CH533619A - Phenyl-substd pyrrole derivs with anti- - inflammatory activity - Google Patents

Phenyl-substd pyrrole derivs with anti- - inflammatory activity

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Publication number
CH533619A
CH533619A CH1373470A CH1373470A CH533619A CH 533619 A CH533619 A CH 533619A CH 1373470 A CH1373470 A CH 1373470A CH 1373470 A CH1373470 A CH 1373470A CH 533619 A CH533619 A CH 533619A
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Switzerland
Prior art keywords
pyrrole
lower alkyl
acid
bis
methyl
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Application number
CH1373470A
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German (de)
Inventor
Yoshida Norio
Horigome Tsuneyoshi
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Sankyo Co
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Publication of CH533619A publication Critical patent/CH533619A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/323—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Phenyl-substd. pyrrole derivs with anti-inflammatory activity. Cpds. of formula (I): (where straight- or branched lower alkyl, X and Y are same or different H, straight- or branched lower alkyl halogen, lower alkoxy or N-di(lower alkyl) amino, X and Y cannot be H at the same time). (I) have anti-inflammatory activity with very low toxicity and are prepd. by reacting a 4 acylpyrrole deriv, with an acid.

Description

  

  
 



   Die vorliegende Erfindung bezieht sich auf ein Verfahren zur Herstellung von Pyrrolderivaten der Formel
EMI1.1     
 worin der Rest R einen geradkettigen oder verzweigten niederen Alkylrest, z.B. einen Methyl-, Äthyl-, Propyloder Isopropylrest, und X und Y, welche gleiche oder verschiedene Bedeutungen haben, Wasserstoffatome, geradkettige oder verzweigte niedere Alkylreste, wie z.B.



  Methyl-, Äthyl-, Propyl- oder Isopropylreste, Halogenatome, wie z.B. Chlor-, Brom-, Jod- oder Fluoratome, niedere Alkoxygruppen, wie z.B. Methoxy-, Äthoxy-, Propoxy- oder Isopropoxygruppen, oder N-Di-(nieder -alkyl)-aminogruppen, wie z.B. Dimethylamino- oder Diäthylaminogruppen, bedeuten mit der Bedingung, dass sowohl X als auch Y nicht gleichzeitig Wasserstoffatome sind.



   Als Pyrrolderivate, welche mit Phenylgruppen substituiert sind, sind bisher 2,3-Diphenyl-5-methylpyrrol und 2,3-Bis(p-methoxyphenyl)-pyrrol in  Australian Journal of   Chemistry ,    Bd. 19, S. 1871 (1966) und    Journal    of Medicinal Chemistry , Bd.   9    S. 527 (1966) beschrieben worden. Irgendwelche entzündungshemmende Wirkungen dieser Verbindungen sind bisher weder in Vorschlag gebracht noch geoffenbart worden.



   Aufgrund von verschiedenen Versuchen mit Pyrrolderivaten wurde nun überraschenderweise festgestellt.



  dass die neuen phenylsubstituierten Pyrrolderivate der Formel (I) eine starke entzündungshemmende Wirkung bei ausserordentlich niedriger Toxizität aufweisen, wogegen die bisher bekannten Verbindungen keine solche Wirkung ausüben.



   Erfindungsgemäss lassen sich die Pyrrolderivate der Formel (I) dadurch herstellen, dass man ein 4-Acylpyrrolderivat der Formel
EMI1.2     
 worin R, X und Y die obigen Bedeutungen haben und
R' eine Kohlenwasserstoffgruppe, wie z.B. eine gerad linige oder verzweigte niedere Alkylgruppe,   eineAryl-    gruppe oder eine Aralkylgruppe bedeutet, mit einer Säure behandelt.



   Bei der Durchführung des vorliegenden Verfahrens gelangt man leicht zu den Pyrrolderivaten der Formel (I), indem man die 3-Acylpyrrolderivate der Formel (II) mit einer Säure, vorzugsweise unter Verwendung eines inerten Lösungsmittels, welches die Umsetzung nicht nachteilig beeinflusst, behandelt. Beispiele solcher iner ter Lösungsmittel sind Wasser, wässrige Alkohole und wässriges Dioxan. Als Säure kann man beispielsweise eine Mineralsäure, wie z.B. Schwefelsäure,   Salisäure    und Bromwasserstoffsäure, verwenden. Die Umsetzung erfolgt vorzugsweise in 70 bis 80%iger Schwefelsäure.



