DE2620179A1 - Beta:adrenergic-blocking, amino-hydroxy-propoxy isoquinoline derivs. - prepd. by reacting epoxy-propoxy-(2)-acyl-isoquinolines with amines - Google Patents
Beta:adrenergic-blocking, amino-hydroxy-propoxy isoquinoline derivs. - prepd. by reacting epoxy-propoxy-(2)-acyl-isoquinolines with aminesInfo
- Publication number
- DE2620179A1 DE2620179A1 DE19762620179 DE2620179A DE2620179A1 DE 2620179 A1 DE2620179 A1 DE 2620179A1 DE 19762620179 DE19762620179 DE 19762620179 DE 2620179 A DE2620179 A DE 2620179A DE 2620179 A1 DE2620179 A1 DE 2620179A1
- Authority
- DE
- Germany
- Prior art keywords
- isoquinoline
- tetrahydro
- hydroxy
- propoxy
- methoxy
- 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.)
- Withdrawn
Links
- 150000001412 amines Chemical class 0.000 title claims description 3
- ZXANWDLSOHPBQA-UHFFFAOYSA-N 4-amino-1-propoxy-2H-isoquinolin-3-one Chemical compound NC1=C(N=C(C2=CC=CC=C12)OCCC)O ZXANWDLSOHPBQA-UHFFFAOYSA-N 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 4
- -1 alkyl radical Chemical class 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 150000007513 acids Chemical class 0.000 claims description 7
- 150000002537 isoquinolines Chemical class 0.000 claims description 5
- WPWHSFAFEBZWBB-UHFFFAOYSA-N 1-butyl radical Chemical group [CH2]CCC WPWHSFAFEBZWBB-UHFFFAOYSA-N 0.000 claims description 3
- KFDZREAPSAUXNE-UHFFFAOYSA-N 6-[2-hydroxy-3-(propan-2-ylamino)propoxy]-3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound C1N(C=O)CCC2=CC(OCC(O)CNC(C)C)=CC=C21 KFDZREAPSAUXNE-UHFFFAOYSA-N 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- NAXTXOKAQGHJFA-UHFFFAOYSA-N 1-[5-[3-(tert-butylamino)-2-hydroxypropoxy]-3,4-dihydro-1h-isoquinolin-2-yl]ethanone Chemical compound C1=CC=C(OCC(O)CNC(C)(C)C)C2=C1CN(C(=O)C)CC2 NAXTXOKAQGHJFA-UHFFFAOYSA-N 0.000 claims description 2
- RTCHUYAJCIJOIH-UHFFFAOYSA-N 1-[5-[3-(tert-butylamino)-2-hydroxypropoxy]-6-methoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethanone Chemical compound C1N(C(C)=O)CCC2=C(OCC(O)CNC(C)(C)C)C(OC)=CC=C21 RTCHUYAJCIJOIH-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- DYJWGBLOWUSKCN-UHFFFAOYSA-N 1-[6-[2-hydroxy-3-(propan-2-ylamino)propoxy]-7-methoxy-3,4-dihydro-1h-isoquinolin-2-yl]propan-1-one Chemical compound CC(C)NCC(O)COC1=C(OC)C=C2CN(C(=O)CC)CCC2=C1 DYJWGBLOWUSKCN-UHFFFAOYSA-N 0.000 claims description 2
- LCSJKMNBFMONQB-UHFFFAOYSA-N 1-[6-[3-(tert-butylamino)-2-hydroxypropoxy]-3,4-dihydro-1h-isoquinolin-2-yl]ethanone Chemical compound CC(C)(C)NCC(O)COC1=CC=C2CN(C(=O)C)CCC2=C1 LCSJKMNBFMONQB-UHFFFAOYSA-N 0.000 claims description 2
- DMGALLXUWXRUOM-UHFFFAOYSA-N 1-[8-[3-(tert-butylamino)-2-hydroxypropoxy]-7-methoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethanone Chemical compound C1CN(C(C)=O)CC2=C(OCC(O)CNC(C)(C)C)C(OC)=CC=C21 DMGALLXUWXRUOM-UHFFFAOYSA-N 0.000 claims description 2
- JKEQHZZKYMHIHP-UHFFFAOYSA-N 5-[2-hydroxy-3-(propan-2-ylamino)propoxy]-6-methoxy-3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound C1N(C=O)CCC2=C(OCC(O)CNC(C)C)C(OC)=CC=C21 JKEQHZZKYMHIHP-UHFFFAOYSA-N 0.000 claims description 2
- VNXLVPSZXFPODM-UHFFFAOYSA-N 6-[2-hydroxy-3-(propan-2-ylamino)propoxy]-7-methoxy-1-methyl-3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound CC1N(C=O)CCC2=C1C=C(OC)C(OCC(O)CNC(C)C)=C2 VNXLVPSZXFPODM-UHFFFAOYSA-N 0.000 claims description 2
- AVNBXHHPSLIAFU-UHFFFAOYSA-N 6-[2-hydroxy-3-(propan-2-ylamino)propoxy]-7-methoxy-3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound C1N(C=O)CCC2=C1C=C(OC)C(OCC(O)CNC(C)C)=C2 AVNBXHHPSLIAFU-UHFFFAOYSA-N 0.000 claims description 2
- LFJMSMXUOMXUMK-UHFFFAOYSA-N 6-[3-(tert-butylamino)-2-hydroxypropoxy]-7-methoxy-3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound C1N(C=O)CCC2=C1C=C(OC)C(OCC(O)CNC(C)(C)C)=C2 LFJMSMXUOMXUMK-UHFFFAOYSA-N 0.000 claims description 2
- XIMLCIZPDHAENW-UHFFFAOYSA-N 8-[3-(tert-butylamino)-2-hydroxypropoxy]-7-methoxy-3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound C1CN(C=O)CC2=C(OCC(O)CNC(C)(C)C)C(OC)=CC=C21 XIMLCIZPDHAENW-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- UWIYVDARIRFERZ-UHFFFAOYSA-N 1-[5-[2-hydroxy-3-(propan-2-ylamino)propoxy]-3,4-dihydro-1h-isoquinolin-2-yl]ethanone Chemical compound C1N(C(C)=O)CCC2=C1C=CC=C2OCC(O)CNC(C)C UWIYVDARIRFERZ-UHFFFAOYSA-N 0.000 claims 1
- NMNMMLVRTDWRHH-UHFFFAOYSA-N 1-[6-[2-hydroxy-3-(propan-2-ylamino)propoxy]-1-methyl-3,4-dihydro-1h-isoquinolin-2-yl]ethanone Chemical compound CC1N(C(C)=O)CCC2=CC(OCC(O)CNC(C)C)=CC=C21 NMNMMLVRTDWRHH-UHFFFAOYSA-N 0.000 claims 1
- XQUUMEVHTHUXGO-UHFFFAOYSA-N 1-[6-[3-(tert-butylamino)-2-hydroxypropoxy]-7-methoxy-3,4-dihydro-1h-isoquinolin-2-yl]ethanone Chemical compound C1N(C(C)=O)CCC2=C1C=C(OC)C(OCC(O)CNC(C)(C)C)=C2 XQUUMEVHTHUXGO-UHFFFAOYSA-N 0.000 claims 1
- FRZFHNKLXIMBRF-UHFFFAOYSA-N 5-[3-(tert-butylamino)-2-hydroxypropoxy]-6-methoxy-3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound C1N(C=O)CCC2=C(OCC(O)CNC(C)(C)C)C(OC)=CC=C21 FRZFHNKLXIMBRF-UHFFFAOYSA-N 0.000 claims 1
- CFVQRDGDSMXDOR-UHFFFAOYSA-N 6-[3-(tert-butylamino)-2-hydroxypropoxy]-3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound C1N(C=O)CCC2=CC(OCC(O)CNC(C)(C)C)=CC=C21 CFVQRDGDSMXDOR-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 abstract description 10
- 108010079452 beta Adrenergic Receptors Proteins 0.000 abstract description 10
- 230000000903 blocking effect Effects 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 238000010992 reflux Methods 0.000 abstract description 4
- 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 abstract description 2
- 206010002383 Angina Pectoris Diseases 0.000 abstract description 2
- 206010058177 Hyperkinetic heart syndrome Diseases 0.000 abstract description 2
- 206010020772 Hypertension Diseases 0.000 abstract description 2
- 208000001871 Tachycardia Diseases 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 208000009157 neurocirculatory asthenia Diseases 0.000 abstract description 2
- 230000006794 tachycardia Effects 0.000 abstract description 2
- 230000000213 tachycardiac effect Effects 0.000 abstract description 2
- 230000002792 vascular Effects 0.000 abstract description 2
- 208000019622 heart disease Diseases 0.000 abstract 2
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 230000000747 cardiac effect Effects 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 208000035475 disorder Diseases 0.000 abstract 1
