CS277109B6 - Nonionic contrast means and process for preparing thereof - Google Patents

Abstract

Triiodo-5-aminoisophthalamides in which the amino and one of the amide nitrogen groups are substituted are indicated. The compounds have at least two hydroxyl groups and low viscosity and osmolality. Processes for the preparation of the compounds are indicated.

Description

The invention relates to a non-ionic contrast agent and to a process for the manufacture of active substances.

The radiographic contrast medium for the visibility of the cardiovascular system and the body cavities must be of low viscosity, highly water-soluble, non-toxic and of high iodine content. Low viscosity is necessary for rapid application, for immediate replacement of fast flowing blood, such as in cardioangiography or urography, or in the case of computed tomography with contrast enhancement. In order to be nontoxic, this compound must be very hydrophilic, must be nonionic in nature and have an osmolality close to that of the body environment. Although the prior art nonionic monomer media are characterized by acceptable biocompatibility and appropriate viscosity, they are hyperosmolar to the body environment. Typically, at a diagnostically appropriate concentration of 300 mg I / ml, they significantly exceed a physiological value of 310 mOsm. The hyperosmolality of these solutions necessarily frees the cells of water by destroying the cell membranes, disrupting the electrolyte balance and damaging the lining of the blood vessels or body cavities. Hyperosmolality has also been found to be one of the causes of vascular pain that is invariably caused by hyperosmolar contrast media.

Most of the nonionic contrast media, whether monomeric or oligomeric, are aromatic amides with one or more lower aliphatic polyhydroxyalkyl and nitrogen-linked acyl groups and annular carboxamido and amino groups. The triiodinated benzene ring contains a number of functional groups in a tight spatial arrangement. Several amide-linked hydroxyalkylamines are described in the prior art. Examples of such amines are: serinol; 1-amino-2,3-propanediol; 1-methylamino-2,3-propanediol; aminotetritols; ethanolamine; diethanolamine or tromethamine.

Replacement of the carboxyl groups at positions 1 and 3 with the same hydroxylamines is associated with considerable structural constraints, since practically available substituents are either too small to solubilize the molecule or too large to result in a low viscosity solution (cf. Nycomed, US U.S. Patent No. 4,021,481 and U.S. Patent No. 3,701,771, Schering AG, U.S. Patent No. 4,547,357, Bracco, U.S. Patent No. 4,001,323). For this reason, improved compounds have been created in which the hydroxyalkylamino groups are different from one another (cf. Schering AG, U.S. Pat. No. 4,364,921). However, the synthesis of these compounds is complex and associated with high costs.

U.S. Patent Nos. 3,701,771, 4,001,323, 4,021,481, 4,364,921, 4,547,357, and US Patent Application No. 214,663 (July 1, 1988) disclose examples of various compounds cited as suitable. for non-toxic contrast media.

The invention provides a nonionic contrast agent based on an asymmetric triiodoisophthalic acid diamide wherein a substituted nitrogen is bonded to the remaining ring position, one of the carboxyl groups being amidated with an unsubstituted amino group and the other carboCS 277109 B6 xyl group being amidated with an amino group substituted with at least one monohydroxy group. The molecule contains at least two hydroxyl groups.

The present invention provides a nonionic acylamido substituted tri-iodophthalic acid diamide contrast agent in which only one of the amide nitrogen atoms is at least monosubstituted. These compounds can be synthesized at low cost in good yield and are obtained in a high degree of purity. The compounds have been found to have low osmolality, while at the same time exhibiting a mild to low viscosity.

The compounds of the invention will in most cases be represented by the following general formula (I)

in which

R-j. represents a hydrogen atom, a lower alkyl group or a hydroxyalkyl group, wherein the alkyl group contains 1 to 3, usually 1 to 2 carbon atoms and the hydroxyalkyl group contains at least 0.5 hydroxyl groups per carbon to n-1 hydroxyl groups, n being the number of atoms carbon; the hydroxyalkyl group contains from 2 to 6, usually from 2 to 4 carbon atoms; .......... '

R ₂ represents a mono- or polyhydroxyalkyl radical having 2 to 6 carbon atoms, usually 2 to 4 carbon atoms and contains at least one hydroxyl group and not less than n-2 and not more than n-1 hydroxy groups, wherein n is the number of carbon carbon;

R ₃ represents a lower alkyl group, a hydroxy (lower) alkyl group or a lower alkoxy (lower) alkyl group wherein the alkyl moiety contains 1 to 4 carbon atoms, usually 1 to 3 carbon atoms, and the alkoxy moiety contains 1 to 3 carbon atoms, usually 1 to 2 carbon atoms, wherein the number of oxy groups ranges from 0 to n-1, where n is the number of carbon atoms, or two R ₃ groups may together form a bridge of 0 to 2 carbon atoms, preferably 1 carbon atom, i.e. R ₃ represents a group of formula

CONH (CH ^^ - CON)

R ₄ represents a hydrogen atom, a lower alkyl group, or a mono- or polyhydroxyalkyl group, the alkyl and hydroxyl groups being as defined above for analogous groups.

The alkyl groups may be straight or branched.

Usually the chain is straight and the carbon atoms are usually other than quaternary.

Alkyl moiety in mono- or polyhydroxyalkyl groups

R ₄ and R ₂ usually contain 2 to 6 carbon atoms, in particular 2 to 4 carbon atoms. Preferably, these groups contain 1 to 5 hydroxy groups, usually 1 to 3 hydroxy groups. These hydroxy groups may be primary, secondary or tertiary. Examples are tris-hydroxymethylmethyl, hydroxyethyl, dihydroxypropyl and trihydroxybutyl. The carbamates can be prepared using 3-amino-1,2-propanediol, serinol or aminotetritols, i.e., threitol and erythritol, either in the form of a mixture of D, L or in the form of optically pure isomers, ethanolamine or diethanolamine or tromethamine, or its derivatives, wherein the hydroxy groups are temporarily protected. R ₄ represents a hydrogen atom or a lower alkyl group, preferably a hydrogen atom or a methyl group. R ₃ represents a lower alkyl group or an oxyalkyl group having 1 to 6 carbon atoms, usually 1 to 4 carbon atoms, preferably methyl, hydroxymethyl or hydroxyethyl. Examples which may be mentioned are alkoxyalkyl groups having 1 to 1 carbon atoms, preferably 1 to 2 carbon atoms, and alkyl groups having 1 to 3 carbon atoms, in particular methoxymethyl. Alternatively, the two R ₃ groups may be taken together to form a bond, a methylene group or an ethylene group, in particular a methylene group. R ₄ represents a hydrogen atom, an alkyl group or a mono- or polyhydroxyalkyl group having 1 to 6 carbon atoms, usually having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, hydroxyethyl and dihydroxypropyl.

By way of example, monomeric compounds may be mentioned

5- [N- (2-hydroxyethyl) methoxyacetamido] -2,4,6-triazolo-3- [N- (1,3,4-trihydroxybut-2-yl)] carbamoylbenzamide;

5- [N- (2-hydroxyethyl) hydroxyacetamido] -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] carbamoylbenzamide;

5- [N- (2,3-dihydroxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] carbamoylbenzamide;

5- [N- (2,3-dihydroxypropyl) glycolamido] -2,4,6-triazole-3- [N- (2-hydroxyethyl)] carbamoylbenzamide;

5- [N- (1,3,4-trihydroxybut-2-yl) acetamido] -2,4,6-triiodo-3- ['N- (2-hydroxyethyl)] carbamoylbenzamide;

5- [N- (methyl) glycolamido] -2,4,6-triazole-3- [N- (1,3,4-trihydroxyerythrobut-2-yl) carbamoylbenzamide;

5- [N- (2-hydroxyethyl) acetamido] -2,4,6-triazolo-3- [N- (1,3,4-trihydroxythreobut-2-yl)] carbamoylbenzamide.

Examples of interesting dimer compounds include: bis - [β-N- (2,3-dihydroxypropylcarbamoyl) -5-carbamoyl] -2,4,6-triiodo-N- (2,3-dihydroxypropyl) anilide malonic acid;

malonic acid bis - [β-N- (2,3-dihydroxypropylcarbamoyl) -5-carbamoyl] -2,4,6-triiodo-N- (2-hydroxyethyl) anilide; and bis - [[3-N- (1,3,4-trihydroxybut-2-ylcarbamoyl) -5-carbamoyl] -2,4,

Malonic acid 6-triiodo-N-methylanilide.

The compositions of the invention contain about 50 to 52% iodine, usually about 51% iodine; have a solution viscosity of 300 mg I / ml at 37 ° C in the range of about 4 to 5 cps and an osmolality of 300 mg I / ml at ° C for an aqueous solution in the range of about 275 to 400, preferably about 285 to 375 mOsm, the osmolality of the pharmaceutical composition ranges from about 300 to 400, preferably from about 325 to about 390 mOsm.