  Die Reaktionstemperatur ist nicht von Bedeutung, liegt aber vorzugsweise im Bereiche von 800C bis 1500C. Die Reaktionsdauer hängt weitgehend von der Reaktionstemperatur und der Art der Ausgangsmaterialien und der Reaktionsmittel ab. Im allgemeinen liegt die Reaktionsdauer bei ungefähr 10 Minuten bis 1 Stunde. Nach beendeter Umsetzung kann man das gewünschte Produkt aus dem Reaktionsgemisch in an sich bekannter Weise gewinnen. So kann man beispielsweise das Reaktionsgemisch in Eiswasser giessen, das erhaltene Gemisch mit einem geeigneten Lösungsmittel extrahieren, den Extrakt mit Wasser waschen und trocknen und hierauf das Lösungsmittel abdestillieren, um das gewünschte Produkt zu erhalten. Das so erhaltene Produkt kann durch Umkristallisieren weiter gereinigt werden.

  Beispiele von nach diesem Verfahren erhältlichen Pyrrolderivaten der Formel   (1)    sind die folgenden:   5-Methyl-2,3-bis-(p-methoxyphenyl)-pyrrol   
Smp. 127,5 bis 128,50C.



     5-Äthyl-2,3-bis-(p-methoxyphenyl)-pyrrol   
Smp. 152 bis   153,5OC.   



     5-n-Propyl-2,3-bis-(p-methoxyphenyl)-pyrrol   
Smp. 101,5 bis 1020C.



  5-Methyl-2-(p-chlorphenyl)-3-(p-methoxyphenyl)-pyrrol
Smp. 78 bis 820C.



  5-Methyl-2,3 -bis-(p-chlorphenyl)-pyrrol
Smp. 132,5 bis   133,5oC.   



  5-Methyl-2,3 -bis-(p-dimethylaminophenyl)-pyrrol
Smp.   110,5 bis      112oC.   



     5-Methyl-2,3-bis-(p-tolyl)-pyrrol   
Smp. 104,5 bis 105,50C.



   Die erfindungsgemäss erhältlichen Verbindungen werden vorzugsweise in Form von pharmazeutischen Präparaten zusammen mit einem inerten, nicht toxischen Trägermittel, Verdünnungsmittel oder einem Überzug verwendet.



   Diese Präparate lassen sich im allgemeinen oral in Einheitsdosierungen, wie z.B. Tabletten oder Kapseln.



  verabreichen.   Wenngleich    die optimalen Mengen der erfindungsgemäss erhältlichen und anzuwendenden Verbindungen je nach der zu verwendenden Verbindung und je nach der Art der Erkrankung verschieden sind, so kann man doch generell sagen, dass die täglich zu verabreichenden Dosierungen bei Erwachsenen im Bereiche von ungefähr 50 bis 500 mg liegen, wobei die vorgenannte tägliche Gesamtmenge nicht einmal, sondern unterteilt dreimal oder mehrere Male pro Tag verabreicht werden.



   Sämtliche als Ausgangsmaterialien für das vorliegende Verfahren zu verwendenden Verbindungen der Formel (II) sind neue Verbindungen und können dadurch erhalten werden, dass man ein Benzil-monooximderivat der Formel
EMI1.3     
  worin X und Y die obigen Bedeutungen haben, mit einem   -Diketonderivat    der Formel
EMI2.1     
 worin R und R' die obigen Bedeutungen haben, in Ge genwart eines Reduktionsmittels, wie z.B. Zinkstaub und Essigsäure, umsetzt.



   Herstellung der Ausgangsmaterialien  (1)   5-Methyl-4-acetyl-2,3-bis-(p-methoxyphenyl)-pyrrol   
In 25 cm3 Essigsäure löst man 2,85 g p,p'-Dimeth oxybenzil-monooxim und 1,1 g Acetylaceton indem man das Gemisch erhitzt, worauf man der Lösung 4 g Zink staub zusetzt. Das erhaltene Gemisch wird hierauf wäh rend 1 Stunde unter Rückfluss erhitzt. Dann wird der Zinkstaub abfiltriert und mit Essigsäure gewaschen. Die
Waschwasser und das Filtrat werden in 300cm3 Eis wasser gegossen und die erhaltenen Niederschläge durch
Filtrieren isoliert und mit Wasser gewaschen, wobei man
3 g des gewünschten Produktes in Kristallform erhält.



