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PL97544B1 - METHOD OF MANUFACTURING NEW DERIVATIVES OF AMINOIMIDAZOLOIZOCHINOLINE - Google Patents

METHOD OF MANUFACTURING NEW DERIVATIVES OF AMINOIMIDAZOLOIZOCHINOLINE Download PDF

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PL97544B1
PL97544B1 PL1973190223A PL19022373A PL97544B1 PL 97544 B1 PL97544 B1 PL 97544B1 PL 1973190223 A PL1973190223 A PL 1973190223A PL 19022373 A PL19022373 A PL 19022373A PL 97544 B1 PL97544 B1 PL 97544B1
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carbon atoms
acid addition
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Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt Te Boedapest Hongarije
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/08Vasodilators for multiple indications
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • HELECTRICITY
    • H01ELECTRIC ELEMENTS
    • H01JELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J23/00Details of transit-time tubes of the types covered by group H01J25/00
    • H01J23/02Electrodes; Magnetic control means; Screens
    • HELECTRICITY
    • H01ELECTRIC ELEMENTS
    • H01JELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J25/00Transit-time tubes, e.g. klystrons, travelling-wave tubes, magnetrons
    • H01J25/34Travelling-wave tubes; Tubes in which a travelling wave is simulated at spaced gaps

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  • Urology & Nephrology (AREA)
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Abstract

The novel aminopyrazoloisoquinoline derivatives of the formula <IMAGE> in which A denotes an alkoxy group containing 1 to 4 carbon atoms and D denotes hydrogen, acyl, alkyl or aralkyl, have a favourable effect on the activity of the heart. They are prepared by treating compounds of the general formula <IMAGE> in which A has the above meaning and R denotes an alkyl, aralkyl or aryl group, with a strong alkaline solution. Compounds of the formula I are thus obtained, in which D denotes hydrogen which can be replaced by an acyl group. This hydrogen can also be replaced by an alkyl or aralkyl group by reaction with an aldehyde or ketone and subsequent reduction of the resulting intermediate. [GB1438819A]

Description

Przedmiotem wynalazku jest sposób wytwarza¬ nia nowych pochodnych aminoimidazoloizochinoli¬ ny o ogólnym wzorze 1, w którym A oznacza gru¬ pe alkoksylowa zawierajaca 1—4 atomów wegla, D oznacza rodnik alkilowy, o 1—4 atomach wegla, rodnik aryloaikilowy o 7—10 atomach wegla, rod¬ nik cykloalkilowy, Y oznacza atom wodoru, grupe nitrylowa, grupe karlboksyamidowa, rodnik alkilo¬ wy o 1—4 atomach wegla lub rodnik fenylowy, e- wentualnie w postaci ich soli addycyjnych z kwa¬ sami. Stwierdzono, ze zwiazki o wzorze 1, powoduja zmniejszenie oporu perfuzji w naczyniach wienco¬ wych, przyspieszanie perfuzji, zmniejszenie zuzy¬ cia tlenu przez miesien sercowy, poprawe stosun¬ ku ilosci tlenu dostarczanego do ilosci tlenu pot¬ rzebnego, bedacego miara dotlenienia serca, a tak¬ ze korzystnie wplywaja na wydajnosc pracy ser¬ ca. Wytwarzanie nowych pochodnych aminoimidazo- lowych o ogólnym wzorze 1 sposobem wedlug wy¬ nalazku polega na tym, ze zwiazek o wzorze ogól¬ nym 2 lub jego sól addycyjna z kwasem, w któ¬ rym to wzorze A i Y maja wyzej podane znacze¬ nie a X oznacza atom chlorowca, poddaje sie re¬ akcji z pierwszorzedowa lub druigorzedowa sola metalu alkalicznego lub metalu ziem alkalicznych i cyjanamidu a nastepnie otrzymany zwiazek w któ¬ rym D oznacza atom wodoru poddaje sie reakcji z odpowiednim aldehydem lub ketonem i otrzyma¬ ny produkt redukuje do zwiazku o ogólnym wzo¬ rze 1, w którym D oznacza grupe