-pipen- dinyl]ethyl]-1,3-dimethyl-1H-purin-2,6-dion, smp. 232,5°C (forbindelse 2).
Pi lignende mide fremstilledes også: 3,7-dihydro-1,3-dimethyl-7-[2-[4-(7-methyMH-indol-3-yl)-1-piperi-30 dinyl]ethyl]-1H-purin-2,6-dion, smp. 200,2°C (forbindelse 3), 7-[3-[4-(5-fluor-1H-indol-3-y!)-1-piperidinyl]propyl]-3,7-dihydro--1,3-dimethyl)-1H-purin-, 2,6-dion,(E)-2-butendisyresalt (1:1), smp. 232,3°C (forbindelse 4), 7-[2-[4-(5-fluor-1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dihydro-1,3-35 dimethyl-1H-purin-2,6-dion, smp. 168,4°C (forbindelse 5), 7-[3-[4-(5-chlor-1H-indol-3-yl)-1-piperidinyl]propyl]-3,7-dihydro- 1,3-dimethyl-1H-purin-2,6-dion, smp. 105,8°C (forbindelse 6),
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9 7-[2-[4-(5-chlor-1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dihydro-1,3--dimethyl-1H-purin-2,6-dion, smp. 225,0°C (forbindelse 7), 3.7- dihydro-7-[2-[4-(5-methoxy-1H-indol-3-y))-1-piperidinyl]ethyl]--1,3-dimethyMH“purm-2,6-dion, smp. 205,0°C (forbindelse 8), 05 3,7-dihydro-7-[3-[4-(5-methoxy-1H-indol-3-yl)-1-piperidinyl]pro- pyl]-1 ,3-dimethyMH-purin-2,6-dion, smp. 104,4°C (forbindelse 9), 3.7- dihydro-1,3-dimethyl-7-[3-[4-(7-methyMH-indol-3-yl)-1-piperi-dinyl]propyl]-1H-purin-2,6-dion,(E)-2-butendisyresalt (1:1), smp.
228,1°C (forbindelse 10), 10 7-[2-[4-(5-brom-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]- -3,7-dihydro-1,3-dimethyl-1H-purin-2,6-dion,monohydrochlorid, smp. 258,9°C (forbindelse 11), og 7-[2-[4-(6-fluor-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]--3,7-dihydro-1,3-dimethyl-1H-purin-2,6-dion, smp. 163,5°C 15 (forbindelse 12).
Eksempel 3
En blanding af 4,5 dele 7-(3-chlorpropyl)-3,7-dihydro-1,3-di-20 methyMH-purin-2,6-dion,monohydrochlorid, 3 dele 3-(4-p?peridinyl)- -1H-indol, 8 dele natriumcarbonat, 0,1 dele natriumiodid og 240 dele 4-methyl-2-pentanon omrørtes og tilbagesvaledes i 20 timer. Det hele filtreredes varmt, og filtratet inddampedes. Remanensen rensedes ved søjlekromatografi over silikagel under anvendelse af en blanding 25 af trichlormethan og methanol (92:8 vol/vol) som elueringsmiddel.
De rene fraktioner opsamledes, og elueringsmidlet afdampedes. Remanensen omdannedes til (E)-2-butendisyresaltet i 2-propanol.
Saltet frafiltreredes og tørredes, hvilket gav 3,9 dele (48%) 3.7- dihydro-7-[3-[4-(1H-indol“3-yl)-1-piperidinyl]propyl]-1,3- 30 -dimethyl-1H-purin-2,6-dion,(E)-2“butendisyresalt (1:1), smp.
222,7°C (forbindelse 13).
Pi lignende måde fremstilledes også: 7-[3-[4-(6-fluor-1H-indol-3-yl)-1-piperidinyl]propyl]-3,7-dihydro--1,3-dimethyl-1H-purin-2,6-dion, smp. 128,0°C (forbindelse 14), 35 3,7-dihydro-7-[4-[4-(1H-mdol-3-yl)-1-piperidinyl]butyl]-1,3-di- methyMH-purin-2,6-dion,(E)-2-butendrsyresalt (2:1), smp. 227,7°C (forbindelse 15), og
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10 7-[4-[4-(6-fluor-1H-indol-3-yl)-1-piperidinyl]butyl]-3,7-dihydro-1,3--dimethyl-1H-purin-2,6-dion, smp. 151,8°C (forbindelse 16).
