DE1768553C - Square brackets on 3 (N alkyl acyl amino) 2,4,6 trijod phenoxy square brackets on alkoxy alkanoic acids and these contain de X-ray contrast media - Google Patents

Description

Each invention relates to new ones

2,4, e-trijpd-pne] l |

my form)
J

the general

—AlkyJen —O - CH- COOH,

wherein alkyl is a lower alkyl radical having 1 to 4 carbon atoms, and acyl is an aliphatic acyl radical with 2 to 4 carbon atoms, alkylene is an alkylene radical with 2 to 4 carbon atoms and R a lower alkyl group having 1 to 4 carbon atoms or the phenyl group, and not toxic metal and amine salts and their esters with lower alcohols.

These substances are for use as shading components in X-ray contrast media suitable.

The preferred shading compound is 2 - {Ύ - [3 "- (N - ethyl - acetylamino) -2", 4 ", 6" - triiodophenoxy] ethoxy} propionic acid or its non-toxic metal and amine salts and their Esters with lower alcohols.

The X-ray contrast media, which compounds of the above general formula in addition to suitable Contain carrier substances are particularly suitable for use in oral cholecystography.

The use of jc- [3-acylamino-2,4,6-triiodophenoxyj-alkanoic acids is used as shading components in X-ray contrast media, such as from Patent No. 19 923 of the Office for Invention and Patents in East Berlin, the German patent specification 1 179 336, the publications of Felder and P i t r έ, Il Farmaco, 15, No. 6 (1960), pp. 609 to 631, and von Cassebaum, Die Pharmazie, 15, No. 6 (1960), pp. 310-316, has been repeatedly proposed and extensively studied. On the one hand, these previously known, mostly urine-permeable compounds are for intravenous use too toxic as an X-ray contrast medium and are on the other hand generally in the biliary organs insufficiently concentrated and are therefore inferior to the cholecystographic agents commonly used today. Only in the case of 2- (3-acetylamino-2,4,6-triiodo-phenoxy) -caproic acid does urgency recede, and the Concentration in the bile reaches useful levels. In the extensive clinical trial of this However, the substance clearly showed that the contrast density that could not be achieved for many applications sufficient. ,

The same applies to the recently published patent No. 47 994 of the Office for Inventions and Patents in East Berlin known low N-alkylated S ^ ö-triiodo-S-acyiamino-phenoxyfetl acids,

The contrast media according to the invention do not have these disadvantages. «3

The following tables show the characteristic data of the contrast agent compounds A ₁ B, C, D, E, F, G and H according to the invention, which are decisive for bile contrast media, and the structurally related compounds I ur <d K which are not structurally linked to the Arm'd nitrogen atom , those of the previously mentioned, structurally comparable, previously known compounds L, M and N ₁ which have not yet found any practical use, as well as the data of two bile contrast agents O and P used in practice are listed. The data were always determined using identical methods and under identical external conditions.

• A: 2- {2 '- [3' ^f - (N-Ethyl-acetyIamino) -2 " _i 4", 6 "-triiodophenoxy] -ethoxy-propionic acid.

B: 2- {2 '- [3 "- (N-methyl-propionylamino) -

2 ", 4", 6 "-triiodophenoxy] ethoxy! Propionic acid.

C: 2- {2 '- [3 "- (N-methyl-acety! Amino) -

2 ", 4", 6 "-triiodophenoxy] ethoxy! Butyric acid.

D: 2- {2 '- [3 "- (N-ethyl-acetylamino) -

2 ", 4", 6 "-triiodophenoxy] ethoxy! Butyric acid.

E: 2- {2 '- [3 "- (N-methyl-acetylamino) -

2 ", 4", 6 "-triiodophenoxy] ethoxy! Phenylacetic acid.

F: 2- {2 '- [3 "- (N-Ethyl-acetylamino) -2", 4 ", 6" -triiodophenoxy] -ethoxy} -phenylacetic acid.

G: 2- {3 '- [3 "- (N-methyl-acetyIamino) -2", 4 ", 6" -triiodophenoxy / propoxy ! -phenylacetic acid.

H: 2- {3 '- [3 "- (N-EthyI-acetylamino) -2", 4 ", 6" -triiodophenoxy-propoxy ! -phenylacetic acid.

1: 2- [2 '- (3 "-Acetylamino-2", 4 ", 6" -triiodo-phenoxy) -ethoxy] -propionic acid.

K: 2- [2 '- (3 "-Acetylamino-2" 4 ", 6", -triiodophenoxy) ethoxy] phenylacetic acid.

L: a- [3- (N-Methyl-acetylamino) -2,4,6-triiodophenoxy] -acetic acid (Patent No. 47 994 of the Office for Invention and Patents in East Berlin).

M: a- (3-Acetylamino-2,4,6-triiodo-phenoxy) -butyric acid (Patent No. 19 923 of the Office for Invention and Patents in East Berlin).

N: «- (3-Acetylamino-2,4,6-triiodo-phenoxy) -caproic acid (German patent specification 1179 336).

O: α-Ethyl-0- (3-hydroxy-2,4,6-triiodo-phenyl) propionic acid [Acidum Iophenoicum].

P: /? - [3- (Dimethylamino-methylen-amino) -2,4,6-triiodo-phenyl] -propionic acid [Iopodate].

Table I shows:

a) The compatibility of the X-ray contrast medium compounds according to the invention is completely sufficient for safe oral use.

b) The oil excretion values and the excretion ratios Bile / urine are about 10 times in the compounds according to the invention cheaper than with the structurally closest related compounds that are not alkylated on the amide nitrogen atom I and K and the structurally comparable] Vörbekänntert compounds L, M and N. The bilitropism of compounds A to H but is also much more pronounced than with the practical proven, constitutionally but not comparable biliary contrast media Ö and P.

