DE1937211B2 - 4,7,10,13-tetraoxahexadecane-1,16dloyl-bts- (3-carboxy-2,4,6-triiodo-ani-Nd) and its salts, processes for the preparation of these compounds and X-ray contrast media containing these compounds - Google Patents

Description

and its non-toxic, readily water-soluble metal and / or amine salts.

2. Process for the preparation of the compound according to claim 1 and its non-toxic, good Water-soluble metal and / or amine salts, characterized in that 3-amino-2,4,6-triiodobenzoic acid with an acid halide or a mixed anhydride of 4,7,10, 13 - tetraoxahexadecane -1,16-dicarboxylic acid and then the compound obtained, if appropriate, into its non-toxic, readily water-soluble Metal and / or amine salts transferred,

3. X-ray contrast medium, characterized in that it is used as the shading component 4,7,10,13 - tetraoxahexadecane - 1,16 - dioyl - bis (3-carboxy-2,4,6-triiodanilide) or its non-toxic, readily water-soluble metal and / or amine salts contains.

The present invention is the new 4,7,10,13-tetraoxahexadecane - l, 16-dioyl-bis- (3-carboxy-2,4,6-triiodo-anilide) the formula

COOH

COOH

NH-CO- CH ₂ - CH ₂ - [O - CH ₂ - CH _{2] 3} - O - CH ₂ - CH ₂ - CO - HN JJ

or its non-toxic, readily water-soluble metal and / or amine salts.

The invention also relates to a process for the preparation of the aforementioned compounds according to Claim 2 and a new X-ray contrast medium according to Claim 3, which is used as a shading component Compounds according to claim 1 contains.

These compounds are said to be preferably parenteral Bile contrast media (in the form of saline solutions) may be used.

Have bile contrast agents administered orally, as far as they are known to this day, the disadvantage that they only occur several hours after their administration Allow contrast images of the biliary organs. The image quality is also different Extremely dependent on circumstances and therefore often unreliable.

The previously known intravenously administrable bile contrast media, on the other hand, are in the bile insufficient concentration. A roughly equal part of the input ends up in the urine.

The parenteral cholecystography agent most frequently used to date also always leads occasionally again to fatal incidents (La Radiologie Medtca, Vol. LH, July 1966, p. 626 bis 657).

There is accordingly a need for a bile contrast agent which can be administered intravenously is particularly specifically concentrated in the bile, has only moderate urgency

'and is well tolerated. The crossing of the Contrast medium taken from the bloodstream into the bile at a particularly high speed; i.e. that Contrast media should have a high biliary transport maximum.

It has now been found, surprisingly, that 4,7,10,13-tetraoxahexadecane-l, 16-dioyl-bis- (3-carboxy-2,4,6-triiodo-anilide) (Substance A) To see these specifics, a parenteral biliary contrast medium is required Has properties to a particularly high degree.

The following tables! II and III show the ratios quantitatively, in comparison

with the two previously known, in parenteral cholecystography means Substances B and C already in practical use. The data were always based on identical methods and under identical external conditions Conditions determined.

Substance A:

4,7,10,13-tetraoxahexadecane-1,16-dioyl-bis- (3-carboxy * 2,4,6-triiodo-anilide).

Substance B;

Substance C;

¹ 4

Adipinoyl-bis- (3-carboxy-2,4,6-triiodo-anilide) (See United States patent 2 776 241).

gyyiy
(Acidum ioglyeamjcum)
(See U.S. Patent No. 2,776,241).

Tabel:

link

Toxicity

DL ₃₁₁

mg / kg mouse intravenous injection time

30 seconds

120 seconds elimination of the contrast medium

in% of the i.v. input of 100 mg / kg

in rabbits after 3 hours

bile

urine

Elimination ratio

Bile / urine

A.
B.
C.

5100
2400
4200

5200 3400 4200

77 37 30th

18th
38
41

4.3

0.98

0.73

Evaluation of cholecystography

Three pairs of dogs weighing 7 to 10 kg underwent comparative cholecystographic exams subjected, using the X-ray contrast agents A, B and C, which in the form of their N-methylglucamine salts in doses accordingly 66.9 mg iodine / kg body weight were administered intravenously. Each pair of animals was successively at intervals subjected to these cholecystographic examinations with each of the three compounds for 5 days, namely according to the scheme of the Latin square in the following:

1st pair: A, B, C

2nd pair: B, C, A

3rd pair: C, A, B

The test results are shown in Table II, with the quality of the contrast images obtained in cholecystographic indices according to Hoppe (cf. J. O. H ο ρ ρ e, J. American Pharmaceutical Association Sei. Vol. 48, pp. 368 to 379 [1959]). The compound A shows the highest cholecystographic indices.