The compositions of the invention are formulated in accordance with conventional conditions. Typically, these aqueous-based formulations containing a physiologically acceptable calcium salt in the form of a chelate, for example with ethylenediaminetetraacetic acid, are a buffer having a pH in the range of about 6.5 to 7.5, in particular about 7, which buffer may be from the group consisting of tris, carbonate, citrate and combinations thereof. Other ingredients that may be included include bicarbonate, phosphate, etc. The chelate calcium salt may generally be present in an amount of from about 5 to about 15, typically about 10 mg / 100 ml, while the buffer content is generally from about 5 to about 15 mg / 100 ml. about 2 to 10 mM.

The invention further relates to a process for the preparation of the compounds of the formula I which comprises:

(a) compounds of formula (V). CO ₂ H ₂ in which the hydroxyl groups contained in R 1 and R ₂ are optionally protected are converted by reaction with a compound of the general formula

R ₃ CO - X in which:

X is a halogen atom or an ester moiety, and R ₃ is as defined above, in catalytically active solvents such as pyridine, dimethylamide or dimethylformamide, and optionally by subsequent deprotection to the final products of formula I wherein R ₄ is hydrogen, or to intermediates of formula I 'in which R ₄ is R ₃ CO-, and these intermediates, optionally with protected hydroxy groups, are then optionally converted by alkylation under basic conditions with reagents containing R ₄ , optionally after subsequent deprotection, to end products of formula I wherein R _{4 is} not hydrogen;

b) compounds of formula VI cox

in which

R ₅ is R význam or hydrogen;

R ₆ has the meanings of _R2 or is hydrogen and

X represents a halogen atom or represents an ester residue, is reacted with ammonia or with hydroxyalkylamines containing radicals R-j and _R2 and the hydroxy groups are optionally protected and thereafter if desired, removing the protecting group.

However, conventional reactions can also be combined to produce the compounds of the invention in the following manner. Thus, for example, the compounds of the invention can be prepared from a compound of formula II cox

in which

R ₁ and R ₂ have the meanings given above and

X represents a lower alkyl group or a halogen atom.

The compounds of formula (II) are prepared by reacting hydroxyalkylamine (NHR 3), in which the hydroxyl groups are optionally protected, with a commercially available 5-nitroisophthalic acid monoester, whereupon the remaining carboxyl group is activated. Such activation is suitably achieved when X is a halogen atom such as a chlorine atom, a bromine atom, an iodine atom or an alkoxy group, preferably a chlorine atom and a methoxy group.

The ester group of monoesters of 5-nitro isophthalic acid treatment aminolyzuje hydroxyalkylamine HNR ^ R ₂ defined above or aminolysis can be achieved first by treatment with ammonia. The remaining carboxyl group is then activated as described above. If the hydroxyl groups of the NR ₁₁ R ₂ moiety are not protected and could be attacked by activation, they can be conveniently protected by conventional means, such as O-acetylation or isopropylidination.

The compound of formula II can be crystallized from water or from lower alcohols in the usual manner.

After treatment with anhydrous ammonia or ammonium hydroxide to give an asymmetric isophthaldiamide, the compound obtained is hydrogenated, triiodinated and acylated in the usual manner to give a compound of formula III wherein ^R 1 ' ^is 2' ^and 3 ^is as defined above.

The reduction and iodination is carried out by standard methods using palladium on carbon or Raney nickel as catalysts in water or lower alcohols, and hydrogen, optionally under elevated pressure. The resulting 5-aminoisophthalic acid diamide is then iodinated by known methods. The compound is then recovered from the reaction mixture as a crystallizate, the crystalline product is washed, dried and acylated, also by known methods. Thus, activated acyl derivatives of the formula R ₃ CO-X in which X is halogen or the same anhydride-forming acyl group and catalytically active solvents such as pyridine, dimethylamide or dimethylformamide may be used.

If compounds of formula I are to be prepared in which R ₄ is other than hydrogen, the alkylation is carried out by standard methods. Except for the lower alkyl groups usually introduced in the initial stage of the synthesis, the reaction in which the hydroxyalkyl radicals are introduced is typically carried out as the last stage of the synthesis. Thus, the alkylation can be carried out in a high-boiling glycol type solvent such as ethylene or propylene glycol and at a highly basic pH which is achieved by the addition of sodium methoxide, sodium hydroxide or other inorganic or organic bases.

Alternatively, in some cases, for purification purposes where by-products are difficult to remove by conventional purification methods, it is preferred to maintain the presence of one carboxyl group up to the last stages of the reaction sequence so that the compound can be dissolved in water as a salt and then precipitate or precipitate it by treatment with an inorganic acid. Preferred salts include ammonium, sodium, potassium, calcium, barium or lithium salts.

Yet another such alternative process is based on the reduction, iodination and acetylation of compounds of formula (II) wherein X is a hydroxyl group as described above to give a compound of formula (IV)

COOH

R.

(IV

R

Even in which

R _HR R ₂ and R ₃ have the abovementioned meanings.

The hydroxyl groups are protected from activation of the carboxyl group. It is also desirable to diacylate the anilide by introducing a R ₃ CO group when said nitrogen atom could be undesirably attacked during activation of the carboxyl group. The carboxyl group can be activated as described above, preferably in the form of an acid chloride, although mixed anhydrides such as tert-butyloxycarbonyl derivatives can also be used. The compounds of formula IV can be crystallized in the usual manner from an aprotic solvent and then reacted with ammonium hydroxide or ammonia, followed by the last step of alkylation.

Effective amidation usually requires the use of either an excess of the amidation base as an acid binding agent, or alternatively the presence of tertiary amines such as triethylamine, tributylamine, pyridine or inorganic bases such as bicarbonate or carbonate.

If undesirable by-products are present, a further synthesis variant may be used. Thus, the alkylation of the anilide can be performed before the amidation. Alkylation of compounds of formula IV wherein R 1, R ₂ and R ₃ are as defined above may be carried out by known methods described above.

During the alkylation to introduce the substituent R ₄ , the protecting groups R ₃ CO are removed and thus the hydroxyl groups of the substituents R 1 and R ₂ (as well as the substituent R ₄ , if present) must be protected again from activation of the carboxyl group and subsequent amidation with ammonia. Acetyl groups are most commonly used for this purpose.

In the subsequent final step, if the hydroxyl groups are still protected, such as when the alkylation is not carried out as a last step, the protecting groups can be removed by conventional standard methods, for example by exposure to ion exchange resins, or acids or bases in catalytic amounts in alcoholic or aqueous solvents.

The removal of the salts can be carried out by known methods. Thus, salts can be removed by ion exchange resins, either using a mixed bed or in separate columns, individually containing anionic or cation exchange resins. Alternatively, the compounds of formula I may be absorbed onto a polystyrene absorbent neutral resin and then eluted.

After removal of the salts, the product can be crystallized from lower solvents, preferably lower alcohols. Decolorization can be achieved by boiling in an aqueous solution of activated carbon under reflux.

The dimer is usually prepared from benzamide with an alkylated atom

1-4 of the nitrogen of the amino group and with the remaining carbonyl group activated, for example in the form of chlorocarbonyl. The dibasic acid is used in an activated form, in particular in the form of diacyldichloride in an organic aprotic polar solvent. The ring-bound chlorocarbonyl is then hydroxyalkylamidated to give the final product.

The compounds of the invention and the compounds of formula I are stable in aqueous solutions; these compounds readily form supersaturated solutions, which also remain stable. The solutions can be heat treated in an autoclave by standard methods. At diagnostically useful iodine concentrations, the compounds have an osmolality which is typically very close to the physiological osmolality values. At the same time, the viscosity of the solution is low. Thus, the purpose of the present invention was achieved, ie to overcome the previously recognized mutual exclusivity of both factors, i.e. low osmolality and low viscosity. As a result, the novel compounds have excellent local and systematic tolerability. Said compounds have good biocompatibility and have a high iodine content, especially in comparison with hitherto available nonionic X-ray contrast agents.

Data of the benzamide derivative group for compound 11 (point 5) and compound 19 (point 6) were collected as examples of properties. For comparison purposes, Table I also lists the data of compounds known in the art.