alkilowa, cyklo- alkilowa lub aralkilowa ewentualnie bez wydzie¬ lenia produktu posredniego i/lub otrzymany zwia- zek o ogólnym wzorze 1, w którym Y oznacza grupe nitrylowa przeprowadza sie za pomoca hy¬ drolizy^w zwiazek o ogólnym wzorze 1, w któ¬ rym Y oznacza grupe karboksyamidowa i/lub o- trzymany zwiazek o ogólnym wzorze 1 przeprowa- io dza sie w jego sól addycyjna z kwasem, lub otrzy¬ mana sól addycyjna z kwasem zwiazku o ogólnym wzorze 1 przeprowadza sie w wolna zasade. Testy farmakologiczne wykonywano sposobami nizej opisanymi na psach uspionych za pomoca Nembutalu podawanego dozylnie w ilosci 25 mg/kg. Badanie wplywu zwiazku na tetnicze cisnienie krwi. Srednie cisnienie krwi mierzono w krwio¬ obiegu, w tetnicy szyjnej psa, wprowadzajac do niej urzadzenie pomiarowe Stathama z elektromanome- trem Hellige^ i rejestrujac sygnaly w sposób cia¬ gly za pomoca wielosciezkowego rejestratora Helli- ge'a. Wyniki badan podano w tablicy I. Badanie rozszerzania naczyn wiencowych. Po¬ miar perfuzji w naczyniach wiencowych oparto na badaniach procesów cieplnych. Do zatoki wienco¬ wej wiprowadzano staly strumien zimnej cieczy (por. Szekeres L., Papp J. Gy., Fischer E., Acta Physiol.Acad.Sei.Hunig. 33, 115 (1969) i za pomoca Micrographu typu KIPP rejestrowano sygnaly z te- rmoelementu znajdujacego sie w tej zatoce. Opór 97 54497 544 wiencowy wyrazono w dowolnie przyjetych jedno¬ stkach jako stosunek sredniego tetniczego cisnienia krwi (mim Hg) do perfuzji naczyn wiencowych (ml/min/100 g). Wyniki przedstawiono w talblicy II. Badania dotleniowe serca. W trakcie badan per- fuzji naczyn wiencowych prowadzono równiez po¬ miary stopnia nasycenia krwi tlenem, zasysajac pompka perystaltyczina krew z zatoki Wiencowej, ze stala szybkoscia, przepuszczajac ja iprzez Oxy- meter typu KIPP i zawracajac do zyly skrzelowej. Wyniki pomiarów rejestrowano w sposób ciagly. Stopien nasycenia krwi tetniczej 'tlenem i zawar¬ tosci hemoglobiny we krwi oznaczano za pomoca hemometru Zeissa. Na podstawie tych danych o- bliczano ilosc tlenu zuzywanego w lewej komorze serca (ml/100 g/lmdn). W celu scharakteryzowania utleniajacego meta¬ bolizm miesnia sercowego i okreslenia stopnia wy¬ korzystania dostarczonego tlenu obliczano takze stosunek ilosci tlenu dostarczanego do ilosci tlenu 'potrzebnego. Szczególy mozna znalezc w pracy L. Szekeresa, J. Gy. Pappa i E. Fischera, opubliko¬ wanej w European J. Pharmaed., 2 1 (1967). Wyni¬ ki badan zamieszczono w tablicy III. Badanie wydajnosci pracy lewej komory serca. Wydajnosc pracy tej komory serca okreslano na podanego przez Lichtlielda i Wilcoxona (J. Phar- mac.exp.Ther. 96, 99 (1949). TablicaI / Dawka (mg) (kg) podawana dozylnie 1 2 4 n 6 Tetnicze cisnienie krwi | Wartosc podstawowa (Hgmm) 127 124 105 Wartosc po podaniu dawki (Hgmm) 104 92 67 Róznica % — 18 — 26 — 36 Kompozycje farmaceutyczne zawieraja jako sklad-- nik aktywny zwiazek o wzorze 1 lub jego sól oraz dopuszczalne w lecznictwie, obojejtne, nietoksyczne nosniki lulb rozcienczalniki organiczne lub nieor¬ ganiczne. Produkty te mozna stosowac w postaci tabletek, kapsulek, czopków itp., w postaci pólstalej, jak na przyklad masc lulb cieklej, takiej jak roztwory, e- mulsje lub zawiesiny. Leki te moga zawierac ma¬ terialy pomocnicze, takie jak stabilizatory, srodki emulgujace i zwilzajace, sole i bufory zmieniajace cisnienie osmotyczne, dopuszczalne w lecznictwie Tablica II Dawka (mg/kg) po¬ dana dozylnie 1 2 4 n 6 Perfuzja w nczyniach wiencowych (ml /min/ 100 g) wartosc podstawowa 24 82 84 wartosc po dodaniu dawki 87 100 108 róznica + 4 + 22 -)- 29 Opory perfuzji w naczyniach wiencowych (Hgmm/ /ml/ /min/ /100g) wartosc podstawowa 1,86 1,90 1,33 wartosc po dodaniu