- 102000005962 receptors Human genes 0.000 abstract 1
- 108020003175 receptors Proteins 0.000 abstract 1
- 230000033764 rhythmic process Effects 0.000 abstract 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 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 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
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- HBFXVTVOSLPOEY-UHFFFAOYSA-N ethoxyethane;2-propan-2-yloxypropane Chemical compound CCOCC.CC(C)OC(C)C HBFXVTVOSLPOEY-UHFFFAOYSA-N 0.000 description 1
- YKWNUSJLICDQEO-UHFFFAOYSA-N ethoxyethane;propan-2-ol Chemical compound CC(C)O.CCOCC YKWNUSJLICDQEO-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011835 investigation Methods 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
- 239000008101 lactose Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
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- 210000000056 organ Anatomy 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- DURULFYMVIFBIR-UHFFFAOYSA-N practolol Chemical compound CC(C)NCC(O)COC1=CC=C(NC(C)=O)C=C1 DURULFYMVIFBIR-UHFFFAOYSA-N 0.000 description 1
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- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- GMJHUSJLZXFFQJ-UHFFFAOYSA-N soquinolol Chemical compound C1N(C=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C GMJHUSJLZXFFQJ-UHFFFAOYSA-N 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
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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)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
eue Isochinolin-Derivate new isoquinoline derivatives
Es sind eine Reihe von Substanzen bekannt, die ß-Rezeptoren blockierend wirken, d.h. Substanzen, die ß-Rezeptoren besetzen, ohne diese zu erregen. Diese Verbindungen haben aber der, Nachteil, dass die ß-blockierende Wirksamkeit entweder nicht spezifisch ein Organ betrifft oder dass ihre Verträglichkeit nicht optimal ist bzw. dass der Abstand zwischen therapeutisch wirksamer Dosis und toxischer Dosis (therapeutischer Index) nicht sehr gross ist (vgl. Forth, Henschler, Rummel: Pharmakologie und Toxikologie, Wissenschaftsverlag Mannheim 1975, 5. 122 - 125).A number of substances are known that block the ß-receptors act, i.e. substances that occupy ß-receptors without stimulating them. These Compounds, however, have the disadvantage that the ß-blocking effectiveness either does not specifically affect an organ or that their tolerance is not optimal is or that the distance between the therapeutically effective dose and the toxic dose (therapeutic index) is not very large (cf. Forth, Henschler, Rummel: Pharmakologie and Toxikologie, Wissenschaftsverlag Mannheim 1975, pp. 122-125).
Gegenstand der Erfindung sind neue Isochinolin-Derivate der allgemeinen Formel I in der R1 ein Wasserwstoffatom oder eine Methylgruppe, R2 ein Wasserstoffatom oder einen niederen Alkylrest, R3 ein Wasserstoffatom oder eine Methoxygruppe und R einen Iso-4 propyl- oder tertiären Butylrest bedeuten sowie deren Salze mit physiologisch verträglichen'Säuren.The invention relates to new isoquinoline derivatives of the general formula I in which R1 is a hydrogen atom or a methyl group, R2 is a hydrogen atom or a lower alkyl radical, R3 is a hydrogen atom or a methoxy group and R is an iso-4-propyl or tertiary butyl radical and salts thereof with physiologically compatible acids.
Gegenstand der Erfindung ist weiter ein Verfahren zur Herstellung der Verbindungen der allgemeinen Formel I, welches darin besteht, dass man eine Verbindung der Formel II in der R1, R2 und R3 die oben angegebene Bedeutung haben und R5 die Gruppe oder Hal-Cfl2-CHOH- ist, worin Hal ein Halogenatom bedeutet, mit einem Amin der allgemeinen Formel R4NH2 in der R4 die obengenannte Bedeutung hat, zur Umsetzung bringt und die so erhaltenen Verbindungen gegebenenfalls in ihre Salze mit physiologisch verträglichen Säuren überführt.The invention also relates to a process for the preparation of the compounds of the general formula I, which consists in that a compound of the formula II in which R1, R2 and R3 have the meaning given above and R5 is the group or Hal-Cfl2-CHOH-, in which Hal denotes a halogen atom, reacts with an amine of the general formula R4NH2 in which R4 has the abovementioned meaning and, if appropriate, converts the compounds thus obtained into their salts with physiologically acceptable acids.
Die erfindungsgemässe Reaktion kann in An- oder Abwesenheit eines Lösungsmittels durchgeführt werden. Geeignete Lösungsmittel sind z.B. niedere Alkohole, vorzugsweise Isopropanol.The inventive reaction can in the presence or absence of one Solvent are carried out. Suitable solvents are e.g. lower alcohols, preferably isopropanol.
Die Umsetzung wird vorzugsweise bei der Siedetemperatur des Lösungsmittels durchgeführt; sie gelingt aber auch bei Raumtemperatur.The reaction is preferably carried out at the boiling point of the solvent carried out; but it also works at room temperature.
Die bislang nicht bekannten Epoxy- und Chlorhydrin-Verbindungen, die als Ausgangsmaterial für die Herstellung der neuen Substanzen dienen, lassen sich in bekannter Weise durch Umsetzung der entsprechenden Isochinolin-Derivate mit Epichlorhydrin darstellen.The previously unknown epoxy and chlorohydrin compounds that can serve as the starting material for the production of the new substances in a known manner by reacting the corresponding isoquinoline derivatives with epichlorohydrin represent.
Die neuen Verbindungen können als solche oder in Form ihrer Salze mit physiologisch verträglichen Säuren angewendet werden. Geeignete Säuren sind z.B. Salzsäure, Schwefelsäure, Phosphorsäure, Essigsäure, Malonsäure, Bernsteinsäure, Zitronensäure, Weinsäure, Milchsäure, Diamidosulfonsäure, Schleimsäure, Maleinsäure und Fumarsäure.The new compounds can be used as such or in the form of their salts can be used with physiologically compatible acids. Suitable acids are e.g. hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, malonic acid, succinic acid, Citric acid, tartaric acid, lactic acid, diamidosulfonic acid, mucic acid, maleic acid and fumaric acid.
Die neuen Verbindungen zeichnen sich durch eine hohe ß-Rezeptoren blockierende Wirksamkeit und geringe Toxizität aus.The new compounds are characterized by high ß-receptors blocking effectiveness and low toxicity.
