NO121611B - - Google Patents

Description

Amino-triiodophenoxy compounds with shading

effect.

The present invention relates to hitherto unknown iodine compounds, which can be used as shadowing components in X-ray contrast agents.

in

- The previously unknown iodine compounds with a shading effect are / 3-(N-alkylacylamino)-2,4,6-triiodo-phenoxy_7-alkoxy-alkanoic acids with the general formula I

where alkyl means an alkyl group with 1-4, preferably 1-2 carbon atoms,

acyl means an alkanoyl group with 2-4", preferably 2, carbon atoms, alkylene denotes an alkylene group with 2-4 carbon atoms, and R denotes an alkyl group with 1-4 carbon atoms or a phenyl group, as well as their metal and amine salts and their esters with lower alcohols .

Preferred shade-giving amino-triiodophenoxy compounds are 2-(2'-/3"-(N-methyl (or ethyl)-acetylamino)-2",4"»6"-triiodo-phenoxy_7-ethoxy)-propionic or butyric acid and these non-toxic metal or amine salts of acids and their esters with lower alcohols, as these are absorbed particularly well from the intestinal system, and among these 2-(2'-^3M<->(N-ethyl-acetylamino)-2 is particularly preferred ", 4",6"-triiodo-phenoxy(7-ethoxy)-propionic acid and its non-toxic metal or amine salts and its esters with lower alcohols, as these have given particularly good results in the pharmacological and clinical testing, showing a good tolerability and at the same time a high bilitropism, provides particularly good contrast images of the biliary organs and has a significantly lower nephrotoxicity (influence on the functioning of the kidneys) than the currently predominantly used oral bile contrast agents"

The shade-giving compounds in question are quite suitable for use in oral cholecystography. However, when formulated appropriately, they are e.g.

also applicable for X-ray production of body cavities

As can be seen, for example, from East German Patent Document No. 19,923, West German Patent Document No. 1,179,336 and the publications by Felder and Pitre, Il Farmaco 15, No. 6 (1960), pages 609 - 631, and by Cassebaum, Die Pharmazie 1£, No. 6 (1960),

pages 310 - 3l6, is the application of cx. -^3-acylamino-2,4»6"-triiodo-phenoxy-7-alkane acids as shadowing components in X-ray contrast agents have repeatedly been proposed and the possibilities therefore thoroughly investigated. These known compounds, which for the most part are excreted well with the urine, are on on the one hand too toxic for intravenous use as X-ray contrast agents and on the other hand are usually insufficiently concentrated in the bile organs, and they are therefore inferior to the currently commonly used cholecystography agents. Only in 2-(3-acetylamino- 2,4,6-triiodo-phenoxy)-caproic acid, the urinary excretion is less, and the concentration of the compound in the bile reaches usable values" In the extensive clinical testing of this substance, however, it became clear that the achieved contrast effect is insufficient for many purposes < >

The same applies to the lower N-alkylated 2,4»6-triiodo-3-acylamino-phenoxy-alkanecarboxylic acids, which have recently become known from East German patent

letter no 47°994°

The compounds according to the present invention do not exhibit these disadvantages.

Tables I and II below show the decisive properties for bile contrast agents of the contrast agent compounds A, B, C, D, E and F according to the invention compared to the corresponding properties of the structurally most closely related compounds G and H, in the above-mentioned structurally comparable known compounds I, K and L, which have so far not found any practical application, and also the properties of two practically used bile contrast agents M and N. The properties have been determined according to identical methods and under identical external conditions.

A: 2-(2'-[3"-(N-ethyl-acetylamino)-2",1",6"-triiodo-phenoxy-ethoxy)-propionic acid.

B: 2-(2,-/~3"-(N-methyl-propionylamino)-2",<i>+",6"-triiodo-phenoxyY7-etoxy)-propionic acid.

C: 2-(2'-[3"-(N-methyl-acetylamino)-2",4",6"-triiodo-phenoxy-ethoxy)-butyric acid.

D: 2-(2'-[3"-(H-ethyl-acetylamino)-2",M-",6"-triiodo-phenoxy-7-ethoxy)-butyric acid.

E: 2-(2'-/3"-(N-methyl-acetylamino)-2",4",6"-triiodo-phenoxy?-ethoxy)-phenylacetic acid

F: 2-(2'-[3"-(N-ethyl-acetylamino)-2",4",6"-triiodo-phenoxy/-ethoxy)-phenylacetic acid.

G: 2-(2<*->(3"-acetylamino-2",4",6"-triiodo-<f>enoxy)-ethoxys7-propionic acid). H: 2-[2,-(3"-acetylamino-2",4",6"-triiodo-phenoxy)-ethoxy]7-phenylacetic acid.

I: -/3-(N-methyl-acetylamino)-2,4,6-triiodo-phenoxy-acetic acid,

East German Patent Document No. 47,994.

K: *-(3-acetylamino-2,4,6-triiodo-phenoxy)-butyric acid,

East German Patent Document No. 19,923.

L: «-(3-acetylamino-2,4,6-triiodo-phenoxy)-caproic acid,

West German Patent Document No. 1,179,336.

H: *-ethyl-p-(3-hydroxy-2,4,6-triiodo-phenyl)-propionic acid,

/ Acidum Iophenoicunj/.

N: ((3-dimethylamino-methylene-amino)-2,4,6-triiodophenyl-7-propionic acid,

/ Iopodate/.

This table I shows:

a) The tolerability of the X-ray contrast agent compounds referred to here is fully sufficient for risk-free oral use. b) The bile excretion values and excretion ratios bile/urine for the compounds according to the invention are approx. lo times as favorable as for those in

structurally most closely related compounds G and H, not alkylated at the araide nitrogen atom, and for the structurally comparable known compounds I, K and L. The bilitropism of compounds A - F is then also much more pronounced than with those used in practice, but in constitutional regarding not comparable, bile contrast agents M and N.

With the compounds A, B, C, D, E and F according to the invention, excellent contrast images of the biliary organs are usually obtained after oral administration, cf. table II, showing results of cholecystographies (average value of 2 - 1 individual attempts).