Table I.

mouse r i, v. rexicity rat ! V, Elimination <■ It KgntrmtmiK ^e l ^s in "/» der After 3 hours Rabbits « 2.9 via OS j 425 D ^ 50 per qs j 445 j, Y, -Enter. IQO ms / KS 1.2 connection 1600 ms / kg 2860 Urine | 2.3 * 390 19-5 43 »l | e / urine 1.8 1850 370 540 GaJIe (12) 2.9 5.3 A. 1850 415 > 4000 485 39-31 8th 2.5 1640 520 ~ 2150 (.35) 20.1 2.0 B. 1660 405 395 23 15 * 0.14 C. 1600 550 > 4000 23.5 12.5 0.76 D. 1400 265 35 * 6th 0.25 E. 1850 1480 23 4th 0.13 F. 5800 820 32 7th 0.6 G 4000 1500 10 60.2 0.4 H 3000 1400 14th 29 I Li I. 8000 450 8.5 53.9 K 1500 345 22nd 83 L. 1360 240 410 13.7 30.4 M. 855 10-11 30th N 17.5 13.4 O 12.3 P. 15.4

* With 50 mg / kg.

With the compounds A, B, C, D, E, F, G and H according to the invention, very good contrast images of the biliary organs are generally achieved after oral administration: see Table II in which the results of cholecystographies (mean values of two to four individual attempts) are listed.

Table II

t l / a
1 / b Cholecystography: 4 hours | Body weight per os 8 hours | 24 hours 1 / b 1.5
2.75 6 hours | 3.5
3.25 2.5
2.75 I. l / a
1 / b Hoppe's cholecystographic indices 1.2 3
3 2.2 2.2 connection 2 B Values from 0 to a maximum of 4 2
2.5 2 2
3.25 1
4th l / a
1 / b 1.75 2.5
3.25 3 I.
2 B * in dogs (1), in cats (2) after administration of a) 100 mg resp. 1.25
1.75 2.5 2.75
2.75 3.25 A. l / a
1 / b
2 B b) 200 mg test substance / kg " 2.25 2
2.5 2.75 B. l / a
1 / b
2 B 2 hours | 1.5
2.75
2 2.75 2.5
3.5
2.25 2.5
2.75
3.25 ** C. l / a
1 / b 2 1.5
1
1.5 2
3.25
2.25 2.5
2.5
3.25 2
2.5
4th l / a
1 / b
2 / a
2 B 0.5 2.5
0.5 2
1.75
2.5 2.5
2.5 2
1
^ i ' D. 1 / b 1
2 1
2
1
1 2.5
2 2
3.5
2.5
3.5 1.5
4th
3
3.5 1 / b 0 1.5
3
2
3 0.2 0.2 E. 0.5
0.5 1.5 0.2 2 0.5 F. 1.5 G 0.5
2 H 0.5
0.5 K 1.5 P. 0.5 0 1

* Hoppe cholecystographic index S, 476 to 481,

! ' ^(Λ After 36 hours 3.73,

See Margolin et al ,, J.

Also compounds in which the alkylene radical 4. Has carbon atoms, as well as the salts and esters point towards those known on priarity day superior to comparable X-ray contrast media Properties on,

The connection A γ / is already very detailed detailed pharmacological and clinical studies subject to: Compared to »IODOPANEQIC ACID« [«-Ethyl- / j '- (3-arnino-2,4,6-triiodo-pheny]) - propionic acid] - a frequently used oral bile contrast medium - compound A proved itself in a double-blind experiment superior in terms of the quality of the biliary organ display. Then residues, which reduce the image quality, did not appear.

Compound A also has a much lower nephrotoxicity than "IODOPANOIC ACID". the Influence on the functioning of the kidneys by contrast medium was measured by the reduction the ability of the kidneys to excrete aminohippuric acid (PAH) - after 200 mg / kg subcutaneously - and creatinine - after 50 ml 5% subcutaneously. 1 hour after injection of 1 jnl contrast medium-Na-saline solution directly in the left renal artery of anesthetized rabbits was the clearance function of the two kidneys (treated with contrast agent on the left, untreated on the right). The results are listed in Table III: Average values from five tests each.

The data in Table IH show that compound A is much better tolerated than "IODOPANOIC ACID". The latter, in contrast to Compound A, decreases the clearance function of the kidneys very considerable even at low concentrations.

Table III

ί A. 1 Conc. In% right P. A. H. Clearance ml / minute 2.77 Creatinine -27.6 connection “JODOPANOE- j
OaT ΤΠ "C 1 7.6 Left 2.45 Left -47 ACID" 1 8.5 6.9 2.9 2.02 -12 0.5 8.2 6.8 Δ % right 3.41
2.85 1.30 -99
-76 0.25 10.0
8.7 8.9 - 9.2 3.35 2.55 -82 1
0.5 11.2 0.21
2.31 -20 0.05
0.67 0.25 3.06 + 7.8 0.60 -98
-73 -72

right / left = right / left kidney.

Conc. - concentration of the contrast agent.

G. M i J1 e r et al, Switzerland, medical weekly, 99, pp. 577 to 581 (1968), have shown that for the evaluation of bile contrast media biliary transport maximum (Tm), d. H. the organism's transport capacity for the contrast medium in question represents a decisive factor and an increase in the dosage beyond this capacity is pointless, as it does not lead to increased bile excretion and no improvement in the density of the shadows. The higher the transport maximum, the greater the density of shadows and the better the X-ray contrast images are achieved.

Table IV

connection

“JODOPANOE
ACID"

Biliary transport maxima (Tm) in the dog
(Mean values from four tests each)

two cases achieved excellent contrast images of the biliary tract.

The new compounds can be used as free acids or in the form of their non-toxic metal and amine salts or their esters are used.

Possible metal salts are: the sodium, lithium, calcium and / or magnesium salts; as Amine salts preferably the N-methylglucamine, diethanolamine or morpholine salts.