The data in Tables I and II demonstrate the significant advance over Compound A. the well-known compounds B and C similar constitution in terms of tolerance, biliary tract and shadow density clearly after.

Table II

Cholezisiouraphy

(Holezyslographic indices according to Hoppe; values from 0 4:
ü = negative. 1 = weak, 2 = sufficient. 3 = good. 4 = very good

Cholecystography

C'holczystographic indices according to Hoppe; Values from 0-4: 0 = negative, I = weak, 2 = sufficient, 3 = good, 4 = very good.

Means from all values

Ver Time 1 pair 2 pairs 3rd pair binding (min) Average Average Average A. 15th 0.75 1.75 1.5 30th 1.5 2.25 1.75 45 2.0 2.75 2.25 60 2.25 3.0 2.5 90 2.25 3.25 2.5 120 45 3.25 2.75 240 2.5 3.0 2.75 360 2, r 3.25 2.75 480 2.5 3.0 2.5

1.33 1.83 2.33 2.58 2.66 2.83 2.75 2.83 2.66

Ver Time 1 pair 2 pairs 3rd pair middle nding (min) Average Average Average from all
Values B. 15th 0.25 0.75 0.25 0.41 30th 0.75 1.5 0.5 0.91 45 1.0 1.5 1.0 1.16 60 1.5 1.5 1.25 1.41 90 1.75 2.0 1.25 1.66 120 2.0 2.0 1.5 1.83 240 2.5 2.25 2.25 2.33 360 2.75 2.25 2.25 2.41 480 2.5 1.75 1.75 2.00 C. 15th 0.5 0.5 0 0.33 30th 0.75 1.0 0.75 0.83 45 1.0 1.0 1.25 1.08 60 1.5 1.25 1.25 1.33 90 1.5 1.25 2.0 1.58 120 1.5 1.5 2.0 1.66 240 1.5 1.75 2.25 1.83 360 1.75 1.75 2.5 2.00 480 1.25 2.0 2.5 1.91

35

40

45

50 Also with regard to the kinetics of biliary excretion the compound A obtained according to the invention is the previously used intravenous bile contrast media Clearly superior to B and C.

G. Miller et al., Switzerland, med. Wochenschrift, 99, 577-581 (1968) have shown that the biliary transport maxima for the assessment and appropriate dosage of intravenously administered GaI ·

lenkontrastmitteln of authoritative ^"1 · importance

The greater the individual ability of an intrave

nasal cholecystography means, rapidly from the

Blood flow through the biliary organs recorded

and to be eliminated through this, ever higher

so the biliary transport maximum lies, the greater ßere shadow densities and thus all the better X-ray contrast images; the biliary organs can be preserved will.

An increase in the dosage beyond the transport capacity of the biliary organs door the contrast agent in question has no improvement whatsoever Contrast images result. The excess of contrast medium is excreted by the kidneys, see chap which is evident from the increased kidney excretion when the application speed is increased becomes visible (Fig. i, 2 and 3). Any excess burdens the organism completely unnecessarily and diminishes the safety margin of the X-ray examination. to

In the table ItI and the F i g. 1, 2 and 3 are the Data on the determination of the biliary transport maxima of compounds A, B and C are shown.

15 methodology

Anesthetized dogs were puffed up by catheterizing the bile duct and ureter the biliary and urinary secretions collected and analyzed.

After the galls and urinary secretion become stable was the x-ray contrast to be checked medium solution infused into the left jugulanene.

The infusion rate was gradually increased increases:

1. 0.81 µΜkg " ¹ min" ¹ in the first 180 minutes (μΜ = micromoles),

dkg "" 3.24 μΜ kg 'min' from the? 00. up to the 420th minute.

2. Ϊ.62 μΜ kg ' ¹ min " ¹ from the 180th to the 300th minute,

The bile and urine were collected every 30 minutes. The iodine content of the samples was measured using of an auto analyzer. The X-ray contrast medium quantities were derived from the iodine levels. expressed in micromoles, calculated which per kg of animal and minute were eliminated.

Intravenous
infusion Table III urine Connection B Urine. iM kg 'min' urine μΜ kg ' ' min "' 0.020 CaIIc 0.006 0.005 Time 0.029 0.029 0.034 0.054 (min) 0.81 Determination of biliary transport maxima 0.066 0.176 0.070 0.108 0.81 Average of 4 experiments on dogs. secretion 0.080 0.286 0.086 V; binding C 0.145 30th 0.81 Connection Λ 0.092 0.319 0.103 (•Everyone 0.164 60 0.81 bile 0.114 0.348 0.110 0.00? 0.182 90 0.81 0.070 0.228 0.342 0.190 0.13? 0.308 120 0.01 0.401 0.357 0.385 0.287 0.291 0.387 150 1.62 0.488 0.448 0.460 0.370 0.361 0.467 180 1.62 0.527 0.533 0.472 0.431 0.412 0.498 210 1.62 0.542 0.841 0.475 0.565 0.425 0.698 240 1.62 0.533 1.225 0.477 0.637 0.469 0.921 270 3.24 0.637 1,526 0.461 0.685 0.552 0.999 300 3.24 0.749 1.644 0.464 0.680 0.580 1,157 330 3.24 0J86 0.454 0.13-tetran * 0.624 Ift-Hirwi 360 3.24 0.794 The 4.7.1 0.651 390 0.785 0.640 420 0.914 0.720 0.828 0.732 0.907 comment

