NO138908B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE IMIDAZO AND PYRAZOLO-ISOKINOLIN DERIVATIVES - Google Patents

ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE IMIDAZO AND PYRAZOLO-ISOKINOLIN DERIVATIVES Download PDF

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NO138908B
NO138908B NO2694/73A NO269473A NO138908B NO 138908 B NO138908 B NO 138908B NO 2694/73 A NO2694/73 A NO 2694/73A NO 269473 A NO269473 A NO 269473A NO 138908 B NO138908 B NO 138908B
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hydrogen
carbon atoms
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Kalman Takacs
Laszlo Szekeres
Kalman Harsanyi
Gyula Papp
Andras Neszmelyi
Eva Benedek
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Chinoin Gyogyszer Es Vegyeszet
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic 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
    • C07D471/02—Heterocyclic 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
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs 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
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J23/00—Details of transit-time tubes of the types covered by group H01J25/00
    • H01J23/02—Electrodes; Magnetic control means; Screens
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J25/00—Transit-time tubes, e.g. klystrons, travelling-wave tubes, magnetrons
    • H01J25/34—Travelling-wave tubes; Tubes in which a travelling wave is simulated at spaced gaps

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  • Nitrogen Condensed Heterocyclic Rings (AREA)
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Description

Foreliggende oppfinnelse angår fremstillingen av nye imidazo-[5,l-a]-, hhv. pyrazolo-[5,l-a]-isokinolinderivater med den generelle formel I hvor den femleddede kondenserte ring mellom nitrogenatomene, hhv. ved siden av nitrogenatomet, har en amino-, substituert amino- eller acylaminogruppe. The present invention relates to the production of new imidazo-[5,1-a]-, or pyrazolo-[5,1-a]-isoquinoline derivatives with the general formula I where the five-membered condensed ring between the nitrogen atoms, resp. next to the nitrogen atom, has an amino, substituted amino or acylamino group.

I den generelle formel: In the general formula:

er A en alkoxygruppe med 1-4 carbonatomer, is A an alkoxy group with 1-4 carbon atoms,

I IN

B er -N=C-NH-D hvor D er hydrogen, alkyl med 1-4 carbonatomer, B is -N=C-NH-D where D is hydrogen, alkyl with 1-4 carbon atoms,

fenylalkyl med 7-10 carbonatomer, benzoyl, fenyl-lavere alkanoyl, alkanoyl med 1-4 carbonatomer eller kloracetyl, og Y er hydrogen, cyano eller lavere alkyl. phenylalkyl of 7-10 carbon atoms, benzoyl, phenyl-lower alkanoyl, alkanoyl of 1-4 carbon atoms or chloroacetyl, and Y is hydrogen, cyano or lower alkyl.

Det har vist seg at forbindelsene med den generelle formel I It has been found that the compounds of the general formula I

minsker motstanden av koronargjennomstrømningen, fremmer gjennom- reduces the resistance of the coronary flow, promotes through-

strømningen, minsker oxygenforbruket av hjertemuskelen, forbedrer kvotienten: Og-tilbud/Og-krav, som uttrykker hjertets oxygenisering, the flow, reduces the oxygen consumption of the heart muscle, improves the quotient: Og supply/Og demand, which expresses the oxygenation of the heart,

og påvirker virkningsgraden av hjertearbeidet på gunstig vis. and affects the efficiency of the heart's work in a favorable way.

Forbindelsene med den generelle formel I er kondenserte The compounds of the general formula I are condensed

aminoimidazol-, hhv. aminopyrazol-derivater, hvis kondenserte representanter med isokinolinring ikke tidligere er beskrevet. aminoimidazole-, respectively aminopyrazole derivatives, whose condensed representatives with an isoquinoline ring have not previously been described.

Forbindelsene med formel I fremstilles ifølge oppfinnelsen The compounds of formula I are produced according to the invention

ved at by that

a) 3-amino-iinidazo-[5 ,1-a ]-isokinolinderivater med formel I, hvor A og Y er som ovenfor angitt, og D er hydrogen, fremstilles a) 3-amino-iinidazo-[5,1-a]-isoquinoline derivatives of formula I, where A and Y are as indicated above, and D is hydrogen, are prepared

ved at en forbindelse med den generelle formel: in that a compound with the general formula:

eller et syreaddisjonssalt derav, hvor A og Y er som ovenfor angitt, og X er halogen, omsettes med et alkalimetall- eller jordalkalimetallsalt av cyanamid, eller med alkali-hydrogen-cyanamid, eller b) 3-arain°-imidazo-[5>l-a]-isokinolinderivater med den gener-eller formel I, hvor A er som ovenfor angitt, D er hydrogen eller acyl som ovenfor angitt, og Y er hydrogen, lavere alkyl eller fenyl, fremstilles ved at et isokinolyl-acetamidoxim med den generelle formel: or an acid addition salt thereof, where A and Y are as indicated above, and X is halogen, is reacted with an alkali metal or alkaline earth metal salt of cyanamide, or with alkali hydrogen cyanamide, or b) 3-arain°-imidazo-[5> 1-a]-isoquinoline derivatives of the gene or formula I, where A is as indicated above, D is hydrogen or acyl as indicated above, and Y is hydrogen, lower alkyl or phenyl, are prepared by an isoquinolyl acetamidoxime of the general formula:

hvor A er som ovenfor angitt, og Y<1> er hydrogen, lavere alkyl eller fenyl, omsettes med sulfonsyrehalogenid i overskudd eller i en ekvimolar mengde, eller carboxylsyrederivater som acyleringsmiddel, eller where A is as stated above, and Y<1> is hydrogen, lower alkyl or phenyl, is reacted with sulphonic acid halide in excess or in an equimolar amount, or carboxylic acid derivatives as acylating agent, or

c) forbindelse med den generelle fomel I, hvor A og Y er som ovenfor angitt, og D er acyl som ovenfor angitt, fremstilles c) compound of the general formula I, where A and Y are as above, and D is acyl as above, is prepared

ved at en forbindelse med den generelle formel I hvor D er hydro- in that a compound of the general formula I where D is hydro-

gen, acyleres med carboxylsyrederivater av tilsvarende acylgrupper som acyleringsmiddel, eller gene, is acylated with carboxylic acid derivatives of corresponding acyl groups as an acylating agent, or

d) forbindelser med formel I hvor D er hydrogen, alkyl med 1-4 carbonatomer eller fenylalkyl med 7 - IO carbonatomer, og d) compounds of formula I where D is hydrogen, alkyl with 1-4 carbon atoms or phenylalkyl with 7-10 carbon atoms, and

Y er hydrogen, lavere alkyl eller fenyl, fremstilles ved at en forbindelse med den generelle formel: Y is hydrogen, lower alkyl or phenyl, is prepared by a compound of the general formula:

hvor A, D og Y er som ovenfor angitt, oppvarmes i et oppløsnings-middel eller i en smelte, eller underkastes vandig eller alkalisk hydrolyse, eller where A, D and Y are as above, heated in a solvent or in a melt, or subjected to aqueous or alkaline hydrolysis, or

e) forbindelser med formel I hvor D er de ovenfor angitte acylgrupper, fremstilles ved at en forbindelse med den generelle e) compounds of formula I where D is the above-mentioned acyl groups, are prepared by a compound with the general

formel: formula:

hvor Y er som ovenfor angitt, og R er alkyl med 1-3 carbonatomer, fenyl, fenyl-lavere alkyl eller klormethyl, cykliseres i et moderat alkalisk medium, i et oppløsningsmiddel eller i en smelte, eller where Y is as above, and R is alkyl of 1-3 carbon atoms, phenyl, phenyl-lower alkyl or chloromethyl, is cyclized in a moderately alkaline medium, in a solvent or in a melt, or

f) forbindelser med formel I hvor D er alkyl med 1-4 carbonatomer eller fenylalkyl med 7-10 carbonatomer fremstilles ved f) compounds of formula I where D is alkyl with 1-4 carbon atoms or phenylalkyl with 7-10 carbon atoms are prepared by

at den tilsvarende forbindelse med formel I hvor D er hydrogen, omsettes med et alkanal med 1-4 carbonatomer eller med et fenylalkanal med 7-10 carbonatomer, hvorpå det dannede produkt reduseres, eller that the corresponding compound with formula I where D is hydrogen is reacted with an alkane with 1-4 carbon atoms or with a phenylalken with 7-10 carbon atoms, whereupon the product formed is reduced, or

g) forbindelser med formel I hvor D er hydrogen, fremstilles ved at en tilsvarende forbindelse med formel I hvor D er en av g) compounds of formula I where D is hydrogen, are prepared by a corresponding compound of formula I where D is one of

de ovenfor angitte acylgrupper, hydrolyseres, fortrinnsvis med natriumhydroxyd. the above-mentioned acyl groups are hydrolysed, preferably with sodium hydroxide.