Die ß-Rezeptoren blockierende Wirksamkeit kann an den ß-Rezeptoren des Herzens, des Blutgefäßsystems und des Bronchialsystems nachgewiesen werden. Einige der neuen Verbindungen blockieren besonders die ß-Rezeptoren des Herzens, was sie für den Einsatz gegen funktionelle Herzbeschwerden geeignet erscheinen lässt.The ß-receptor blocking effectiveness can be at the ß-receptors of the heart, the blood vessel system and the bronchial system can be detected. Some of the new compounds block the heart's ß-receptors in particular, which makes them appear suitable for use against functional heart problems.
Die besondere ß-Rezeptoren blockierende Wirksamkeit am Herzen im Vergleich zu der des Gefäß systems wurde durch Aufnahme des EKG bzw. durch Messung des Blutdruckes am Meerschweinchen ermittelt [vgl. J.R.C.Baird und J. Linnell (1972) J. Pharm.The special ß-receptor blocking effectiveness on the heart in comparison that of the vascular system was determined by recording the EKG or by measuring the blood pressure determined on guinea pigs [cf. J.R.C.Baird and J. Linnell (1972) J. Pharm.
Pharmac. 24, 880-885 und H.R. Kaplan, H.R und M.A. Commarato (1973) J. Pharmacol. Exp. Ther. 185, 395-405]. Zur Untersuchung des Effekts gegenüber broncho-dilatierend wirksamen Mitteln wird die Hemmung des Isoprenalin-Effektes am Bronchialsystem des Meerschweinchens herangezogen [vgl. H. Konzept, H.Pharmac. 24, 880-885 and H.R. Kaplan, H.R and M.A. Commarato (1973) J. Pharmacol. Exp. Ther. 185, 395-405]. To investigate the effect on broncho-dilating effective means is the inhibition of the isoprenaline effect on the bronchial system of the Guinea pigs used [cf. H. Concept, H.
und R. Rössler (1940) Arch. exp. Path. Pharmak. 195, 71-743.and R. Rössler (1940) Arch. exp. Path. Pharmac. 195, 71-743.
Für die Untersuchungen wurden folgende Substanzen verwendet: 2-Acetyl-1,2,3,4-tetrahydro-6-(2-hydroxy-3-isopropylamino-pro poxy)-isochinolin (A), 2-Acetyl-l, 2,3, 4-tetrahydro-6-(2-hydroxy 3-isopropylamino-propoxy)-7-methoxy-isochinolin (B), 2-Formyl-1,2,3,4-tetrahydro-5-(2-hydroxy-3-isopropylamino-propoxy)-isochinolin (C), 2-Formyl-1,2,3,4-tetrahydro-5-(2-hydroxy-3-tert.The following substances were used for the investigations: 2-Acetyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylamino-pro poxy) -isoquinoline (A), 2-acetyl-1,2,3,4-tetrahydro-6- (2-hydroxy 3-isopropylamino-propoxy) -7-methoxy-isoquinoline (B), 2-Formyl-1,2,3,4-tetrahydro-5- (2-hydroxy-3-isopropylamino-propoxy) -isoquinoline (C), 2-formyl-1,2,3,4-tetrahydro-5- (2-hydroxy-3-tert.
butylamino-propoxy)-isochinolin (D). Als Vergleichssubstanzen dienten Prindolol (E), Propranolol (F), Practolol (G).butylamino-propoxy) -isoquinoline (D). Served as comparison substances Prindolol (E), Propranolol (F), Practolol (G).
Tabelle 1 gibt die experimentell für A, B und F ermittelten intravenösen Dosen an (Effektivdosis an den ß-Rezeptoren des Herzens, Blutgefoßsystems und Bronchialsystems = ED - Herz, ED -Blutgefäße, ED - Bronchialsystem).Table 1 gives the experimentally determined intravenous for A, B and F. Doses (effective dose at the ß-receptors of the heart, blood vessel system and bronchial system = ED - heart, ED - blood vessels, ED - bronchial system).
Tabelle 1
Tabelle 3 zeigt die überlegene therapeutische Breite der neuen Substanzen gegenüber bekannten ß-Rezeptoren-Blockern. Die Werte in Spalte I entsprechen denen in Tabelle 1 / ED - Herz, jedoch liegen die Werte generell niedriger, weil die Tiere mit Reserpin vorbehandelt wurden. Die Untersuchungen zur Toxizität wurden an Albinomäusen bei intravenöser Applikation durchgeführt. Die erhaltenen Werte sind in Spalte II angegeben.Table 3 shows the superior therapeutic index of the new substances compared to known ß-receptor blockers. The values in column I correspond to those in Table 1 / ED - Heart, however, the values are generally lower because the animals have been pretreated with reserpine. The toxicity studies were carried out on albino mice carried out with intravenous administration. The values obtained are in column II specified.
Tabelle 3
Als Indikationsgebiet der neuen Verbindungen kommen funktionelle Herzbeschwerden wie Tachykardie oder Herzklopfen, tachykarde Herzrhythmusstörungen; Extrasystolie, Angina pectoris, hyperkinetisches Herzsyndrom u.ä. sowie Hypertonie in Frage.Functional heart problems are the indication areas for the new compounds such as tachycardia or palpitations, tachycardiac arrhythmias; Extrasystole, Angina pectoris, hyperkinetic heart syndrome, etc. as well as hypertension in question.
Als Darreichungsformen sind Tabletten, Kapseln und peroral oder parenteral applizierbare Lösungen geeignet. Als Dosis sind bei peroraler Applikation etwa 1 - 200 mg, bei intravenöser Applikation etwa 0,1 - 20 mg pro Mensch und Tag vorgesehen.The dosage forms are tablets, capsules and orally or parenterally applicable solutions suitable. The dose for peroral application is about 1 - 200 mg, for intravenous administration about 0.1 - 20 mg per person and day.
Herstellung der bislang nicht beschriebenen Ausgangsmaterialien.Production of the raw materials not previously described.
A. N-Acyl-isochinolin-Derivate a) 46,0 g 1,2,3, 4-Tetrahydro-6-hydroxy-isochinolin-hydro bromid werden mit 85 ml Formamid 1 Stunde bei 140°C unter Rühren umgesetzt. Nach Abkühlen auf 100°C gibt man 216 ml Wasser hinzu, wobei das Reaktionsprodukt auskristallisiert. Man erhält 34,0 g 2-Formyl-1,2, 3, 4-tetrahydro-6-hydroxy-isochinolin, Fp=l85,5 - 1860C (Äthanol).A. N-Acyl-isoquinoline derivatives a) 46.0 g of 1,2,3,4-tetrahydro-6-hydroxy-isoquinoline-hydro bromide are reacted with 85 ml of formamide for 1 hour at 140 ° C. with stirring. To Cooling to 100 ° C., 216 ml of water are added, the reaction product crystallizing out. 34.0 g of 2-formyl-1,2,3,4-tetrahydro-6-hydroxy-isoquinoline are obtained, mp = 185.5 - 1860C (ethanol).
Analog erhält man: 2-Formyl-1,2,3,4-tetrahydro-6-hydroxy-7-methoxy-isochinolin, Afp=172,5 - 174°C. The following is obtained analogously: 2-formyl-1,2,3,4-tetrahydro-6-hydroxy-7-methoxy-isoquinoline, Afp = 172.5-174 ° C.
b) Ein Gemisch von 57,6 g 1,2,3,4-Tetrahydro-6-hydroxy-isochinolin-hydrobromid, 22,6 g wasserfreies 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 Methylen chlorid. Nach Eindampfen der Alethylenchlorid-Auszüge löst man den Rückstand in verdünnter Natronlaugeaerhitzt 30 Minuten auf dem siedenden Wasserbad und fällt das Reaktionsprodukt durch Einleiten von Kohlendioxid aus. Die abgesaugte Substanz wird aus Äthanol umkristallisiert. Man erhält 43,5 g 2-Acetyl-1,2,3,4-tetrahydro-6-hydroxy-isochinolin, Fp=135 - 13600 (Äthanol - Diisopropyläther). b) A mixture of 57.6 g of 1,2,3,4-tetrahydro-6-hydroxy-isoquinoline hydrobromide, 22.6 g of anhydrous sodium acetate and 76.6 g of acetic anhydride in 300 ml of methylene chloride is kept at the boil for 1 hour under reflux. Add 300 ml of water, the organic phase is separated off and the aqueous phase is extracted again with methylene chloride. After evaporation of the alethylene chloride extracts, the residue is dissolved in Dilute caustic soda is heated on a boiling water bath for 30 minutes and falls the reaction product 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 are obtained, Mp = 135-13600 (ethanol - diisopropyl ether).
