DE2547789C3 - 5-Hydroxypropionylamino-2,4,6-triiodoisophthalic acid bis (dihydroxypropylamides), process for their preparation and X-ray contrast media containing them - Google Patents

Description

in which - C ₃ H ₅ (OH) ₂ denotes the 1,3-dihydroxyisopropyl radical or the 2,3-dihydroxypropyl radical.

2. 5 - α - hydroxypropionylamino - 2,4,6 - triiodoisophthalic acid - to - (1,3 - dihydroxyisopropylamide).

3. Process for the preparation of the 5-hydroxypropionylamino - 2,4,6 - triiodo - isophthalic acid - bis- (dihydroxypropyl-amide) according to patent claim 1, characterized in that a reactive functional derivative of 5-amino- or 5-nitro-isophthalic acid of the general formula (I I)

CO-X

where Y is hydrogen or iodine atoms, Z is an α-hydroxypropionylamino group, its hydroxyl function can be masked by easily reversible acylation or etherification, or an amino or nitro group and —CO - X mean reactive acid or ester radicals, with a dihydroxypropylamine, the hydroxy functions of which can be masked by esterification, acetalization or ketalization, and, if appropriate, reacted after reduction of the 5-nitro group to the 5-amino group, the aromatic nucleus is triiodinated and the aromatic amino group acylated by reaction with a reactive derivative of a hydroxypropionic acid of the general formula (III)

CH ₃ -CH-CO-X
OH

(HI)

whose hydroxyl function is also masked by slightly reversible acylation or etherification can be and wherein —CO — X is a reactive acid or ester radical.

4. X-ray contrast media, particularly suitable for vasography, urography and for visualization fo of the aquarium spaces, containing 5 - hydroxypropionylamino - 2,4 as shading components, 6 - triiodo - isophthalic acid - bis - (dihydroxypropylamide) according to claim 1.

The present invention relates to the new 5-hydroxypropionylamino-2,4,6 which are readily soluble in water - triiodo-isophthalic acid - bis - (dihydroxypropylamide) of the general formula (1)

CONH-C ₃ H ₅ (OH) ₂

CH ₃ -CHCONH I CONH-C ₃ H ₅ (OH) ₂
OH

wherein -C ₃ H ₅ (OH) _{2 is} 1,3-dihydroxyisopropyl [-CH (CH ₂ OH) ₂ ] or 2,3-dihydroxypropyl [-CH ₂ -CH (OH) -CH ₂ OH], Process for their production and non-ionic X-ray contrast media, which are particularly suitable for vasography, urography and for displaying the liquor spaces, and which contain the above-mentioned compounds as shading components.

5 - acylamino - 2,4,6 - triiodo isophthalic acid - diamide and their use in X-ray contrast media are known from CH-PS 5 44 551. They contain exclusively simple, unsubstituted aliphatic acetyl groups or at best propionyl or Butyryl groups. Your carbamide groups

(Ar) -CO-N

are usually derived from secondary amines, which allow these bulky substituents to rotate freely hinder on the 2,4,6-triiodo aromatic. This creates additional centers of asymmetry, which in the Synthesis lead to the formation of several racemates, which can usually hardly be separated. R. B a rk e, "Röntgenkontrastmittel", p. 277, G. T h i e m e, Leipzig 1970, J. H. Ackermann et al., Tetrahedron Letters 44 (1969), pp. 3879 and 4487, see also CH-PS 5 44 551 columns 12/13, in particular Column 12 c) Syn anti-isomerization.

The previously known relevant 5-acylamino-2,4,6-triiodo-isophthalic acid diamides, which differ from primary Derive amines are only sparingly soluble in water, which makes them useful in aqueous X-ray contrast medium solutions excludes.

The corresponding diamides, which are derived from secondary amines, have the disadvantage that they obtained in the synthesis as mixtures of isomers which cannot be separated. The application of However, solutions of not absolutely pure and isomer-free compounds in humans are not acceptable. For example, have impurities of less than 5% in a comparable water-soluble one X-ray contrast agent the iodomethanesulfonic acid «, y-dihydroxyisopropylamide (CH-PS 5 50 003) the intracisternal tolerance halved compared to the pure connection.

Of the previously known relevant compounds, this is earned under the non-proprietary name METRIZAMIDE S-acetylamino-S-N-methyl-acetylamino-2,4,6-triiodo-benzoyl-glucosamine that has become known special

icht. Compare with connection no. 11 of US-PS ₁₇ OI771, GB-PS 13 21 591, CH-PS 5 44 551, OE-PS 134 and DT-OS 20 31 724; Publications by Γ Almen, S. Salvesen, K. G ο 1 ma ι 'eta fcadiologia Suppl. 335 (1973), 1 - 13, 233 - 75, 2-38. It has practically unlimited solubility in water and is also well tolerated. Disadvantages are its difficult accessibility, the presence in the form of a practically inseparable mixture of isomers and, in particular, its poor stability, which significantly limits the usability and makes handling more difficult.

The compounds of the general formula (I) according to the invention have the disadvantages of the comparable ones already known connections.