Ifølge en fordelaktig utførelsesform av fremgangsmåten ifølge alternativ a) kan aminoimidazolderivatene fremstilles ved omsetning av forbindelsene med den generelle formel: hvor X er halogen, med natriumcyanamid, idet det som mellomprodukt dannede N-monosubstituerte cyanamid ringsluttes med nitrogenet i det isobasiske isokinolin under guanidinutvikling til en forbindelse med den generelle formel: According to an advantageous embodiment of the method according to alternative a), the aminoimidazole derivatives can be prepared by reacting the compounds with the general formula: where X is halogen, with sodium cyanamide, the N-monosubstituted cyanamide formed as an intermediate being ring-closed with the nitrogen in the isobasic isoquinoline during guanidine evolution to a connection with the general formula:

(Reaksjonsskjerna 1) (Reaction nucleus 1)

Ovenstående reaksjonsrekke kan utføres med slike forbindelser hvor Y er hydrogen eller cyano. Forbind- The above series of reactions can be carried out with such compounds where Y is hydrogen or cyano. Connect-

elsene med den generelle formel II ringsluttes ved Bischler-Napieralsky-reaksjonen på det med halogencarboxylsyre acylerte derivat av det tilsvarende 2-fenylethylaminderivat. the els of the general formula II are ring-closed by the Bischler-Napieralsky reaction on the halocarboxylic acid acylated derivative of the corresponding 2-phenylethylamine derivative.

Ved alternativ b) av fremgangsmåten ifølge oppfinnelsen kan amino-imidazol-derivatene også fremstilles ved acylering av amidoximet med den generelle formel: In alternative b) of the method according to the invention, the amino-imidazole derivatives can also be prepared by acylation of the amidoxime with the general formula:

i basisk medium. Det er kjent at ved acylering av amidoximer dannes O-acylderivater. [Chem. Reviews, 62, 155 (1962)]. Enkelte av disse O-acylderivater, f.eks. tosylatene, avspaltes fra de enkle amidoximer i form av syrer og ved en Beckmann-omleiring dannes N-substi- in basic medium. It is known that O-acyl derivatives are formed when amidoximes are acylated. [Chem. Reviews, 62, 155 (1962)]. Some of these O-acyl derivatives, e.g. the tosylates, are cleaved from the simple amidoximes in the form of acids and by a Beckmann rearrangement N-substi-

tuert cyanamid. (Reaksjonsskjema 2). tuated cyanamide. (Reaction scheme 2).

Ved alternativ c) av fremgangsmåten utføres In alternative c) of the procedure is carried out

acyleringen i pyridin, som acyleringsmiddel anvendes carboxylsyreklorid eller carboxylsyreanhydrid. the acylation in pyridine, carboxylic acid chloride or carboxylic anhydride is used as acylating agent.

Fremstillingen av forbindelsene med den generelle formel III er The preparation of the compounds of the general formula III is

beskrevet i ungarsk patent 156.811. described in Hungarian patent 156,811.

I det tilfelle at de kondenserte aminoimidazolringderivater med formel Ia fremstilles fra amidoximforbindelsene med den generelle formel III, består muligheten for fremstilling av slike forbindelser med formel Ia hvor den exocycliske aminogruppe allerede er acylert (NH-Ac), når man anvender et overskudd av acyleringsmidlet. In the event that the condensed aminoimidazole ring derivatives of formula Ia are prepared from the amidoxime compounds of the general formula III, the possibility exists for the preparation of such compounds of formula Ia where the exocyclic amino group is already acylated (NH-Ac), when an excess of the acylating agent is used.

Amino-pyrazolderivatet med den generelle formel: fåes ved oppvarmning av oxadiazol-5-onet av forbindelsen med den generelle formel: The amino-pyrazole derivative of the general formula: is obtained by heating the oxadiazol-5-one of the compound of the general formula:

(Reaksjonsskjema 3) (Reaction scheme 3)

Oxadiazol-5-on-forbindelsene mister carbondioxyd, som kjent fra litteraturen [j. Heterocyclic Chem. , ]"_, 59 (1970)], men bare unntagelsesvis fåes et homogent produkt [Chem. Ber. 105» 813 (1972)]. The oxadiazol-5-one compounds lose carbon dioxide, as known from the literature [j. Heterocyclic Chem. , ]"_, 59 (1970)], but only exceptionally is a homogeneous product obtained [Chem. Ber. 105» 813 (1972)].

Ovenstående reaksjon kan ifølge alternativ d) The above reaction can according to alternative d)

av foreliggende fremgangsmåte of the present method

enten utføres med godt utbytte under smeltning, eller i et apolart oppløsningsmiddel, fortrinnsvis ved oppvarmning i xylen eller tetralin. Reaksjonen ble utført over 100°C. De samme produkter kan fremstilles ved alkalisk hydrolyse av forbindelsene med den generelle formel IV (D=H) ved kokepunktet. either carried out with good yield under melting, or in an apolar solvent, preferably by heating in xylene or tetralin. The reaction was carried out above 100°C. The same products can be prepared by alkaline hydrolysis of the compounds of the general formula IV (D=H) at the boiling point.

Forbindelsene med den generelle formel IV kan fremstilles ved Bischler-Napieralsky-reaksjonen, ved hvilken man ringslutter de tilsvarende N-[2-fenyl-ethyl]-l,2,4-oxadiazolon-5,3-yl-acétamid-derivater. The compounds of the general formula IV can be prepared by the Bischler-Napieralsky reaction, in which the corresponding N-[2-phenyl-ethyl]-1,2,4-oxadiazolon-5,3-yl-acetamide derivatives are ring-closed.

De på den exocycliske aminogruppe substituerte Ia og Ib derivater fremstilles ved to metoder. The Ia and Ib derivatives substituted on the exocyclic amino group are prepared by two methods.

De ovenfor fremstilte forbindelser med formel Ia eller lb med usubstituert aminogruppe kan omsettes ved acylering, ved reduktiv alkylering ved azomethinderivatet, eller man kan gå ut fra 1,2,4-oxadiazol-5-on-forbindelser med den generelle formel IV som allerede er substituert på N (reaksjonsskjema 4)• The above prepared compounds of formula Ia or lb with unsubstituted amino group can be reacted by acylation, by reductive alkylation with the azomethine derivative, or one can proceed from 1,2,4-oxadiazol-5-one compounds of the general formula IV which are already substituted on N (reaction scheme 4)•

hvor D er alkyl, cycloalkyl eller aralkyl, og Y og A er som ovenfor angitt. where D is alkyl, cycloalkyl or aralkyl, and Y and A are as indicated above.

Om ovenstående derivater substituert på det exocycliske nitrogen fører til forbindelsesgruppe Ia (aminoimidazolgruppen) eller forbindelsesgruppen Ib (arainopyrazolgruppen), kan entydig bevises når man går ut fra forbindelsene med struktur Ia eller Ib, hvis struktur er kjent, og det exocycliske nitrogen senere substitueres med gruppen D, f.eks. ved reduserende kondensering. Whether the above derivatives substituted on the exocyclic nitrogen lead to compound group Ia (the aminoimidazole group) or compound group Ib (the arainopyrazole group) can be unequivocally proven when starting from the compounds of structure Ia or Ib, whose structure is known, and the exocyclic nitrogen is later substituted with the group D, e.g. by reducing condensation.

I dette tilfelle kan det fra det N^-substituert-l,2,4-oxa-diazol-5-on med den generelle formel IV erholdte produkt identi-fiseres . In this case, the product obtained from the N 1 -substituted-1,2,4-oxa-diazol-5-one of the general formula IV can be identified.

I andre tilfelle kan der ved hjelp av protonresistens - spektroskopi bestemmes om en forbindelse hører til gruppen Ia eller Ib, når begge kondenserte femleddede ringer inneholder en eneste C-H-binding, er de i Ia bundet til N, og i Ib til C, og da er fore-komststedet for metinprotonet karakteristisk for strukturen. In the second case, proton resistance spectroscopy can be used to determine whether a compound belongs to group Ia or Ib, when both condensed five-membered rings contain a single C-H bond, in Ia they are bound to N, and in Ib to C, and then is the location of the methine proton characteristic of the structure.

Aminopyrazolderivater med den generelle formel Ib og deres N-acylderivater kan også fremstilles fra forbindelsene med den generelle formel: Aminopyrazole derivatives of the general formula Ib and their N-acyl derivatives can also be prepared from the compounds of the general formula:

hvor R er en eventuelt med halogen, nitro eller alkoxy substituert alkyl-, aryl- eller aralkylgruppe, Y er hydrogen, nitroso, nitro, carboxamido, alkyl eller en eventuelt ned én eller flere halogen-atomer, alkoxy- eller nitrogrupper substituert aralkyl-, fenyl-eller feriylazogruppe. where R is an alkyl, aryl or aralkyl group optionally substituted with halogen, nitro or alkoxy, Y is hydrogen, nitroso, nitro, carboxamido, alkyl or an optionally down one or more halogen atoms, alkoxy or nitro groups substituted aralkyl-, phenyl or ferriylazo group.

Ved oppvarmning kan N-acylderivatet fremstilles i et moderat alkalisk medium i en smelte eller i et oppløsningsmiddel ifølge reaksjonsskjema 5: By heating, the N-acyl derivative can be prepared in a moderately alkaline medium in a melt or in a solvent according to reaction scheme 5:

eller dannes ved intensiv alkalisk hydrolyse som forbindelsene med formel Ib, hvor D er hydrogen. or formed by intensive alkaline hydrolysis as the compounds of formula Ib, where D is hydrogen.

Nar forbindelsene med den generelle formel I omsettes med organiske syrer eller mineralsyrer eller de tilsvarende baser fri-gjøres fra disse salter, kan syreaddisjonssaltene av forbindelsene med den generelle formel I fremstilles. When the compounds of the general formula I are reacted with organic acids or mineral acids or the corresponding bases are released from these salts, the acid addition salts of the compounds of the general formula I can be prepared.