   Die Kristalle werden aus einer Mischung von Benzol und Petroläther umkristallisiert, wobei man zu farblosen, plattenförmigen Kristallen vom Schmelzpunkt 191 bis
1930C gelangt.



   Analyse für   Ca1HI2lO3N:   
Ber.: C 75,20 H 6,31 N 4,18
Gef.: C 75,14 H 6,36 N 4,04 (2)   5-Methyl-4-acetyl"2,3-bis-(p-chlorphenyl)-pyrrol   
In 25 cm3 Essigsäure werden 3 g p,p'-Dichlorbenzil -monooxim und 1,1 g Acetylaceton durch Erhitzen gelöst und die Lösung dann mit 4g Zinkstaub versetzt.



  Das erhaltene Gemisch wird hierauf während 1 Stunde unter Rückfluss erhitzt. Das Reaktionsgemisch wird in gleicher Weise wie sub (1) behandelt, wobei man 3,1 g des gewünschten Produktes in Form von Kristallen erhält. Die Kristalle werden aus Äthylacetat umkristallisiert, wobei man   helibraune    Nadeln vom Smp. 238,50C (unter Zersetzung) erhält.



  Analyse für   C19H13ONCl3:   
Ber.: C 66,29 H 4,39 N 4,07   C1    20,60
Gef.: C 66,59 H 4,65 N 4,00 Cl 20,29
Die Erfindung wird durch die folgenden Beispiele erläutert.



   Beispiel I    5-Methyl-2,3-bis-(p-wzethoxyphenyl)-pyrrol   
Zu 300 mg   5-Methyl-4-acetyl-2,3 -bis-(p-methoxyphe-    nyl)-pyrrol gibt man 20cm3 70%ige Schwefelsäure hinzu, worauf man die erhaltene Lösung während 10 Minuten unter Rühren auf   1300C    erhitzt. Das Reaktionsgemisch wird dann in Eiswasser gegossen. Hierauf wird der erzeugte Niederschlag mit Äthylacetat extrahiert und der Extrakt nacheinander mit Wasser, 5%iger wässriger Bicarbonatlösung und Wasser gewaschen und schliesslich über wasserfreiem Natriumsulfat getrocknet. Das Lösungsmittel wird aus dem Extrakt abdestilliert, wobei man   240mg    der gewünschten kristallinen Substanz erhält. Diese Substanz wird aus wässrigem Äthanol umkristallisiert, wobei man farblose, plattenförmige Kristalle vom Smp. 127,5 bis 128,50C erhält.



  Analyse für   Cl9HlgOwN:   
Ber.: C 77,79 H 6,53 N 4,77
Gef.: C 77,52 H 6,76 N 4,49
Beispiel 2    5-Methyl-2,3-.bis-(p-chlorpEzenyl)-pyrrol   
Zu 500 mg 5-Methyl-4-acetyl-2,3-bis(p-chlorphenyl) -pyrrol gibt man   10 cm3    80%ige Schwefelsäure hinzu, worauf man die erhaltene Lösung während 30 Minuten unter Rühren auf 1500C erhitzt. Dann wird das Reaktionsgemisch in gleicher Weise wie in Beispiel 1 behandelt, wobei man 390 mg des gewünschten Produktes in Form von Kristallen erhält.

  Die Kristalle werden aus wässrigem Äthanol umkristallisiert, wobei man zu farblosen Nadeln vom Smp. 132,5 bis 133,50C gelangt:   Analyse    für   C17H13NCl3:   
Ber.: C 67,57 H 4,33 N 4,64
Gef.: C 67,29 H 4,60 N 4,48
Beispiel 3    5-n-Propyl-2,3- bis-(p-niethoxyphenyl)-pyrrnl   
Zu 500 mg 5-n-Propyl-4-n-butyryl-2,3-bis-(p-methoxyphenyl)-pyrrol werden 10 cm3 80%ige Schwefelsäure hinzugegeben, worauf man die erhaltene Lösung während 30 Minuten unter Rühren auf 1500C erhitzt. Nach dem Kühlen wird das Reaktionsgemisch in der gleichen Weise wie in Beispiel 1 behandelt, wobei man   350mg    des gewünschten Produktes in Form von Kristallen erhält. Die Kristalle werden aus einer Mischung von Äther und Petroläther umkristallisiert, wobei man farblose Prismen vom Smp. 101,5 bis 1020C erhält.