dawki 1,46 1,31 0,71 róznica [ — 22 — 31 — 47 Tablica III Dawka (mg/kg) po¬ dma dozylnie 1 2 4 n 6 Zuzycie tlenu w lewej komorze serca (ml/ /min/ /100g) wartosc podstawowa 9,8 9,4 8,7 wartosc po dodaniu dawki 8,0 7,5 8,7 róznica — 18 — 20 Stosunek ilosci tlenu dostarczonego do 1 ilosci tlenu zuzytego w lewej komorze serca waitosc podstawowa 1,48 1,51 1,77 wartosc po dodaniu dawki 1,68 1,93 2,12 róznica h 14 - 28 - 20 podstawie minutowej pojemnosci serca, wyznaczonej sposobem inluzji zimnej cieczy (Szekeres L., Papp J. Gy., Fischer E., Acta Physiol.AcadjSci.Hunig. 33, 115 (19G9), sredniego tetniczego cisnienia krwi, uzy¬ cia tlenu w lewej komorze serca (ml/min/100 g) oraz pracy lewej komory serca (mkg/min). Wyniki poda¬ no w tablicy IV. Toksycznosc. Dokladne badanie toksycznosci, pro¬ wadzono na szczurach o ciezarze 150—200 g. Dawke wstrzykiwano do zyly ogonowej w ciagu co najwy¬ zej 5 sekund w ilosci 0,2 ml/100 g. Wartosci LD50 i granice tolerancji okreslano z liczby szczurów zde¬ chlych w ciagu 24 godzin, korzystajac ze sposobu Tablica IV 60 65 Dawpa (mg/kg) po¬ dawana do- | zylnie 1 2 4 n 6 Wydajnosc pracy lewej komory serca | wartosc podstawowa 0,35 0,36 0,27 wartosc po dodaniu dawki 0,49 0,46 0,35 róznica *f 40 4-28 + 22 zarobki i/lub inne substancje aktywne farmaka- logicznie. Przyklad I. 6,0 g technicznego cyjanamidu \97 544 wapnia miesza sie, ogrzewajac z 15 ml wody i do¬ daje 8,0 nil 10% roztworu wodorotlenku sodowego. Calosc utrzymuje sie w temperaturze 50—60°C w ciagu 15 minut. Nastepnie odsacza sie wytracony osad. Do przesaczu dodaje sie 150 ml alkoholu i mieszanine utrzymuje sie w stanie wrzenia. Do wrzacej mieszaniny dodaje sie w ciagu 0,5 godzi¬ ny, 2,7 g chlorowodorku l-chlorometylo-6,7-dwu- metoksy-S^^dwuwodofoizOchinoliny i calosc gotu¬ je w ciaigu 4 godzin. Nastepnie mieszanine zateza do sucha pod zmniejszonym cisnieniem, dodaje do pozostalosci 50 ml wody, krystaliczny produkt od¬ sacza pod zmniejszonym cisnieniem i suszy. Otrzy¬ muje sie 1,8 g 3-amino-5,6-dWuwodoro-8,9-dwu- metoksyimidazo(5,l- a)izochinoliny. Temperatura krzepniecia 232—236°C. Produkt oczyszcza sie na drodze krystalizacji z alkoholu. Dla wzoru C13H15N302 obliczono: C 63,55% H 6,16% N 17,33% znaleziono: C 63,42% H 6,3£% N 16,92% Widmo NMR produktu w roztworze CDC13 — DMSO wykazalo obecnosc protonu wystepujacego w pozycji 1 przy 6,70 ppm. Do 2,3 g 3-amino-5,6-dwuwodoro-8,9-dwuimetok- syimidazo (5,1-a) izochinoliny dodaje sie 1,1 g [ben¬ zaldehydu oraz 20 ml absolutnego alkoholu i calosc utrzymuje sie w stanie wrzenia w ciagu 5 godzin. Po oziebieniu krystalizuje sie 3,1 g 3-bonzyli- denoamino-5,6-dwuwodoro 8,9 dwumetoksyimidazo -a)izochinoliny o temperaturze topnienia 250—252°C 176°C (z alkoholu). Dla wzoru C2oH19N302 obliczono: C 72,05% H 5,75% N 12,01% znaleziono: C 72,35% H 5,80% N 12,69% 1.6 g tak otrzymanego produktu rozpuszcza sie w 100 ml metanolu i ido roztworu dodaje 0,5 gbo¬ rowodorku sodu w ciagu 0,5 godziny. Nastepnie roztwór pozostawia sie na pewien czas w tempera¬ turze pokojowej. Po odparowaniu rozpuszczalnika do pozostalosci dodaje sie wode. Wykrystalizowa¬ ny produkt odsacza sie i suszy. Otrzymuje sie 1,7 g 3-benzyloamino-5,6-dwuwodoro-8,9-dwumeto- ksyimidazo(5,l-a)izochinoliny o temperaturze top¬ nienia 135°C. Dla wzoru C20H21N3O2 obliczono: C 71,62% H 6,31% N 12,53% znaleziono: C 71,52% H 5,98% N 12,42% 1.7 g tak otrzymanego produktu rozpuszcza sie w goracym metanolu i cieiply roztwór zakwasza sie etanolowym roztworem chlorowodoru. Po Ozie¬ bieniu 'krystalizuje 1,4 g chlorowodoriku 3-benzylo- amino-5,6-dwuwodoro-8,9-dwumeitoksyimidazo (5,1- -a)izoch!inoliny o tem/peraturtze /topienia 250—252°C. Dla wzoru C2oH22N302Cl