New derivatives of tri-iodo-amino benzene carboxylic acids,a process for making them and their use

DESCRIPTION

TO A PATENT APPLICATION

IN THE ·

GROSSI-IERZOGTUM LUXEMBURG

PROCESS FOR THE PREPARATION OF NEW DERIVATIVES OF TRIIODIZED AMINOBENZENE CARBONIC ACIDS. '

OESTERREICHISCHE STICKSTOFFWERKE AG

Process for the preparation of new derivatives of triiodinated aminobenzene carboxylic acids

The present invention relates to a process for the preparation of new derivatives of triiodinated aminobenzoidarboxylic acids of the general formula I of the formula sheet, in which A is a hydrogen atom, a carboxyl group or the group of the formula V of the formula sheet, hydrogen, an alkyl or alkenyl radical with a maximum of 4 carbon atoms, an alkoxyalkyl radical with a maximum of 6 carbon atoms, a benzyl or phenyl radical, R_? a lower alkyl or alkenyl radical or the radical -Rgk-COOH or the radicals R ^ and R₂ - 2 - together with the H atom represent a morpholino, pipex'idino, or pyrrolidino radical, Rg hydrogen, a.

Alkyl radical with a maximum of 4 carbon atoms or an alkylenecarboxylic acid radical with a maximum of 4 carbon atoms, R ^ hydrogen or a lower alkyl radical, R- an alkyl or alkenyl radical with a maximum of 4 carbon atoms, an alkoxyalkyl radical with a maximum of 6 carbon atoms,>

a benzyl or phenyl radical or R ^ and R ^ together:

with the nitrogen a pyrrolidino, piperidino or

Represent morpholino radical and Rg a straight chain:

or branched alkylene radical with a maximum of 5 carbon atoms, where in the Palle that Rg denotes the lower alkyl or alkenyl radical; represents either A is the carboxyl group or <

Rg denotes the alkylenecarboxylic acid radical, their lower alkyl esters or their pharmaceutically acceptable salts, which, due to the amphoteric character of the compounds of the formula I, are salts with organic or organic bases or with inorganic or organic acids.

'i. I.

Compounds of the formula I are particularly preferred!

where R ^ is as defined above, R_ß Methyl, ethyl or allyl, Rg denotes the ethylene or ^ -Kethyläthylencarbonsäurerest and R ^ and R ^ each methyl or ethyl, where A is hydrogen or those compounds in which Rg is the remainder.

- 3 î⁷ . ·

-CHp-CH-COOH _f in the R₇ Hydrogen. Is methyl or ethyl, R ^ is hydrogen, methyl or ethyl and R ^ and R $ are methyl or together with the nitrogen atom are the morpholino radical, A is hydrogen and 2₁ as defined in formula I, as well as their lower alkyl esters and their pharmaceutically acceptable salts.

The compounds according to the invention are X-ray contrast media for visualizing the gallbladder, which are characterized by low toxicity, good absorbability and rapid elimination from the body. These are mostly so-called rapid cholecystography agents, 80% or more of which are excreted within 5 hours of being entered, so that administration and examination can be carried out on a dough. Some compounds of this group can also be used as intravenous contrast media, for example the compound N ~ £ 3- (1 * -3^M.-0xapenta-methylenamino-äthylidenamino) -2,4,6-triiodobenzoyl ^ ß-amino-propionic acid with an iv toxicity of 1.75 gAs can be used both as peroral and intravenous bile contrast media, a combination that is very rare. The compound shows a after intravenous administration. Maximum concentration in the bile of about 900 mg% after id administration of about 760 mg ^ and 79% is excreted in the latter after 5 hours. In addition to this and other connections with

Oxapenta-methylening with favorable properties such as the H- £ 3 ~ (lS3^a“Oxapentamethyleneamino-äthyliden ~ amino) -2 ♦, 4», 6 '-trijodbenzoyl3- “ß amino- (jG-methylpropionic acid with an iv toxicity of 1.27 g / kg and an 89% excretion after 5 hours would be also, for example, the compounds W-Q3- (1'-dimethylamino-ethylideneamino) -2,4,6-triiodobenzoyl-β-amino- (fr '-methyl-propionic acid_r W- £ 3- (1 * -Dimethylamino-ethylideneamino) 2,4,6-triiodobenzoyl ^ -Ni-methoxy-propyl) -β-aminopropionic acid and rI- £ 3- (1 '-ethylamino-ethylideneamino) -2 To mention 4,6- triiodobinzoyl ^ -B-raethyl-β-aminopropionic acid because of its good properties. .