They are characterized by the following properties:

They are the first nonionic 2,4,6-triiodo-benzene derivatives which are readily soluble in water and which are not mixtures of isomers.
Contrary to expectations, the optically active compounds of the formula I are generally even more soluble in water than their corresponding racemates.

This phenomenon is very astonishing as it is well known to every professional - which, by the way, too it was observed in the case of the new compounds present here - that pure compounds are a have significantly lower solubility than their impure crude products.

Means with these compounds as active ingredient have all the advantages of the water-soluble, nonionic X-ray contrast media on, but do not have the disadvantages of the solutions proposed so far afflicted. The advantages are: The aqueous solutions have no electrical conductivity, the Influence on the nervous conduction system is reduced, which is associated with less irritation of the Nerve roots z. B. in the representation of the liquor spaces.

The osmotic pressure of the aqueous solutions is reduced by half or more compared to corresponding salt solutions.
This improves the general tolerance, especially in dehydrated patients, and allows good organ images even in patients with damaged kidneys.

The disadvantages of the solutions proposed so far are: The previous water-soluble nonionic ones X-ray contrast compounds consisting of 2,4,6-triiodinated aromatics are mixtures of isomers, that cannot be cleaned perfectly. In addition, their stability is still insufficient. The highly water soluble aliphatic iodomethanesulfonamides - see GB-Pa 13 59 908 - are again far less stable. Their urinary rate is suitable for use as a Urographic agents are usually not sufficient. This affects the usability as general applicable X-ray contrast media and also increases the burden on the organism Foreign matter.

Their stability is sufficient for any handling. It exceeds that of the iodomethanesulfonic acid ay-dihydroxyisopropylamide (1) mentioned above and that of METRIZAM1DES (2) by far. Aqueous solutions of the new X-ray contrast media can be subjected to heat sterilization without decomposition, while solutions of (1) and (2) must not be heated to above 40 or 60 ° C. During the heat sterilization of (1) and (2) so large amounts of iodide are released that this procedure has to be disregarded. Solutions of (1) and (2) must therefore be sterile-filtered after their preparation and stabilized by lyophilization.
Your urine excretion rate

ίο is enough to that of the common urography agents approach. This extends the range of applications as an X-ray contrast medium considerably, since urography the most common x-ray diagnosis is which requires water-soluble x-ray contrast media.

The rapid excretion also increases the burden on the organism from exogenous substances diminished, although this advantage does not appear in the determination of acute toxicity occurs.

ίο your general tolerance e.g. B. after intraperitoneal or intravenous application is excellent and is not used practically by anyone today X-ray contrast medium exceeded. Their intra-carotid tolerance is just as outstanding as well as their maximum tolerance for the central nervous system (CNS). The intracerebral and intracisternal toxicity are unusually low. The good solubility in water, the extraordinary high general and local tolerability, rapid elimination from the organism through the urinary tract and the high stability are the prerequisites for the superior suitability of the new compounds of formula (I) as shading components in X-ray contrast media for vasography, urography and the visualization of the liquor spaces.

These advances over the prior art include the introduction of the hydrophilic α-hydroxypropionyl radical

H ₃ C-CH-CO-

OH

Thanks to.

The following tables show the properties that are decisive for the intended use

the new shading components A, B, C and D,

those of the structurally closest partially known compounds E and F,
of two compounds G and H proposed for practical use, the optimal compounds from CH-PS 5 44551,
of the best readily water-soluble iodine methanesulfonamide 1 from CH-PS 5 50 003, which is proposed as an X-ray contrast medium,
as well as the one built according to classical principles

and as a saline solution used modern vasography means K. that also for the Representation of the liquor spaces is suitable,

listed.

The data were obtained in all cases using identical methods and under the same external conditions definitely. They are therefore quantitatively comparable with one another.

It means

A = L-5-a-hydroxypropionyliimino-2,4,6-triiodo-

isophthalic acid bis (!, 3 dihydroxyisopropy 1-

amide) (example 1),
B = DX-Sa-Hydroxypropionylamino ^ Aö-trijod-

isophthalic acid bis (i, 3-dihydrox j isopropyl-

amide) (example 2),
C = LSa-hydroxypropionylamino ^ Ao-triiodo-

isophthalic acid bis (2,3-dihydroxypropylamide) (Example 3),

D = D.L-S-a-Hydroxypropionylamino ^ Ao-triiodisophthalic acid-bis- (2,3-dihydroxypropylamide)

(Example 4),
E = S-acetylamino ^ Ao-triiodo-isophthalic acid-bis-

(1,3-dihydroxyisopropylamide), F = S-acetylamino ^ Ao-triiodo-isophthalic acid-bis- (2,3-dihydroxypropylamide)

(CH-PS 5 44551: NYEGAARD connection

No. 47),
G = 5-acetylamino-2,4,6-triiodo-isophthalic acid bis (N-methyl-2,3-dihydroxypropylamide) (CH-PS 5 44 551: NYEGAARD compound

No. 9),
H = S-Acetylamino-SN-methyl-acetylamino-2,4,6-triiodo-benzoyl-glucosamine (non-proprietary name [international non-proprietary name INN] = METRIZAMIDE)

(CH-PS 5 44 551: NYEGAARD connection no.11),
= Iodomethanesulfonic acid ay-dihydroxyisopropylamide

(CH-PS 5 50 003),
K = 5,5 '- (Adipoyldümino) -bis- (2,4,6-triiodo-N-methyl-isophthalamic acid (non-proprietary name [IN R] = ACIDUM IOCARMICUM).