De farmakologiske undersøkelser ble utført på narkotiserte hunder (nembutal 25 mg/kg i.v.) ved hjelp av følgende metoder. The pharmacological investigations were carried out on anesthetized dogs (nembutal 25 mg/kg i.v.) using the following methods.

1. Arterietrykkpåvirkende effekt. Det midlere arterietrykk ble målt i hodepulsåren hos hundene på blodig vis ved hjelp av et Statham-måleinstrument med et Hellige-elektromanometer, og de målte 1. Arterial pressure influencing effect. The mean arterial pressure was measured in the carotid artery of the dogs in a blood manner using a Statham measuring instrument with a Hellige electromanometer, and they measured

verdier ble kontinuerlig registrert på en Hellige-multiskriver. Resultatene er sammenfattet i tabell I. 2. Koronarutvidende effekt. Koronargjennomstrømningen ble målt med en termodilusjonsprosess, som virker på basis av en stasjonær vedvarende kold væskeinfusjon i Sinus Coronarius [Szekeres L., Papp J. Gy., Fischer E.,: Acta Physiol. Acad. Sei. Hung. 3_3_, 115 (1969)], og ble kontinuerlig registrert på en KIPP-mikrograf ved hjelp av et likeledes i Sinus Coronarius innført termoelement, og uttrykt i ml/min/lOO g. Koronarmotst anden ble angitt i en selvvalgt enhet på basis av kvotienten av arteriemiddeltrykket (mmHg) og koronar-gjennomstrømningen, som ble målt i Sinus Coronarius (ml/min/100 g). Resultatene er sammenfattet i tabell II. 3- Den hjerteoxygenerinqspåvirkende effekt. Under de nevnte hunde-forsøk ble samtidig med målingen av koronargjennomstrømningen også oxygenmetningen av blodprøven kontinuerlig registrert, som ble om-suget fra Sinus Coronarius gjennom målekuvetten av KIPP-oxymeteret med peristaltisk pumpe med stasjonær hastighet og ble ført tilbake i brachialvenen. Herunder ble også oxygenmetningen av det arteriøse blod bestemt, og med et Zeiss-manometer ble likeledes hemoglobin-innholdet i blodet bestemt. Under kjennskap til disse data ble oxygenforbruket av det venstre hjertekammer beregnet (ml/100 g/min). For å karakterisere den oxydative stoffveksel av hjertemuskelen og den tilstrekkelige oxygentilførsel ble også 02-tilbud/^-kra v-kvotienten beregnet. [For ytterligere detaljer se: Szekeres L., Papp J. Gy., Fischer, E.: European J. Pharmacol., 2, 1 (1967)]. Resultatene er sammenfattet i tabell III. 4. Effekten som påvirker virkningsgraden av arbeidet i det venstre hjertekåmmer. Ifølge Szekeres, L., Papp, J. Gy., Fischer, E: Acta Physiol. Acad. Sei. Hung. 3_3_, 115, (1969) ble minuttvolumet og arteriemiddeltrykket registrert ved "kold væske-infusjons"-metoden, og arbeidet av det venstre hjertekammer beregnet fra dette, videre ble, som allerede beskrevet, -forbruket av det venstre hjertekammer beregnet, og derved på basis av kvotienten: arbeidet av det venstre hjertekammer (mkg/min): 02-forbruk av det venstre hjertekammer (ml/min/lOO g) ble også målet for effekten som påvirket virkningsgraden av arbeidet av det venstre hjertekammer bestemt. Resultatene er sammenfattet i tabell IV. 5. Toksisitet. De akutte toksisitetsundersøkelser ble utført på rotter med en kroppsvekt på 150 - 200 g. Dosen ble i løpet av maksi-malt 5 sekunder innsprøytet i et volum av 0,2 ml/100 g i halevenen. LD^0-verdien og toleransegrensene ble bestemt ved metoden til Litchf ield og Wilcoxon på basis av antallet dyr som døde i løpet av 24 timer [j. Pharmacol. exp. Ther. 96, 99, (1949)]. values were continuously recorded on a Hellige multi-printer. The results are summarized in table I. 2. Coronary dilating effect. Coronary flow was measured with a thermodilution process, which works on the basis of a stationary continuous cold fluid infusion in the Sinus Coronarius [Szekeres L., Papp J. Gy., Fischer E.,: Acta Physiol. Acad. Pollock. Hung. 3_3_, 115 (1969)], and was continuously recorded on a KIPP micrograph by means of a thermocouple also introduced into the Sinus Coronarius, and expressed in ml/min/lOO g. Coronary resistance was indicated in a self-selected unit based on the quotient of mean arterial pressure (mmHg) and coronary flow, which was measured in the Sinus Coronarius (ml/min/100 g). The results are summarized in table II. 3- The effect affecting cardiac oxygenation. During the aforementioned dog experiments, at the same time as the measurement of the coronary flow, the oxygen saturation of the blood sample was also continuously recorded, which was aspirated from the Sinus Coronarius through the measuring cuvette of the KIPP oximeter with a peristaltic pump at a stationary speed and was returned to the brachial vein. During this, the oxygen saturation of the arterial blood was also determined, and with a Zeiss manometer the hemoglobin content in the blood was also determined. Knowing these data, the oxygen consumption of the left heart chamber was calculated (ml/100 g/min). In order to characterize the oxidative metabolism of the heart muscle and the sufficient oxygen supply, the 02-offer/^-demand quotient was also calculated. [For further details see: Szekeres L., Papp J. Gy., Fischer, E.: European J. Pharmacol., 2, 1 (1967)]. The results are summarized in table III. 4. The effect affecting the efficiency of the work in the left heart combs. According to Szekeres, L., Papp, J. Gy., Fischer, E: Acta Physiol. Acad. Pollock. Hung. 3_3_, 115, (1969) the minute volume and arterial mean pressure were recorded by the "cold liquid infusion" method, and the work of the left heart ventricle was calculated from this, further, as already described, the consumption of the left heart ventricle was calculated, and thereby on basis of the quotient: the work of the left heart ventricle (mkg/min): 02 consumption of the left heart ventricle (ml/min/lOO g) was also the measure of the effect affecting the efficiency of the work of the left heart ventricle determined. The results are summarized in table IV. 5. Toxicity. The acute toxicity studies were carried out on rats with a body weight of 150 - 200 g. The dose was injected in a volume of 0.2 ml/100 g into the tail vein within a maximum of 5 seconds. The LD^0 value and tolerance limits were determined by the method of Litchfield and Wilcoxon on the basis of the number of animals that died within 24 hours [j. Pharmacol. exp. Ther. 96, 99, (1949)].

Forbindelsene med den generelle formel I og deres salter kan anvendes i farmasien i form av preparater inneholdende virkestoffet og ikke-toksiske-inerte, farmasøytisk anvendbare, organiske eller uorganiske bærere. Preparatene anvendes i fast form (f.eks. tabletter, tabletter med filmovertrekk, dragéer, enterosolventdragéer, piller, kapsler) i flytende form (f.eks. suspensjoner, oppløsninger eller emulsjoner. Som bærere kan talkum, stivelse, gelatin, vann, polyalkylenglycol, osv., anvendes. Preparatene kan likeledes inneholde andre hjelpemidler, f.eks. fuktemidler, emulgerings- eller suspensjonsmidler, og slike salter og puffere som forandrer det osmotiske trykk og letter nedbrytning og/eller de kan inneholde ytterligere farmasøytisk aktive stoffer. The compounds of the general formula I and their salts can be used in pharmacy in the form of preparations containing the active ingredient and non-toxic-inert, pharmaceutically usable, organic or inorganic carriers. The preparations are used in solid form (e.g. tablets, film-coated tablets, dragees, enterosolvent dragees, pills, capsules) in liquid form (e.g. suspensions, solutions or emulsions. As carriers, talc, starch, gelatin, water, polyalkylene glycol , etc., are used. The preparations may likewise contain other aids, e.g. wetting agents, emulsifying or suspending agents, and such salts and buffers which change the osmotic pressure and facilitate breakdown and/or they may contain further pharmaceutically active substances.

Eksempel la Example la

6 g teknisk calciumcyanamid suspenderes i 15 ral vann under oppvarmning, og 8 ml av en 10%-ig natriumhydroxydoppløsning tilsettes. Blandingen oppvarmes i 15 minutter ved 50 - 60°C, og bunnfallet f raf Utreres. Til filtratet tilsettes 150 ml alkohol, og blandingen oppvarmes under tilbakeløp til kokning. Til den kokende oppløsning tilsettes i løpet av en halv time 2,7 g 1-klormethyl-6,7-dimethoxy-3,4-dihydro-isokinolin-hydroklorid. Reaksjonsblandingen kokes i 4 timer og inndampes så i vakuum til tørrhet. Residuet tilsettes 50 ml vann, det krystallinske stoff frafiltreres og tørres. Man får 1,8 g 3~amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isokinolin.. Smp. 232 - 236°C. Produktet renses ved omkrystallisa-sjon fra alkohol. 6 g of technical calcium cyanamide are suspended in 15 ral of water while heating, and 8 ml of a 10% sodium hydroxide solution is added. The mixture is heated for 15 minutes at 50 - 60°C, and the precipitate is removed. 150 ml of alcohol is added to the filtrate, and the mixture is heated under reflux to boiling. 2.7 g of 1-chloromethyl-6,7-dimethoxy-3,4-dihydro-isoquinoline hydrochloride are added to the boiling solution over the course of half an hour. The reaction mixture is boiled for 4 hours and then evaporated in vacuo to dryness. The residue is added to 50 ml of water, the crystalline substance is filtered off and dried. 1.8 g of 3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline are obtained. M.p. 232 - 236°C. The product is purified by recrystallization from alcohol.