Analog erhält man: 2-Acetyl-1,2,3,4-tetrahydro-6-hydroxy-1-methyl-isochinolin, Fp=16l - 16200. The following is obtained analogously: 2-acetyl-1,2,3,4-tetrahydro-6-hydroxy-1-methyl-isoquinoline, Mp = 16l - 16200.
c) Zu einem Gemisch von 86,3 g l,2,3,4-Tetrahydro-6-hydroxy 7-methoxy-isochinolin-hydrochlorid, 138,2 g Kaliumcarbonat, 600 ml Methylenchlorid und 480 ml Wasser tropft man innerhalb einer Stunde 55,5 g Propionylchlorid bei Raumtemperatur zu. Nach 18 Stunden trennt man die organische Phase ab und extrahiert die wässrige Phase noch zweimal mit Methylenchlorid. Die Methylenchloridauszüge werden getrocknet und eingedampft. Man erhält 65,8 g 1,2,3, 4-Tetrahydro-6-hydroxy-7-methoxy-2-propionylisochinolin, Fp=116 - 118°C (Essigsäureäthylester - Diisopropyläther).c) To a mixture of 86.3 g of l, 2,3,4-tetrahydro-6-hydroxy 7-methoxy-isoquinoline hydrochloride, 138.2 g of potassium carbonate, 600 ml of methylene chloride and 480 ml of water are added dropwise within one hour 55.5 g of propionyl chloride at room temperature. Separates after 18 hours the organic phase is removed and the aqueous phase is extracted twice more with methylene chloride. The methylene chloride extracts are dried and evaporated. 65.8 g are obtained 1,2,3,4-Tetrahydro-6-hydroxy-7-methoxy-2-propionylisoquinoline, m.p. 116-118 ° C (ethyl acetate - diisopropyl ether).
d) 122,3 g 5-Benzyloxy-1,2,3,4-tetrahydro-6-methoxy-isochinolin-hydrochlorid, 140 ml Ameisensäure und 700 ml Formamid werden 2, 5 Stunden unter Rückfluss erhitzt. Man giesst dann auf 2 kg Eis und extrahiert mit Methylenchlorid. Nach Eindampfen der Methylenchloridlösung unter vermindertem Druck zur Trockne wird der Rückstand aus Methanol/Wasser umkristallisiert. Man erhält 102,3 g 5-Benzyloxy-2-formyl-l, 2, 3, 4-tetrahydro-6-methoxy-isochinolin, Fp=117,5 - ll8,50C.d) 122.3 g of 5-benzyloxy-1,2,3,4-tetrahydro-6-methoxy-isoquinoline hydrochloride, 140 ml of formic acid and 700 ml of formamide are refluxed for 2.5 hours. It is then poured onto 2 kg of ice and extracted with methylene chloride. After evaporation the methylene chloride solution under reduced pressure to dryness, the residue becomes the end Recrystallized methanol / water. 102.3 g of 5-benzyloxy-2-formyl-1 are obtained, 2,3,4-tetrahydro-6-methoxy-isoquinoline, m.p. 117.5-118.50C.
89,2 g 5-Benzyloxy-2-formyl-l, 2, 3,4-tetrahydro-6-methoxy-isochinolin werden in 450 ml Eisessig gelöst und in Gegenwart von 4,5 g zeiger Palladiumkohle bei Raumtemperatur und Normaldruck hydriert. Nach Beendigung der Wasserstoffaufnahme wird vom Katalysator abgesaugt und unter vermindertem Druck zur Trockne eingedampft. Die Umkristallisation des Rückstandes aus Äthanol ergibt 57,2 g 2-Formyl-1,2,3,4-tetrahydro-5-hydroxy-6-methoxyisochinolin, Fp=172,5 - 173,5°C. 89.2 g of 5-benzyloxy-2-formyl-1,2,3,4-tetrahydro-6-methoxy-isoquinoline are dissolved in 450 ml of glacial acetic acid and in the presence of 4.5 g of pointer palladium carbon hydrogenated at room temperature and normal pressure. After the hydrogen uptake has ceased is filtered off with suction from the catalyst and evaporated to dryness under reduced pressure. Recrystallization of the residue from ethanol gives 57.2 g of 2-formyl-1,2,3,4-tetrahydro-5-hydroxy-6-methoxyisoquinoline, Mp = 172.5-173.5 ° C.
Analog erhält man: 2-Formyl-1,2,3,4-tetrahydro-6-hydroxy-7-methoxy-1-methyl-isochinolin, Fp=175 - 1760C. The following is obtained analogously: 2-formyl-1,2,3,4-tetrahydro-6-hydroxy-7-methoxy-1-methyl-isoquinoline, Mp = 175-1760C.
e) Ein Gemisch aus 122,3 g 5-Benzyloxy-1,2,3,4-tetrahydro-6-methoxy-isochinolin-hydrochlorid, 36,1 g Natriumacetat, 81,7 g Acetanhydrid und 500 ml Methylenchlorid wird 1 Stunde am Sieden gehalten. Nach dem Abkühlen versetzt man mit 500 ml Wasser, trennt die organische Phase ab und dampft unter vermindertem Druck zur Trockne ein. Man erhält 99,5 g 2-Acetyl-5-enzyloxy-1,2,3,4-tetrahydro-6-methoxy-isochinolin, Fp=94 - 950C (Essigsäureäthylester - Diisopropyläther).e) A mixture of 122.3 g of 5-benzyloxy-1,2,3,4-tetrahydro-6-methoxy-isoquinoline hydrochloride, 36.1 g of sodium acetate, 81.7 g of acetic anhydride and 500 ml of methylene chloride are added for 1 hour kept simmering. After cooling, 500 ml of water are added and the organic phase and evaporated to dryness under reduced pressure. You get 99.5 g of 2-acetyl-5-enzyloxy-1,2,3,4-tetrahydro-6-methoxy-isoquinoline, m.p. 94-950C (Ethyl acetate - diisopropyl ether).
Hieraus erhält man analog d) 2-Acetyl-1,2,3,4-tetrahydro-5-hydroxy-6-methoxy-isochinolin, Fp=l86 - 187,5 C. This gives analogously to d) 2-acetyl-1,2,3,4-tetrahydro-5-hydroxy-6-methoxy-isoquinoline, Fp = 186-187.5C.
B. (3-Chlor-2-hydroxy-propoxy)- und (2,3-Epoxy-propoxy)-N-acyl-isochinolin-Derivate a) Zu einem Gemisch aus 26,6 g 2-Formyl-1,2,3,4-tetrahydro-6-hydroxy-isochinolin und 42,5 g Epichlorhydrin tropft man bei 60°C eine Lösung von 6,8 g Natriumhydroxid in 90 ml Wasser innerhalb 1 Stunde zu. Man hält das Reaktionsgemisch noch 1 Stunde bei dieser Temperatur, lässt abkühlen und extrahiert mehrmals mit Methylenchlorid.B. (3-chloro-2-hydroxy-propoxy) - and (2,3-epoxy-propoxy) -N-acyl-isoquinoline derivatives a) To a mixture of 26.6 g of 2-formyl-1,2,3,4-tetrahydro-6-hydroxy-isoquinoline and 42.5 g of epichlorohydrin are added dropwise to a solution of 6.8 g of sodium hydroxide at 60.degree in 90 ml of water within 1 hour. The reaction mixture is kept for a further 1 hour at this temperature, allowed to cool and extracted several times with methylene chloride.
