CH494576A - 3-n-alkylacylamino-2 4 6-triiodophenoxy-alkoxyalkanoic - Google Patents

Abstract

(A) Cpds. (I) R=(1-4C) alkyl or Ph, R1=(1-4C) alkyl Ac=(2-4C) aliphatic acyl A=(2-4C) alkylene. (B) Metal and amine salts of (I) (C) Esters of (I). X-ray contrast agents, esp. for oral cholecystotraphy. I (R1=Et, Ac=MeCO, A=CH2CH2, R=Me) has LD50=1380 mg/kg (p.o). Administration of 100 mg/kg in rabbit, gave, after 3 hr., 24.2 mg/kg, in the gall-bladder and 10.93 mg/kg in the urine. Adult dose - ca 3 g.

Description

       

  
 



  Process for the production of new X-ray contrast media
The main patent relates to X-ray contrast media which, as shading components, are the new [3- (N-alkyl-acylamino) -2,4,6-triiodo-phenoxyjalkoxyalkanoic acids of the formula
EMI1.1
 wherein Alk is an alkyl radical with 1 to 5 carbon atoms, acyl is an aliphatic acyl radical, alkylene is an alkylene radical with 2 to 4 carbon atoms and A is a lower alkyl radical or the phenyl radical whose metal and / or amine salts or their esters with lower alcohols contain, as well as the Process for the production of these X-ray contrast media, which is characterized in that one (3-acylamino-2,4,6triiodo-phenoxy) -alkoxyalkanoic acid of the formula
EMI1.2
 where acyl is an aliphatic acyl radical,

   Alkylene represents an alkylene radical with 2 to 4 carbon atoms and A represents a lower alkyl radical or the phenyl radical, correspondingly alkylated on the nitrogen atom and then the resulting shading component is processed into a pharmaceutically acceptable form suitable for use as an X-ray contrast medium by mixing with one or more ingredients.



   These X-ray contrast media are particularly suitable for use in cholecystography. When appropriately prepared, however, they can also be used, for example, for bronchography, lymphography, hysterosalpingography and for displaying body cavities.



   The subject of the present additional patent is the process for the production of the present new X-ray contrast media according to claim I of the main patent, which is characterized in that a 3- (N-alkyl-acylamino) -2,4,6-triiodophenol of the formula
EMI1.3
 in which Alk is an alkyl radical having 1 to 5 carbon atoms and acyl is an aliphatic acyl radical, by condensation with an ester of a haloalkoxyalkanoic acid of the formula
EMI1.4
 wherein alkylene is an alkylene radical with 2 to 4 carbon atoms and A is a lower alkyl radical or the phenyl radical, etherified, then the ester group is saponified and the resulting shading component is processed into a pharmaceutically acceptable form intended for use as an X-ray contrast medium by adding one or several ingredients.



   The etherification is generally carried out in the presence of a condensing agent consisting of an alkali alcoholate or alkali carbonate.



   Example I 2- {2 '- [3 - (N-Ethyl-acetylamino) -2 ", 4", 6 "-trij od-phenoxy] ethoxy) propionic acid ethyl ester: This is obtained from 16.7 g of 3- (N ethyl acetylamino) -2,4,6-triiodophenol (0.03 mol) by reacting with 5.94 g of 2- (2'-chloroethoxy) propionic acid ethyl ester in the presence of 0.033 mol of sodium ethylate in 20 ml of ethanol by refluxing for 40 hours at a bath temperature of 95-100 ° C. The solvent is evaporated off and the residue is taken up in 180 ml of chloroform and 100 ml of water.



  The organic phase is separated off, washed with water, dried and evaporated.



   The residue (16.4 g, that is 77% of theory) consists of resinous, crystalline 2- {2 '- [3 "- (N-2ithyl-acetylamino) - 2", 4 ", 6!' - triiodo - phenoxy] - ethoxy) - propionic acid - ethyl ester.



   Thin-layer chromatogram on silica gel: Ruf = 0.78 (benzene / ethanol / glacial acetic acid = 30: 16: 8).



   Analysis: Calculated for Cz7H22JANO5; Mol Wt: 701.09.



   C: calc .: 29.12%; found: 29.42%.



   J: calc .: 54.31%; found: 52.90%.



   Free acid: 15.2 g of the above ethyl ester (0.021 mol) are saponified by boiling for 1 hour with 1.6 g of sodium hydroxide in 30 ml of methanol and 90 ml of water. The methanol is distilled off, the aqueous residue extracted with diethyl ether and then acidified. The product which separates out is extracted with ethyl acetate. The extract is evaporated.



  The residue crystallizes and can now be recrystallized from a little ethyl acetate or 50% aqueous ethanol.



  Yield: 8.5 g (= 60% of theory).



  Melting point: 150-151 C.