The process according to the invention is characterized in that derivatives of triiodinated aminobenzenecarboxylic acids of the general formula II of the formula sheet with compounds of the general formula III of the formula sheet, where in formula II Y is a halogen atom or the remainder of the formula VI of the formula sheet, A 'is a hydrogen atom, a carboxyl group, a carboxyl group esterified by aliphatic alcohols, an acid chloride group or the group of the formula VII on the formula sheet, in the Ιΐθ a lower alkyl or alkenyl radical, the radicals R ^ .COOH or. R.^e and X “is hydrogen, the other than the radical -COR ^ is defined, where R $ hydrogen, an alkyl radical with a maximum of 4 carbon atoms, an alkylenearboxylic acid radical with a maximum of 4 carbon atoms or an alkylenecarboxylic acid lower alkyl ester radical in which the acid component» has a maximum of 4 carbon atoms , means, where in the formulas II and III R ^, E ^, R ^ and Rg are as defined in formula I and in the Peale that Βθ represents a lower alkyl or alkenyl radical, either A 'denotes a carboxyl group or its alkyl group or R $ denotes an alkyl group substituted by a carboxy or carboalkoxy group, with at least 1 mol of halides of pentavalent phosphorus, preferably in an inert organic solvent, in the compounds obtained or their hydrochlorides in aromatic nucleus IN ANY acid chloride groups then with amines of the

Formula IV of the formula sheet, in which Rq and Κθ are defined as stated above, reacted and saponified existing ester groups if desired.

The process products obtained in this way can be isolated as free amphoteric compounds, as esters or as salts both with bases and with acids.

The procedure can be carried out in two main variants. According to a variant, compounds of the formula II in which X 'represents a hydrogen atom, that is to say 3-amino-2,4,6-triiodobenzoyl chloride or 3-amino-2,4,6-triiodobenzoic acid amides derived therefrom with acid amides of the formula III, in which means that X is the remainder of R_nCO- represents, y ο implemented. The reaction temperature here can be 20-100 0, with an increased temperature accelerating the reaction. It is expedient to work in a suitable solvent such as toluene, chloroform, ether, ethyl acetate or dioxane. The amide of the formula III, which must then be present in excess, can also serve as a solvent. In this case, POCl ^ is preferably used as the halide of phosphorus, which is expediently used in an amount of at least 1 mol of POCl ^ per mole of the compound of the formula II.

However, the amide group can also be bonded to the benzene nucleus and the reaction can be carried out with an amine of the formula III (X = H). In this variant of the method, it is advisable to use at room temperature and in the presence of at least 1 mole of phosphorus pentachloride per mole of the compound of the formula. II to work, with sieve chlorinated hydrocarbons having proven particularly useful as solvents.

The product of the reaction of both process variants can be isolated either as a hydrochloride or as a base, which the latter was released by alkalizing the reaction solution. If Y in formula II is a halogen atom, the acid chloride group must then be converted into the amide group, which is easily possible by reaction with the corresponding amines. If A 'in formula I is also an acid chloride group, this also becomes at the same time^- converted into the amide group, which is to be taken into account when calculating the amount of the amine of the formula IV.

Ester groups present in the molecule can then be saponified in the usual way. The compounds obtained can be obtained from the mostly alkaline saponification solution as salts of the acids or free acids. But they can also be isolated as salts with acids. Obtaining the free carboxylic acids of the formula I is particularly favorable if the aqueous solution of the salt of these carboxylic acids of the formula I or the salts of these preliminary compounds with acids are equated to the pH of the free amidinecarboxylic acid by means of acids or bases. These then mostly precipitate as amorphous products and can, if necessary, be purified by recrystallization. The melting points of the amorphous products are not characteristic.

Particularly suitable salts of the compounds according to the invention are sodium, lithium and ammonium alums, salts of alkaline earth metals and salts of non-toxic organic bases such as glucosamine, methylglucosamine, ethanolamine, diethanolamine, glucamine and methylglucamine.

Salts

The amidines, including the esters, are, for example, the chlorohydrates, sulfates, acetates, fumarates, succinates and tartrates.

Due to the structure, isomerisms can occur. The individual isomers can be so stable that they can be isolated in pure form. These isomers are also the subject matter of the present invention.

The compounds of the formulas IIï III and IV are known and can be obtained by methods described in the literature. In this connection, reference is made to Austrian patents Nos. 209.895 and 224.264 as well as German patents Nos. 1,117,135 and 1,082,368.

The preparation of the compounds according to the invention is to be explained in more detail in the following examples.

Example 1î · .133.3 S 3-Amino-2,4,6-triiodobenzoyl chloride are dissolved in toluene, 37.5 ml of dimethylformamide and 31.3 ml of POCl ^ are added and the solution is then refluxed for 1 hour. The resulting hydrochloride of 3-dimethylaminomethyleneimino-2,4,6-triiodobenzoyl chloride is filtered off with suction after cooling and washed with ether. This product is then covered with a layer of ether, water is added and 250 ml of 4N NaOH are added dropwise while cooling with ice and stirring well. After separating the ethereal layer, it is washed with ice water, dried over NaCl and evaporated. The oily residue from evaporation is dissolved in hot cyclohexane, treated with activated charcoal and the solution is filtered clear. When it cools down slowly, it crystallizes. S 123.3? g yellow 3-dimethylaminomethyleneamino-2,4,6-trijodbenzoyl chloride, mp = 100-105 ° 0 '

58.8 g of the acid chloride obtained are dissolved in chloroform and a solution of 30.0 g of methyl N-allyl-β-aminopropionate in chloroform is added. The reaction mixture begins to boil, to complete the reaction it is refluxed for a further 2 hours, then the solution is washed with water, 5% tartaric acid and KgCO ^ solution, dried over CaClg and evaporated. The residue is dissolved in hot methanol, 30.0 g of N- (3-dimethylaminomethylonamino “2,4,6triiodobenzoyl) -N-allyl“ ß-aminopropionsäurem®thyl “Coter with melting point 86-98 ° C crystallize on concentration of the mother liquor to a third another 22.0 g of melting point ~ 85 - 100 ° C.

g of the ester are dissolved in excess aqueous NaOH at • ./10

- ίο • 80 ° C saponified, the resulting solution filtered clear and adjusted to pH 6 with HCl cold. The amorphous.:. · Precipitation was ground under egg water, sucked off and dried in a desiccator. The yield is 22.0 g of amorphous N “(3-dimethylaminomethyleneamino-2,4,6-triiodobenzoylpN-allyl-ß-aminoproplonic acid. Mp = 94-106 ° C.

Example 2: '·.

6.76 g of N- (3AÄminö-2,4,6-tr iodobenzoyl) -N-phenyl ~ ß ~ aminopropionßäm'emethylester are in toluene abs. solved and. after adding 1.5 ml of dimethylformamide and 1.25 ml of POClg for 1 hour. The oil that separates out is separated off after it has cooled down, dissolved in methanol and. like again with ether. Crystallization occurs when rubbed with zither. Yield 6.2 g of brownish hydrochloride of N- (3-pimethylaminomethyleneamino-2,4,6-triodobenzyl) -H-phenyl-ß ~ aminopropionic acid methyl ester, m.p. 130-1 ^ 5 ° 0. By treatment with excess NaHCO ^ the ester base is obtained therefrom with a melting point of ~ 70-77 ° 0, which can be saponified in the same way as in Example 1 with aqueous lye. The melting point of the amorphous N- (3-bimethylaminomethyleneamino-2,4,6-trijodbenzoyl) N-phenyl-β-aminopropionic acid is 92-116 ° 0.

EXAMPLE 3 18.0 g of the acid chloride prepared according to Example 1 are dissolved in chloroform, and methyl aminocaproate, dissolved in chloroform, is added. The reaction mixture heats up to boiling. Boiling is continued for 90 minutes and then the chloroform solution is washed with water, aqueous tartaric acid solution and KgCO ^ solution, with CaCl₂ dried and evaporated ./11 “11. The evaporation residue is dissolved in hot methanol and filtered clear. 14.0 g of N- (3-dimethylaminomethyleneamino ~ 2,4,6-triiodobenzoyl) ~ ί • aminocaproic acid methyl ester, pp - 139 ~ 142 ° C, crystallize out of the solution, when the mother liquor is concentrated, a further 6.2 g of the same product, melting point = 128-140 ° C. For saponification, 18.0 g of this ester are suspended in 2N NaOH and boiled until it is completely dissolved. After filtration, the pH is adjusted to 5 with dilute HCl, the acid being oily and solidifying on cooling with ice water. After suctioning off and drying in a desiccator, 12.0 g of amorphous N ~ (3-dimethylaminomethyleneamino-2,4,6-trijodbenzoyl) ~ taminocaproic acid, melting point - 90 - 100 ° 0. ·

Example 4t *

213.2 g of 3-amino-2,4,6-triiodobenzoyle chloride are dissolved in chloroform, 174 g of dimethylacetamide are added and 153 g of POCl ^ are added dropwise over 20 minutes, the mixture heating to boiling. The boiling is continued for 8 hours and, after cooling, the accumulated ·. Sucked off crystals. The crystals were suspended in ether and shaken with ice-cold, dilute NaOH until everything was in solution. When narrowing the with Na₉So ^ dried ether phase, 127.0 g of 3- (1 '-Dime t'nylamino-ethylideneamino) -2,4, o-triiodobenzoyl chloride of melting point 127-130 ° C crystallize.¹

39.13 g of this acid chloride are dissolved in chloroform, 25.0 g of methyl N- (3 ”methoxypropyl) -ß-aminopropicnate are added dropwise, heating occurs, and the reaction mixture is boiled for 40 minutes. The solution obtained is washed with water and KHOO, solution, dried over NagSO ^ and evaporated. The evaporation residue is boiled with 0.7 N methanolic NaOH until saponification is complete, and then the solution

12mittöD. distilled off. The residue is dissolved in water and the acid is precipitated with glacial acetic acid, filtered off with suction and dried in vacuo. 16.8 g of amorphous'-dimethylaminoethylideneamino) -2,4,6-triiodobenzoyl / '- N- meth. oxypropyl) ß-aminopropionic acid, mp = 90-110 ° 0.

Example 5t.

213 * 2 g of 3 ~ amino-2,4> 6-triiodobenzoyl chloride are dissolved in chloroform, 135 g of acetanilide and then within 15 minutes 153 g of POCl ^ are added and the solution is boiled for 8 hours. After cooling, the resulting crystals are filtered off with suction. The crystals are suspended in chloroform and, while stirring, cold dilute NaOH is added to form a solution. The chloroform phase is separated off, washed with water, dried over NagSO ^ and concentrated, 220 g of S-O'-phenylamino-ethylidsnamino) 2,4,6-triiodobenzoyl chloride, melting point 172-170 ° C., crystallize.

52.0 g of the acid chloride are dissolved in chloroform and 26.0 g of methyl N-methyl-β-amino ^ -methylpropionate are added. After the exothermic reaction has subsided, the solution is boiled for a further 30 minutes, then washed with water and KHCO ^ solution, dried over NagSO ^ and evaporated. The evaporation residue is boiled in approx. 1 N methanolic NaOH until complete saponification. After the solvent has been distilled off, the residue is taken up in water and glacial acetic acid is added until the acid has completely precipitated. It is filtered off with suction and the precipitate is dried. The yield is 56.0 g of amorphous N- / 3- (Γ- “Phenylamin oäthylIdenamino) -2,4,6-tri j odbenz oy ^ -N-methyl-ß-amino- <4 methylpropionic acid, mp = 142-166 ° C..

' ./13 — 13 —

Example 6s

53.3 g of 3-amino-2,4,6-triiodobenzoyl chloride are dissolved in chloroform, 39 g of N-acetylmorpholine and 45 g of FOCl ^ are added and the mixture is boiled for 6 hours. After cooling, the accumulated crystals are filtered off with suction, washed with chloroform and dried. Kian receives 61.0 g of the hydrochloride of 3- (l '~ -3-oxapentamethyleneamino-ethylideneamino) -2,4, ό-trijod-benzoylohlorid, mp = from 240 ° C ser.

27-2 g of this product are suspended in chloroform, the amidine base is set free by adding triethylamine and this is reacted with 12.0 g of ethyl β-aminopropionate. After the reaction has subsided, the reaction mixture is boiled for a further 15 minutes, the chloroform solution obtained is washed with water, dried over NagSO ^ and. evaporated. The evaporation residue is refluxed with about 0.6 N methanolic aqueous NaOH until saponification. After the solvent has been distilled off, it is taken up in water, the acid formed is precipitated with glacial acetic acid, filtered off with suction and thickened. 24.8 g of amorphous N- / T- (1'-3-0xapentamethyleneamino-ethylideneamino) -2,4,6-trijodbenzoyl7 ~ ß ~ amino propionic acid, melting point 133-145 ° C. are obtained.

Example 7î

27.2 g of acid chloride hydrochloride, prepared according to Example 6, are suspended in chloroform, triethylamine is added to liberate the amidine and 11.7 g of methyl β-amino - ^ - methylpropionate are added and the solution is boiled for 20 minutes. The work-up, saponification and precipitation of the end product takes place ./14

- 14 in the same way as in example 6. This gives 25.5 g of 'amorphous N- / 3 ”(1¹ -3 “0xapentamethylenan) .ino-ethylideneamino) · 2,4,6-trij oâbeïizojrl7-fi-amino ~ d -methylpropionic acid, melting point - 131 - 148 ° C. The acid crystallizes on the ethyl acetate with a melting point of - 291–294 ° C.

If the chloroform solution of the conversion of acid chloride with aminocarboxylic acid ester is washed with Ι-eye, evaporated and taken up in methanol, the methyl ester of H- / J- (1¹ -3^{! l}“Oxapentamethyleneamino-ethylideneamino) -2,4,6-triiodobenzoyX7“ ß-sjäino “CZ“ ethylpropionic acid, mp ~ 166 172 ° C.

35.0 g N “/ 7“ (1¹-3 "Oxapentamethyleneamino-ethylideneamino) 2,4,6-trijodbenzoyl7 ~ ß" a®.ino- [(-methylpropionic acid are dissolved in 250 ml of hot water after adding 25 ml of 4N HCl. On cooling, the salt crystallizes out. After filtering off with suction and drying, 32.0 g of hydrochloride of N- / 3- (1 '-3 *' oxapentamethylene-aminb-ethylideneamino) -2,4,6-triiodohenzoyl / "ß-amino-Ä-methylpropionic acid are obtained, Mp = slow at 235 ° C

Melting, from 255 ° 0 decomposition.

Example 8 «

32.8 g of methyl N- (3-acetylamino-2,4,6-triiodobenzoyl) -β-amino- <X-methylpropionate are dissolved in methylene chloride and 13.35% of FCl ^ are added. This suspension is carried out for 17 hours, during which the reaction products gradually dissolve; while cooling with ice, morpholine is then added until the alkaline reaction remains. After about 45 hours of standing at ./15

A f * W "I" α ^

Room temperature is used by the angofaliéner. The crystals are filtered off with suction and the filtrate is washed with water, dried and evaporated '-3-Oxapentame thylonamino-ätbylidenamino) -2,4,6-trlJ odbenzoy ^' ^ aniino • ~ zZ-methylpropionic acid precipitated. Yield 15.8 g; the product is identical to the compound obtained in Example 7. .

Example 9:

24.0 g of N- (3-amino-2,4, β-tri iodobenzoyl) -aminoacetic acid ethyl ester are dissolved in chloroform, 6.2 g of N-acetylmorpholine and 7.4 g of POCI3 are added and. the solution boiled for 5 hours. After standing overnight, the product is filtered off with suction, the still moist crystals are dissolved in methanol, boiled and aqueous KaOH is added until saponification is complete. The solvent is then distilled off, the residue is taken up in water, filtered clear and adjusted to pH 5 with dilute HCl. The amorphous acid which precipitates out is brought to crystallization by gentle warming, filtered off with suction while cold and dried at 110.degree. The yield is 12.5 g of N- / I- ('1 * -3 "Oxapentametbylenamino-ethylideneamino) -2,4,6triiodobenzoyl7-aminoacetic acid, mp = 265-270 ° C decomp.

Example 10:

21.32 g of 3-amino-2,4,6-triiodobenzoylochloride are dissolved in chloroform, 17.2 g of N-propionylmorpholine and 18.0 g of POCl ^ are added and the mixture is boiled for 5 hours. After cooling, the resulting crystals are filtered off with suction and washed with chloroform. ./16

- 16 and dried. 23.4 g of 3- (1 '-3 "0xapentamothylen ~ amino-propylideneamino) -2,4,6-trijodbenzoylchloride hydrochloride are obtained. The amidine base is produced analogously to Example 4 and has a melting point of 147-151 ° C.

27 »80 g of the acid chloride hydrochloride are suspended in chloroform, triethylamine and then 12.0 g. After cooling, the reaction solution is washed with water and dilute HCl, dried over Na 2 SO, and evaporated. The evaporation residue is heated with aqueous-methanolic NaOH until complete saponification. After the solvent has been distilled off, it is taken up in water, filtered clear, the acid is precipitated with glacial acetic acid and filtered off with suction. After treatment with water and vacuum drying, 25.6 g of amorphous N - / ^ - (l ^ "Oxapentamethyleneamino-propylideneamino) -2,4,6-trijodbenzoyl7-ß-amino- [(-methylpropionic acid, melting point 130-145 ° C. '

Example 11î

53.3 g of 3-amino-2,4,6-triiodobenzoyl chloride are dissolved in chloroform, mixed with 48 g of dimethyl amide monomethyl ester and 45 g of POCl ^ and boiled for 7 hours. The solution is then poured onto ice, the chloroform phase is separated off, washed with dilute NaOH and water, dried and. evaporated. The evaporation residue / becomes ether¹ taken up, the insoluble fraction (10.4 g) sucked off and the solution evaporated to dryness. 45.2 g of 3- (3'-chloroformyl2 ', 4¹, 6'-triiodanilino) -3-dimethylamino-propylidene- (3) carboxylic acid methyl ester in oily form, which is immediately further A './17

Λ r »- ​​I i can be implemented.

• The crude acid chi or id is dissolved in chloroform, methylamine is introduced in excess and the reaction mixture is boiled for 10 minutes. It is then washed with water, dried over NagSO ^ and evaporated. The evaporation residue is saponified in aqueous methanolic NaOH at boiling point, the methanol is distilled off, diluted with water and, after clear filtration, the acid is liberated with glacial acetic acid. When heated, the first amorphous precipitate becomes crystalline. The crystals are filtered off with suction and boiled with methanol.

Yield 16.9 g of 3 “(3MT ~ Hethyl ~ carbamyl“ 2 ', 4', 6'-triiodanilino) -3-dimethylamino ~ propylidene (3) -carboxylic acid with a melting point of 264 - 268 ° C.

Example 12:

53.3 g of 3-amino-2,4,6-triiodobenzoyl chloride are dissolved in chloroform, 37.8 g of morpholide succinic acid monomethyl ester and 30.6 g of POCl3 are added and the solution is boiled for 6 hours. After standing above power, the accumulated crystals are filtered off with suction, washed with chloroform and dried. The yield is 24.5 g of hydrochloride of 3 “(3 '~ chloroformyl-2', 4 ', 6'-triiodanilino) -3 ~ (3ⁿ-oxapentamethylcnamino) “propylidene“ (3) -carbonic acid methyl ester. The amidine base is prepared as in Example 4, it has a melting point of mp = 132-134 ° 0 »

14.9 g of the acid chloride hydrochloride are suspended in chloroform, methylamine is introduced in excess and the solution is boiled for 10 minutes. After cooling, it is washed with water and dilute acetic acid, the chloroform phase is dried and evaporated. The evaporation residue is boiled with aqueous methanolic NaOH until complete saponification, the solvent by evaporation; removed and the residue taken up in water. The acid is set free at the boiling point with glacial acetic acid. It precipitates in crystalline form, is filtered off with suction and dried.

Yield 11.0 g of 3- (3 * -N-methyl-carbamyl-2 ', 4', 6'-triiodanilino) -3- (3-oxapentamethylenamino) -propylidene- (3) -carboxylic acid of m.p. = 265 - 270 ° C.

Example 13t

22.8 g of 3 ~ amino ~ 5 ~ R ^ Qthylce.rbamyl-2,4_fß-trijodbcmzooGäure are suspended in dioxane, mixed with 25 ml of dimethylformamide and 25 ml of POCl ^ and boiled for 90 minutes. The reaction mixture is then evaporated to dryness in vacuo and 200 ml of water are carefully added to the residue. The resulting crystals are filtered off with suction, dissolved in water by adding NaOH, filtered until clear and precipitated again with dilute HCl. 23.5 g of 3-dimethylaminomethyleneamino-5 “N“ methylcarbamyl-2,4,6-trijodbenzoic acid chlorohydrate are obtained, mp - from 300 ° C. decomp. '

Example 14t

53,1 & 3-Amino “5 ~ N-methylcarbamyl-2,4,6-triiodobenzoyl chloride are suspended in chloroform, 52.2 g of dimethylucetamide and 121.8 g of POCl ^ are added and the solution is boiled for 4.5 hours. After cooling, the product is sucked off, suspended in chloroform and brought into solution by adding triethylamine. The chlorofoil solution is separated off, • ./19

- 19 washed with water, dried over NaCl and evaporated; The evaporation residue crystallizes from ether and gives 18.3 g of 3- (1 · -Dimethylamino-äthylidenamino) -5-W-methylcarbamyl2,4,6-trijcdbenzoylchlorid, mp = 235 ° 0 Zera »

17.1 g of this acid chloride are dissolved in chloroform, 11.7 g of β-amino-οϊ-methyl-propionic acid methyl ester are added and the mixture is boiled for 1 hour. The reaction solution is washed with water, dried and evaporated. The evaporation residue is saponified by boiling with excess aqueous methanolic NaOH. After distilling off the solvent, it is dissolved in water, filtered clear and acidified with 4N HCl. 6.3 g of hydrochloride gradually crystallize out of the solution¹-Dimethylamino-ethyliclßnamino) 5-K-methylcarbamyl-2,4,6-triiodobenzoylZ-ß-amino-Λ -methylpropionic acid, melting point - 266-273 ° C.

Example 15 », · ·

6 ^ 4 g of N- (3-amino ~ 2,4,6-triiodobenzoyl) -H-ethyl-ß-aminopropionic acid are dissolved in chloroform by adding 1.5 g of dimethylformamide and 3.0 g of POCl ^ and heating . On boiling (90 minutes) an oily reaction product separates out, which, after cooling and decanting off the solvent, is dissolved in dilute aqueous NaOH. After clear filtration, 3.7 g of amorphous N- (3-dimethylamino-methylene-amino-2,4, β-triiodobenzoyl) -N-ethyl [beta] -amino-propionic acid, m.p. 105-125, fall on acidification with dilute HCl to pH -5 ° C.

./20

- 20 In a manner analogous to the preceding examples, the following compounds are preparedί

H- (3-Dimethylam5.no-methylenamino-2,4 »6-triiodbonzoyl) aminoacetic acid, mp = 256-259 ° 0

I.

N- (3 “dimethylamino-methylenamino-2₁4th 6-triiodobenzoyl) -N methylamino & acetic acid, mp => 135-140 ° 0

N- (3-M-methylamino-methylenamino-2,4> 6-triiodobenzoyl) -bumino-propionic acid. Mp - 208-214 ° C

N- (3 ~ Dimethylaiüino-methyl.enamino-2,4 »6-triiodobenzoyl) -Nlaethyl-β-aminopropionic acid, mp = 138-150 ° G

N- (3-Dimethylamino-methylene-amino-2,4,6-triiodobenzoyl) -Nisopropyl-ß-aminopionic acid, mp = 125-135 ° 0

N (3 "DimethylaminO" ffiöthylenamino-2,4 "6" -triiodobenzoyl) -N ~ (fr * -methoxypropyl) -ß-aminopropionic acid

M.p. 158-164 ° 0

N- (3 “Diniethylamino“ m®thylenamino “2,6-triiodobenzoyl) -ßamino- [(-methyl-propionic acid) mp = 110-125 ° 0

N- / T- (3'-Oxapentamethyleneaminomethyleneamino) -2,4,6-trijodbenzoylT-ß-amino-oi-methyl-propionic acid. Mp »123-140 ° C'-ethylamino-ethylideneamino) -2_f 4,6-triiodobenzoyl, N-methyl-β-aminopropionic acid, m.p.

N-allyl-ß-aminopropionic acid

Mp = 122-139 ° C

N- / 3- (1 * -Xthylamino-ethylideneamino) -2,4,6-triiodobenzoyl / ß-amino- o (-methylpropionic acid. Mp. = 148-157 ° C

N- / 3- (1 * -Dimethylamino-ethylideneamino) -2,4,6-triiodbexizoyl / N-allyl-β-aminopropionic acid, m.p. 199-200 ° 0

N- / 3- (1¹-Dimethylamino ~ ethylideneamino) -2,4,6-trij odbenzoy ^ 7 ~ ß-amino- (X-methyl-propionic acid, mp = 159-166 ° C

N- / J- (1'-Dimethylamino-ethylideneamino) -2,4,6-trijodbenzoylT

N-methyl-ß-amino-c4-methyl-propionic acid. . '

Mp «181-187 ° 0

N- / 3- (1 · -'-Methoxypropylamino-ethylideneamino) -2,4,6-trijodbenz oylT'-ß-amino- o (-met hyl-propionic acid. Mp = 120-135 ° 0.

N- / 3- (1¹-Phenylamino-ethylideneamino) -2,4,6-triiodbenz oyl / ~ N ~ allyl-ß-aminopropionic acid mp = 135-146 ° C

N- / 3- (1¹-Phenylamino-ethylideneamino) -2,4,6-trij odbenz oylÿMï (3-mozo-propyl) -ß-amino-propionic acid

Mp «120-131 ° C

N- / 3- (1'-Phenylamino-ethylideneamino) -2,4,6-triiodobenzoyl / -βamino- o (-methylpropionic acid m.p.

N- / 3- (1'-Pentamethyleneamineb-ethylideneamino) -2 _f 4,6-triiodobenzoylI-N-allyl-ß-aminopropionic acid

Mp = 148-158 ° C

22 N- / 3- (1 '-Pöntatfiethylenamino-äthyliclenamino) -2,4,6-trijod-benzoyl7 ~ K- (-methoxypropyl) -ß-aminopropionic acid

Mp = 87 - 120 ° C

H- / J- (1 '“3'^,~ OxapentamethylenaminO “âthylidenamino) -2,4,6tri j odb enzoyi / -N-met hyl-ß-amino-propionic acid

Mp = 154-156 ° G

N- / 3- (1'-3-oxapentamethyleneamino-ethylideneamino) -2,4,6-triiodobenzoyl-7-N-ethyl-ß-aminopropionic acid

Mp = 130-133 ° C

N- / 3 (1'-3-oxapentamethyleneamino-ethylideneamino) -2,4,6-triiodobenzoyl-7-N-allyl-ß-aminopropionic acid. · J

Mp = 120 - 128 ° C

N- / 3- (1 '-3 "" Oxapentamethyleneamino-thylideneamino) -2,4,6triiodobenzoyl7-N-isopropyl-β-aminopropionic acid, mp = 140-152 ° C

N- / 3- (1 '-3^{, l}-0xapentamethylenamlno-äthylidenamino) -2,4,6trij odbenzoyl / -N - (- methoxypropyl) -ß-aminopropionic acid

M.p. 109-115 ° G.

N- / 3- (1 '-3-0xapentamethyleneamino-âthylidenamino) -2,4,6tri iodobenzoly7 ~ N-benzyl-ß-amin.o- ^ -methyl-propionic acid

Pp = 191 - 196 ° C ί

N- / 3- (l'-3Oxapentamethylenamino-äthylidenamino) -2,4,6- · trij ο db enz oy17 “N-propyl-ß-amino-butter acid

Mp = 125-155 ° C '. ./23 I

I.