obliczono: C 64,59% H 5,96% N 11,31% Cl 9,53% znaleziono: C 64,48% H 6,02% N 11,50% Cl 9,31% Zwiazek tak otrzymany zwieksza kurczliwosc o 40% przy dawce 1—2 mg/kg w ciagu 26—28 minut, zwieksza pojemnosc minutowa serca o 30% u us¬ pionych psów przy dawce 2 mg/kg, przy czym e- fekt ten trwa 16 minut. Przy dawce 2 mg/ikg zmniejsza sie opór plucnego ukladu naczyniowego w ciagu 22 minut. Podanie zwiazku poprawia wy¬ dajnosc pracy serca u uspionych psów. Przy daw¬ ce 0,5 mg/kg zwieksza sie o 77% perfuzja w u- dzie u uspionych psów w ciagu 16 minut. Przy da¬ wce 1 mk/kg, zwieksza sie perfuzja w ukladzie szyjnym o 31% w ciagu 24 minut. In situ zwiazek, przy dawce 2 mg/kg, podwyzsza o 104% próg ele- 'ktryczny wlókienek w miesniach przedsionka ser¬ ca u kotów, a w miesniach komory serca kotów zwieksza to próg o 50% przy dawce 2 mg/kg w cia¬ gu 41 minut i o 812% przy dawce 4 mg/kg. Przyklad II. 2,45 g 3-amino-<5,6-dwuwodoro- -8,9-dwumetoksyimidazo(5,!l-a)izochinoliny ogrzewa sie w ciagu 3 godzin z 1,2 ml aldehydu maslowego i 45 ml bezwodnego etanolu. Polowe ilosci rozpusz. czalniików oddestylowuje sie i do pozostalosci do¬ daje sie 1,0 ml aldehydu maslowego. Mieszanine re- akcyjna gotuje sie przez 3 godziny i nastepnie chlodzi do temperatury pokojowej. W czasie 30 mi¬ nut mieszajac dodaje sie 0,6 g borowodorku sodo¬ wego. Mieszanine reakcyjna gotuje sie przez 30 mi¬ nut i nastepnie odparowuje do suchej pozostalosci. Do pozostalosci dodaje sie 15 ml wody i saczy wy¬ dzielony produlkt. Otrzymuje sie 2,1 g jednowodzia- nu 3-ibuty'loamino-5,6-dwuwodoro-<8,9-dwumetoksy- imidazo(5,l-a)izochinoliny. Temperatura topnienia 134—136°C (z 96% etanolu). Analiza: obliczono: C 63,93% H 7,89% N 13,16% znaleziono: C 63,62% H 7,98% N 12,88% PL PL PL PL PL PLThe subject of the invention is a method for preparing new aminoimidazoloisoquinoline derivatives of the general formula I, wherein A denotes an alkoxy group containing 1-4 carbon atoms, D denotes an alkyl radical containing 1-4 carbon atoms, an arylalkyl radical containing 7-10 carbon atoms, a cycloalkyl radical, Y denotes a hydrogen atom, a nitrile group, a carboxamide group, an alkyl radical containing 1-4 carbon atoms or a phenyl radical, optionally in the form of their acid addition salts. It has been found that compounds of formula 1 cause a reduction in perfusion resistance in coronary vessels, acceleration of perfusion, reduction of oxygen consumption by the heart muscle, improvement of the ratio of the amount of oxygen supplied to the amount of oxygen needed, which is a measure of the oxygenation of the heart, and also have a beneficial effect on the efficiency of the heart. The preparation of new aminoimidazole derivatives of general formula I by the method according to the invention consists in reacting a compound of general formula II or an acid addition salt thereof, in which A and Y have the above-mentioned meanings and X is a halogen atom, with a primary or secondary salt of an alkali metal or alkaline earth metal and cyanamide, and then the obtained compound, in which D is a hydrogen atom, is reacted with the appropriate aldehyde or ketone, and the obtained product is reduced to a compound of general formula I, in which D is an alkyl, cycloalkyl or aralkyl group, optionally without isolating the intermediate product, and/or the obtained compound of general formula I, in which Y is a nitrile group, is converted by means of The compound of general formula 1, in which Y is a carboxamide group, is hydrolyzed and/or the obtained compound of general formula 1 is converted into its acid addition salt, or the obtained acid addition salt of the compound of general formula 1 is converted