Die über Natriumsulfat getrocknete organische Phase wird eingedampft und der Rückstand mit Diäthyläther verrieben. The organic phase, dried over sodium sulfate, is evaporated and the residue triturated with diethyl ether.
Man erhält 29,0 g 6-(2,3-Epoxy-propoxy)-2-formyl-1,2, 3,4-tetrahydro-isochinolin, Fp=78 - 790C (Essigsäureäthyl ester - Diäthyläther). 29.0 g of 6- (2,3-epoxy-propoxy) -2-formyl-1,2,3,4-tetrahydroisoquinoline are obtained, Mp = 78-790C (ethyl acetate - diethyl ether).
Analog erhält man: 2-Acetyl-6-(2,3-epoxy-propoxy-1,2,3,4-tetrahydro-isochinolin, Fp=69 9 - 70°C (Essigsäureäthylester - Diäthyläther). The following is obtained analogously: 2-acetyl-6- (2,3-epoxy-propoxy-1,2,3,4-tetrahydro-isoquinoline, Mp = 69 9 ° -70 ° C. (ethyl acetate - diethyl ether).
6-(2,3-Epoxy-propoxy)-2-formyl-1,2,3,4-tetrahydro-7-methoxy-isochinolin, Fp=121 - 121,5°C (Essigsäureäthylester). 6- (2,3-epoxy-propoxy) -2-formyl-1,2,3,4-tetrahydro-7-methoxy-isoquinoline, Mp = 121 ° -121.5 ° C. (ethyl acetate).
2-Acetyl-6-(2,3-apoxy-propoxy)-1,2,3,4-tetrahydro-7-methoxy-isochinolin, Fp=lll - 1120C (Essigsäureäthyl ester - Diisopropyläther). 2-acetyl-6- (2,3-apoxy-propoxy) -1,2,3,4-tetrahydro-7-methoxy-isoquinoline, Mp = III - 1120C (ethyl acetate - diisopropyl ether).
6-(2,3-Epoxy-propoxy)-1,2,3,4-tetrahydro-7-methoxy-2-propionyl-isochinolin, Fp.=67 - 680C (Diäthyläther). 6- (2,3-epoxy-propoxy) -1,2,3,4-tetrahydro-7-methoxy-2-propionyl-isoquinoline, M.p. = 67-680C (diethyl ether).
2-Acetyl-6-(2, 3-epox>propoxy)-1, 2,3, 4-tetrahydro-7-methoxy-l-methyl-isochinolin, Fp=1240C (Essigsäureäthylester -Diisopropyläther). 2-acetyl-6- (2, 3-epoxy> propoxy) -1, 2,3, 4-tetrahydro-7-methoxy-1-methyl-isoquinoline, Mp = 1240C (ethyl acetate-diisopropyl ether).
2-Formyl-5-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-6-methoxy-isochinolin, Fp=67 - 680C (Diäthyläther). 2-formyl-5- (2,3-epoxy-propoxy) -1,2,3,4-tetrahydro-6-methoxy-isoquinoline, Mp = 67-680C (diethyl ether).
2-Acetyl-5-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-6-methoxy-isochinolin, Fp=86,5 - 870C (Essigsäureäthylester -Diisopropyläther). 2-acetyl-5- (2,3-epoxy-propoxy) -1,2,3,4-tetrahydro-6-methoxy-isoquinoline, Mp = 86.5-870C (ethyl acetate-diisopropyl ether).
2-Acetyl-6-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-7-methoxy-l-methyl-isochinolin, Fp=119 - 1230C (Essigsäureäthylester - Diisopropyläther). 2-acetyl-6- (2,3-epoxy-propoxy) -1,2,3,4-tetrahydro-7-methoxy-1-methyl-isoquinoline, Mp = 119-1230C (ethyl acetate - diisopropyl ether).
2-Acetyl-7-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-isochinolin, Fp.=80,5 - 820C (Essigsäureäthylester - Diisopropyläther). 2-Acetyl-7- (2,3-epoxy-propoxy) -1,2,3,4-tetrahydro-isoquinoline, m.p. = 80.5 - 820C (ethyl acetate - diisopropyl ether).
b) Ein Gemisch aus 22,1 g 2-Acetyl-1,2,3,4-tetrahydro-6 hydroxy-7-methoxy--isochinolin, 27,8 g Epichlorhydrin und 0,2 ml Piperidin wird 18 Stunden bei 10°C unter Rühren umgesetzt. Nach Eindampfen unter vermindertem Druck zur Trockne wird der Rückstand in 75 ml Chloroform aufgenommen, Chlorwasserstoff eingeleitet und erneut zur Trockne eingedampft. Das erhaltene 2-Acetyl-6-(3-chlor-2-hydroxypropoxy)-1, 2,3, 4-tetrahydro-7-methoxy-isochinolin wird ohne Reinigung weiterverarbeitet.b) A mixture of 22.1 g of 2-acetyl-1,2,3,4-tetrahydro-6 hydroxy-7-methoxy-isoquinoline, 27.8 g of epichlorohydrin and 0.2 ml of piperidine are stirred at 10 ° C. for 18 hours implemented. After evaporation to dryness under reduced pressure, the residue becomes taken up in 75 ml of chloroform, passed in hydrogen chloride and again to dryness evaporated. The obtained 2-acetyl-6- (3-chloro-2-hydroxypropoxy) -1, 2,3,4-tetrahydro-7-methoxy-isoquinoline is processed further without cleaning.
c) Zu einem Gemisch aus 53,2 g 2-Formyl-1,2,3,4-tetrahydro-5-hydroxy-isochinolin und 83,3 g Epichlorhydrin tropft man bei 600C eine Lösung von 13,6 g Natriumhydroxid in 180 ml Wasser innerhalb 1 Stunde zu. Man hält das Reaktionsgemisch noch 1 Stunde bei dieser Temperatur, lässt abkühlen und extrahiert mehrmals mit Methylenchlorid.c) To a mixture of 53.2 g of 2-formyl-1,2,3,4-tetrahydro-5-hydroxy-isoquinoline and 83.3 g of epichlorohydrin are added dropwise to a solution of 13.6 g of sodium hydroxide at 60.degree in 180 ml of water within 1 hour. The reaction mixture is kept for a further 1 hour at this temperature, allowed to cool and extracted several times with methylene chloride.
Die über Natriumsulfat getrocknete organische Phase wird eingedampft und der Rückstand durch Säulen-Chromatographie über feuchtes Kieselgel (11,5 % Wasser) gereinigt. The organic phase, dried over sodium sulfate, is evaporated and the residue by column chromatography over moist silica gel (11.5% water) cleaned.
Durch Eluieren mit einem Gemisch Chloroform-Essigsäureäthylester (30:1) und Eindampfen erhält man 59,7 g 5-(2,3-Epay-propoxy)-2-formyl-1,2,3,4-tetrahyaro-isochinolin als farbloses Ö1. By eluting with a mixture of chloroform and ethyl acetate (30: 1) and evaporation give 59.7 g of 5- (2,3-Epay-propoxy) -2-formyl-1,2,3,4-tetrahyaro-isoquinoline as colorless oil 1.
