DK141964B - Analogifremgangsmaade til fremstilling af isoquinolinderivater eller salte deraf med fysiologisk acceptable syrer - Google Patents
Analogifremgangsmaade til fremstilling af isoquinolinderivater eller salte deraf med fysiologisk acceptable syrer Download PDFInfo
- Publication number
- DK141964B DK141964B DK485375AA DK485375A DK141964B DK 141964 B DK141964 B DK 141964B DK 485375A A DK485375A A DK 485375AA DK 485375 A DK485375 A DK 485375A DK 141964 B DK141964 B DK 141964B
- Authority
- DK
- Denmark
- Prior art keywords
- isoquinoline
- tetrahydro
- propoxy
- hydroxy
- diethyl ether
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 6
- 238000000034 method Methods 0.000 title claims description 5
- 239000002253 acid Substances 0.000 title description 8
- 150000007513 acids Chemical class 0.000 title description 5
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical class C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 title description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Natural products CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- -1 2-hydroxy-3-isopropylamino-propoxy Chemical group 0.000 claims description 8
- 238000001704 evaporation Methods 0.000 claims description 4
- 230000008020 evaporation Effects 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 150000002537 isoquinolines Chemical class 0.000 claims description 3
- 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- AJLVCVJPQIDMLV-UHFFFAOYSA-N 5-[2-hydroxy-3-(propan-2-ylamino)propoxy]-3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound C1N(C=O)CCC2=C1C=CC=C2OCC(O)CNC(C)C AJLVCVJPQIDMLV-UHFFFAOYSA-N 0.000 claims 1
- 239000012043 crude product Substances 0.000 claims 1
- 239000000047 product Substances 0.000 claims 1
- 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 claims 1
- 238000001953 recrystallisation Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000126 substance Substances 0.000 description 8
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 7
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 7
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 210000004204 blood vessel Anatomy 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- FHKXBLWFZZQMER-UHFFFAOYSA-N 6-(oxiran-2-ylmethoxy)-3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound C=1C=C2CN(C=O)CCC2=CC=1OCC1CO1 FHKXBLWFZZQMER-UHFFFAOYSA-N 0.000 description 3
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- 239000007795 chemical reaction product Substances 0.000 description 3
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- 239000012230 colorless oil Substances 0.000 description 3
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- 241000700199 Cavia porcellus Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
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- 238000004519 manufacturing process Methods 0.000 description 2
- DURULFYMVIFBIR-UHFFFAOYSA-N practolol Chemical compound CC(C)NCC(O)COC1=CC=C(NC(C)=O)C=C1 DURULFYMVIFBIR-UHFFFAOYSA-N 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 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
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- USVPGYXADKFDAI-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinolin-6-ol;hydrobromide Chemical compound Br.C1NCCC2=CC(O)=CC=C21 USVPGYXADKFDAI-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
- HJGVZPVRLJMHLZ-UHFFFAOYSA-N 1-[5-(oxiran-2-ylmethoxy)-3,4-dihydro-1h-isoquinolin-2-yl]ethanone Chemical compound C1N(C(=O)C)CCC2=C1C=CC=C2OCC1CO1 HJGVZPVRLJMHLZ-UHFFFAOYSA-N 0.000 description 1
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- 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
- REHVPMWAQZHMID-UHFFFAOYSA-N 5-hydroxy-3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound C1N(C=O)CCC2=C1C=CC=C2O REHVPMWAQZHMID-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- VHKOSSFXJPIOLB-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound C1N(C=O)CCC2=CC(O)=CC=C21 VHKOSSFXJPIOLB-UHFFFAOYSA-N 0.000 description 1
- AXWNTORKYNWNRD-UHFFFAOYSA-N 7-methoxy-6-(oxiran-2-ylmethoxy)-3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound COC1=CC=2CN(C=O)CCC=2C=C1OCC1CO1 AXWNTORKYNWNRD-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
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- 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
- 239000004593 Epoxy Substances 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
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- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 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
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- 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
- 230000003213 activating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
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- 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
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 1
- 150000003945 chlorohydrins Chemical class 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000010828 elution Methods 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
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 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
- 125000005843 halogen group Chemical group 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
- 229960001317 isoprenaline Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 231100000053 low toxicity 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
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 208000009157 neurocirculatory asthenia Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229960001749 practolol Drugs 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 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
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
OD FREMLÆGGELSESSKRIFT 1^1964 (tt
\RE
DANMARK <5” lntc|i c 07 D 217/06 §(21) Ansøgning nr. 4853/75 (22) Indleveret den 28· okt · 1975 (23) Løbedeg 28. Okt. 1975 (44) Ansøgningen fremlagt og mOn
fremlæggelsesskriftet offentliggjort den 2o· JU-L. 1 9oU
DIREKTORATET FOR .
