NO760327L - - Google Patents

Description

Dicarboxylic acid derivatives of triiodo-isophthalic acid-monoamino acid amides, process for producing

position of these and application of them as. x-ray contrast agents,

The present invention relates to new X-ray contrast agents, which as shadowing components contain new dicarboxylic acid derivatives of triiodo-isophthalic acid monoamino acid amides of general formula I

wherein A denotes an aminoacyl residue and

X a direct bond or a straight-chain or branched hydrocarbon chain with 1 - 14-C atoms which may be interrupted by one or more oxygen or sulfur atoms, and where R^ and R^ are different and denote a hydroxyl group or

the group

where R^ and R^' independent of each

others denote a hydrogen atom, a lower alkyl group which may optionally be substituted with hydroxyl groups, or where R^ and R^ together with the nitrogen atom may denote

, a heterocyclic residue which may be interrupted by a further heteroatom, as well as physiologically applicable salts with bases.

As physiologically compatible salts with bases, amine salts come into consideration, for example glucamine-, N-methyl-glucamine-, N,N-dimethylglucamine-, ethanolamine-, diethanolamine-, morpholine salts etc. as well as salts of basic amino acids of arbitrary configuration, such as lycine, ornithine, arginine, histidine, etc., respectively their lower alkyl esters or amides, whereby the latter may optionally be substituted with lower alkyl groups,■ and/or metal salts, for example sodium, lithium, calcium and/or magnesium salts or mixtures thereof.

R,,°9R. must together with the nitrogen atom preferably denote the pyrrolidine, morpholine or piperazine residue.

Among lower alkyl groups R and R. are to be understood residues with 1-10 carbon atoms, preferably those with 1-6 ca.r carbon atoms, such as methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, tert. butyl, pentyl and hexyl groups.

The aminoacyl residue A is derived from a normal aminocarbon acid. The aminocarbon acid can have an arbitrary configuration. There may be one or two amino groups in any position, although α-aminocarboxylic acids are preferred. Furthermore, the amino carboxylic acids can also be unsaturated, branched, polybasic and usually substituted, e.g. with hydroxyl, mercapto, optionally substituted aryl, cycloalkyl or heterocyclic groups. Furthermore, the amino group can be substituted with aliphatic, aromatic or mixed aromatic-aliphatic residues.

Preferred is an aminoacyl residue A of general formula II

where provided n=0 R^ denotes a hydrogen atom, a lower alkyl group or a phenyl group, and where

R^ denotes a hydrogen atom, a lower alkyl group with 1 - 6 carbon atoms which can be straight chain or branched and optionally sub-substituted with one or more hydroxyl, lower carboxy, aminocarbonyl, amino, aryl, mercapto , lower alkylmercapto- or heterocyclic groups, or where

R,_ and R, together can denote a ring-forming propylene-r.(-CH2-CH2-CH2-') or 2-hydroxy-

or if N=1 R,- and R^ denote a hydrogen atom.

Examples of preferred aminocarboxylic acids include: Alanine, glycine, sarcosine, serine, O-methylserine, threonine, O-methyl-threonine, leucine, isoleucine, cysteine, S-methyl-cysteine, methionine, lysine, ornithine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, histidiny tryptophan, phenylalanine, tyrosine, proline, oxy-proline, N-phenylalanine, N-benzylalanine, valine, and also b-amino acids such as B-alanine.

The new compounds of general formula I or their physiologically compatible salts are excellent shadowing substances for the production of X-ray contrast agents, whereby they are applicable in medical practice in the form of the free acid, the salt or the salt mixture. They can be used in the form of their water-soluble salts as injection preparations for urography, angiography and myelography. Preferably, they are suitable for urography.

The new compounds exhibit the properties required of X-ray contrast agents. They exhibit low toxicity, excellent general and neural compatibility, good local compatibility and little impact on the circuit. Furthermore, they are distinguished by reduced subjective side effects when used in angiography, and by surprisingly rapid and high excretion via the renal system at minimal

• entry into the bile.

The following table 1 shows with 5,5'-(3,6-dioxaoc-tandioy1-diimino-bis[2,4,6-1 rijodo-3-(2-methoxy-1-methylcarbamoyl-ethyl)-isophthalamic acid] that the new compounds are excreted significantly faster and more completely via the urinary tract than the traditional X-ray contrast agents B, C, D, E and F.

A = 5,5'-(3,6-dioxaoctandio1-diimino-bis[2,4,6-triiodo-3-(2-meth-oxy-1-methylcarbamoy l-e t hy 1)-i soft ha lamic acid ] .'