into the free base. Pharmacological tests were performed by the methods described below on dogs anesthetized with Nembutal administered intravenously at 25 mg/kg. The effect of the compound on arterial blood pressure was examined. Mean blood pressure was measured in the circulating blood, in the dog's carotid artery, by introducing a Statham measuring device with a Hellige electromanometer into it and recording the signals continuously using a Hellige multipath recorder. The study results are given in Table I. Coronary vasodilation study. The measurement of coronary perfusion was based on studies of thermal processes. A constant stream of cold liquid was introduced into the coronary sinus (see Szekeres L., Papp J. Gy., Fischer E., Acta Physiol. Acad. Sei. Hunig. 33, 115 (1969) and signals from a thermocouple located in this sinus were recorded using a KIPP micrograph. Coronary resistance was expressed in arbitrarily accepted units as the ratio of mean arterial blood pressure (mim Hg) to coronary vessel perfusion (ml/min/100 g). The results are presented in Table II. Oxygenation studies of the heart. During the coronary vessel perfusion studies, the degree of blood oxygen saturation was also measured by sucking blood from the coronary sinus with a peristaltic pump. The coronary sinus was circulated at a constant rate, passing it through a KIPP-type oxygenometer and returning it to the branchial vein. The measurement results were continuously recorded. The degree of oxygen saturation of arterial blood and the hemoglobin content in the blood were determined using a Zeiss hemometer. Based on these data, the amount of oxygen consumed in the left ventricle was calculated (ml/100 g/lm/dn). In order to characterize the oxidative metabolism of the myocardium and determine the degree of utilization of the supplied oxygen, the ratio of the amount of oxygen supplied to the amount of oxygen required was also calculated. Details can be found in the work by L. Szekeres, J. Gy. Papp, and E. Fischer, published in European J. Pharmaed., 21 (1967). The results are presented in Table III. Examination of the left ventricular function. The function of this ventricle was determined according to the method given by Lichtlield and Wilcoxon (J. Pharmac. exp. Ther. 96, 99 (1949). Table I / Dose (mg) (kg) administered intravenously 1 2 4 n 6 Arterial blood pressure | Basal value (Hg mm) 127 124 105 Value after dose administration (Hg mm) 104 92 67 Difference % — 18 — 26 — 36 The pharmaceutical compositions contain as an active ingredient a compound of formula 1 or a salt thereof and therapeutically acceptable, inert, non-toxic carriers or diluents, organic or inorganic. These products can be used in the form of tablets, capsules, suppositories, etc., in semi-solid form, as well as for example, an ointment or liquid form such as solutions, emulsions, or suspensions. These drugs may contain auxiliary materials such as stabilizers, emulsifying and wetting agents, salts, and buffers to modify the osmotic pressure, permitted in therapy. Table II Dose (mg/kg) administered intravenously 1 2 4 n 6 Coronary perfusion (ml /min/ 100 g) basal value 24 82 84 value after adding the dose 87 100 108 difference + 4 + 22 -)- 29 Coronary perfusion resistance (Hg mm/ /ml/ /min/ /100 g) basal value 1.86 1.90 1.33 value after adding the dose 1.46 1.31 0.71 difference [ — 22 — 31 — 47 Table III Dose (mg/kg) subcutaneous intravenous 1 2 4 n 6 Oxygen consumption in the left ventricle (ml/ /min/ /100g) basal value 9.8 9.4 8.7 value after adding the dose 8.0 7.5 8.7 difference — 18 — 20 Ratio of the amount of oxygen delivered to the amount of oxygen consumed in the left ventricle basal value 1.48 1.51 1.77 value after adding the dose 1.68 1.93 2.12 difference h 14 - 28 - 20 based on the minute cardiac output, determined by the cold liquid ingestion method (Szekeres L., Papp J. Gy., Fischer E., Acta Physiol. AcadjSci. Hunig. 33, 115 (19G9), mean arterial blood pressure, left ventricular oxygen consumption (ml/min/100 g), and left ventricular cardiac function (mkg/min). The results are given in Table IV. Toxicity. A detailed toxicity study was conducted on rats weighing 150-200 g. The dose was injected into the tail vein within a maximum of 5 seconds at a rate of 0.2 ml/100 g. LD50 values and tolerance limits were determined from the number of rats that died within 24 hours, using the method Table IV 60 65 Dose (mg/kg) administered intravenously 1 2 4 n 6 Left ventricular cardiac function | value Basic 0.35 0.36 0.27 Value after adding the dose 0.49 0.46 0.35 Difference *f 40 4-28 + 22 Excipients and/or other pharmacologically active substances. Example 1. 6.0 g of technical calcium cyanamide is mixed with 15 ml of water under heating and 8.0 ml of 10% sodium hydroxide solution is added. The whole is kept at 50-60°C for 15 minutes. Then the precipitate is filtered off. 150 ml of alcohol is added to the filtrate and the mixture is kept at boiling. To the boiling mixture are added over a period of 0.5 hour 2.7 g of 1-chloromethyl-6,7-dimethoxy-S-(2-dihydroquinoline) hydrochloride and The whole is boiled for 4 hours. Then the mixture is concentrated to dryness under reduced pressure, 50 ml of water are added to the residue, the crystalline product is filtered off under reduced pressure and dried. 1.8 g of 3-amino-5,6-dihydro-8,9-dimethoxyimidazo(5,1-a)isoquinoline are obtained. Freezing point 232-236°C. The product is purified by crystallization from alcohol. For the formula C13H15N3O2 the following was calculated: C 63.55% H 6.16% N 17.33% found: C 63.42% H 6.3£% N 16.92%. The NMR spectrum of the product in CDCl3 — DMSO solution shows the presence of a proton at the position 1 at 6.70 ppm. To 2.3 g of 3-amino-5,6-dihydro-8,9-dimethoxyimidazo(5,1-a)isoquinoline are added 1.1 g of [benzaldehyde] and 20 ml of absolute alcohol and the mixture is kept at boiling for 5 hours. After cooling, 3.1 g of 3-benzylideneamino-5,6-dihydro-8,9-dimethoxyimidazo-a)isoquinoline crystallizes, melting point 250-252°C 176°C (from alcohol). For the formula C2oH19N3O2 the following was calculated: C 72.05% H 5.75% N 12.01% Found: C 72.35% H 5.80% N 12.69% 1.6 g yes The product obtained is dissolved in 100 ml of methanol and 0.5 g of sodium borohydride is added to the solution over a period of 0.5 hour. The solution is then left for some time at room temperature. After evaporation of the solvent, water is added to the residue. The crystallized product is filtered off and dried. 1.7 g of 3-benzylamino-5,6-dihydro-8,9-dimethoxyimidazo(5,1-a)isoquinoline is obtained, melting point 135°C. For the formula C20H21N3O2 the following was calculated: C 71.62% H 6.31% N 12.53% Found: C 71.52% H 5.98% N 12.42% 1.7 g of the product thus obtained is dissolved in hot methanol and the warm solution is acidified with ethanolic hydrogen chloride. After cooling, 1.4 g of 3-benzylamino-5,6-dihydro-8,9-dimethyloxyimidazo(5,1-a)isoquinoline hydrochloride crystallizes out, melting at 250-252°C. For the formula C20H22N3O2Cl the following was calculated: C 64.59% H 5.96% N 11.31% Cl 9.53% found: C 64.48% H 6.02% N 11.50% Cl 9.31%. The compound thus obtained increases contractility by 40% at a dose of 1-2 mg/kg within 26-28 minutes, increases cardiac output by 30% in anesthetized dogs at At a dose of 2 mg/kg, this effect lasts for 16 