CH424782A - Process for the preparation of tetrahydroisoquinoline derivatives - Google Patents

Process for the preparation of tetrahydroisoquinoline derivatives

Info

Publication number
CH424782A
CH424782A CH987462A CH987462A CH424782A CH 424782 A CH424782 A CH 424782A CH 987462 A CH987462 A CH 987462A CH 987462 A CH987462 A CH 987462A CH 424782 A CH424782 A CH 424782A
Authority
CH
Switzerland
Prior art keywords
sep
acetates
preparation
formula
products
Prior art date
Application number
CH987462A
Other languages
German (de)
Inventor
Zoltan Dipl Ing Chem Meszaros
Szentmiklosi Pet Dipl-Ing-Chem
Czibula Iren
Original Assignee
Chinoin Gyogyszer Es Vegyeszet
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Chinoin Gyogyszer Es Vegyeszet filed Critical Chinoin Gyogyszer Es Vegyeszet
Publication of CH424782A publication Critical patent/CH424782A/en

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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
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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

Description

  

  Verfahren zur Herstellung von     Tetrahydroisochinolinderivaten       Es wurde gefunden, dass Verbindungen der For  mel  
EMI0001.0002     
    (in welchen die Bedeutung von A eine     3,4-Diäthoxy-          benzal-gruppe    ist, während R Wasserstoff, eine Al  kyl-,     Aralkyl-    oder     Arylgruppe    bedeutet)     wertvolle            Eigenschaften    besitzen, die sich von den für ähn  liche Verbindungen     bekannten    Eigenschaften in meh  rerer Hinsicht unterscheiden, und dass diese Verbin  dungen in der Pharmazie verwendet werden können.

    Es ist nämlich bekannt, dass Verbindungen, welche  einen     Isochinolinring    enthalten, allgemein     spasmoly-          tische    Eigenschaften besitzen. Die gemäss der Erfin  dung hergestellten Verbindungen     ( Tetrahydroper-          parinderivate )    weisen zum Teil bedeutend stärkere       spasmolytische    Wirkung auf bzw.     können    sie auf  Grund ihrer     analgetischen,        vasodilatorischen    oder  blutdrucksenkenden Wirkung verwendet werden.  



       Erfindungsgemäss    werden die Verbindungen der       Formel    1 hergestellt, indem man eine Verbindung der  Formel  
EMI0001.0021     
    in Gegenwart eines wasserbindenden Kondensations  mittels bei einer Temperatur unter 100  C in sau  rem Medium einer ringschliessenden Kondensation  unterwirft.  



  Bei der     Durchführung    des Verfahrens nach der  Erfindung kann als Kondensationsmittel z. B.     Phos-          phoroxychlorid    oder     Phosphorpentoxyd    verwendet    werden. Die Reaktion wird zweckmässig in einem       organischen    Lösungsmittel, z. B. in Benzol oder       Chloroform,        durchgeführt.    Nach erfolgter Kondensa  tion kann dann das Reaktionsgemisch angesäuert wer  den, worauf das überschüssige Kondensationsmittel  (z. B.     Phosphoroxychlorid)    durch Zusetzen von Was  ser zersetzt und das Lösungsmittel abgetrieben wird.

        Die Verbindung wird in diesem Fall -in Form des       salzsauren        Salzes    erhalten, aus welchem es gege  benenfalls in weitere Salze     überführt    werden kann.  



  Die Produkte des     erfindungsgemässen        Verfahrens     können durch an sich     bekannte    Verfahrensschritte,  gegebenenfalls nach Vermischen mit     Zusatzmitteln,     in     pharmazeutische    Präparate überführt werden.

   Die  Produkte sind besonders für die Verwendung in kom  binierten     pharmazeutischen        Präparaten    geeignet, wo  bei als weitere     Wirkstoffe        analgetisch    oder     tranquillie-          rend    wirkende Verbindungen,     atropinähnlich    wir  kende     Verbindungen    bzw.     antiphlogistisch,        spasmoly-          tisch,        choleretisch    und     vasodilatorisch    wirkende Mit  tel zugesetzt werden können.

      <I>Beispiel 1</I>  104 g     3,4-Diäthoxyphenyl-acetyl-3,4-diäthoxy-          phenyläthylamid        (F:    108-109  C) werden in 250     ml     Benzol 2 Stunden lang in     Gegenwart    von 50 g     Phos-          phoroxychlorid    zum Sieden erwärmt.     Hierauf    wer  den etwa 200-220     ml    Benzol abgetrieben.

   Der hell  gelbe, dickflüssige Rückstand wird     mit    300     ml        96-          prozentigem        Alkohol    und 30     ml    konzentrierter Salz  säure versetzt. Das     Reaktionsgemisch        erwärmt    sich  und wird durch weiteres Erwärmen zu leichtem Sie  den gebracht. Es wird ein Teil der     Benzol-Alkohol-          Lösung    abgetrieben, worauf die heisse Lösung unter       Umrühren        abgekühlt    wird.

   Das Produkt scheidet     in     Form von glitzernden hellgelben     Kristallen    aus, wel  che     filtriert,        mit        Alkohol    gewaschen und bei 70 bis  80 C getrocknet werden. Es werden     104-105    g       6,7,3',4'-Tetraäthoxy-benzal    - 1,2,3,4 -     tetrahydroiso        -          chinolin-4HCl    erhalten. F. 206-208  C.

   Das Produkt       kann    aus einem 2- bis 3fachen Volumen an     Alkohol          umkristallisiert    werden, worauf 96 g eines bei 210  bis 212  C     schmelzenden        Produktes    erhalten werden.  



       Ähnlicherweise    kann auch das     Hydrobromid    (F<B>--</B>  200-202' C) hergestellt werden. Das     Hydrojodid,     aus dem Hydrochlorid oder aus dem     Hydrobromid     in wässeriger Lösung durch Zusetzen von     Kalium-          jodid        erhältlich,        schmilzt    bei 2l2-214  C.  



  Durch Umsetzen der Base mit der entsprechen  den Säure oder einem     Alkalisalz    derselben können  z. B. die folgenden weiteren Salze hergestellt werden:  
EMI0002.0067     
  
    <U>Salze</U> <SEP> Schmelzpunkt <SEP>  C
<tb>  Hydrogenfluorid <SEP> 55-69
<tb>  Nitrat <SEP> 98-100
<tb>  Sulfat <SEP> 173-174.
<tb>  Phosphat <SEP> 165-168
<tb>  Rhodanid <SEP> 115-160
<tb>  Azetat <SEP> 114-116
<tb>  Oxalat <SEP> 160-161
<tb>  Tartarat <SEP> 130-133
<tb>  p-Nitrophenyl-lactat <SEP> 91-99
<tb>  o-Phenoxy-benzoat <SEP> 112-116
<tb>  Xanthen-carbonat <SEP> 116-119     
EMI0002.0068     
  
    Dimethoxy-phenylazetat <SEP> 106-110
<tb>  Diäthoxy-phenylazetat <SEP> 73-78-85
<tb>  p-Chlor-phenyl-propionat <SEP> 83-86
<tb>  Tropanat <SEP> 100-103
<tb>  Mandelat <SEP> 80-84-85
<tb>  Phenoxyazetat <SEP> 113
<tb>  Dimethoxybenzoat <SEP> 108-110
<tb>  Malonat 

  <SEP> 140-141
<tb>  Äthylbenzo-chinolisyl-azetat <SEP> 117-119
<tb>  Yatrenat <SEP> 182-184       Die Salze     können    aus Alkohol     umkristallisiert     werden.  



  Die     pharmakologische    Untersuchung des salz  sauren Salzes ergab die folgenden Ergebnisse:     Toxi-          zität        DL50    =<B>19,0</B>     mg/kg    i. v. 95,0     mg/kg    s. c. und  über 1000     mg/kg    p. o.     (bei    Mäusen).

   Bei narkotisier  ten     Katzen    zeigte eine     25-mg/k,-,-Dosis        duodenal    ver  abreicht eine     starke    Depression des Blutdruckes     (bei     dem selben Versuch zeigte      Perparin     selbst bei       400-mg/kg-Dosen    keine Wirkung;

   das bedeutet, dass  die     duodenale    Resorption     wesentlich    besser     ist    als im  Falle des      Perparin ).    In einer     Tyrode-Lösung        wurde     am Darm von Mäusen beobachtet, dass die     spasmoly-          tische    Wirkung der Substanz     ED5o    = 0,056 mg be  trägt (bei      Perparin     beträgt     derselbeWert    0,108 mg).  In der Gegenwart von Blutserum beträgt derselbe  Wert     ED5o    = 0,250 mg (bei      Perparin     0,756 mg).

    <I>Beispiel 2</I>  104 g     3,4-Diäthoxy-phenyl-azetyl-3,4-diäthoxy-          phenyl-äthyl-amid    (F:     108-109'    C) werden in  250     ml    Benzol 2 Stunden lang in     Gegenwart    von  50 g     Phosphoraxychlorid    zum Sieden erwärmt.  



  Das Reaktionsgemisch wird hierauf mit 300     ml     Wasser und 30     ml        konzentrierter        Salzsäure    versetzt,  worauf unter     Umrühren    das Benzol abgetrieben     wird.     Der     Rückstand    wird warm filtriert und     abgekühlt.     Das Produkt fällt in Form von hellgelben Kristallen  aus, die filtriert, gewaschen und bei 80-90  C ge  trocknet werden. Es werden 110 g     6,7,3',4'-Tetra-          äthoxy-benzal-1,2,3,4-tetrahydro-isochinolin-HCl    er  halten. F: 202-206  C.

   Aus     einem        2,5fachen    Volu  men an Wasser     umkristallisiert    werden 103 g hell  gelber     Kristalle        gewonnen.    F: 211-212  C.



  Process for the preparation of tetrahydroisoquinoline derivatives It has been found that compounds of the formula
EMI0001.0002
    (in which the meaning of A is a 3,4-diethoxybenzal group, while R is hydrogen, an alkyl, aralkyl or aryl group) have valuable properties that differ from the properties known for similar compounds in meh differ in other respects, and that these compounds can be used in pharmacy.

    This is because it is known that compounds which contain an isoquinoline ring generally have spasmolytic properties. The compounds prepared according to the invention (tetrahydroperparin derivatives) sometimes have a significantly stronger spasmolytic effect or they can be used because of their analgesic, vasodilatory or blood pressure-lowering effect.



       According to the invention, the compounds of the formula 1 are prepared by adding a compound of the formula
EMI0001.0021
    subjected to a ring-closing condensation in the presence of a water-binding condensation means at a temperature below 100 C in an acidic medium.



  When carrying out the method according to the invention, for. B. phosphorus oxychloride or phosphorus pentoxide can be used. The reaction is conveniently carried out in an organic solvent, e.g. B. in benzene or chloroform carried out. After condensation has taken place, the reaction mixture can then be acidified, whereupon the excess condensation agent (e.g. phosphorus oxychloride) is decomposed by adding water and the solvent is driven off.

        In this case, the compound is obtained in the form of the hydrochloric acid salt, from which it can optionally be converted into further salts.



  The products of the process according to the invention can be converted into pharmaceutical preparations by process steps known per se, optionally after mixing with additives.

   The products are particularly suitable for use in combined pharmaceutical preparations, where compounds with analgesic or tranquillising effects, compounds similar to atropine or anti-inflammatory, spasmolytic, choleretic and vasodilatory agents can be added as further active ingredients.

      <I> Example 1 </I> 104 g of 3,4-diethoxyphenyl-acetyl-3,4-diethoxyphenylethylamide (F: 108-109 C) are dissolved in 250 ml of benzene for 2 hours in the presence of 50 g of phosphorus oxychloride heated to the boil. Then who expelled about 200-220 ml of benzene.

   300 ml of 96 percent alcohol and 30 ml of concentrated hydrochloric acid are added to the light yellow, viscous residue. The reaction mixture warms up and is brought to light by further heating. Part of the benzene-alcohol solution is driven off, whereupon the hot solution is cooled while stirring.

   The product separates out in the form of glittering, light yellow crystals, which are filtered off, washed with alcohol and dried at 70 to 80 C. 104-105 g of 6,7,3 ', 4'-tetraethoxy-benzal-1,2,3,4-tetrahydroiso-quinoline-4HCl are obtained. F. 206-208 C.

   The product can be recrystallized from a 2 to 3 times the volume of alcohol, whereupon 96 g of a product melting at 210 to 212 ° C. are obtained.



       The hydrobromide (F <B> - </B> 200-202'C) can also be produced in a similar manner. The hydroiodide, obtainable from the hydrochloride or from the hydrobromide in aqueous solution by adding potassium iodide, melts at 2l2-214 C.



  By reacting the base with the corresponding acid or an alkali salt thereof can, for. B. the following other salts are produced:
EMI0002.0067
  
    <U> Salts </U> <SEP> Melting point <SEP> C
<tb> hydrogen fluoride <SEP> 55-69
<tb> nitrate <SEP> 98-100
<tb> Sulphate <SEP> 173-174.
<tb> Phosphate <SEP> 165-168
<tb> Rhodanide <SEP> 115-160
<tb> acetate <SEP> 114-116
<tb> Oxalate <SEP> 160-161
<tb> Tartarate <SEP> 130-133
<tb> p-nitrophenyl lactate <SEP> 91-99
<tb> o-Phenoxy-benzoate <SEP> 112-116
<tb> Xanthene carbonate <SEP> 116-119
EMI0002.0068
  
    Dimethoxyphenyl acetate <SEP> 106-110
<tb> Diethoxy-phenyl acetate <SEP> 73-78-85
<tb> p-chloro-phenyl-propionate <SEP> 83-86
<tb> tropanate <SEP> 100-103
<tb> Mandelat <SEP> 80-84-85
<tb> phenoxyacetate <SEP> 113
<tb> Dimethoxybenzoate <SEP> 108-110
<tb> malonate

  <SEP> 140-141
<tb> Ethylbenzoquinolisyl acetate <SEP> 117-119
<tb> Yatrenat <SEP> 182-184 The salts can be recrystallized from alcohol.



  The pharmacological investigation of the acidic salt gave the following results: Toxicity DL50 = <B> 19.0 </B> mg / kg i. v. 95.0 mg / kg s. c. and over 1000 mg / kg p. o. (in mice).

   In anesthetized cats, a 25 mg / k, -, - dose administered duodenally showed a severe depression of blood pressure (in the same experiment, Perparin showed no effect even at 400 mg / kg doses;

   this means that duodenal absorption is much better than in the case of Perparin). In a Tyrode solution on the intestines of mice, it was observed that the spasmolytic effect of the substance is ED50 = 0.056 mg (with Perparin the same value is 0.108 mg). In the presence of blood serum, the same value is ED5o = 0.250 mg (with Perparin 0.756 mg).

    <I> Example 2 </I> 104 g of 3,4-diethoxyphenyl-acetyl-3,4-diethoxyphenyl-ethyl-amide (F: 108-109 'C) are in 250 ml of benzene for 2 hours in The presence of 50 g of phosphorus oxychloride is heated to boiling.



  300 ml of water and 30 ml of concentrated hydrochloric acid are then added to the reaction mixture, whereupon the benzene is driven off with stirring. The residue is filtered warm and cooled. The product precipitates in the form of pale yellow crystals, which are filtered, washed and dried at 80-90C. There are 110 g of 6,7,3 ', 4'-tetra-ethoxy-benzal-1,2,3,4-tetrahydro-isoquinoline-HCl he keeps. F: 202-206 C.

   Recrystallized from a 2.5-fold volume of water, 103 g of light yellow crystals are obtained. F: 211-212 C.

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung von Isochinolinderiva- ten der Formel EMI0002.0122 worin A die 3,4-Diäthoxy-benzalgruppe und R Was serstoff, eine Alkyl-, Aralkyl- oder Arylgruppe be deuten, dadurch gekennzeichnet, dass man eine Ver bindung der Formel EMI0003.0006 in Gegenwart eines wasserbindenden Kondensations- mittels bei einer Temperatur unter 100 C in saurem Medium ringschliessend kondensiert. PATENT CLAIM Process for the preparation of isoquinoline derivatives of the formula EMI0002.0122 wherein A is the 3,4-diethoxybenzal group and R hydrogen, an alkyl, aralkyl or aryl group, characterized in that one is a compound of the formula EMI0003.0006 in the presence of a water-binding condensation agent at a temperature below 100 C in an acidic medium, ring-closing condensation. UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch, dadurch ge- kennzeichnet, dass man als Kondensationsmittel Phosphoroxychlorid verwendet. 2. Verfahren nach Patentanspruch oder Unter anspruch 1, dadurch gekennzeichnet, dass man Salze der Produkte mit Mineralsäuren oder organischen Säuren herstellt. 3. SUBClaims 1. Method according to claim, characterized in that phosphorus oxychloride is used as the condensing agent. 2. The method according to claim or sub-claim 1, characterized in that salts of the products with mineral acids or organic acids are prepared. 3. Verfahren nach Unteranspruch 2, dadurch ge- kennzeichnet, dass man die Halogenide, Nitrate, Sul fate, Phosphate, Rhodanide, Azetate, Oxalate, Tartrate, Lactate, Benzoate, Xanthen-carbonate, Di- alkoxy-phenylazetate, Propionate, Tropanate, Man delate, Phenoxy-azetate, Dialkoxy-benzoate, Process according to dependent claim 2, characterized in that the halides, nitrates, sulphates, phosphates, rhodanides, acetates, oxalates, tartrates, lactates, benzoates, xanthene carbonates, dialkoxyphenyl acetates, propionates, tropanates, mandrels are delate , Phenoxy acetates, dialkoxy benzoates, Malo- nate oder Yatrenate der Produkte herstellt. Malonate or Yatrenate of the products.
CH987462A 1961-08-30 1962-08-17 Process for the preparation of tetrahydroisoquinoline derivatives CH424782A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUCI000380 1961-08-30
HUCI000390 1962-04-10

Publications (1)

Publication Number Publication Date
CH424782A true CH424782A (en) 1966-11-30

Family

ID=26318367

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CH781566A CH425793A (en) 1961-08-30 1962-08-17 Process for the preparation of tetrahydroisoquinoline derivatives
CH987462A CH424782A (en) 1961-08-30 1962-08-17 Process for the preparation of tetrahydroisoquinoline derivatives
CH781466A CH424783A (en) 1961-08-30 1962-08-17 Process for the preparation of tetrahydroisoquinoline derivatives

Family Applications Before (1)

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Application Number Title Priority Date Filing Date
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Country Status (5)

Country Link
CH (3) CH425793A (en)
DK (1) DK104513C (en)
FI (1) FI40718B (en)
FR (1) FR2057M (en)
GB (1) GB1011554A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664781B (en) * 2013-12-13 2015-12-09 浙江普洛康裕制药有限公司 Drotaverine hydrochloride crystal formation I and crystal form II and preparation method
CN103694171B (en) * 2013-12-13 2016-06-29 浙江普洛康裕制药有限公司 Drotaverine hydrochloride crystal form II I and form IV and preparation method thereof

Also Published As

Publication number Publication date
FI40718B (en) 1969-01-31
FR2057M (en) 1963-10-07
CH425793A (en) 1966-12-15
CH424783A (en) 1966-11-30
GB1011554A (en) 1965-12-01
DK104513C (en) 1966-05-31

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