B = 5,5'-(adipoyl-diimino)-bis-(2,4,6-triiodo-N-methylisophthalic acid (iocarminic acid)

C = 5-acetamido-2,4,6-triiodo-N-methylisophthalamic acid (iothalamic acid)

D = 3-acetamido-5-acetamidomethyl-2,4,6-triiodobenzoic acid (iodamide)

E - 5-acetamido-N-(2-hydroxyethyl)-2,4,6-triiodo-isophthalamic acid

(ioxythalamic acid)

The removal by means of the bile also takes place with a high specificity of renal excretion in relation to known substances, such as e.g. iocarminic acid.

Likewise, the new dimeric substances are significantly better compatible than the known substances, which is evident from the following table 2, which indicates toxicity data measured on rats after intravenous administration.

The neural compatibility. was examined after intracerebral, intracistefna 1 administration and after injection into Arteria carotis comm. Thereby it turned out that the new compounds with regard to the cerebral compatibility were significantly superior in relation to known compounds, and with regard to the cisternal compatibility at least as good as the known comparison compounds.

For this reason, the new shade-giving compounds, especially in the form of their aqueous salt solutions, are suitable as injection preparations for urography.

They can be used as solutions with 5-45% bound iodine. Such salt solutions contain the equivalent per 100 ml approx.

10 - 100 g of the new compounds.

The invention further relates to a method for producing compounds of general formula I, which method is characterized in that a compound of general formula III

where R 1 , R 2 and A have the meanings given in formula I, are reacted in a manner known per se with a derivative of a dicarboxylic acid of general formula IV

wherein X has the meaning given in formula I, and Hal denotes a chlorine or bromine atom,

and optionally transferred in a physiologically compatible salt with a base.

The reaction of a compound of general formula III with a derivative of a dicarboxylic acid of general formula IV is carried out at temperatures between 0 and 140°C, preferably at room temperature in an inert solvent, such as e.g. dimethylacetamide, dimethylformamide, dioxane, toluene, etc.

The compounds used as starting materials are, with the exception of the new starting compound DL-5-amino-2,4,6-triiodo-N-(2-methoxy-1-methylcarbamoylethyl)-isophthalamic acid and DL-N-(3-amino- 2,4,6-triiodo-5-methylcarbamoylbenzoyl)-O-methyl-serine described in DOS No. 2,207,950.

These new starting compounds can be prepared as follows: DL-N-(2-methoxy-1-methylarbornoylethyl)-5-nitro-isophthalamic acid methyl ester

To 526.9 g (1.55 mol) of 0 3-methyl-1-DL-serine-methylamide hydrochloride in 3.75 liters of water, 378.0 g of sodium bicarbonate were added, and with stirring and ice-cooling over the course of 3 hours, 365, 4 g (1.5 mol) of 3-methoxycarbonyl-5-nitrobenzoyl chloride in 1.3 liters of acetone added dropwise. The mixture was then further stirred for 1 1/2 hours at room temperature, the product separated, washed salt-free with water and dried in a vacuum at 70°C.

Yield: 397.0 g (78%) with m.p. 167 - 168°C.

Analysis: C-^H^N^ (<3>39.3)

DL-N-(2-methoxy-1-methylcarbamoylethyl)-5-nitro-isophthalamic acid

169.7 g' (0.5 mol) DL-N-(2-methoxy-1-methylcarbamoyl-ethyl)-5-nitro-isophthalamic acid methyl ester with melting point 167 - 168°C. in 3 liters of dioxane was after the addition of 1.1 liters 0.5 n

caustic soda, stirred for 2 hours at room temperature. Then a further 0.4 liters of water was added, the dioxane was distilled off in vacuum, the acid precipitated with concentrated hydrochloric acid, separated, washed salt-free with water and dried in vacuum at 70°C.

Yield: 322.0 g (99%) at m.p. 164 - 166°C.

Analysis:<C>13<H>15<N>3<0>7 (<3>25.3)

DL-5-amino-2,4,6-triiodo-N-(2-methoxy-1-methylcarbamoy1-ethyl)-i softhalamic acid

488 g (1.5 mol) DL-N-(2-methoxy-1-methylcarbamoylethy1)-5-nitro-isophthalamic acid with a melting point of 164 - 166°C in 3.75 liters of water were dissolved neutrally and hy -hydrogenated at room temperature with 10% Raney nickel as catalyst at approx. 120 ato. After removal of the catalyst, the hydrogenation solution was added dropwise to a solution while stirring at 75-80°C. of 1.5 liters of concentrated hydrochloric acid, 0.3 liters of 94% chlorine iodine in 9.75 liters of water over the course of 3 hours and then stirred for 4 hours at 75 - 80°C. After further stirring at room temperature overnight, the precipitate was separated, carefully washed salt-free with water and dried in vacuum at 70°C.

Yield 837.8 g (83%). with sm.p. 265°C (during decomposition).

