CH509990A - Sulphonamides and process for the manufacture thereof - Google Patents

Sulphonamides and process for the manufacture thereof

Info

Publication number
CH509990A
CH509990A CH787369A CH787369A CH509990A CH 509990 A CH509990 A CH 509990A CH 787369 A CH787369 A CH 787369A CH 787369 A CH787369 A CH 787369A CH 509990 A CH509990 A CH 509990A
Authority
CH
Switzerland
Prior art keywords
halogen
formula
lower alkoxy
cpds
substituted
Prior art date
Application number
CH787369A
Other languages
German (de)
Inventor
Bretschneider Hermann Dr Prof
Helmut Dr Egg
Peter Dr Quitt
Original Assignee
Hoffmann La Roche
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
Priority claimed from CH787569A external-priority patent/CH509992A/en
Priority claimed from CH1136566A external-priority patent/CH500176A/en
Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche
Priority to CH787369A priority Critical patent/CH509990A/en
Publication of CH509990A publication Critical patent/CH509990A/en

Links

Classifications

    • 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
    • C07D295/22—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 with hetero atoms directly attached to ring nitrogen 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/52—Y being a hetero atom
    • C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
    • C07C311/57—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/59—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings having nitrogen atoms of the sulfonylurea groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/28—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

(A) Cpds. of the formulae:- (I) R1 = H R2 = OH, or together with R' = keto R3 = phenyl opt. subst. by one or more halogen, lower alkyl, lower alkoxy, lower alkylthio, acetyl, amino, acylamino, diacylimido, or lower alkoxy and/or halogen substd. benzamidoethyl; 5-6 membered nitrogen heterocycle attached by the nitrogen atom n = 3 or 4. (B) N-(p-Chlorobenzenesulphonyl)-3,5-dimethyl-1-pyrazole carboxamide. Cpds. I and VI have blood-sugar depressing activity.

Description

  

  
 



  Verfahren zur   Herstellung    von Sulfonamiden
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von   Sulfonylharnstoffderivaten    der Formel I
EMI1.1     
 in der R Phenyl, das durch Halogen, Niederalkyl-, Niederalkoxy-, Niederalkylthio-, Acetyl-, Amino-, Acylamino- oder Diacylimidogruppen oder durch Niederalkoxyund/oder Halogen substituiertes Benzamidoäthyl substituiert sein kann; oder einen 5- oder 6gliedrigen, N-verknüpften stickstoffhaltigen heterocyclischen Ring und n die Zahl 3 oder 4 bedeutet.



   Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man eine Verbindung der Formel
EMI1.2     
 bei erhöhter Temperatur mit Alkali behandelt.



   Die Umsetzung wird z.B. bei Rückflusstemperatur des Reaktionsgemisches durchgeführt. Als Alkali kann z.B. Natronlauge verwendet werden.



   Unter niederen Alkylgruppen, die in durch das Symbol R repräsentierten Resten enthalten sind, sollen geradkettige oder verzweigte Alkylgruppen mit 1-6 Kohlenstoffatomen verstanden werden. Beispiele dafür sind Methyl, Äthyl, Propyl, Isopropyl, Butyl, Pentyl, Hexyl und deren Isomeren. Ein durch das Symbol R dargestelltes Halogenphenyl ist vorzugsweise Chlorphenyl. Eine durch das Symbol R dargestellte Acylaminophenylgruppe kann aliphatische oder aromatische Acylreste enthalt ten. Beispiele für solche Gruppen sind Acetaminophenyl oder Benzoylaminophenyl. Eine Diacylimidophenylgruppe ist beispielsweise die Phthalimidophenylgruppe. Ein durch Alkoxy- und/oder Halogen substituierter Benzamidoäthylphenylrest ist z.B. der p-(2-Methoxy-5-chlorbenzamido)-äthylphenylrest.

  Beispiele für 5- oder   öglied    rige stickstoffhaltige heterocyclische Ringe sind Piperidin und Pyrrolidin.