Analyse: C.-H.cN-O, Analysis: C.-H.cN-O,

I NMR-spektret av produktet (AEI-RS 60 MHz) opptrer protonet i stilling 1 i en oppløsning CDCl^-DMSO ved 6,70 ppm. In the NMR spectrum of the product (AEI-RS 60 MHz), the proton appears in position 1 in a solution CDCl^-DMSO at 6.70 ppm.

Eksempel lb Example lb

50 ml pyridin tilsettes til 13,2 g 6,7-dimethoxy-3,4-dihydro-isokinolyl-(l)-acetamidoxim, hvorefter 9,5 g tosylklorid tilsettes under omrøring og avkjøling i løpet av 15 minutter. Reaksjonsblandingen omrøres i 2 timer ved 70°C og hensettes en natt i kjøleskap. Det utskilte produkt frafiltreres, vaskes med absolutt alkohol og tørres. Man får 9»2 g 3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,l-a]-isokinolin-hydroklorid. Smp.: 272 - 274°C (fra alkohol). For å frigjøre basen oppløses hydrokloridsaltet i varmt vann, og oppløsningen gjøres alkalisk med 10%-ig natriumhydroxydoppløsning. Basen krystalliserer og er identisk med det i eksempel la beskrevne produkt. 50 ml of pyridine is added to 13.2 g of 6,7-dimethoxy-3,4-dihydro-isoquinolyl-(1)-acetamidoxime, after which 9.5 g of tosyl chloride is added while stirring and cooling during 15 minutes. The reaction mixture is stirred for 2 hours at 70°C and left overnight in a refrigerator. The separated product is filtered off, washed with absolute alcohol and dried. 9.2 g of 3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline hydrochloride are obtained. M.p.: 272 - 274°C (from alcohol). To release the base, the hydrochloride salt is dissolved in warm water, and the solution is made alkaline with 10% sodium hydroxide solution. The base crystallizes and is identical to the product described in example la.

Eksempel lc Example lc

På samme måte som angitt i eksempel lb, fåes ved anvendelse av 29 g 6,7-dimethoxy-3,4-dihydro-isokinolyl-(l)-acetamidoxim og 13 ml benzoylklorid 25,6 g 3_amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isokinolin-hydroklorid, idet produktet er identisk med produktet fra eksempel lb. In the same way as stated in example 1b, by using 29 g of 6,7-dimethoxy-3,4-dihydro-isoquinolyl-(1)-acetamidoxime and 13 ml of benzoyl chloride, 25.6 g of 3-amino-5,6-dihydro- 8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline hydrochloride, the product being identical to the product from example lb.

Det samme produkt fåes når der i ovenstående reaksjon isteden-for benzoylklorid anvendes klormaursyre-ethylester. The same product is obtained when, in the above reaction, chloroformic acid ethyl ester is used instead of benzoyl chloride.

Eksempel 2 Example 2

60 ml pyridin tilsettes til 14,56 g 6,7~diethoxy-3,4-dihydro-isokinolyl-(l)-acetamidoxim, hvorefter 7»6 g benzoylklorid tildryppes til blandingen under omrøring og avkjøling. Oppløsningen omrøres i 1 time ved 50 - 6o°C, og oppløsningsmidlet fordampes i vakuum. Residuet suspenderes i ethylacetat, og man får 12,65 g 3-amino-5,6-dihydro-8,9-diethoxy-imidazo-[5,l-a]-isokinolin-hydroklorid-mono-hydrat. Smp. 206 - 208°C (fra alkohol). Analyse: C^H^N^OgCl 60 ml of pyridine are added to 14.56 g of 6,7~diethoxy-3,4-dihydro-isoquinolyl-(1)-acetamidoxime, after which 7.6 g of benzoyl chloride are added dropwise to the mixture while stirring and cooling. The solution is stirred for 1 hour at 50 - 6o°C, and the solvent is evaporated in vacuo. The residue is suspended in ethyl acetate, and 12.65 g of 3-amino-5,6-dihydro-8,9-diethoxy-imidazo-[5,1-a]-isoquinoline hydrochloride mono-hydrate are obtained. Temp. 206 - 208°C (from alcohol). Analysis: C^H^N^OgCl

Ovenstående hydrokloridsalt oppløses i 70 ml varmt vann, og oppløsningen avfarves med dyrekull, frafiltreres og gjøres alkalisk med 10%-ig natriumhydroxydoppløsning. Man får 9,7 g 3-amino-5,6-dihydro-8,9-diethoxy-imidazo-[5,l-a]-isokinolin. Smp. 212 - 2l4°C (fra alkohol). The above hydrochloride salt is dissolved in 70 ml of warm water, and the solution is decoloured with animal charcoal, filtered off and made alkaline with 10% sodium hydroxide solution. 9.7 g of 3-amino-5,6-dihydro-8,9-diethoxy-imidazo-[5,1-a]-isoquinoline are obtained. Temp. 212 - 2l4°C (from alcohol).

Analyse: -RjqN-C^Analysis: -RjqN-C^

Eksempel 3 Example 3

3,2 g teknisk calciumcyanamid omrøres med 9 ml 10%-ig natrium-hydroxydoppløsning i 15 minutter ved 6o - 70°C, og blandingen filtreres. Til filtratet tilsettes 80 ml alkohol, blandingen oppvarmes til kokning, og til den kokende oppløsning tilsettes 3,34 9 1-(1-klorethyl)-6,7-dimethoxy-3,4-dihydro-isokinolin-hydroklorid. 3.2 g of technical calcium cyanamide are stirred with 9 ml of 10% sodium hydroxide solution for 15 minutes at 6o - 70°C, and the mixture is filtered. 80 ml of alcohol is added to the filtrate, the mixture is heated to boiling, and 3.34 g of 1-(1-chloroethyl)-6,7-dimethoxy-3,4-dihydro-isoquinoline hydrochloride is added to the boiling solution.

(Arch. d. Pharm. 277. 177, 139). Blandingen kokes i 5 timer, inndampes så, og residuet tilsettes vann. Man får 2 g 1-met hy1-3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isokinolin. (Arch. d. Pharm. 277. 177, 139). The mixture is boiled for 5 hours, then evaporated, and water is added to the residue. 2 g of 1-methyl-3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline are obtained.

Smp. 248 - 250°C (fra absolutt alkohol). Temp. 248 - 250°C (from absolute alcohol).

Analyse: C-^^^N^^ Analysis: C-^^^N^^

Eks empel Ij . Ex empel Ij.

Til 200 mg 3-(6,7-dimethoxy-3,4-dihydro-l-isokinolyl)-methyl-5-benzyl-1,2,4-oxadiazol tilsettes 5 ml xylen, og reaksjonsproduktet kokes under tilbakeløp i 8 timer. Efter avkjøling tilsettes IO ml bensin til blandingen. Man får 170 mg 2-fenyl-acetyl-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,l-a]-isokinolin. Smp. 225 - 227°C (fra butanol). 5 ml of xylene is added to 200 mg of 3-(6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-5-benzyl-1,2,4-oxadiazole, and the reaction product is refluxed for 8 hours. After cooling, 10 ml of petrol is added to the mixture. 170 mg of 2-phenyl-acetyl-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline is obtained. Temp. 225 - 227°C (from butanol).

Analyse: c2i<H2>1N3°3Analysis: c2i<H2>1N3°3

Eksempel 5a Example 5a

5 g 3_(6,7-dimethoxy-3,4-dihydro-l-isokinolyl)-methyl-A - 1,2,4-oxadiazolin-5-on smeltes på et metallbad ved en temperatur på 180 - 200°C. Efter avkjøling blir det stabiliserte produkt oppløst i 30 ml 5%-ig vandig saltsyre under oppvarmning, oppløsningen fra-filt reres og gjøres alkalisk med 10%-ig natriumhydroxyd. Det krystalliserte produkt frafiltreres , vaskes med vann og tørres. Man får 3 9 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isokinolin. Smp. 216 - 217°C (fra alkohol). 5 g of 3_(6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-A-1,2,4-oxadiazolin-5-one is melted in a metal bath at a temperature of 180 - 200°C. After cooling, the stabilized product is dissolved in 30 ml of 5% aqueous hydrochloric acid while heating, the solution is filtered and made alkaline with 10% sodium hydroxide. The crystallized product is filtered off, washed with water and dried. 3 9 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline is obtained. Temp. 216 - 217°C (from alcohol).

Analyse: c13Hi5<N>3°2 Analysis: c13Hi5<N>3°2

I NMR-spektret av produktet opptrer protonet i stilling 1 ved 5,85 ppm. In the NMR spectrum of the product, the proton appears in position 1 at 5.85 ppm.

Eksempel 5b Example 5b

65 ml xylen tilsettes til 13 g 3-(6,7-dimethoxy-3,4-dihydro-l- * isokinolyl)-methyl-A -1,2,4-oxadiazolin-5-on, hvorefter reaksjonsblandingen kokes i 3 timer under tilbakéløp. Efter avkjøling fra-filt reres det krystallinske materiale og tørres. Man får 10 g 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isokinolin, og produktet er identisk med produktet fra eksempel 5a. 65 ml of xylene is added to 13 g of 3-(6,7-dimethoxy-3,4-dihydro-1-*isoquinolyl)-methyl-A-1,2,4-oxadiazolin-5-one, after which the reaction mixture is boiled for 3 hours during reverse run. After cooling from the filter, the crystalline material is stirred and dried. 10 g of 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline are obtained, and the product is identical to the product from example 5a.