II i

44- / 3- (1 '-ß ^ Oxapentamethylenamino-äthylidenamino) - ^, 4,6tri iodobenzoyl7 "ß - amino- ά -ethylpropionic acid

Mp = 125-130 ° G

14- / 3- (1 '-Diethylamino-propylideneamino) -2,4,6-triiodobenzoyl / N-methyl-β-aminopropionic acid. Mp = 80-115 ° C

N- / 3- (1'-Diethylamino-propylideneamino) -2,4,6-tri j odbenzoy] ^ "N - (* - methoxypropyl) -ß-amine propionic acid. (sticky product)

N- / 3- (1 '-Diet hylamino-propylidenamino) -2,4,6-tri; Iodbenz oyl7 ~

N-allyl-ß-aminopropionic acid, m.p. 93-105 ° 0

N- / I- (1'-Diethylamino-propylideneamino) -2,4 »6-triiodobenzoyl /" ß-amino - ^ - methyl-propionic acid m.p. 113-123 ° C

14- / 3- (1'-Diethylamino-propylideneamino) -2,4 »6-triiodobenzoyl / N-methyl-β-amino-c (-metlayl-propionic acid

Pp «105-115 ° C

N- / J- (1 · -3 '' - Oxapentamethyl & namino-propylidenamino) -2,4,6tri, iodbenzoy / 7-N-methyl-ß-amino-propionic acid mp - 114 - 125 ° C '

N- / 3 (1'-3-0xapentemethyleneamino-propylideneamino) -2,4,6tri j odb enz oyl7-U-ethyl-ß-amin o-propionic acid.

. Mp - 110-125 ° C

N- / 3- (1 '-3^{, l}~ 0xapentamethylenainino-propylidenamin.o) -2,4,6tri iodbeiisoy] 7 "^N~^Allesyl "ß"^amino~ P^roP.^{ionic acid}

Fp «110 - 125 ° 0 ./24 · Ύ ** 24 ·»

Π - ^ '3- (π «-3^K~ 0xapentamethyleneamino-propylideneamino) -2,4,6-triiodobenzoyl ^ N'Hnethyl'-ß-ainine © «O-methyl-propionic acid _: pps 128-140 ° C

3- (3 »-M-Allyl-carbamyl-2 ', 4', 6 '4r iiodanilino) -3-methylamino-propylidene- (3) -carboxylic acid Fo» 125-134 ° C

3- (3 "-N-methyl-carbamyl-2 *, 4 *, 6 * -triiodanilino) -3-diathylandno-propylidene- (3) -carboxylic acid, mp = 209-213 ° C

3- (3 '~ N-ethyl “caT'bamyl-2i_i4’_lW6'wtrljodan3J.ino) -3 “dicIthylamino-propylidene- (3) -carboxylic acid, mp = 118-128 ° C

3- (3 '-N-allyl-carbajnyl-2', 4 ' ₍6'-triiodanilino) -3-diethylamino-propylidene- (3) -carboxylic acid, mp = 109-130 ° C

3- ^ 3 '- (3 *' “0xapentamethylene-carbamyl) -2 ', 4^f,6⁴ -tri j odanilino3-3 “diâthylamino * -propylidene- (3) -carboxylic acid • mp = 142-150 ° C

3-£3⁴“(3^K“0xapGntamethylene-carbaiayl)“ 2 ', 4 *, 6'-triiodanilino3-3- (3^w'-oxapentamethyleneamino) -propylidene- (3)' carboxylic acid, m.p. 145-155 ° C

3- (1 '-Diraethylamino-âthylïdenamiïio) -5 «N * methyl carbamyl2,4,6-trijodbenzoic acid hydrochloride

Mp = 243-249 ° C dec.

( 1 ’ -3^1f-Oxapentamethyleneamino-ethylidenaniino) 2,4,6-triiodobenzoyig-ß-aminobutyric acid

N £ 3 “(1 * -3^M.-Oxapentaniethylenaiiiiïio-2'-methyl-propj^rlldenamino) ~ 2,4,6-trijodbenzoyl ^ -ß-amino-ty-methylpropionic acid 'mp = 110-125 ° C

- 25 '-3 "~ Oxapentamethyleneamino" 2' -methyl-propylidenamino) -2,4, ö-trijödbenzoyl ^ -Wy ^ methoxypropyl-propionic acid * Mp »85-100^cC.

N ~ £ 3 ~ (1'-methylamino-ethylideneamino) -2,4,6-trijodbenzoyl-ß-amino-Ov-methylpropionic acid

By treating with alkali hydroxides or solutions of. organic amines, the acids can be converted into the corresponding salts. The salts are isolated as an amorphous product by evaporation, by crystallization from suitable solvents such as water or alcohols or by precipitation from them using solvents.

For example, can the sodium salt N- (3-dimethylamino-methylenamino «2,4,6« -triiodobenzoyl) ~ aminoacetic acid be precipitated from the aqueous solution with acetone? Mp = 1S0-2O7 ° C.