   Die Ausgangsstoffe der Formel II können in Analogie zu der im nachstehenden Beispiel beschriebenen Verfahrensweise hergestellt werden (vgl. auch die belgische Patentschrift Nr. 702 280).



   Die erfindungsgemäss erhältlichen Verbindungen der allgemeinen Formel I zeichnen sich durch eine aussergewöhnliche blutzuckersenkende Aktivität bei oraler Applikation aus. Die Verbindungen haben eine kurze Verweilzeit im Organismus und werden weitgehend unverändert ausgeschieden. Sie können daher als Heilmittel in Form pharmazeutischer Präparate Verwendung finden, welche sie in Mischung mit einem geeigneten pharmazeutischen, organischen oder anorganischen inerten Trägermaterial enthalten.



   Beispiel
0,5 g   4,5-Tetramethylen-N-(N'-p-toluolsulfonylcarba-    moyl)-oxazolidinon werden in 10 ml 1 n Natronlauge gelöst und 1 Stunde auf dem siedenden Wasserbad erwärmt. Nach dem Abkühlen wird die Lösung mit 2n Salzsäure angesäuert, wobei sich ein öl abscheidet, das beim Stehen bei Raumtemperatur kristallisiert. Die Kristalle werden abfiltriert, mit Wasser gewaschen und getrocknet. Der   l-(p-Toluolsulfonyl)-3-(cis-2-hydroxycyclo-    hexyl)-harnstoff schmilzt bei   156-160 C.   

 

   Das Ausgangsmaterial kann wie folgt hergestellt werden:  
Eine Lösung von 4 g 4,5-Tetramethylenoxazolidinon in 75 ml absolutem Benzol wird mit 6 ml p-Toluolsulfonylisocyanat versetzt und 4 Stunden zum Rückfluss erhitzt. Das Lösungsmittel wird darauf im Vakuum verdampft und der Rückstand aus absolutem Äther und anschliessend aus Methanol umkristallisiert. Man erhält   4,5- Tetramethylen - N      - (N '    -p-toluolsulfonylcarbamoyl) -oxazolidinon vom Schmelzpunkt 135-1380. 



  
 



  Process for the preparation of sulfonamides
The present invention relates to a process for the preparation of sulfonylurea derivatives of the formula I.
EMI1.1
 in which R is phenyl which can be substituted by halogen, lower alkyl, lower alkoxy, lower alkylthio, acetyl, amino, acylamino or diacylimido groups or by lower alkoxy and / or halogen substituted benzamidoethyl; or a 5- or 6-membered, N-linked nitrogen-containing heterocyclic ring and n is the number 3 or 4.



   The inventive method is characterized in that a compound of the formula
EMI1.2
 treated with alkali at elevated temperature.



   The implementation is e.g. carried out at the reflux temperature of the reaction mixture. The alkali can e.g. Caustic soda can be used.



   Lower alkyl groups contained in radicals represented by the symbol R are to be understood as meaning straight-chain or branched alkyl groups with 1-6 carbon atoms. Examples are methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and their isomers. Halophenyl represented by the symbol R is preferably chlorophenyl. An acylaminophenyl group represented by the symbol R may contain aliphatic or aromatic acyl radicals. Examples of such groups are acetaminophenyl or benzoylaminophenyl. A diacylimidophenyl group is, for example, the phthalimidophenyl group. A benzamidoethylphenyl radical substituted by alkoxy and / or halogen is e.g. the p- (2-methoxy-5-chlorobenzamido) ethylphenyl radical.

  Examples of 5- or Ö-membered nitrogen-containing heterocyclic rings are piperidine and pyrrolidine.



   The starting materials of the formula II can be prepared analogously to the procedure described in the example below (cf. also Belgian patent specification No. 702 280).