The new [3- (N-alkyl-acylamino) -2,4,6-triiodo-phenoxy] -alkoxy-alkanoic acids of the formula I are obtained by in a manner known per se

a) a (3-acylamino-2,4,6-triiodophenoxy) alkoxyalkanoic acid the formula

0.69 to 0.77 micromoles · kg " ¹ * min - ¹ 0.22 to 0.23 micromoles · kg" ¹ * min - ¹

60

O - alkylene - O - CH - COOH

1
R.

From Table IV it can be seen that the transport maximum of compound A according to the invention is that of the standard preparation »IODOPANOIC ACID« by well exceeds the triple,

This compound A has also proven itself to be a very good oral bile contrast medium in humans;

With a dose of 3 g of compound A, five of eight cases (5 $ & 3 rf) were very good and in N-acyl

Wherein acyl is an aliphatic acyl radical with 2 to 4, preferably with 2 carbon atoms, Alkylene is an alkyl radical having 2 to 4 carbon atoms and R is a lower alkyl radical 1 to 4 carbon atoms ödcf represents the Pnenyifest, Alkvlieft on the nitrogen atom. or

I 768

b) a 3- (N-ÄlkyUacylamiho) 4,4,6-trijöd-phenöl der Fofniel

OH

Alkyl

Acyl

wherein alkyl is a lower alkyl radical having 1 to 4, preferably 1 to 2 carbon atoms and Acyl denotes an aliphatic acyl radical with 2 to 4, preferably with 2 carbon atoms, in the presence of basic condensing agents with a reactive alkoxy ^ alkanoic acid derivative of the formula

X - alkylene - O - CH - COOR '

I.
R.

wherein X is a reactive radical of a strong acid and - COOR 'a carboxylic acid ester or represents a carboxylic acid salt group and alkylene and R have the meaning defined under a),

tim then sets the iifld if necessary Carbonate ester group saponified

and then the compound obtained according to a) or b)

in one for use as an X-ray contrast medium suitable, pharmaceutically acceptable form ver * works, for example by mixing with one or more ingredients.

The reactive radical X consists of a strong acid

ίο preferably from a halogen radical, chlorine, bromine and iodine or a sulfate or sulfonate residue, such as. B.

an alkyl or aryl sulfonate radical (R - SO ₂ O -).

Accordingly, one can use the new, shadow-giving ones

[S-CN-alkyl-acylaminoJ-i ^ .o-triiodo-phenoxyJ-alkoxyalkanoic acids Prepare by a (3-acylamino-2,4,6-triiodo-phenoxy) -alkoxy-alkanoic acid in alkaline Environment with a reactive alkyl ester of a strong acid, in particular with an alkyl halide, sulfate or sulfonate converts.

so you can also get the connection you want obtained by adding, in a manner known per se, a 3 (N-alkyl-acylamino) -2,4,6-triJ3d-phenol in the presence of an alkali metal alcoholate or alkali metal carbonate condensed with a haloalkoxyalkanoic acid ester

as and optionally then the ester group saponified.

Typical examples of shading components according to the present invention are:

Compounds of the formula I, namely:

No. Alkyl Acyl Alkylene R. Acetyl -CHj-CH ₂ - Methyl- Acetyl - CHj - CHj - Ethyl- Acetyl - CHj - CH ₂ - Phenyl 1 ethyl Acetyl - CHj - CH ₂ - Methyl- Acetyl -CH - CHj - Methyl- Acetyl -CH ₂ -CHj - Ethyl- Acetyl GH ₁ -CH ₂ -CH ₂ - Methyl- = 2- {2 '- [3 "- (N-Ethyl-acetylamino) -2", 4 ", 6" -triiodo-phenoxy] -ethoxy} -propionic acid Acetyl - CH ₂ - CH ₂ - Methyl- Butyroyl ; -CH ₂ -CH ₂ - Ethyl- 2 methyl Propionyl - CH ₂ -CHj - Methyl- Acetyl - CHj - CHj - Propyl 3 Propyl Propionyl - CHj - CHj Methyl- Acetyl -CH ₂ -CHj- Propyl 4th Butyl Butyroyl - CHj - CHj - Methyl- Acetyl - CH ₂ - CHj - Butyl 5 methyl Acetyl -CH ₂ -CHj- Ethyl- Acetyl -CHj-CH ₂ - Phenyl 6th ethyl = 2- {2 '- [3 "- (N-Methyl-acetylamino) -2" ₎ 4 ", 6" -triiodo-phenoxy] -ethoxy} -butyric acid = 2- {2 '- [3 "- (N-Ethyl-acetylamino) -2", 4 ", 6" -triiodo-phenoxy] -ethoxy} -phenylacetic acid 7th methyl ethyl methyl 8th methyl Butyl ethyl ethyl 9 methyl 10 ethyl Vn ethyl • 12 ethyl 13th 14th 15th 16 17th

as well as their non-toxic alkali, alkaline earth or Alkanolamine salts and their methyl, ethyl and isopropyl esters.

example 1

2- {2 '- [3 "- (N-EthyI-acetyIamino) -2", 4 ", 6" -triiodo-phenoxy] -ethoxy} -propionic acid ^5s

17.85 gj 2- [2 '- (3 "-Acetylamino-2", 4 ", 6" -trijod-phen -] - propionic acid (0.028 mol), dissolved in 30 ml 4N normal aqueous potassium hydroxide solution (0.12 mol) , dropwise over 20 minutes with 6.5 g of ethyl iodide (0.042 mol) in 3 ml of acetone with stirring at 30 to 35 ° C. stirring is continued for 4 hours at 40 ⁰ C, diluted with 200 ml water, the solution decolorized by Addition of a little NaHSO ₃ and the product precipitates by adding concentrated hydrochloric acid. The sticky precipitate is separated from the aqueous phase by extraction with ethyl acetate. The extract is washed with water and with activated charcoal

209 618/235

257

decolorized and evaporated to dryness, after which crystallization soon occurs, the 2 * {2 '<3 "- (N * Ählli ^ 4 ^ '' ijdhHh}

yy> jpyH} propionic acid (15.8 g) melts after two recrystallization from 50% ethanol at 150 to 11

Analysis: calculated for C ₁₅ H ₁₈ I ₃ NO ₅ .

Equivalent Weight: Calculated 673.06;

found 676.

C: calculated 26.76%;

found 26.85%.

J: calculated 56.57%;

found 56.65%.