PATENT-OG VAREMÆRKEVÆSENET (3°) Prioritet begeeret fra den
15- nov. 1974, 2454198, BE 30. apr. 1975e 2519163* BE
(7i) KNOLL AG, Ludwigshafen am Rhein, Postfach 2.t0805, BE.
(72) Opfinder: Albert Westermann, Mohnstr. 46, 67 Ludwigshafen/Rhein, DE:
Prank Zimmermann, Am Wieebrunnen 25* 6730 Neuetadt-Haardt, DE: Dirk Wuppermann, Hinter den Ruestern 28, 6713 Freinsheim* DE: Ludwig Fried*» rich, Nib elungens tr. 8a, 6831 Bruehl, BE: Manfred Raschack, Donners— bergstr. 7, 6714 Weisenheim am Sand, DE.
(74) Fuldmægtig under sagens behandling:
Dansk Patent Kontor ApS. _ (54) Analogifremgangsmåde til fremstilling af isoquinolinderivater eller salte deraf med fysiologisk acceptable syrer.
Der kendes en række stoffer, der virker blokerende på β-receptorer, dvs. stoffer, som bindes til g-receptorer uden at aktivere disse. Disse forbindelser har imidlertid den ulempe, at den g-blokerende virkning enten ikke specifikt vedrører et organ, eller at deres tålelighed ikke er optimal, eller at afstanden mellem terapeutisk virksom dosis og toksisk dosis (terapeutisk indeks) ikke er særlig stor.
Opfindelsen angår en analogifremgangsmåde til fremstilling af hidtil ukendte i s o quino1in-derivater med den almene formel 141964 2 e4hh-cho-gh-cho-0 .
2 i 2 ^ν\ OH lip L ji h-o-e^ (i) R 0 p 7 hvori E er et hydro genatom eller en methylgruppe, R et hydrogen- ζμ atom eller en methoxy gruppe og E en isopropyl- eller tertiær but-ylgruppe, eller deres salte med fysiologisk acceptable syrer.
Denne fremgangsmåde til fremstilling af forbindelserne med den almene formel X er ejendommelig ved, at man bringer en forbindelse med formlen e3aJUi -e£ (ii) E o 2 3 5 hvori E og E har den ovenfor angivne betydning, og Rr er gruppen CB^ - CH- eller Hal-CH^-CHOH-, hvori Hal er et halogenatom, til ^cr 4 4 omsætning med en amin med den almene formel E HH,-,} hvori E har den ovennævnte betydning, og eventuelt overfører den således opnåede forbindelse til et salt med en fysiologisk acceptabel syre.
Den nævnte reaktion kan gennemføres i nær- eller fraværelse af et opløsningsmiddel. Egnede opløsningsmidler er f.eks. lavere alkoholer, fortrinsvis isopropanol.
Omsætningen gennemføres fortrinsvis ved kogetemperatur for opløsningsmidlet; den lykkes imidlertid også ved stuetemperatur.