Eksempel 4 05
En blanding af 5 dele 7-(3-chlorpropyl)-3,7-dihydro-1,3-di-methyMH-purin-2,6-dion,monohydrochlorid, 4 dele 3-(1,2,3,6--tetrahydro-4-pyridinyl)-1H-indol, 8 dele natriumcarbonat og 240 dele 4-methyl-2-pentanon omrørtes i 22 timer ved tilbagesvalings-10 temperatur. Det hele omrørtes indtil stuetemperatur opnåedes. Produktet frafiltreredes og omrørtes i vand. Efter filtrering vaskedes produktet med vand og omrørtes i vand og en ækvivalent mængde eddikesyre. Blandingen behandledes med ammoniumhydroxid.
Det udfældede produkt frafiltreredes, vaskedes med vand og om-15 rørtes i en blanding af acetonitril og 2-propanol. Produktet frafiltreredes, vaskedes med acetonitril og tørredes, hvilket gav 7 dele (98%) 7-[3-[3,6-dihydro-4-(1H-indol-3-yl)-1(2H)-pyridinyl]propyl]--3,7-dihydro-1,3-dimethyl-1H-purin-2,6-dion, smp. 243,2° C (forbindelse 17).
20 På lignende mide fremstilledes også: 7-[4-[3,6-dihydro-4-(1H-indol-3-yl)-1(2H)-pyridinyl]butyl]-3,7-di-hydro-1,3-dimethyl-1H-purin-2,6-dion, smp. 198,3° C (forbindelse 18), og 7-[4-[4-(5-fluor-1H-indol-3-yl)-1-piperidinyl]butyl]-3,7-dihydro-25 -1,3-dimethyl-1H-purin-2,6-dion,(E)-2-butendisyresalt (1:1), smp.
210,6°C (forbindelse 19).
Eksempel 5 30 En blanding af 6 dele 7-(3-chlorpropyl)-3,7-dihydro-3-dimethyl- -1H-purin-2,6-dion,monohydrochlorid/ 5 dele 5-brom-3-(1,2,3,6--tetrahydro-4-pyridinyl)-1H-indol,monohydrat, 10 dele natriumcarbonat, 0,2 dele natriumiodid og 135 dele Ν,Ν-dimethylacetamid omrørtes og opvarmedes natten over ved 90°C. Reaktionsblandingen ind-35 dampedes til tørhed. Remanensen omrørtes i vand. Produktet eks-traheredes med trichlormethan. Ekstrakten tørredes, filtreredes og inddampedes. Remanensen rensedes ved søjle kromatografi over silika-
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11 gel under anvendelse af en blanding af trichlormethan og methanol (90:10 vol/vol) som elueringsmiddel. De rene fraktioner opsamledes, og elueringsmidlet afdampedes. Remanensen udkrystalliseredes fra acetonitril. Produktet frafiltreredes og tørredes, hvilket gav 3,2 05 dele (’36%) 7-[3-[4-(5-brom-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyri-dinyl]propyl]-3,7-dihydro-1,3-dimethyl-1H-purin-2,6-dion, smp.
195,1°C (forbindelse 20).
Eksempel 6 10
En blanding af 3,8 dele 7-(2-chlorethyl)-3,7-dihydro-1,3-di-methy!-1H-purin-2,6-dion, 3 dele 3-(3,6-dihydro-1 (2H)-pyridinyl)--1H-indol, 8 dele natriumcarbonat, 0,1 del kaliumiodid og 270 dele methylbenzen omrørtes og tilbagesvaledes i 20 timer. Reaktions-15 blandingen filtreredes varmt, og filtratet inddampedes. Remanensen
rensedes ved søjlekromatografi over sili kagel under anvendelse af en blanding af trichlormethan og methanol (92:8 vol/vol) som elueringsmiddel. De rene fraktioner opsamledes, og elueringsmidlet afdampedes. Remanensen ud krystal liseredes fra 2-propanon. Produk-20 tet frafiltreredes og tørredes i vakuum ved 120°C, hvilket gav 3,1 dele (51,6%) 3,7-dihydro-7-[2-[3,6-dihydro-4-(1H-indol-3-yl)-1(2H)--pyridinyl]ethyl]-1,3-dimethyl-1H-purin-2,6-dion, smp. 196,5°C
(forbindelse 21).