CS

Basic properties of nonionic monomeric X-ray contrast media

tr ο ο μ X X! υ χ> ν β o φ ω β ω in ε X N Q β μ ο 0 XI οι 44 οο μ • tr 'Φ> β · η tr ο > N 44 CM • μ -P r-10H 0> Ν Λ β Μ · μ β μ β tr ε> ω > μ o β X ιο ax:> ω ε μ _ _L ι χ ε β 44 Μ 0 υ 'Φ ο 44 μ β ε Μ 44 β - 0 0 β> Μ Φ 0 χ »Β · γ-ι 0 μ 44 44 β β β 0 0 Ό. ε ε 4J -Ρ 'μ μ μ μ Ν> β 0 0 0 0 Μ4 m μ μ a τ) η β ο ε 1 χ> \ Ν • μ · μ η 0 Η 0 μ β β tr μ μ ε 'φ ε 0 44 β X U1 ε β ο β 44 Ο υι Φ ο ο ο ε 0 0 μ > 44 ι · μ 0 0 Ή 44 β > μ ν μ and 0 4J μ β υ r — 1 Μ 'μ ε β 0 · π 44 β β Η • μ 0 β ω 44 μ tr 0> ευ - 44 0 0 0 ω ω do a • μ β β ο γ ο > 44 0 μμ -

Ή

44 β 44> Ul β O 0 β —I β

O β 44 r -> 44 O

Φ | dP H £ in

CM η <Μ μ μ ιη μ r — l ι — Ι ι — Ι ι — Ι μ > Ν > Ν > Ν > Ν > Ν > Ν β β d β β β ιη ιη »» ι — Ι CM ι — I CM μ γ * Η μ γΗ μ μ τ — 1

X 00 ιο 00 ΙΟ ΙΟ γ4 i — 1 ιμ μ μ μ > Ν > Ν > Ν > Ν > Ν > Ν β β β β β β ΙΟ ΙΟ μ ΙΟ μ μ i — 1 i — 1 μ μ μ μ

ιη μ ο 00 ο ο 00 ο μ 00 σι CM ιο χ ιο ιη μ μ

ο ι — 1 X ο ιη ο ιη X ο ΙΟ ΙΟ ο ΙΟ ιο ο ιη μ μ

μ X ιο χ rH μ Η * » · » »» ΙΟ μ μ μ μ

co μ

oo μ

oo μ

and in σι r-4 β β

ι — Ι ι — Ι 0 β Φ β • Η β β * · Η β β • μ β 0 μ ε β φ Φ X ε 0 μ > ο > ο φ β μ μ β β Λ and and X 0 0 0 0 0 0 μ μ Η Η Η Η ω ω

literature data; other data were collected in our laboratory

All solutions were pharmaceutically formulated except where otherwise indicated.

The observed low osmolality and low toxicity have hitherto been achieved only with nonionic dimers, but they cannot be used in general uro- and angiography due to their high viscosity, which is at least twice as high for a comparable solution concentration.

The novel compounds exhibit excellent general biocompatibility. High osmolality is the cause of vascular pain and a major side effect in imaging the peripheral vasculature of the respective parts (cf. Sovak, Μ., Current Contrast Media and Ioxilan, Comparative Evaluation of Vascular Pain by Aversion Conditioning, Ihvestigative Radiology, September, 1988 Supp.). This is one of the major diagnostic procedures in vascular radiology. The novel compounds of this invention are virtually painless in these procedures. Due to their physicochemical and pharmacological properties, the novel compounds are useful as water-soluble contrast media for the visualization of urinary excretory pathways and cardiovascular systems and body cavities, and generally for enhancing contrast in computed tomography. Injectable solutions of the novel compounds can be prepared by dissolving in water and adding standard physiologically compatible buffers and stabilizers such as chelating agents. The compounds are also suitable for enteral administration when formulated with carriers generally used in pharmacology. Dimers are mainly used for myelograms.

For intravascular administration, the respective compositions contain the compounds of the invention at a concentration of 20 to 80% (w / v). Iodine concentrations of from 150 to 400 mg / ml are preferred.

The following examples illustrate the invention but do not limit it in any way.

Example 1

Preparation of 5-nitro-3- [N- (1,3,4-trihydroxythreo-but-2-yl)] - carbamoylbenzoic acid (2) by amidation of monomethyl ester

5-nitroisophthalic acid (1) (threo) -2-amino-1,3,4-butanetriol

22.5 g (0.1 mol) of the starting material (1) are mixed with 30.25 g (0.25 mol) of (threo) -2-amino-1,3,4-butanetriol and the suspension is heated to 110-120 ° C. Thin layer chromatography showed complete conversion to the desired product and the reaction solution was poured into 200 mL of 1N hydrochloric acid to precipitate the desired product. The mixture was cooled overnight and then the product was filtered off and washed with ice-cold water (2 x 20 ml). Drying under reduced pressure gave 21.0 g (yield 67%) of a white solid (2).

Example 2

Preparation of methyl 5-nitro-3- [Ν- (1,3,4-trihydroxythreo-but-2-yl)] carbamoylbenzoate (3) by esterification of 5-nitro-3- [Ν- (1,3,4- trihydroxythreo-but-2-yl)] carbamoylbenzoic acid (2) dimethylsulfate

15.7 g (0.05 mol) of the title compound (2) are dissolved in 55 ml of 1 N sodium hydroxide solution and the solution obtained is cooled to less than 20 ° C. Then, 9.45 g (0.075 mol) of dimethyl sulfate was added to the cooled solution over 5 minutes and the pH was maintained between 8 and 10 by occasional addition of 5N sodium hydroxide solution. The solution was stirred for about 12 hours at room temperature and then the insoluble solid was filtered off. The pasty solid is washed twice with 50 ml of cold water each time and dried under reduced pressure. 11.8 g (72% yield) of the powdery product (3) are obtained.

Example 3

Preparation of 5-nitro-3- [N- (1,3,4-trihydroxy-threo-but-2-yl)] - carbamoylbenzamide (4) by amidation of methyl-5-nitro-3- [N- (1,3, 4-trihydroxy-threo-but-2-yl)] carbamoyl benzoate (3)

Dissolve 10.0 g (0.0305 mol) of ester (3) in 50 ml of methanol and add 20 ml (about 0.3 mol) of concentrated ammonium hydroxide to the obtained solution. The resulting suspension is heated in a sealed vessel at 50-60 ° C for 30 minutes, during which time the reaction is complete as determined by thin layer chromatography. Methanol and ammonium hydroxide were removed by distillation and replaced with 50 ml of water. After cooling overnight, the insoluble product was filtered off and washed twice with 5 ml of cold water. Drying under reduced pressure gave 7.15 g (75% yield) of the white mixed amide (4).

Example 4

Production of 5-nitroisophthalic acid monomethyl ester monochloride (5) by chlorination of 5-nitroisophthalic acid monomethyl ester (1) with thionyl chloride

225 g (1 mol) of the title compound (1) are dissolved in 0.5 liter of ethyl acetate and 0.1 ml of N, N-dimethylformamide is added as a catalyst. The solution was heated to 70 ° C and then 219 mL (3 mol) of thionyl chloride was added over 1.25 hours. The temperature was maintained at 70 ° C for 2 hours.

The thionyl chloride was distilled off by adding three times 200 ml of ethyl acetate and the product was dissolved in 250 ml of hot ethyl acetate and precipitated by the addition of 1 liter of cyclohexane. The product obtained is washed twice with 200 ml of cyclohexane and dried at 50 DEG C. under reduced pressure. 216 g (89%) of a white solid (5) are obtained.

Example 5

Preparation of methyl 5-nitro-3- [N- (trans-2,2-dimethyl-6-hydroxy-1,3-dioxepan-5-yl)] carbamoylbenzoate (6) by amidation of 5-nitroisophthalic acid monomethyl ester monochloride (5) ) aminodioxepane

100 g (0.411 mol) of monoester monochloride (5) are dissolved in 1 liter of absolute tetrahydrofuran and 132.8 g (0.825 mol) of solid are added in portions over 15 minutes while maintaining the temperature below 25 ° C using an ice bath. aminodioxepane. Thereafter, the heterogeneous mixture was stirred for 30 minutes at room temperature, where the reaction was detected by thin layer chromatography.

The insoluble amine hydrochloride was filtered off and tetrahydrofuran was removed from the filtrate by distillation. The residue is dissolved in 400 ml of ethyl acetate at near boiling point and the solution is then allowed to stand for several days until crystallization of the product is complete. The solid product is filtered off, washed twice with 50 ml of ethyl acetate each time and dried under reduced pressure. 82.4 g (55% yield) of an off-white product (6) are obtained.