De hidtil ukendte epoxy- og chlorhydrinforbindelser, der tjener som udgangsmaterialer til fremstillingen af de omhandlede forbindelser, kan fremstilles på kendt måde ved omsætning af de tilsvarende iso-quinolin-derivater med epichlorhydrin.
De omhandlede forbindelser kan anvendes som sådanne eller i form af deres salte med fysiologisk acceptable syrer. Egnede syrer er f.eks. saltsyre, svovlsyre, phosphorsyre, eddikesyre, malonsyre, ravsyre, citronsyre, vinsyre, mælkesyre, diamidosulfonsyre, slimsyre og malein-syre.
3 141964
De omhandlede forbindelser udmærker sig ved en høg β-receptor-hloke-rende virkning og ringe toksicitet. Den β-receptor-blokerende virkning kan påvises på hjertets,blodkarsystemets og bronchialsystemets β-receptorer. Kogle af forbindelserne blokerer især hjertets β-recep-torer, hvad der antagelig vil gøre dem egnet til anvendelse mod funktionelle hjertelidelser.
Den særlige β-receptor-blokerende virkning på hjertet i sammenligning med virkningen på karsystemet er blevet bestemt ved optagelse af EKG henholdsvis ved måling af blodtrykket hos marsvin (jfr. J.R.C. Baird og J. Linnell (1972), J.Pharm.Pharmac. 24, 880-885,og H.R. Kaplan, H.R. og M.A. Commarato (1973)? Pharmacol.EDcp.Ther. 185, 395-4-05).
Til undersøgelse af effekten overfor broncho-dilaterende virkende midler anvendes hæmningen af isoprenalin-effekten på marsvins bronchi-alsystem (jfr. H. Konzett, Ξ. og R. Bossier, (194-0) Arch.e:xp..Path. Pharmak. 1££, 71-74).
Til undersøgelserne blev følgende stoffer anvendt: 2-Acetyl-l ,2,3,4-tetrahydro-6- (2-hydroDcy-3-isopropylamino-propoDty)-isoquinolin (A.), 2-acetyl-l, 2,3,4-tetrahydro-6-(2-hydroDcy-3-isopropyl-amino-propoDcy)-7-methoD^-isoquinolin (B) , 2-formyl-1,2,3,4-tetrahydro- 5-(2-hydroDq7-3-isopropylamino-propoDcy)-isoquinolin (C), 2-formyl-1,2,3, 4-tetrahydro-5-(2-hydroDcy-3-tert.butylamino-propoxy)-isoquinol±n (D).
2-f ormyl-1,2,3,4-tetrahydro-6-( 2-hydroDq7-3-isopropylamino-propoDcy )-isoquinolin (E), 2-formyl-l,2,3,4-tetΓahydΓO-6-(2-hydΓo:xy-3-isopro-pylamlno-propo:xy )-7-metho:xy-isoquinolin (P), 2-acetyl-l,2,3,4—tetra-hydro-6- (2-hydroDcy-3-tert. butylamino-propoxy )-7-methoxy-isoquinolin (G), 2-formyl-l,2,3,4—tetrahydro-6-(2-hydroxy-3-tert.butylamino-pro-poDq7)-7-methoDq7-isoquinolin (H).
Som sammenligningsstoffer anvendtes prindolol (e), propanolol (f)og practolol (g).
Tabel 1 angiver de eksperimentelt for A, B, E-H og f bestemte intravenøse doser (effektivdosis på hjertets, blodkarsystemets og bronchialsystemets β-receptorer = ED - hjerte, ED - blodkar, ED - bronchialsystem).