25 Eksempel 7
En blanding af 5 dele 3,7-dihydro-7-[2-[4-(1H-indol-3-yl)-1--piperldinyI]ethyl]-1,3-dimethyl-1H-purm-2,6-dion, 16 dele 2-propa-nol og 160 dele 2-propanol, mættet med gasformigt hydrogenchlorid, 30 omrørtes i 1 time ved 70°C. Efter afkøling til 20°C frafiltreredes produktet, vaskedes to gange med 24 dele acetonitril og tørredes, hvilket gav 4,3 dele (79%) 3,7-dihydro-7-[2-[4-(1H-indol-3-yl)-1--piperidinyl] ethyl ]-1,3-dimethyl-1H-purin-2,6-dion,monohydrochlo-rid, smp. 273,0°C (forbindelse 22).
35
DK 163996 B
12
Eksempel 8
Til en omrørt blanding af 5 dele 3,7-dihydro-7-[2-[4-(1H-indol--3-yl)-1-piperidinyl]ethyl]“1,3-dimethyl-1H-purin-2,6-dion og 100 05 dele 2-methoxyethanol sattes 3 dele 85% phorphorsyre-opløsning.
Efter omrøring i 30 minutter frafiltreredes produktet, vaskedes med 40 dele methanol og ud krystalliseredes fra 90 dele Ν,Ν-dimethyl-formamid ved 0°C. Produktet frafiltreredes, vaskedes med 16 dele methanol og tørredes, hvilket gav 3,4 dele (57%) 3,7-dihydro-7-[2-10 -[4-(1H-indol-3-yl)-1-piperidinyl] ethyl ]-1,3-dimethyl-1H-purin-2,6- -dion,phosphat (1:1), smp. 254,7°C (forbindelse 23).
På samme måde og under anvendelse af passende syrer fremstilledes også: 3.7- dihydro-7-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-1,3-di- Ί5 methyl-1H-purin-2,6-dio.n,sulfat (1:1), smp. 253,7°C (forbindelse 24) , 3.7- dihydro-7-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl3“1,3-di-methyl-1H-purin-2,6-dion,methansulfonat, smp. 243,1°C (forbindelse 25) .
20
Eksempel 9
Til en omrørt opløsning af 5 dele 3,7-dihydro-7-[2-[4-(1H--indol-3-yl)-1-piperidinyl]ethyl]-1,3-dimethyl-1H-purin-2,6-dion i 25 160 dele 2-propanol og en lille mængde Ν,Ν-dimethylformamid sattes en opløsning af 3,5 dele (+)-2,3-dihydroxybutandisyre i methanol.
Det hele omrørtes i 30 minutter under tilbagesvaling. Efter afkøling frafiltreredes produktet og tørredes, hvilket gav 6,5 dele (97,3%) (+)-3,7-dihydro-7-[2-[4-(1H-indol-3-yl)-1-piperidinyl] ethyl ]-1,3-30 -dimethyl-1H-purin-2,6-dion [R-(R*, R*)]-2,3-dihydroxybutandisyre- salt (1:1) R 64,488; smp. 218,2°C (forbindelse 26).
På samme måde og under anvendelse af en passende syre fremstilledes også: 3.7- dihydro-7-[2-[4-(1H-indol-3-y|)-1-piperidinyl]ethyl]-1,3-di-
35 methyl-1H-purin-2,6-dion,(Z)-2-butendisyresalt (1:1), smp. 166,9°C
(forbindelse 27).
Claims (6)
1. IH-indol-3-yl-holdig 1,3-dimethyMH-purin-2,6-dion med formlen 05 ch3 ν J-N-Alk-N τίΗ (I) ** ^ W R eller et farmaceutisk acceptabelt syreadditionssalt deraf, hvori Alk repræsenterer en bivalent lavere alkyl-gruppe, 15. er hydrogen, lavere al kyl, halogen, lavere alkyloxy eller hydroxy, og den punkterede linie indikerer en eventuel dobbeltbinding mellem 3- og 4-carbonatomerne i piperidin-kernen.