   The 3- (N-Ethylacetylamino) -2,4,6-triiodophenol used as starting material is prepared as follows:
To a solution of 105.6 g of 3-acetylamino-2,4,6trijodophenol (0.2 mol) in 100 ml of 4N KOH (0.8 mol) are 31 g of ethyl iodide (0.2 Mol), dissolved in 16 ml of acetone, added dropwise. The reaction solution is stirred at 40-450 ° C. for 3 hours. After cooling, it is extracted with diethyl ether. The aqueous phase is freed from the dissolved ether by evacuation and then poured into 600 ml of 4% hydrochloric acid.



   The precipitate is reprecipitated from dilute sodium hydroxide solution with hydrochloric acid.



   For further purification of the 3- (N ethyl-acetylamino) -2,4,6-triiodophenol thus formed, its relatively sparingly soluble ammonium salt is isolated.



   After release from the salt, 78 g (= 70% of theory) of pure 3- (N-ethylacetylamino) - 2,4,6 - triiodo - phenol with a melting point are finally obtained
1470 c.



   Analysis: calculated for CloHloJ> NO2 equivalent weight: calculated: 556.91; found: 555.



   C: calc .: 21.56%; found: 21.60%.



   J: calc .: 68.37%; found: 68.32%.



   Thin-layer chromatogram on silica gel: Rf = 0.62 (ethyl acetate / isopropanol / ammonia = 11: 7: 4).



   A by-product of the ethereal extract is the ethyl ether of 3 - (N-ethyl-acetylamino) -2,4,6-triiodophenol.



   Example 2
2- {2 '- [3 "- (N-Methyl-acetylamino) -2", 4 ", 6" -triiodophenoxy] -ethoxy) -phenylacetic acid
67 g of sodium 3 - (N-methyl-acetylamino) -2,4,6-triiodo-phenolate (0.118 mol), dissolved in 60 ml of hot dimethylacetamide, are added dropwise with stirring to 30 g of 2- (2'- Ethyl chloroethoxy) phenylacetate added. The reaction mixture is stirred at 110 ° C. for 40 hours.



   The product obtained is saponified in aqueous methanol with sodium hydroxide solution.



   The crude 2- (2 '- [3 "- (N-methyl-acetylamino) -2", 4 ", 6" - trij od-phenoxy] ethoxy} -phenylacetic acid is dissolved in a little hot ethanol and added cyclohexylamine converted into the cyclohexylamine salt, which crystallizes out of its alcoholic solution.



  The salt is separated off, dissolved in plenty of water and decomposed by adding dilute hydrochloric acid.



   In this way, 50.2 g of product with a melting point of 83-840 C. Yield: 54% of theory.



   Analysis: calculated for Ci9Hi8JsNO5 equivalent weight: calc .: 721.08; found: 723.



   C: calc .: 31.64%; found: 31.63%.



   J: calc .: 52.80%; found: 52.82%.



   Thin-layer chromatogram on silica gel: Rf = 0.46 (flow agent: ethyl acetate / isopropanol / ammonia = 11: 74).



   3 - (N-Methyl-acetylamino) -2,4,6-triiodo-phenol is prepared as follows: 1. 18.5 g of 3-methylaminophenol, 25 ml of water, 25 ml of glacial acetic acid and 25 ml of acetic anhydride are added during 2 Heated to 700 ° C. for hours and then evaporated to dryness in vacuo. The residue is taken up in ethyl ether and the solution is allowed to crystallize. This gives 10.7 g of 3- (N-methyl-acetylamino) phenol with a melting point of 1150 C.

 

  2. 5 g of 3- (N-methyl-acetylamino) -phenol in 250 ml of glacial acetic acid are heated to 600 ° C. and slowly mixed with 30 g of 45% iodine chloride with vigorous stirring.



  After the addition has ended, the mixture is stirred at the same temperature for a further 3 hours. Now, in the course of one hour, 35 g of sodium acetate, dissolved in a minimum of water, are added dropwise to the reaction solution. After a further hour, 600 ml of water are added.



   The deposited precipitate is filtered off and washed with sodium bisulfite-containing water. The 3- (N-methyl-acetylamino) 2,4,6-triiodophenol obtained in this way is purified by reprecipitation from aqueous sodium hydroxide with hydrochloric acid and subsequent recrystallization from 80% acetic acid.



  Melting point: 170-1710 C.



  Equivalent weight: 543; calculated: 542.9


    

Claims (1)

PATENT CLAIM Process for the production of X-ray contrast media according to claim I of the main patent, characterized in that a 3- (N-alkyl-acylamino) -2,4,6-triiodophenol of the formula EMI3.1 wherein Alk is an alkyl radical having 1 to 5 carbon atoms and acyl is an aliphatic acyl radical, by condensation with an ester of a haloalkoxyalkanoic acid of the formula EMI3.2 wherein alkylene is an alkylene radical with 2 to 4 carbon atoms and A is a lower alkyl radical or the phenyl radical, etherified, then the ester group is saponified and the resulting shading component is processed into a pharmaceutically acceptable form intended for use as an X-ray contrast medium by adding one or several ingredients. SUBClaim Process according to patent claim, characterized in that the etherification is carried out in the presence of a condensation agent consisting of an alkali alcoholate or alkali carbonate.