141964 4
Tabel 1 ~ΡΓΠ—Ττρπτιρ.Ττι —
Stof ED-hJerte ED-blodkar a! system A 13 mg/kg 80 mg/kg 71 mg/kg B 5,5 " 10 " >40 " E 6,6 " 6,5 " P 2,4 " 2,8 " G- 7,6 " 5,8 " H 1,5 n 2,9 " f 1,2 " 1,2 " 0,18 "
Deraf fremkommer for disse stoffer følgende virkningsforbold:
Jabel 2
Stof Hjerte : blodkar Hjerte : bronchialsystem Å 1 : 6,2 1 : 5,5 B 1 : 1,8 1 : >7,2 E 1:1 E 1 : 1,2 S’ 1 : 0,8 H 1 : 1,9 f 1:1 1 : 0,15
Det ses, at kvotienterne f or Α,Β ,E,P, G og H er -væsentligt gunstigere end kvotienterne for sammenligningsforbindelsen. Dette gælder især for forholdet mellem hjerte- og bronchialvirksom dosis, d.v.s. anvendelsen af hjerte virksomme doser fører ikke til en negativ påvirkning af bronchi-alsystemet.
Tabel 3 viser den overlegne terapeutiske bredde af de omhandlede stoffer i forhold til kendte β -receptor-blokerende midler. Værdierne i spalte I svarer til dem i tabel 1/ED-hJerte, dog ligger værdierne generelt lavere, fordi dyrene var forbehandlet med reserpin. Undersøgelserne af toksiciteten blev gennemført på albinomus ved intravenøs indgift. De opnåede værdier er angivet i spalte II.
141964 5
Tabel 5 ' —γ-
Stof ED - hjerte ID^0 C 0,18 mg/kg 148 mg/kg D 0,041 " 128 " e 0,071 " 22,6. " f 0,33 " 24,4 " g__4,37__121
Tabel 3 viser, at C og D ved høj virkning kun er lidt toksiske, d.v.s. bar i forhold til sammenligningsforbindelserne e, f og g en væsentligt gunstigere terapeutisk bredde. Denne ligger for de omhandlede forbindelser i størrelsesordenen på ca. 800 til over 3000, for sammen-ligningsforbindelserne derimod på ca. 30 til noget over 300.
Som indikationsområde for de omhandlede forbindelser kommer på tale funktionelle hjertelidelser, såsom tachykardi eller hjertebanken, ta-chykarde hjerterytmeforstyrrelser, extrasystolie, angina pectoris, hyperkinetisk hjertesyndrom samt hypertoni.
Som indgiftsformer egner sig tabletter, kapsler og peroralt eller parenteralt indgivelige opløsninger. Som dosis anvendes ved peroral indgift ca. 1-200 mg, ved intravenøs indgift ca. 0,1-20 mg pr. menneske og dag.
Fremstilling af hidtil ikke beskrevne udgangsmaterialer.
A. K-Acyl-isoquinolin-derivater a) 46,0 g l,2,3?4-tetrahydro-6-hydroxy-isoquinolin-hydrobromid omsættes med 85 ml formamid i 1 time ved 140°C under omrøring. Efter afkøling til 100°C tilsættes 216 ml vand, hvorved reaktionsproduktet udkrystalliserer. Man får 34,0 g 2-formyl-l,2,354-tetrahydro-6-hydroxy-isoquinolin, smp. 185,5-186°C (ethanol).
Analogt får man: 2-Eormyl-l ,2,3,4-tetrahydro-6-hydroxy-7-methoxy-isoquinolin, smp. 172,5-174°C.
6 1Λ196Λ b) En blanding af 57,6 g 1,2,3,4-tetrahydro-6-hydroxy-isoquinoiin-hydrobromid, 22,6 g vandfrit natriumacetat og 76,6 g eddike-syreahhydrid i 300 ml methylenchlorid holdes i 1 time under kogning under tilbagesvaling. Han tilsætter 300 ml vand, skiller den organiske fase fra og ekstraherer den vandige fase atter med methylenchlorid. Efter inddampning af methylenchlor-id-udtrækkene opløser man remanensen i fortyndet natriumhydroxidopløsning, omrører i 30 minutter på kogende vandbad og udfælder reaktionsproduktet ved tilledning af carbondioxid.