Table 1 and 2 explanations

Intravenous toxicity:

Concentration of the injection solutions:

mgJ / ml.

Injection rate: 20 g J / kg / 60 ". Intraperitoneal toxicity:

Concentration of the injection solutions:

mgJ / ml.
Intracerebral toxicity:

5 ml / kg were always administered.

The concentrations were varied. Intracisternal toxicity:

Concentrations of the solutions: 400 mgJ / ml.

Intracarotid toxicity:
Injection into the carotid of the rat. Concentration and injection rate as for iv toxicity.

The concentrated required for a comparative study of the compounds E and F aqueous solutions could not be prepared because of insufficient solubility.

Ver Soluble wedge in water 60 ° C Thin film 1, Rf 0.2 0 = Minor spots am in% (g / V) at "C 115 chromatogram 1, R _f 0.28 manure on silica gel (F 254) , Rf 0.17 32 with 200 μg with run , R _f 0.14 40 medium A and B , R _r 0.23 20 ^G C 40 "C Number of spots, R _f , R _f 0.16 A. 89 104 34 A: , R _r O, 38 B: , R _f 0.28 B. 30th 30th 0.5 A ': 1, R _f 0.43 C. 15.7 21 A: , R _r 0.16 1.5 B: , R _f 0.16 D. 14th 20th A ': A: 4, R _f 0.19; B ': 0.27; E. 0.2 A: 0.34; B: 0.37 F. 0.5 0.8 A: B: 3, Rf 0.34; B: 0.4; G 55 0.49 A: 1 + 4, R _f 0.3 + (0.11; 0.36; 0.49: 0.64) B: 2 + 1, R _f 0.19; H -80 0.14 + (0.24)

Eluent:

A = methylene chloride / methanol = 10: 3.

A '= chloroform / methanol / ammonia (25%) = 6: 3: 1.

B = ethyl acetate / ethanol / ammonia (25%) = 15: 7: 6.

B '= methyl ethyl ketone / acetic acid / H ₂ O = 15: 3: 5.

Table 2

Ver
binding Toxicity DL ₅
mouse ο in mgJ / kg intra-
cerebral
(48 h) Rabbits
intracisternal rat
intra-
carotid ideal Urinary discharge
divorce
Rabbits viscosity in centipoise
aqueous solutions 400 mg
J / ml intravenous
(12 days) intra-
peritoneal
(12 days) 1500 (48 h) in the
iv dose
of 200 mg
J / kg after 3 h "C containing
300 mg
J / ml 40.6
16.1 A.
E. 21800 > 20,000 820 250 6500 77 20th
37 8.95
4.70 F.
G 15 700 - 81

continuation

Vcr- toxicity DU ₀ in mgJ / kg

binding

mouse

intravenous intra- intra-

peritoneal cerebral

(12 days) (12 days) (48 h)

Rabbit Ratle intracisternal inlra-

carotid ideal

(48 h)

H 10 200 *) 4,800 1400 100 I. 4 700 385 89 K 5,500 280 37

4000
-5000

Urinary excretion
Rabbits
in the
iv dose
of 200 mg
J / kg after 3 h

Viscosity in centipoisc

78

50

aqueous solutions
revealing

300 mg 4 (K) mg

J ml .l / m!

11.7
5.98

77.8
26.9

*) FL W ei 11 et al. have on 170th Am. Chem. Soc. Meeting, Chicago, August 1975, for Compound H a DL ₅₀ I. v. Mouse of 23.8 g / kg, that is 11.4 g J / kg, genannl.

results
Tables 1 and 2 show:

The compounds according to the invention are uniform, pure and free from isomers. They are easily soluble in water. Your general tolerance is optimal. In terms of compatibility, they generally outperform the best previously known compounds G, H, I and K considerable. Compound A intravenous tolerance is far higher than that of the best X-ray contrast media used practically until today.

Concentrated solutions of Compound A are less viscous and therefore more easily injectable than that the best known compound H.

The structurally closest prior known isomer-free Compounds E and F are by far less water soluble than the corresponding new ones Hydroxyacylamides. You are yourself for determining their intravenous, intracerebral and intracisternal Toxicity far too insoluble.

The previously known non-ionic, water-soluble components used as shading components in X-ray contrast media The proposed compounds G and H represent inseparable mixtures of isomers.

The also previously known nonionic, water-soluble iodomethanesulfonic acid amide derivative I has comparatively significantly lower tolerances.

Compound K shows the pharmacological parameters of a well-established X-ray contrast medium with a similar scope and serves as a comparison.

stability

Aqueous solutions of the new relevant compound A, the comparable previously known compound H and from iodomethane sulfonic acid a ^ '- dihydroxyisopropylamide (Compound 1) were examined.

Solutions of the compounds filled in under nitrogen A and H with a content corresponding to 400 mg J / ml were during 30 'and 15 hours (h) heated to 120 C. pH, iodide content and aspect were examined (Table 3).