2. Forbindelse ifølge krav 1, KENDETEGNET ved, AT den er udvalgt fra gruppen bestående af 7-[2-[4-(1H-indol-3-yl)-1-piperi- 20 dinyl]ethyl]-3,7-dihydro-1,3-dimethyl-1H-purin-2,6-dion samt farmaceutisk acceptable syreadditionssalte deraf.
3. Farmaceutisk præparat til behandling af ikke-humane, varmblodede dyr, KENDETEGNET ved, AT det omfatter en passende farmaceutisk bærer og som aktiv bestanddel en farmaceutisk aktiv 25 mængde af en forbindelse ifølge krav 1 med formlen f* YYs*i CH -N-Alk-N 3° 3 8 W<K R eller et farmaceutisk acceptabelt syreadditionssalt deraf, hvori 35 Alk repræsenterer en bivalent lavere alkyl-gruppe, R er hydrogen, lavere alkyl, halogen, lavere alkyloxy eller hydroxy, og den punkterede linie indikerer en eventuel dobbeltbinding mellem 3- og 4-carbonatomerne i piperidin-kernen. DK 163996B
4. Præparat ifølge krav 3, KENDETEGNET ved, AT den aktive forbindelse er udvalgt fra gruppen bestående af 7-[2-[4-(1H-indol--3-yl)-1-piperidinyl]ethyl]-3,7-dihydro-1,3-dimethyl-1H-purin-2,6--dion samt farmaceutisk acceptable syreadditionssalte deraf.
5. Fremgangsmåde til fremstilling af 1H-indol-3-yl-holdige 1,3- dimethyl-1H-purin-2,6-dioner med formlen CIi3 Υ'Λ /ΓΛ / v
10 CH3-k^-N-Alk-N m (I) ® · \ 7 R eller et farmaceutisk acceptabelt syreadditionssalt deraf, hvori 15 Alk repræsenterer en bivalent lavere al kyl-gruppe, R er hydrogen, lavere alkyl, halogen, lavere alkyloxy eller hydroxy, og den punkterede linie indikerer en eventuel dobbeltbinding mellem 3- og 4-carbonatomerne i piperidin-kernen, KENDETEGNET ved, AT man omsætter et mellemprodukt med formlen 20 ch3-n ])—n-q1 (ii) o 25 med et piperidin med formlen Q2"N\ (III) , 30 , 0 R hvori Q betegner en gruppe -Alk-W og Q„ er hydrogen eller 1. d Q er hydrogen og Q betegner en gruppe -Alk-W, 55 hvori W er en reaktiv fraspaltelig gruppe, idet omsætningen fortrinsvis udføres i et reaktions-inert opløsningsmiddel, eller ved at man eventuelt omdanner en forbindelse med formel (I) til en forbin- DK 163996 6 delse med formel (I) i henhold til velkendte metoder til omdannelse af funktionelle grupper, og, om ønsket, bringer forbindelserne med formel (I) på en terapeutisk aktiv, non-toxisk syreadditionssalt-form ved behandling med en egnet syre, eller omvendt omdanner syre-05 additionssaltet til den frie baseform med alkali, og/eller ved at man fremstiller stereokemisk isomere former deraf.