Det frasugede stof omkrystalliseres af ethanol. Man får 4-3,5 g 2-acetyl-l,2,3,4-tetrahydro-6-hydroxy-isoquinolin, smp. 135“1560C (ethanol - diisopropylether).
B. (3-Chlor-2-hydroxy-propoxy)- og (2,3-epoxy-propoxy)-E-acyl-iso-quino1in-derivater.
a) Til en blanding af 26,6 g 2-formyl-1,2,3,4-tetrahydro-6-hydr-oxy-isoquinolin og 42,5 g epichlorhydrin drypper man ved 60°C en opløsning af 6,8 g natriumhydroxid i 90 ml vand i løbet af en time. Man holder reaktionsblandingen i endnu 1 time ved denne temperatur, lader køle af og ekstraherer flere gange med methylenchlorid. Den over natriumsulfat tørrede organiske fase inddampes, og remanensen rives med diethylether. Man får 29,0 g 6-(2,3-epoxy-propoxy)-2-formyl-1,2,3,4-tetr ahydro-iso-quinolin, smp. 78-79°C (eddikesyreethylester - diethylether).
Analogt får man: 2-Acetyl-6-(2,3-epoxy-propoxy)-1,2,3,4-tetr ahydro-iso quinolin, smp. 69-70°C (eddikesyreethylester - diethylether).
6- (2,3-Epoxy-propoxy)-2-formyl-1,2,3,4-tetrahydro-7-methoxy-isoquinolin, smp. 121-121,5°C (eddikesyreethylester).
2-Acetyl-6-(2,3-epoxy-propoxy)-l,2,3,4-tetrahydro-7-methoxy-isoqainolim, smp. 111-112°C (eddikesyreethylester - diisopropylether) .
b) - En blanding af 22,1 g 2-acetyl-l/2,3,4-tetrahydro-6-hydroxy- 7- methoxy-isoquinolin, 27,8 g epichlorhydrin og 0,2 ml piperi-din omsættes 18 timer ved 100°C under omrøring. Efter inddampning under formindsket tryk til tørhed optages remanensen 7
U196A
i 75 ml chloroform; der tilledes hydrogenchlorid og inddampes på ny til tørhed,Det opnåede 2-acetyl-6-(3-chlor-2-hydroxy-propoxy)-l,2,3,4-tetrahydro-7-methoxy-isoquinolin viderefor-arbejdes uden rensning.
c) Til en blanding af 53»2 g 2-formyl-1,2,3,4-tetrahydro-5-hydr-oxy-isoquinolin og 83,3 g epichlorhydrin drypper man ved 60°0 :en opløsning af 13,6 g natriumhydroxid i 180 ml vand i løbet af 1 time. Man holder reaktionsblandingen i endnu 1 time ved denne temperatur, lader køle af og ekstraherer flere gange med methylenchlorid. Den over natriumsulfat tørrede organiske fase inddampes, og remanensen renses ved søjle-Tsromatografi over fugtig kiselgel (11,5% 'vand). Ved eluering med en blanding chloroform-eddikesyreethylester (30:1) og inddampning får man 59,7 g 5-(2,3-epoxy-propoxy)-2-formyl-l,2,3,-4-tetra-hydro-isoquinolin som en farveløs olie.
Analogt får man: 2-Acety1-5-(2,3-epoxy-propoxy)-l,2,3,4-tetrahydro-isoquinolin (farveløs olie).
Fremstilling af slutprodukter.
Eksempel 1
En blanding af 24,7 g 2-acetyl-6-(2,3-epoxy-propoxy)-l,2,3,4-tetra-hydro-isoquinolin og 73,1 g tertiært butylamin holdes i 72 timer under omrøring ved kogning. Man inddamper under formindsket tryk til tørhed og optager remanensen i diethylether. Efter afkøling og frasugning får mån 25,1 g 2-acetyl-l,2,3,4-tetrahydro-6-(2-hydroxy-3-tert.butylamino-pr opoxy ) - is o quino 1 in, smp. 74-75°C (eddikesyreethylester - diethylether) .