minutes. At a dose of 2 mg/kg, the resistance of the pulmonary vascular system decreases within 22 minutes. Administration of the compound improves cardiac efficiency in anesthetized dogs. At a dose of 0.5 mg/kg, femoral perfusion increases by 77% in anesthetized dogs within 16 minutes. At a dose of 1 mg/kg, carotid perfusion increases by 31% within 24 minutes. In situ, the compound, at a dose of 2 mg/kg, increases the electrical threshold of fibrils in the atrial muscles of the heart in cats by 104%, and in the ventricular muscles of the heart in cats, this threshold increases by 50% at a dose of 2 mg/kg in in 41 minutes and by 812% at a dose of 4 mg/kg. Example II. 2.45 g of 3-amino-5,6-dihydro-8,9-dimethoxyimidazo(5,1-alpha)isoquinoline are heated for 3 hours with 1.2 ml of butyraldehyde and 45 ml of absolute ethanol. Half of the solvent is distilled off, and 1.0 ml of butyraldehyde is added to the residue. The reaction mixture is boiled for 3 hours and then cooled to room temperature. During 30 minutes, 0.6 g of sodium borohydride is added with stirring. The reaction mixture is boiled for 30 minutes and then evaporated to dryness. To the residue, add 15 ml of water and filter the separated product. 2.1 g of 3-butylamino-5,6-dihydro-8,9-dimethoxyimidazo(5,1-a)isoquinoline monohydrate are obtained. Melting point: 134-136°C (from 96% ethanol). Analysis: Calculated: C 63.93% H 7.89% N 13.16% Found: C 63.62% H 7.98% N 12.88% PL PL PL PL PL PL

Claims (2)

Zastrzezenia patentowe 30 1. Sposób wytwarzania nowych pochodnych a- minoimidazoloizochinoliny o ogólnym wzorze 1, w którym A oznacza grupe alkoiksylowa o 1—4 ato¬ mach wegla, Y oznacza atom wodoru, grupe ni¬ trylowa, grupe karboksyamidowa, grupe alkilo- 35 wa zawierajaca 1—4 atomów wegla lub grupe fe- nylowa, D oznacza grupe alkilowa o 1—4 atomach wegla, grupe aralkilowa o 7—10 atomach wegla, ' grupe cykloalkilowa, ewentualnie w postaci ich soli addycyjnych z kwasami, znamienny tym, ze -40 zwiazek o ogólnym wzorze 2, w którym A i Y maja wyzej podane znaczenie a X oznacza atom chlorowca lub jego sól addycyjna z kwasem po¬ ddaje sie reakcji z pierwszorzedowa lub drugo- rzedowa sola metalu alkalicznego lub metalu ziem 45 alkalicznych i cyjanamidu a nastepnie otrzymany zwiazek w którym D oznacza atom wodoru pod¬ daje sie reakcji z odpowiednim aldehydem lub ketonem i otrzymany produkt redukuje do zwia¬ zku o ogólnym wzorze 1, w którym D oznacza 50 grupe alkilowa, cykloalkilowa lub aralkilowa, e- wentualnie bez izolowania produktu posredniego, a nastepnie otrzymany zwiazek o ogólnym wzorzePatent claims 30 1. A method for preparing new aminoimidazole isoquinoline derivatives of the general formula 1, in which A is an alkyl group with 1-4 carbon atoms, Y is a hydrogen atom, a nitrile group, a carboxamide group, an alkyl group containing 1-4 carbon atoms or a phenyl group. nyl, D denotes an alkyl group with 1 to 4 carbon atoms, an aralkyl group with 7 to 10 carbon atoms, a cycloalkyl group, optionally in the form of their acid addition salts, characterized in that -40 a compound of the general formula 2, in which A and Y have the meanings given above and X denotes a halogen atom or its acid addition salt is reacted with a primary or a secondary alkali metal or metal salt alkaline earth metals and cyanamide, and then the resulting compound, in which D is a hydrogen atom, is reacted with a suitable aldehyde or ketone and the resulting product is reduced to a compound of the general formula 1, in which D is an alkyl, cycloalkyl or aralkyl group, optionally without isolating the intermediate product, and then the resulting compound of the general formula 1 przeprowadza sie w jego sól