  Analyse für   C4,H2302N:   
Ber.: C 78,47 H 7,21 N 4,36
Gef.: C 78,19 H 7,50 N 4,23
Beispiel 4   
5-Methyl-2 -(p-chlorplenyl)-3- (p-metloxyphenyl)-pyrrol   
Zu 500 mg   5 -Methyl-4-acetyl-2- (p-methoxyphenyl)-3 -      ,(p-chlorphenyD-pyrrol    werden   20 cm3      70geige    Schwefelsäure hinzugegeben, worauf man die erhaltene Lösung während 10 Minuten unter Rühren auf 1300C erhitzt. Nach dem Kühlen wird das Reaktionsgemisch in der gleichen Weise wie in Beispiel 1 behandelt, wobei man 400g des gewünschten Produktes in Kristallform erhält. Die Kristalle werden aus Petroläther umkristallisiert, wobei man farblose Prismen vom Smp. 78 bis 820C erhält.

 

  Analyse für   Cl8HlssONCl:   
Ber.: C 72,61 H 5,38 N 4,71 Cl 11,93
Gef.: C 72,48 H 5,52 N 4,65 Cl 11,66
Beispiel 5
5-Methyl-2   ,3-bis-(p-dimethylaminophenyl)-pyrrol   
Zu 300 mg 5-Methyl-4-acetyl-2,3-bis-(p-dimethylaminophenyl)-pyrrol gibt man 20 cm3 80%ige Schwefelsäure hinzu und erhitzt die erhaltene Lösung während  30 Minuten und unter Rühren auf   1 300C.    Nach dem Kühlen wird das Reaktionsgemisch in Eiswasser gegossen und das Gemisch durch Zugabe einer 20%igen Natriumhydroxydlösung alkalisch gestellt und mit Benzol extrahiert. Der Extrakt wird mit Wasser gewaschen und über wasserfreiem Natriumsulfat getrocknet und das Lösungsmittel abdestilliert, wobei man   220 mg    des gewünschten Produktes in Form von blassbraunen Kristallen erhält.

  Die Kristalle werden aus einer Mischung von Äther und Petroläther umkristallisiert, wobei man   hellbraune    Prismen vom Smp. 110,5 bis   11 20C    erhält.

 

  Analyse für   C2,H25N3:   
Ber.: C 78,96 H 7,89 N 13,16
Gef.: C 78,68 H 8,02 N 12,97
Beispiel 6    5-Methyl-2,3-bis-(p-rnethyiphenyi)-pyrrnl   
Zu 500 mg 5-Methyl-4-acetyl-2,3-bis-(p-methylphenyl)-pyrrol gibt man   20 cm3    70%ige Schwefelsäure hinzu und erhitzt die erhaltene Lösung während 15 Minuten unter Rühren auf 1500C. Nach dem Kühlen wird das Reaktionsgemisch in der gleichen Weise wie in Beispiel 1 behandelt, wobei man   370mg    des gewünschten Produktes in Form von Kristallen erhält. Diese Kristalle werden aus einer Mischung von Benzol und Petroläther umkristallisiert, wobei man farblose Prismen vom Smp.



  104,5 bis 1050C erhält.



     Analyse    für   C19H19N:   
Ber.: C 87,31 H 7,33 N 5,36
Gef.: C 87,07 H 7,60 N 5,14 



  
 



   The present invention relates to a process for the preparation of pyrrole derivatives of the formula
EMI1.1
 wherein the radical R is a straight-chain or branched lower alkyl radical, e.g. a methyl, ethyl, propyl or isopropyl radical, and X and Y, which have the same or different meanings, hydrogen atoms, straight-chain or branched lower alkyl radicals, e.g.



  Methyl, ethyl, propyl or isopropyl radicals, halogen atoms, e.g. Chlorine, bromine, iodine or fluorine atoms, lower alkoxy groups, e.g. Methoxy, ethoxy, propoxy or isopropoxy groups, or N-di (lower-alkyl) -amino groups, e.g. Dimethylamino or diethylamino groups mean with the condition that both X and Y are not hydrogen atoms at the same time.