Analogt får man: 2-Acetyl-l,2,3,4-tetrahydro-6-(2-bydroxy-3-tert.butylamino-propoxy)-7-methoxy-isoquinolin, smp. 97-98°C (eddikesyreethylester - diiso-propylether), udbytte: 85% af det teoretiske.
8 uim 2-Eormyl-l ,2,3, 4—tetr ahydro-6- ( 2-hydr oxy-3-tert. butyl amino-pr opoxy) -7-methoxy-isoquio.olin, smp. 114-, 5-115,5°C (eddikesyreethylester - diethyl etber) , udbytte: 87% af det teoretiske.
2-Acetyl-l ,2,3,4-tetrahydro-6-(2-hydroxy-3-isopropylamino-propoxy)-7-methoxy-iso quino1in, smp. 90-91°0 (eddikesyreethylester - diethyl-ether), udbytte: 90% af det teoretiske.
2-Acetyl-l ,2,3,4-tetrahydro-5- (2-hydroxy-3-isopropylamino-pr opoxy )-isoquinolin, smp. 92-93°0 (eddikesyreethylester - diisopropyletber), udbytte: 93% af det teoretiske.
2-Acetyl-l, 2,3,4-t etr ahydro-5- ( 2-hydroxy-3-tert. butyl amiao-pr opoxy) -isoquinolin, smp. 99-100°C (eddikesyreethylester - hexan), udbytte: 86% af det teoretiske.
Eksempel 2
En blanding af 23,3 g 6-(2,3-epoxy-propoxy)-2-formyl-l,2,3,4—tetra-hydro-isoquinolin og 73,1 g tertiært butylamin omsættes analogt med eksempel 1. Derved får man den rå base som en farveløs olie. Til overførelse til det neutrale mucat opvarmer man remanensen i den tidob-belte mængde ethanol med et ækvivalent slimsyre (10,5 g) i 30 minutter under tilbage svaling. Efter afkøling får man 34-,2 g 2-formyl- 1,2,3,4-tetr ahydro-6-(2-hydroxy-3-tert ,butylamino-propoxy)-isoquinolin-mucat, smp. 173-174-,5°0 (vandigt methanol - diethylether).
Analogt får man: 2-Eormyl-l ,2,3,4-tetrahydro-5- ( 2-hydr oxy-3-t er t. butyalmino-pr opoxy)-isoquinolin-mucat, smp. 215-216°C (sønderdeling) (vand - acetone), udbytte: 93% af det teoretiske.
Eksempel 3 23,3 g 6-(2,3-epoxy-propoxy)-2-formyl-1,2,3,4—tetrahydro-isoquinolin holdes med 59,1 g isopropylamin i 100 ml isopropanol i 5 timer under kogning under tilbagesvaling. Der inddampes, og remanensen rives med 150 ml diethylether. Man får 27,5 g 2-formyl-1,2,3,4-tetrahydro-6-(2-hydroxy-3-isopropylamino-propoxy)-isoquinolin, smp. 56,5-58°C.
Claims (2)
- 2-Acetyl-l ,2,3, 4-tetrahydro-6- ( 2-hydrosy-3-isopropylamino-propoxy)-isoqniaolin, smp. 75-76°C (eddikesyreethylester - diethylether), udbytte: 79% af det teoretiske, smp. (hydrochlorid) 120-121°C.2-Formyl-l ,2,3,4-tetrahydro-6- ( 2-hydroxy-3-isopropylamino-propoxy)-7-methoxy-i s o quino1in, smp. 100-101°C (eddikesyreethylester - diiso-propylether), udbytte: 97% af det teoretiske.