Thin layer chromatogram:

Medium: silica gel GF 254 (Merck) mobile phase: chloroform / glacial acetic acid = 19/1 Rf: 0.32

Solubilities:

Insoluble in water, sparingly soluble in cold methanol and ethanol, moderately soluble in cold Chloroform, very easily soluble in boiling methanol, ethanol and chloroform.

is added with stirring. Still others are stirred 3 hours at 40 ° C.

Isolation of the ethylated on the nitrogen atom The product is made by diluting the reaction solution with 50 ml of water and extracting neutral substances with ethyl ether and acidification of the aqueous phase with 18% hydrochloric acid, one ktebrige Precipitation occurs. This is taken up in ethyl acetate, washed with water and evaporated *

Oven freed from solvent.

The evaporation residue is taken up in a little fresh, ihdendem ethyl acetate (5 ml) and held for 30 minutes at the boiling point of this solvent, after which the 2- {2 '- [3 "- (N-

Ethyl - propionyl - amino) - 2 ', 4', 6 '- triiodo - phenoxy] propionic acid--äthoxyj gradually crystallized melting point: 105 to 106 ⁰ C..

Analysis: calculated for C ₁₆ H ₂₀ I ₃ NO ₅ .

ao equivalent weight: calculated 687.06;

found 686. C: calculated 27.97%; found 27.88%. J: calculated 55.42%; found 55.26%.

Sodium and N-methylglucamine:> 100 g / ml wäCrige solution at 20 ^c C.

The 2- [2 "- (3" -acetyiamino-2 ", 4", 6 " - trijod - phenoxy) ethoxy] propionic acid is produced as follows:

a) Ethyl 2- (2'-chloroethoxy) propionate is obtained from 30 g of 2- (2'-chloroethoxy) propionitrile in 30 ml of ethanol by passing in HCl gas for 2 hours, stirring in the imino ether hydrochloride obtained in 200 g of crushed ice and extracting the product thus formed with diethyl ether. Bp: 96 to 100 ° C / 12 to 14 m / m; Yield: 23.8 g (57.5%).

b) Ethyl 2- [2 '- (3 "-AcetyIamino-2", 4 ", 6" -triiodophenoxy) ethnoxy] propionate is obtained by reacting 14.7 g of 3-AcetyIamino-2,4,6-triiodophenol with 5.6 g of ethyl 2- (2'-chloroethoxy) propionate in the presence of 0.037 mol of sodium ethylate in about 20 ml of ethanol through 40-door cooking.

Yield: Ii g; Mp. (After recrystallization from ethanol): 148 to 151 ° C.

c) 2- [2 '- (3 "-AcetyIamino-2", 4 ", 6" -trijod-phenoxy) -ethoxy] propionic acid is obtained by saponifying the ethyl ester (6.1 g) with 0.5 g of sodium hydroxide in _3J 30 ml of methanol and a total of 120 ml of water and subsequent acidification of the sodium salt solution.

Yield: 4.95 g (85%); M.p .: 173-175 ° C.

6o

Example 2

2- {2 '- [3 "- (N-Ethy] -propionyIamino) -2", 4 ", 6" -triiodo-phenoxy] -ethoxy} -propionic acid

6.6 g of 2- [2 '- (3 "-PropionyIamino-2", 4 ", 6" -triiodophenoxy) ethoxy] propionic acid (0.01 mol), dissolved in ml of aqueous 3.33 n-Ka! ; Lye (0.04 mol) are mixed with 2.35 g of ethyl iodide, which is dissolved in 1.5 ml of acetone thin-layer chromatogram:

Medium: silica gel GF 254 mobile phase: benzene / chloroform / glacial acetic acid = 7: 3: 2 Rf: 0.65

Solubilities:

Insoluble in water, but easily soluble in lower alcohols and in chloroform.

The 2- [2 '- (3 "-propionylamino-2", 4 ", 6" -triiodo-phenoxy) -ethoxy] -propionic acid used as starting material is obtained by reacting 86.6 g of 3-propionylamino-2,4 , 6-triiodophenol with 32.8 g of 2- (2-chloroethoxy) propionic acid ethyl ester in the presence of 0.176 mol of sodium ethylate in 140 ml of ethanol by refluxing for 40 hours and subsequent saponification of the 2- [2 '- (3 "- propionylamino-2 ", 4", 6 "-trijod-phenoxy) -ethoxy] -propionic acid ethyl ester (45.9 g, mp .: 129-130 ⁰ C; R _F = 0.60 [aul silica gel with benzene / chloroform / Glacial acetic acid = 7: 3: 2]] with 3.2 g sodium hydroxide in 200 ml ethanol and 50 ml water by refluxing for 1 hour, diluting the reaction solution with 500 ml water and subsequent acidification of the sodium salt solution. Yield (after recrystallization from Ethanol): 37.5 g (85%); mp ^: 149 to 151 ° C; Rf = 0.33 (on silica gel with ethyl acetate / isopropanol / ammonia = 55:35:20).

Example 3

2- {2 '- [3 "- (N-MethyI-propionylamino) -2", 4 ", 6" -triiodo-phenoxy] -ethoxy} -propionic acid

To 19.8 g of 2- [2 '- (3 "-propionylamino-2", 4 ", 6" -triiodophenoxy) ethoxy] propionic acid (0.03 mol) in 35 m of water containing 7.9 g of 85 % potassium hydroxyc (0.12 mol), a solution of 6.4 g of methyl iodine in 3 ml of acetone is added dropwise. The reaction solution is stirred ^{at 40 ° C. for 3 hours.}

Isolation of the obtained, on the nitrogen tone

2257

I 768

Methylated product is carried out according to that in Example 2 described Metheide,

The raw, still resinous product is iri 15 ml ■ Ethyl acetate added. Very gradually crystallized the desired 2- {2 '- [3 "- (N-methyl-propiöriylaminoJ-a ^^^ jo ^^ tfijod-phefioxyi-atKoxyJ-pfopionsaufe iri pure form.

Yield: 12.4 g (61.6% of theory). Melting point: 113 to 115 ⁰ C.
Analysis: calculated for C ₁₅ H ₁₈ I ₃ NO ₅ .

