SE442298B - 2, 3-dimethyl-4-(2, 3-dichlorphenyl)-1, 4-dihydropyridin-3, 5-dicarboxioxygen-3-methylester-5-ethylester in optically active form. - Google Patents
2, 3-dimethyl-4-(2, 3-dichlorphenyl)-1, 4-dihydropyridin-3, 5-dicarboxioxygen-3-methylester-5-ethylester in optically active form.Info
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- SE442298B SE442298B SE8303617A SE8303617A SE442298B SE 442298 B SE442298 B SE 442298B SE 8303617 A SE8303617 A SE 8303617A SE 8303617 A SE8303617 A SE 8303617A SE 442298 B SE442298 B SE 442298B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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Abstract
Description
85Û36l7= 8 med den glattmuskelrelaxerande effekten. I vissa fall har de vaso- dilaterande effekterna också haft en negativ effekt på hjärtats kontraktilitet. 5 Det framgår därav att utvecklingen av specifika glattmuskelrelaxe- rande medel som saknar sidoeffekter kan erbjuda en terapeutisk fördel i arteriell hypertension och för behandling av ischemisk hjärtsjukdom och av akut sviktande hjärta. Vidare kan sådana medel också vara användbara i behandling av andra tillstånd med förhöjd 70 aktivering av inälvsglattmuskulaturen. 85Û36l7 = 8 with the smooth muscle relaxing effect. In some cases, they have The dilating effects also had a negative effect on the heart contractility. It appears from this that the development of specific smooth muscle relaxation remedies that lack side effects can offer a therapeutic benefit in arterial hypertension and for the treatment of ischemic heart disease and of acutely failing heart. Furthermore, such means can also be useful in the treatment of other conditions with elevated 70 activation of the intestinal smooth muscles.
Det har nu överraskande visat sig att föreningen enligt formel 1 5 . l ššš//¿\ H Ü <1 > H3C00C]i I COOCZHS »A \ 20 H3C T CH3 H besitter en specifik muskelrelaxerande effekt som relaterar till det perifera vaskulära systemet varvid föreningen saknar sidoeffekter. 25 Substansen är avsedd att administreras oralt eller parenteralt för akut eller kronisk behandling av ovan nämnda kardiovaskulära sjukdomstillstånd.It has now surprisingly been found that the compound of formula 1 5. l ššš // ¿\ H Ü <1> H3C00C] i I COOCZHS »A \ 20 H3C T CH3 hrs possesses a specific muscle relaxing effect related to the peripheral vascular system with the compound having no side effects. The substance is intended to be administered orally or parenterally for acute or chronic treatment of the above mentioned cardiovascular disease state.
Den nya föreningens biologiska effekter har testats och de olika 30 tester som genomförts kommer att visas och förklaras nedan.The biological effects of the new compound have been tested and the various 30 tests performed will be shown and explained below.
