DE2454198C2 - Isoquinoline derivatives, processes for their preparation and medicines - Google Patents
Isoquinoline derivatives, processes for their preparation and medicinesInfo
- Publication number
- DE2454198C2 DE2454198C2 DE2454198A DE2454198A DE2454198C2 DE 2454198 C2 DE2454198 C2 DE 2454198C2 DE 2454198 A DE2454198 A DE 2454198A DE 2454198 A DE2454198 A DE 2454198A DE 2454198 C2 DE2454198 C2 DE 2454198C2
- Authority
- DE
- Germany
- Prior art keywords
- isoquinoline
- heart
- tetrahydro
- acetyl
- medicines
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title claims 2
- 239000003814 drug Substances 0.000 title description 2
- 238000000034 method Methods 0.000 title description 2
- 238000002360 preparation method Methods 0.000 title description 2
- 229940079593 drug Drugs 0.000 title 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000126 substance Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 210000004204 blood vessel Anatomy 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- -1 2,3-epoxypropoxy Chemical group 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical group C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- KXTIMMJONYFHCM-UHFFFAOYSA-N 1-(6-hydroxy-3,4-dihydro-1h-isoquinolin-2-yl)ethanone Chemical compound OC1=CC=C2CN(C(=O)C)CCC2=C1 KXTIMMJONYFHCM-UHFFFAOYSA-N 0.000 description 1
- SBJSXRGEXNGDCA-UHFFFAOYSA-N 1-[6-(oxiran-2-ylmethoxy)-3,4-dihydro-1h-isoquinolin-2-yl]ethanone Chemical compound C=1C=C2CN(C(=O)C)CCC2=CC=1OCC1CO1 SBJSXRGEXNGDCA-UHFFFAOYSA-N 0.000 description 1
- DVRXCMRXLKMMSL-UHFFFAOYSA-N 1-[6-[2-hydroxy-3-(propan-2-ylamino)propoxy]-3,4-dihydro-1h-isoquinolin-2-yl]ethanone Chemical compound C1N(C(C)=O)CCC2=CC(OCC(O)CNC(C)C)=CC=C21 DVRXCMRXLKMMSL-UHFFFAOYSA-N 0.000 description 1
- WAJJRRYXWISHGP-UHFFFAOYSA-N 1-[7-methoxy-6-(oxiran-2-ylmethoxy)-3,4-dihydro-1h-isoquinolin-2-yl]ethanone Chemical compound COC1=CC=2CN(C(C)=O)CCC=2C=C1OCC1CO1 WAJJRRYXWISHGP-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010003671 Atrioventricular Block Diseases 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- 208000010271 Heart Block Diseases 0.000 description 1
- 206010058177 Hyperkinetic heart syndrome Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010033557 Palpitations Diseases 0.000 description 1
- 208000000418 Premature Cardiac Complexes Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000004044 bronchoconstricting agent Substances 0.000 description 1
- 230000003435 bronchoconstrictive effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- OYJXTOVLKZDGFK-UHFFFAOYSA-N ethanol;2-propan-2-yloxypropane Chemical compound CCO.CC(C)OC(C)C OYJXTOVLKZDGFK-UHFFFAOYSA-N 0.000 description 1
- WDCDAAMJNUHOIY-UHFFFAOYSA-N ethyl acetate;2-propan-2-yloxypropane Chemical compound CCOC(C)=O.CC(C)OC(C)C WDCDAAMJNUHOIY-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229960001317 isoprenaline Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 208000009157 neurocirculatory asthenia Diseases 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 230000000213 tachycardiac effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
in der R ein Wasserstoffatom oder die Methoxygruppe bedeutet, sowie deren Salze mit physiologisch verträglichen Säuren.in which R denotes a hydrogen atom or the methoxy group, as well as their salts with physiological compatible acids.