Equivalent Weight: Calculated 673.06;

found 669.

C: calculated 26.77%;

found 26.84%.

J: calculated 56.57%;

found 56.40%.

Thin layer chromatogram:

Medium: silica gel GF 254 mobile phase: benzene / chloroform / glacial acetic acid = 7: 3: 2 Rf: 0.53

Solubilities:

Practically insoluble in water, but very easily soluble in methanol, ethanol and chloroform. The sodium and N-methylglucamine salts are easily soluble in water (> 100 g / 100 ml solution at 20 ° C).

Example 4

2- {2 '- [3 "- (N-Ethyl-acetylamino) -2", 4 ", 6" -triiodophenoxy] -ä: hoxy} -butyric acid

5.5 g 2- [2 '- (3 "-AcetyIamino-2", 4 ", 6" -triiodo-phenoxy) -ethoxy] -butyric acid (0.0084 mol), dissolved in 8 ml of 4N KOH (0.032MoI), are mixed with 2 g of ethyl iodide (0.0125 mol), dissolved in 1 ml of acetone, added. The mixture is stirred at 40 ° C. for 4 hours.

The N-ethylated product is isolated by the method described in Example 1. Yield: 4.5 g.

After recrystallization from a little ethyl acetate, this new compound melts at 131 ° C.

Analysis: calculated for
Equivalent weight:

The 2- [2 '- (3 "-Acetyiamiriö-2" _i 4 "j6" -tfijöd-p "henöxy) -ethoxy]' - büttefsätffe used as Ausgarigsmaterial is produced as follows *

a) 8.5 g of 2- (2'-Ghiöräthoxy) -buiyronitrii (Lingo, J.-Amen ehern, Soc _.; 61, S, 1574 [1939]) is dissolved in 15 ml of ethanol for 2 hours with HCl -Gas treated and then refluxed for 4 hours. The imino ether hydrochloride formed in the process

[Cl - CH ₂ - CH ₂ - O - CH (C ₂ H ₅ ) - C (OC ₂ H ₅ ] = NH- HCl]

is saponified with ice water, with 2- (2'-chloroethoxy) -butyric acid-äthyle.ster is obtained.

is b.p .: 104-108 ° C / 12 mm Hg; Yield: 5.25 g (45%); / if- 1.4400.

b) 12.6 g of 3-acetylamino-2,4,6-triiodo-phenol are mixed with 5 g of 2- (2'-chloroethoxy) butyric acid ethyl ester in the presence of 0.026 mol of sodium ethylate in

^ao about 20 ml of ethanol converted to ethyl 2- [2 '- (3 "-acetylamino-2", 4 ", 6" -triiodophenoxy) ethoxy] butyric acid by boiling for 24 hours.
Yield: 7.5 g; Mp (after recrystallization au;

_a5 ethanol): 120 ° C. R _F = (on silica gel with chloroform / glacial acetic acid = 19/1).

c) The 2- [2'-3 "-Acetylamino-2", 4 ", 6" -trijod-phenoxy) -ethoxy] -butyric acid is saponified by the ethyl ester [b)] (1.5 g) with 3.5 ml 1N NaOH in 8 ml of methanol and 24 ml of water is obtained by boiling for 1 hour and subsequent acidification of the sodium salt solution.
Yield: 1.1g (89%); Fp. (After recrystallizing from 50% ethanol): 163 bi:

165 ° C.

Rf = 0.195 (on silica gel with chloroform / glacial acetic acid = 19/1).

Analysis:

C: calculated 25.51%; found 25.53%

J: calculated 57.77%; found 57.81%

45

Example 5

2- {2 '- [3 "- (N-Methyl-acetylamino) -2", 4 ", 6" -triiodo-phenoxy] -ethoxy} -butyric acid

calculated 687.06; found 690. calculated 27.97%; found 28.08%. calculated 55.42%; found 55.60%.

Thin layer chromatogram:

Medium: silica gel GF 254 _So

Eluent: chloroform / glacial acetic acid = 19/1 Rf: 0.41

Solubilities:

Insoluble in water, but easily soluble in lower alcohols and in chloroform. Sodium- and N-methylglucamine salt:> 100 g / 100 ml aqueous solution at 20 ° C.

^r 5.5 g of 2- [2 '- (3 " ⁱ acetylamino-2", 4 ", 6" -trijod-phen oxy) -ethoxyl-butyric acid, dissolved in 8 ml of 4N-KOH, are mixed with 1.8 g of methyl iodide , dissolved in 1 ml of Acetor by stirring at 40 ⁰ C for 4 hours.

The product is isolated by the method described in Example 1.

Mp. (After recrystallization from a little ethyl acetate): 118 to 120 ° C.

Yield: 2.95 g (52.5% of theory).
Analysis: calculated for C ₁₅ H ₁₈ I ₃ NO ₅ .

Equivalent weight: calculated 673.03;

found 678.

C: calculated 26.77%;

found 26.80%.

J: calculated 56.57%;

found 56.40%.

g = 0.41 (on silica gel with chloroform / Eisessij 19/1).

2257

Solubilities;

Insoluble in water, but easily soluble in lower alcohols and in Öilordfdfnii
Sodium and N-methylglükarhin salt: ~ 100 g / lOÖmi aqueous solution of 20 "G.

Example 6

{y
2 ", 4", 6 "-triiodo-phenoxy] -ethoxy} -valeric acid

Solubilities:

Insoluble in water, but easily soluble in methanol. 3 "

The 2- [2 '- (3 "* acetylamino-2", 4 ", 6" -triiodo-phenoxy) -ethoxy] -valerian acid used as starting material is made as follows:

35

ίο

6.65 g 2- [2 '- (3 "'Acetylamino-2", 4 ", 6" -triiodo-phenoxy) -ethoxy] -valeric acid (~ 0.01 mol), dissolved in ΙΟ ml of aqueous 4 η-potassium hydroxide solution (0.040 mol), 2.35 g of ethyl iodide, dissolved in 1.5 ml of acetone, are added. The mixture is stirred for 4 hours at 40 ^° C.