Table 3

Ver parameter Alisgang values .W / 120 C 15 h 120 C binding A. PH 7.43 7.29 5.15 IpH -0.14 -2.28 mg J '/ ml 0.15 0.3 1.8 IJ ' + 0.15 ■ 1 1.65 aspect clear colorless solution clear colorless solution clear slightly colored solution H pH 6.54 6.45 2.65 IpH -0.09 -3.89 mg J '/ ml 0.66 1.71 40.60 IJ ' + 1.05 λ 39.94 aspect clear solution slightly colored solution brown suspension I- black sediment

Aqueous solutions of iodomethanesulfonic acid <*,> - dihydroxyisopropylamide - compound I - with a content of 300 mg J / ml were kept at 37 and 60 ° C. pH and iodide content were measured. The following results were obtained (Table 4).

Table 4

PH
I pH
mg J 7 ml

draws that a reactive functional derivative can be obtained in any order in a manner known per se of 5-amino- or 5-nitro-isophthalic acid of the general formula (II)

CO-X

Baseline values

7.35

0.0

6.8

-0.55

0.15

63 h / 60 ° C

4.71

-2.64

1.05

co-x

From the data of Tables 3 and 4 gives: Aqueous solutions of the compound A can be heat-sterilized (30 '12O ⁰ C or 60' 100 ⁰ C). Solutions of the previously known compound H decompose so considerably in the heat that heat sterilization must be ruled out. This product (METRIZ-AMID) is therefore used in the form of the lyophilisate as an X-ray contrast medium. The manufacturer also recommends avoiding the heating of aqueous solutions above 60 ^{° C.} The relative instability significantly affects the handling and safety of METRIZAMID.

Solutions of compound I are up to 37 ° C stable, but begin already at 60 ⁰ C very slowly release iodide. The compounds of the formula (I) do not have these serious disadvantages.

Thanks to their excellent properties, the compounds of general formula (I) are on the most areas of application of water-soluble X-ray contrast media are excellently suited, for example for vasography, urography, arthrography and for the representation of the liquor spaces as well to make body cavities visible, for example - after the addition of viscosity-increasing agents Agents - for bronchography and (hystero) salpingography. A significant advantage over the known vasographics and urography agents is their far lower, comparatively reduced to about half, osmotic pressure. This makes the remedies much better for dehydrated patients, for example tolerate. The contrast of functionally impaired kidneys, which in general is a Difficult diagnostic problem is caused by contrast media with low osmotic pressure much improved.

Particularly suitable areas of application are Representation of the cardiovascular system and cercbral angiography. Because of their non-ionic These connections are also structured to represent the liquor spaces, for example for Radiculography, ventriculography and myclographic are very specific.

For use as an X-ray contrast medium, aqueous solutions are usually used Compound of the general formula (I) in individual cases also mixtures, prepared from 2 or more highly purified end compounds of the formula (I) in aqueous solution, into consideration.

The process for the production of the asehaUengebcnclc Components in X-ray contrast media usable new 5-hydroxypropionylamino-2,4, 6 - iriiodo - isophthalic acid - bis - (dihydroxypropylamide) of the general formula (I) is thus in which Y is hydrogen or iodine atoms, Z is an α-hydroxypropionylamino group, whose hydroxyl function can be masked by easily reversible acylation or etherification, or an amino or Nitro group, and —CO - X reactive acid or

xo denote ester radicals with a dihydroxypropylamine, the hydroxyl functions of which can be masked by esterification, acetalization or ketalization, and, optionally after reduction of the 5-nitro group to the 5-amino group, the aromatic nucleus

triiodinated and the aromatic amino group acylated by reaction with a reactive derivative of a Hydroxypropionic acid of the general formula (IU)

CH ₃ - CH - CO - X
OH

(III)

whose hydroxyl function can also be masked by easily reversible acylation or etherification and wherein —CO — X is a reactive acid or ester radical means.

Suitable reactive acid derivatives for the reactions are preferably: their Anhydrides with inorganic and organic acids such as with hydrohalic acids (acid halides), with hydrazoic acid (azides) with phosphoric acid derivatives, with carboxylic acids odei Carbonic acid half-esters, or their reactive esters, e.g. B. their easily accessible alkyl, aryl or cyanomethyl esters.

The reactive acid radical X in the formulas (II) unc (III) accordingly means the acid radical of an inorganic or organic acid, such as -Cl, -Br, - J a phosphite radical, the azide radical, an acyloxyrcsi or an alkoxy-carbonyloxy radical or the res' a reactive ester group, such as. B. - O-alkyl- - O-aryl or - O - CH ₂ -C = N.

As Dihydroxypropyiaminc or their derivatives the following compounds are preferably used for the reaction: 1,3-dihydroxyisopropylamine (Se linol), 2,3-dihydroxypropylamine and ketals, acetals or easily cleavable ethers thereof, for example 5-amino-2,2-dimethyl-1,3-dioxane, 4-aminomethyl 2,2-dimethyl-1,3-dioxolane, 1-benzyloxy-3-hydroxyisopropylamine (O-benzylserinol).

Preferred Reagcnticn door the implementation mi a dihydroxypropylamine or its derivatives with masked hydroxy functions are the acid halo gcnide of the general formula (II), in which --CO -> accordingly acid halide radicals, Y iodine atoms and 2 a -hydroxypropionylamino radical, its hydroxyl function is preferably maskicri by acyl groups.