With compound F, particularly good images of the bile ducts have been obtained in cat experiments after oral administration, which are usually only obtained with intravenously administered cholecystography agents.

Compound A has already been subjected to very thorough pharmacological and clinical detailed investigations: In relation to iodopanoic acid («-ethyl-p-(3-amino-2,4,6-triiodo-phenyl)-propionic acid) - a frequently used oral bile contrast agent - showed compound A was superior in double-blind trials with regard to the quality of biliary organ imaging. Intestinal remnants, which reduce imaging quality, did not occur.

Compound A also exhibits a much lower nephrotoxicity than iodopanic acid. The influence of contrast agents on the functioning of the kidneys was measured by the reduction of the kidneys' ability to excrete para-aminohippuric acid

(PAH) - after subcutaneous administration of 2oo mg/kg - and creatinine - after subcutaneous administration of 5o ml of 5% solution. 1 hour after injection of 1 ml of contrast medium-sodium salt solution directly into the left renal artery in anesthetized rabbits, the clearance function of both kidneys was compared (the left treated with contrast medium, the right untreated). The results are shown in Table III, which indicates average values of five trials.

Table III shows that compound A is much better tolerated than iodopanic acid. Iodopanic acid reduces - in contrast to compound A - the clearance function of the kidneys, even at low concentrations.

This compound has also proven to be a particularly good oral biliary contrast agent in humans: With a dose of 3 g of compound A, in 5 out of 8 cases (5 women and 3 men) very good and in 2 cases excellent contrast images of the biliary tract were obtained .

The previously unknown compounds in question can be used as free acids or in the form of their non-toxic metal and amine salts or their esters. As metal salts, e.g. sodium, lithium, calcium and magnesium salts are used as amine salts, N-methylglucamine, diethanolamine and morpholine salts can preferably be used.

The compounds according to the invention can be prepared in different ways. Thus one can

a) alkylating a (3-acylamino-2,4,6-triiodo-phenoxy)-alkoxy-alkanoic acid of the general formula III

where acyl denotes an alkanoyl group with 2-4, preferably 2, carbon atoms, alkylene denotes an alkylene group with 2-4 carbon atoms, and R denotes an alkyl group with 1-4 carbon atoms or a phenyl group, at the nitrogen atom, or b) in the presence of basic condensing agents react a 3-(N-alkyl-acylamino)-2,4,6-triiodo-phenol with the general formula IV where alkyl denotes an alkyl group with 1-4, preferably 1-2, carbon atoms, and acyl denotes a . alkanoyl group with 2-4, preferably 2, carbon atoms, with a reactive alkoxyalkanoic acid derivative of the general formula V

where X denotes a reactive residue of a strong acid, and -COOR' denotes a carboxyl-

acid ester group or a carboxylic acid salt group, while the alkylene and R have it below

a) indicated meaning, and optionally then saponify the carboxylic acid ester group.

The reactive residue X of a strong acid preferably consists of a halogen atom

such as chlorine, bromine and iodine, or a sulfate or a sulfonate residue, e.g. an alkyl or aryl sulfonate residue (R-SO 2 O-).

One can thus prepare the mentioned shade-giving / 3-(N-alkyl-acylaroino)-2,4,6-triiodo-phenoxy_7-alkoxy-alkanoic acids by reacting in an alkaline environment a (3-acylamino-2,4,6- triiodo-phenoxy)-alkoxy-alkanoic acid with a reactive alkyl ester of a strong acid, in particular with an alkyl halide, sulfate or sulfonate.

However, the desired compounds can also be prepared by condensing a 3-(N-alkyl-acylamino)-2,t,6-triiodo-phenol with a haloalkoxyalkanoic acid ester in the presence of an alkali metal alcoholate or alkali metal carbonate and optionally then saponifying the ester group.

The production of and the properties of these hitherto unknown shade-giving compounds according to the invention can be seen from the examples below.

Example 1

2-( 2'-/" 3"-( N-Etvl-acetvlamino)- 2", 4", 6"- triiodo-phenoxy 7- ethoxy^- propionic acid

To 17.85 g of 2-/~2l<->(3"-acetylamino-2",4",6"-triiodo-phenoxy)-ethoxy_7-propionic acid (0.028 mol), dissolved in 30 ml of 4N aqueous potassium hydroxide solution (0.12 mol), add 6.5 g of ethyl iodide (0.042 mol) in 3 ml of acetone dropwise over 20 minutes while stirring at 3o 35°C. It is further stirred for 4 hours at 4o°C, after which it is diluted with 2oo ml of water, and the resulting solution is decoloured by the addition of a small amount of NaHSO„, after which the product is precipitated by the addition of concentrated hydrochloric acid. The sticky precipitate is separated from the aqueous phase by extraction with ethyl acetate. The extract is washed with water, decolorized with activated charcoal and evaporated to dryness, after which crystallization soon occurs. The thus obtained 2-(2,-/~3"-(N-ethyl-acetylaniino)-2",4", 6"-triiodo-phenoxy_7-ethoxy)-propionic acid (15.8 g) melts after 2 recrystallizations from 50% ethanol, at 150-151°C.

Analysis: calculated for C^,.H^<gJg>NO,.

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)

Developer: Chlorophon/glacial vinegar in the ratio 19:1 Rp value: o.32

Solubilities: The compound is insoluble in water, slightly soluble

in cold methanol and ethanol, moderately soluble in cold chloroform,

extremely easily soluble in boiling methanol, ethanol and chloroform. Sodium and N-methylglucamine salt: i* loo g/loo ml aqueous solution at 2o°C

The 2-/~2,-(3,,-acetylamino-2",4",6"-triiodo-phenoxy)-ethoxy_7-propionic acid used as starting material is prepared in the following way:

a) 2-(2<1->chloroethoxy)-propionic acid ethyl ester.

This compound is prepared from 30 g of 2-(2'-chloroethoxy)-propionitrile in 30 ml of ethanol

by supplying HCl gas for 2 hours, stirring the imino ether hydrochloride formed in this way into 200 g of crushed ice and extracting the product formed in this way with diethyl ether. The boiling point is 96 - loo°C/12 - 14 mm Hg. The yield is 23.8 g (57.5%). b) 2-[2,-(3"-Acetylamino-211,4,,6"-triiodo-phenoxy)-ethoxy-7-propionic acid ethyl ester.