2. Verfahren zur Herstellung der Verbindungen nach Anspruch 1, dadurch gekennzeichnet, daß man in an sich bekannter Weise eine Verbindung der allgemeinen Formel II2. Process for the preparation of the compounds according to claim 1, characterized in that one is in on known way a compound of the general formula II
CH2 CH-CH2OCH 2 CH-CH 2 O
O
/^v/\ ^N — C — CH, (Π)O
/ ^ v / \ ^ N - C - CH, (Π)
in der R die oben angegebene Bedeutung hat, mit Isopropylamin zur Umsetzung bringt und die so erhaltenen Verbindungen gegebenenfalls in ihre Salze mit physiologisch verträglichen Säuren überführt.in which R has the meaning given above, reacts with isopropylamine and the resulting Compounds optionally converted into their salts with physiologically acceptable acids.
3. Arzneimittel, enthaltend eine Verbindung gemäß Anspruch 1 zusammen mit den pharmazeutisch üblichen Hilfs- und TrägerstofTen.3. Medicament containing a compound according to claim 1 together with the pharmaceutically customary ones Auxiliary and carrier materials.
Es sind bereits eine ganze Reihe von Substanzen bekannt, die^S-Rezeptoren blockieren, d. h. Substanzen, die jß-Rezeptoren besetzen, ohne diese zu erregen. Diese Substanzen haben jedoch den Nachteil, daß die^S-blockierende Wirksamkeit entweder nicht spezifisch ein Organ betrifft oder daß ihre Verträglichkeit nicht optimal ist.A number of substances are already known which block ^ S-receptors, i. H. Substances that Occupy jß receptors without exciting them. However, these substances have the disadvantage that the ^ S-blocking Effectiveness either does not specifically affect an organ or that its tolerance is not optimal.
Eine hohe Organspezifität ist besonders für solche Verbindungen erforderlich, die zur Behandlung von kardialen
Erkrankungen dienen sollen. Ist diese nicht vorhanden, besteht die Gefahr, daß eine am Herzen wirksame Dosis
gleichzeitig an anderen Organsystemen (Gefäßsystem, Bronchialsystem) pharmakologisch wirksam wird, d. h.
Nebenwirkungen können auftreten.
Es wurden nun Substanzen gefunden, deren Wirkung spezifisch am Herzen eintritt.A high organ specificity is particularly necessary for those compounds which are intended to be used for the treatment of cardiac diseases. If this is not available, there is a risk that a dose effective on the heart will be pharmacologically effective at the same time on other organ systems (vascular system, bronchial system), ie side effects can occur.
Substances have now been found whose effect occurs specifically on the heart.
Die Erfindung betrifft den Gegenstand Jer Ansprüche.The invention relates to the subject matter of the claims.
Die Herstellung der erfindungsgemäßen Verbindungen kann in An- oder Abwesenheit eines Lösungsmittels durchgeführt werden. Geeignete Lösungsmittel sind z.B. niedere Alkohole, vorzugsweise Isopropanol. Die Umsetzung wird vorzugsweise bei der Siedetemperatur des Lösungsmittels durchgeführt; sie gelingt aber auch bei Raumtemperatur.The compounds according to the invention can be prepared in the presence or absence of a solvent be performed. Suitable solvents are, for example, lower alcohols, preferably isopropanol. the The reaction is preferably carried out at the boiling point of the solvent; but it also works at room temperature.
Die Verbindungen können als solche oder in Form ihrer Salze mit physiologisch verträglichen Säuren angewendet werden. Solche Säuren sind z.B. Salzsäure, Schwefelsäure, Phosphorsäure, Essigsäure, Malonsäure, Bernsteinsäure, Zitronensäure, Weinsäure, Milchsäure, Diamidosulfonsäure und Schleimsäure.The compounds can be used as such or in the form of their salts with physiologically acceptable acids will. Such acids are e.g. hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, malonic acid, Succinic acid, citric acid, tartaric acid, lactic acid, diamidosulfonic acid and mucic acid.