Instead of acyl protecting groups, easily cleavable ether groups such as. B. Benzyl, di and triphenyl methyl ether groups are used will.

In this variant of the process, the hydroxypropionyl radical with the aromatic amino group is therefore first used linked and only then the reaction with a dihydroxypropylamine or a derivative made of it.

This can be done, for example, by first adding a 5-amino-2,4,6-trijo (l-isophthalic acid dihalide with an acylating reagent of the general formula (III) and then with a dihydroxypropylamine implements.

But you can also, for example, 5-amino-2,4,6-triiodo-isophthalic acid dichloride first react with a dihydroxypropylamine and then add the product obtained to the aromatic Acylate amino group with a reagent of formula (III).

Instead of derivatives of 5-amino-isophthalic acid, however, corresponding derivatives can also be used analogously React the 5-nitro-isophthalic acid with a dihydroxypropylamine and then to known per se Way, reduce the nitro group to the amino group, triiodine the aromatic nucleus and the acylate aromatic amino group.

The cleavage of the acyl, ether, acetal or ketal groups masking the hydroxyl functions usually does not require any particular reaction stage. The cleavage of the acyl group takes place approximately at Work-up and isolation of the conversion products by hydrolysis in alkaline, the acetal, ketal or ether protection groups in an acidic environment.

In the compounds of the formula (I), normal iodine atoms can be counteracted by known methods exchange radioactive iodine. The synthesis of the compounds can also be carried out using radioactively labeled Perform iodine compounds, whereby end products I containing radioactive iodine are formed. the radioactive compounds can be used for special diagnostic purposes, such as. B. for scintigraphy or for specific functional diagnoses.

example 1

L-5 - «- Hydroxypropionylamino-2,4,6-triiodisophthalic acid-bis- (1,3-dihydroxyisopropylamide)

A. To 28.4 g (0.04 moles) of L-5- (α-acetoxypropionylamino) -2,4,6-irijocl-isophthalic acid dichloride 15 g (0.08 mol) of tributylamine are dissolved in 150 ml of dimethyl acetamide joined. The solution is warmed to 50 C and, while stirring, 9.1 g (0.1 mol) 1,3-Dihydroxyisopropylamine (2-amino-1,3-propanediol) dissolved in 80 ml of dimethylacetamide was added. To The implementation is complete in a few hours. The reaction solution is completely evaporated in vacuo. The oily residue is stirred into 350 ml of methylene chloride with vigorous turbines. The resulting precipitate is filtered off and repeatedly suspended in warm methylene chloride.

Yield: 30 g of L-5 - («- acetoxypropionylamino) -2,4,6 - triiodoisophthalic acid - bis - (1,3 - dihydroxyisopropylamide) corresponding to 92% of theory.

Melting point: 185-187 "C.

This compound is dissolved in water with activated charcoal decolorized, brought to pH 11 by adding concentrated sodium hydroxide solution, heated to 40 ° C and NaOH is added until the pH remains constant, d. H. the acetoxy group is completely saponified. The solution is now desalted by means of a cation exchange resin and an anion exchange resin and then evaporated to dryness and optionally by filtration on aluminum oxide or silica gel further purified and recrystallized from ethanol.

ίο Yield: 20 g of L-5-a-hydroxypropionylamino-2,4, 6 - triiodoisophthalic acid - bis - (1,3 - dihydroxyisopropylumid) (65% of theory).

Melting point: approx. 300 ⁰ C decomposition without melting. [«]? = -2.01 ° (c = 10, in water).

is thin layer chromatogram (TLC) on silica gel: with eluent methylene chloride / methanol = 10: 3. R _f = 0.2.

C ₁₇ H ₂₂ J ₃ N ₃ O ₈ : calcd. C 26.27% J 48.99%; found C 26.37% J 48.79%.

The compound is easily soluble in water. From a solution containing 10 g of product per 10 ml, After standing for days in the refrigerator (4 ° C.), 2.3 g of product crystallize out. In methanol is the Solubility also practically unlimited. In ethanol

The solubility at room temperature is approx. 10%, at the boiling point there is miscibility.

B. L - 5 - α - hydroxypropionylamino - 2,4,6 - triiodoisophthalic acid - bis - (1,3 - dihydroxyisopropylamide) is also obtained if the

τ, ο 1,3-dihydroxyisopropylamine replaced by the equivalent amount of its ketal with acetone, the 5-amino-2,2-dimethyl-1,3-dioxane (CH-PS 5 50 003, column 10). The L-5- (a-acetoxypropionyl: imino) -2,4,6-triiodoisophthalic acid - bis - (2,2 - dimethyl -1,3 - dioxan - 5 - ylamide) obtained as a direct reaction product can be eliminated by recrystallization Clean isopropanol perfectly. Treatment with a little 0.1N hydrochloric acid immediately cleaves the ketal groups and solution occurs. The solution is then adjusted to pH 11 using concentrated sodium hydroxide solution as in A), the acetoxy group being saponified in the 5-α position.