This compound is obtained by reacting 14.7 g of 3-acetylamino-2,4,6-triiodo-phenol

with 5.6 g of 2-(2'-chloroethoxy)-propionic acid ethyl ester in the presence of o.o37 mol sodium ethylate in approx. 2o ml of ethanol at 4o hours of boiling. The yield is 11 g, the melting point (after recrystallization from ethanol) is 148 - 151°C.

c) 2-[2<1->(3"-Acetylamino-2",4",6"-triiodo-phenoxy)-ethoxy-7-propionic acid. This compound is obtained by saponification of 6.1 g of the ethyl ester with 0.5 g of sodium hydroxide in 30 ml of methanol and a total of 120 ml of water and subsequent acidification of the sodium salt solution. The yield is 4.95 g (85%), the melting point is 173 - 175°C. Example 2

2-(2,-/3"-(N-Ethyl-propionylamino)-2",4",6"-triiodo-phenoxy_7-ethoxy)-propionic acid.

To 6.6 g of 2-[2,-(3"-propionylamino-2",4,6"-triiodo-phenoxy)-ethoxy_7-propionic acid (0.01 mol), dissolved in 12 ml of water at 3.33N potassium hydroxide solution (0.04 mol), add, while stirring, 2.35 g of ethyl iodide dissolved in 1.5 ml of acetone. It is stirred for a further 3 hours at 4o°C.

The isolation of the product ethylated at the nitrogen atom takes place by diluting the reaction solution with 50 ml of water, extracting neutral substances with ethyl ether and acidifying the aqueous phase with 18% hydrochloric acid, whereby a sticky fine is formed, which is taken up in ethyl acetate, washed with water and freed from solvent by evaporation.

The evaporation residue is taken up in a small amount of fresh boiling ethyl acetate (5 ml) and held for 30 minutes at the boiling point of this solvent, after which 2-(2'-/3"-(N-ethyl-propionylamino)-2",4",6 "-triiodo-phenoxy_7-ethoxy)-propionic acid little by little crystallizes.

The melting point is lo5 - lo6°C.

Analysis: calculated for C,CH- J„NOc

lo 2o 3 5

Equivalent weight: calculated-; 687.06, found: 686

C: calculated: 27.97%, found 27.83%

■J: calculated: 55.42?,, found S5.26%

Thin layer chromatogram: Medium: Silica gel "GF 254"

Developer: Benzene/chloroform/glacial vinegar in the ratio 7:3:2

RF value: °t<65>

Solubilities: The substance is insoluble in water, but easily soluble in lower

alcohols and 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-triiodo-

phenol with 32.8 g of 2-(2-chloroethoxy)-propionic acid ethyl ester in the presence of o.176 mol of sodium ethylate in 14o ml of ethanol by boiling for 4o hours under reflux and subsequent saponification of the obtained 2-/2,-(3" -propionylamino-2",4',,6"-triiodophenoxy)-ethoxy_7-propionic acid ethyl ester (45.9 g, melting point 129 - 13o°C, Rp value: o.6o (on silica gel with benzene/chloroform/glacial acetic in the ratio 7:3:2)) with 3.2 g of sodium hydroxide in 200 ml of ethanol and 50 ml of water by boiling for 1 hour under reflux, diluting the reaction solution with 500 ml of water and subsequently acidifying the sodium salt solution. The yield is (after recrystallization from ethanol) 37.5 g (85% of theoretical), melting point 149 - 151°C. Rp value: o.33

(on silica gel using ethyl acetate/isopropanol/ammonia in the ratio 55:35:2o).

Example 3

2-(2'-[3"-(N-Methyl-propionylamino)-2",4",6"-triiodo-phenoxy_7-ethoxy)-propionic acid.

To 19.8 g of 2-[2l<->(3"-propionylamino-2",4",6"-triiodo-phenoxy)-ethoxy_7-propionic acid (0.03 mol) in 35 ml of water containing 7.9 g A solution of 6.4 methyl iodide in 3 ml of acetone is added dropwise to the 85% potassium hydroxide solution (0.12 mol). The reaction solution is stirred for 3 hours at 4o°C.

The isolation of the product obtained, methylated at the nitrogen atom, takes place

according to the method described in example 2.

The crude, still resinous product is taken up in 15 ml of ethyl acetate. Just after

slightly crystallizes out the desired 2-(2W3H-(N-methyl-propionylamino)-2",4",6',-triiodo-phenoxy_7-ethoxy)-propionic acid in pure form.

The yield is 12.4 g (61.6% of the theoretical).

Melting point: 113 - 115°C.

Analysis: calculated for C^H^gJgNOg

Equivalent weight: calculated: 673.06, found: 669.

C: calculated: 26.77%, found: 26.84%

J: calculated: 56.57%, found: 56.4o%

Thin layer chromatogram: Medium: Silica gel "GF 254"

Developer: Benzene/chloroform/glacial vinegar in the ratio 7:3:2.

Rp value: o.53

Solubilities: The substance is practically insoluble in water, but extremely light

soluble in methanol, ethanol and chloroform.

The sodium and N-methylglucamine salt are both extremely easily soluble in water (XLoo g/loo ml solution at 2o°C).

Example 4

2-(2,-/3"-(N-Ethyl-acetylamino)-2",1+",6"-triiodo-phenoxy_7-ethoxy)-butyric acid.

To 5.5 g of 2-/2'-(3"-acetylamino-2",4",6"-triiodo-phenoxy)-ethoxy_7-butyric acid (0.oo84 mol), dissolved in 8 ml of 4N potassium hydroxide solution (o. o32 mol), add 2 g of ethyl iodide (o.ol25 mol) dissolved in 1 ml of acetone. The resulting mixture is stirred for 4 hours at 40°C.

The isolation of the N-ethylated product takes place according to the method described in example 1.

Yield: 4.5 g.