Mit den Verbindungen lassen sich speziell die./?-Rezeptoren des Herzens blockieren, ohne daß die^ö-Rezeptoren des Gefaßsystems oder Bronchialsystems merklich beeinflußt werden. Die^S-rezeptorenblockierende Wirksamkeit am Herzen und Gefäßsystem wurde durch Aufnahme des EKGs bzw. durch Messung des Blutdrucks an demselben Tier (Meerschweinchen) gemessen (vgl. Baird, J. R. C. und J. Linell [1972] J. Pharm. Pharmac. 24, 880-885 und Kaplan, H. R. und M. A. Commarato [1973] J. Pharmacol. Exp. Ther. 185,395-405). Zur Untersuchung der bronchokonstriktorischen Wirksamkeit wird die Hemmung des Isoprenalin-EfFektes am Bronchialsystem des Meerschweinchens herangezogen (vgl. Konzett, H. und Rössler R. [1940] Arch. exp. Path.With the compounds can specifically the./? -receptors of the heart block without the ^ ö -receptors the vascular system or bronchial system are noticeably affected. The ^ S-receptor blocking effectiveness on the heart and vascular system was monitored by recording the EKG or by measuring the blood pressure the same animal (guinea pigs) measured (cf. Baird, J. R. C. and J. Linell [1972] J. Pharm. Pharmac. 24, 880-885 and Kaplan, H. R. and M. A. Commarato [1973] J. Pharmacol. Exp. Ther. 185,395-405). For examination the bronchoconstrictor effectiveness is the inhibition of the isoprenaline effect on the bronchial system of the guinea pig (cf. Konzett, H. and Rössler R. [1940] Arch. exp. Path.
Pharmak. 195, 71-74).Pharmac. 195, 71-74).
Die nachfolgende Übersicht gibt die experimentell ermittelten intravenösen Dosen (Effektivdosis an den .^-Rezeptoren des Herzens, Blutgefäßsystems und Bronchialsystems = ED-Herz, ED-Blutgefäße, ED-Bronchialsystem) des 2-Acetyl-l,2,3,4-tetrahydro-6-(2-hydroxy-3-isopropyl-amino-propoxy)-isochinolins (A) und 2-Acetyl-l^^^-tetrahydro-o^-hydroxy-S-isopropyl-amino-propoxyJ^-methoxy-isochinolins (B) im Vergleich zu l-Isopropylamino-3-(l-naphthyloxy)-propan-2-ol-hydrochlorid = Propranolol (C) an.The following overview gives the experimentally determined intravenous doses (effective dose at the . ^ - Receptors of the heart, blood vessel system and bronchial system = ED heart, ED blood vessels, ED bronchial system) des 2-acetyl-l, 2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylamino-propoxy) -isoquinoline (A) and 2-acetyl-l ^^^ - tetrahydro-o ^ - hydroxy-S-isopropylamino-propoxyJ ^ -methoxy-isoquinolines (B) compared to l-isopropylamino-3- (l-naphthyloxy) propan-2-ol hydrochloride = propranolol (C).
ED-Herz ED-Blutgefäße ED-BrochialsystemED heart ED blood vessels ED brochial system
A 13 mg/kg 80 mg/kg 71 mg/kgA 13 mg / kg 80 mg / kg 71 mg / kg
B 5,5 mg/kg 10 mg/kg >40 mg/kgB 5.5 mg / kg 10 mg / kg> 40 mg / kg
C 1,2 mg/kg 1,2 mg/kg 0,18 mg/kgC 1.2 mg / kg 1.2 mg / kg 0.18 mg / kg
Daraus ergeben sich für diese beiden Substanzen folgende Wirksamkeitsverhältnisse:This results in the following ratios of effectiveness for these two substances:
Herz : Blutgefäße Herz : BronchialsystemHeart: blood vessels Heart: bronchial system
A 1 : 6,2 1 : 5,5A 1: 6.2 1: 5.5
B 1 : 1,8 1 : >7,2B 1: 1.8 1:> 7.2
C 1:1 1 : 0,15C 1: 1 1: 0.15
Es ist ersichtlich, daß die Dosenverhältnisse für die Substanzen wesentlich günstiger sind als die für die Vergleichsverbindung ermittelten. Das gilt insbesondere für das Verhältnis von herzwirksamer zu Bronchialsystemwirksamer Dosis, d. h. die Applikation von herzwirksamen Dosen führt nicht zu einer negativen Beeinflussung des Bronchialsystems.It can be seen that the dose ratios for the substances are significantly more favorable than those for the comparison compound determined. This applies in particular to the ratio of the more effective to the heart to the more effective to the bronchial system Dose, d. H. the application of doses that act on the heart does not lead to a negative influence the bronchial system.