Table HI and the graphs (FIGS. I to 3) show that the compound A obtained according to the invention has a significantly greater office transport maximum (transport capacity) than the two previously known compounds B and C. _ss

The transporliuaxima are roughly as follows: A: 0.83 to 0.91 μΜ kg ¹ mm ¹

-i

B: 0.45 to 0.47 μΜ kg " ¹ min" C: 0.65 to 0.73 μΜ kg " ¹ min" ¹ .

60

The transport capacity of connection A is almost twice as large as that of the previously known, bis Intravenous biliary contrast medium most widely used today B.

Apparently due to the faster elimination of Galkn from connection A the biliary organs are also expanded somewhat more, which is the density of the shadows increased again.

(3-carboxy-2,4.6-triiodo-anilide) is mainly used in Form of its concentrated, aqueous, non-toxic Metal and / or amine salt solutions used.

The following metal salts are preferably considered: the sodium and / or lithrum salt; as amine salts preferably alkanolamine salts, for example the N-methylglucamine, diethanolamine or the Mprpfaeftnsalz. Mixtures of these can also be used Salts are used. In some cases one can also emen part of the alkali ions by Ca or Replace Mg ions.

The invention ^, lO ^ VTetraoxahexadeean-1,16-droyl - bis - (3 -carboxy-24,6-triiodine-smilid) is thus made by salt formation as well as mixing with one or more carriers processed into a pharmaceutically acceptable form suitable for use as a parenteral X-ray contrast medium.

Ab ^ urehalogemd of 4,7,10,1 - TetraoitaheXadecan-l, 16-dicarboxylic acid is invented by iler

moderate reaction, preferably the acid chloride of the formula

j

^L O- CH ₂ - CH ₂ - CO - Cl)

used.

As mixed anhydrides of 4,7, I 0,13-Tetraoxaliexadecan-Uo-dicarboxylic acid come into consideration: their anhydrides with phosphoric acids (ζ. Β. a 4,7,10, 13 - tetraoxahexadecane -1,16 - dioyl - diphosphite), with Hydrazoic acid, with carboxylic acids or with carbonic acid half-esters.

Production of 4,7,10,13-tetraoxahexadecane-1,16-dioyl-bis- (3-carboxy-2,4,6-triiodanilide)

10.3 g of 3-amino-2,4,6-triiodo-benzoic acid (0.02 mol), suspended in 20 ml of dimethylacetamide, are mixed with 3.65 g of 4,7,10,13-tetraoxahexadecane at 95 ° C. 1,16-dicarboxylic acid dichloride was added and the mixture was then stirred ^{at 95 to 100 ° C. for a further 3 hours.}

The reaction mixture is stirred into about 200 ml of water. The excreted product is after after decanting the water dissolved in 4 ml of 30% sodium hydroxide and 200 ml of water, with Akti.kohle decolorized and added dropwise to 100ml water containing 5ml 36% hydrochloric acid.

The resulting precipitate (11.1 g; mp. 125 to 130 ^r C) in 18 ml water, 2 ml of 30% ammonium hydroxide containing dissolved, mixed with 20 ml of saturated ammonium chloride solution and for 2 days at 5 ° C, wherein the ammonium salt of 4.7,10.13-tetraoxahexadecane-1,16-dioyl-bisi (3-carboxy-2,4,6-triiodo-anilide) separates out.

This is filtered off, dissolved in water and mixed with hydrochloric acid, the free acid separating out. This has the following characteristic data on:

Melting point: 125 C (sintering at 110 C).

Analysis for C ₂₆ H ₂₆ J ₆ N ₂ O ₁₀ : Molecular weight: 1287.92 (after drying in vacuo at 120 ° C):

Calculated ... C 24.24. J 59.12%;

found .... C 24.26. J 59.07%.

Thin layer chromatogram:

on silica gel with butanol / glacial acetic acid / water = 3: 2: 1 as FHeßflrittel: Rf = 0J3.

Solubilities:

Salts:

Solubilities in water at 20 ^° C.: sodium salt: about 100% (w / v), N-methylglucamine salt: about 100% (w / v).