Analysis:<C>13H14J3N305(673.0)

DL-N-(3-methoxycarbonyl-5-nitrobenzoyl)-O-methylserine

Txl a solution of 130.9 g (1.1 mol) 0 3-DL-methylserine and 252.0 g (3.0 mol) sodium bicarbonate was added dropwise over the course of 2 hours at 5°C and with stirring a solution of 243.6 g (1.0 mol) of 3-methoxycarbonyl-5-nitrobenzpyl chloride in 1 liter of acetone. The mixture was then stirred for another 1 hour at 5°C and 2 hours at room temperature, after which undissolved components were filtered off, the filtrate was shaken three times with ether, the aqueous phase was acidified with concentrated hydrochloric acid and the precipitated oil was extracted twice with vinegar. The combined acetic ester extracts were then washed with water, washed with sodium sulfate, the acetic ester was distilled off in vacuo and the residue was stirred with 3.0 liters of ether for 1 hour at room temperature. The product was then separated, washed with ether and dried in vacuum at 50°C.

Yield: 197.1 g (60%) with m.p. 167 - 168°C.

Analysis:<C>13<H>14<N>2<0>8 (<3>26>3) DL-O-methy1-N-(3-methylcarbamoy1-5-nitrobenzoy1)-serine To a solution of 163 .1 g (0.5 mol) DL-N-(3-methoxy-carbonyl-5-nitrobenzoyl)-0-methylserine with melting point 167 - 168°C in 1.5 liters of methahol was added at 0°C 0.1 liters liquid methylamine, and the solution was allowed to stand for 2 days at room temperature. The solution was then filtered, evaporated in vacuo, post-distilled several times with methanol, after which the residue in 1.5 liters of water was treated with active carbon. After removal of the active carbon, the solution was acidified with concentrated hydrochloric acid, stirred for 4 hours at room temperature, after which the precipitate was separated, washed salt-free with water and dried in vacuum at 60°C.

Yield: 148.5 g (91%) with m.p. 192 - 193°C.

Analysis: C13H15N3O7 (325.3)

DL-N-(3-amino-2,4,6-triiodo-^5-methylcarbamoy 1-benzoyl-0-methylserine

130.1 g (0.4 mol) of DL-O-methyl-N-(3-methylcarbamoyl-5-nitrobenzoyl)-serine with a melting point of 192 - 193<C>C in 0.8 liters of water was added with 2n ammonia dissolved neutrally and hydrogenated at room temperature with 10% Raney nickel as catalyst at 120 ato.

After removal of the catalyst, water was added to the solution to 44.8 liters, and after addition of 0.8 liters of concentrated hydrochloric acid and 0.8 liters of 2n KJCl 2 solution, the solution was stirred for 3 days at room temperature. The precipitate was then separated, washed carefully without salt with water and dried in a vacuum at 70°C.

Yield: 248.8 g (92%) with m.p. 253 - 254°C (during decomposition).

Assay: C13H14J3N305(673.0)

Example 1 DL-5,5'-adipoyl-diimino-bis[2,4,6-triiodo-N-(2-methoxy-1-methylearbam.oy lethy 1)-isophthalamic acid]

To 134.6 g (0.2 mol) DL-5^amino-2,4,6-triiodo-N-(2-methoxy-1-methylcarbamoylethyl)-isophthalamic acid with melting point 265°C (under decomposition) dissolved in 240 ml of dimethylacetamide, 17.6 ml (0.12 mol) of hexanedioic acid dichloride were added dropwise over the course of 15 minutes under water cooling, and the mixture was stirred at room temperature overnight. A further 4 ml of the diacid chloride were then added, after which the mixture was stirred for a further 5 hours at room temperature, and after the addition of some water the mixture was evaporated in vacuo. The residue was then heated with 1 1/2 liters of water to boiling, stirred overnight at room temperature, after which the precipitate was separated, and neutrally dissolved in 1 1/2 liters of water with the addition of concentrated ammonia, after which the solution was treated for 3 hours with activated carbon . After removal of the carbon, the solution was acidified with concentrated hydrochloric acid, stirred overnight, after which the product was separated, heated with 1 1/2 liters of water for a short time to boiling, separated hot, carefully washed with water and dried in vacuo at 70° C.

Yield: 97.4 g (67%) with m.p. 299 - 301°C (under decomposition). Analysis: C32H34J6^ 6012 i1456' 1)

Example 2 5,5'-(3,6-dioxaoctanedio1-diimino)-bis[2,4,6-triiodo-3-(2-methoxy-1-methylcarbamoylethyl)-isophthalamic acid]

The preparation took place analogously to what is described in example 1<y>ed acylation of 101 g (0.15 mol) DL-5-amino-2,4,6-triiodo-N-(2-methoxy-1-methylcarbamoylethyl) )isophthalic acid with a melting point of 265°C (under decomposition) in 180 ml of dimethylacetamide with a total of 16.6 ml of 3,6-dioxaoctanoic acid dichloride.