Die neuen Verbindungen besitzen weiter eine ausgezeichnete Verträglichkeit und zeigen keine Wirkung als Kalziumantagonisten. Die LD50-Werte (ermittelt nach i. v.-Gabe an der Maus) betragen in mg/kg für A 130, für B 100 und für C 25 mg/kg.The new compounds are also extremely well tolerated and show no activity as calcium antagonists. The LD 50 values (determined after intravenous administration to the mouse) are in mg / kg for A 130, for B 100 and for C 25 mg / kg.
Als Inriikationsgebiet der neuen Verbindungen kommen funktionelle Herzbeschwerden wie Tachykardie oder Herzklopfen, tachykarde Herzrhythmusstörungen, Extrasystolie, Angina pectoris oder hyperkinetisches Herzsyndrom in Frage.Functional heart problems such as tachycardia or Palpitations, tachycardiac arrhythmias, extrasystole, angina pectoris or hyperkinetic heart syndrome in question.
Als Darreichungsform sind Tabletten, Kapseln und peroral oder parenteral applizierbare Lösungen geeignet. Als Dosis sind bei peroraler Applikation etwa 20-200, bei intravenöser Applikation etwa 2-20 mg pro Mensch und Tag vorgesehen.Tablets, capsules and solutions that can be administered orally or parenterally are suitable as the dosage form. The dose for peroral administration is around 20-200 mg per person, and for intravenous administration it is around 2-20 mg and day provided.
a) Ein Gemisch von 57,6 g l^^^-Tetraliydro-o-hydroxy-isochinolin-hydrobromid, 22,6 g wasserfreiem Natriumacetat und 76,6 g Essigsäureanhydrid in 300 ml Methylenchlorid wird 1 Stunde unter Rückfluß am Sieden gehalten. Man gibt 300 ml Wasser hinzu, trennt die organische Phase ab und extrahiert die wäßrige Phase nochmals mit Methylenchlorid. Nach Eindampfen der Methylenchlorid-Auszüge löst man den Rückstand in verdünnter Natronlauge, rührt 30 Minuten auf dem siedenden Wasserbad und fallt das Reaktionsprodukt durch Einleiten von Kohlendioxid aus. Die abgesaugte Substanz wird aus Ethanol umkristallisiert. Man erhält 43,5 g 2-Acetyl-l,2,3,4-tetrahydro-6-hydroxy-isochinolin, Fp 135-136°C (Ethanol - Diisopropylether).a) A mixture of 57.6 g l ^^^ - Tetraliydro-o-hydroxy-isoquinoline hydrobromide, 22.6 g anhydrous Sodium acetate and 76.6 g of acetic anhydride in 300 ml of methylene chloride is refluxed for 1 hour Kept simmering. 300 ml of water are added, the organic phase is separated off and the aqueous phase is extracted Phase again with methylene chloride. After evaporation of the methylene chloride extracts one dissolves the Residue in dilute sodium hydroxide solution, stirred for 30 minutes on a boiling water bath and the reaction product precipitated by introducing carbon dioxide. The sucked off substance is recrystallized from ethanol. 43.5 g of 2-acetyl-1,2,3,4-tetrahydro-6-hydroxy-isoquinoline, melting point 135-136 ° C. (ethanol - diisopropyl ether).
Zu einem Gemisch aus 28,7 g 2-Acetyl-l,2,3,4-tetrahydro-6-hydroxy-isochinolin und 42,5 g Epichlorhydrin tropft man bei 600C eine Lösung von 6,8 g Natriumhydroxid in 90 ml Wasser innerhalb 1 h zu. Man hält das Reaktionsgemisch noch 1 h bei dieser Temperatur, läßt abkühlen und extrahiert mehrmals mit Methylenchlorid. Die über Natriumsulfat getrocknete organische Phase wird eingedampft und der Rückstand mit Essigsäureethylester/Diethylether verrieben. Man erhält in 82%iger Ausbeute 2-Acetyl-6-(2,3-Epoxypropoxy)-l,2,3,4-tetrahydro-:so-chinolin, Fp 69-700C (Essigsäureethylester - Diethylether).To a mixture of 28.7 g of 2-acetyl-l, 2,3,4-tetrahydro-6-hydroxy-isoquinoline and 42.5 g of epichlorohydrin are added dropwise at 60 0 C a solution of 6.8 g of sodium hydroxide in 90 ml Water within 1 h. The reaction mixture is kept at this temperature for a further 1 hour, allowed to cool and extracted several times with methylene chloride. The organic phase, dried over sodium sulfate, is evaporated and the residue is triturated with ethyl acetate / diethyl ether. In 82% yield is obtained 2-acetyl-6- (2,3-epoxypropoxy) -l, 2,3,4-tetrahydro-: so-quinoline, mp 69-70 0 C (ethyl acetate - diethyl ether).