The L - 5 - (α - acetoxypropionylamino) - 2,4,6 - triiodine - isophthalic acid dichloride required as the starting material for A and B is made as follows:

a) 400 g (0.72 mol) of S-amino ^ ao-triiodo-isophthalic acid are introduced into 200 ml of thionyl chloride and stirred for 6 hours at boiling heat. the resulting solution is evaporated. The return

so it was taken up in dry ethyl acetate and again evaporated to dryness. The evaporation residue is dissolved in 40 (X) ml of ethyl acetate and an ice-cold solution of 500 g of sodium chloride Stir 200 g of sodium bicarbonate into 2.5 l of water

ss The organic layer is replaced by the aqueous layer separated, wash ge with aqueous sodium chloride solution by treating with anhydrous CaI cium chloride dried and then fully evaporated.

do Yield: 420 g of 5-amino-2,4,6-triiodo-isophthalic acid rcdichlorid (97.5% of theory).

This acid chloride can be installed from toluene uinkii.
Melting point:> 300 "C.

i.s b) 300 g (0.503 mol) 5-amino-2,4,6-triiodo-isophthal acid dichloride in 1200 ml dimethyl acetamide 187 (1.26MoI) (L) -2-acctoxypropionyl chloride are added dropwise with stirring at 3 to 5 ° C

After standing overnight at room temperature, the solution is evaporated in vacuo to a volume of about 400 ml. The oily evaporation residue is stirred into ice water. A crystalline precipitate is formed.

Yield: 353 g of L-5 - («- acetoxypropionylamino) -2,4,6-triiodo-isophthalic acid dichloride (98% of theory).

This crude product is purified by suspending it in warm non-alcoholic chloroform.

Melting point: 219-220 ° C; [α]? = -13.0 "(c = 5, in CHCl ₃ ).

C ₁₃ H ₈ Cl ₂ J ₃ NO ₅ : Cl calcd.9.98%; found 10.2%.

TLC on silica gel: with solvent benzene / methanol = 10: 2. Stains made visible by treatment with Cl ₂ vapors and spraying with 4,4'-diamino-2,2'-dimethyldiphenyl and a little KI dissolved in aqueous acetic acid. R _f = 0.46.

Example 2

D, L-5-a-hydroxypropionylamino-2,4,6-triiodisophthalic acid-bis- (1,3-dihydroxyisopropylamide)

70.9 g (0.1 mol) D, L-5 - («- Aeetoxypropionylamino) -2,4,6-triiodo-isophthalic acid dichloride are analogous to Example 1 with 56.5 g (0.62 mol) 2- Amino-1,3-propanediol implemented and worked up. 56.5 g (73.5% of theory) D ^ -Sa-hydroxypropionylamino - 2,4,6 - triiodo - isophthalic acid - bis - (1,3 - dihydroxyisopropylamide), which after recrystallization from aqueous ethanol are obtained, are obtained 300 ⁰ C melts with decomposition.

TLC on silica gel: with mobile phase chloroform / methanol / ammonia (25%) = 6: 3: 1. R _f = 0.17.

C ₁₇ H ₂₂ J ₃ N ₃ O ₈ : calc. J 48.99%; found J 48.97%.

The racemic compound is less soluble in water than the corresponding optically active compound.

The solubility in water is 30 g / 100 ml solution at 2O ⁰ C.

The intermediate D, L-5- (a-acetoxypropionylamino) - 2,4,6 - triiodo - isophthalic acid - dichloride is prepared analogously to Example 1 from D, L-2-acetoxypropionyl chloride. Melting point: 21O ⁰ C.

Example 3

L-S-a-Hydroxypropionylamino ^ Ao-triiodisophthalic acid-bis- (D, L-2,3-dihydroxypropylamide)

A. To 34.6 g (0.049 mol) of 5-L - («- acetoxypropionylamino) -2,4,6-triiodo-isophthalic acid dichloride and 18 g (0.098 mol) of tributylamine in 200 ml of dimethylacetamide are 13.2 g (0.145 mol) of racemic 2,3-dihydroxypropylamine 1 - amino - 2,3 - propanediol) added dropwise and, as described in Example 1, reacted and worked up. That obtained after treatment with sodium hydroxide solution and desalting with an ion exchanger Raw product, 28.5 g (73.5% of theory), can be obtained by recrystallization from very little water or better can be purified from aqueous ethanol.

Melting point: 281 --283 ⁰ C decomposition.

[«] * - = -0.78" (c = 10, in water).

TLC with eluent ethyl acetate / ethanol / ammonia (25%) = 15: 7: 6. R _f = 0.23.

C _n H ₂₂ I ₃ N ₃ O ₈ : calcd. C 26.27% J 48.99%; found C 26.14% J 48.96%.

The compound is very easily soluble in water and somewhat less soluble in ethanol.

B. The product is obtained analogously to Example 1 B) if the 2,3-dihydroxypropylamine is used in the reaction replaced by the equivalent amount of 4-amino-2,2-dimethyl-1,3-dioxolane. Through this measure can be the immediate reaction product, in this case the 5- (a-acetoxypropionylamino) - 2,4,6 - triiodo - isophthalic acid - bis - (2,2 - dimethyl-1,3-dioxolan-4-yl-amide), in an easy-to-clean form practically insoluble in water ίο.