Fra en 96%-ig alkoholisk oppløsning av produktet fåes ved tilsetning av alkohol i saltsyre hydrokloridsaltet: 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,l-a]-isokinolin-hydroklorid-dihydrat i krystallinsk form. Smp. 128 - 130°C. From a 96% alcoholic solution of the product, the hydrochloride salt is obtained by adding alcohol to hydrochloric acid: 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline hydrochloride dihydrate in crystalline shape. Temp. 128 - 130°C.

Analyse: C, oH„rtNo0, Cl Analysis: C, oH„rtNo0, Cl

13 20 3 4 13 20 3 4

Eksempel 5c Example 5c

20 ml av en 10%-ig natriumhydroxydoppløsning tilsettes til !»D 9 3-(6,7-dimethoxy-3,4-dihydro-l-isokinolyl)-methyl-A -l,2,Zf-oxadiazolin-5-on, og reaksjonsblandingen kokes i 8 timer under til-bakeløp. Efter avkjøling fåes 0,9 g 2-amino-5,6-dihydro-8>9~ dimethoxy-pyrazolo-[5>l-a]-isokinolin i krystallinsk form. Produktet er identisk med produktet fra eksempel 5a. 20 ml of a 10% sodium hydroxide solution is added to !»D 9 3-(6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-A -1,2,Zf-oxadiazolin-5-one , and the reaction mixture is refluxed for 8 hours. After cooling, 0.9 g of 2-amino-5,6-dihydro-8>9~ dimethoxy-pyrazolo-[5>1-a]-isoquinoline is obtained in crystalline form. The product is identical to the product from example 5a.

LD^0-verdien for produktet og de 95%-ige toleransegrenser er som følger: 70 (34 - 148) mg/kg. The LD^0 value for the product and the 95% tolerance limits are as follows: 70 (34 - 148) mg/kg.

Produktet nedsetter arteriet rykket i en dose på 1-4 mg/kg i.v., øker koronargjennomstrømningen, minsker koronarmotstanden, minsker oxygenforbruket av hjertemuskelen og forbedrer, dvs. øker, kvotienten som uttrykker oxygeneringen av hjertet: 02-tilbud/A^-krav og påvirker derved virkningsgraden av hjertearbeidet gunstig. De oven-nevnte forhold viser at forbindelsen under forholdene ved dyreforsøk tilsvarer kravene til antiangina-midler. The product reduces arterial tension in a dose of 1-4 mg/kg i.v., increases coronary flow, decreases coronary resistance, decreases oxygen consumption by the heart muscle and improves, i.e. increases, the quotient expressing the oxygenation of the heart: 02 offer/A^ claim and affects thereby improving the efficiency of the heart's work. The above-mentioned conditions show that the compound under the conditions of animal experiments corresponds to the requirements for antianginal agents.

Eksempel 6a Example 6a

50 ml alkohol og 10 ml 10%-ig natriumhydroxydoppløsning tilsettes til 1,75 g 3-(6,7-dimethoxy-3,4-dihydro-l-isokinolyl)-methylr 5-fenyl-1,2,4-oxadiazol, og reaksjonsblandingen kokes under tilbake-løp i 3 timer. Derefter avdampes alkoholen under vakuum, og residuet tilsettes vann. Man får 1,2 g 2-benzoyl-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-f 5 ,1-a ] -isokinolin , og produktet er identisk med produktet fra eksempel 17. 50 ml of alcohol and 10 ml of 10% sodium hydroxide solution are added to 1.75 g of 3-(6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl 5-phenyl-1,2,4-oxadiazole, and the reaction mixture is refluxed for 3 hours. The alcohol is then evaporated under vacuum, and water is added to the residue. 1.2 g of 2-benzoyl-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline is obtained, and the product is identical to the product from example 17.

Eksempel 6b Example 6b

Til 1 g 3-(6,7-dimethoxy-3,4-dihydro-l-isokinolyl)-methyl-5-fenyl-1,2,4-oxadiazol tilsettes 10 ml xylen, og reaksjonsblandingen kokes under tilbakeløp i 8 timer. Efter avkjøling fåes 0,9 9 av det krystallinske 2-benzoyl-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5»1-a]-isokinolin, som er identisk med det i eksempel 6a beskrevne produkt. To 1 g of 3-(6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-5-phenyl-1,2,4-oxadiazole, 10 ml of xylene is added, and the reaction mixture is refluxed for 8 hours. After cooling, 0.9 g of the crystalline 2-benzoyl-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5»1-a]-isoquinoline is obtained, which is identical to the product described in example 6a .

Eksempel 7 Example 7

25 ml alkohol og 7 ml 4o%-ig natriumhydroxydoppløsning tilsettes til 1 g 3-(6,7-dimethoxy-3,4-dihydro-l-isokinolyl)-methyl-5-fenyl-1,2,4-oxadiazol, og reaksjonsblandingen kokes under tilbakeløp i 8 timer. Derefter avdampes alkoholen under vakuum, og residuet tilsettes vann. Man får 0,6 g 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isokinolin i krystallinsk form, og produktet er identisk med produktet fra eksempel 5. 25 ml of alcohol and 7 ml of 40% sodium hydroxide solution are added to 1 g of 3-(6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-5-phenyl-1,2,4-oxadiazole, and the reaction mixture is refluxed for 8 hours. The alcohol is then evaporated under vacuum, and water is added to the residue. 0.6 g of 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline is obtained in crystalline form, and the product is identical to the product from example 5.

Eksempel 8a Example 8a

2 g 3-(6,7-dimethoxy-3,4-dihydro-l-isokinolyl)-methyl-4-benzyl- A2-l,2,4-oxadiazolin-5-on smeltes på et metallbad. Efter avkjøling omkrystalliseres produktet fra benzen, og man får 1,2 g 3-benzylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isokinolin. Smp. 135°C. 2 g of 3-(6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-4-benzyl-A2-1,2,4-oxadiazolin-5-one are melted on a metal bath. After cooling, the product is recrystallized from benzene, and 1.2 g of 3-benzylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline is obtained. Temp. 135°C.

Analyse: C2 <H>^<n><o>2 Analysis: C2 <H>^<n><o>2

I NMR-spektret av produktet opptrer protonet i st dlling 1 ved 6,85 ppm. In the NMR spectrum of the product, the proton appears in position 1 at 6.85 ppm.

Eksempel 8b Example 8b

IO ml xylen tilsettes til 1,5 g 3-(6,7-dimethoxy-3,4-dihydro-1-isokinolyl)-methyl-4-benzyl-A 2-1,2,4~oxadiazolin-5-on, og blandingen kokes under tilbakeløp i 2 timer. Efter avkjøling fåes 1,1 g 3-benzylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isokinolin i krystallinsk form, og produktet er identisk med produktet fra eksempel 8a. 10 ml of xylene is added to 1.5 g of 3-(6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-4-benzyl-A 2-1,2,4~oxadiazolin-5-one, and the mixture is refluxed for 2 hours. After cooling, 1.1 g of 3-benzylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline is obtained in crystalline form, and the product is identical to the product from example 8a.

Eksempel 8c Example 8c

1,1 g benzaldehyd og 20 ml absolutt alkohol tilsettes til 1.1 g of benzaldehyde and 20 ml of absolute alcohol are added

2,3 g 3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isokinolin, og reaksjonsblandingen kokes under tilbakeløp i 5 timer. Efter av-kjøling fåes 3,1 g krystallinsk 3~benzyliden-amino-5,6-dihydro-8,9-dimethoxy -imidazo-[5 , l-a ] -isokinolin . Smp. 176°C (fra alkohol). 2.3 g of 3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline, and the reaction mixture is refluxed for 5 hours. After cooling, 3.1 g of crystalline 3-benzylidene-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline are obtained. Temp. 176°C (from alcohol).

Analyse: C2oH19N1°2 Analysis: C2oH19N1°2

1,6 g av ovenstående produkt oppløses i 100 ml methanol, og 0,5 g natriumborhydrid tilsettes til oppløsningen i løpet av en halv time. Oppløsningen hensettes i 1 time ved værelsetemperatur, og oppløsningsmidlet fjernes. Til residuet tilsettes vann, hvorefter produktet krystalliserer. Produktet frafiltreres og tørres. Man får 1,7 g 3-benzylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,l-a]- 1.6 g of the above product is dissolved in 100 ml of methanol, and 0.5 g of sodium borohydride is added to the solution over the course of half an hour. The solution is allowed to stand for 1 hour at room temperature, and the solvent is removed. Water is added to the residue, after which the product crystallizes. The product is filtered off and dried. 1.7 g of 3-benzylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-

isokinolin. Produktet er identisk med produktet fra eksempel 8a. 17 g av ovenstående produkt oppløses i varm methanol, og den varme oppløsning syres med methanol i saltsyre. Efter avkjøling fåes 1,4 g 3-benzylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,l-a]-isokinolin-hydroklorid i krystallinsk form. Smp. 250 - 252°C. isoquinoline. The product is identical to the product from example 8a. 17 g of the above product are dissolved in hot methanol, and the hot solution is acidified with methanol in hydrochloric acid. After cooling, 1.4 g of 3-benzylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline hydrochloride is obtained in crystalline form. Temp. 250 - 252°C.