Yield: 54.3 g (49%). with sm.p. 238 - 240°C (under decomposition) Analysis:<C>32<H>34<J>6<N>6<0>14 (<1>488.1)

Example 3 5,5'-(4-thiaheptandio1-diimino)-bis[2,4,6-triiodo-3-(2-methoxy-1-methylcarbamoylethyl)-isophthalamic acid]

The preparation took place analogously to example 1 using 101 g (Oj15 mol) of DL-5-amino-2,4,6-triiodo-N-(2-methoxy-1-methylcarbamoylethyl)-isophthalamic acid with a melting point of 265°C (under decomposition ) in 180 ml of dimethylacetamide and a total of 17.6 ml of 4-thiaheptanic acid dichloride.

Yield: 45.5 g (41%) with m.p. 240°C (during decomposition).

Analysis:<C>32<H>34<J>6<N>6°12<S><t>1488»1)'

Example 4 5,5'-adipoyl-diimino-bis(2,4,6-trij<p>d-N-methylearbamoylmethylisophthalamic acid)

The preparation took place analogously to what is described in example 1. starting from 5-amino-2, 4, 6-triiodo-N-methylcarbamoylmethyl-isophthalamic acid with melting point 252 - 253°C (under decomposition) in dimethyl lacetamide and hexanedioic acid dichloride.

Yield: 80% with m.p. 277 - 278°C (during decomposition)..

Analysis: C^H^J^O^ (1368.0)

Example 5 5,5'-(3,6-dioxaoetandioyl-diimino)-bis[2,4,6-triiodo-3-(methylcarbamoylmethyl)-isophthalamic acid]

The preparation took place analogously to what is described in example 1 from 63 g (0.1 mol) of 5-amino-2,4,6-triiodo-N-methyl-1-carbamoylmethylisophthalamic acid with a melting point of 252 - 253°C (under decomposition at 120 ml of dimethylacetamide and a total of 9.8 ml of 3,6-dioxaoctanoic acid dichloride.

Yield: 53.4 g (76%) with m.p. 274 - 276°C (during decomposition). Analysis: C^H^J^O^ (<1>400.0)

Example 6 DL-5,5'-adi.poly 1-diimino-bis[N-(2,4,6-triiodo-3-methylcarbamoylbenzoyl)-alanine]

64.3 g (0.1 mol)' DL-N-(3-amino-2,4,6-triiodo-5-methyl-carbamoylbenzoyl)-alanine with melting point 252 - 253°C (under decomposition) in 120 ml dimethylacetamide was added dropwise at 5°C over the course of 10 minutes with stirring to 8.8 ml of hexanedioic acid dichloride and stirred overnight at room temperature. Then a further 1.0 ml of hexanedioic acid dichloride was added, and the mixture was stirred overnight, and after the addition of 10 ml of water evaporated in vacuo. The residue was stirred with 700 ml of water overnight, separated the precipitate, after which this was heated with 700 ml of water to boiling and was then stirred until it reached room temperature, after which the preparation after separation and subsequent washing with water was dried in vacuum at 70°C. The yield of impure product was 59.4 g (85%) with a melting point of 258 - 260°C (under decomposition). For purification, the compound was dissolved in 1500 ml of water with the addition of concentrated ammonia to a neutral state, after which the solution was treated with 2.5 g of active carbon, the carbon was removed, and after acidification with concentrated hydrochloric acid, the solution was stirred overnight. The precipitate was then stirred with 1 liter of water, separated, carefully washed with water and dried in vacuum at 70°C.

Yield: 44.4 g (64%) with m.p. 264 - 266°C (during decomposition).

Analysis: C^H^J^O^ (<1>396.0)

Example 7 DL-3,3'-(4-thiaheptandio1-diimino)-bis-[N-(2,4,6-triiodo-5-methylcarbamoyl-benzoyl)-αIgnin]

The preparation took place analogously to what is described in example 6 from 225 g (0.35 mol) DL-N-(3-amino-2,4,6-triiodo-methylearbamoylbenzoyl)-alanine with a melting point of 252 - 253°C ( during cleavage) in 420 ml of dimethylacetamide and 38 ml of 4-thiaheptanoic acid dichloride.

Yield: 146.7 g (59%) with m.p. 265. - 266°C (during decomposition). Analysis: C H J N O S (1428.0)

Example 8 DL-3, 3'-(3, 6-dioxapctandio1-diimino)-bisfN-(2,4,6-triiodo-5-methylcarbamoylbenzoyl)-alanine]

The preparation took place analogously to what is described in example 6 from DL-N-(3-amino-2,4,6-triiodo-5-methylcarbamoy1-benzoy1)-alanine with melting point 252 - 253°C (under decomposition) in di-meth<y>lacetamide and 3,6-dioxaoctanoic acid dichloride. Sm.p. 289 - 290°C (during decomposition).