6. Fremgangsmåde ifølge krav 5 til fremstilling af 7-[2-[4-(1H--indol-3-yl)-1-piperidiny!]ethyl]-3,7-dihydro-1,3-dimethyl-1H-punn--2,6-dion eller et farmaceutisk acceptabelt syreadditionssalt deraf, TO KENDETEGNET ved, AT man omsætter 7-(2-halogenethyl)-3,7-di-hydro-1,3-dimethyl-1H~purin-2,6-dion med 3-(4-piperidinyl)-1H-indol i et reaktions-inert opløsningsmiddel, eventuelt i nærvær af en base, og om ønsket bringer den siledes opnåede forbindelse på en terapeutisk aktiv, non-toxisk syreadditionssalt-form ved behandling med 15 en egnet syre, eller omvendt omdanner syreadditionssaltet til den frie base-form med alkali. 20 25 30 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65656184 | 1984-10-01 | ||
| US06/656,561 US4548939A (en) | 1984-10-01 | 1984-10-01 | 1H-Indol-3-yl containing 1,3-dimethyl-1H-purine-2,6-diones |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK444085D0 DK444085D0 (da) | 1985-09-30 |
| DK444085A DK444085A (da) | 1986-04-02 |
| DK163996B true DK163996B (da) | 1992-04-27 |
| DK163996C DK163996C (da) | 1992-09-21 |
Family
ID=24633577
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK444085A DK163996C (da) | 1984-10-01 | 1985-09-30 | 1h-indol-3-yl-holdige 1,3-dimethyl-1h-purin-2,6-dioner, fremgangsmaade til fremstilling af forbindelserne samt farmaceutiske praeparater med indhold deraf |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4548939A (da) |
| EP (1) | EP0177087B1 (da) |
| JP (1) | JPH0653742B2 (da) |
| CN (1) | CN1011311B (da) |
| AT (1) | ATE60604T1 (da) |
| AU (1) | AU576386B2 (da) |
| CA (1) | CA1262348A (da) |
| DE (1) | DE3581577D1 (da) |
| DK (1) | DK163996C (da) |
| ES (1) | ES8609324A1 (da) |
| FI (1) | FI83220C (da) |
| GR (1) | GR852375B (da) |
| IE (1) | IE58747B1 (da) |
| NO (1) | NO162069C (da) |
| NZ (1) | NZ213498A (da) |
| PT (1) | PT81229B (da) |
| ZA (1) | ZA857553B (da) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH648559A5 (de) * | 1981-07-20 | 1985-03-29 | Siegfried Ag | Theophyllinderivate und verfahren zu deren herstellung. |
| US4742057A (en) * | 1985-12-05 | 1988-05-03 | Fujisawa Pharmaceutical Co., Ltd. | Antiallergic thiazole compounds |
| EP0303507B1 (en) * | 1987-08-13 | 1993-07-28 | Glaxo Group Limited | Indole derivatives |
| GB8719167D0 (en) * | 1987-08-13 | 1987-09-23 | Glaxo Group Ltd | Chemical compounds |
| DK733788A (da) * | 1988-01-14 | 1989-07-15 | Fujisawa Pharmaceutical Co | Indolylpiperidinderivater og fremgangsmaade til fremstilling deraf |
| GB8819024D0 (en) * | 1988-08-10 | 1988-09-14 | Glaxo Group Ltd | Chemical compounds |
| DE8817122U1 (de) * | 1988-12-22 | 1993-02-04 | Boehringer Ingelheim Kg, 55218 Ingelheim | Neue Xanthinderivate mit Adenosinantogenistischer Wirkung |
| DK292A (da) * | 1991-11-29 | 1992-01-02 | Tanisake Kk | Middel |
| DE4414113A1 (de) * | 1994-04-22 | 1995-10-26 | Merck Patent Gmbh | 3-Indolylpiperidine |
| JP2010530901A (ja) * | 2007-06-22 | 2010-09-16 | ハイドラ バイオサイエンシズ インコーポレイテッド | 障害を治療するための方法および組成物 |
| WO2009140517A1 (en) | 2008-05-14 | 2009-11-19 | Hydra Biosciences, Inc. | Compounds and compositions for treating chemical warfare agent-induced injuries |
| US8318728B2 (en) | 2008-05-14 | 2012-11-27 | Hydra Biosciences, Inc. | Compounds and compositions for treating chemical warfare agent-induced injuries |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2322470A1 (de) * | 1973-05-04 | 1974-11-21 | Boehringer Sohn Ingelheim | Neue indolyl-piperidino-(bzw. 1,2,5,6tetrahydro-pyridyl-)butyrophenone und verfahren zu ihrer herstellung |