After recrystallization from a small amount of ethyl acetate, this hitherto unknown compound melts at 131°C.

Analysis: calculated for C^ H^ JJ^ O^

Equivalent weight: calculated: 687.06, found: 69o.

C: calculated: 27.97%, found: 28.o8%.

J: calculated: 55.42%, found: 55.6o%.

Thin layer chromatogram: Medium: Silica gel "GF 254"

Developer: Chloroform/glacial vinegar in a ratio of 19:1.

Rp value: o.41

Solubilities: The substance is insoluble in water, but easily soluble in lower alcohols and in chloroform.

Sodium and N-methylglucamine salt: ^loog/loo ml aqueous solution

at 2o°C.

The 2-/2,-(3"-acetylamino-2",4",6"-triiodo-phenoxy)-ethoxy-7-butyric acid used as starting material is prepared in the following way:

a) 8.5 g of 2-(2<1->chloroethoxy)-butyronitrile (Lingo, J. Amer. chem. Soc. 61,

1574 (1939)) dissolved in 15 ml of ethanol is treated for 2 hours with gaseous hydrogen chloride and then boiled for 4 hours under reflux. The imino ether hydrochloride obtained in this way has the formula .

Cl-CH/,-CHo-0-CH(C.H(.)-C(OC-Hc.) = NH.HC1

saponified with ice water, whereby 2-(2'-chloroethoxy)-butyric acid ethyl ester is obtained. The boiling point is lo4 - lo8°C/12 mm Hg, the yield is 5.25 g (45%), nD = 1.44oo.

b) 12.6 g of 3-acetylamino-2,4,6-triiodo-phenol is reacted in the presence of o.o26 mol of sodium urea ethylate for approx. 20 ml of ethanol with 5 g of 2-(2'-chloroethoxy)-butyric acid ethyl ester at 24 hours of boiling, whereby 2-/2'-(3"-acetylamino-2",4",6"-triiodo-phenoxy is formed )-ethoxy_7- butyric acid ethyl ester. The yield is 7.5 g, melting point (after recrystallization from ethanol): 12o°C. R^ value: o.41 (on silica gel with chloroform/glacial acetic acid in a ratio of 19:1). c) 2-/21-(3"-Acetylamino-2",4",6"-triiodo-phenoxy)-ethoxy_7-butyric acid is obtained by saponification of the ethyl ester obtained under b) (1.5 g) with 3.5 ml IN sodium hydroxide solution in 8 ml methanol and 24 ml water by boiling for 1 hour and subsequent acidification of the sodium salt solution. The yield is 1.1 g (89% of the theoretical), melting point (after recrystallization from 50% ethanol): 163 - 165°C. The R^ value is o.195 (on silica gel with chloroform/glacial acetic acid in a ratio of 19:1).

Analysis: C: calculated: 25.51%, found: 25.53%.

J: calculated: 57.77%, found: 57.81%.

Example 5

2-(2,-/3"-(N-Methyl-acetylamino)-2l,,4",6,,-triiodo-phenoxy_7-ethoxy)-butyric acid.

5.5 g of 2-/2'-(3"-acetylamino-2",4",6"-triiodo-phenoxy)-ethoxy_7-butyric acid dissolved in 8 ml of 4N potassium hydroxide solution is reacted with 1.8 g of methyl iodide, dissolved in 1 ml of acetone, by stirring for 4 hours at 4o°C.

The isolation of the product obtained takes place according to the method described in example 1.

Melting point (after recrystallization from a small amount of ethyl acetate):

118 - 12o°C.

Yield: 2.95 g (52.5% of the theoretical).

Analysis: calculated for C lo H lo J o N0C o

Equivalent weight: calculated: 673.o3, found: 678.

C: calculated: 26.77%, found: 26.8o%

J: calculated: 56.57%, found: 56.4o%

Rp value: o.41 (on silica gel with chloroform/glacial acetic acid in a ratio of 19:1). Solubilities: The substance is insoluble in water, but easily soluble in lower alcohols and in chloroform.

Sodium and N-methylglucamine salt: »Jloo g/loo ml aqueous solution at 2o°C.

Example 6

2-(2,-/3"-(N-Ethyl-acetylamino)-2",4,',6,,-triiodo-phenoxy_7-ethoxy)-valeric acid.

To 6.65 g of 2-[2,-(3"-acetylamino-2",4<n>,6,,-triiodo-phenoxy)-ethoxy_7-valeric acid (^0.ol mol), dissolved in d lo ml of aq. 4N potassium hydroxide solution (0.040 mol), add 2.35 g of ethyl iodide, dissolved in 1.5 ml of acetone. It is stirred for 4 hours at 4o°C.

The isolation of the product ethylated at the nitrogen atom takes place according to the method described in the preceding examples.

5.15 g of amorphous 2-(2'-/3MN-ethyl-acetylamino)-2",4",6"-triiodophenoxy_7-ethoxy)-valeric acid are obtained. The yield corresponds to 74% of the theoretical.

Analysis: calculated for C._H„.J.NO,-

±1 i-i- to b

Equivalent weight: calculated: 7ol.12, found: 715

Solubilities: The substance is insoluble in water, but easily soluble in methanol.

The 2-[2'-(3"-acetylamino-2",4",6"-triiodo-phenoxy)-ethoxy_/-valeric acid used as starting material is prepared in the following way:

a) 2-(2'-chloroethoxy)-valeric acid ethyl ester.

27.5 g of 2-(2'-chloroethoxy)-valeronitrile, dissolved in 40 ml of ethanol, treated for 2 hours

under ice-cooling with hydrogen chloride gas, after which the resulting reaction mixture is allowed to stand overnight and then boiled for 4 hours under reflux, whereby the formed iminoether hydrochloride of the formula

Cl-CH2-CH2-0-CH-(C3H7)-C(OC2H5) <=> NH.HC1

secreted. The reaction mixture is stirred into ice water, whereby 2-(2<*->chloro-ethoxy)-valeric acid ethyl ester is formed, which is extracted with ethyl ether and distilled after evaporation of the ether. The boiling point is 119 - 124°C/12 mm Hg, yield 11.2 g (31.6% of the theoretical).