Analog erhält man: 2-Acetyl-5-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-isochinolin (farbloses Ö1). The following is obtained analogously: 2-acetyl-5- (2,3-epoxy-propoxy) -1,2,3,4-tetrahydroisoquinoline (colorless Ö1).
2-Acetyl-6- (2, 3-epoxy-propoxy) -1,2,3, 4-tetrahydro-1-methyl-isochinolin (farbloses 01). 2-acetyl-6- (2,3-epoxy-propoxy) -1,2,3,4-tetrahydro-1-methyl-isoquinoline (colorless 01).
2-Formyl-6-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-7-methoxy-l-mtthyl-isochinolin, Fp=101 - 102,50C (Essigsäureäthylester - Diäthyläther). 2-formyl-6- (2,3-epoxy-propoxy) -1,2,3,4-tetrahydro-7-methoxy-1-methyl-isoquinoline, Mp = 101-102.50 ° C. (ethyl acetate - diethyl ether).
2-Formyl-8-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-7 methoxy-isochinolin, Fp=73 - 740C (Essigsäureäthylester - Diisopropyläther). 2-formyl-8- (2,3-epoxy-propoxy) -1,2,3,4-tetrahydro-7 methoxy-isoquinoline, Mp = 73-740 ° C. (ethyl acetate - diisopropyl ether).
2-Acetyl-8-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-7 methoxy-isochinolin (farbloses Öl).2-acetyl-8- (2,3-epoxy-propoxy) -1,2,3,4-tetrahydro-7 methoxy-isoquinoline (colorless oil).
Herstellung der Endprodukte Beispiel 1 Ein Gemisch aus 24,7 g 2-Acetyl-6-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-isochinolin und 73,1 g tertiärem Butylamin wird 72 Stunden unter Rückfluss am Sieden gehalten.Preparation of the end products Example 1 A mixture of 24.7 g of 2-acetyl-6- (2,3-epoxy-propoxy) -1,2,3,4-tetrahydro-isoquinoline and 73.1 g of tertiary butylamine is refluxed for 72 hours.
Man dampft unter vermindertem Druck zur Trockne ein und nimmt den Rückstand in Diäthyläther auf. Nach Abkühlen und Absaugen erhält man 25,1 g 2-Acetyl-1,2,3,4-tetrahydro-6-(2-hydroxy-3-tert.butylamino-propoxy)-isochinolin, Fp=74 -750C (Essigsäureäthylester - Diäthyläther).It is evaporated to dryness under reduced pressure and the Residue in diethyl ether. After cooling and suction, 25.1 g of 2-acetyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-tert-butylamino-propoxy) -isoquinoline are obtained, Mp = 74-750C (ethyl acetate - diethyl ether).
Analog erhält man: 2-Acetyl-1, 2, 3, 4-tetrahydro-6- (2-hydroxy-3-tert .butylaminopropoxy)-7-methoxy-isochinolin, Fp=97 - 980C (Essigsäureäthylester - Diisopropyläther), Ausbeute: 85 % der Theorie.The following is obtained analogously: 2-acetyl-1, 2, 3, 4-tetrahydro-6- (2-hydroxy-3-tert .butylaminopropoxy) -7-methoxy-isoquinoline, mp = 97-980C (ethyl acetate - Diisopropyl ether), yield: 85% of theory.
2-Formyl-1,2,3,4-tetrahydro-5-(9-hydroxy-3-tert.butylaminopropoxy)-6-methoxy-isochinolin, Fp=67 - 680C (Diäthyläther-Diisopropyläther), Ausbeute: 85 % der Theorie.2-formyl-1,2,3,4-tetrahydro-5- (9-hydroxy-3-tert-butylaminopropoxy) -6-methoxy-isoquinoline, Mp = 67-680 ° C. (diethyl ether-diisopropyl ether), yield: 85% of theory.
2-Acetyl-1,2,3,4-tetrahydro-5-(2-hydroxy-3-tert.butylaminopropoxy)-6-methoxy-isochinolin, Fp=57 - 580C, Ausbeute: 55 % der Theorie.2-acetyl-1,2,3,4-tetrahydro-5- (2-hydroxy-3-tert-butylaminopropoxy) -6-methoxy-isoquinoline, Mp = 57-580 ° C., yield: 55% of theory.
2-Formyl-1, 2,3, 4-tetrahydro-6-(2-hydroxy-3-tert.butylaminopropoxy)-7-methoxy-l-methyl-isochinolin, Fp=133,5 - 135,50C (Essigsäureäthylester - Diisopropyläther), Ausbeute: 80 % der Theorie.2-formyl-1, 2,3, 4-tetrahydro-6- (2-hydroxy-3-tert-butylaminopropoxy) -7-methoxy-1-methyl-isoquinoline, Mp = 133.5-135.50C (Ethyl acetate - diisopropyl ether), yield: 80% of theory.
2-Acetyl-1,2,3,4-tetrahydro-6-(2-hydroxy-3-tert.butylamino propoxy)-7-methoxy-1-methyl-isochinolin, Fp=77 - 780C (Di äthyläther), Ausbeute: 40 der Theorie.2-acetyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-tert-butylamino propoxy) -7-methoxy-1-methyl-isoquinoline, Mp = 77-780C (diethyl ether), yield: 40% of theory.
2-Acetyl-1,2,3,4-tetrahydro-7-(hydroxy-3-tert.butylamino propoxy)-isochinolin, Fp=88 - 89,5°C (Essigsäureäthylester -Diisopropyläther), Ausbeute: 98 % der Theorie.2-acetyl-1,2,3,4-tetrahydro-7- (hydroxy-3-tert-butylamino propoxy) -isoquinoline, Mp = 88-89.5 ° C (ethyl acetate-diisopropyl ether), yield: 98% of theory.
2-Formyl-1,2,3,4-tetrahydro-6-(2-hydroxy-3-tert.butylamino propoxy)-7-methoxy-isochinolin, Fp.=114,5 - 115,50C (Essigsäureäthylester - Diäthyläther), Ausbeute: 87 % der Theorie.2-formyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-tert-butylamino propoxy) -7-methoxy-isoquinoline, Melting point = 114.5-115.50 ° C. (ethyl acetate - diethyl ether), yield: 87% of theory.
2-Acetyl-1,2,3,4^tetrahydro-6-(2-hydroxy-3-isopropylamino~ propoxy)-7-methoxy-isochinolin, Fp=90 - 910C (Essigsäureäthylester - Diäthyläther), Ausbeute: 90 % der Theorie. Das Mucat dieser Verbindung, welches sich aus Wasser/Aceton umkristallisieren lässt, zersetzt sich bei 179,5- 1800C.2-acetyl-1,2,3,4 ^ tetrahydro-6- (2-hydroxy-3-isopropylamino ~ propoxy) -7-methoxy-isoquinoline, Mp = 90-910C (ethyl acetate - diethyl ether), yield: 90% of theory. The mucate of this compound, which can be recrystallized from water / acetone, decomposes at 179.5-1800C.
1,2,3,4-Tetrahydro-6-(2-hydroxy-3-isopropylamino-propoxy)-7-methoxy-2-propionyl-isochinolin, Fp=8O - 80, 5°C (Essigsäureäthylester - Diäthyläther), Ausbeute. 94 % der Theorie.1,2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylamino-propoxy) -7-methoxy-2-propionyl-isoquinoline, Mp = 80-80.5 ° C. (ethyl acetate - diethyl ether), yield. 94% of theory.
2-Acetyl~1,2,3ß4-tetrahydro-5-(2-hydroxy-3-isopropylaminow propoxy)isocflinolin, Fp=92 - 93°C (Essigsäureäthylester -Diisopropyläther),Ausbeute: 93 % der Theorie.2-acetyl ~ 1,2,3ß4-tetrahydro-5- (2-hydroxy-3-isopropylaminow propoxy) isocflinoline, Mp = 92-93 ° C. (ethyl acetate-diisopropyl ether), yield: 93% of theory.
