CH516557A - Antiphlogistic cinnamamides - Google Patents

Antiphlogistic cinnamamides

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Publication number
CH516557A
CH516557A CH1442871A CH1442871A CH516557A CH 516557 A CH516557 A CH 516557A CH 1442871 A CH1442871 A CH 1442871A CH 1442871 A CH1442871 A CH 1442871A CH 516557 A CH516557 A CH 516557A
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Switzerland
Prior art keywords
formula
sep
acid
radicals
compound
Prior art date
Application number
CH1442871A
Other languages
German (de)
Inventor
Manfred Dr Kleemann
Wolfgang Dr Grell
Gerhard Dr Dahms
Hans Dr Machleidt
Albrecht Dr Eckenfels
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Thomae Gmbh Dr K
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Priority claimed from AT1091167A external-priority patent/AT280283B/en
Priority claimed from AT1075768A external-priority patent/AT285606B/en
Priority claimed from AT1075568A external-priority patent/AT281821B/en
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
Priority claimed from CH343471A external-priority patent/CH516554A/en
Publication of CH516557A publication Critical patent/CH516557A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/64—Acyl halides
    • C07C57/72—Acyl halides containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/224—Phosphorus triamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/535—Organo-phosphoranes
    • C07F9/5352—Phosphoranes containing the structure P=C-
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5407—Acyclic saturated phosphonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5456—Arylalkanephosphonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/59—Hydrogenated pyridine rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Title compounds of formula (I): (where R1 is Br or I and R2 is piperidino or morpholino), which are antiphlogistics and antipyretics, are prepared by eliminating the residues D from a compound of formula (II): (where the residues D are both OH or both acyloxy, incl. sulphonyloxy). (II; D = OH or carboxylic acyloxy) can be converted into (I) by e.g. reacting with HI at slightly elevated temperature. (II; D = sulphonyloxy can be converted into (I) by e.g. reacting with an alkali iodide.

Description

  

  Verfahren zur Herstellung neuer Zimtsäureamide    Die Erfindung betrifft ein     Verfahren    zur Herstellung  neuer Zimtsäureamide der Formel 1  
EMI0001.0001     
    worin  R1 ein Brom- oder Jodatom und  R2 einen Piperidino- oder Morpholinorest bedeuten,  das dadurch gekennzeichnet ist, dass man aus einer Ver  bindung der Formel 2  
EMI0001.0002     
    worin die beiden Reste D beide Hydroxyl- oder beide  Acyloxyreste, beispielsweise Sulfonyloxyreste bedeuten,  die beiden Reste D abspaltet.  



  Dabei geht man zweckmässig so vor, dass man  a) falls D für Hydroxyl- oder Acyloxygruppen steht, aus  einer Verbindung der Formel 2 die Hydroxyl- oder  Acyloxygruppen unter Bildung einer Doppelbindung  beispielsweise durch Umsetzung mit     Jodwasserstoff-          säure    bei leicht erhöhten Temperaturen, z.B. bei 50 C,  zweckmässigerweise in einem Lösungsmittel, z.B. Eis  essig, eliminiert; oder  b) falls D für Sulfonyloxygruppen steht, aus einer Ver  bindung der Formel 2 die entsprechenden Sulfonsäure-    reste unter Bildung einer Doppelbindung durch Um  setzung mit einem Alkalijodid, zweckmässigerweise  in einem Lösungsmittel, z.B. in Methyläthylketon,  vorzugsweise     bei    der     Siedetemperatur    des verwende  ten Lösungsmittels eliminiert.  



  Die bei dem Verfahren verwendeten Ausgangsstoffe  sind neu und lassen sich nach bekannten Methoden dar  stellen.  



  Die Herstellung einer Dihydroxy-Verbindung der For  mel 2 erfolgt beispielsweise durch Umsetzung eines ent  sprechenden Zimtsäureamids mit Silberacetat und Jod  in Eisessig und anschliessender Umsetzung mit     methano-          lischer    Salzsäure.  



  Eine Diacyloxy- oder Disulfonyloxy-Verbindung der  Formel 2 erhält man durch Umsetzung einer     Dihydroxy-          Verbindung    der Formel 2 mit einem entsprechenden     Car-          bonsäureanhydrid    bzw. Sulfonsäurechlorid.  