Den nya föreningen erhålles enligt i och för sig kända metoder. 35 fi* "ë-.fïfi u vrf w; ._.~._ Ãàiï -__; ra . _ e» aß-der, ah :g 10 15 25 30 8303617-8 Sâïunda, al) reageras en förening enligt formeï Ila CI C1 (Ile) : EH H3CfiCfi0CH3 0 0 med en förening med formeï Illa "H2~\\ <¿;n _c=cH-c I/ (1IIa) CH OC H 3 2 5 för att ge en förening enligt formeï I, elïer az) reageras en förening enïigt forma] 11b í:j:\Tí/c1 V \\}f/l\t1 ÉH I H3c%-c-fioc2H5 (IIb} 0 0 med en förening enïigt formeï IIIb NH *\ 2\\\ ,«/ C=CH-C (IIID) CH OCH 3 3 till biïdning av en förening enïigt formeï 1; eïïer <1 :av fw v.,,',.__:r__,¿ ' =$Ä...š.-. a; fr' Poem f; 'un 850561748 bï) reageras en förening enligt formel IV 1 5 _\*c1 c\_g H/ \D i 10 med föreningarna enligt formlerna Va och Illa - o\\ / 0013 c-cH -c (v ) X 2 § a m3 o is NH¿\ /ocznâ c=cH-c (111a) \ m3/ \' o 20 till bildning av en förening enligt formel I, eller b2) reageras en förening enligt formel IV ovan med föreningarna enligt formlerna Vb och Vlb 25 0% /ocznß _ c-cH2-c\ (vn) cn3/ o NHÄ nens, 30 \c=cH-c (m) cH3 \“o till bildning av en förening enligt formel I; eller šeeïf; Qïfifïzlrxfïf l0 l5 20 25 30 35 8503617-8 5 c1) reageras en förening enligt formel [Ia med en förening enligt formel VIa // O C-CH2-C// (VIG) 3 °2"s o \ cH i närvaro av ammoniak till bildning av en förening enligt formeln I, eller c2) reageras en förening enligt formel Ilb med en förening enligt formel VIb o¿_ ,,o 'fc-cnz-c' (v1b) CH // \ocH 3 3 i närvaro av ammoniak, till bildning av en förening enligt formeln I; eller dl en förening enligt formel IV ovan reageras med föreningarna enligt Formlerna Va och Vb ovan i närvaro av ammoniak, till bild- ning av en förening enligt formeln I.The new compound is obtained according to methods known per se. 35 fi * "ë-.fï fi u vrf w; ._. ~ ._ Ãàiï -__; ra. _ e »aß-der, ah: g 10 15 25 30 8303617-8 Sâïunda, al) react a compound of formula IIa CI C1 (Ile) : EH H3C fi C fi0 CH3 0 0 with a compound of formeï Illa "H2 ~ \\ <¿; n _c = cH-c IN/ (1IIa) CH OC H 3 2 5 to give a compound of formula I, or az) a compound is reacted according to form 11b í: j: \ Tí / c1 V \\} f / l \ t1 EH IN H3c% -c- fi oc2H5 (IIb} 0 0 with a compound of the same form IIIb NH * \ 2 \\\, «/ C = CH-C (IIID) CH AND 3 3 to form a compound of formula 1; egg <1 : av fw v. ,, ', .__: r __, ¿ '= $ Ä ... š.-. a; fr ' Poem f; 'un 850561748 bï) react a compound of formula IV 1 5 _ \ * c1 c \ _g H / \ D i With the compounds of formulas Va and IIIa - o \\ / 0013 c-cH -c (v) X 2 § a m3 o is NH¿ \ / ocznâ c = cH-c (111a) \ m3 / \ 'o To form a compound of formula I, or b2) a compound of formula IV above is reacted with the compounds according to formulas Vb and Vlb 25 0% / ocznß _ c-cH2-c \ (vn) cn3 / o NHÄ nens, 30 ° C = cH-c (m) cH3 \ “o to form a compound of formula I; or šeeïf; Qï fi fïzlrxfïf l0 l5 20 25 30 35 8503617-8 5 c1) reacting a compound of formula [Ia with a compound of formula formula VIa // O C-CH2-C // (VIG) 3 ° 2 "s O \ cH in the presence of ammonia to form a compound of formula I, or c2) reacting a compound of formula IIb with a compound of formula formula VIb o¿_ ,, o 'fc-cnz-c' (v1b) CH // \ ocH 3 3 in the presence of ammonia, to form a compound of formula I; or a compound of formula IV above is reacted with the compounds according to Formulas Va and Vb above in the presence of ammonia, to compound of a compound of formula I.