2-(2'-chloroethoxy)-valeric acid ethyl ester can also be prepared by reaction

of 2-chloro-valeric acid ethyl ester with ethylene oxide according to D. Klamann et al, Liebigs Ann. Chem. 71o, 59 - 7o (1967) b) 2-(2,-(3"-Acetylamino-2",4",6"-triiodophenoxy)-ethoxy_7-valeric acid ethyl ester. This compound is prepared from 19 g of 3-acetylamino-2,4,6-triiodo-phenol by boiling for 40 hours with 8.3 g of 2-(2<*->chloroethoxy)-valeric acid ethyl ester in the presence of o.o4 mol of sodium ethylate for about. 3o ml of ethanol. The product is isolated after evaporation of the solvent by washing with a small amount of ethyl ether, absorption of the solid product in ethyl acetate, extraction with water and sodium carbonate solution and evaporation of the ethyl acetate. After recrystallization from ethanol, the melting point is llo - 111°C. Rp value: o.61 (silica gel with chloroform/glacial acetic acid in a ratio of 19:1). c) 2-[2'-(3"-Acetylamino-2",4",6"-triiodo-phenoxy)-ethoxy-7-valeric acid. This compound is obtained by saponification of the ethyl ester produced under b) (1.8 g)

with 3.5 ml IN hydroxide solution in 10 ml methanol and 30 ml water by boiling for 1 hour, evaporation of the methanol, extraction of the aqueous solution with ethyl ether and acidification of the aqueous phase with hydrochloric acid. After recrystallization from 50% ethanol, the melting point is 151°C. Rp value: o.31 (on silica gel with chloroform/glacial acetic acid in a ratio of 19:1).

Example ^

2-(2,-/3*,-(N-Methyl-acetylamino)-2",4",6"-triiodo-phenoxy_7-ethoxy)-valeric acid.

To 6.65 g of 2-/2'-(3"-acetylamino-2",4",6,,-triiodo-phenoxy)-ethoxy_7-valeric acid (10.00 mol) in 10 ml of 4N potassium hydroxide solution is added a solution of 2.15 g of methyl iodide in 1.5 ml of acetone, and the reaction mixture is stirred for 3 - 4 hours at 4o° C. The isolation of this product methylated at the nitrogen atom is carried out according to the method described in the above examples.

3.1 g of amorphous product with a melting point of 100°C is obtained.

Analysis: calculated for C^gH^JgNOg

Equivalent weight: calculated: 687.o9, found: 692

C: calculated: 27.97%, found: 28.25%

J: calculated: 55.42", found: 55.18%

Solubilities: The substance is insoluble in water, but easily soluble in lower

alcohols.

Example 8

2-(2l-/3"-(N-Methyl-acetylamino)-2",4",6"-triiodo-phenoxy_7-ethoxy)-phenylacetic acid.

3.5 g of 2-/2f<->(3"-acetylamino-2",4",6"-triiodo-phenoxy)-ethoxy_7-phenylacetic acid (0.oo5 mol) is dissolved in 6 ml of water, which contains o, o2 mol of potassium hydroxide, and a solution of 1.1 g (0.075 mol) methyl iodide in o.5 ml of acetone is added dropwise to the solution at 2o°C with stirring. It is stirred for a further 3-4 hours at 4o°C, after which the reaction solution is diluted with 5o ml of water, and neutral substances are removed by extraction with ethyl ether.

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

The obtained 2-(2'-/3"-(N-methyl-acetylamino)-2",4",6"-triiodo-phenoxy_7-ethoxy)-phenylacetic acid (3.5 g) melts at 10-103°C . The product is amorphous.

Analysis: calculated for C.QH.oJ„N0c

Equivalent weight: calculated: 721.08, found 728.5.

Thin layer chromatogram: Medium: Silica gel "GF 254"

Developer: Chloroform/glacial vinegar in a ratio of 19:1

Rp value: o.61

Solubilities: The substance is insoluble in water, but easily soluble in lower alcohols.

The 2-[2'-(3"-acetylamino-2",4",6"-triiodophenoxy)-ethoxy_7-phenylacetic acid used as starting material is prepared in the following way:

a) »-(2-chloroethoxy)-benzyl chloride.

To 49.2 g of benzaldehyde-bis-(2-chloroethyl)-acetal L Arbuzova et al, Chem. Abstracts

55, 19318 dc (1961), boiling point 16o - 162°C/2mm Hg7 in 39 ml of acetyl chloride add o.5 ml of thionyl chloride. For 3o seconds, hydrogen chloride gas is introduced into the reaction solution, after which it is heated with stirring for 1 hour at 55 - 6o°C. The reaction mixture is then allowed to stand overnight, after which it is subjected to

fractional distillation. The resulting α-(2-chloroethoxy)-benzyl chloride boils at 128-130°C/2 mm Hg. The yield is 37 g (9o% of the theoretical).

b) α-(2-chloroethoxy)-benzyl cyanide.

This compound is prepared by heating for 3 hours while stirring 17 g

^-(2-chloroethoxy)-benzyl chloride with 9 g of copper (I) cyanide in 15 ml of toluene at 12o - 15o°C. The boiling point is 145 - 147°C/ 2 mm Hg, the yield is 11.5 g (7o% of the theoretical).

c) 2-(2'-chloroethoxy)-phenylacetic acid ethyl ester.

This compound is prepared from 9.8 g of the nitrile obtained under b) by dissolution

of the nitrile in 15 ml of ethanol, addition of hydrogen chloride gas at 15 - 2o°C, boiling for 4 hours under reflux and saponification of the imino ether hydrochloride thus obtained with ice water. The boiling point is 155 - 157°C/2 mm Hg, the yield is log (84% of the theoretical).

2-(2'-chloroethoxy)-phenylacetic acid ethyl ester can also be prepared by reacting 2-chloro-phenylacetic acid ethyl ester with ethylene oxide in the presence of tetraethylammonium bromide according to Klamann, Liebigs Annalen der Chemie 71o, 59 - 7o (1967) . d) 2-[2t<3"-Acetylamino-2",4",6"-triiodo-phenoxy)-ethoxy_7-phenylacetic acid ethyl ester.