  Die erfindungsgemäss hergestellten neuen     Zimtsäure-          amide    der Formel 1 besitzen wertvolle pharmakologische  Eigenschaften, insbesondere eine antiphlogistische und  antipyretische Wirkung.  



  Im Kaolin- und Carrageenin-Ödem-Test an der Ratte  sind die Verbindungen der Formel 1 dem Phenylbutazon  bezüglich der therapeutischen Breite überlegen.  



  Die nachstehenden Beispiele dienen zur     näheren    Er  läuterung der Erfindung:  <I>Beispiel 1</I>  4-Brom-zimtsäurepiperidid  0,5 g (1,5 mMol)     &alpha;,ss-Dihydroxy-B-(4-bromphenyl)-            -propionsäurepiperidid    (Fp. 112 bis 113 C, hergestellt  durch Umsetzung von 4-Brom-zimtsäurepiperidid mit  Silberacetat, Jod und anschliessende Umsetzung mit     me-          thanolischer    Salzsäure) werden in 15 ml Eisessig gelöst  und mit 0,24 ml 67%iger     Jodwasserstoffsäure    (0,32 g =  2,5     mMol    Jodwasserstoff) versetzt, wobei sich allmählich  ein Niederschlag bildet. Man lässt über Nacht bei 20 C  stehen und erhitzt dann 5 Stunden auf 60 C.

   Das Reak-      tionsgemisch wird zur Entfernung von Jod mit wässriger  Natriumthiosulfatlösung versetzt und mit Chloroform ex  trahiert. Nach Waschen des organischen Extraktes mit  verdünnter Natronlauge, verdünnter Salzsäure und Was  ser wird getrocknet und im Vakuum eingedampft.     Durch     Säulenchromatographie an Kieselgel (Benzon/Aceton =  3 : 1) lassen sich 30 mg (77% d.Th.) farblose Kristalle vom  Fp. 130 bis 133 C isolieren.  



  <I>Beispiel 2</I>  4-Brom-zimtsäurepiperidid  Ein Gemisch aus 1,0 g (2,4 mMol)     &alpha;,ss-Diacetoxy-ss-          -(4-bromphenyl)-propionsäurepiperidid    (Fp. 92 bis 93 C,  hergestellt aus     &alpha;,ss-Dihydroxy-ss-(4-bromphenyl)-propion-          säurepiperidid    und Essigsäureanhydrid in Gegenwart von  Pyridin), 0,46 ml 67%iger wässriger Jodwasserstoffsäure  (0,62 g = 4,8 mMol Jodwasserstoff) und 20 ml Eisessig       lässt    man 20 Stunden bei 20 C stehen und erwärmt dann  noch 5 Stunden auf 40 C. Man gibt einige ml wässrige  Natriumthiosulfatlösung zu und extrahiert das Gemisch  mit Chloroform.

   Die Chloroformphase wird mit verdünn  ter Natronlauge, verdünnter Salzsäure und Wasser gewa  schen und nach dem Trocknen im Vakuum eingedampft.  Mit dem Rückstand führt man eine     säulenchromatogra-          phische    Trennung an Kieselgel durch (Benzol/Aceton =  9 : 1), wobei 100 mg (14% d.Th.)     4-Brom-zimtsäurepi-          peridid    vom Fp. 132 bis 133 C erhalten werden.  



  <I>Beispiel 3</I>  4-Brom-zimtsäurepiperidid  1,3 g (2 mMol     &alpha;,ss-Di-(p-toluolsulfonyloxy)-ss-(4-brom-          phenyl)-propionsäurepiperidid    (Fp. 150 bis 151  C, herge  stellt aus     a,ss-Dihydroxy-ss-(4-brompheny)-propionsäure-          piperidid    und p-Tolulsulfochlorid in Gegenwart von     Pyr-          idin)    und 1,8 g (12 mMol) Natriumjodid werden in 50 ml  Methyläthylketon 16 Stunden auf 80 C erhitzt. Ent  standenes Jod wird durch Schütteln mit wässriger     Na-          triumthiosulfatlösung    reduziert.