   The compounds of general formula I obtainable according to the invention are distinguished by an exceptional blood sugar-lowering activity when administered orally. The compounds have a short residence time in the organism and are excreted largely unchanged. They can therefore be used as medicaments in the form of pharmaceutical preparations which they contain as a mixture with a suitable pharmaceutical, organic or inorganic inert carrier material.



   example
0.5 g of 4,5-tetramethylene-N- (N'-p-toluenesulfonylcarba- moyl) -oxazolidinone are dissolved in 10 ml of 1N sodium hydroxide solution and heated for 1 hour on a boiling water bath. After cooling, the solution is acidified with 2N hydrochloric acid, an oil separating out, which crystallizes on standing at room temperature. The crystals are filtered off, washed with water and dried. The l- (p-toluenesulfonyl) -3- (cis-2-hydroxycyclohexyl) urea melts at 156-160 C.

 

   The starting material can be made as follows:
A solution of 4 g of 4,5-tetramethyleneoxazolidinone in 75 ml of absolute benzene is mixed with 6 ml of p-toluenesulfonyl isocyanate and refluxed for 4 hours. The solvent is then evaporated in vacuo and the residue is recrystallized from absolute ether and then from methanol. 4,5-tetramethylene-N - (N'-p-toluenesulfonylcarbamoyl) -oxazolidinone with a melting point of 135-1380 is obtained.

Claims (1)

PATENTANSPRUCH PATENT CLAIM Verfahren zur Herstellung von Sulfonylharnstoffderivaten der Formel I EMI2.1 in der R Phenyl, das durch Halogen, Niederalkyl-, Niederalkoxy-, Niederalkylthio-, Acetyl-, Amino-, Acylamino- oder Diacylimidogruppen oder durch Niederalkoxy- und/oder Halogen substituiertes Benzamidoäthyl substituiert sein kann; oder einen 5- oder 6gliedrigen, N-verknüpften stickstoffhaltigen heterocyclischen Ring und n die Zahl 3 oder 4 bedeutet, dadurch gekennzeichnet, dass man eine Verbindung der Formel II EMI2.2 bei erhöhter Temperatur mit Alkali behandelt. Process for the preparation of sulfonylurea derivatives of the formula I. EMI2.1 in which R is phenyl which can be substituted by halogen, lower alkyl, lower alkoxy, lower alkylthio, acetyl, amino, acylamino or diacylimido groups or by lower alkoxy and / or halogen substituted benzamidoethyl; or a 5- or 6-membered, N-linked nitrogen-containing heterocyclic ring and n is the number 3 or 4, characterized in that one is a compound of the formula II EMI2.2 treated with alkali at elevated temperature. UNTERANSPRUCH Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man eine Verbindung der Formel II, in der n = 4 und R = p-Tolyl ist, als Ausgangsstoff verwendet. SUBClaim Process according to patent claim, characterized in that a compound of the formula II in which n = 4 and R = p-tolyl is used as the starting material.
CH787369A 1966-08-08 1967-07-07 Sulphonamides and process for the manufacture thereof CH509990A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CH787369A CH509990A (en) 1966-08-08 1967-07-07 Sulphonamides and process for the manufacture thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH787569A CH509992A (en) 1966-08-08 1966-08-08 Process for the preparation of sulfonamides
CH1136566A CH500176A (en) 1966-08-08 1966-08-08 Sulphonamides and process for the manufacture thereof
CH787469A CH509991A (en) 1966-08-08 1966-08-08 Sulphonamides and process for the manufacture thereof
CH787369A CH509990A (en) 1966-08-08 1967-07-07 Sulphonamides and process for the manufacture thereof

Publications (1)

Publication Number Publication Date
CH509990A true CH509990A (en) 1971-07-15

Family

ID=27429108

Family Applications (1)

Application Number Title Priority Date Filing Date
CH787369A CH509990A (en) 1966-08-08 1967-07-07 Sulphonamides and process for the manufacture thereof

Country Status (1)

Country Link
CH (1) CH509990A (en)

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