This compound is prepared from 15.8 g of 3-acetylamino-2,4,6-triiodo-phenol by boiling for 40 hours with 8 g of 2-(2'-chloroethoxy)-phenylacetic acid ethyl ester in the presence of o.o3 mol of sodium ethylate for approx. . 2o ml of ethanol. After distilling off the solvent, the product is isolated by taking up in 2oo ml of ethyl acetate, washing with water and sodium carbonate solution and distilling off the ethyl acetate. Melting point (after recrystallization from 95% ethanol): 136 - 137°C. Rp value: o.64 (on silica gel with benzene/chloroform/glacial acetic acid in the ratio 7:3:2).

e) 2-(2'-(3"-Acetylamino-2",4",6"-triiodo-phenoxy)-ethoxy_7-phenyl-acetic acid. This compound is obtained by saponification of the ethyl ester obtained under d) (3.65 g)

in 30 ml of 50% ethanol with 6 ml of 1N sodium hydroxide solution by boiling for 1 hour, evaporating the ethanol and acidifying the aqueous phase with hydrochloric acid.

The crude product is taken up in 15 ml of boiling ethyl acetate, whereby dissolution first occurs and crystallization shortly thereafter. The yield is 2.4 g (68% of the theoretical), melting point: 181-182°C, Rp value: o.41 (on silica gel with benzene/chloroform/glacial acetic acid in the ratio 7:3:2).

Example 9

2-(2'-[3i^(N-Ethyl-acetylamino)-2",4",6"-triiodo-phenoxy-7-ethoxy)-phenylacetic acid.

To 3.5 g of 2-[2'-(3"-acetylamino-2",4",6"-triiodo-phenoxy)-ethoxy_7-phenyl-acetic acid 0v>0.oo5 mol) in 7 ml of 2.85N potassium hydroxide solution (o.o2 mol) a solution of 1.72 g of ethyl iodide in 1 ml of acetone is added, and the reaction mixture is stirred in

3-4 hours at 4o°C.

The product ethylated at the nitrogen atom is isolated according to the method described in example 8.

Melting point 85 - 9o°C (the substance is amorphous), yield 3.25 g (89.5% of the theoretical).

Analysis: calculated for ^20^20^3N<^5

Equivalent weight: calculated: 735.13, found 745.

Thin layer chromatogram: Medium: Silica gel "GF 254"

Developer: Chloroform/benzene/glacial vinegar in the ratio 3:7:2.

Rp value: o.63.

Solubilities: The substance is insoluble in water, but easily soluble in lower alcohols.

The above-described, hitherto unknown compounds can be used for administration purposes together with any suitable carrier, particularly in the form of

tablets, granules, capsules, dragées, globules, enemas, suspensions or solutions. Oral preparations are usually preferred.

Both the free acids and their metal and amine salts or their esters can be used.

Example 10

2-(2,-/3"-(N-ethyl-acetylamino)-2,<1>,4",6"-triiodo-phenoxy-7-ethoxy)-propionic acid

Production according to method b:

Ethyl Ester:

This is obtained from 16.7 g of 3-(N-ethyl-acetylamino)-2,4,6-triiodo-phenol (o.o3 mol)

by reaction with 5.94 g of 2-(2'-chloroethoxy)-propionic acid ethyl ester in the presence of o.o33 mol of sodium ethylate in 2o ml of ethanol at 4o hours of boiling, reflux cooling takes place at a bath temperature of 95-loo°C. The solvent is evaporated, and the residue is taken up in 180 ml of chloroform and 100 ml of water. The organic phase is separated, washed with water, dried and evaporated. The residue (16.4 g,

which corresponds to 77% of the theoretical) consists of resinous, crystalline 2-(2'-/3"-(N-ethyl-acetylamino)-2",4",6"-triiod-phenoxy7-ethoxy)-propionic acid -ethyl ester.

Thin-layer chromatogram on silica gel: R^-value = o.78 (benzene/methanol/glacial acetic acid in the ratio 3o:16:8).

Analysis: calculated for C^H^JgNO,., molecular weight: 7ol,o9.

C: calculated: 29.12%, found: 29.42%.

J: calculated: 54.31%, found: 52.9o%.

Free acid:

15.2 g of the above-mentioned ethyl ester (0.021 mol) is 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 is extracted with diethyl ether and acidified. The thus precipitated product is extracted with ethyl acetate. The extract is evaporated. The residue is crystallized and can now be recrystallized from a little ethyl acetate or 50% aqueous ethanol.

Yield: 8.5 g (6o% of the theoretical).

Melting point: 15o - 151°C.

The 3-(N-ethyl-acetylamino)-2,4,6-triiodo-phenol used as starting material is prepared as follows: To a solution of 105.6 g (0.2 mol) 3-acetylamino-2,4,6 -triiodo-phenol in 10 ml (0.8 mol) of 4N potassium hydroxide solution is added dropwise at room temperature with stirring 31 g (0.2 mol) of ethyl iodide, dissolved in 16 ml of acetone. The reaction solution is stirred for 3 hours at 4o - 45°C. The aqueous phase is freed from dissolved ether by evacuation and is then poured into 600 ml of 4% hydrochloric acid.

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

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

After liberation of the salt, 78 g (70% of the theoretical) of pure 3-(N-ethyl-acetylamino)-2,4,6-triiodo-phenol with a melting point of 147°C are obtained.

Analysis: calculated for C, H, J„NO„

J ° lo lo 3 2

Equivalent weight: calculated: 556.91, found: 555

C: calculated: 21.56%, found: 21.6o%

J: calculated: 68.37%, found: 68.32%. Thin-layer chromatogram on silica gel: Rp = o.62 (ethyl acetate/isopropanol/ammonia in the ratio 11:7:4).

The ethyl ether of 3-(N-ethyl-acetylamino)-2,4,6-triiod-phenol is found as a by-product in the ethereal extract.