   As pyrrole derivatives which are substituted with phenyl groups, 2,3-diphenyl-5-methylpyrrole and 2,3-bis (p-methoxyphenyl) -pyrrole are in Australian Journal of Chemistry, Vol. 19, p. 1871 (1966) and Journal of Medicinal Chemistry, Vol. 9 p. 527 (1966). Any anti-inflammatory effects of these compounds have so far not been suggested or disclosed.



   On the basis of various experiments with pyrrole derivatives, it has now been found, surprisingly.



  that the new phenyl-substituted pyrrole derivatives of the formula (I) have a strong anti-inflammatory effect with extremely low toxicity, whereas the compounds known to date have no such effect.



   According to the invention, the pyrrole derivatives of the formula (I) can be prepared by using a 4-acylpyrrole derivative of the formula
EMI1.2
 wherein R, X and Y have the above meanings and
R 'is a hydrocarbon group, e.g. represents a straight or branched lower alkyl group, an aryl group or an aralkyl group, treated with an acid.



   When carrying out the present process, the pyrrole derivatives of the formula (I) are easily obtained by treating the 3-acylpyrrole derivatives of the formula (II) with an acid, preferably using an inert solvent which does not adversely affect the reaction. Examples of such inert solvents are water, aqueous alcohols and aqueous dioxane. The acid can be, for example, a mineral acid such as e.g. Use sulfuric acid, salic acid and hydrobromic acid. The reaction is preferably carried out in 70 to 80% strength sulfuric acid.



  The reaction temperature is not important, but is preferably in the range from 80 ° C. to 1500 ° C. The reaction time depends largely on the reaction temperature and the nature of the starting materials and the reactants. In general, the reaction time is about 10 minutes to 1 hour. After the reaction has ended, the desired product can be obtained from the reaction mixture in a manner known per se. For example, the reaction mixture can be poured into ice water, the mixture obtained can be extracted with a suitable solvent, the extract can be washed with water and dried and the solvent can then be distilled off in order to obtain the desired product. The product thus obtained can be purified further by recrystallization.

  Examples of pyrrole derivatives of the formula (1) obtainable by this process are the following: 5-methyl-2,3-bis (p-methoxyphenyl) pyrrole
M.p. 127.5 to 128.50C.



     5-ethyl-2,3-bis (p-methoxyphenyl) pyrrole
M.p. 152 to 153.5OC.



     5-n-propyl-2,3-bis (p-methoxyphenyl) pyrrole
M.p. 101.5 to 1020C.



  5-methyl-2- (p -chlorophenyl) -3- (p-methoxyphenyl) pyrrole
M.p. 78 to 820C.



  5-methyl-2,3-bis (p-chlorophenyl) pyrrole
M.p. 132.5 to 133.5 ° C.



  5-methyl-2,3-bis (p-dimethylaminophenyl) pyrrole
M.p. 110.5 to 112oC.



     5-methyl-2,3-bis (p-tolyl) pyrrole
M.p. 104.5-105.50C.



   The compounds obtainable according to the invention are preferably used in the form of pharmaceutical preparations together with an inert, non-toxic carrier, diluent or a coating.



   These preparations can generally be administered orally in unit doses, e.g. Tablets or capsules.



  administer. Although the optimal amounts of the compounds obtainable and to be used according to the invention differ depending on the compound to be used and depending on the nature of the disease, it can generally be said that the daily dosages for adults are in the range of approximately 50 to 500 mg , the aforementioned total daily amount not being administered once, but divided three or more times per day.



   All of the compounds of the formula (II) to be used as starting materials for the present process are novel compounds and can be obtained by using a benzil monooxime derivative of the formula
EMI1.3
  wherein X and Y have the above meanings, with a diketone derivative of the formula
EMI2.1
 wherein R and R 'have the above meanings in the presence of a reducing agent, e.g. Zinc dust and acetic acid.



   Preparation of starting materials (1) 5-methyl-4-acetyl-2,3-bis (p-methoxyphenyl) pyrrole
2.85 g of p, p'-dimethoxybenzil-monooxime and 1.1 g of acetylacetone are dissolved in 25 cm3 of acetic acid by heating the mixture, after which 4 g of zinc dust are added to the solution. The mixture obtained is then refluxed for 1 hour. The zinc dust is then filtered off and washed with acetic acid. The
Wash water and the filtrate are poured into 300 cm3 of ice water and the resulting precipitates through
Filter isolated and washed with water, being
3 g of the desired product is obtained in crystal form.