- 2-Formyl-l ,2,3,4—tetrahydro-5- ( 2-hydroxy-3-isopropylamino-propoxy) -isoquinolin, smp. 50-51°C (diethylether), udbytte: 77% af det teoretiske, smp. (mucat) 104—105°C (methanol - diethylether). Eksempel 4- Det ifølge Ilb opnåede produkt opvarmes med 59,1 g isopropylamin og 100 ml methanol i 10 timer i autoklav til 100°0. Efter inddampning under formindsket tryk til tørhed rives remanensen med diethylether. Efter omkrystallisation af råproduktet af eddikesyreethylester-diethyl-ether får man 8,9 g 2-acetyl-l,2,3?4—tetΓahydΓo-6-(2-hyciro:5cy-3-iso-pΓopylamino-pΓopo:xy)-7-metho:xy-isoquinol:in, smp. 89-90°C. PATEHIIBÅT. Aualogifremgangsmåde til fremstilling af isoquinolin-derivater med formlen R4KH-CHo-CH-CHo-0-k£ . i ΑΛ 0H lo l Jl F-C-R^ H^w'n 2 7> hvori R er et hydrogenatom eller en methylgruppe, R et liydrogenatom eller en methoxygruppe og R^ en isopropyl- eller tertiær butylgruppe,
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762620179 DE2620179A1 (de) | 1975-10-28 | 1976-05-07 | Neue isochinolin-derivate |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2454198A DE2454198C2 (de) | 1974-11-15 | 1974-11-15 | Isochinolin-Derivate, Verfahren zu ihrer Herstellung und Arzneimittel |
| DE2454198 | 1974-11-15 | ||
| DE2519163 | 1975-04-30 | ||
| DE2519163A DE2519163C2 (de) | 1975-04-30 | 1975-04-30 | 2-Formyl-1,2,3,4-tetrahydro-5-(2-hydroxy-3-tert.butyl-aminopropoxy)-isochinolin, dessen Salze, Verfahren zu deren Herstellung und ihre Verwendung |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK485375A DK485375A (da) | 1976-05-16 |
| DK141964B true DK141964B (da) | 1980-07-28 |
| DK141964C DK141964C (da) | 1980-12-08 |
Family
ID=25767970
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK485375A DK141964C (da) | 1974-11-15 | 1975-10-28 | Analogifremgangsmaade til fremstilling af isoquinolinderivatereller salte deraf med fysiologisk acceptable syrer |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US4013663A (da) |
| JP (1) | JPS6026785B2 (da) |
| AR (1) | AR206061A1 (da) |
| AT (1) | AT345294B (da) |
| CH (1) | CH596183A5 (da) |
| DD (1) | DD122530A5 (da) |
| DK (1) | DK141964C (da) |
| ES (1) | ES442612A1 (da) |
| FI (1) | FI59090C (da) |
| FR (1) | FR2290902A1 (da) |
| GR (1) | GR60361B (da) |
| HU (1) | HU171604B (da) |
| IE (1) | IE42035B1 (da) |
| IL (1) | IL48393A (da) |
| LU (1) | LU73806A1 (da) |
| NL (1) | NL181360C (da) |
| NO (1) | NO144109C (da) |
| PL (1) | PL100139B1 (da) |
| SE (1) | SE407800B (da) |
| SU (1) | SU552898A3 (da) |
| YU (1) | YU36930B (da) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4129565A (en) * | 1975-07-11 | 1978-12-12 | Nisshin Flour Milling Co., Ltd. | Isocarbostyril derivatives |
| GB1504424A (en) * | 1975-08-09 | 1978-03-22 | Beecham Group Ltd | Isoquinoline-derived aminoethers |
| DE3135831A1 (de) * | 1981-09-10 | 1983-04-28 | Hoechst Ag, 6230 Frankfurt | 9,10-substituierte 2-mesitylimino-3-alkyl-3,4,6,7-tetrahydro-2h-pyrimido(6,1-a)isochinolin-4-one, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1058822A (en) * | 1963-07-30 | 1967-02-15 | Ici Ltd | 3-amino-2-hydroxypropoxy heterocyclic derivatives |