addycyjna z kwa¬ sem, lub otrzymana sól addycyjna z kwasem 55 zwiazku o ogólnym wzorze 1 przeprowadza sie w wolna zasade.1 is converted into its acid addition salt, or the obtained acid addition salt of the compound of general formula 1 is converted into the free base. 2. Sposób wytwarzania nowych pochodnych a- minoimidazoloizochinoliny o ogólnym wzorze 1, w którym A oznacza grupe alkoksylowa o l^l ato- 60 mach wegla, Y oznacza atom wodoru, grupe ni¬ trylowa, grupe karboksyamidowa, grupe alkilowa zawierajaca 1—4 atomów wegla lub grupe feny- lowa, D oznacza grupe alkilowa o 1—4 atomach wegla, grupe aralkilowa o 7—10 atomach wegla, 65 grupe cykloalkilowa, ewentualnie w postaci ich97 544 soli addycyjnych z kwasami, znamienny tym, ze zwiazek o ogólnym wzorze 2, w którym A i Y maja wyzej podane znaczenie a X oznacza atom chlorowca lub jego sól addycyjna z kwasem pod¬ daje sie reakcji z pierwszorzedowa lub drugorze- dowa sola metalu alkalicznego lub metalu ziem alkalicznych i cyjanamidu a nastepnie otrzymany zwiazek w którym D oznacza atom wodoru podr daje sie reakcji z odpowiednim aldehydem lub ke¬ tonem i otrzymany produkt redukuje do zwiazku o ogólnym wzorze 1, w którym D oznacza grupe 8 alkilowa, cykloalkilowa lub aralkilowa, ewentu¬ alnie bez izolowania produktu posredniego, otrzy¬ many zwiazek o wzorze ogólnym 1, w którym Y oznacza grupe nitrylowa przeprowadza sie za po¬ moca hydrolizy w zwiazek o wzorze ogólnym 1, w którym Y oznacza grupe karboksyamidowa, nastepnie otrzymany zwiazek o ogólnym wzorze 1 przeprowadza sie w jego sól addycyjna z kwasem, lub otrzymana sól addycyjna z kwasem zwiazku o ogólnym wzorze 1 przeprowadza sie w wolna zasade. i VNHD Wzór 1 Wzór 2 LZG Z-d 3 w Pab., zam. 658-78, nakl. 105+20 egz. Cena 45 zl2. A method for preparing new aminoimidazole isoquinoline derivatives of the general formula 1, in which A is an alkoxy group with 1-60 carbon atoms, Y is a hydrogen atom, a nitrile group, a carboxamide group, an alkyl group containing 1-4 carbon atoms or a phenyl group, D is an alkyl group with 1-4 carbon atoms, an aralkyl group with 7-10 carbon atoms, a 65 cycloalkyl group, optionally in the form of acid addition salts thereof, characterized in that the compound of the general formula 2, in which A and Y have the meanings given above and X is a halogen atom or an acid addition salt thereof is reacted with a primary or secondary salt alkali metal or alkaline earth metal and cyanamide and then the obtained compound in which D is a hydrogen atom is reacted with a suitable aldehyde or ketone and the obtained product is reduced to a compound of general formula 1, in which D is an alkyl, cycloalkyl or aralkyl group, optionally without isolating the intermediate product, the obtained compound of general formula 1, in which Y is a nitrile group, is converted by hydrolysis into a compound of general formula 1, in which Y is a carboxamide group, then the obtained compound of general formula 1 is converted into its acid addition salt, or the obtained acid addition salt of the compound of general formula 1 is converted into the free base. and VNHD Formula 1 Formula 2 LZG Z-d 3 in Pab., order no. 658-78, item no. 105+20 copies. Price PLN 45
PL1973190223A 1972-06-30 1973-06-29 METHOD OF MANUFACTURING NEW DERIVATIVES OF AMINOIMIDAZOLOIZOCHINOLINE PL97544B1 (en)

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PL1973184281A PL94060B1 (en) 1972-06-30 1973-06-29 Fused-ring isoquinoline derivatives[gb1438819a]
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PL1973184281A PL94060B1 (en) 1972-06-30 1973-06-29 Fused-ring isoquinoline derivatives[gb1438819a]
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