Uppfinningen avser också varje utföringsform av förfarandet enligt vilket man utgår från en förening som erhållits som en mellanprodukt i något förfarandesteg och man genomför det felande processteget eller man avbryter processen i något steg eller vid vilket man bildar ett utgångsmaterial under reaktionsbetingelserna eller vid vilket en reaktionskomponent, möjligen i form av dess salt, är närvarande.The invention also relates to each embodiment of the method according to which is based on a compound obtained as an intermediate in any procedural step and the incorrect process step is performed or one interrupts the process at some stage or at which one forms a starting material under the reaction conditions or in which a reactant, possibly in the form of its salt, is present.
Den nya föreningen kan beroende på valet av utgångsmaterial och förfarande föreligga som optiska antipoder eller racemat. 85Û36l 7-8 ID l5 20 25 30 35 Isomerblandningen som erhålles kan beroende på fysikalisk-kemiska skillnader hos komponenten separeras i de tvâ stereoisomera rena antipoderna exempelvis medelst kromatografi och/eller fraktionerad kristallisation.The new association can, depending on the choice of starting material and method present as optical antipodes or racemates. 85Û36l 7-8 ID l5 20 25 30 35 The isomer mixture obtained may depend on the physicochemical differences of the component are separated into the two stereoisomeric pure the antipodes, for example by chromatography and / or fractionation crystallization.
Det erhållna racematet kan separeras enligt kända metoder exempelvis medelst rekristallisation ur ett optiskt aktivt lösningsmedel, medelst mikroorganismer, eller medelst en reaktion med optiskt aktiva syror som bildar salter utav föreningen och separering av de sålunda erhållna salterna, exempelvis medelst olika löslighet av de diastereomera salterna från vilka antipoderna kan frigöras genom påverkan av ett lämpligt medel. Lämpliga användbara optiskt aktiva syror är exempelvis L- och D-formerna av vinsyra, di-o-tolyl- vinsyra, äppelsyra, mandelsyra, kamfersulfonsyra eller kinasyra.The resulting racemate can be separated by known methods, for example by recrystallization from an optically active solvent, by microorganisms, or by a reaction with optical active acids which form salts of the compound and separation of the salts thus obtained, for example by means of different solubilities of the diastereomeric salts from which the antipodes can be released by the influence of an appropriate means. Suitable usable optically active acids are, for example, the L- and D-forms of tartaric acid, di-o-tolyl- tartaric acid, malic acid, mandelic acid, camphorsulfonic acid or Chinese acid.
Företrädesvis isoleras den mer aktiva delen av de två antipoderna.Preferably, the more active part of the two antipodes is isolated.
Utgängsmaterialen är kända eller om de är nya kan erhållas enligt i och för sig kända förfaranden.The starting materials are known or if they are new can be obtained according to per se known procedures.
Vid klinisk användning administreras föreningen enligt uppfinningen vanligtvis oralt, rektalt eller medelst injektion i form av en farmaceutisk beredning, vilken innehåller den aktiva komponenten som fri bas i kombination med en farmaceutiskt acceptabel bärare.In clinical use, the compound of the invention is administered usually orally, rectally or by injection in the form of a pharmaceutical preparation, which contains the active ingredient as a free base in combination with a pharmaceutically acceptable carrier.
Med den nya föreningen enligt uppfinningen avses den fria aminbasen oavsett om föreningen är generellt eller specifikt beskriven, såsom i exemplen vari uttryck kan förekomma som icke helt anger detta.The novel compound of the invention refers to the free amine base whether the association is generally or specifically described, as in the examples in which expressions may occur which do not fully indicate this.
Bäraren kan vara en fast, halvfast eller flytande spädningsmedel eller en kapsel. Dessa farmaceutiska beredningar är ett ytterligare ändamål med uppfinningen. Vanligtvis är mängden aktiv förening mellan 0.l och 99 viktprocent av beredningen, lämpligen mellan 0.5 och 20 viktprocent i beredningar för injektion och mellan 2 och 50 viktprocent i beredningar för oral administrering. 10 15 20 25 Exempel 2 (metod cï, c 8303617-8 7 Den dagliga dosen av aktiv substans varierar och är beroende på typen av administrering men som en allmän regel är den 100 till l000 mg/dag av aktiv substans vid peroral administrering och 5 till 1000 mg/dag vid intravenös administrering.The carrier can be a solid, semi-solid or liquid diluent or a capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount is active compound between 0.1 and 99% by weight of the preparation, preferably between 0.5 and 20% by weight in preparations for injection and between 2 and 50% by weight in formulations for oral administration. 10 15 20 25 Example 2 (method cï, c 8303617-8 7 The daily dose of active substance varies and depends on type of administration but as a general rule it is 100 more 1000 mg / day of active substance by oral administration and 5 to 1000 mg / day when administered intravenously.
Följande illustrerar principen och anpassningen av uppfinningen emellertid utan att vara begränsad därtill. Temperaturer är givna i °C. l 2) Exempel l (metod a , a Framställning av 2,6 -dimetyl-4-(2,3-diklorfenyl)-l,4~di- bxeteexciéín:êtâ:dítetëeaxl§xta:ë:de§x1e§ter:â:et11e§ter_ 2,87 g 2,3-diklorbensylidenacetylättiksyrametylester och l,3 g 3-aminokrotonsyra etylester löstes i l0 ml tertiär butanol. Reak- tionsblandningen tilläts stå vid rumstemperatur under 4 dagar, varefter tertiärbutanolen avdunstades och återstoden löstes och rördes med en mindre mängd isopropyleter, varvid föreningen kri- stalliserade. Efter rekristallisation ur isopropyleter erhölls ren 2,6~dimetyl-4-(2,3-diklorfenyl)-l,4-dihydropyridin-3,5-dikarboxyl- syra-3-metylester-5-etylester. Smp. l45°C. Utbyte 75%. 2) 5,74 g 2,3-diklorbensylidenacetylättiksyra metylester, 2,6 g etyl- acetoacetat och 2,8 ml konc. NH3 löstes i 25 ml tert. butanol.The following illustrates the principle and adaptation of the invention however, without being limited thereto. Temperatures are given in ° C. l 2) Example 1 (method a, a Preparation of 2,6-dimethyl-4- (2,3-dichlorophenyl) -1,4-di- bxeteexciéín: êtâ: dítetëeaxl§xta: ë: de§x1e§ter: â: et11e§ter_ 2.87 g of 2,3-dichlorobenzylideneacetylacetic acid methyl ester and 1.3 g 3-Aminocrotonic acid ethyl ester was dissolved in 10 ml of tertiary butanol. Reactive the ion mixture was allowed to stand at room temperature for 4 days, after which the tertiary butanol was evaporated and the residue was dissolved and was stirred with a small amount of isopropyl ether, the compound being stalled. After recrystallization from isopropyl ether was obtained pure 2,6-dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid acid-3-methyl ester-5-ethyl ester. M.p. 145 ° C. Yield 75%. 2) 5.74 g of 2,3-dichlorobenzylideneacetylacetic acid methyl ester, 2.6 g of ethyl acetoacetate and 2.8 ml conc. NH3 was dissolved in 25 ml of tert. butanol.
Reaktionsblandningen tilläts stå i rumstemperatur under 5 dagar, varpå den tertiära butanolen avdunstades och återstoden löstes i isopropyleter. Efter avkylning kristalliserade föreningen och efter rekristallisation ur isopropyleter erhöils ren 2,6-dimetyl-4- (2,3-diklorfenyl)~l,4-dihydropyridin-3,5-dikarboxylsyra-3-metylester- -5-etylester. Smp. l45°C. Utbyte 591. ssn3617~ß l0 l5 20 30 " Utbyte 22%. Enantiomerisk renhet >98%.The reaction mixture was allowed to stand at room temperature for 5 days. whereupon the tertiary butanol was evaporated and the residue was dissolved in isopropyl ether. After cooling, the compound crystallized and after recrystallization from isopropyl ether, pure 2,6-dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester -5-ethyl ester. M.p. 145 ° C. Yield 591. ssn3617 ~ ß l0 l5 20 30 Yield 22%. Enantiomeric purity> 98%.