   Man dampft im Vakuum  ein, gibt zum Rückstand Chloroform und Wasser, trennt  die Chloroformphase im Scheidetrichter ab, wäscht sie  mit verdünnter Natronlauge, verdünnter Salzsäure und  Wasser, trocknet über Natriumsulfat und entfernt das       Lösungsmittel    im Vakuum. Der Rücksand wird aus Es  sigester unter Verwendung von Aktivkohle umkristalli  siert. Ausbeute: 0,45 g (76% d.Th.), Fp. 132 bis 133 C.  



  Analog wurden folgende Verbindungen hergestellt:  
EMI0002.0019     
  
    3-Brom-zimtsäurepiperidid, <SEP> Fp. <SEP> 95 <SEP> - <SEP> 99 C
<tb>  4-Brom-zimtsäuremorpholid, <SEP> Fp. <SEP> 142 <SEP> - <SEP> 144 C
<tb>  3-Brom-zimtsäuremorpholid, <SEP> Fp. <SEP> 80 <SEP> - <SEP> 81 C
<tb>  4-Jod-zimtsäurepiperidid, <SEP> Fp. <SEP> 134 <SEP> - <SEP> 135 C
<tb>  3-Jod-zimtsäurepiperidid, <SEP> Fp. <SEP> 109 <SEP> - <SEP> 110 C
<tb>  4-Jod-zimtsäuremorpholid, <SEP> Fp. <SEP> 175 <SEP> - <SEP> 177 C
<tb>  3-Jod-zimtsäuremorpholid, <SEP> Fp. <SEP> 100 <SEP> - <SEP> 101 C       Die erfindungsgemäss hergestellten Verbindungen der  Formel I lassen sich nach an sich bekannten Methoden  in übliche pharmazeutische Anwendungsformen, gegebe  nenfalls in Kombination mit anderen Wirksubstanzen,    einarbeiten.

   Die Einzeldosis beträgt bei Erwachsenen  200,00 mg bis 600,00 mg, bevorzugt 300,00 mg bis       400,00    mg und die Tagesdosis 400,00 mg bis<B>1</B>200,00 mg,  bevorzugt 600,00 mg bis 800,00 mg.



  Process for the production of new cinnamic acid amides The invention relates to a process for the production of new cinnamic acid amides of the formula 1
EMI0001.0001
    where R1 is a bromine or iodine atom and R2 is a piperidino or morpholino radical, which is characterized in that a compound of the formula 2
EMI0001.0002
    where the two radicals D are both hydroxyl or both acyloxy radicals, for example sulfonyloxy radicals, the two radicals D are split off.



  It is advisable to proceed in such a way that a) if D stands for hydroxyl or acyloxy groups, the hydroxyl or acyloxy groups are obtained from a compound of formula 2 with formation of a double bond, for example by reaction with hydriodic acid at slightly elevated temperatures, e.g. at 50 ° C, conveniently in a solvent, e.g. Ice vinegar, eliminated; or b) if D stands for sulfonyloxy groups, the corresponding sulfonic acid radicals from a compound of formula 2 to form a double bond by reaction with an alkali iodide, conveniently in a solvent, e.g. eliminated in methyl ethyl ketone, preferably at the boiling point of the solvent used.



  The starting materials used in the process are new and can be presented using known methods.



  A dihydroxy compound of formula 2 is produced, for example, by reacting a corresponding cinnamic acid amide with silver acetate and iodine in glacial acetic acid and then reacting it with methanolic hydrochloric acid.



  A diacyloxy or disulfonyloxy compound of the formula 2 is obtained by reacting a dihydroxy compound of the formula 2 with a corresponding carboxylic acid anhydride or sulfonic acid chloride.



  The new cinnamic acid amides of formula 1 prepared according to the invention have valuable pharmacological properties, in particular an anti-inflammatory and anti-pyretic effect.



  In the kaolin and carrageenin edema test on rats, the compounds of formula 1 are superior to phenylbutazone with regard to the therapeutic range.