| US3910924A (en) * | 1972-04-13 | 1975-10-07 | Otsuka Pharma Co Ltd | 3,4-Dihydrocarbostyril derivatives and a process for preparing the same |
-
1975
- 1975-01-01 AR AR261211A patent/AR206061A1/es active
- 1975-10-28 DK DK485375A patent/DK141964C/da not_active IP Right Cessation
- 1975-10-30 US US05/627,291 patent/US4013663A/en not_active Expired - Lifetime
- 1975-10-31 IL IL48393A patent/IL48393A/xx unknown
- 1975-11-10 IE IE2447/75A patent/IE42035B1/en unknown
- 1975-11-11 SU SU2188555A patent/SU552898A3/ru active
- 1975-11-11 YU YU2848/75A patent/YU36930B/xx unknown
- 1975-11-12 DD DD189422A patent/DD122530A5/xx unknown
- 1975-11-12 CH CH1468375A patent/CH596183A5/xx not_active IP Right Cessation
- 1975-11-13 SE SE7512765A patent/SE407800B/xx not_active IP Right Cessation
- 1975-11-13 NL NLAANVRAGE7513301,A patent/NL181360C/xx not_active IP Right Cessation
- 1975-11-13 LU LU73806A patent/LU73806A1/xx unknown
- 1975-11-14 AT AT869575A patent/AT345294B/de not_active IP Right Cessation
- 1975-11-14 HU HU75KO00002752A patent/HU171604B/hu not_active IP Right Cessation
- 1975-11-14 PL PL1975184714A patent/PL100139B1/pl unknown
- 1975-11-14 ES ES442612A patent/ES442612A1/es not_active Expired
- 1975-11-14 FR FR7534861A patent/FR2290902A1/fr active Granted
- 1975-11-14 GR GR49369A patent/GR60361B/el unknown
- 1975-11-14 JP JP50137694A patent/JPS6026785B2/ja not_active Expired
- 1975-11-14 FI FI753213A patent/FI59090C/fi not_active IP Right Cessation
- 1975-11-14 NO NO753832A patent/NO144109C/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK141964C (da) | 1980-12-08 |
| AU8626175A (en) | 1977-05-12 |
| NO144109C (no) | 1981-06-24 |
| DK485375A (da) | 1976-05-16 |
| JPS5175078A (da) | 1976-06-29 |
| US4013663A (en) | 1977-03-22 |
| HU171604B (hu) | 1978-02-28 |
| LU73806A1 (da) | 1976-06-11 |
| AT345294B (de) | 1978-09-11 |
| GR60361B (en) | 1978-05-19 |
| JPS6026785B2 (ja) | 1985-06-25 |
| FI753213A7 (da) | 1976-05-16 |
| IE42035L (en) | 1976-05-15 |
| NL181360B (nl) | 1987-03-02 |
| YU36930B (en) | 1984-08-31 |
| DD122530A5 (da) | 1976-10-12 |
| ATA869575A (de) | 1978-01-15 |
| FR2290902A1 (fr) | 1976-06-11 |
| ES442612A1 (es) | 1978-03-16 |
| NL181360C (nl) | 1987-08-03 |
| IL48393A (en) | 1979-01-31 |
| CH596183A5 (da) | 1978-03-15 |
| SU552898A3 (ru) | 1977-03-30 |
| IL48393A0 (en) | 1975-12-31 |
| SE407800B (sv) | 1979-04-23 |
| NO144109B (no) | 1981-03-16 |
| NL7513301A (nl) | 1976-05-18 |
| AR206061A1 (es) | 1976-06-23 |
| FI59090B (fi) | 1981-02-27 |
| YU284875A (en) | 1982-06-18 |
| FR2290902B1 (da) | 1978-07-28 |
| PL100139B1 (pl) | 1978-09-30 |
| IE42035B1 (en) | 1980-05-21 |
| SE7512765L (sv) | 1976-05-17 |
| FI59090C (fi) | 1981-06-10 |
| NO753832L (da) | 1976-05-19 |
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| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |