Process for obtaining new derivatives of triiodinated aminobenzene carboxylic acids

<td>POLAND REPUBLIC CHINA</td><td>PATENT DESCRIPTION</td><td colspan="2">85383 The patent description has been reprinted due to errors noted</td>

<td></td><td>Additional patent to patent</td><td>MKP</td><td>CO7c 101/48 C07c 123/00</td>

<td></td><td>- Submitted: 20.07.73 (P. 164196)</td><td></td><td></td>

<td>OFFICE</td><td>Priority: 21.07.72 Republic Federal . German</td><td colspan="2">cl¹. C07C 101/48 C07C 123/00</td>

<td>PATENT PRL</td><td>The application was announced: 01.10.74 * Patent description published: 15.12.1978</td><td></td><td>READING ROOM Ur Patent era Ι? - '*. *. Ί · · ϊ |</td>

Inventor: Patent holder: chemie Linz Aktiengesellschaft, Linz. (Austria)

A method for the production of new derivatives of aminotrihydriobenzenecarboxylic acids

The subject of the invention is a process for the preparation of new derivatives of thiobiotobenzenecarboxytic acids of the general formula 1 in which R1 is a hydrogen atom, an alkyl radical of at most 4 carbon atoms, an alkoxyalkyl group of at most 6 carbon atoms or a benzyl radical, R₂ is a lower alkyl radical or a group -R₆-COOH or R1 and R radicals₂ together with the nitrogen atom they form a morpholine or piperidine group, R3 is a hydrogen atom, an alkyl radical with up to 4 carbon atoms or an alkylene carboxylic acid group with up to 4 carbon atoms, R4 is a hydrogen atom or a lower alkyl radical, R_s is an alkyl radical of at most 4 carbon atoms, an alkoxyalkyl group of at most 6 carbon atoms, a benzyl or phenyl radical, or the radicals R4 and R5 together with the nitrogen atom form a piperidine or morpholine group, and R₆ is a straight-chain or branched alkylene radical with a maximum of 5 carbon atoms, wherein if R₂ is a lower alkyl radical, then R3 is an alkylene carboxylic acid group, and pharmacologically acceptable salts thereof with inorganic or organic bases or acids.

&lt;Favorable. the compounds of formula I in which R₁ has the meaning given above, R₂ is a methyl, ethyl or allyl radical, R3 is an ethylene or α-methylethylene carboxylic acid group, and R4 and R_s are methyl or ethyl, hydrogen and also compounds. of formula 1 in which R₂means a group of formula 6, in which R7 is a hydrogen atom, a methyl or ethyl radical, R3 is a hydrogen atom, a methyl or ethyl radical, and R4 and Rs are a methyl radical or together with the nitrogen atom form a morpholino group, and Ri has the above meaning and pharmaceutically acceptable ones. salts.

Compounds of formula J are x-ray contrast agents for gall bladder examination. They show low toxicity, good ability to resorb and quickly eliminate from the body. These are especially agents for rapid cholecystrography, as after 5 hours of administration up to 80% or more is secreted, which allows administration of the agent and conducting the examination on the same day. Some compounds of this group can also be used as intravenous contrast agents. Yes for

383 example N- [3- / 1'-3 '-oxapenta-methyleneamino-ethylideneamino / -2,4,6-triiodi-benzoyl] -0-aminopropionic acid with iv toxicity 1.75 g / kg can be used in the form of oral and intravenous bile contrast agent, which is a very rare combination. This compound shows iv after administration. The maximum concentration in the bile is about 900 mg%, after administration of id - about 760 mg% and in the latter case after 5 hours it is secreted in 79%. . Low protein binding, which is usually below 50%, also speaks for good secretion. As examples of preferred compounds with an oxapentamethylene moiety, N- / 3 - // ^ '- oxapentamethylene-amino ^-ethylideneamino / - 2', 4 *, 6''Tiodiodebenzoyl] O [amino-α-methylpropionic acid with IV toxicity can also be mentioned. 1.27 g / kg and 89% excretion. After 5 hours, N- [3-dimethylamino-ethylideneamino / - 2,4-> - triiodobenzene] - / 3-amino-methylpropionic acid, ^ [- / K- dimethylamino-ethylideneamino / - 2,4,6-triethylbenzenzoyl] -Nyγ^>(methoxypropylol-aminopropionic acid) and N- {3 · (3-ethylamino! thiideneamino) -2,4, 3,3-triiodobenzoyl] N-methyl-aminopropionic acid.

The method of producing new compounds of formula 1, in which all symbols have the above-mentioned meaning, according to the invention is that the derivative of the amino tri-benzobenzenecarboxylic acid of general formula 2, in which Y is a halogen atom and X * is a hydrogen atom, is reacted with a compound of the formula general formula 5 in which R₉ is a hydrogen atom, an alkyl radical of at most 4 carbon atoms or a lower alkylenecarboxylic acid ester group with at most 4 carbon atoms in the acid component, and R &lt;and Rs. have the above meanings, and with at least 1 POCI mole₃ at a temperature of 20-100 ° C, preferably in an inert solvent. organic, then in the obtained compound or in its hydrochloride the present groups of acid chlorides are reacted with an amine of formula 4 in which Ri has the above meaning and R_e is a lower alkyl radical or a group -R₆&lt;OOalkyl or R1 and R radicals₈ together with the nitrogen atom they form a morpholine or piperidine group, if R_and means lower radical. alkyl, then R9 is a lower alkylenecarboxylic acid ester group, or a derivative of the amino tri-benzobenzenecarboxylic acid of general formula 2, wherein X * is &lt;OR₉wherein R9 is a hydrogen atom, an alkyl radical of at most 4 carbon atoms, or a lower alkylenecarboxylic acid alkyl ester group of at most 4 carbon atoms in the acid component, and Y is a group of formula 7, where Rj is as defined above and R₈ is a lower alkyl radical or a group -R₆ -COOalkyl or R1 and R radicals₈ together with the nitrogen atom they form a morpholine or piperidine group, if R₈ is a lower alkyl radical, it is R₉ is a group of lower alkylenecarboxylic acid ester, is reacted with a compound of formula 3 in which X ** is hydrogen and R4 and R5 are as defined above, and with at least 1 mole of PC15 at room temperature, preferably in a chlorinated hydrocarbon as solvent , or a derivative of the amino tri-benzobenzenecarbolyl acid of the general formula 2, wherein X 'is a hydrogen atom and Y is a group of formula 7, where Rj is as defined above and R₈ is a lower alkyl radical or a group -R₆-COOalkyl or the radicals Rj and R8 together with the nitrogen atom form a morpholine or piperidine group, are reacted with a compound of formula 5 in which R₉ is hydrogen, an alkyl radical of at most 4 carbon atoms. or a lower alkylenecarboxylic acid alkyl group. with at most 4 carbon atoms in the acid component, and R4 and R5 have the above meanings, if R₈is a lower alkyl radical, it is R₉ is a lower alkylenecarboxylic acid alkyl group with at least 1 mole of POC1₃ at 20-100 ° C, preferably in an inert organic solvent and in the compounds obtained the ester groups are saponified and the acid or base groups present are converted into salts or acids or bases are released from such salts.

According to the first and third variants of the process, compounds of formula .2, in which X 'is a hydrogen atom, i.e. 3-amino-2,4,6-triiodobenzene chloride or 3-ammo-2,4 acid amides derived therefrom, The 6-triiodobenzoate is reacted with the acid amides of formula 5. The reaction is carried out at a temperature of * 20-100 ° C, the elevated temperature accelerating the reaction. The process is carried out in a suitable solvent such as toluene, chloroform, ether, ethyl acetate or dioxane. The excess of the amide of formula 5 can also be used as the solvent in the first variant of the method.₃in an amount of at least 1 mole of POC1₃ per mole of the compound of formula 2.

According to a second variant of the process, the acid amide group can be bonded to the benzene ring and the reaction is carried out with an amine of formula 3 in which X "is a volume of hydrogen. In this variant, the reaction is preferably carried out at room temperature and in the presence of at least 1 mole of phosphorus pentachloride per 1 mole of the compound of formula 2, in particular chlorinated hydrocarbons are used as the solvent.

The products in these variants can be isolated either as hydrochlorides or as bases, the latter being released by basifying the reaction mixture. In the case where the symbol Y in formula 2 is a halogen atom, then the acid chloride group is converted to an amide group, which can easily be carried out by reaction with. amines.

The ester groups present in the molecule are then saponified in a known manner. The obtained compounds can be isolated from the most often alkaline solutions after saponification as acid salts or as free acids. one can

383 also isolate them as salts with acids. Preferably, the free carboxylic acids of formula 1 are isolated in such a way that in an aqueous salt solution of these carboxylic acids of formula 1 or in. the salts of these compounds are adjusted by means of acids or bases of the pH value of free amidinecarboxylic acid. The products are then released in the amorphous form and can optionally be purified by recrystallization. Melting points of amorphous products are not characteristic.

The salts of the compounds of formula I are especially sodium, lithium and ammonium salts, alkaline earth metal salts and salts of non-toxic organic bases such as glucosamine, methylglucosamine, ethanolamine, diethanolamine, glucamine. and methylglucamine,

As amidine salts, also esters, are mentioned, for example, hydrochlorides, sulfates, acetates, fumarates, succinates and tartrates. r

Due to their structure, the compounds of formula I may exist in the form of isomers. The individual isomers are so stable that they can be isolated in pure form. These isomers are also included in the invention.

Compounds of formulas 2, 3 and · 4 are known and can be prepared in known manner, for example according to Austrian Patent Nos. 209895 and 224264 and German Patent Nos. 117135 and 1082368.

The following examples explain the method according to the invention in more detail.

Example 1. 133.3 g of 3-amino-2,4,6-triiodobenzoyl chloride are dissolved in toluene, 37.5 g of dimethylformamide and 31.3 ml of POC1 are added₃ and the solution boils under reflux for 1 hour. The precipitated 3-dimethylaminomethyleneimino-2,4,6-triiodobenzoyl chloride hydrochloride is sucked off after cooling and washed with ether. Then the product is covered with a layer of ether, added water and added dropwise, cooling with ice and stirring vigorously, 250 ml of 4N NaOH solution. After separation of the ether layer, it is washed with ice water, dried over NaCl and evaporated. The oily residue is dissolved in hot cyclohexane, treated with activated charcoal and the solution is filtered to a transparent state. At slow. on cooling crystallizes 123.37 g of yellow 3-dimethylaminomethyleneamino-2,4,6-triiodobenzoyl chloride with a melting point of 100-105 ° C.

58.8 g of the acid acid obtained are dissolved in ddoroformk and added. a solution of 30 N-methyl allyl amine propionic acid methyl chloride in chloroform. The reaction mixture begins to boil, in order to complete the reaction it is boiled for another 2 hours under reflux condenser, after which the solution is washed with water, 5% tartaric acid and K solution₂ WHAT₃, dried over CaCl₂ and evaporates ·. The residue is dissolved hot in methanol, then 30.0 g of N- (3-dimethylaminomethyleneamino) methyl-thyldodbenzoyl / -N-allyl-0-aminopropionic acid methyl ester melting at 86-98 ° C , after concentrating the mother liquors to one-third, a further 22.0 g of compound are obtained, m.p. 85-100 ° C.

g of this ester is saponified with an excess of aqueous NaOH at SO 2 C, the solution obtained is filtered to transparent and the pH is adjusted to 6 with HCl cold. The amorphous charge is triturated with water, ice, sucked off and dried in a desiccator. 22.0 g 'of amorphous N- / 3-diimethylpaminpmethylenepaminp-2,4,6-tri triprobenzoyl / -NalUllo / 3-aminoρropionPwegp are obtained, mp 94-106 ° C.

Example II 6.76 g of N- / 3 &lt;imino-2,4, 3,3-tribenzoylρ / -N4enyl # aminopropionic acid methyl ester is dissolved in absolute toluene and after addition of 1.5 ml dimethylformamide and 1.25 ml POC1₃boils within 1 hour. The oil that separates out is separated after cooling. dissolved in methanol and precipitated again with ether. Crystallization occurs when trituration with ether. 6.2 g of brown N- / 3-dimethylpaminomethylpaminp-2,4-methyl acid hydrochloride are obtained₅6-trójjodofc ^ y ^^ ^^_and/ ^^ en ^ y ^] ^^ Thi aminopropionic, mp 13O-135 ° C. By treatment with excess NaHCO₃ a base ester with a melting point of 70-77 ° C is obtained, which can be saponified in analogy to Example 1 with an aqueous liquor solution. The melting point of the amorphous N-ZS-dimethylaminomethyleneamino-2,4,6-triiodopbenzoyl / -N-phenyl-p-amo-p-p-povidic acid is 92-116 ° C.

Example III. 18.0 g of the acid chloride prepared according to Example 1 are dissolved in chloroform and 9.5 g of e-aminocaproic acid methyl ester dissolved in chloroform are added. The mixture is heated to boiling. The cooking is continued for 90 minutes, after which the chloroform solution is washed with water, aqueous tartaric acid solution and K solution.₂.WHAT₃, dried over CaCl₂ and evaporates. The evaporation residue is hot dissolved in methanol and filtered to a clear state. 14.0 g of N- / 3-dimethylpaminomethyleneamino-2,4,6-triiodinobenzoylp-e-aminocaproic acid methyl ester, crystallizing from this solution, melting at 139-142 ° C., after concentrating the mother liquors, 6.2 g of this crystallize. of the product itself, melting at 128-140 ° C. To saponify, 18.0 g of this ester are suspended in 2N NaOH solution and boiled until completely dissolved. After filtration, the pH is adjusted to 5 with and

383 diluted hydrochloric acid, whereby the acid separates in oily form and solidifies on cooling with ice water. After filtration and drying in a desiccator, 12, Og of amorphous N- / 3 &lt;1-dimethylaminomethyleneamino-2,4,6-triiodio-benzoyl / - aminocaproic acid are obtained with a melting point of 90-1W * C.

Example IV 213.2 g of 3- * min-2,4,6-triiodobenzoyl chloride are dissolved in chloroform, 174 g of dimethylacetamide are added, and 153 g of POCl 3 are added dropwise within 20 minutes, the mixture being heated to boiling. The cooking is continued for 8 hours and after cooling the separated crystals are filtered off. The crystals are suspended in ether and shaken with ice-cold, diluted NaOH until completely dissolved. During the concentration dried over Na₂SO4 of the ether phase crystallizes 127.0g of 3- / 1'-dimethylaminoethylideneamino / 2,4,6 * triiodiodenzoyl chloride with a melting point of 127-130 ° C.

39.13 g of this acid chloride dissolves. in chloroform, 25.0 g of N73-methoxyproxy / XJ-aminopropionic acid methyl ester are added dropwise, the mixture being heated and the mixture boiled for 40 minutes. The resulting solution is washed with water. and KHCO3 solution, dried over Na2O * and evaporated. The residue is boiled with 0.7 N methanolic NaOH until completely saponified, and the solvent is distilled off. The residue is dissolved in water and the acid precipitates with glacial acetic acid, sucked off and dried under reduced pressure. 16.8 g of amorphous N {3- (1'-dimethylaminoethylideneamino) -2,4,6-triiodobenzoyl] -N-yamethoxypropyl / y-aminopropionic acid are obtained with a melting point of 90 ^ 110.^Φ(0

Example V. 213.2 g of 3-andno-2,4,6-triiodobenzoyl chloride are dissolved in chloroform, 135 g of acetanilide are added, followed by 153 g of POC1 within 15 minutes₃, after which the solution boils for 8 hours. After cooling, the precipitated crystallization is suction filtered. The crystals are suspended in chloroform and mixed with cold diluted NaOH solution, forming a solution. The chloroform phase is separated, washed with water, dried over Na₂SO4 and concentrated, obtaining 220 g of 3-crystalline 3 -ffffic, methyl-tertiary-teri-imi / 1-friethobenzenzoyl chloride, mp 172-178 ° C.

52.0 g of this acid chloride are dissolved in chloroform and 26.0 g of N-methyl-0-amino-α-methylpropionic acid methyl ester are added. After the exothermic reaction is complete, the mixture is boiled for 30 minutes, then washed with water and KHCO3 solution, dried over NaSO * and evaporated. The residue boils around 1N methanolic sodium hydroxide solution until completely saponified. After distilling off the solvent, the residue is taken up in water and mixed with glacial acetic acid to completely precipitate the acid. It is sucked off and the precipitate is dried. 56.0 g of amorphous N {3- / 1 '"phenylamino-ethylideneamino] -2,4,6-triiodobenzoyl] -N-methyl- / 3-amiro-metic> propionic acid are obtained at mp 142-166 "° C.

Example VI. 53.3 g of 3-amino-2,4,6'-triiodobenzoyl chloride are dissolved in chloroform, 39 g of Nacetylmorpholine and 45 g of POC1 are added.₃ and cooks for 6 hours. After cooling, the precipitated crystals are filtered off, washed with chloroform and dried. 61.0 g of Syr-S ^ chloride hydrochloride are obtained, N-tetyleneamino-ethylideneamino / -2,4,6-tri-dobenzene> melting point from 240 ° C. with decomposition.

27.2 g of this product are suspended in chloroform, releases the amidine base by adding triethylamine and reacts with 12.0 g of domino propionic acid ethyl ester. - After the reaction is completed, the mixture is boiled for another 15 minutes, the chloroform solution obtained is washed with water, dried over Na₂SO4 and evaporates. The saponification residue is mixed with about 0.6η methanol-sodium hydroxide solution and boiled under reflux. After distilling off the solvent, the residue is taken up in water, precipitated with glacial acetic acid, sucked off and dried. He receives. 24.8 g of amorphous Ν- [3 * / Γ-3 ”-> xapentamethyleneaminoethylidene> amiIO) / - 2,4,6-tΓÓj <M> o ^ e5rz> oi0)} X ^ amirxpro? 145 ° C.

Example VII. 27.2 g of the acid chloride hydrochloride prepared according to Example 6 are suspended in chloroform, triethylamine is added to release amidine and 11.7 g of O-imino-methylpropionic acid methyl ester and the solution is boiled for 20 minutes. Processing, saponification and precipitation of the final product takes place according to example VI. 25.5 are obtained. g - amorphous acid N-3yΓ-3^M-Aphexamethylene> amino-ethylidene> amln> - 2,4,6-triiodobenzoyl] -0-amino-methylpropionic melting point 131-148 ° C. Acid crystallizes from ethyl acetate, mp 291 294 ° C.

If the chloroform solution is washed with lye, evaporated and dissolved in methanol after the reaction of the acid chloride with an aminocarboxylic acid ester, then the methyl ester Ν-3- / Γ-3 "oxapentamethyleneamino-ethylideneamino / - 2,4,6-triiodobenzoyl] - ^ amino is crystallized. methylpropionic melting point 166 172 ^ (0.

35.0 g of N- [3yΓ-3 ”oxapenίamethylene> amine> / ethylldenoamino, 2,4,6-triiodobenzoyl] / 3-βmino / 1 / methylpropionic acid is dissolved hot in 250 ml of water after adding 25 ml 4n HCl. After cooling

383 crystallizes the salt. After filtration and drying, 32.0 g of N- [3- / 1'-3 '-oxapen * tamethylene-amino-ethylideneamino / 2,4,6- · triiodinate> yl] 0-amino-α-methylpropionic acid hydrochloride are obtained. which, at 235 ° C, slowly begins to melt and decomposes from 255 ° C.

Example 8 32.8 g of N- / 3-acetylamino-2,4,6-triiodiousenzoyl / O * amino-α- methyl ester. -methylpropionate is dissolved in methylene chloride and 13.35 g of PCI5 are added. This suspension. The mixture is stirred for 17 hours, the reaction products gradually going into solution, then morpholine is added under ice-cooling until a stable alkaline reaction. The mixture is left for about 45 hours at * room temperature, the precipitated crystals are filtered off, the filtrate is washed with water, dried and evaporated. As a residue, 43.5 g of a light oil are obtained, which, as in the previous examples, are saponified with a water-methanol solution of NaOH, and then * precipitated from the aqueous solution with HCl. N-3- (r-3 "-oxapentamethyleneamino-ethylideneamino) -2,4,6-triiodobenzoyl] 0-amino-α-methylpropionic acid in the amount of 15.8 g. The product obtained is identical to the compound obtained in Example VII.

Example IX. 24.0g of N- (3 / amino-2,4,6) triiodobenzoyl) aminoacetic acid ethyl ester are dissolved in chloroform, 6.2 g of N-acetylmorpholine and 7.4 g of POCl 3 are added and the solution boils for 5 hours. After standing overnight, suction is sucked off, the still wet crystals are dissolved in methanol, boiled and added aqueous NaOH until fully saponified. Then the solvent is evaporated, the residue is taken up in water, clarified and the pH adjusted with n diluted HCl^l5. The amorphous acid precipitated in this way is crystallized by light heating, cold suction and drying at 110^QC. 12.5 g of N- [3- (1'-3 "o) -capentamethyleneamino / ethylideneamino // 2,4,6-triiodobenzoylol-aminoacetic acid are obtained, mp 265-270 ° C with decomposition.

Example X. 21.32 g of 3-amino-2,4,6-triiodobenzoyl chloride are dissolved in chloroform, 17.2 g of N-propionylmorpholine and 18.0 g of POCU are added and cooked for 5 hours. After cooling, the precipitated crystals are suction filtered, washed with chloroform and dried. 23.4 3- / r-3 "*> xai-intamethylene-amino-propylideneamino / -2,4,6-triiodobienzoyl chloride hydrochloride are obtained. An amidine base with a melting point of 147-151 ° C is obtained in analogy to Example 4,

27.80 g of acid chloride hydrochloride are suspended in chloroform, added to release the amidine base with triethylamine, followed by 12.0 g of O-amino <x-methylppionic acid methyl ester. After cooling, the solution is washed with water and dilute HCl, dried over NaSO4 and evaporated. The residue is heated to complete saponification with aqueous methanol NaOH. The solvent is distilled off, the residue is taken up in water, filtered to a clear state, the acid precipitates with glacial acetic acid and suction filtered. After treatment with water and drying under reduced pressure, 25.6 g of amorphous acid N- [3 - // '- 3 "/ oxapentamethylene-amino-propylideneamino) - 2,4,6-trĄ ^^ cd ^ c ^ le ^ are obtained. isoilk> j8 ^^^ mi ^ O 'd <netropionic with a melting point of 130-145 ° C.

Example XI. 53.3 g of 3-amino-2,4,6-tetrahydroxide chloride are dissolved in chloroform, 48 g of monkmethyl succinic acid dimethyl ester and 45 g of POO3 are added, and the solution is poured on ice. , the chloroform phase is separated, washed with diluted. ro ;;. v / jrcn. NaOH and water, dried, evaporated. . The residue is taken up in ether, the part 10.4 is suction filtered 3) and the solution is evaporated to dryness. 45.2 g of 3 · / 3'- € ΜηΓω ^ · 7? Methyl ester are obtained. · Lo 2 * - \ 6 '&lt;swarm · doanilino / - 3-dimethylamino-p-phenylidene / 3 / - carboxylic acid in the form of an oil which is nitrogens ;. keep going.

The crude acid chloride is dissolved in chloroform, downstream from mciy4 * mm. in excess and boils the mixture for 10 minutes. Then washed with water, dried over Na₂SO.4 and evaporates. The residue yy zb with Λΐ + ζΛ / οζΌ sodium methanol hydroxide at reflux, the methanol is distilled off, the residue is diluted with water and, after filtration to clear, the acid is released with glacial acetic acid. When heating, the amorphous precipitate initially crystallizes. The crystals are suction filtered and boiled in methanol. 16.9 are obtained. g of 3- / 3'-N-mttylkkaΓbamylo-2 \ 4 'acid, 6^,carboxylic acid-3-dimethoxyamino-3-carboxylic acid with a melting point of 264-268 ° C.

Example XII. 53.3 g of 3-amino-2,4,6-tetrahydrogen chloride are dissolved in chloroform, added

37.8 g of morpholld acid monomethyl ether and 30.6 g of IPOCI3 and the solution boils within 6 hours.

After standing overnight, the precipitated crystals are suction filtered, washed with chloroform and dried. 24.5 g of 3- / 3-acid methyl ester hydrochloride are obtained^,-chlorofkrmylk-2 ', 4', 6 * / tojiodoanilino / - 3- / 3 "-oxapentamttyltaminamine / -propylidene- / 3 / - carboxylic acid. The amidine base is obtained as described in Example 4 and has a melting point of 132-134 ° C.

14.9 g of acid chloride hydrochloride are suspended in cidol ^ &lt;^^ &lt;^ rm_J^^, excess methylamine and the solution cooks within 10 minutes. After cooling, it is washed with water and dilute acetic acid, dried with the chloroform phase and evaporated. The residue is boiled with a methanol-water solution

383

NaOH until completely saponified, the solvent is evaporated and the residue taken up in water. The acid is released with glacial acetic acid at reflux. It precipitates in crystalline form, after which it is suction filtered and dried. 10 g of 3- (3 * -N-methyl-carbamyl-2 ', 4' / * - triiodoanetine / -3 / 3 "oxapentamethyleneamino / -propylidene / 3 / -carboxylic acid are obtained, m.p. 265-270 ° C.

By analogy with the methods described in the above examples, the following compounds are also obtained:

N- / 3 <dimethylaminoethyleneamino-2,4, 3,3-triiodioyl / aminoacetic acid, m.p. 256-259 ° C, N- / 3-dimethylamino-methyleneamino-2,4,6-triiodobenzoyl / -N-methylaminoacetic acid m.p. 135-140 ° F N- / 3-dimethylamino-methyleneamino-2,4,6-triiodobenzoyl / O-aminopropionic acid with a melting point of 208-214 ° C, N- / 3> dimethyleneamino-methyleneamino-2,4-acid , 6-triiodobenzoylc / -N-methyl-aminoprionic acid, m.p. 138-15O ° C, N- / 3-dimethylamino-methyleneamino-2,4,6-tri-benzobenzoyl / -N-isopropyl-O-aminopropionic acid, m.p. 125-135 ° C, N- / 3-dimethylamino-methyleneamino-2,4-acid _>6-triiodobenzoyl / -N- (methoxypropyl) methyl-propionic acid *, m.p. 158-164 ° C, N- (3-dimethylamino-methyleneamino-2,4,6-triiodiodenzoyl) -d-amino-α-methylpropionic acid melting point 110-125 ° C, N- {3- / 3 '/ ok »p-thiuratylenomethylin ^ aminol-2,4,6-triiodinobenzoyl] - O-amino-α-methylpropionic acid, m.p. 123-140 ° C , N- (3- / 1 * - tyloaminto </ tylidentαamnnl-2,4,6-triiodimethnoyl] -N-methyl-0-aminopropionic acid, m.p. 133-149 ° C, N43- / Γ-ethylmn'K> -ethia <tenoami.no/-2,4,6-triiodobenzoyl] -0 amino-α-methylpropionic acid, m.p. 148-157® C, N- (3- / 1-acid * d ^ wmm «^ and ^ 5lkM ^^ O-ethylidenoaimn <^ - - 2,4,6-triiodobenzoyl] - Jaminn-α-methylpropionic acid, m.p. 159-166 ° C, N43 - V-dimethyl acid] min -ethylideneaminol-2,4.6-tri-benzobenzoyl] -N-methyl-0-amino-α-methylpropionic melting point 181-187 ° C, N43 - // '- 7 * -methoxypropylaminoethylideneamino (-2, 4, 6-triiodobenzoyl) -1-amino-α-methylpropionic acid, m.p. 120-135 ° C, N43- / 1 °' phenylamincaethylideneamidine / - 2,4,6-tri-benzoyl] -N- / 3 "- methoxypropyl / -O-aminopropionic compound, m.p. 120-131 ° C, N- [3- (i'-phenylamino-ethylideneamino) -2,4,6-tri-thio-benzoyl] -0-amino-α-methyl-propionic acid, m.p. 153 -180 ° C, N43-l'-pentamethylene-ααnincaetylidene (oι .minol-2,4,6 / triiodobienzoyl] - N - ^ - methoxypropyl / O - minopropionic acid, m.p. 87-12O ° C, N- (3- / 1'-3 "l> kupentamethyltinoamino-eiididnoalnino / - 2 , 4,6-triiodobenzoyl] / N-methyl-O-aminopropionic, mp 154-158 ° C, N-^ 3-1 acid^,-3^,° olkHαpntamethylene Inino- / tylideneamino / - 2,4,6-tri-iodithtoyloyl] - · N-ethyl-3-aminorpopionic with melting point 130-138 ° C, Nf ^ / 1-3 "acid / axapentamethyleneamino! Tylideneamino / - 2, 4,6-i-iiodo-benzoyl] -N / isopropylS-amb-Propionic acid, m.p. 140-152 ° C, N- (3- / 1'-3-oxapentametic acid, lamino-ethylide n-quinine / -2,4,6-tri-iodithiodoyl] -Ny '-methoxypropylO-aminopropionic with a melting point of 1O9 -115 ° C, N- {3 · / l'-3 ”-oxaIXϊntaInetylenoaInino-eiylidenoίαnino / -2,4,6- triiodienzenzoyl) -N / benzylO-amino-α-methylpropionic acid, m.p. 191-196 ° C, N ^ J1 ^ Woksasentamety 1600— ^ 0- ^ 1 ienoamino / - 2,4,6-thiiodobenzoyl] - N-propyloe 'min-butyric acid, m.p. 125-155 ° C, N- (3- / 1 * -3 " / oxap ^ n-tamethylene <a ^ mineo-tildeencylminol-2,4,6-triiodioyloyl] - 0-amino-I / ethylpropionic acid, m.p. 1.25-13O ° C, N- [37l]^L-dimethyl α-propyl dimethylamino // 2,4,6-triiodimethnoyl] - N / methyl / 0 aminopropionic melting point 8O-115 ° C, N ^ 3- / Γ-dimethylamino-pro-yididnoamino / - 2,4,6-tri odobenzoyl] - N-methoxypropyl β-aminopropionic acid (sticky product), N-] 3-di-diϋ-ethylpypiideneamino acid) -2,4,6-ΓΓ-diiodo-benzoyl] -0-amino-α-methyl-propionic acid, m.p. 113-123 ° C,