  The following examples serve to explain the invention in more detail: <I> Example 1 </I> 4-Bromo-cinnamic acid piperidide 0.5 g (1.5 mmol) α, ss-dihydroxy-B- (4-bromophenyl) - Propionic acid piperidide (melting point 112 to 113 ° C., produced by reacting 4-bromocinnamic acid piperidide with silver acetate, iodine and subsequent reaction with methanolic hydrochloric acid) are dissolved in 15 ml of glacial acetic acid and mixed with 0.24 ml of 67% hydroiodic acid (0 , 32 g = 2.5 mmol hydrogen iodide) are added, a precipitate gradually forming. It is left to stand at 20 ° C. overnight and then heated to 60 ° C. for 5 hours.

   Aqueous sodium thiosulphate solution is added to the reaction mixture to remove iodine and it is extracted with chloroform. After washing the organic extract with dilute sodium hydroxide solution, dilute hydrochloric acid and what water, it is dried and evaporated in vacuo. Column chromatography on silica gel (benzone / acetone = 3: 1) allows 30 mg (77% of theory) of colorless crystals with a melting point of 130 to 133 ° C. to be isolated.



  <I> Example 2 </I> 4-Bromo-cinnamic acid piperidide A mixture of 1.0 g (2.4 mmol) α, ss-diacetoxy-ss- (4-bromophenyl) -propionic acid piperidide (m.p. 92 to 93 C, prepared from α, ß-dihydroxy-ss- (4-bromophenyl) -propionic acid piperidide and acetic anhydride in the presence of pyridine), 0.46 ml of 67% aqueous hydroiodic acid (0.62 g = 4.8 mmoles of hydrogen iodide ) and 20 ml of glacial acetic acid are left to stand at 20 ° C. for 20 hours and then heated to 40 ° C. for a further 5 hours. A few ml of aqueous sodium thiosulfate solution are added and the mixture is extracted with chloroform.

   The chloroform phase is washed with dilute sodium hydroxide solution, dilute hydrochloric acid and water and, after drying, evaporated in vacuo. The residue is separated by column chromatography on silica gel (benzene / acetone = 9: 1), 100 mg (14% of theory) of 4-bromocinnamic acid piperidide of melting point 132 to 133 ° C. being obtained .



  <I> Example 3 </I> 4-Bromo-cinnamic acid piperidide 1.3 g (2 mmol α, ss-di- (p-toluenesulfonyloxy) -ss- (4-bromophenyl) -propionic acid piperidide (m.p. 150 to 151 C, made from a, ss-dihydroxy-ss- (4-bromopheny) -propionic acid piperidide and p-toluene sulfochloride in the presence of pyridine) and 1.8 g (12 mmol) of sodium iodide are dissolved in 50 ml of methyl ethyl ketone 16 Hours at 80 ° C. The iodine formed is reduced by shaking with aqueous sodium thiosulphate solution.

   It is evaporated in vacuo, chloroform and water are added to the residue, the chloroform phase is separated off in a separating funnel, washed with dilute sodium hydroxide solution, dilute hydrochloric acid and water, dried over sodium sulfate and the solvent is removed in vacuo. The back sand is recrystallized from Es sigester using activated carbon. Yield: 0.45 g (76% of theory), melting point 132 to 133 C.



  The following connections were made in the same way:
EMI0002.0019
  
    3-bromo-cinnamic acid piperidide, <SEP> m.p. <SEP> 95 <SEP> - <SEP> 99 C
<tb> 4-Bromo-cinnamic acid morpholide, <SEP> mp. <SEP> 142 <SEP> - <SEP> 144 C
<tb> 3-Bromo-cinnamic acid morpholide, <SEP> melting point <SEP> 80 <SEP> - <SEP> 81 C
<tb> 4-iodo-cinnamic acid piperidide, <SEP> mp. <SEP> 134 <SEP> - <SEP> 135 C
<tb> 3-iodo-cinnamic acid piperidide, <SEP> mp. <SEP> 109 <SEP> - <SEP> 110 C
<tb> 4-iodo-cinnamic acid morpholide, <SEP> melting point <SEP> 175 <SEP> - <SEP> 177 C
<tb> 3-iodocinnamic acid morpholide, <SEP> melting point <SEP> 100 <SEP> - <SEP> 101 C The compounds of the formula I prepared according to the invention can be converted into customary pharmaceutical application forms by methods known per se, if necessary in combination with other active ingredients.