b) 24,7 g 2-Acetyl-6-(2,3-epoxy-propoxy)-l,2,3,4-tetrahydro-isochinolin und 59,1 g Isopropylamin werden in 100 ml Isopropanol 5 Stunden unter Rückfluß am Sieden gehalten. Das Lösungsmittel wird entfernt und der Rückstand mit Diethylether verrieben. Man erhält 24,3 g 2-Acetyl-l,2,3,4-tetrahydro-6-(2-hydroxy-3-isopropylamino-propoxy)-isochinolin, Fp 75-76°C (Essigsäureethylester - Diethylether).b) 24.7 g of 2-acetyl-6- (2,3-epoxy-propoxy) -1, 2,3,4-tetrahydro-isoquinoline and 59.1 g of isopropylamine are in 100 ml of isopropanol kept boiling under reflux for 5 hours. The solvent is removed and the Triturated residue with diethyl ether. 24.3 g of 2-acetyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylamino-propoxy) -isoquinoline are obtained, Mp 75-76 ° C (ethyl acetate - diethyl ether).
Das Hydrochloric! (Fp 120- 121°C) wird durch Versetzen einer Lösung der Base in Isopropanol mit ethanolischer Salzsäure und Zusatz von Essigsäureethylester erhalten.The Hydrochloric! (Melting point 120-121 ° C.) is obtained by adding a solution of the base in isopropanol with ethanolic solution Hydrochloric acid and the addition of ethyl acetate are obtained.
a) 46,0 g !^,S^-Tetrahydro-o-hydroxy-isochinolin-hydrobromid werden mit 126 g Acetamid 1 Stunde bei 1400C unter Rühren umgesetzt. Nach Abkühlen auf 1000C gibt man 216 ml Wasser hinzu, wobei 2-Acetyll,2,3,4-tetrahydro-6-hydroxy-7-methoxy-isochinolin auskristallisiert.a) 46.0 g! ^, S ^ -tetrahydro-o-hydroxy-isoquinoline hydrobromide are reacted with 126 g of acetamide 1 hour at 140 0 C with stirring. After cooling to 100 0 C are added 216 ml of water, with 2-Acetyll, crystallized 2,3,4-tetrahydro-6-hydroxy-7-methoxy-isoquinoline.
Hierzu werden 42,5 g Epichlorhydrin gegeben und anschließend bei 6O0C eine Lösung von 6,8 g Natriumhydroxid in 90 ml Wasser innerhalb 1 Stunde zugetropft. Man hält das Reaktionsgemisch noch 1 h bei dieser Temperatur, läßt abkühlen und extrahiert mehrmals mit Methylenchlorid. Die über Natriumsulfat getrocknete organische Phase wird eingedampft und der Rückstand mit Diethylether verrieben. Man erhält 34,8 g 2-Acetyl-6-(2,3-epoxy-propoxy)-l,2,3,4-tetrahydro-7-methoxy-isochinolin, Fp 111-112°C (Essigsäureethylester - Diisopropylether).For this purpose, 42.5 g of epichlorohydrin are added, and then added dropwise at 6O 0 C a solution of 6.8 g of sodium hydroxide in 90 ml of water within 1 hour. The reaction mixture is kept at this temperature for a further 1 hour, allowed to cool and extracted several times with methylene chloride. The organic phase, dried over sodium sulfate, is evaporated and the residue is triturated with diethyl ether. 34.8 g of 2-acetyl-6- (2,3-epoxy-propoxy) -l, 2,3,4-tetrahydro-7-methoxy-isoquinoline, melting point 111-112 ° C. (ethyl acetate - diisopropyl ether) are obtained.
b) Ein Gemisch aus 27,7 g 2-Acetyl-6-(2,3-epoxy-propoxy)-l,2,3,4-tetrahydro-7-methoxy-isochinolin und 59,1 g Isopropylamin wird 72 Stunden unter Rückfluß am Sieden gehalten. Man dampft unter vermindertem Druck zur Trockne ein und verreibt den Rückstand mit warmem Diethylether. Nach Abkühlen und Absaugen erhält man 30,3 g 2-Acetyl-l,2,3,4-tetrahydro-6-(2-hydroxy-3-isopropylamino-propoxy)-7-methoxy-isochinolin, Fp 90-910C (Essigsäureethylester - Diethylether).b) A mixture of 27.7 g of 2-acetyl-6- (2,3-epoxy-propoxy) -1, 2,3,4-tetrahydro-7-methoxy-isoquinoline and 59.1 g of isopropylamine is 72 hours under Reflux kept at the boil. It is evaporated to dryness under reduced pressure and the residue is triturated with warm diethyl ether. After cooling and filtration with suction gives 30.3 g of 2-acetyl-l, 2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylamino-propoxy) -7-methoxy-isoquinoline, mp 90-91 0 C (Ethyl acetate - diethyl ether).
Claims (1)
Isochinolin-Derivate der allgemeinen Formel 1Patent claims:
Isoquinoline derivatives of the general formula 1
Priority Applications (27)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2454198A DE2454198C2 (en) | 1974-11-15 | 1974-11-15 | Isoquinoline derivatives, processes for their preparation and medicines |
| AR261211A AR206061A1 (en) | 1974-11-15 | 1975-01-01 | PROCEDURE FOR THE PRODUCTION OF NEW 2-ALCANOYL (C1-C4) -1, 2, 3, 4-TETRAHYDRO-8-RESPECTIVELY 7-, 6- OR 5- (2-HYDROXY-3-ALKYL (C3-C4) - AMINOPROPOXI) -ISOQUINOLINS OF 2-ALKANOYL (C1-C4) -1, 2, 3, 4-TETRAHYDRO-8-RESPECTIVELY 7- OR 5- (2-HYDROXY-3-ALKYL (C3-C4) -AMINOPROPOXI) -6 -METOXY-ISOKINOLINS AND 2-ALKANOYL (C1-C4) -1, 2, 3, 4-TETRAHYDRO-8-RESPECTIVELY 6- OR 5- (2-HYDROXY-3-ALKYL (C3-C4) -AMINOPROPOXI) - 7-METHOXY-ISOQUINOLINES EVENTUALLY METHYLATED IN POSITION 1 |
| ZA00756776A ZA756776B (en) | 1974-11-15 | 1975-10-28 | Isoquinoline compounds |
| DK485375A DK141964C (en) | 1974-11-15 | 1975-10-28 | METHOD OF ANALOGY FOR THE PREPARATION OF ISOQUINOLINE DERIVATIVES SALTS THEREOF WITH PHYSIOLOGICALLY ACCEPTABLE ACIDS |
| GB4454175A GB1478245A (en) | 1974-11-15 | 1975-10-29 | Isoquinoline compounds a method for their production and pharmaceutical compositions containing such compounds |
| US05/627,291 US4013663A (en) | 1974-11-15 | 1975-10-30 | Isoquinoline compounds |
| IL48393A IL48393A (en) | 1974-11-15 | 1975-10-31 | Substituted (3-amino-2-hydroxy propoxy)1,2,3,4-tetrahydro isoquinolines |
| AU86261/75A AU493975B2 (en) | 1975-11-03 | Isoquinoline compounds | |
| BE161599A BE835267A (en) | 1974-11-15 | 1975-11-05 | NEW DERIVATIVES OF ISOQUINOLEIN, THEIR PREPARATION AND USE |
| IE2447/75A IE42035B1 (en) | 1974-11-15 | 1975-11-10 | Isoquinoline compounds, a method for their production, and pharmaceutical compositions containing such compounds |
| YU2848/75A YU36930B (en) | 1974-11-15 | 1975-11-11 | Process for obtaining new isoquinoline derivatives |
| SU2188555A SU552898A3 (en) | 1974-11-15 | 1975-11-11 | The method of obtaining derivatives of isoquinoline or their salts |