Analyse: C2QH22<Ng02Cl>Analysis: C 2 QH 2 2 <NgO 2 Cl>

Forbindelsen forhøyer i en dose på 1 - 2 mg/kg kont raktiliteten med 4o% i ca. 26 - 28 minutter. Minuttvolumet økes med 30% av produktet på narkotiserte hunder, ved en anvendt dose på 2 mg/kg, og virkningens varighet er 16 minutter. Forbindelsen nedsetter motstanden av lungekarområdet i en dose på 2 mg/kg med 25% i 22 minutter. Virkningsgraden av hjertefunksjonen hos den narkotiserte hund forbedres. I en dose på o,5 mg/kg var den femorale gjennom-strømning hos en narkotisert hund øket med 77% i 16 minutter. i en dose på 1 mg/kg ble gjennomstrømningen av carotis-karområdet øket med 31% i 24 minutter. I stilling in situ ble den elektriske fibrillære terskel for forkammermuskelen hos katten øket med 10% av en dose på 2 mg/kg. I stilling in situ ble den elektriske fibrillære terskel av hjertekammermuskelen hos katten øket med 50% med en dose på 2 mg/kg og med 82% med en dose på 4 mg/kg. In a dose of 1 - 2 mg/kg, the compound increases contractility by 40% for approx. 26 - 28 minutes. The minute volume is increased by 30% of the product in anesthetized dogs, at an applied dose of 2 mg/kg, and the duration of the effect is 16 minutes. The compound reduces the resistance of the pulmonary vascular area in a dose of 2 mg/kg by 25% for 22 minutes. The efficiency of the heart function in the anesthetized dog is improved. At a dose of 0.5 mg/kg, the femoral flow in an anesthetized dog was increased by 77% for 16 minutes. at a dose of 1 mg/kg, the flow of the carotid vessel area was increased by 31% for 24 minutes. In the in situ position, the electrical fibrillar threshold of the cat atrial muscle was increased by 10% by a dose of 2 mg/kg. In the in situ position, the electrical fibrillar threshold of the heart ventricle muscle in the cat was increased by 50% with a dose of 2 mg/kg and by 82% with a dose of 4 mg/kg.

Eksempel 9a Example 9a

70 ml 10%-ig natriumhydroxydoppløsning og 400 ml alkohol tilsettes til 10 g 3-(6,7-dimethoxy-3,4-dihydro-l-isokinolyl)-methyl-4-benzyl-A i-l ,2 ,4-oxadiazolin-5-on, og reaks jonsblandingen kokes under tilbakeløp i 1 time. Derpå inndampes blandingen til tørrhet i vakuum, og residuet tilsettes vann. Man får 8 9 2-benzylamino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,l-a]-isokinolin. Smp. 156°C (fra alkohol). Analyse: C^H^CX, 70 ml of 10% sodium hydroxide solution and 400 ml of alcohol are added to 10 g of 3-(6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-4-benzyl-Al-1,2,4-oxadiazolin- 5-on, and the react ion mixture is boiled under reflux for 1 hour. The mixture is then evaporated to dryness in a vacuum, and water is added to the residue. 8 9 2-Benzylamino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline is obtained. Temp. 156°C (from alcohol). Analysis: C^H^CX,

Eksempel 9b Example 9b

0,6 g benzaldehyd og 10 ml absolutt alkohol tilsettes til 1,2 g 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isokinolir og reaksjonsblandingen kokes under tilbakeløp i 4 timer. Efter av-kjøling fåes 1,1 g 2-benzyliden-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,l-a]-isokinolin i krystallinsk form. Smp. l63°C. 0.6 g of benzaldehyde and 10 ml of absolute alcohol are added to 1.2 g of 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinol and the reaction mixture is refluxed for 4 hours. After cooling, 1.1 g of 2-benzylidene-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline is obtained in crystalline form. Temp. 163°C.

Analyse: C^H^ 02 Analysis: C^H^ 02

0,9 g av ovenstående produkt oppløses i 100 ml methanol, og oppløsningen tilsettes 0,2 g natriumborhydrid. Oppløsningen hensettes i 1 time, hvorefter oppløsningsmidlet avdampes i vakuum. Td residuet tilsettes vann. Man får 0,8 9 2-benzylamino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isokinolin. Produktet er identisk med produktet fra eksempel 9a. 0.9 g of the above product is dissolved in 100 ml of methanol, and 0.2 g of sodium borohydride is added to the solution. The solution is allowed to stand for 1 hour, after which the solvent is evaporated in vacuo. Water is added to the residue. 0.8 9 2-benzylamino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline is obtained. The product is identical to the product from example 9a.

5,7 g av ovenstående produkt oppløses i 80 ml aceton, og opp-løsningen gjøres sur med absolutt alkohol i saltsyre. Man får 5,5 2-benzylamino-5,6-dihydro-dimethoxy-pyrazolo-[5,l-a]-isokinolin-hydroklorid i krystallinsk form. Smp. 206 - 208°C. 5.7 g of the above product are dissolved in 80 ml of acetone, and the solution is acidified with absolute alcohol in hydrochloric acid. 5,5 2-benzylamino-5,6-dihydro-dimethoxy-pyrazolo-[5,1-a]-isoquinoline hydrochloride is obtained in crystalline form. Temp. 206 - 208°C.

Analyse: C^H^N^Cl Analysis: C^H^N^Cl

NMR-spektret for produktet viser protonet i stilling 1 ved 5,73 ppm. The NMR spectrum of the product shows the proton in position 1 at 5.73 ppm.

Eksempel IO Example IO

14 ml 10%-ig natriumhydroxydoppløsning og 80 ml alkohol tilsettes til 2 g 3-(6,7-diethoxy-3,4-dihydro-l-isokinolyl)-methyl-4-benzyl-A-I,2,4-oxadiazolin-5-on, og reaksjonsblandingen kokes under tilbakeløp i 1 time. Derpå inndampes blandingen til tørrhet, og residuet tilsettes vann. Man får 1,5 g 2-benzylamino-5,6-dihydro-8,9-diethoxy-pyrazolo-[5,1-a]-isokinolin. Smp.,130 - 131°C (fra butanol). 14 ml of 10% sodium hydroxide solution and 80 ml of alcohol are added to 2 g of 3-(6,7-diethoxy-3,4-dihydro-1-isoquinolyl)-methyl-4-benzyl-A-1,2,4-oxadiazolin-5 -on, and the reaction mixture is refluxed for 1 hour. The mixture is then evaporated to dryness, and water is added to the residue. 1.5 g of 2-benzylamino-5,6-dihydro-8,9-diethoxy-pyrazolo-[5,1-a]-isoquinoline is obtained. M.p. 130 - 131°C (from butanol).

Analyse: C^H^C^ Analysis: C^H^C^

Eksempel 11 Example 11

5 ml acetanhydrid tilsettes til 1 g 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,l-a]-isokinolin, reaksjonsblandingen oppvarmes i IO minutter på vannbad, hvorefter blandingen hensettes i 1 time. Blandingen helles på is, og man får 0,8 9 2-acetylamino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,l-a]-isokinolin i krystallinsk form. 5 ml of acetic anhydride is added to 1 g of 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline, the reaction mixture is heated for 10 minutes on a water bath, after which the mixture is allowed to stand for 1 hour. The mixture is poured onto ice, and 0.8 9 2-acetylamino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline is obtained in crystalline form.

Smp. 223°C (fra 75%-ig alkohol). Temp. 223°C (from 75% alcohol).

Analyse: ^^ H-^ yN^ O^ Analysis: ^^ H-^ yN^ O^

Eksempel 12 Example 12

20 ml kloroform og 1,4 g kaliumcarbonat tildryppes til 2,45 g 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5 »1-a]-isokinolin. Blandingen omrøres ved værelsetemperatur i 5 timer, og 20 ml vann tilsettes. Kloroformfasen fraskilles, tørres over natriumsulfat og inndampes. Man får 2 g 2-kloracetyl-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,l-a]-isokinolin. Smp. 152 - 154°C (fra alkohol). 20 ml of chloroform and 1.4 g of potassium carbonate are added dropwise to 2.45 g of 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5»1-a]-isoquinoline. The mixture is stirred at room temperature for 5 hours, and 20 ml of water is added. The chloroform phase is separated, dried over sodium sulphate and evaporated. 2 g of 2-chloroacetyl-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline are obtained. Temp. 152 - 154°C (from alcohol).

Analyse: G^H^NgO^C! Analysis: G^H^NgO^C!

Eksempel 13 Example 13

30 ml acetanhydrid tilsettes til 8 9 3-amino-5,6-dihydro-8,9" dimethoxy-imidazo-[5,1-a]-isokinolin, og blandingen oppvarmes i en halv time på vannbad. Blandingen helles så i 150 ml isvann. Opp-løsningen nøytraliseres med natriumcarbonat , og de utskilte krystaller f rafiltreres. Man får 6,2 g 3-acetylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,l-a]-isokinolin. Smp. 225°C (fra absolutt alkohol). 30 ml of acetic anhydride is added to 8 9 3-amino-5,6-dihydro-8,9" dimethoxy-imidazo-[5,1-a]-isoquinoline, and the mixture is heated for half an hour on a water bath. The mixture is then poured into 150 ml of ice water. The solution is neutralized with sodium carbonate, and the separated crystals are filtered off. 6.2 g of 3-acetylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline are obtained. 225°C (from absolute alcohol).