2-Acetyl-1,2,3,4-tetrahydro-5-(2-hydroxy-3-tert.butylamino propoxy)isochinolin, Fp=99 - 1000C (Essigsäureäthylester -Hexan), Ausbeute: 86 % der Theorie.2-acetyl-1,2,3,4-tetrahydro-5- (2-hydroxy-3-tert-butylamino propoxy) isoquinoline, Mp = 99-1000 ° C. (ethyl acetate-hexane), yield: 86% of theory.
2-Formyl-1,2,3,4-tetrahydro-5-(2-hydroxy-3-isopropylaminopropoxy)-6-methoxy-isochinolin, Fp=92 - 92,50C (Essigsäureäthylester - Diäthyläther), Ausbeute: 93 , der Theorie.2-formyl-1,2,3,4-tetrahydro-5- (2-hydroxy-3-isopropylaminopropoxy) -6-methoxy-isoquinoline, Mp = 92-92.50C (ethyl acetate - diethyl ether), yield: 93, of theory.
2-Acetyl-1,2,3,4-tetrahydro-6-(9-hydroxy-3-isopropylaminonropoxy)-l-methyl-isochinolin, Fp=99 - 1000C (Essigsäureäthylester - Diisopropyläther), Ausbeute: 41 % der Theorie.2-acetyl-1,2,3,4-tetrahydro-6- (9-hydroxy-3-isopropylaminonropoxy) -l-methyl-isoquinoline, Mp = 99-1000 ° C. (ethyl acetate - diisopropyl ether), yield: 41% of theory.
2-Formyl-1,2,3,4-tetrahydro-6-(2-hydroxy-3-isopropylamino propoxy)-7-methoxy-l-methyl-isochinolin, Fp=llO - llloC (Essigsäureäthylester - Hexan), Ausbeute: 64 % der Theorie.2-formyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylamino propoxy) -7-methoxy-1-methyl-isoquinoline, Melting point: 110 - llloC (ethyl acetate - hexane), yield: 64% of theory.
Beispiel 2 Ein Gemisch aus 23,3 g 6-(2, 3-Epoxy-propoxy)-2-formyl-l, 2,3,4-tetrahydro-isochinolin und 73,1 g tertiärem Butylamin wird analog Beispiel 1 umgesetzt. Dabei erhält man die rohe Base als farbloses Öl. Zur Überführung in das neutrale Mucat erhitzt man den Rückstand in der zehnfachen Menge Äthanol mit einem Äquivalent Schleimsäure (10,5 g) 30 Minuten unter Rückfluss. Nach dem Abkühlen erhält man 34,2 g 9-Formyl-1,2,3,4-tetrahydro-6-(2-hydroxy-3-tert .butylamino-propoxy)-isochinolin-mucat, Fp=L73 - 174,50C (wässriges Methanol - Diäthyläther). Example 2 A mixture of 23.3 g of 6- (2,3-epoxy-propoxy) -2-formyl-l, 2,3,4-tetrahydroisoquinoline and 73.1 g of tertiary butylamine are analogous to the example 1 implemented. The crude base is obtained as a colorless oil. For transfer to the neutral mucat is heated the residue in ten times the amount of ethanol one equivalent of mucic acid (10.5 g) under reflux for 30 minutes. After cooling down 34.2 g of 9-formyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-tert-butylamino-propoxy) -isoquinoline-mucate are obtained, Mp = L73-174.50C (aqueous methanol - diethyl ether).
Analog erhält man: 1,2,3, 4-Tetrahydro-6-(2-hydroxy-3-tert.butylamino-propoxy) 7-methoxy-2-propionyl-isochinolin-mucat, Fp=167 - 1680C (Zersetzung) (Wasser - Aceton), Ausbeute: 91 % der Theorie.The following is obtained analogously: 1,2,3,4-tetrahydro-6- (2-hydroxy-3-tert-butylamino-propoxy) 7-methoxy-2-propionyl-isoquinoline-mucate, Mp = 167-1680C (decomposition) (water - acetone), yield: 91% of theory.
2-Formyl-1,2,3,4-tetrahydro-5-(2-hydroxy-3-tert.butylamino propoxy)-isochinolin-mucat, Fp=215 - 216°C (Zersetzung) (Wasser - Aceton), Ausbeute: 93 % der Theorie. Das entsprechende Acetat schmilzt bei 150,5 - l5l,50C (Isopropanol - Diäthyl äther).2-formyl-1,2,3,4-tetrahydro-5- (2-hydroxy-3-tert-butylamino propoxy) isoquinoline mucate, Mp = 215-216 ° C. (decomposition) (water - acetone), yield: 93% of theory. The corresponding Acetate melts at 150.5 - 15 l, 50 ° C (isopropanol - diethyl ether).
2-Formyl-1,2,3,4-tetrahydro-8-(2-hydroxy-3-tert.butylaminopropoxy)-7-methoxy-isochinolin-mucat, Fp=201 - 2020C (Zer setzung) (Wasser - Aceton), Ausbeute: 64 % der Theorie.2-formyl-1,2,3,4-tetrahydro-8- (2-hydroxy-3-tert-butylaminopropoxy) -7-methoxy-isoquinoline mucate, Mp = 201-2020C (decomposition) (water - acetone), yield: 64% of theory.
2-Acetyl-1,2,3,4-tetrahydro-8-(2-hydroxy-3-tert.butylaminopropoxy)-7-methoxy-isochinolin-mucat, Fp=182°C (Zersetung) (wässriges Methanol - Äther), Ausbeute: 43 % der Theorie.2-acetyl-1,2,3,4-tetrahydro-8- (2-hydroxy-3-tert-butylaminopropoxy) -7-methoxy-isoquinoline mucate, Mp = 182 ° C. (decomposition) (aqueous methanol - ether), yield: 43% of theory.
Beispiel 3 23,3 g 6-(2,3-Epoxy-propoxy)-2-formyl-1,2,3,4-tetrahydro isochinolin werden mit 59,1 g Isopropylamin in 100 ml Isopropanol 5 Stunden unter Rückfluss am Sieden gehalten. Es wird eingedampft und der Rückstand mit 150 ml Diäthyläther verrieben. Man erhält 27,5 g 2-Formyl-1,2,3,4-tetrahydro-6-(2-hydroxy-3-isopropylamino-propoxy)-isochinolin, Fp=56,5 -58°C. Example 3 23.3 g of 6- (2,3-epoxy-propoxy) -2-formyl-1,2,3,4-tetrahydro isoquinoline with 59.1 g of isopropylamine in 100 ml of isopropanol for 5 hours Reflux kept at the boil. It is evaporated and the residue with 150 ml of diethyl ether rubbed in. 27.5 g of 2-formyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylamino-propoxy) -isoquinoline are obtained, Mp = 56.5-58 ° C.
Das Hydrochlorid wird durch Versetzen einer Lösung der Base in Isopropanol mit äthanolischer Salzsäure und Zusatz von Essigsäureäthylester erhalten, Fp=147 - 1480C.The hydrochloride is made by adding a solution of the base in isopropanol obtained with ethanolic hydrochloric acid and the addition of ethyl acetate, mp = 147 - 1480C.
Analog erhält man: 2-Acetyl-1,2,3,4-tetrahydro-6-(2-hydroxy-3-isopropylaminopropoxy)-isochinolin, Fp=75 - 760C (Essigsäureäthylester -Diäthyläther), Ausbeute: 79 %der Theorie, Fp (Hydrochlorid) = 120 - 121OC.The following is obtained analogously: 2-acetyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylaminopropoxy) -isoquinoline, Mp = 75-760C (ethyl acetate-diethyl ether), yield: 79% of theory, melting point (Hydrochloride) = 120 - 121OC.