   The single dose for adults is 200.00 mg to 600.00 mg, preferably 300.00 mg to 400.00 mg and the daily dose 400.00 mg to 1 200.00 mg, preferably 600.00 mg to 800.00 mg.

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung neuer Zimtsäureamide der Formel I EMI0002.0022 in der R1 ein Brom- oder Jodatom und R2 einen Piperi- dino- oder Morpholinorest bedeuten, dadurch gekenn zeichnet, dass man aus einer Verbindung der Formel 2 EMI0002.0025 worin die beiden Reste D beide Hydroxyl- oder beide Acyloxyreste bedeuten, die beiden Reste D abspaltet. UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass die beiden Reste D Sulfonyloxyreste be deuten. 2. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man die Umsetzung in einem Lösungsmit tel durchführt. 3. PATENT CLAIM Process for the production of new cinnamic acid amides of the formula I. EMI0002.0022 in which R1 is a bromine or iodine atom and R2 is a piperidino or morpholino radical, characterized in that a compound of the formula 2 EMI0002.0025 where the two radicals D are both hydroxyl or both acyloxy radicals, the two radicals D are split off. SUBClaims 1. The method according to claim, characterized in that the two radicals D are sulfonyloxy radicals. 2. The method according to claim, characterized in that the reaction is carried out in a solvent tel. 3. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man aus einer Verbindung der Formel 2 mit Jodwasserstoffsäure zwei Hydroxy- oder zwei Acyl- oxygruppen abspaltet. 4. Verfahren nach Unteranspruch 1, dadurch gekenn zeichnet, dass man aus einer Verbindung der Formel 2 mit einem Alkalimetalljodid zwei Sulfonyloxyreste ab spaltet. 5. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man 4-Bromzimtsäurepiperidid herstellt. 6. Verfahren nach Patentanspruch, dadurch gekenn zeichnet> dass man 3-Bromzimtsäurepiperidid herstellt. 7. Process according to patent claim, characterized in that two hydroxyl or two acyl oxy groups are split off from a compound of formula 2 with hydriodic acid. 4. The method according to dependent claim 1, characterized in that two sulfonyloxy radicals are cleaved from a compound of formula 2 with an alkali metal iodide. 5. The method according to claim, characterized in that 4-bromocinnamic acid piperidide is produced. 6. The method according to claim, characterized in that> 3-bromocinnamic acid piperidide is produced. 7th Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man 4-Jodzimtsäurepiperidid herstellt. B. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man 4-Jodzimtsäuremorpholid herstellt. Process according to patent claim, characterized in that 4-iodocinnamic acid piperidide is produced. B. The method according to claim, characterized in that 4-iodocinnamic acid morpholide is produced.
CH1442871A 1967-12-01 1968-11-29 Antiphlogistic cinnamamides CH516557A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
AT1091167A AT280283B (en) 1967-12-01 1967-12-01 Process for the preparation of new cinnamic acid amides
AT1075768A AT285606B (en) 1968-11-05 1968-11-05 Process for the production of new cinnamic acid amides
AT1075568A AT281821B (en) 1968-11-05 1968-11-05 Process for the production of new cinnamic acid amides
CH343471A CH516554A (en) 1968-11-05 1968-11-29 Process for the production of new cinnamic acid amides

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CH516557A true CH516557A (en) 1971-12-15

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4283404A (en) * 1979-09-04 1981-08-11 Richardson-Merrell Inc. Aroylethenylpiperidinobutyrophenone antipsychotic agents
US4284636A (en) 1979-09-04 1981-08-18 Richardson-Merrell Inc. Cinnamoylpiperidinobutyrophenone antipsychotic agents

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4283404A (en) * 1979-09-04 1981-08-11 Richardson-Merrell Inc. Aroylethenylpiperidinobutyrophenone antipsychotic agents
US4284636A (en) 1979-09-04 1981-08-18 Richardson-Merrell Inc. Cinnamoylpiperidinobutyrophenone antipsychotic agents

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