Analyse: ci^ i7^ 3Q3 Analysis: ci^ i7^ 3Q3

Eksempel 14 Example 14

30 ml kloroform og 1,4 9 kaliumcarbonat tilsettes til 2,45 9 3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isokinolin, og under omrøring tildryppes blandingen 1,15 9 kloracetylklorid. Blandingen omrøres ved værelsetemperatur i 5 timer, og tilsettes 20 ml vann. Kloroformfasen fraskilles, tørres over natriumsulfat og inndampes. Man får 1,4 g 3-kloracetylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,l-a]-isokinolin. Smp. 25l°C (fra alkohol). 30 ml of chloroform and 1.4 9 potassium carbonate are added to 2.45 9 3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline, and while stirring, mixture 1 is added dropwise, 15 9 chloroacetyl chloride. The mixture is stirred at room temperature for 5 hours, and 20 ml of water is added. The chloroform phase is separated, dried over sodium sulphate and evaporated. 1.4 g of 3-chloroacetylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline is obtained. Temp. 25l°C (from alcohol).

Analyse: C^H^NgOgCl Analysis: C^H^NgOgCl

Eksempel 15 Example 15

1 g teknisk calciumcyanamid suspenderes i 5 ml vann,og 1,4 ml 10%-ig natriumhydroxydoppløsning tilsettes. Blandingen omrøres i 15 minutter ved 50 - 60°C, og bunnfallet frafiltreres. 50 ml alkohol tilsettes til filtratet, og blandingen oppvarmes til kokning. 1 g a-brom-6,7-dimethoxy-3,4-dihydro-l-isokinolyl-acetonitril tilsettes til den kokende oppløsning. Reaksjonsblandingen kokes videre i 4 timer og inndampes til tørrhet. Til residuet tilsettes vann. Man får 0,6 g l-cyano-3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isokinolin. Smp. 236°C (fra alkohol). Analyse: ClZfHlZN^02 1 g of technical calcium cyanamide is suspended in 5 ml of water, and 1.4 ml of 10% sodium hydroxide solution is added. The mixture is stirred for 15 minutes at 50 - 60°C, and the precipitate is filtered off. 50 ml of alcohol is added to the filtrate, and the mixture is heated to boiling. 1 g of α-bromo-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile is added to the boiling solution. The reaction mixture is further boiled for 4 hours and evaporated to dryness. Water is added to the residue. 0.6 g of 1-cyano-3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline is obtained. Temp. 236°C (from alcohol). Analysis: ClZfHlZN^O 2

Eksempel 16 Example 16

15 ml vann og 0,7 9 benzoylklorid tilsettes til 1 g 3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-i sokinolin, hvorefter reaksjonsblandingens pH-verdi under avkjøling og omrøring holdes på 10 - 11 ved tilsetning av 10%-ig natriumhydroxydoppløsning. Man får 1»39 3-benzoylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isokinolin. Smp. 258°C (fra alkohol). 15 ml of water and 0.79 benzoyl chloride are added to 1 g of 3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-i soquinoline, after which the pH value of the reaction mixture while cooling and stirring is kept at 10 - 11 by adding a 10% sodium hydroxide solution. 1.3 g of 3-benzoylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline is obtained. Temp. 258°C (from alcohol).

Analyse: (^H^N^O^ Analysis: (^H^N^O^

Eksempel 17 Example 17

1 g 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,l-a]-isokinolin omsettes med 0,7 g benzoylklorid ved den i eksempel 15 beskrevne fremgangsmåte, og man får 1 g 2-benzoyl-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,l-a]-isokinolin. Smp. 185°C (fra alkohol). 1 g of 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline is reacted with 0.7 g of benzoyl chloride by the method described in example 15, and 1 g of 2-benzoyl -amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline. Temp. 185°C (from alcohol).

Analyse: C^<P>^<qN>-O., Analysis: C^<P>^<qN>-O.,

Eksempel 18 Example 18

Til 0,5 g acetylamino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isokinolin tilsettes IO ml 2 N saltsyre, hvorefter reaksjonsblandingen kokes under tilbakeløp i en halv time. Efter avkjøling fåes 0,5 g 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isokinolin -hydroklorid-dihydrat i krystallinsk form. Produktet er identisk med produktet fra eksempel 5. Smp. 128 - 130°C. To 0.5 g of acetylamino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline is added 10 ml of 2 N hydrochloric acid, after which the reaction mixture is boiled under reflux for half an hour. After cooling, 0.5 g of 2-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline hydrochloride dihydrate is obtained in crystalline form. The product is identical to the product from example 5. Smp. 128 - 130°C.

Eksempel 19 Example 19

Til 1,3 g 3-acetylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[ 5,1-a ]-isokinolin tilsettes 15 ml 5%-ig natriumhydroxydoppløsning, hvorefter blandingen kokes i 1 time under tilbakeløp. Efter avkjøl-ing fåes 0,8 g 3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,l-a]-isokinolin i krystallinsk form. Produktet er identisk med produktet fra eksempel 1. Smp. 234 - 236°C. To 1.3 g of 3-acetylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline is added 15 ml of 5% sodium hydroxide solution, after which the mixture is boiled for 1 hour under reflux. After cooling, 0.8 g of 3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline is obtained in crystalline form. The product is identical to the product from example 1. Smp. 234 - 236°C.

Eksempel 20 Example 20

10 ml xylen tilsettes til 1 g 3-(6,7-dimethoxy-3,4-dihydro-1-isokinolyl)-methyl-5-propyl-l,2,4-oxadiazol, og reaksjonsblandingen kokes under tilbakeløp i 8 timer. Oppløsningsmidlet avdampes i vakuum, og residuet omkrystalliseres fra vandig alkohol. Man får 0,7 g 2-butyryi-amino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5 ,1-a ] - isokinolin-hemihydrat. Smp. 125 - 127°C. Analyse: C-j^^N^O.- x 1/2 H20 10 ml of xylene is added to 1 g of 3-(6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-5-propyl-1,2,4-oxadiazole, and the reaction mixture is refluxed for 8 hours. The solvent is evaporated in vacuo, and the residue is recrystallized from aqueous alcohol. 0.7 g of 2-butyrylamino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline hemihydrate is obtained. Temp. 125 - 127°C. Analysis: C-j^^N^O.- x 1/2 H 2 O

Eksempel 21 Example 21

4 ml alkohol og ml 10%-ig natriumhydroxydoppløsning tilsettes til 140 mg 3-(6,7-dimethoxy-3,4-dihydro-l-isokinolyl)-methyl-4-ethyl-A 2-1,2 ,4-oxadiazolin-5-on , og reaks jonsblandingen kokes under tilbakeløp i 2 timer. Oppløsningsmidlet fordampes under vakuum, 4 ml of alcohol and ml of 10% sodium hydroxide solution are added to 140 mg of 3-(6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-4-ethyl-A 2-1,2,4-oxadiazoline -5-one, and the react ion mixture is boiled under reflux for 2 hours. The solvent is evaporated under vacuum,

og residuet tilsettes vann. Man får 81 mg 2-ethylamino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,l-a]-isokinolin. Smp. 114 - ll6°C (fra bensin:carbontetraklorid). and water is added to the residue. 81 mg of 2-ethylamino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline is obtained. Temp. 114 - 116°C (from gasoline: carbon tetrachloride).

Analyse: ci5HioN3°2 Analysis: ci5HioN3°2

Eksempel 22 Example 22

2,45 g 3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5^l-a]-isokinolin oppvarmes med 1,2 ml butyraldehyd og 45 ml vannfri ethanol 2.45 g of 3-amino-5,6-dihydro-8,9-dimethoxy-imidazo-[5^1-a]-isoquinoline are heated with 1.2 ml of butyraldehyde and 45 ml of anhydrous ethanol

i 3 timer. Den halve mengde av oppløsningsmidlet avdestilleres og residuet tilsettes 1,0 ml butyraldehyd. Reaksjonsblandingen kokes 1 3 timer, og avkjøles så til værelsetemperatur. I løpet av 30 minutter tilsettes 0,6 g natriumborhydrid under omrøring. Reaksjonsblandingen kokes i 30 minutter og inndampes så til tørrhet. Til residuet tilsettes 15 ml vann og det utskilte produkt frafiltreres. Man får 2,1 g 3-butylamino-5,6-dihydro-8,9-dimethoxy-imidazo- [ 5 , l-a] -isokinolin-monohydrat . Smeltepunkt 134-136°C for 3 hours. Half the amount of the solvent is distilled off and 1.0 ml of butyraldehyde is added to the residue. The reaction mixture is boiled for 13 hours, and then cooled to room temperature. During 30 minutes, 0.6 g of sodium borohydride is added while stirring. The reaction mixture is boiled for 30 minutes and then evaporated to dryness. 15 ml of water is added to the residue and the separated product is filtered off. 2.1 g of 3-butylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline monohydrate is obtained. Melting point 134-136°C

(fra 96 %-ig ethanol). (from 96% ethanol).

Analyse: Analysis:

Beregn.: C% = 63,93; H% = 7,89; N% = 13,16; Calc.: C% = 63.93; H% = 7.89; N% = 13.16;

Funnet : C% = 63,62; H% = 7,98; N% = 12,88. Found : C% = 63.62; H% = 7.98; N% = 12.88.

Eksempel 23 Example 23

1 ml 1%-ig natriumhydroxydoppløsning og 4 ml alkohol tilsettes til 140 ml 3-(6,7-dimethoxy-3,4-dihydro-l-isokinolyl)-methyl-4-ethyl- A -l,2,4-oxadiazolin-5-on og reaksjonsblandingen kokes i 2 timer under tilbakeløp. Derpå inndampes blandingen til tørrhet og residuet tilsettes vann. Man får 81 mg 2-ethylamino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,l-a]-isokinolin med smeltepunkt 114-116°C. 1 ml of 1% sodium hydroxide solution and 4 ml of alcohol are added to 140 ml of 3-(6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-4-ethyl- A -1,2,4-oxadiazoline -5-one and the reaction mixture is boiled for 2 hours under reflux. The mixture is then evaporated to dryness and water is added to the residue. 81 mg of 2-ethylamino-5,6-dihydro-8,9-dimethoxy-pyrazolo-[5,1-a]-isoquinoline with a melting point of 114-116°C is obtained.

Analyse: <c>15<H>i9<N>3°2 Analysis: <c>15<H>i9<N>3°2

beregnet: C% = 65,91, H% = 7,01, N% = 15,38 calculated: C% = 65.91, H% = 7.01, N% = 15.38

funnet : C% = 65,92, H% = 6,93, N% = 15,13. found: C% = 65.92, H% = 6.93, N% = 15.13.

Eksempel 24 Example 24

0,5 g 3-(6,7-dimethoxy-3,4-dihydro-l-isokinolyl)-methyl-4-ethyl- A -1,2,4-oxadiazolon-5-on smeltes i oljebad ved 150°C 0.5 g of 3-(6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-4-ethyl- A -1,2,4-oxadiazolon-5-one is melted in an oil bath at 150°C

og oppvarmes derpå i ytterligere 5 minutter ved denne temperatur. Efter avkjøling tilsettes 20 ml vann til reaksjonsblandingen. and is then heated for a further 5 minutes at this temperature. After cooling, 20 ml of water is added to the reaction mixture.

Man får 0,4 5 g 3-ethylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,l-a]-isokinolin-monohydrat med smeltepunkt 128-130°C (fra 50%-ig ethanol). 0.45 g of 3-ethylamino-5,6-dihydro-8,9-dimethoxy-imidazo-[5,1-a]-isoquinoline monohydrate with melting point 128-130°C (from 50% ethanol) is obtained.

Analyse: <C>15<H>19<N>3<0>2.<H>2<0>Analysis: <C>15<H>19<N>3<0>2.<H>2<0>

beregnet: C% = 61,83, H% = 7,26, N% = 14,39, calculated: C% = 61.83, H% = 7.26, N% = 14.39,

funnet : C% = 62,11, H% = 7,23, N% = 14,56. found: C% = 62.11, H% = 7.23, N% = 14.56.

Claims (1)

Analogifreargangsmåte ved fremstilling av terapeutisk aktive imidazo- og pyrazolo-isokinolin-derivater med den generelle formel:Analogue procedure in the preparation of therapeutically active imidazo- and pyrazolo-isoquinoline derivatives of the general formula: hvor A er alkoxy med 1-4 carbonatomer,where A is alkoxy with 1-4 carbon atoms, B er -N=C-NH-D hvor D er hydrogen, alkyl med 1-4 carbonatomer, fenylalkyl med 7 - IO carbonatomer, benzoyl, fenyl-lavere alkanoyl, alkanoyl med 1-4 carbonatomer eller kloracetyl,B is -N=C-NH-D where D is hydrogen, alkyl with 1-4 carbon atoms, phenylalkyl with 7-10 carbon atoms, benzoyl, phenyl-lower alkanoyl, alkanoyl with 1-4 carbon atoms or chloroacetyl, Y er hydrogen, cyano eller lavere alkyl, karakterisert ved at a) 3_amino-imidazo-[5>1-a]-isokinolinderivater med formel I, hvor A og Y er som ovenfor angitt, og D er hydrogen, fremstilles ved at en forbindelse med den generelle formel:Y is hydrogen, cyano or lower alkyl, characterized in that a) 3_amino-imidazo-[5>1-a]-isoquinoline derivatives of formula I, where A and Y are as indicated above, and D is hydrogen, are prepared by a compound with the general formula: eller et syreaddisjonssalt derav, hvor A og Y er som ovenfor angitt, og X er halogen, omsettes med et alkalimetall- eller jordalkalimetallsalt av cyanamid, eller med alkali-hydrogen-cyanamid, eller b) 3-amino-imidazo-[5,1-a]-isokinolinderivater med den gener-eller formel I, hvor A er som ovenfor angitt, D er hydrogen eller acyl som ovenfor angitt, og Y er hydrogen, lavere alkyl eller fenyl, fremstilles ved at et isokinolyl-acetamidoxim med den generelle formel:or an acid addition salt thereof, where A and Y are as indicated above, and X is halogen, is reacted with an alkali metal or alkaline earth metal salt of cyanamide, or with alkali hydrogen cyanamide, or b) 3-amino-imidazo-[5,1 -α]-isoquinoline derivatives of the gene or formula I, where A is as indicated above, D is hydrogen or acyl as indicated above, and Y is hydrogen, lower alkyl or phenyl, are prepared by an isoquinolyl-acetamidoxime of the general formula : hvor A er som ovenfor angitt, og Y<1> er hydrogen, lavere alkyl eller fenyl, omsettes med sulfonsyrehalogenid i overskudd eller i en ekvimolar mengde, eller carboxylsyrederivater som acyleringsmiddel, eller c) forbindelser med den generelle formel I, hvor A og Y er som ovenfor angitt, og D er acyl som ovenfor angitt, fremstilles ved at en forbindelse med den generelle formel I hvor D er hydrogen, acyleres med carboxylsyrederivater av tilsvarende acylgrupper som acyleringsmiddel, eller d) forbindelser med formel I hvor D er hydrogen, alkyl med 1-4 carbonatomer eller fenylalkyl med 7-10 carbonatomer, og Y er hydrogen, lavere alkyl eller fenyl, fremstilles ved at en forbindelse med den generelle formel:where A is as indicated above, and Y<1> is hydrogen, lower alkyl or phenyl, is reacted with sulphonic acid halide in excess or in an equimolar amount, or carboxylic acid derivatives as acylating agent, or c) compounds of the general formula I, where A and Y is as stated above, and D is acyl as stated above, is prepared by a compound of the general formula I where D is hydrogen, is acylated with carboxylic acid derivatives of corresponding acyl groups as an acylating agent, or d) compounds of formula I where D is hydrogen, alkyl with 1-4 carbon atoms or phenylalkyl with 7-10 carbon atoms, and Y is hydrogen, lower alkyl or phenyl, is prepared by a compound of the general formula: hvor A, D og Y er som ovenfor angitt, oppvarmes i et oppløsnings-middel eller i en smelte, eller underkastes vandig eller alkalisk hydrolyse, eller e) forbindelser med formel I hvor D er de ovenfor angitte acylgrupper, fremstilles ved at en forbindelse med den generelle formel:where A, D and Y are as indicated above, are heated in a solvent or in a melt, or subjected to aqueous or alkaline hydrolysis, or e) compounds of formula I where D is the acyl groups indicated above, are prepared by a compound with the general formula: hvor Y er som ovenfor angitt, og R er alkyl med 1-3 carbonatomer, fenyl, fenyl-lavere alkyl eller klormethyl, cykliseres i et moderat alkalisk medium, i .et oppløsningsmiddel eller i en smelte, eller f) forbindelser med formel I hvor D er alkyl med 1-4 carbonatomer eller fenylalkyl med 7-10 carbonatomer fremstilles ved at den tilsvarende forbindelse med formel 1 hvor D er hydrogen, omsettes med et alkanal med 1-4 carbonatomer eller med et fenylalkanal med 7-10 carbonatomer, hvorpå det dannede produkt reduseres, eller g) forbindelser med formel I hvor D er hydrogen, fremstilles ved at en tilsvarende forbindelse med formel I hvor D er en av de ovenfor angitte acylgrupper, hydrolyseres, fortrinnsvis med nat riumhydroxyd.where Y is as stated above, and R is alkyl with 1-3 carbon atoms, phenyl, phenyl-lower alkyl or chloromethyl, is cyclized in a moderately alkaline medium, in a solvent or in a melt, or f) compounds of formula I where D is alkyl with 1-4 carbon atoms or phenylalkyl with 7-10 carbon atoms is prepared by reacting the corresponding compound of formula 1 where D is hydrogen with an alkane with 1-4 carbon atoms or with a phenylalken with 7-10 carbon atoms, after which the the product formed is reduced, or g) compounds of formula I where D is hydrogen are prepared by hydrolysing a corresponding compound of formula I where D is one of the acyl groups stated above, preferably with sodium hydroxide.
NO732694A 1972-06-30 1973-06-29 ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE IMIDAZO AND PYRAZOLO-ISOKINOLIN DERIVATIVES NO138908C (en)

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CZ20014099A3 (en) * 1999-05-19 2002-04-17 The Procter & Gamble Company Heterocyclic compounds containing imidazole ring and pharmaceutical preparation in which the compounds are comprised
US6552033B1 (en) 2000-05-16 2003-04-22 The Procter & Gamble Co. Imidazo-containing heterocyclic compounds, their compositions and uses
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