Example 6

Preparation of 3- [N- (trans-2,2-dimethyl-6-hydroxy-1,3-dioxepan-5-yl)] carbamoylbenzamide (7) by amidation of methyl-5-nitro-3- [N- (trans- 2,2-Dimethyl-6-hydroxy-1,3-dioxepan-5-yl) carbamoyl benzoate (6) with ammonium hydroxide

A Parr pressure reactor (800 mL) was charged with 80 g (0.22 mol) of the title compound (6), 110 mL of methanol and 225 mL (3.38 mol) of 15N ammonium hydroxide solution. The reaction vessel was sealed and heated in a water bath at 50 ° C for 2 hours at which time TLC indicated completion of the reaction. The heterogeneous reaction mixture is then mixed with 100 ml of water and stripped to give a foam. The foam is then suspended in 100 ml of water, the suspension is filtered and the residue on the filter is washed twice with 50 ml of water each. 60.4 g (79% yield) of a white solid (7) are obtained.

Example 7

Preparation of 5-amino- (hydrochloride) -3- [Ν- (X, 3,4-trihydroxy-threo-but-2-yl)] carbamoylbenzamide (8) by reduction and deprotection of 5-nitro-3- [N - (trans-2,2-dimethyl-6-hydroxy-1,3-dioxepan-5-yl)] carbamoylbenzamide (7) with hydrogen and palladium on carbon and hydrochloric acid

A 2 liter Parr pressure reactor was charged with 58 g (0.16 mol) of the title compound (7), 410 ml of 1N hydrochloric acid solution and 5.8 g of palladium on carbon (10% palladium on carbon, 1%). Pd weight / weight). Thereafter, the reaction vessel is connected to a hydrogenation apparatus and the apparatus is shaken at a hydrogen pressure of 350 kPa for 2 hours at which time 90% conversion to the product can be determined by high performance liquid chromatography (8). The palladium catalyst is filtered off and the acetone formed during deprotection is removed under reduced pressure at 50 ° C. The resulting clear solution (8) (450 mL, 90% yield) was used directly for iodination.

Example 8

Preparation of 5-amino-2,4,6-triiodo-3- [N- (1,3,4-trihydroxy-threo-but-2-yl)] carbamoylbenzamide (9) by iodination of 5-amino- (hydrochloride) -3 - [N- (1,3,4-trihydroxy-threo-but-2-yl)] carbamoylbenzamide (8)

0.14 mol of the title compound (8) in 450 ml of 1N hydrochloric acid solution is heated to 85 ° C and then 135 ml (0.49 mol) of iodine chloride are added. The reaction mixture was heated at 85 ° C for 1 h. After this time, the reaction can be determined to be complete by high performance liquid chromatography. The reaction mixture is cooled to 25 DEG C. and then extracted twice with 200 ml of cyclohexane, 3 times with 300 ml of dichloromethane and 5 times with 200 ml of chloroform, until all of the violet color is removed from the aqueous layer. The resulting light yellow solution was then recirculated on a column containing 800 g of Duolite-A340 resin and 266 g of Dowex 50W-X8 resin. The resin was washed with 6 liters of water and the solution was concentrated to a volume of 300 ml at which point a white crystalline solid began to crystallize. The product was filtered off to give 40 g (0.06 mol) of a white solid (9). Yield 43%.

Example 9

Preparation of 5-diacetylamino-2,4,6-triiodo-3- [N- (1,3,4-triacetoxy-threo-but-2-yl)] carbamoylbenzamide (10) by acetylation of 5-amino-2,4,6 - Tri-3- [N- (1,3,4-trihydroxy-threo-but-2-yl)] - carbamoylbenzamide (9) with acetic anhydride g (0.14 mol) of the title compound (9) is mixed with 500 ml (4.95 mol) acetic anhydride at 70 ° C with vigorous stirring. 0.36 ml (0.004 mol of perchloric acid catalyst) was then added to the reaction mixture, which raised the temperature to 85 [deg.] C. The reaction mixture was stirred at 85 [deg.] C. for 1 hour to give a homogeneous mixture. To neutralize perchloric acid, 0.33 g (0.004 mol) of sodium acetate was added and the solvent was removed to give a thick brown oil which was diluted with 200 mL of butyl acetate at 70 ° C and the solvent was removed. The stripping process was repeated twice to give a brown foam to give 113 g of product (10), i.e. 0.13 mol, yield 93%.

Example 10

Preparation of 5- [N- (2-hydroxyethylacetamido)] - 2,4,6-triiodo-3- [N- (1,3,4-trihydroxythreo-but-2-yl)] carbamoylbenzamide (11) by deacetylation / and alkylation of 5-diacetylamino-2,4,6-triiodo-3- [N- (1,3,4-triacetoxy-threo-but-2-yl)] carbamoylbenzamide (10) with sodium methoxide and 2-chloroethanol

113 g (0.13 mol) of the title compound (10) are dissolved in 500 ml of methanol, to which 55 g (0.25 mol) of 25% sodium methoxide are added at 50 ° C. After 5 hours, high performance liquid chromatography indicated that deacetylation was complete and the solution was neutralized by the addition of 10 g of ion exchange resin (Dowex 50 W-X4). The resin was filtered off and the filtrate was concentrated to 400 ml. The neutral methanolic solution was heated to 45 ° C and 129 g (0.34 mol) of sodium phosphate dodecahydrate and 18.2 ml (0.272 mol) of 2-chloroethanol were added.

The reaction mixture was stirred at 45 ° C for 48 hours. 4.7 ml (0.07 mol) of chloroethanol and 14.7 g (0.07 mol) of sodium methoxide were added to the reaction. After 71 hours, the reaction is complete according to high performance liquid chromatography. The insoluble salts (89 g) were removed by filtration and the solution was neutralized with 7 ml of 6N hydrochloric acid solution. The solution is concentrated to give 94 g of a brown foam (11). Yield 0.12 mol (92%).

Example 11

Production of 5-nitro-3- [N- (2,3-dihydroxypropyl)] carbamoylbenzoic acid (12) by amidation of 5-nitroisophthalic acid monomethyl ester (1)

3-amino-1,2-propanediol

225 g (1 mol) of the starting material (1) are mixed with 227.8 g (2.5 mol)

The 3-amino-1,2-propanediol and the heterogeneous mixture were heated at 110-120 ° C for 1 hour. At this time, the reaction is complete and the homogeneous mixture is mixed with 1 liter of water and 170 ml of concentrated hydrochloric acid. The mixture is cooled for several days to completely precipitate the product and the solid is filtered off and washed twice with 50 ml of cold water each time. Drying under reduced pressure gave 193 g (68% yield) of a white solid (12).

Example 12

Preparation of 5-amino- (hydrochloride) -3- [N- (2,3-dihydroxypropyl)] - carbamoylbenzoic acid (13) by reduction of 5-nitro-3- [N- (2,3-dihydroxypropyl)] carbamoylbenzoic acid (12) ) hydrogen in the presence of pallaadium on carbon

180 g (0.634 mol) of the nitro derivative (12) are mixed with 1 liter of water and 60 ml of concentrated hydrochloric acid and 18 g of 10% palladium on carbon are added. The suspension is hydrogenated at 0.2 to 0.4 MPa and, as long as the pressure remains constant, the reaction is complete according to high performance liquid chromatography and thin layer chromatography. The palladium on carbon is filtered off and the homogeneous solution is used for the next reaction without isolation of the product. The compound (13) is obtained in an approximate yield of 98%.

Example 13

Preparation of 5-amino-2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] - carbamoylbenzoic acid (14) by iodination of 5-amino- (hydrochloride) -3- [N- (2,3) (dihydroxypropyl)] carbamoylbenzoic acid (13) iodine chloride

About 0.62 mol of the title compound (13) in 1.5 liters of water was further diluted with water to a total volume of 4 liters and heated to 85 ° C. After 20 minutes, 499 mL (2.05 mol) of a 4.1 M iodine chloride solution was added and the temperature was maintained at 90 ° C for 6-8 hours. After this time, the reaction is complete by HPLC. The homogeneous mixture is cooled and extracted with 500 ml of a 9: 1 mixture of 1,2-dichloroethane and cyclohexane, then twice with 250 ml of 1,2-dichloroethane twice. The aqueous layer is then concentrated by distillation to a volume of 0.9 liters and cooled for several days to completely precipitate a solid. Filtration, washing with cold water (twice 100 ml) and drying under reduced pressure gave 286 g (yield 73%) of a reddish-brown colored product (14).

Example 14

Preparation of 5-diacetylamino-2,4,6-triiodo-3- [N- (2,3-diacetoxypropyl) carbamoylbenoic acid (15) by acetylation of 5-amino-2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl) -carbamoylbenzoic acid (14) with acetic anhydride

100 g (0.158 mol) of the starting material (14) are mixed with 300 ml (3.16 mol) of acetic anhydride and 0.2 ml of 70% perchloric acid and the mixture is heated at 80 to 90 ° C for 8 hours. The resulting mixture was neutralized with anhydrous sodium acetate (0.25 g) and acetic anhydride and acetic acid removed by distillation at 70-80 ° C. The oily residue is azeotroped twice with 100 ml of butyl acetate, then dissolved in 250 ml of ethyl acetate and in this state is directly used for chlorination. The product (15) is obtained in an approximate yield of 90%.