Exempel 3 Besfüvsfifls. svfeflsmisß å-â-ëieeïvl-ß-Lëtdí*Pïfsflxll-l-é-fliflyäre- evtiëiß-êé-eißflibexxlåvffckmsfxl25:e: 20,0 g racemisk 2,6-dimetyl-4-(2,3-diklorfenyl)-l,4-dihydropyridin- -3,5-dikarboxylsyra-3-metylester och 22,0 g brucin.löstes i 750 ml metanol. Efter justering av volymen till 300 ml genom evaporering tilläts blandningen stå vid rumstemperatur över natten. De erhållna kristallerna uppsamlades genom filtrering och omkristalliserades två gånger ur metanol. Det så erhållna brucinsaltet behandlades med l N natriumhydroxid och vattenfasen tvättades tre gånger med diklormetan. Surgörning med utspädd saltsyra gav (-) 2,6-dimetyl-4-(2,3- -diklorfenyl)-l,4-dihydropyridin-3,5-dikarboxylsyra-3-metylester.Example 3 Besfüvsfi fl s. svfe fl smisß å-â-ëieeïvl-ß-Lëtdí * Pïfs fl xll-l-é- fl i fl yäre- evtiëiß-êé-eiß fl ibexxlåvffckmsfxl25: e: 20.0 g of racemic 2,6-dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridine- -3,5-Dicarboxylic acid 3-methyl ester and 22.0 g of brucine were dissolved in 750 ml methanol. After adjusting the volume to 300 ml by evaporation the mixture was allowed to stand at room temperature overnight. They received the crystals were collected by filtration and recrystallized twice from methanol. The brucine salt thus obtained was treated with 1 N sodium hydroxide and the aqueous phase was washed three times with dichloromethane. Acidification with dilute hydrochloric acid gave (-) 2,6-dimethyl-4- (2,3- -dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester.
Moderluten från den ursprungliga kristallisationen koncentrerades genom indunstning och upparbetades på samma sätt som beskrivits ovan varvid erhölls (+)2,6-dimetyl-4-(2,3-diklorfenyl)-l,4-dihydropyridin-3,5-dikarboxyl- syra~3-metylester. Utbyte 42%. Enantiomerisk renhet 90%.Mother liquor from it the initial crystallization was concentrated by evaporation and worked up in the same manner as described above to obtain (+) 2,6-dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid acid ~ 3-methyl ester. Yield 42%. Enantiomeric purity 90%.
Erë-'flëtëllflífls ett?aš-šimeívl-5-í2¿3;di' 13¿5ldÃkE“É9šYl5X'É'§'ÉèÉY1eåtÉ'l5leÉYleÉtÉr Till 4,3 g (-)2,6-dimetyl-4-(2,3-diklorfenyl)-l,4-dihydropyridin-3,5- -dikarboxylsyra-3-metylester och 4,1 g tetrabutylammoniumvätesulfat i l2 ml 2 N natriumhydroxid sattes 2,3 g jodetan i 12 ml diklormetan.Erë- 'fl ëtëll fl í fl s ett? Aš-šimeívl-5-í2¿3; di' 13¿5ldÃkE “É9šYl5X'É'§'ÉèÉY1eåtÉ'l5leÉYleÉtÉr To 4.3 g of (-) 2,6-dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridine-3,5- dicarboxylic acid 3-methyl ester and 4.1 g of tetrabutylammonium hydrogen sulphate In 12 ml of 2 N sodium hydroxide was added 2.3 g of iodoethane in 12 ml of dichloromethane.