Isolation of the ethylated on the nitrogen atom Product is carried out according to the method described in the previous examples.

5.15 g of amorphous 2- {2 '- [3 "- (N-ethyl-ao icetyIamino) -2", 4 ", 6" -triiodophenoxy] ethoxy} valeric acid are obtained. That's 74% of theory.

Analysis: calculated for C ₁₇ H ₂₂ I ₃ NO ₅ .

Equivalent Weight: Calculated 701.12; as

found 715.

Fp. (After recrystallization from ethanol) S HO bii ill "Cl

Rf! 0.61 (silica gel with chloroform / ice sif = 19/1).

c) 2- [2 ^/ <3 "-Acetylarninö- = 2" _j 4 ' ^/ , 6 "-tnjod-phenÖxy> ethoxyj-valerjansäure is obtained by saponifying the ethyl ester [B)], 1.8 £ _s with 3, 5 ml of 1N ^ NaOH in 10 ml of methanol and 30 fril of water by boiling Istüridiges, evaporating the methanol, extracting the aqueous solution with ethyl ether and acidifying the aqueous phase with hydrochloric acid.

Melting point (after recrystallization from 50% ethanol): 151 ° C.

Rf = 0.31 (on silica gel with chloroform / glacial acetic acid = 19/1).

a) Ethyl 2- (2'-chloroethoxy) valerate: 27.5 g 2- (2'-chloroethoxy) valeronitrile, dissolved in 40 ml of ethanol, are cooled with ice for 2 hours treated with HCi gas, left to stand overnight and then for 4 hours boiled under reflux, the imino ether hydrochloride formed,

Cl - CH ₁ - CH ₂ - O - CH (C ₃ H ₇ ) - C (OCA) = NH · HCl

ruled out. The reaction mixture is in Stirred ice water, the 2- (2'-chloroethoxy) valeric acid ethyl ester is formed. This is extracted with ethyl ether and distilled after the ether has evaporated.

* B.p .: 119 to 124 ° C / 12 mm Hg; Yield: 11.2 g (31.6%).

Ethyl 2- (2'-chloroethoxy) valerate is also obtained by reacting ethyl 2-chloroethoxy with ethyl oxide according to ₅ j D. Klamann et al, Liebigs Ann. Chem; Vol. 710, pp. 59-70 (1967).

b) Ethyl 2- [2 '- (3 "-Acetylamino-2", 4 ", 6" -triiodo-phenoxy) -ethoxyj-valeric acid is obtained from 19 g of S-acetylamino ^ Ao-trijoa-phenol by Boiling for 40 hours with 8.3 g of ethyl 2- (2'-chloroethoxy) vaJerate in the presence of 0.04 moles of sodium ethylate in about 30 ml of ethanol. The After the solvent has evaporated, the product is isolated by washing with thin ethyl ether, The solid product is taken up in ethyl acetate, extracted with water and sodium carbonate solution and evaporating the ethyl acetate.

Example 7

2- {2 '- [3 "- (N-methyl-acetyIamino>
2 ", 4", 6 "-triiodo-phenoxy] -ethoxy} -valeric acid

6.65 g of 2- [2 '- (3 "-Acetylamino-2", 4 ", 6" -trijod-phenoxy) -ethoxy] -valeric acid (~ 0.01 mol) in 10 ml of 4 η-potassium hydroxide solution are with a solution of 2.15 g of methyl iodide in 1.5 ml of acetone and stirred for 3 to 4 hours at 40 ⁰ C. The product methylated on the nitrogen atom is isolated by the method described in the preceding examples.

3.1 g of morphous product with a melting point of ~ 100 ° C. are obtained.

Analysis: calculated for C ₁₈ H ₁₀ I ₃ NO ₆ .

Equivalent Weight: Calculated 687.09;

found 692.

C: calculated 27.97%;

found 28.25%.

J: calculated 55.42%;

found 55.18%.

Solubilities:

Insoluble in water, but easily soluble in lower alcohols.

Example 8

2- {2 '- [3 "- (N-methyl-acetylamino) -2", 4 ", 6" -triiodo-phenoxy] -ethoxy} -phenylacetic acid

3.5 g of 2- [2 "- (3" -acetylamino-2 ", 4", 6 "-triiodo-phenoxy> ätlioxy] -phenylacetic acid (0.005 mol) are in 6 ml of water, which 0.02 mol of potassium hydroxide contains, and treated at 20 ° C with stirring was added dropwise a solution of 1.1 g (0.075 mol) of methyl iodide in 0.5 ml acetone. stirring is continued for 3 to 4 hours at 40 ⁰ C, the reaction solution was diluted with 50 ml Water and removes neutral substances by extraction with ethyl ether.

The aqueous phase is freed from the dissolved ether by evacuation and then with hydrochloric acid acidified.

_r Plf ^ obtained 2- {2 '- [3 "- (N-MethyI-acetyIamino) -2", 4 ", 6" - triiodo - phenoxy] - ethoxy} - phenylacetic acid (3.5 g) melts at 100 to 103 ⁰ C. The product is amorphous.

2257

i-

ϊ 768 553

Analysis; calculated for C ₁ JiHj

Equivalent weight i calculated 721.08;
found 728.5,

Thin layer chromatogram:

Medium; -Kjesdgel GF 254
Solvent; Chloroform / glacial acetic acid = 19/1
R _F ; 0.61

Solubilities;

Insoluble in water, but easily soluble in lower alcohols.