383 N- [3- (1'-d-yytylimino-propylideneamino) -2,4,6-triiodi-benzo] -N-methyl-β-amino-α-methyl-propionic acid.

with a melting point of 105-115 ° C, N- [3 - ('- 3' -oxapeniamethylenetinylin-p-Optlddaminamin) 2,4,6-trifluol-tfollolN-methyl- / tαιminoplopionic acid.

mp 114-125 ° C,.

N- [3-1 '-3 "oxapeniamines of tenoamines <oρrooytiddaminaminO-2,4,6-tri-thio-ll-1-εolio] N-methyl-0-aminopropionic acid, m.p. 110-125 ° C, N-3- (l' - 3 "-oxapentalmttylen <oιmin <ι-propylideneamino) -2,4,6-tri-iodenzenzoyl] -N-ethyl-0-amino-4-ethylpropionic acid, m.p. 128-140 ° C, 3- (3'-N-α-Hiiokaibamyl- 2 ', 4 \ 6' -Triiodoanilino) -3-methylamino-propylidene- (3) -carboxylic acid with a melting point of 125-134 °, 3- (3'-N-methyl-carbamyl), 6'-triiodoanilino) -3-diethylamino-propyidene- (3) -carboxylic acid, m.p. 209-213 ° C, 3- (3 * -N) -etylolŁαbίιαeyko2^,,4^L, 6'-t-iodoanilino) -3-diethylaminoplopylidene- (3krrDxyl), m.p. 118-128 ° C, 3 <3 * (N · d ^ o-kωbamytll2 *, 4 ', 6'-triiodoanίlino) -3 -dimethylamino-p-phenylidene (3) -carboxylic acid, m.p. 109-130 ° C, 3- [3 '- (3' -oxapentamethylcarbamyl) -2 *, 4 *, 6-diiodoanilino] -3-diethylamino-propyldiene no <3kartquxyl with a melting point of 142-150 ° C, 3- | 3 '- (3 "-oxapentaethylene glycolamyl) -2', 4 * 6'-triiodoanilinol-3- (3" κk8apeniamethylene <Mιmelo> 1Pylylidene (3) carboxylic acid, m.p. 145-155 ° C, .

N-3 ^^ 1 * -3 "-oxa acid | p ^ niamethyleneamine O-ethylidene &lt;MLmino) -2_t4,6-trijoyenzenzoyl] - 0- * minbutyric acid, melting point 140-150 ° C, N-3 acid (l * -3 "-oksaJp ¢ nilίueetylenoιαeino-2^L-methyl-p-propylidene-α-amino) -2,4 »6-tri-benzobenzoyl] - 0 &lt;-mino-methylpropionic · melting point 110-125 ° C, N- [3- (1 * -3" (OxapeniιiuettyleIlOιaeino-2'-mtetyl- propylideneamino) -2,4,64 triiodobenzoylol-Nt (methoxypropylpropionic acid, m.p. 85-100 ° C, N- (3-0) ^,-methylamino-etylideneamino) -2,4,6-thiojodobenzoyl] -0-areino (α-ethylpropionic acid, m.p. 165-183 ° C),

By treatment with alkali metal hydroxides or organic amine solutions, these acids can be converted into the corresponding salts. Salts are isolated by evaporation as an amorphous product, by crystallization from suitable solvents such as water or alcohols, or by precipitation from solutions with solvents. For example, sodium salt of N ^ 3 (<RTI ID = 0.0> dimethylamino: tylenoamino-2.4 /> - tr <(xol) moly) aminoacetic acid can be precipitated from an aqueous solution with acetone, for example. The product has a melting point of 190-207 ° C.