Example 15

Preparation of 5-diacetylamino-2,4,6-triiodo-3- [N- (2,3-diacetoxypropyl) carbamoylbenzoyl chloride (16) by chlorination of 5-diacetylamino-2,4,6-triiodo-3- [N- (2, 3-diacetoxypropyl) -carbamoylbenzoic acid (15) thionyl chloride

About 0.142 mol of starting material (15) in 225 ml of ethyl acetate is added with the addition of 57 ml (0.78 mol) of thionyl chloride at a temperature of up to 70 ° C, whereupon the temperature is raised to 75-80 ° C and maintained at this temperature. for 1 hour. Thioyl chloride and ethyl acetate were then distilled off under reduced pressure. The residue was azeotroped with butyl acetate (2 x 100 mL) and then dried in vacuo. About 130 g (estimated yield 95%) of a brown foam was directly used for the next amidation step.

Example 16

Preparation of 5-acetylamino-2,4,6-triiodo-3- [N- (2,3-diacetoxypropyl)] - carbamoylbenzamide (17) by amidation of 5-diacetylamino-2,4,6-triiodo-3- [N- ( 2,3-diacetoxypropyl) carbamoylbenzoyl chloride (16) with ammonia

About 0.135 mol of acid chloride (16) is dissolved in 150 ml of absolute Ν, Ν-dimethylacetamide. This solution was cooled to 0-5 ° C and condensed anhydrous ammonia (about 20 mL) was added to the cooled solution using a condenser containing ice / acetone and the reaction mixture was kept in a sealed vessel at room temperature for 24 hours. Then, ammonia and dimethylamide are removed by distillation under reduced pressure. Addition of 500 ml of 1-pentanol precipitated a solid which was filtered off and washed twice with 150 ml of 1-pentanol. Drying under reduced pressure gave 82 g (yield 80.2%) of a red-brown colored solid (17).

Example 17

Preparation of 5-acetylamino-2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] - carbamoylbenzamide (18) by deacetylation of 5-acetylamino-2,4,6-triiodo-3- [N- ( 2,3-diacetoxypropyl) carbamoylbenzamide (17)

81.2 g (0.107 mol) of the title compound (17) is suspended in 203 ml of water and then 16.9 ml (0.322 mol) of a 50% w / w solution of sodium hydroxide in water is added dropwise. Stirring achieves complete dissolution. The resulting solution was degassed for 30 minutes and then 15 ml (0.18 mol) of a 12M hydrochloric acid solution was added. The reaction mixture is then allowed to stand at 4 DEG C., whereupon the precipitated solid is filtered off, washed three times with 50 ml of ice-water, 80 ml of ethanol and dried under reduced pressure. Yield: 54.1 g (yield: 75%) of product (18).

Example 18

Preparation of 5- [N- (2,3-dihydroxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] carbamoylbenzamide (19) by alkylation of 5-acetylamino-2,4, 6-Triiodo-3- [N- (2,3-dihydroxypropyl)] - carbamoylbenzamide (18)

39.7 g (0.059 mol) of the title compound (18) are dissolved in 16.7 ml propylene glycol, 120 ml ethanol and 17.6 ml (0.077 mol) 25% (w / w) sodium methoxide. 9.78 g (0.0885 mol) of chloropropanediol are then added and the mixture is stirred for 1 hour at 25 ° C. The reaction mixture was heated at 33 ° C and stirred for an additional 19 hours, during which time 3.4 ml (0.015 mol) of 25% w / w sodium methoxide was added. The reaction was quenched by the addition of 12M hydrochloric acid solution, after which the reaction mixture was distilled under reduced pressure, 200 ml of water was added to the residue and distilled again. An aqueous solution is obtained which is deionized to 62 g of ion exchange resin (Dowex 50, in an H + cycle) and 140 g of ion exchange resin (Duolite A-340, in the OH-cycle). Elution of the resins with water and concentration yielded 150 g of a solution, to which 1.00 g of activated carbon (Norit Ultra SX) was added and the mixture was heated at 60 ° C for 14 hours. The activated carbon is then filtered off and the resulting aqueous solution is then stirred for 2 hours with the addition of 1.0 g of resin (Dowex 50, in the H ⁺ -cycle) and 4 g of resin (Duolite A-340, in the 0H -cycle). The resin was filtered off and the aqueous solution was distilled to give 50.3 g of an oil which contained 32.8 g (74% yield) of the product (19) in a mixture of glycerol and propylene glycol. This oil was purified as described in the next step.

Example 19

Preparation of 5- [N- (2,3-dihydroxypropyl) acetamido] -? 2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] carbamoylbenzamide (19) by peracetylation, silica gel column purification and subsequent purification deacetylations

Dissolve 16.4 g (0.022 mol) of the title compound (19) in an oil consisting of a mixture of glycerol and propylene glycol (total weight 25.15 g), dilute the solution with 1.74 g (0.022 mol) of pyridine and 115 g. g (1.12 mol) of acetic anhydride and then the mixture is heated at 60 ° C for hours. The reaction mixture is then distilled under reduced pressure to give an oil which is dissolved in 100 ml of chloroform and extracted twice with 50 ml of a 0.1N hydrochloric acid solution each time and twice with 50 ml of a 15% w / v brine each time. The chloroform layer was dried over magnesium sulfate, filtered and distilled to give an oil. This oil was purified on a 900 g silica gel column using a gradient elution starting with a mixture of 5% acetic acid and 95% chloroform and ending with a mixture of 5% acetic acid, 4.% methanol and 91% chloroform. The pure fractions were combined, distilled to give a foam, and 30 ml of methanol and 0.98 g (0.0054 mol) of 25% (w / w) sodium methoxide in methanol were added thereto. After 30 minutes, the solution is distilled, 20 ml of methanol are added to the residue, and the resulting solution is stirred with 1.3 g of resin (Dowex 50, in the H ⁺ -cycle). After adjusting the pH from 12 to 5, the resin was filtered off and the solution was distilled to a foam, 25 ml of water was added to the resulting foam, and the mixture was re-evaporated to give 8.12 g (49% yield) of the title compound. in the title (19) as a solid.

Example 20

Preparation of 5-acetylamino-2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] - carbamoylbenzoic acid (20) by deacetylation of 5-diacetylamino-2,

4,6-triiodo-3- [N- (2,3-diacetoxypropyl)] carbamoylbenzoic acid (15)

720 g (0.9 mol) of the title compound (15) are dissolved in 500 ml of methanol and 345 ml (1.5 mol) of 25% (w / w) sodium methoxide in methanol are added. After a reaction time of 45 to 50 ° C, the reaction mixture is distilled under reduced pressure, acidified with 124 ml (1.5 mol) of a 12M hydrochloric acid solution and the salts are filtered off. The filtrate was distilled under reduced pressure to give an oil which was diluted with 680 mL of n-propanol. After crystallization at 4 ° C, the resulting solid (20) is filtered off, washed twice with 300 ml of n-propanol and dried under reduced pressure. Yield 391 g (64%).

Example 21

Preparation of 5- [N- (2,3-dihydroxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2,

3-dihydroxypropyl)] carbamoylbenzoic acid in the form of the sodium salt (21) by alkylation of 5-acetylamino-2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] carbamoylbenzoic acid (20)

100 g (0.148 mol) of the title compound (20) are dissolved in 400 ml of methanol. Subsequently, 140/6 g (0.37 mol) of sodium phosphate dodecahydrate (solid) was added to the obtained solution, followed by dropwise addition of 32.7 g (0.296 mol) of chloropropanediol and 24.1 g (0.111 mol) of 25% (w / w) sodium methoxide in methanol. The reaction mixture was heated at 40 ° C for 10 hours, during which time 8.0 g (0.0368 mol) of 25% sodium methoxide was added portionwise. The salts are filtered off and the methanolic filtrate is acidified with 3.5 ml of a 12M hydrochloric acid solution, evaporated on a rotary evaporator to give a thick oily product (21), which is used directly for the next reaction step.

Example 22

Preparation of 5- [N- (2,3-diacetoxypropyl) acetamido] -2,4,6-triazole-3- [N (2,3-diacetoxypropyl)] carbamoylbenzoic acid (22) acetylation of the sodium salt of 5- [N- (2,3-dihydroxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] carbamoylbenzoic acid (21)

114 g (0.148 mol) of the title compound (21) as an oil are diluted with 11.7 g (0.148 mol) of pyridine and 605 g (5.92 mol) of acetic anhydride and stirred at 65-70 ° C for 2 hours. . The reaction mixture is then distilled to give an oil which is further azeotroped with twice 100 ml of butyl acetate and the residue is partitioned between 300 ml of water and 200 ml of a 3: 1 mixture of toluene and ethyl acetate. The aqueous layer is extracted three times with 100 ml of 3: 1 toluene / ethyl acetate each and acidified with 22.5 ml of hydrochloric acid in the presence of 300 ml of ethyl acetate. The acidified aqueous layer was separated and extracted twice with ethyl acetate (100 mL). The three later washed ethyl acetate extracts were combined, dried over magnesium sulfate, filtered and evaporated. 118 g (87%) of solid product (22) are obtained.

Example 23

Preparation of 5- [N- (2,3-diacetoxypropyl) acetamido] -2,4,6-triazole-3- [N- (2,3-diacetoxypropyl)] carbamoylbenzooyl chloride (23) by chlorination of 5- [N- (2 3, 3-diacetoxypropyl) acetamido] -2,4,6-triazolo-3- [N- (2,3-diacetoxypropyl)] carbamoylbenzoic acid (22)

113.6 g (0.124 mol) of the title compound (22) are dissolved in 100 ml of ethyl acetate at 55 ° C. Thionyl chloride (44 g, 0.37 mol) was added dropwise and the mixture was heated under reflux for 2 hours, then evaporated on a rotary evaporator to give an oil which was azeotroped with twice 50 ml of butyl acetate. A foam is obtained which is dissolved in 200 ml of chloroform and the chloroform solution is extracted with

100 ml of 0.2 M phosphate buffer pH 6.7. The organic layer was dried (MgSO 4), filtered and evaporated. 115 g (98% yield) of solid product (23) are obtained.

Example 24

Preparation of 5- [N- (2,3-diacetoxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2,3-diacetoxypropyl)] carbamoylbenzamide (24) by amidation of 5- [N- (2,

3-diacetoxypropyl) acetamido] -2,4,6-triazole-3- [N- (2,3-diacetoxypropyl) carbamoylbenzoyl chloride (23)

105 g (0.111 mol) of the title compound (23) are dissolved in 400 ml of acetonitrile and anhydrous ammonia is added to the obtained solution using a solid carbon dioxide cooler at 0 ° C. After 3 hours at reflux, the reaction is complete. The salts are filtered off and the filtrate is evaporated to give 98.8 g (96% yield) of solid product (24).

Example 25

Preparation of 5- [N- (2,3-dihydroxypropyl) acetamido] -2,4,6-triazole-3- [N- (2,

3-dihydroxypropyl) carbamoylbenzamide (19) by deacetylation of 5- [N- (2,3-diacetoxypropyl) acetamido] -2,4,6-triazole-3- [N- (2,3-diacetoxypropyl) carbamoylbenzamide (24)

98.7 g (0.106 mol) of the title compound (24) are dissolved in 250 ml of methanol, and 2.30 g (0.0106 mol) of 25% (w / w) are added to the solution obtained at 25 ° C. sodium methoxide in methanol. After 15 minutes, the solution was distilled off under reduced pressure to give an oil. To the oil was added 200 mL of methanol, and then the mixture was stirred with 6.0 g of ion exchange resin (Dowex 50, in H ⁺ -cycle) with a pH drop from 12 to 6. Then the resin was filtered off and the resulting solution distilled to give a foam. . To this foam was added 320 mL of water and 3.0 g of activated carbon (Norit SX), the mixture was heated at reflux for 7 hours, then filtered, the filtrate was deionized by stirring with 3 g of resin (Dowex 50, in H ⁺ -cycles) and 12 g resin (Dowex

XUS-40123, (OH-cycl), the mixture was filtered and the filtrate was evaporated. 79.2 g (96% yield) of solid product (19) are obtained.

Example 26

Preparation of 5-methoxyacetylamino-2,4,6-triiodo-3- [N- (1,3,4-trihydroxy-threo-but-2-yl)] carbamoylbenzamide (25) by methoxyacetylation of 5-amino-2,4,6 -triiodo-3- [N- (1,3,4-trihydroxy-threo-but-2-yl)] carbamoylbenzamide (9) methoxyacetyl chloride

100 g (0.15 mol) of the title compound are suspended in

250 ml of N, N-dimethylacetamide at 25 ° C and 68 ml (0.75 mol) of methoxyacetyl chloride are added to the suspension obtained over 30 minutes. The reaction mixture was stirred at 35 ° C for 5 hours, after which time the reaction was determined to be complete by HPLC. The reaction was quenched by the addition of 97 g (0.45 mol) of sodium methoxide and the mixture was stirred at 0 ° C for 2 hours. The solution is neutralized by the addition of Dowex 50W-X4 resin, the mixture is filtered and the filtrate is diluted with 700 ml of n-butanol. A white precipitate precipitated immediately and was filtered to give 80.6 g (0.11 mol, 73% yield) of an off-white solid (25).

Example 27

Preparation of 5- [N- (2,3-dihydroxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2-hydroxyethyl)] carbamoylbenzoic acid as the sodium salt (27) by alkylation of ioxithalamic acid (26)

966 g (1.5 mol) of ioxithalamic acid (26) are dissolved in 1.5 liter of 1N sodium hydroxide solution at room temperature.

The solution is heated to 75 ° C and then 223.8 g (2.03 mol) of 3-chloro-1,2-propanediol and approximately 0.4 L of 5N hydroxide solution are added simultaneously over a period of 1.25 hours. sodium.

The reaction mixture was heated at 80-90 ° C for an additional 2.5 hours. At this point, high performance liquid chromatography analysis indicated that the reaction was complete (about 90% conversion to the desired product).

The reaction mixture is then neutralized by the addition of about 3 ml of concentrated hydrochloric acid and then evaporated. About half of the foam residue is taken up with 0.4 liters of water. Cooling gave a white crystalline solid, which was filtered off and washed with ice-cooled water. Drying gave 249 g of crystalline product (27).

Example 28

Preparation of 5- [N- (2,3-diacetoxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2-acetoxyethyl)] carbamoylbenzoic acid (28) by acetylation of sodium 5- [N- (2 3,4-dihydroxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2-hydroxyethyl)] carbamoyl benzoate (27) g (0.067 mol) of the title compound (27) is added to 102 ml with stirring. (1.080 mol, 16.0 equivalents) of acetic anhydride at 25 ° C. Then pyridine (5.4 mL, 0.067 mol, 1.0 equivalent) was added and the temperature was raised to 85 ° C; the reaction mixture is maintained at this temperature for 1 hour, when the reaction is complete according to thin layer chromatography. The homogeneous reaction mixture was evaporated under reduced pressure to give a thick oil which was dissolved in 50 ml of ethyl acetate and evaporated again. The oil obtained is dissolved in 260 ml of water and extracted four times with 100 ml of a 2: 1 mixture of toluene and ethyl acetate. The aqueous layer was acidified with 12N hydrochloric acid solution (11 ml) and extracted three times with 50 ml of ethyl acetate each time. The organic layer is dried over magnesium sulfate, then the filtrate is evaporated to give a foam (28) and this foam is used directly for the next reaction step. 55 g (0.065 mol, yield 97%) of the product are obtained.

Example 29

Preparation of 5- [N- (2,3-diacetoxypropyl) acetamido] -2,4,6-triazole-3- [N- (2-acetoxyethyl)] carbamoylbenzoyl chloride (29) chlorination of 5- [N- (2,3) -diacetoxypropyl) acetamido] -2,4,6-triazole-3- [N- (2-acetoxyethyl) carbamoylbenzoic acid (28) g (0.065 mol) of the title compound (28) is dissolved in 170 ml of 1,2 -dichloroethane and the solution obtained is heated to 85 ° C. Then, 9.8 mL (0.134 mol, 2.0 equivalents) of thionyl chloride was added. After 3 hours, the reaction is complete by TLC. The reaction mixture was evaporated under reduced pressure to give an oil which was redissolved in 50 ml of butyl acetate and the solution was evaporated again. 51.9 g (0.060 mol, yield 92%) of the product is isolated as a yellow foam (29).

Example 30

Preparation of 5- [N- (2,3-diacetoxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2-acetoxyethyl)] carbamoylbenzamide (30) by amidation of 5- [N- (2,3- diacetoxypropyl) acetamido] -2,4,6-triazole-3- [N- (2-acetoxyethyl)] carbamoylbenzoyl chloride (29)

51.9 g (0.060 mol) of the title compound (29) are dissolved in 200 ml of acetonitrile and anhydrous ammonia is added in excess to the obtained solution at 10 ° C. After 4 hours, the reaction is complete by TLC. The reaction mixture was filtered to remove ammonium chloride and the solvent was removed. 47 g (0.056 mol, yield 93%) of a yellow oil (30) are obtained.