Analysis: C^H^J^O^ (<1>428.0)

Example 9 3,3'-adipoyl-diimino-bis[N-(2,4,6-triiodo-5-m.ethylcarbamoy 1-benzoyl)glyein]

The production took place analogously to what has been described

in example 6 starting from 59.8 g (0.095 mol) N-(3-amino-2,4,6-triiodo-5-methylcarbamoyl-benzoyl)-glycine with melting point 265 - 266°C (under decomposition) in 114 ml dimethylacetamide and 8.7 ml of hexanedioic acid dichloride.

Yield: 55.6 g (85%) with m.p. 262 - 263°C (during decomposition).

Analysis: C^H^J^O-^(1368.0)

Example 10 3,3'-(3,6-dioxaoctanedioyl-diimino)-bis[N-2, 4, 6-triiodo-5-methylearbarnoyl-benzoyl)-sarcosine]

The preparation took place analogously to what is described in example 6 from 64.3 g (0.1 mol) N-(3-amino-2,4,6-triiodo-5-methylcarbamoy1-benzoyl)-sarcosine with melting point 228 - 229°C (under decomposition) in 120 ml of dimethylacetamide and 11.5 ml of 3,6-dioxaoctanoic acid dichloride.

Yield: 26.2 g (37%) with m.p.^272°C (under cleavage). Analysis: C30tf30J6<N>6<0>12 (<1>428.0)

Example 11 5,5'-adipoyl-diimino-bis(2,4,6-triiodo-N-carbamoyl-methyl-isophthalamic acid)

The preparation took place analogously to what is described in example 1 from 5-amino-2,4,6-triiodo-N-carbamoyl-1-methylisophthalic acid with melting point 248 - 249°C (under decomposition) and hexanedioic acid dichloride in dimethylacetamide.

Yield 37% with melting point 255 - 260°C (under decomposition).

Example 12 5,5'-(3,6,9-trioxaundecandioyldiimino)-bis-[2,4,6-triiodo-N-(2-methoxy-1-methylcarbamoyl-ethyl)-isophthalamic acid]

The production took place analogously to what is described in example 1 from DL-5-amino-2,4,6-triiodo-N-(2-methoxy-1-methyl-1-carbamoylethy1)-isophthalic acid with a melting point of 265°C (below cleavage) and 3,6,9-trioxaundecanedioic acid dichloride in dimethylacetamide.

Yield: 49.5% with m.p.^250°C (under cleavage)..

Analysis:<C>^<H>^<J>^O-^(1532.1)

Example 13 5,5'-(3,6-dioxaoctanedioyldiimino)-bis-[2,4,6-.

tri iodo-N-methy1-N-(me.thylcarbamoylmethy 1)-isophthalamic acid]

The preparation took place, analogously to what is described in example 1, from 5-amino-2,4,6-triiodo-N-methyl-N-methylcarb-amoylmethy1-isophthalamic acid with a melting point of 238 - 240°C (under decomposition) and 3,6-dioxaoctanoic acid dichloride in dimethylacetamide.

Yield: 62% with m.p. ^ 260°C (during decomposition).

Analysis: C^H^J^O^ (1428.0)

Example 14 5,5'-(3,6-dioxaoctanedioyldiimino)-bis[N-(3-carbamoyl-2,4,6-triiodobenzoyl)-glycine]

The preparation took place analogously to what is described in example'6 from N-(5-amino-3-carbamoyl-2, 4, 6-triiodobenzoyl)-glycine with a melting point of 272 - 273°C (under decomposition) and 3,6-dioxaoctanoic acid dichloride in dimethylacetamide. The compound's melting point 293 - 295°C (under decomposition).

Analysis: C^H^N^ (<1>371.9)

Example 15 5,5<1->adipoyldiimino-bis(2,4,6-triiodo-N-methyl-N-methy lcarbamoy lmethy 1-isoftha lamic acid.)

The production took place analogously to what is described

in example 1. starting from 5-amino-2, 4,tr i j od-N-methyl 1-N-methyl lcarbamoyl lmethy lisof tha lamic acid with melting point 238 - 240°C (under decomposition) and hexanedioic acid dichloride in dimethyl lacetamide.

Yield of the preparation: 45.8% with sm . p. 250°C (during decomposition).