   The crystals are recrystallized from a mixture of benzene and petroleum ether, giving colorless, plate-shaped crystals with a melting point of 191 to
1930C.



   Analysis for Ca1HI2lO3N:
Calculated: C 75.20 H 6.31 N 4.18
Found: C 75.14 H 6.36 N 4.04 (2) 5-methyl-4-acetyl "2,3-bis (p-chlorophenyl) pyrrole
3 g of p, p'-dichlorobenzil monooxime and 1.1 g of acetylacetone are dissolved in 25 cm3 of acetic acid by heating, and 4 g of zinc dust are then added to the solution.



  The resulting mixture is then refluxed for 1 hour. The reaction mixture is treated in the same way as sub (1), 3.1 g of the desired product being obtained in the form of crystals. The crystals are recrystallized from ethyl acetate, giving light brown needles with a melting point of 238.50 ° C. (with decomposition).



  Analysis for C19H13ONCl3:
Calc .: C 66.29 H 4.39 N 4.07 C1 20.60
Found: C 66.59 H 4.65 N 4.00 Cl 20.29
The invention is illustrated by the following examples.



   Example I 5-methyl-2,3-bis (p-wzethoxyphenyl) pyrrole
20 cm3 of 70% strength sulfuric acid are added to 300 mg of 5-methyl-4-acetyl-2,3-bis (p-methoxyphenyl) -pyrrole, whereupon the resulting solution is heated to 130 ° C. for 10 minutes while stirring. The reaction mixture is then poured into ice water. The precipitate produced is then extracted with ethyl acetate and the extract is washed in succession with water, 5% strength aqueous bicarbonate solution and water and finally dried over anhydrous sodium sulfate. The solvent is distilled off from the extract, 240 mg of the desired crystalline substance being obtained. This substance is recrystallized from aqueous ethanol, giving colorless, plate-shaped crystals with a melting point of 127.5 to 128.50 ° C.



  Analysis for Cl9HlgOwN:
Calculated: C 77.79 H 6.53 N 4.77
Found: C 77.52 H 6.76 N 4.49
Example 2 5-methyl-2,3-bis (p-chloropezenyl) pyrrole
10 cm3 of 80% strength sulfuric acid are added to 500 mg of 5-methyl-4-acetyl-2,3-bis (p-chlorophenyl) pyrrole, whereupon the resulting solution is heated to 150 ° C. for 30 minutes while stirring. The reaction mixture is then treated in the same way as in Example 1, 390 mg of the desired product being obtained in the form of crystals.

  The crystals are recrystallized from aqueous ethanol, resulting in colorless needles with a melting point of 132.5 to 133.50C: Analysis for C17H13NCl3:
Calc .: C 67.57 H 4.33 N 4.64
Found: C 67.29 H 4.60 N 4.48
Example 3 5-n-Propyl-2,3-bis (p-niethoxyphenyl) -pyrrnl
10 cm3 of 80% sulfuric acid are added to 500 mg of 5-n-propyl-4-n-butyryl-2,3-bis (p-methoxyphenyl) pyrrole, whereupon the resulting solution is heated to 150 ° C. for 30 minutes while stirring . After cooling, the reaction mixture is treated in the same way as in Example 1 to obtain 350 mg of the desired product in the form of crystals. The crystals are recrystallized from a mixture of ether and petroleum ether, colorless prisms with a melting point of 101.5 to 1020 ° C. being obtained.



  Analysis for C4, H2302N:
Calculated: C 78.47 H 7.21 N 4.36
Found: C 78.19 H 7.50 N 4.23
Example 4
5-methyl-2 - (p-chloroplenyl) -3- (p-metloxyphenyl) pyrrole
20 cm3 of 70% sulfuric acid are added to 500 mg of 5-methyl-4-acetyl-2- (p-methoxyphenyl) -3 -, (p-chlorophenyD-pyrrole, whereupon the solution obtained is heated to 130 ° C. for 10 minutes while stirring After cooling, the reaction mixture is treated in the same way as in Example 1, 400 g of the desired product being obtained in crystal form The crystals are recrystallized from petroleum ether to give colorless prisms with a melting point of 78 to 820 ° C.