| CS757597A CS188258B2 (en) | 1974-11-15 | 1975-11-11 | Method of producing derivatives of 2-acyl-1,2,3,4-tetrahydro-/2-hydroxy-3-aminopropoxy/isoquinoline |
| DD189422A DD122530A5 (en) | 1974-11-15 | 1975-11-12 | |
| CH1468375A CH596183A5 (en) | 1974-11-15 | 1975-11-12 | |
| LU73806A LU73806A1 (en) | 1974-11-15 | 1975-11-13 | |
| SE7512765A SE407800B (en) | 1974-11-15 | 1975-11-13 | WAY TO PRODUCE ISOKINOLINE DERIVATIVES |
| NLAANVRAGE7513301,A NL181360C (en) | 1974-11-15 | 1975-11-13 | METHOD FOR PREPARING OR MANUFACTURING A PHARMACEUTICAL PREPARATION WITH BETA RECEPTORS LOCKING OPERATION; METHOD FOR PREPARING THE COMPOUNDS |
| NO753832A NO144109C (en) | 1974-11-15 | 1975-11-14 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE ISOQINOLINE DERIVATIVES |
| FI753213A FI59090C (en) | 1974-11-15 | 1975-11-14 | FOERFARANDE FOER FRAMSTAELLNING AV ISOKINOLINDERIVAT ANVAENDBARA SAOSOM BETA-RESEPTORBLOCKERARE |
| HU75KO00002752A HU171604B (en) | 1974-11-15 | 1975-11-14 | Process for preparing new derivatives of isoquinoline |
| AT869575A AT345294B (en) | 1974-11-15 | 1975-11-14 | PROCESS FOR THE PRODUCTION OF NEW ISOCHINOLINE DERIVATIVES AND THEIR SALT |
| ES442612A ES442612A1 (en) | 1974-11-15 | 1975-11-14 | Isoquinoline compounds |
| JP50137694A JPS6026785B2 (en) | 1974-11-15 | 1975-11-14 | Method for producing new iriquinoline derivatives |
| FR7534861A FR2290902A1 (en) | 1974-11-15 | 1975-11-14 | ISOQUINOLEINE DERIVATIVES ACTIVE AGAINST B RECEPTORS |
| GR49369A GR60361B (en) | 1974-11-15 | 1975-11-14 | New isoquinoline derivatives |
| PL1975184714A PL100139B1 (en) | 1974-11-15 | 1975-11-14 | METHOD OF MAKING NEW DERIVATIVES OF ISOCHINOLINE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2454198A DE2454198C2 (en) | 1974-11-15 | 1974-11-15 | Isoquinoline derivatives, processes for their preparation and medicines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE2454198A1 DE2454198A1 (en) | 1976-05-20 |
| DE2454198C2 true DE2454198C2 (en) | 1986-08-07 |
Family
ID=5930904
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2454198A Expired DE2454198C2 (en) | 1974-11-15 | 1974-11-15 | Isoquinoline derivatives, processes for their preparation and medicines |
Country Status (5)
| Country | Link |
|---|---|
| BE (1) | BE835267A (en) |
| CS (1) | CS188258B2 (en) |
| DE (1) | DE2454198C2 (en) |
| GB (1) | GB1478245A (en) |
| ZA (1) | ZA756776B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH495983A (en) * | 1968-02-09 | 1970-09-15 | Sandoz Ag | Process for the preparation of levorotatory 4- (2-hydroxy-3-isopropylaminopropoxy) indole |
-
1974
- 1974-11-15 DE DE2454198A patent/DE2454198C2/en not_active Expired
-
1975
- 1975-10-28 ZA ZA00756776A patent/ZA756776B/en unknown
- 1975-10-29 GB GB4454175A patent/GB1478245A/en not_active Expired
- 1975-11-05 BE BE161599A patent/BE835267A/en not_active IP Right Cessation
- 1975-11-11 CS CS757597A patent/CS188258B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS188258B2 (en) | 1979-02-28 |
| GB1478245A (en) | 1977-06-29 |
| DE2454198A1 (en) | 1976-05-20 |
| BE835267A (en) | 1976-05-05 |
| ZA756776B (en) | 1976-10-27 |
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