Example 16 5,5'-(4-thiaheptandioyldiimino)-bis-(2,4,6-triiodo - N-methy 1 - N-methy 1 ca r ba m oy Ime thy 1 - i s o-phthalic acid )

The production took place analogously to what is described

in example 1 starting from 5-amino-2,4,6-triiodo-N-methyl-N-methylcarb-amoylisothalamic acid with melting point 238 - 240°C (under decomposition) and 4-thiaheptanoic acid dichloride in dimethylacetamide. Sm.p. '~~/ 260°C (during decomposition).

Analysis: G^^J^C^S (1428.1)

Example 17 DL-5,5'-adipoyldiimino-bis-[2,4,6-triiodo-N-.

(1-methylearbamoylethy1)-isophthalamic acid]

The preparation took place analogously to what is described in example 1 from DL-5-amino-2,4,6-triiodo-N-(1-methylcarbamoy1-ethyl)-isophthalic acid with a melting point of 208 - 209°C (under decomposition) and hexanedioic acid dichloride in dimethylacetamide. Sm.p. 277 - 278°G (during cleavage).

Analysis: C^H^J^O^ (1396.0)

Example 1 18 5, 5 1 - (3, 6,9--trioxaundecandioyldiimino)-bis-(2,4,6-triiodo-N-methylcarbamoylmethyl-iso-phthalamic acid)

The preparation took place analogously to what is described in example 1 from 5-amino-2,4,6-triiodo-N-methylcarbamoylmethyl-isophthalamic acid with a melting point of 252 - 253°C (under decomposition) and 3,6,9-trioxaundecanedioic acid dichloride in dimethylacetamide. The melting point of the preparation = 260°C. (under cleavage).

Analysis:<C>30<H>3C)<J>6<N>6<0>13 (<1>444.0)

Example 19 DL-5,5'-(3,6,9-1rioxaundecandi oyldiimino)-bis-[2,4,6-triiodo-N-(1-methylcarbamoylethyl)-isophthalamic acid]

The preparation took place analogously to what is described in example 1 from DL-5-amino-2, 4, 6-triiodo-N-(1-methylcarbamoyly-ethyl)-is of thalamic acid and 3,6,9-trioxaundecanedioic acid- dichloride in dimethyl lacetamide.

Yield 31% with sm.p. at 260°C (during decomposition).

Analysis: C^H^N^ (1472jl)

Example 20 DL-5,5'-adipoyldiimino-bis[N-(2,4,6-triiodo-3-methylcarbamoylbenzoyl)-O-methylserine]

The preparation took place analogously to what is described in example 6 from DL-N-(3-amino-2,4,6-triiodo-5-methylcarbamoy1-benzoyl)-O-methylserine with m.p. 267 - 268°C (under decomposition and hexanedioic acid dichloride in dimethylacetamide.

Yield 66% with sm.p. 289 °-'290 °C (under decomposition).

Analysis:<C>32<H>34<J>6<N>6012(1456.1)

Example 21 DL-5,5'-(3,6-dioxaoctandioyldiimino)-bis-[N-(2,4,6-triiodo-3-methylcarbamoylbenzoyl)-0-methylserine]

The production took place analogously to what is described

in example 6 starting from DL-N-(3-amino-2,4,6-triiodo-5-methylcarbamoyl-benzoyl)-O-methylIserine with m.p. 267 - 268°C (under decomposition) and 3,6-diocaoctanodioic acid dichloride in dimethylacetamide. The connection's sm.p. 272 - 274°C (during decomposition).

Analysis: C^H^J^O^ (<1>488.1)

Example 22 3,3'-(3,6-dioxaoctanedioyldiimino)-bis-[N-(2,4,6-triiodo-5-methylcarbamoylbenzoyl)glycine]

The preparation took place analogously to what is described in example 6 from N-(3-amino-2,4,6-triiodo-5-methylcarbamoyl-benzoyl)-glycine with m.p. 265 - 266°C (under decomposition) and 3,6-dioxaoctanoic acid dichloride in dimethylacetamide. The connection, sm.p. 292 - 294°C (during decomposition).

Analysis:<C>28<H>26<J>6<N>6°12 (<1>400'°)

Example 23 3,3'-adipoyldiimino-bis-[N-(2,4,6-triiodo-5-methylcarbamoylbenzoyl)-sarcosine]

The production took place analogously to what is described

in example 6 starting from N-(3-amino-2,4,6-triiodo-5-methylcarbamoyl-benzoyl)-sarcosine with m.p. 228 - 229°C (under decomposition) and hexanedioic acid dichloride in dimethylacetamide.

Yield 46% with sm.p. 273 - 275°C (under decomposition).