Example 4

5-D, L - »- hydroxypropionylamino-2,4,6-triiodisophthalic acid bis (D, L-2,3-dihydroxypropylamide)

85 grams (0.12 moles) of D, L-5- (α-acetoxypropionylamino) -2,4,6-triiodo-isophthaloyl dichloride are analogous to Example 3 with 32.8 g (0.36 mol) of racemic 1-amino-2,3-propanediol implemented and processed.

62.7 g (68% of theory) 5-D, L - * - Hydroxy propionylamino - 2,4,6 - triiodine - isophthaloyl-bis (D, L-2,3-dihydroxypropylamide) are obtained, which after recrystallization from a little water at 285-286 ° C melts with decomposition.

D. C: mobile phase chloroform / methanol / ammonia J ₅ (25%) = 6: 3: 1. R _r = 0.16.

C _n H ₂₂ J ₃ N ₃ O ₈ : calc. J 48.99%; found J 48.86%. This compound, in which all three asymmetric carbon atoms are present as a racemate, is somewhat less soluble than the compound of Example 3 for the preparation of which the optically active (L) -lactic acid derivative was used.

The solubility in water at 20 ° C is 14%, at 40'C and 20% at 60 ⁰ C 34% (w / v).

The enantiomorphic forms, all 3 of which are asymmetric, are much more soluble in water C atoms are present in the optically active form.

Example 5

5 - «- hydroxypropionylamino-2,4,6-triiodo-

isophthous acid bis (2,3-dihydroxypropylamide)

with three optically active carbon atoms

L - 5 - (λ - acetoxypropionylamino) - 2,4,6 - triiodoisophthalic acid dichloride is analogous to example 3 once with L- and the other time with D-I-amino 2,3-propanediol implemented. This produces the two expected isomeric compounds

1. 5-L-α-HydΓOxypΓopionylamino-2,4,6-triiodo-isophthalic acid-bis- (L-2,3-dihydroxypropylamide)

^so and

2.5-L-a-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid-bis- (D-2,3-dihydroxypropylamide) receive.

Both compounds have practically unlimited solubility in water.

Example 6

L-5 - «- hydroxypropionylamino-2,4,6-triiodisophtha! Acid c" bis- (1,3-dihydroxyisopropyl amide)

A. 47.9 g (0.2 mol) of 5-nitro-isophthalic acid dimethyl ester are mixed with 22.8 g (0.25 mol) of 1,3-dihydrox) isopropylamine (Serinol) and stir (-5 for 5 hours) heated to 140- 150 ° C the fn expectant methanol is distilled off dei After cooling, the residue is taken up in a little water and aufgi stehcngelasse several hours at 0 ⁰ C..:

15 16

The excreted 5-nitroisophthalic acid-bis- (l, 3-di- droxypropionylamino - 2,4,6 - triiodo - isophthalic acid-

hydroxyisopropylamide) is filtered off and dried. bis- (1,3-dihydroxy-isopropylamide) (14.1 g).

Quantity: 57.2 g; Mp 194 ° C. Melting point: approx. 300 ⁰ C decomp.

D. C: Rf 0.26; Mobile phase chloroform / methanol / Among those in the previous examples, ammonia = 6: 3: 1, R _f 0.67; Compounds written with methyl ethyl ketone / 5 are generally glacial acetic acid / water = 15: 3: 5. Derivatives of L-lactic acid are preferred as they have both

57.1 g of it are dissolved in 250 ml of ethanol under slightly better solubility and also more easily accessible than the system warming and after the addition of 5 glO% derivatives of D, L-lactic acid or glyceric acid. Palladium-carbon hydrogenated. The catalyst is filtered off derivatives of the more difficult to access D-lactic acid and the filtrate is evaporated to dryness. _Compared to those of L-lactic acid, the 10 would not have any residue in a mixture of 1 liter of water and would offer obvious advantages.

Entered 20 ml of concentrated hydrochloric acid and under The particularly preferred compound is that

vigorous stirring at 30 - 50 ° C with 5 - » - hydroxypropionylamino - 2,4,6 - triiodine - iso -

305 ml 1 N potassium iodine dichloride (KJCl ₂ ) solution, phthalic acid - bis - (1,3 - dihydroxyisopropylamide).

puts. The reaction mixture is stirred for 15 The new 3-hydroxypropionylamino-2,4,6-triiodo

14 - 20 hours at 50 - 60 ° C. After cooling, isophthalic acid bis (dihydroxypropylamide) of the general

the formed 5-amino-2,4,6-triiodo-isophthalic formula (I) are predominantly in the form of their

acid-bis- (1,3-dihydroxyisopropylamide) filtered off, aqueous solutions used,

with dilute sodium bisulfite solution and water. Depending on the intended use, approx. 15 to

washed and dried. 84.6 g of the solutions are obtained - g / v, i.e. 100% ig = 100 g /

binding d. see 75% of theory based on 5-nitro 100 ml solution - with a content of about 60 to

isophthalic acid bis (1,3-dihydroxyisopropylamide). approx. 500 mg J / ml for use. Concentrated Lo-

Melting point: 275 ° C with decomposition. sings are preferred. The type of application