Blandningen återloppskokades i 30 minuter under omrörning, den organiska fasen frânskildes, torkades och indunstades. Aterstoden behandlades med eter och den utfällda tetrabutylammoniumjodided filtrerades ifrån. Indunstning av filtratet och omkristallisation ur diisopropyleter gav (-)2,6-dimetyl-4-(2,3-diklorfenyl)-l,4-dihydropyridin-3,5-di- karboxylsyra~3-metylester-5-etylester. Smältpunkt l44°. Utbyte 86%. [alågö -50,1 (c=2,0, metanol). v i e ' - oea Qflëtígïï l0 20 25 30 35 8303617-8 Biologiska försök Den antihypertensiva effekten hos föreningen testades på medvetna, ohämmade spontanhypertensiva råttor (SHR) av Okamoto-stammen.The mixture was refluxed for 30 minutes with stirring, the organic the phase was separated, dried and evaporated. The residue was treated with ether and the precipitated tetrabutylammonium iodide was filtered from. Evaporation of the filtrate and recrystallization from diisopropyl ether gave (-) 2,6-dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridine-3,5-di- carboxylic acid ~ 3-methyl ester-5-ethyl ester. Melting point l44 °. Yield 86%. [alga] -50.1 (c = 2.0, methanol). v i e '- oea Q fl ëtígïï l0 20 25 30 35 8303617-8 Biological experiments The antihypertensive effect of the compound was tested on conscious, uninhibited spontaneous hypertensive rats (SHR) of the Okamoto strain.
Djuren hade preparerats genom tidigare inplantation av inlagda katetrar i kroppsaortan via femoralartären. Medelartärblodtrycket (MABP) och hjärthastigheten mättes kontinuerligt. Efter en 2 timmars kontrollperiod administrerades den förening som skulle studeras genom oral intubering med 2-timmarsintervaller suspenderad i meto- cel-lösning (5 ml/kg kroppsvikt). De kumulerade doserna var l, 5 och 25 umol/kg kroppsvikt. Det antihypertensiva svaret, d v s reduktionen av BP vid varje dos uttrycktes som en procent av det initiala kontroll-BP-värdet och avsattes mot dosen på en logarit- misk skala. Den dos som skulle ge §Q_prgcentsKreduktion_av BP bestämdes sedan genom interpolering. Resultaten visas i tabell l.The animals had been prepared by previous implantation of inpatients catheters in the aortic artery via the femoral artery. Mean arterial blood pressure (MABP) and heart rate were measured continuously. After a 2 hour control period, the compound to be studied was administered by oral intubation at 2-hour intervals suspended in cell solution (5 ml / kg body weight). The cumulative doses were 1, 5 and 25 μmol / kg body weight. The antihypertensive response, i.e. the reduction of BP at each dose was expressed as a percentage of it initial control BP value and plotted against the dose of a logarithmic misk scale. The dose that would give §Q_prgcentsKreduktion_av BP was then determined by interpolation. The results are shown in Table 1.
Specificiteten mot glattmuskelrelaxation undersöktes som följer: s ifnïëv 'W g s Den isolerade portalvenspreparationen från Nistar-råttor monterades i ett organbad tillsammans med en stimulerad, isolerad papillar- hjärtmuskelpreparation från samma djur. Den integrerade kontraktili- tetsaktiviteten hos portalvensglattmuskel och toppkraftsamplituden hos papillära, myokardiella preparationen avlästes. De respektive aktiviteterna under en 30 minuters kontrollperiod angavs som l002 och de uppkomna aktiviteterna under påverkan av ett medel som skulle studeras uttrycktes som procent därav. Medlet administrerades med lO minuters intervaller och potensen för vasodilatation (-log ED50 för portalvenen) och den för myokardiell depression (-log ED50 för papillarmuskeln) bestämdes genom interpolering ur det koncentration-effektförhâllande som bestämts i varje experiment.The specificity for smooth muscle relaxation was examined as follows: s ifnïëv 'W g s The isolated portal vein preparation from Nistar rats was mounted in an organ bath together with a stimulated, isolated papillary cardiac muscle preparation from the same animal. The integrated contract the activity of the portal vein smooth muscle and the peak force amplitude in papillary, myocardial preparation was read. The respective the activities during a 30 minute control period were stated as l002 and the activities arising under the influence of a means such as to be studied was expressed as a percentage thereof. The agent was administered at 10 minute intervals and the potency of vasodilation (-log) ED50 for portal vein) and that for myocardial depression (-log) ED50 for the papillary muscle) was determined by interpolation from it concentration-power ratio determined in each experiment.