Analysis: C^H^J^O-^ (1396.0)

Example 24 5,5'-malony1-diimino-'bis(2,4,6-triiodo-N-methylcarbamoylmethylisophthalamic acid)

To a solution of 62.9 g (0.1 mol) of 5-amino-2,4,6-triiodo-N-methylcarbamoylmethyl-isophthalamic acid with m.p. 252 - 253°C (during decomposition) in dioxane brought to boiling with stirring, 6.8 ml (0.07 mol) malonic acid dichloride in 70 ml dioxane was added dropwise, after which the mixture was stirred under reflux for 5 hours, after which the product was separated, washed with hot dioxane bg dried in vacuum. The preparation was then treated for several hours with hot alcohol, separated, washed with hot alcohol and dried in a vacuum.

Yield: 40.3 g (61%) with m.p. 273 - 275°C. (during decomposition).

Analysis: C^<H>^<J>^O-^(1,325.9)

Example 25 DL-5,5'-malony1-diimino-bis[2,4,6-triiodo-N-(2-methoxy-1-methylcarbamoylethyl)-isophthalamic acid

The preparation took place analogously to what is described in example 1 from DL-5-amino-2,4,6-triiodo-N-(2-methoxy-1-methyl-1-carbamoylethy1)-isophthalamic acid with m.p. 265°C (under decomposition) and malonic acid dichloride in dioxane.

Yield: 49% with m.p. 250 - 252°C (during decomposition)

Analysis: C^H^J^O^(1,424.0)

Example 26 3,3'-malony1-diimino-bis-[N-(2,4,6-triiodo-5-methylcarbamoylbenzoyl)-glycine]

The preparation took place analogously to what is described in example 1 from N-(3-amino-2,4,6-triiodo-5-methylcarbamoyl-benzoyl)-glycine with m.p. 265 - 266°C finds cleavage) in dioxane with malonic acid dichloride. Sm.p. 268 - 270°C (under decomposition).. Analysis: C^H^J^O.^ (1.325.9)

Example 27 5,5'-oxalyl-diimino-bis(2,4,6-triiodo-N-.

methylcarbamoylmethy1-isophthalamic acid)

The preparation took place analogously to what is described in example 1 from 5-amino-2,4,6-triiodo-N-methylcarbamoylmethy1-i softha lamic acid with m.p. 252 - 2.53°C (under decomposition) and oxalic acid dichloride in dioxane.

Yield: 46% with m.p. 306 - 305°C (under decomposition).

Analysis:<C>24<H>18<J>6<N>6<0>10 (<1.>311.9)

Example 28 DL-5,5'-oxaly1-diimino-bis[2,4,6-triiodo-N-(2-methoxy-1-methylcarbamoylethyl)-isophthalamic acid]

The preparation took place analogously to what is described in example 1 from DL-5-amino-2, 4,6-triiodo-N-(2-methoxy-1-methyl-1-carbamoylethyl)-isophthalamic acid with m.p. 265°C (under decomposition) and oxalic acid dichloride in dioxane.

Yield: 70% with m.p. 288 290°C (during decomposition)..

Analysis:<C>28<H>26<J>6°12<C1>-400*0)

The solution was filled into ampoules or multivials and sterilized at 120°C. It contained 270 mg j/ml.

The solution was filled into ampoules or multivials and sterilized at 120°C. It contained 300 mg j/ml.

The solution was filled into ampoules or multivials and sterilized at 120°C. It contained 380 mg J/ml.

Claims (34)