D. C: R _f 0.22; Mobile phase chloroform / methanol / depends on the vessel to be made visible.

Ammonia = 6: 3: 1. R _f 0.58; with methyl ethyl ketone / 25 For the vasography the solutions are in the

Glacial acetic acid / water = 15: 3: 5. corresponding vessels, especially the blood vessels

B. 70.5 g (0.1 mol) of 5-amino-2,4,6-triiodo-isophthalic injected or infused.

acid-bis- (1,3-dihydroxyisopropylamide) in 250 ml di- For urography, the solutions are intra-

methylacetamide are injected or infused with veins at approx. 0 - 5 ° C while stirring,

dropwise with 60 g (approx. 0.4 mol) of L-2-acetoxypro- 30 for myelography and radiculography

pionyl chloride added. After standing overnight at the solutions after lumbar or suboccipital

Room temperature, the solution is evaporated in a vacuum puncture mstilliert. When ventriculography be

completely one. The evaporation residue is punctured directly into the ventricle.
Dissolved water, decolorized with activated charcoal, by adding

brought to pH 11 by concentrated sodium hydroxide solution, 35 dosage

warmed to 40 ⁰ C and mixed with NaOH for so long, Mveloeraohie about 5-15 ml

until the pH remains constant, i.e. until the acetoxy-radiruloeraphy 'about 3 to 5 ml

protecting group and the by-products of L-2-acet-ventriculography '.'. '.'. '.'. '.'. '.'. eil- 2 ml

oxypropionylchlond conversion to a small extent ge ° ^

formed ester groups on the 1,3-dihydroxyisopropyl 40 The preparation of the X-ray contrast medium solutions

Completely saponified amide functions of the molecule is simple because no salt solutions are prepared

are. The solution will now have to be exhausted with the help of ions.

Exchange resins are desalinated, then to dryness. For example, those according to the above

evaporated and pure 2,4,6-triiodo-iso-

further purified and finally phthalic acid amide from very little ethanol 45 under sterile conditions in the

recrystallized. desired amount of double-distilled water dissolved in

Melting point: approx. 300 ⁰ C decomposition without any serum bottles or ampoules being filled and melting, then sterilized. The present triiodine iso-

[Vp ₀ ⁰ = -2.03 ° (c = 10, in water). phthalic acid amides are not sterilized by heat

C ₁₇ H ₂₂ J ₃ N ₃ O ₈ : calc. J 48.99%; found J 48.82%. 50 decomposes.

Example? Example

,,,. ,. ". , .., 5-a-hydroxypropionylamino-

L-5 - «- Hydroxypropionylamino _: 2,4,6-triiodo-2,4,6-triiodo-isophthalic acid-bis-

isophthalic acid bis _{(1,3-dihydroxyisopropyl amide) J5} (1,3-dihydroxyisopropyl amide) .... 82.5 g

To 23.83 g (0.04 mole) 5-amino-2,4,6-triiodo-iso-sodium bicarbonate 0.24 g

phthalic acid dichloride in 170 ml dimethylacetamide bidistilled water up to Gc-

15 g (0.08 mol) of tributylamine are added. At 50 ⁰ C total volume of 100 ml

9.1 g (0.1 mol) of 1,3-dihydroxy-

isopropylamine (Serinol) added. After a few hours of execution
the reaction solution is evaporated. The residue is stirred into methylene chloride. The 2,4,6-triiodo-isophthalic acid amide derivative is dissolved various 5-amino-2,4,6-triiodo-isophthalic acid-bis- at 37 "C under nitrogen in a little water, (1,3-dihydroxyisopropylamide ) (19 g; melting point: the addition of sodium bicarbonate causes the decomposition of 274 ° C) is filtered off and, as in the example, brought to pH 7 and then described by a game 6B) with 15 g of L-2-acetoxypropionyl Filter with a pore diameter of 0.22 ΐημ chloride implemented.After solvolyzing the condenser, filtered, brought to a volume of exactly 100 ml, the product with sodium hydroxide solution becomes L-5-a-Hy- ^ and under hygienically perfect conditions

17 18

and under nitrogen in vials of 10 and sodium carbonate 0.4 g

ml contents filled and then sterilized. Disodium phosphate of ethylenedi-

Iodine content: 400 mg / ml. amine tetraacetic acid 0.02 g

_o . , _n Bi-distilled water up to the

E.g.el 9 _. to _{order by} 100ml

5-a-hydroxypropionylamino-

2,4,6-triiodo-isophthalic acid-bis-execution

(1,3-dihydroxyisopropylamide) 82 g The components are combined with double-distilled

5-a-Hydroxypropionyiamino- lated water made up to 100 ml, under nitrogen

2,4,6-triiodo-isophthalic acid-bis- ι ο filled into ampoules and then sterilized.

(2,3-dihydroxypropylamide) 20.5 g iodine content: 500 mg / ml.

Claims (1)

Patent claims: 1. 5 - Hydroxypropionylamino - 2,4,6-triiodo - isophthalic acid -bis- (dihydroxypropylamide) of the general formula (I) CONH-C ₃ H ₅ (OH) ₂ CH ₃ -CHCONH
OH (D
CONH-C ₃ H ₅ (OH) ₂