The 4,7,10,13-tetraoxahexadecane-f, 16-dicarboxylic acid dichloride required as an intermediate manufactured as follows:

a) 1484 g of 4,7,10,13-tetraoxahexadecane-l, 16-dinitrile U.S. Patent 2401607) become at 15 ° C a solution of 232 g (2.45 mol) of concentrated sulfuric acid in 290 ml of absolute ethanol. The mixture is refluxed for 15 hours with stirring, cooled, and the reaction solution is poured in 1000 g of ice and 250 g of ammonium sulfate, extracted the formed 4,7,10,13-tetraoxahexadecane-1,16-dicarboxylic acid diethyl ester with methylene chloride, dry * net the extract, the solvent evaporates and the product is distilled.

Yield: 97 g 4,7,10,13-tetraoxahexadecane-1.16-dicarboxylic acid diethyl ester. Boiling point: 190 to 195 ° C / 0.005mm Hg.

b) 97 g of 4,7,10,13-tetraoxahexadecane-1,16-dicarboxylic acid diethyl ester, dissolved in 200 ml of water, become added to a solution of 24.4 g of NaOH in 50 ml of water. The reaction mixture is on for 90 minutes heated in the steam bath.

After cooling, the reaction mixture is extracted with ether. The aqueous phase becomes Dry evaporates. The residue is washed with acetone.

The resulting di-Na salt of 4,7,10,13-tetraoxahexadecane-1,16-dicarboxylic acid (107 g, melting point 102 to 104 ° C. Content 87.8%, yield: 100%) is taken up in about 300 ml of water and the calculated Amount of concentrated hydrochloric acid converted into the free dicarboxylic acid. The reaction solution becomes Dry evaporates.

The residue is taken up in acetone, the precipitated sodium chloride is filtered off and the acetone filtrate is completely evaporated.

The evaporation residue is extracted with diethyl ether. After evaporation, the dried ether extract becomes a residue of 56 g of liquid 4,7,10,13 - tetraoxahexadecane -1,16- dicarboxylic acid.

Yield: 68% of theory. Equivalent weight: 149.5 (calculated 147.2).

c) 4,7,10,13 - tetraoxahexadecane - 1,16 - dicarboxylic acid dichloride is converted from the free acid b) (56 g) by carefully adding about 100 ml of thionyl chloride and then heating to 40 to 50 ° C obtain.

The excess thionyl chloride is evaporated off in vacuo after the reaction solution has been filtered clear. The evaporation residue consists of the desired dicarboxylic acid dichloride.

This compound is practically insoluble in water, but ethyl acetate and chloroform, on the other hand Easily soluble in lower alcohols.

Production of the X-ray contrast media

4,7,10,13 - tetraoxahexadecane - 1,16 - dioyl - bis (3 - carboxy - 2,4,6 - triiodo - anilide) will correspond to c its preferred use as parenteral GaI steering contrast center! usually to injectable or ei processed infusible saline solutions

Aqueous solutions of alkanolamine salts of the compound mentioned are particularly suitable for this purpose possibly with a content of the corresponding sodium or lithium salt or possibly calcium odei Magnesium salt, these solutions usually contain about 140 to 400 mg iodine / ml.

example 1

a) 4,7,1 O, 13-Tetfaoxahexadecan-1,16-dioyl-bis- (3-carboxy-2,4,6 * triiodo-anilide) (Molecular weight 1287.92) 508g

b) N-methylglucamine 117.1 g

c) Mät / iUttihydf oxide 7.6 g

d) Ethylene disodium nitrogen, N'-tetra-acetic acid disodium salt 0.1 g

e) water, double-distilled to 1000 ml

The salt solution is prepared according to the above formulation, adjusted to pH 7.1 ± 0.2, finely filtered, filled into ampoules of 10 and 20 ml and sterilized.

Iodine content: 300 mg / ml.

10

Example 2

4,7,10,13-tetraoxahexadecane-1,15-dioyl-bis- (3-carboxy-2,4,6-tri-

iodine anilide) (1287.92) 254 g

N-methylgukamine 39 g

c) sodium hydroxide 7.78 g

d) Ethylenediamine-tyN'-tetra-acetic acid disodium salt 0.1 g

e) water (double distilled) to 1000 ml

The saline solution is prepared according to the above formulation, adjusted to pH 7.1 ± 0.2, finely filtered, filled into 100 ml bottles and sterile.

Iodine content: 150 mg / ml.

For this purpose 3 sheets of drawings

Claims (1)

19 37 2Π Patent claims: id) of the formula COOH COOH NH - CO - CH ₂ - CH ₂ - [O - CH ₂ - CH ₂ ] ₃ - O - CH ₂ - CH ₂ - CO - HN