1. Dicarboxylic acid derivatives of triiodo-isophthalic acid monoamino acid amides of general formula I in which A denotes an aminoacyl residue, X denotes a direct bond or, a straight chain or branched hydrocarbon chain with 1-14 C atoms, which may be interrupted by one or more oxygen or sulfur atoms, and where R^ and R^ are different and denote a hydroxyl group or laughs the group whereby R^ and R^ independently gig of each other denotes a hydrogen atom, a lower alkyl group which is optionally substituted with hydroxyl groups, or where R 1 and R 4 together with the nitrogen atom denote a heterocyclic residue which may be interrupted by a further hetero atom, as well as their physiologically compatible salts with bases. 2. DL-5, 5'-adipoyl-diimino-bis[2, 4, 6-triiodo-N-(2-methoxy-1-methylcarbamoylethyl)-isophthalamic acid].. 3. 5,5 *-(3,6-dioxaoctandio1-diimino)-bis[2,4,6-triiodo-3- <r> (2-methoxy-1-methylcarb amo <y>l eth <y>1 )-in softhalamic acid]. 4. 5,5'-(4-thiaheptanedioyl-diimino)-bis[2,4,6-triiodo-3-(2-methoxy-1-methylcarbamoylethyl)-isophthalamic acid]. 5. 5, 5'-adipoy 1-diimino-bis (.2, 4, 6-tri j od-N-methylcarbamoy 1-methyl-isophthalamic acid) . 6. 5 , 5 ' -. (3, 6-dioxaoctandio1-diimino)-bis[2,4,6-triiodo-3-(methylcarbamoylmethyl)-isophthalamic acid]. 7. DL-5,5'-adipoyl-diimino-bis[N-(2,4,6-triiodo-3-methyl-carbamoyl-benzoyl)-alanine]. 8. DL-3,3'-(3,6-dioxaoctanedio1-diimino)-bis[N-(2,4,6-triiodo-5-methylcarbamoyl-benzoyl)-alanine]. 9. DL-3,3'-(4-thiaheptanedioyl-diimino)-bis[N-(2,4,6-triiodo-5-methylcarbamoyl-benzoyl)-alanine]. 10. 3,3'-adipoyl 1-diimino-bis[N-(2,4,6-triiodo-S-methyl-1-carbamoyl-benzoyl)-glycine]. 11. 3,3'-(3,6-dioxaoctandio1-diimino)-bis[N-(2,4,6-triiodo-5-methylcarbamoyl-benzoyl)-sarcosine].. 12. 5,5'-adipoyl-diimino-bis(2,4,6-triiodo-N-carbamoylmethyl-isophthalamic acid). 13. 5,5'-(3,6,9-trioxaundecandioyl-diimino)-bis(2,4,6-triiodo^N-(2-methoxy-1-methylcarbamoylethyl)-isophthalamic acid]. 14 . 15. 5,5'-(3,6-dioxaoctanedio1-diimino)-bis[N-(3,carbamoyl-2,4,6-triiodobenzoyl)-glycine]. 16. 5,5'-adipoyl-diimino-bi s(2,4,6-t rij od-N-methyl-N-methyl-. carbamoyl-methyl-isophthalamic acid). 17. 5,5'-(4-thiaheptandio1-diimino)-bis(2,4j 6-triiodo-N-methyl-N-methylcarbamoylmethyl-isophthalamic acid). 18. DL-5,5'-adipoyl-diimino-bis[2,4,6-triiodo-N-(1-methyl-1-carbamoylethyl)-isophthalamic acid]. 19 . 5, 5' - (3, 6, 9-1 rioxaundecandioyl-diimino)-bis (2, 4,' 6-tri j od-N-methylcarbamoylmethyl 1-iso.ph thalamic acid). 20. DL-5,5'-(3,6,9-trioxaundecanedioyl-diimino)-bis[2,4,6-triiodo-N-(1-methylcarbamoylethyl)-isophthalamic acid]. 21. DL-5,5'-adipoyl-diimino-bis[N-(2,4,6-triiodo-3-methyl-carbamoylbenzoyl)-0-methyl-1-serine]. 22. 'DL-5,5'-(3,6-dioxaoctanedioyldiimino)-bis-[N-(2,4,6-triiodo-3-methylcarbamoyl-benzoyl)-O-methyl-serine]. 23. 3,3'-(3,6-dioxaoctanedioyldiimino)-bis-[N-(2,4,6-triiodo-5-methylcarbamoyl-benzoyl)glycine]. 24. 3,3'-adipoyl-diimino-bis-TN-(2,4,6-triiodo-5-methyl-carbamoyl-benzoyl)-sarcosine]. 25. 5,5'-malonyl-diimino-bis(2,4,6-triiodo-N-methylcarbamoyl-methylisophthalamic acid). 26. DL-5,5'-malonyl-diimino-bis[2,4,6-triiodo-N-(2-methoxy-1-methylcarbamoylethyl)-isophthalamic acid].. 27. 3,3'-malonyl-diimino-bis-[N-(2,4,6-triiodo-5-methyl-carbamoylbenzoyl)-glycine]. 28. 5,5'-oxalyl-diimino-bis(2,4,6-triiodo-N-methylcarbamoyl-methyl-isophthalamic acid). 29. DL-5,5'-oxalyl-diimino-bis[2,4,6-triiodo-N-(2-methoxy-1-methylcarbamoylethyl)-isophthalamic acid]. 30. Process for the preparation of compounds of general formula I, characterized in that a compound of general formula III where R^ , R^ and A have the meanings given in formula I, are reacted in a manner known per se with a derivative of a dicarboxylic acid of general formula IV Hal - CO - X - CO - Hal in which X has the meaning given in formula I and Hal denotes a chlorine or bromine atom, and optionally transferred in a physiologically compatible salt with a base. 31. X-ray contrast agent containing at least one compound according to claim 1. 32. X-ray contrast agent containing at least one compound according to claims 2-29. 33. Method for the production of new X-ray contrast agents, characterized in that a compound according to claim 1 together with those common in galenic pharmacy is added. substances are brought into a suitable form for intravenous administration. 34. X-ray contrast medium according to claims 31 - 32, characterized in that it contains a compound according to claim 1 in an aqueous solution, where. the content of the compound according to claim 1 per 100 ml equals 10 - 100 g.