2-Formyl-1,2,3,4-tetrahydro-6-(2-hydroxy-3-isopropylaminopropoxy)-7-methoxy-isochinolin, Fp=100 - 1010C (Essigsäureäthylester - Diisopropyläther), Ausbeute: 97 % der Theorie.2-formyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylaminopropoxy) -7-methoxy-isoquinoline, Mp = 100-1010C (ethyl acetate - diisopropyl ether), yield: 97% of theory.
2-Acetyl-1,2,3,4-tetrahydro-6-(2-hydroxy-3-isopropylaminopropoxy)-7-methoxy-l-methyl-isochinolin, Fp=123,5 - 124,50C (Essigsäureäthylester - Diisopropyläther), Ausbeute: 89 % der Theorie.2-acetyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylaminopropoxy) -7-methoxy-1-methyl-isoquinoline, Mp = 123.5-124.50C (ethyl acetate - diisopropyl ether), yield: 89% of the Theory.
2-Formyl-1,2,3,4-tetrahydro-5-(2-hydroxy-3-isopropylaminopropoxy)-isochinolin, Fp=50 - 510C (Diäthyläther), Ausbeute: 77 % der Theorie. Fp (Mucat)=104 - 1050C (Methanol - Diäthyläther).2-formyl-1,2,3,4-tetrahydro-5- (2-hydroxy-3-isopropylaminopropoxy) isoquinoline, Mp = 50-510 ° C. (diethyl ether), yield: 77% of theory. M.p. (Mucat) = 104-1050C (Methanol - diethyl ether).
Beispiel 4 Das gemäss Bb erhaltene Produkt wird mit 59,1 g Isopropylamin und 100 ml Methanol 10 Stunden im Autoklaven auf 1000C erhitzt. Nach Eindampfen unter vermindertem Druck zur Trockne wird der Rückstand mit Diäthyläther verrieben. Nach Umkristallisieren des Rohproduktes aus Essigsäureäthylester-Diäthyläther erhält man 8,9 g 2-Acetyl-1,2,3,4-tetrahydro-6-(2-hydroxy-3-isopropylamino-propoxy)-7-methoxy-isochinolin, Fp=S9 - 90 C. Example 4 The product obtained according to Bb is mixed with 59.1 g of isopropylamine and 100 ml of methanol heated to 1000C in an autoclave for 10 hours. After evaporation the residue is triturated with diethyl ether under reduced pressure to dryness. After recrystallization of the crude product from ethyl acetate-diethyl ether is obtained 8.9 g of 2-acetyl-1,2,3,4-tetrahydro-6- (2-hydroxy-3-isopropylamino-propoxy) -7-methoxy-isoquinoline, Fp = S9 - 90 C.
Beispiel 5 Auf einer Tablettenpresse werden in üblicher Weise Tabletten folgender Zusammensetzung gepresst: 20,00 mg 2-Acetyl-l, 2, 3,4-tetrahydro-6-(2-hydroxy-3-isopropylamino-propoxy) -isochinolin 100,00 mg Maisstärke 9,00 mg Gelatine 30,00 mg Milchzucker 15,00 mg Talk 1,50 mg Aerosil R (chemisch reine Kieselsäure in submikroskopisch feiner Verteilung) 4,50 mg Kartoffelstärke (als 6%iger Kleister) Beispiel 6 In üblicher Weise werden Dragees folgender Zusammensetzung hergestellt: 2,00 mg 2-Formyl-1,2,3,4-tetrahydro-5-(2-hydroxy-3-isopropyl amino-propoxy) -iso chinolin 50,00 mg Kernmasse. Example 5 Tablets are made in the usual way in a tablet press the following composition pressed: 20.00 mg 2-acetyl-l, 2, 3,4-tetrahydro-6- (2-hydroxy-3-isopropylamino-propoxy) -isoquinoline 100.00 mg corn starch 9.00 mg gelatin 30.00 mg lactose 15.00 mg Talc 1.50 mg Aerosil R (chemically pure silica in submicroscopic fine distribution) 4.50 mg potato starch (as 6% paste) Example 6 In the usual way Dragees produced with the following composition: 2.00 mg of 2-formyl-1,2,3,4-tetrahydro-5- (2-hydroxy-3-isopropyl amino-propoxy) -iso quinoline 50.00 mg core mass.
40,00 mg Verzuckerungsmasse Die Kernmasse besteht aus 9 Teilen Maisstärke, 3 Teilen Milchzucker und 1 teil luviskol R VA 64 (Vinylpyrrolidon - Vinylacetat-Mischpolymerisat 60 : 40, vgl. Pharm. Ind. 1962, 586).40.00 mg saccharification mass The core mass consists of 9 parts of corn starch, 3 parts milk sugar and 1 part luviskol R VA 64 (vinylpyrrolidone - vinyl acetate copolymer 60: 40, see Pharm. Ind. 1962, 586).
Die Verzuckerungsmasse besteht aus 5 Teilen Rohrzucker, 2 Teilen Maisstärke, 2 Teilen Calciumcarbonat und 1 Teil Talk.The saccharification mass consists of 5 parts cane sugar, 2 parts Corn starch, 2 parts calcium carbonate and 1 part talc.
Die so hergestellten Dragees erden anschliessend mit einem magensaftresistenten Überzug versehen.The coated tablets produced in this way are then grounded with an enteric Cover provided.
Beispiel 7 5,0 g 2-Acetyl-1, 2, 3, 4-tetrahydro-6- (2-hydroxy-3-isopropyl tamino-propoxy)-7-methoxy-isochinolin werden in 2,0 1 Wasser gelöst. Die Lösung wird mit Salzsäure auf pH 7,0 gebracht, mit Kochsalz isotonisch eingestellt und in 2 ml fassende Ampullen steril abgefüllt. Example 7 5.0 g of 2-acetyl-1, 2, 3, 4-tetrahydro-6- (2-hydroxy-3-isopropyl tamino-propoxy) -7-methoxy-isoquinoline are dissolved in 2.0 l of water. The solution is brought to pH 7.0 with hydrochloric acid, adjusted to isotonic with sodium chloride and sterile filled into 2 ml ampoules.
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK485375A DK141964C (en) | 1974-11-15 | 1975-10-28 | METHOD OF ANALOGY FOR THE PREPARATION OF ISOQUINOLINE DERIVATIVES SALTS THEREOF WITH PHYSIOLOGICALLY ACCEPTABLE ACIDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2620179A1 true DE2620179A1 (en) | 1977-05-12 |
Family
ID=8137243
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19762620179 Withdrawn DE2620179A1 (en) | 1975-10-28 | 1976-05-07 | Beta:adrenergic-blocking, amino-hydroxy-propoxy isoquinoline derivs. - prepd. by reacting epoxy-propoxy-(2)-acyl-isoquinolines with amines |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE2620179A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993024461A1 (en) * | 1992-05-22 | 1993-12-09 | Basf Aktiengesellschaft | Tetrahydro and perhydro isoquinolin derivatives and therapeutic agents containing them |
| JP2007518798A (en) * | 2004-01-22 | 2007-07-12 | レスピラトリウス エービー | Bronchial relaxant compound |
-
1976
- 1976-05-07 DE DE19762620179 patent/DE2620179A1/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993024461A1 (en) * | 1992-05-22 | 1993-12-09 | Basf Aktiengesellschaft | Tetrahydro and perhydro isoquinolin derivatives and therapeutic agents containing them |
| JP2007518798A (en) * | 2004-01-22 | 2007-07-12 | レスピラトリウス エービー | Bronchial relaxant compound |
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