Ett “separations"-värde erhölls för varje förening genom att ta medelvärdena för skillnaderna av -log ED50-värdena för vasodilatation respektive myokardiell depression som erhållits i experimenten.A "separation" value was obtained for each compound by taking the mean values for the differences of the -log ED50 values for vasodilation respectively, myocardial depression obtained in the experiments.
Detta logaritmiska separationstal omsattes i numerisk form och infördes i tabell l. ,,¿.«_vf' ,a«s1%¿ . ,. f; -f ' Û u: se” *' __...._-._...,._.,..._... .._.._...-.-....-- - -- 8303617-8 10 Föreningen enligt uppfinningen jämfördes med Nifedipin {2,6-dimety1- -4-(2-nitrofenyï)-1,4-dihydropyridin-3,5-dikarboxy1syra~3,5-dimety1- esterl. 5 Tabeïï 1 _ Förening SHR EDSÛ Kvot 10 enligt Ex. pmol/kg hjärta kärï kroppsvikt 1 4 98 15 Nifedipin 5 15 i Penn QfiALaTYThis logarithmic separation number was converted into numerical form and were introduced in Table 1. ,, ¿. «_ Vf ' , a «s1% ¿ . ,. f; -f ' Û u: se ”* ' __...._-._..., ._., ..._... .._.._...-.-....-- - - 8303617-8 10 The compound of the invention was compared with Nifedipine {2,6-dimethyl- -4- (2-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid ~ 3,5-dimethyl- esterl. 5 Table 1 _ Association SHR EDSÛ Quota 10 according to Ex. pmol / kg heart dear body weight 1 4 98 15 Nifedipine 5 15 and Penn Q fi ALaTY
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8303617A SE442298B (en) | 1978-06-30 | 1983-06-23 | 2, 3-dimethyl-4-(2, 3-dichlorphenyl)-1, 4-dihydropyridin-3, 5-dicarboxioxygen-3-methylester-5-ethylester in optically active form. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE7807404A SE429652B (en) | 1978-06-30 | 1978-06-30 | 2,6-dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl 5-ethyl ester |
| SE8303617A SE442298B (en) | 1978-06-30 | 1983-06-23 | 2, 3-dimethyl-4-(2, 3-dichlorphenyl)-1, 4-dihydropyridin-3, 5-dicarboxioxygen-3-methylester-5-ethylester in optically active form. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| SE8303617L SE8303617L (en) | 1983-06-23 |
| SE8303617D0 SE8303617D0 (en) | 1983-06-23 |
| SE442298B true SE442298B (en) | 1985-12-16 |
Family
ID=26657073
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE8303617A SE442298B (en) | 1978-06-30 | 1983-06-23 | 2, 3-dimethyl-4-(2, 3-dichlorphenyl)-1, 4-dihydropyridin-3, 5-dicarboxioxygen-3-methylester-5-ethylester in optically active form. |
Country Status (1)
| Country | Link |
|---|---|
| SE (1) | SE442298B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2200631A (en) * | 1986-12-22 | 1988-08-10 | Syntex Lab | Resolution of 1,4-dihydropyridine derivatives |
-
1983
- 1983-06-23 SE SE8303617A patent/SE442298B/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2200631A (en) * | 1986-12-22 | 1988-08-10 | Syntex Lab | Resolution of 1,4-dihydropyridine derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| SE8303617L (en) | 1983-06-23 |
| SE8303617D0 (en) | 1983-06-23 |
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