Example 31

Preparation of 5- [N- (2,3-dihydroxypropylacetamido)] - 2,4,6-triazole-3- [N- (2-hydroxyethyl)] carbamoylbenzamide (31) by deacetylation of 5- [N- (2,3- diacetoxypropyl) acetamido] -2,4,6-triazole-3- [N- (2-acetoxyethyl) carbamoylbenzamide (30) g (0.056 mol) of the title compound (30) is dissolved in 240 ml of methanol and the solution obtained 3.9 g (0.3 equivalents) of 25% sodium methoxide are added to bring the pH to about

12. Stir the solution at 25 ° C for 1 hour, after which time deacetylation was complete according to high performance liquid chromatography. The reaction mixture was neutralized with 10 ml of 1N hydrochloric acid solution and the solvent was removed to give an off-white foam (31). 39 g (0.054 mol, yield 97%, purity 98%) of product are obtained, which is recrystallized from hot methanol (5 g in 15 ml, seeded).

Example 32

Production of 5-amino-2,4,6-triiodo-3-chlorocarbonylbenzamide (33) by amidation of 5-amino-2,4,6-triiodoisophthaloyl chloride (32)

300 g (0.503 mol) of the starting material (32) are dissolved in 900 ml

G of tetrahydrofuran and the homogeneous solution were cooled in an ice bath to 5-10 ° C. 92.3 ml (1.38 mol) of concentrated ammonium hydroxide are then added over 10 minutes; the temperature rises to 30 ° C.

The reaction mixture was stirred at room temperature for a total of 90 hours with further addition of ammonium hydroxide (total 25.2 mL, 0.38 mol), then cooled and the insoluble salts were filtered off. The filtrate was washed twice with 200 ml of saturated sodium chloride solution each time.

Tetrahydrofuran was evaporated to give a viscous oil. Addition of 800 ml of ethyl acetate gave a reddish brown solid which was filtered off, washed twice with 100 ml of ethyl acetate and dried, yielding 193 g (yield 66.5%) of the product (33).

Example 33

Production of bis - [(3-chlorocarbonyl-5-carbamoyl) -2,4,6-triiodoanilide] malonic acid (34) by dimerization of 5-amino-2,4,6-triiodo-3-chlorocarbonylbenzamide (33)

Dissolve 20.0 g (34.7 mmol) of the title compound (33) in 100 mL of absolute tetrahydrofuran, heat the solution to 45 ° C, and then add 2.53 mL of malonyl dichloride (26 mmol) over 3 min. formation of a heterogeneous mixture. 100 ml of absolute tetrahydrofuran are then added and the suspension is stirred for 1 hour. After this time, thin layer chromatography indicated that the reaction was complete. The mixture is diluted with 150 ml of butyl acetate and the solid is filtered off, washed twice with 50 ml of butyl acetate each time and dried under reduced pressure. 13.18 g (62% yield) of product (34) are obtained.

Example 34

Preparation of malonic acid bis - [[3-N- (1,3,4-trihydroxy-threo-but-2-ylcarbamoyl) -5-carbamoyl] -2,4,6-triiodanilide] (35) by amidation of bis - [( 3-Chlorocarbonyl-5-carbamoyl) -2,4,6-triiodanilide] malonic acid (34)

8.0 g (6.56 mmol) of the title compound (34) is dissolved in 10 mL of absolute Ν, N-dimethylacetamide, 1.83 mL (13.12 mmol) of triethylamine is added and the solution is cooled to Deň: 18 ° C. 2.64 g (16.4 mmol) of trans-5-amino-2,2-dimethyl-6-hydroxy-1,3-dioxepane are then added over 3 minutes and the homogeneous mixture is stirred at room temperature for 6 hours. After this time, thin layer chromatography indicated that the reaction was complete. The solvent was evaporated, 50 ml of water was added to the residue, and the mixture was heated to 75 ° C for 15 minutes to dissolve the acetonides. The product is obtained by evaporation and precipitation of 100 ml of isopropyl alcohol. The solid was filtered off, washed twice with 20 ml of isopropyl alcohol and dried, yielding 8.6 g (yield 94%) of the product (35).

Example 35

Preparation of 5-N-methylamino-2,4,6-triiodo-3-chlorocarbonylbenzamide (37) by amidation of 5-N-methylamino-2,4,6-triiodoisophthaloyl chloride (36)

305 g (0.5 mol) of the starting material (36) are dissolved in 1 liter of tetrahydrofuran and the solution obtained is cooled to 10 ° C. 100 ml (1.5 mol) of concentrated ammonium hydroxide are then added to the cooled solution over 5 minutes. The temperature rises to about 25 ° C.

The reaction mixture was stirred at room temperature for 65 hours with the addition of additional portions of concentrated ammonium hydroxide at 3.5 ml after 20 hours and 3.5 ml after 44 hours.

After cooling, the insoluble salts and the bis-amide were filtered off and the tetrahydrofuran filtrate was washed twice with 100 ml of saturated sodium chloride solution.

Thereafter, tetrahydrofuran was evaporated and the desired product precipitated from the thick oil by addition of 500 ml of ethyl acetate. Filtration, washing with ethyl acetate and drying afforded 132.1 g (yield 45%) of the desired product (37).

Example 36

Production of bis - [(3-chlorocarbonyl-5-carbamoyl) -2,4,6-triiodo-N-methylanilide] malonic acid (38) by dimerization of 5-N-methylamino-2,4,6-triiodo-3-chlorocarbonylbenzamide ( 37) g (42.3 mmol) of the title compound (37) are dissolved in 100 ml of absolute tetrahydrofuran and the homogeneous solution is heated to 50 ° C. Thereafter, 3.05 ml (31.3 mmol) of malonyl dichloride are added over 2 minutes, a further 50 ml of tetrahydrofuran are added and the suspension is heated for 1 hour, when the reaction is complete by thin layer chromatography.

After diluting with 50 ml of butyl acetate, the product is filtered off, washed twice with 25 ml of butyl acetate and dried. 15.24 g (58% yield) of an off-white solid is obtained (38).

Example 37

Preparation of malonic acid bis - [[3-N- (1,3,4-trihydroxy-threo-but-2-ylcarbamoyl) -5-carbamoyl] -2,4,6-triiodo-N-methylanilide] (39) by transformation Malonic acid bis - [(3-chlorocarbonyl-5-carbamoyl) -2,4,6-triiodo-N-methylanilide] (38) g (8 mmol) of the starting material (38) are dissolved in 15 ml of absolute Ν, Ν- dimethylacetamide and 2.23 ml (16 mmol) of triethylamine. Then 3.22 g (20 mmol) of trans-5-amino-2 are added over 5 minutes,

The 2-dimethyl-6-hydroxy-1,3-dioxepane (aminodioxepane) and the homogeneous mixture were stirred for 8 hours at which time the reaction was complete according to thin layer chromatography.

The dimethylamide was distilled off under reduced pressure and the isopropylidenes were cleaved by addition of an aqueous hydrochloric acid solution at 50 ° C. The water was evaporated on a rotary evaporator and isopropyl alcohol was added to precipitate the product. Filtration, washing with isopropyl alcohol (3 x 10 mL) and drying gave 9.86 g (87% yield) of dimer (39).

Example 38

Preparation of 5- [N- (methyl) -2-acetoxyacetamido] -2,4,6-triiodo-3-chlorocarbonylbenzamide (40) using 5-N- (methyl) amino-2,4,6-triiodo-3- chlorocarbonylbenzamide (36) g (42.3 mmol) of the starting material (36) are dissolved in 50 ml of absolute N, N-dimethylacetamide at room temperature. 6.83 ml (63.5 mmol) of 2-acetoxyacetyl chloride are then added and the mixture is stirred overnight. After this time, the reaction is complete by TLC.

The product is precipitated by the addition of 200 ml of ice-cold water and filtered off. After washing with water, the solid is dissolved in 200 ml of tetrahydrofuran and the solution is extracted with 250 ml of a 3: 1 mixture of saturated sodium chloride and saturated sodium bicarbonate and then 100 ml of saturated sodium chloride. The organic layer was dried over magnesium sulfate and the solvent was removed. 22.1 g (yield 77.2%) of foam (40) are obtained.