| FR2334358A1 (fr) * | 1975-12-12 | 1977-07-08 | Sogeras | Nouveaux medicaments derives de l'indole |
| FR2362628A1 (fr) * | 1976-08-26 | 1978-03-24 | Roussel Uclaf | Nouveaux derives du piperidyl-indole et leurs sels, procede de preparation et application a titre de medicaments |
| EP0011399A1 (en) * | 1978-11-11 | 1980-05-28 | FISONS plc | N-substituted theophyllines, processes for their preparation and pharmaceutical compositions containing them |
| DE2922159A1 (de) * | 1979-05-31 | 1980-12-04 | Boehringer Mannheim Gmbh | Neue xanthin-derivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| US4342870A (en) * | 1980-03-28 | 1982-08-03 | Janssen Pharmaceutica N.V. | Novel 3-(1-piperidinylalkyl)-4H-pyrido[1,2-a]pyrimidin-4-one derivatives |
| US4426383A (en) * | 1980-09-04 | 1984-01-17 | Eisai Co., Ltd. | Theophylline and theobromine derivatives |
| US4359468A (en) * | 1981-02-25 | 1982-11-16 | Boehringer Ingelheim Ltd. | Antiallergic N-[4-(indolyl)-piperidino-alkyl]-benzimidazolones |
| US4443451A (en) * | 1981-07-15 | 1984-04-17 | Janssen Pharmaceutica N.V. | Bicyclic pyrimidin-5-one derivatives |
| CH648559A5 (de) * | 1981-07-20 | 1985-03-29 | Siegfried Ag | Theophyllinderivate und verfahren zu deren herstellung. |
-
1984
- 1984-10-01 US US06/656,561 patent/US4548939A/en not_active Expired - Fee Related
-
1985
- 1985-07-30 CN CN85105804A patent/CN1011311B/zh not_active Expired
- 1985-09-10 CA CA000490317A patent/CA1262348A/en not_active Expired
- 1985-09-16 NZ NZ213498A patent/NZ213498A/en unknown
- 1985-09-18 EP EP85201484A patent/EP0177087B1/en not_active Expired - Lifetime
- 1985-09-18 AT AT85201484T patent/ATE60604T1/de not_active IP Right Cessation
- 1985-09-18 DE DE8585201484T patent/DE3581577D1/de not_active Expired - Fee Related
- 1985-09-27 JP JP60212731A patent/JPH0653742B2/ja not_active Expired - Lifetime
- 1985-09-30 FI FI853763A patent/FI83220C/fi not_active IP Right Cessation
- 1985-09-30 ZA ZA857553A patent/ZA857553B/xx unknown
- 1985-09-30 AU AU48124/85A patent/AU576386B2/en not_active Ceased
- 1985-09-30 NO NO853856A patent/NO162069C/no unknown
- 1985-09-30 IE IE240385A patent/IE58747B1/en not_active IP Right Cessation
- 1985-09-30 DK DK444085A patent/DK163996C/da not_active IP Right Cessation
- 1985-09-30 GR GR852375A patent/GR852375B/el unknown
- 1985-09-30 ES ES547447A patent/ES8609324A1/es not_active Expired
- 1985-10-01 PT PT81229A patent/PT81229B/pt not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ATE60604T1 (de) | 1991-02-15 |
| NO162069C (no) | 1989-11-01 |
| DK444085A (da) | 1986-04-02 |
| EP0177087B1 (en) | 1991-01-30 |
| DK444085D0 (da) | 1985-09-30 |
| FI853763A0 (fi) | 1985-09-30 |
| AU4812485A (en) | 1986-04-10 |
| IE852403L (en) | 1986-04-01 |
| NO853856L (no) | 1986-04-02 |
| JPH0653742B2 (ja) | 1994-07-20 |
| AU576386B2 (en) | 1988-08-25 |
| GR852375B (da) | 1986-01-31 |
| CN1011311B (zh) | 1991-01-23 |
| CA1262348A (en) | 1989-10-17 |
| FI83220B (fi) | 1991-02-28 |
| PT81229B (pt) | 1987-11-30 |
| DE3581577D1 (de) | 1991-03-07 |
| EP0177087A3 (en) | 1986-06-11 |
| DK163996C (da) | 1992-09-21 |
| ES8609324A1 (es) | 1986-07-16 |
| FI853763L (fi) | 1986-04-02 |
| CN85105804A (zh) | 1986-10-22 |
| NO162069B (no) | 1989-07-24 |
| NZ213498A (en) | 1988-04-29 |
| FI83220C (fi) | 1991-06-10 |
| IE58747B1 (en) | 1993-11-03 |
| ZA857553B (en) | 1987-05-27 |
| ES547447A0 (es) | 1986-07-16 |
| JPS6187681A (ja) | 1986-05-06 |
| EP0177087A2 (en) | 1986-04-09 |
| PT81229A (en) | 1985-11-01 |
| US4548939A (en) | 1985-10-22 |
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