Example 11,

2-( 2'-/ 3"-( N- methyl- acetylamino)~ 2 "} 4", 6"- triiodo-phenoxy7- ethoxy)- propionic acid

In an analogous manner as described in detail in example 1, 13 g of 2-[2'-(3"-acetylamino-2",4",6"-triiodo-phenoxy)-ethoxysv7-propionic acid (0.02 mol), dissolved in 2o ml of 4N potassium hydroxide solution, with 4.15 g of methyl iodide (o.o3 mol). The yield is 8.05 g (61.5% of the theoretical).

Melting point: 135°C

Analysis: calculated for C^H^JgNOg

Equivalent weight: calculated: 659,ol, found: 662

C: calculated: 25.51%, found: 25.58%

J: calculated: 57.77%, found: 57.9o% Thin-layer chromatogram on silica gel: Rp = o.38 (Developing agent: chloroform/glacial acetic acid in the ratio 19:1).

Solubilities: in g/loo ml solvent at

Example 12

2-(2'-/3"-(N-methyl-acetylamino)-2",4",6"-triiodo-phenoxy-7-ethoxy)-phenylacetic acid

Production according to method b:

To 67 g of sodium 3-(N-methyl-acetylamino)-2,4,6-triiodo-phenolate

(o.118 mol), dissolved in 6o ml of warm dimethylacetamide, is added dropwise under

raring 3o g 2-(2'-chloroethoxy)-phenylacetic acid ethyl ester. The reaction mixture is stirred at llo°C for 40 hours.

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

The crude 2-(21 -/3 "-(N-methyl-acetylamino)-2,4,6"-triiod-phenoxy/- ethoxy)-phenylacetic acid is dissolved in slightly warm ethanol, and on addition of cyclohexylamine is converted this to the cyclohexylamine salt, which crystallizes out of its alcoholic solution. The salt is separated, dissolved in a large amount of water and decomposed by the addition of dilute hydrochloric acid.

In this way, 50.2 g of product with a melting point of 83-84°C is obtained. The yield is 54% of the theoretical.

Analysis: calculated for CloH1oJoN0

ly lo 0 3

Equivalent weight: calculated: 721.08, found: 723.

C: calculated: 31.64%, found: 31.63%.

J: calculated: 52.8o%, found: 52.82% Thin layer chromatogram on silica gel: Rp = o.46 (developing agent: ethyl acetate/isopropanol/ammonia in the ratio 11:7:4).

Example 13

2-(3'-[3"-(N-methyl-acetylamino)-2",4",6"-triiod-phenoxy7-propoxy)-phenylacetic acid. 9 g of 2-/3'-(3"-acetylamino-2",4",6"-triiodo-phenoxy)-propoxy7-phenylacetic acid are dissolved in 17 ml of water, which contains 0.052 mol of potassium hydroxide, and 2, 56 g of methyl iodide in 1.5 ml of acetone. It is stirred for 3 to 4 hours at 4o°C.

Processing takes place in the manner stated in example .8.

Yield: 8.6 g (94% of theoretical).

Melting point: 78°C (sintering at 71°C)

Analysis: calculated for C^I^<Jg>NOj.

Equivalent weight: calculated: 735.13, found: 738

C: calculated: 32.67%, found: 32.65%

J: calculated: 51.79%, found: 51.76%.

Thin layer chromatogram on silica gel: Rp = o.57. (Developing agent: chloroform/benzene/glacial vinegar in the ratio 3:7:2).

Solubilities: in g/loo ml of solvent at 2o°C

Free acid: Water insoluble

methanol loo

ethanol loo

chloroform loo

Sodium salt: Water 3o%

N-methyl-

Glucamine salt: Water 5o%.

The 2-[3,-(3"-acetylamino-2",4,6"-triiodo-phenoxy)-propoxy7-phenylacetic acid used as starting material is prepared as follows:

a) Benzaldehyde-bis-(3-chloropropyl)-acetate:

63 g of benzaldehyde and 170 g of 3-chloropropanol are boiled under reflux

for 40 hours in 150 ml of toluene in the presence of 0.3 g of p-toluene sulphochloride. The reaction water is removed by azeotropic distillation. The product is distilled.

Boiling point: 127 - 132°C/o.o5 mm Hg, n^0'5 C =1.512.

Yield: 14o.5 g (84.5% of the theoretical).

b) "-(3-Chloropropoxy)-benzyl chloride:

A mixture of 132 g of acetate a) and loo g of acetyl chloride is treated in

1 minute with HCl gas and heated for 2 hours to 7o°C. The reaction product is fractionally distilled.

Boiling point: 128 - 131°C/2 mm Hg, nD<21> C = 1.526.

Yield: 74 g.

c) <*-(3-chloropropoxy)-benzyl cyanide is obtained from 65.7 g of <*-(3-chloropropoxy)-benzyl chloride by heating for 3 hours with 30 g of copper (I) cyanide in 50 ml of toluene.

Boiling point: 148 - 151°C/2 mm Hg, n 21.3 ° =1.515.

Yield: 46.6 g (73.5% of the theoretical).

d) 2-(3'-chloropropoxy)-phenylacetic acid ethyl ester is obtained by treatment

of the nitrile c) (46.2 g) with ethanol-HCl and saponification of the thus formed

iminoether hydrochloride.

Boiling point: 152 - 156°C/2 mm Hg, i^<20>'<5> = 1.5o23.

Yield: 50.35 g (89% of the theoretical).

e) 2-/3'-(3"-acetylamino-2",4",6"-triiodophenoxy)-propoxy7-phenylacetic acid ethyl ester is obtained by heating for 48 hours to the boiling temperature of

52.8 g (0.1 mol) of 3-acetylamino-2,4,6-triiodophenol in the presence of 0.1 mol Na-O-CjH,. with 28.3 g (0.11 mol) 2-(3'-chloro-propoxy)-phenylacetic acid ethyl ester in 70 ml of ethanol.

Melting point: 65 - 67°C.

Yield: 72.2 * (96.5% of the theoretical).

f) 2-/3'-(3"-acetylamino-2",4",6"-triiodo-phenoxy)-propoxy_7-phenylacetic acid is obtained by saponification of the ethyl ester e) (50 g) with NaOH in ethanol/

water.