The 2- [2 '- (3 "-acetylamino - 2 ", 4", 6 "- trtjod - phenoxy - ethoxy] - phenylacetic acid is produced as follows:

a) ft- (2-chloroethoxy) benzyl chloride: 49.2 g of benzaldehyde bis (2-chloroethyl) acetal [Arbuzova et al, Chem. Abstracts, 55, 19318 dc [1961]; Kp .: 160-162 ^c C / 2mm Hg) in 39 ml of acetyl chloride are added to 0.5 ml of thionyl chloride. Pass: HCl gas into the reaction solution for 30 seconds, heat to 55 to 60 ° C. for 1 hour with stirring, leave to stand overnight and subject the reaction mixture to fractional distillation.

ft- (2-chloroethoxy) -benzylcMorid boiling yield at 123 to 130 ^c C / 2 mm Hg. 37 g (90 ° / ₀ of theory).

b) ft- (2-chloroethoxy) benzyl cyanide is carried for 3 hours heating under stirring 17 g of M2-chloroethoxy) -benzylchloridmit9gKupfer (I) cyanide obtained in 15 ml of toluene at 120 to 150 C ^c. Kp .: 145 to 147 ^c C / 2mm Hg. Yield: 11.5 g (70 ° / ₀ of theory).

c) 2 - (2 '- chloroethoxy) - phenylacetic acid - ethyl ester is prepared from 9.8 g of nitrile [b)] obtained by dissolving in 15 ml of ethanol, the introduction of HCl gas at 15 ^C through 2C C, and saponifying the refluxing 4stündiges Irr.inoätherhydrochlorides formed in the process with ice water.

Bp .: 155 to 157 ³ C / 2mm Hg. Yield: 10g (84 ° / ₀ of theory).

2 - (2 '- chloroethoxy) - phenylacetic acid - ethyl ester is also obtained by reacting 2-chlorophenylacetic acid ethyl ester with ethylene oxide in the presence of Tetraüthylammoniumbromid after K I am an n. Liebigs Annalen der Chemie, Vol. 710, pp. 59-70 (1967).

d) 2- [2 '- (3 "-Acety! amino-2", 4 ", 6" -triiodo-phenoxy) -ethoxy] -phenylacetic acid-ethyl ester is obtained from 15.8 g of S-acetylamino ^ Ao-trijod-phetiöi by boiling for 40 hours with 8 g of 2- (2'-chloroethoxy ') phenylacetic acid ethyl ester in the presence of 0.03 mol of sodium ethylate in about 20 ml Ethanol. After the solvent has been distilled off, the product is isolated by take in ethyl acetate (200 ml), wash with water and sodium carbonate solution and distill off of ethyl acetate.

Mp (after Recrystallization from 95 ° / _o igern ethanol). 136-137 C. ^r

Rf = 0.64 (on silica gel with Bdfi / iol / chloro * form / glacial acetic acid —7: 3: 2).

e) 2- [2 '- (3 "-Acetylamif | Q-2", 4 ", 6" -triiodo-pt ethoxy] -phenylacetic acid is obtained Saponification of the ethyl ester [(J)], 3.65 g, \ 50 ° / _q strength ethanol with 6 ml of 1 n-NaOf boiling for ¹ l /. hours Abdarnf ethanol and acidification of the aqueous hydrochloric acid Pl,

The crude product is taken up in 15 nil boiling acetate, with Ai UFd initially crystallizing shortly thereafter. Yield; 2.4 g (68% of theory). Melting point: 181 to 182 ° C., R _F = 0.41 (on silica gel with benzene / chic glacial acetic acid = 7: 3: 2).

Example 9

2- {2 '- [3 "- (N-EthyI-acetylamino) -2", 4 ", 6" -triiodo-phenoxy] -ethoxy} -phenylessi

3.5 g of 2- [2 '- (3 "-acetylamino-2", 4 ", 6" -triji

oxy) -ethoxy] phenylacetic acid (- 0.005 mol) potassium hydroxide 2.85 η (0.02 MoI) are added to Einei of 1.72 g of ethyl iodide in 1 ml of acetone ·

a5 stirred at 40 ^° C. for 4 hours.

The Prodi ethylated on the nitrogen atom according to that described in Example 8 isolated.

85 to 90 ⁰ C (amorphous); Yield: 3.25 g of theory).

Analysis: calculated for C ₂₀ Hj ₀ J ₃ NO ₅ .

Equivalent Weight: Calculated 735.13; found 745.

Thin layer chromatogram:

Medium: silica gel GF 254 mobile phase: chloroform / benzene / glacial acetic acid Rf: 0.63

Solubilities:

Insoluble in water, but slightly 1 lower alcohols.

Example 10

2- {2 '- [3 "- (N-Ethyl-acetylamino) -2", 4 ", 6' ^! -Triiodo-phenoxy] -ethoxy} -propioi production according to method b)

Ethyl ester: This is obtained from 3- (N-Ethyl-acetylamino) -2,4,6-triiodo-phcnol ( by reacting with 5.94 g of 2- (2'-chloroethyl pionic acid ethyl ester in the presence of (sodium ethylate in 20 ml of ethanol, by 4t

'Reflux boilers at a bath temperature ν 100 ⁰ C, the solvent is evaporated. The residue is taken up in 180 ml of chloroform and water. The organic PI, separated, washed with water, evaporated getroe. The residue (16.4g, the \

der Thcorie) ₍ consists of resinous, ki

2- {2 '- [3 "- (N-ÄlhyUacetylamino)'2", 4 " ₁ 6" * tr oxyl-ethyl-oxyl-propionic acid-ethyl acetate.

Thin-layer chromatogram on gravel (- 0.78 (benzene / methanol / glacial acetic acid 30:16

levels for C _{! 7} HssJ _s MO ₅ ; jcht; 701.09,

, net 29.12%; found 29.42%,

, net 54.31%; found 52.90%. *

• e; 15.2 g of the above ethyl ester are saponified by boiling for 1 hour with sodium hydroxide in 30 ml of methanol and. The methanol is distilled off, which was extracted with diethyl ether and acidified. The thereby precipitating extracted with ethyl acetate. The extract npft. The residue crystallizes and a little ethyl acetate or 50% strength ethanol are recrystallized. g (= 60 _% of theory). Melting point:

3- (N-ethyl-!, 4,6-triiodophenol used as starting material is produced as follows

Solution of 105.6 g of 3-acetylaminoenol (0 2MoI) in 100 ml of 4 η KOH ien at room temperature with stirring id (0.2MoI), dissolved in 16 ml of acetone,

The reaction solution is stirred for 3 hours. After cooling down, use extracted. The aqueous phase is freed with dissolved ether and then poured into hydrochloric acid.