 

  Analysis for Cl8HlssONCl:
Calc .: C 72.61 H 5.38 N 4.71 Cl 11.93
Found: C 72.48 H 5.52 N 4.65 Cl 11.66
Example 5
5-methyl-2,3-bis (p-dimethylaminophenyl) pyrrole
20 cm3 of 80% strength sulfuric acid are added to 300 mg of 5-methyl-4-acetyl-2,3-bis (p-dimethylaminophenyl) pyrrole and the resulting solution is heated to 1,300 ° C. for 30 minutes while stirring. After cooling, the reaction mixture is poured into ice water and the mixture is made alkaline by adding a 20% strength sodium hydroxide solution and extracted with benzene. The extract is washed with water and dried over anhydrous sodium sulfate, and the solvent is distilled off, giving 220 mg of the desired product in the form of pale brown crystals.

  The crystals are recrystallized from a mixture of ether and petroleum ether, giving light brown prisms with a melting point of 110.5 to 11 20C.

 

  Analysis for C2, H25N3:
Calc .: C 78.96 H 7.89 N 13.16
Found: C 78.68 H 8.02 N 12.97
Example 6 5-methyl-2,3-bis- (p-methylphenyi) -pyrrnl
20 cm3 of 70% strength sulfuric acid are added to 500 mg of 5-methyl-4-acetyl-2,3-bis (p-methylphenyl) pyrrole and the resulting solution is heated to 150 ° C. for 15 minutes while stirring. After cooling, the reaction mixture is treated in the same manner as in Example 1 to obtain 370 mg of the desired product in the form of crystals. These crystals are recrystallized from a mixture of benzene and petroleum ether, colorless prisms of m.p.



  104.5 to 1050C.



     Analysis for C19H19N:
Calculated: C 87.31 H 7.33 N 5.36
Found: C 87.07 H 7.60 N 5.14

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung von Pyrrolderivaten der Formel EMI3.1 worin der Rest R eine geradlinige oder verzweigte, niedere Alkylgruppe und X und Y, welche gleiche oder verschiedene Bedeutungen haben können, Wasserstoffatome, geradlinige oder verzweigte niedere Alkylgruppen, Halogenatome, niedere Alkoxygruppen oder N-Di -(niederalkyl)-aminogruppen bedeuten mit der Bedingung, dass sowohl X und Y nicht gleichzeitig Wasserstoffatome sind, dadurch gekennzeichnet, dass man ein 4-Acylpyrrolderivat der Formel EMI3.2 worin R, X und Y die obigen Bedeutungen haben und R' einen Kohlenwasserstoffrest darstellt, mit einer Säure behandelt. PATENT CLAIM Process for the preparation of pyrrole derivatives of the formula EMI3.1 wherein the radical R is a straight or branched, lower alkyl group and X and Y, which can have the same or different meanings, hydrogen atoms, straight or branched lower alkyl groups, halogen atoms, lower alkoxy groups or N-di (lower alkyl) amino groups with the condition that both X and Y are not hydrogen atoms at the same time, characterized in that one is a 4-acylpyrrole derivative of the formula EMI3.2 wherein R, X and Y have the above meanings and R 'represents a hydrocarbon radical, treated with an acid. UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man als Säure eine Mineralsäure, wie z.B. SUBCLAIMS A method according to claim, characterized in that the acid used is a mineral acid, e.g. Schwefelsäure, verwendet. Sulfuric acid. 2. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man die Umsetzung durch Erhitzen auf 80 bis 1500C durchführt. 2. The method according to claim, characterized in that the reaction is carried out by heating to 80 to 1500C.
CH1373470A 1969-09-16 1970-09-16 Phenyl-substd pyrrole derivs with anti- - inflammatory activity CH533619A (en)

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US4335136A (en) * 1980-04-18 1982-06-15 E. I. Du Pont De Nemours And Company Anti-inflammatory 4,5-diaryl-α-(polyfluoroalkyl)-1H-pyrrole-2-methanamines
US4318917A (en) * 1981-01-21 1982-03-09 E. I. Du Pont De Nemours And Company Antiinflammatory 2,3-diaryl-5-[2,2,2-trifluoro-1-(trifluoromethyl]ethyl-1H-pyrroles
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OA03484A (en) 1971-03-30

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