Melting point (after treatment in boiling ethyl acetate) : 154 - 157°C.

Yield: 36.5 ? (75% of the theoretical).

Example I4

2-(3,-/3"-(N-ethyl-acetylamino)-2"'j<1>1",6"-triiodo-phenoxy7-propoxy)-phenylacetic acid 9 g 2-/3 •-( <3 >"-acet<y>lamino-<2>" ,<4>" ,<6>"-triiodo-phenoxy)-propoxy7-phenylacetic acid is reacted in the presence of o.o52 mol of KOH with 2.8 g of ethyl iodide.

Yield: 9 g (96% of the theoretical).

Melting point: 76°C (sintering at 7o°C).

Analysis: calculated for C2iH22<J>3N05

Equivalent weight: calculated: 749.16, found: 742

C: calculated: 33.66%, found: 33.88%

J: calculated: 5o.82%, found: 5o.5o% Thin layer chromatogram on silica gel: Rp = o.58. (Developing agent: benzene/chloroform/glacial vinegar in the ratio 7:3:2.)

Solubilities: This hitherto unknown compound is insoluble in water,

on the other hand, extremely easily soluble in methanol, ethanol and chloroform.

The sodium and N-methylglucamine salts are already easily soluble in water at room temperature.

Sodium salt: approx. 28 g/loo ml of water. N-methylglucamine salt: approx. 5o g/loo ml of water.

Example 15

2-(4l-/3l,-(N-methyl-acetylamino)-2",4",6"-triiodo-phenoxy7-butoxy)-phenylacetic acid 37 g 2-/4•-(3"-acetylamino-2" ,4",6"-triiodo-phenoxy)-butoxy7-:phenylacetic acid (0.05 mol) is reacted in the presence of 0.2 mol of potassium hydroxide solution with 8.5 g of methyl iodide.

Yield: 33 g (88% of the theoretical).

Melting point: 75°C (sintering at 68°C).

This initially formed, low-melting, unstable crystal modification of the product is converted by heating in 15o ml of ethyl acetate into its stable modification which melts at 18o - 183 oC.

Analysis: calculated for C..H-„J„NO,-

21 22. o o

Equivalent weight: calculated: 749.16, found: 744

C: calculated: 33.67%, found: 33.58%

J: calculated: 5o.82%, found: 5o.77%.

Thin-layer chromatogram on silica gel: Rp = o.57 (Developing agent: ethyl acetate/isopropanol/ammonia in the ratio 11:7:4).

Solubility: The solubility of the sodium salt is approx. 5o g/loo ml of water, and the solubility of the N-methylglucamine salt approx. loo g/loo ml of water.

The 2-[4'-(3"-acetylamino-2",4",6"-triiodo-phenoxy)-butoxy7-phenylacetic acid used as starting material is prepared analogously to its homologous compound, which is described in example 13 a) , b), c), d), e) and f).

a) Benzaldehyde bis-(4-chlorobutyl) acetate:

Boiling point: 142 - 144°C/o.o7 mm Hg, i^<20»5> = 1.512

b) *-(4-chlorobutoxy)-benzyl chloride:

_ ^qO

Boiling point: 118 - 121 C/o.o5 mm Hg. nD = 1.521

c) (4-chlorobutoxy)-benzyl cyanide:

Boiling point: 16o - 164°C/2 mm Hg.

d) 2-(4<*->chlorobutoxy)-phenylacetic acid ethyl ester:

Boiling point: 149 - 154°C/2 mm Hg. n^0'5 = 1.5o2

e) 2-A•-(3"-acetylamino-2",4",6"-triiodo-phenoxy)-butoxy?-phenylacetic acid ethyl ester:

Melting point: 124°C.

f) 2-/4'-(3"-acetylamino-2",4",6"-triiodo-phenoxy)-butoxy7-phenylacetic acid:

Melting point: 124°C (sintering at 118°C)

Example 16

2-(4'-/3"-(N-ethyl-acetylamino)-2",4",6"-triiodo-phenoxy7-butoxy)-phenylacetic acid

This product is obtained by reacting the compound from example 15 f)

(37 g) with 9.4 g of ethyl iodide in 0.2 mol aqueous potassium hydroxide solution. Yield: 32 g (85% of the theoretical).

Melting point: a) after precipitation: 74°C (sintering at 66°C).

b) after heating in ethyl acetate: 175 - 177°C.

Analysis: calculated for C22H24J3N°5

Equivalent weight: calculated: 763.18, found: 77o

C: calculated: 34.62%, found: 34.60%

J: calculated: 49.89%, found: 49.86% Thin layer chromatogram on silica gel: Rp = o.58 (Developing agent: ethyl acetate/isopropanol/ammonia in the ratio 11:7:4).

Solubilities: sodium salt: 44 g/loo ml water H-methylglucamine salt: approx. loo g/loo ml of water.

Claims (1)

lo Hitherto unknown amino-triiodophenoxy compounds usable as shadowing components in X-ray contrast agents, characterized in that they are _~3-(N-edcyl-acyl-amino)-2,4»6-triiodophenoxyv7-alkoxy-alkanoic acids of the general formula I where alkyl denotes an alkyl group with 1-4, preferably 1-2, carbon atoms, acyl denotes an alkanoyl group with 2-4", preferably 2, carbon atoms, alkylene denotes an alkylene group with 2-4 carbon atoms, and R denotes an alkyl group with 1-4 carbon atoms or a phenyl group, and their non-toxic metal or amine salts and their esters with lower alcohols» 2<> Amino-triiodophenoxy compounds according to claim 1, characterized in that they are 2-(2'-_~3"-(N-methyl (or ethyl)-acetylamino)-2",4",6"-triiodophenoxy7-ethoxy)-propionic or butyric acid and their non-toxic metal or amine salts and their esters with lower alcohols» 3» Amino-triiodophenoxy compound according to claim 2, characterized in that it is 2-(2'-_"3"-(N-ethyl-acetylamino)-2",4<M>,6"-triiodo-fe nox_7-ethoxy)-propionic acid and its non-toxic metal or amine salts and its esters with lower alcohols.