, chlag is made from dilute caustic soda

-en purification of the so formed: tylamino) -2,4,6-triiodo-phenol is de:.

Analysis; calculated for C ₁₁ H ₁ I (JqNOs, AqH! Ya | entge>victit; calculated 659, O |;

f « ^ndcn calculated

calculated found

2.51%;

57.77%; 57.90 ° / o-

Thin layer chromatogram

_on silica gel; Rp = 0.38 (mobile phase: chloroform / glacial acetic acid = 19: 1),

Dissolutions in g / 100 ml solvent at boiling point

temperature

20 20 20

-> n ° C free acid:

^Water ~

Methanol S

Ethanol 4

Chloroform 10

_{Sodium salt:}

^water / · ·; ^χυυ

N-methylglucamine salt:

Water ~ 100

. .... Example 1_

2- {2 '- [3 "- (N-methyl-acetylamino) -2", 4 ", 6" -triiodo-phenoxy] -ethoxy} -phenylacetic acid

Production according to method b)

67 g of Natnum-3- (N-methyl-acetylamino) -2,4,6-tri-

i 60 l means

g (y

Little soluble ammonium salt isolated. 35 iodine phenolate (0.118 mol) dissolved in 60 ml of hot Release from the salt gives dimethylacetamide, are added dropwise with stirring

Pure with 30g2- (2'-chloroethoxy) -phenylacetic acid-ethyl ester of the added. The reaction mixture is at HO ⁰ C

stirred for 40 hours.

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

Dj ^e crude 2- {2 '- [3 "- (N ^ methyl-acetylamino) -2', 4", 6 "-trijod-phenoxy] -ethoxy} phenylacetic acid is dissolved in a little hot ethanol and by addition of ■ _{4S V} on cyclohexylamine converted into the Cyciohexyiaminsalz which auskristallisicrt from its alcoholic solution the salt is separated, dissolved in plenty of water and by the addition of dilute. decomposed hydrochloric acid.

In this way, 50.2 g of product with a melting point of 83 to 84 ° C. are obtained. Yield: 54% of the Theory.

3 g (= 70 ° / ₀ of theory) cetylamino) -2,4,6-triiodo-phenol 147 ⁰ C.

dinet for C ₁₀ H ₁₀ J ₃ NO ₅ .

it weight: calculated 556.91; found

Derecnnet
done
calculated
found

555
^ i, 30 / ";

68.37%; 68.32%. il

G
chromatogram on silica gel thylacetate / isopropanol / ammonia.).

oduct is found in the essential Extiakt 'From 3- (N-AthyUacetylamino) -2,4,6-tri-

Example 11

- (3 "- (N-Methyl-aeetyläiiiifld> iiodo-phenoxy-thoxy-propionic acid

described in detail in example 1, ^{/ 2} ' ^K3 '' ^All r''

55

_{6 (J} ° analysis: calculated for for C _n H ₁₈ J ₃ NO ₅ .

Equivalent Weight: Calculated 721.08;

found 723.

C: calculated 31.64%;

found 31.63% -

J: calculated 52.80%;

found 52.82%.

Thin-layer chromatographfanim

Rg ^ 0,46 ( superplasticizer i _{'ethyl k} 7

g (= 61.5% of theory). Enamel * The hiring compounds described above may be used for administration in conjunction with any suitable carrier, in particular

Tablets, granules, capsules, coated tablets, globules, suspensions or solutions, oral preparations are preferred,
'Both the free acids and their metal and mineral oils or their esters can be used',

The production of some characteristic dosage forms is described below,

a) tablets

5 kg of 2- {2 '- [3 "' - (N'äty! -Acetylamino) -2", 4 ", 6" -triiodophenoxy] ethoxy] propionic acid are made into a paste with 2 liters of starch paste, which contains 100 g of corn starch, in a kneading machine. If the damp If the mass is sticky, a little dry starch is added. Then it is put in a granulating machine granulated and dried in vacuo. The finished granules are then made with 0.5 kg of corn starch and 25 g of magnesium stearate mixed and compressed into tablets with an active ingredient content of 500 mg. ao

b) tablets

5 kg sodium salt of 2- {2 '- [3 "- (N-ethyl-acetyI-amino) - 2 ", 4", 6 "- triiodo - phenoxy] - ethoxy} - propionic acid and 0.75 kg of semolina sugar (sucrose) are mixed with 0.75 kg of corn starch and mixed. the The mixture is moistened with 1000 ml of 50% aqueous alcohol and then in the machine granulated. The granules are dried, sieved, with 0.65 kg of corn starch, 0.05 kg of talc and 0.05 kg Magnesium stearate was added and ζ 10,000 tablets were pressed.

c) coated tablets

The granules obtained according to Example 1 are made by applying 25% of its own weight to sugar syrup coated in a coating pan and then waxed.

c]) capsules

750 g of 2- {2'-p "- (N-Äihyl-acety | amitio) -2 ' ^r , 4", 6 "-trijpcj-fhenaxyHtlicwyl-propionsawre are mixed with 600 g of sesame oil and 100 g of vegetable lecithin to form a paste and filled in looo soft Galatfne capsules,

Claims (3)

Claims; 1 ₁ [3- (N-alkyl-acylamino) -2,4,6-triiodo-phenoxy] -alkoxyajkansäuren of the general formula Ο — Alkylene — Ο — CH- COOK R. N
AlkyK ^ acyl wherein alkyl is a lower alkyl radical having 1 to 4 carbon atoms, acyl is an aliphatic Acyl radical with 2 to 4 carbon atoms, alkylene an alkylene radical with 2 to 4 carbon atoms and R is a lower alkyl radical having 1 to 4 carbon atoms or the phenyl radical, whose non-toxic metal and amine salts and their esters with lower alcohols. 2. 2- {2 '- [3 "- (N-Ethyi-acetyIamino) -2", 4 ", 6" -triiodo-phenoxy] -ethoxy} -propionic acid and theirs non-toxic metal and amine salts and their esters with lower alcohols. 3. X-ray contrast agent marked by the fact that it is used as a switching component contains a compound according to claim 1 in addition to inert carriers.