Example 39

Preparation of 5- [N- (methyl) -2-hydroxyacetamido] -2,4,6-triiodo-3- [N- (1,3,

4-trihydroxy-threo-but-2-yl)] carbamoylbenzamide (41) by amidation

5- [N- (methyl) -2-acetoxyacetamido] -2,4,6-triiodo-3-chlorocarbonylbenzamide (40) and deprotecting

7.0 g (10.35 mmol) of the title compound (40) was dissolved in a mixture of 40 ml of tetrahydrofuran and 1.44 ml (10.35 mmol) of triethylamine and the mixture was cooled to 10 ° C. Then, 2.0 g (12.41 mmol) of solid aminodioxepane was added, the cooling bath was removed and the reaction mixture was stirred at 25 ° C. After 18 hours, the reaction is complete by TLC. The reaction mixture was diluted with 40 mL of tetrahydrofuran and 50 mL of a 3: 1 mixture of saturated sodium chloride and saturated sodium bicarbonate and the layers were separated. The organic layer was washed with brine (2 x 40 mL), dried (MgSO 4) and the solvent was evaporated. It is obtained

6.9 g (82% yield) of foam.

The foam was dissolved in 50 ml of methanol and 0.5 ml of a 4.6N sodium methoxide solution was added. Then the solution is stripped at 50 ° C to give an oil which is then mixed with 50 ml of water and 10 g of resin (Dowex 50, in the H ⁺ -cycle). The reaction mixture was heated at 60 ° C for 30 minutes to give a homogeneous solution, and high performance liquid chromatography indicated the cleavage of the ester and the isopropylidene group.

The resin was filtered off and the resulting solution was recycled through Duolite A 340 resin columns (in a 0H-cycle) and Duwex 50 in an H-cycle until the deionization was complete. The compound is eluted from the columns with water and then clarified by the addition of 0.4 g of activated carbon (Norit Ultra S-X). After 1 hour at 70 ° C, the activated carbon is filtered off and the water is evaporated. 3.8 g (50% of 40) were obtained as a white foam (41).

Example 40

Solution for injection containing 5- [N- (2,3-dihydroxypropyl) acetamido] -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] carbamoylbenzamide (19)

composition of solution for 100 ml content 300 iodine in mg / ml 350 solution for injection 400 Compound (g) 58.87 68.68 78.49 disodium calcium salt of ethylenediaminetetraacetic acid (mg) 10 10 10 Tris (hydroxymethyl) aminomethane (mg) 121 121 121 Water for injection purposes up to volume (ml) 100 ALIGN! 100 ALIGN! 100 ALIGN! osmolality (mOsm / kg) 399 473 510 Viscosity at 37 ° C (cps) 4.1 6.6 10.6

Method:

The disodium salt of ethylenediamine tetraacetic acid, tris (hydroxymethyl) aminomethane, and the contrast agent are dissolved in water for injection and the solution is adjusted to pH 7.0 by adding 1N hydrochloric acid solution. The solutions are then made up to a volume of 100 ml with water for injection, filtered through a 0.22 μπι membrane filter into glass vials, sealed with caps and then autoclaved at 121 ° C for 20 minutes.

Example 41

Injectable solutions containing 5- [N- (2-hydroxyethyl) acetamido] -2,4,

6-triazole-3- [N- (1,2,4-trihydroxy-threo-but-2-yl)] carbamoylbenzamide (11) solution for iodine content in mg / ml solution for injection

100 ml 300 350 400 compound (g) 58.87 disodium ethylenediaminetetraacetic acid (mg) 56

68.68

78,49 trisodium citrate (mg) composition of solution for 100 ml iodine content in mg / ml solution for injection 300 350 400 water for injections up to a volume (ml) 100 osmolality (mOsm / kg) 301 viscosity at 37 ° C (cps) 4, 2

100 ALIGN!

337

6.6

100 ALIGN!

370

13.1

Method:

The disodium salt of ethylenediaminetetraacetic acid, trisodium citrate and contrast medium are dissolved in water for injection and the solution is adjusted to pH 5.0-6.0 with sodium carbonate and carbon dioxide. The solutions are made up to 100 ml with water for injection, filtered through a 0.22 μπι membrane filter into glass vials, capped and kept in an autoclave at 121 ° C for 20 minutes.

From the above results, it is clear that the invention provides novel nonionic contrast media which have considerably more advantageous properties over the compositions available so far. In order to improve the physical properties, in particular osmolality and viscosity, it is possible to diagnose a number of parts of the body, the application of which is easy and almost painless. Despite the large number of compounds that have been synthesized and tested, the compounds of the invention have been found to be more advantageous than the compounds known to date for this purpose. These new properties have been achieved due to the presence of three different nitrogen atoms in the molecule, of which only two are substituted. In addition, the invention provides methods of synthesizing said compounds that are effective and at high yields while allowing the use of readily available starting materials.

While the invention has been described and illustrated in detail by way of examples for ease of illustration, the skilled artisan will appreciate the possible changes and modifications that may be made without departing from the scope of the invention.

Claims (14)

PATENT CLAIMS A nonionic contrast agent of the general formula CONH R ^ CON CONR 1 R (I) containing at least two hydroxy groups in which R 1 represents a hydrogen atom, a lower alkyl group or a lower alkyl group substituted by a hydroxy group, the alkyl having 1 to 6 carbon atoms; R ₂ is a C 2 -C 6 hydroxyalkyl group containing from 1 to n-1 hydroxyl groups, wherein n is the number of carbon atoms; R ₃ represents lower alkyl, lower alkyl substituted by hydroxy or lower alkyl substituted by lower alkoxy, wherein the alkyl and the alkoxy part has from 1 to 6 carbon atoms or two R ₃ may form together a bridge having 0-2 C atoms, i.e. R ₃ represents a group of the formula CONH a AND R ₄ represents a hydrogen atom or a C 1 -C 6 alkyl group containing 0 to n-1 hydroxyl groups, wherein n is the number of carbon atoms. A nonionic monomeric contrast agent as claimed in claim 1, wherein R ₂ contains 4 carbon atoms and 3 hydroxyl groups, R ₃ has a meaning other than a common bridge group and R ₄ contains 2 to 3 carbon atoms and at least one hydroxyl group . Third monomeric nonionic contrast agent according to claim 1, characterized in that R ₂ contains three carbon atoms and two hydroxyl groups, R ₃ is other than a common bridge forming group, and _R4 contains 3 carbon atoms and 2 hydroxyl groups. The fourth non-ionic contrast agent according to claim 3, characterized in that R ₂ and R ₄ have the same meaning. 5. 5- [N- (2-hydroxyethyl) acetamido)] - 2,4,6-triiodo-3- [N- (1,3,4-trihydroxy-threo-but-2-yl)] carbamoylbenzamide. 6. 5- [N- (2,3-Dihydroxypropyl) acetamido] -2,4,6-triiodo-3- [N - (2,3-dihydroxypropyl)] carbamoylbenzamide. 7. 5- [N- (2,3-Dihydroxypropyl) acetamido] -2,4,6-triazole-3- [N- (2-hydroxyethyl)] - carbamoylbenzamide. 8. 5- [N- (methyl) -2-hydroxyacetamido] -2,4,6-triiodo-3- [Ν- (1,3,4-trihydroxy-threo-but-2-yl)] carbamoylbenzamide. 9. Bis- [3- / N- (1,3,4-trihydroxy) threo-but-2-yl] carbamoyl-5-carbamoyl] -2,4,6-triiodo-N- (methyl) anilide acid. 10. An X-ray contrast composition comprising the nonionic contrast composition of item 1 in a physiologically acceptable carrier. 11. An X-ray contrast composition comprising the nonionic contrast composition of item 5 in a physiologically acceptable carrier. 12. An x-ray contrast composition comprising the nonionic contrast composition of item 6 in a physiologically acceptable carrier. 13. A method of determining a physiological state non-invasively using irradiation and a non-ionic contrast agent, wherein the non-ionic contrast agent is a composition according to item 1. 14. A method of preparing compounds of formula I, characterized in that the /> »in which the hydroxyl groups contained in R and R ₂ are optionally protected, are converted by reaction with a compound of formula R ₃ CO-X in which X represents a halogen atom or an ester residue, and R ₃ is as defined in point 1, in catalytically active solvents such as pyridine, dimethylamide or dimethylformamide, and optionally by subsequent deprotection to the final products of formula I in which R ₄ is hydrogen or to intermediates of formula I ' wherein R ₄ is R ₃ CO-, and these intermediates, optionally with protected hydroxy groups, are then optionally converted by basic alkylation with R ₄ -containing reagents, optionally after subsequent deprotection, to the final products of formula (I), wherein R _{4 is} not hydrogen, or is b) compounds of formula VI Even in which R ₅ is R význam or hydrogen; R 8 is R ₂ or is hydrogen and X represents a halogen atom or represents an ester residue, is reacted with ammonia or with hydroxyalkylamines containing radicals R] _ and _R2 and the hydroxy groups are optionally protected and thereafter if desired, removing the protecting group. End of document