DD296419A5 - NEW NON-IONIC CARBOXAMIDE CONTRAST - Google Patents

Abstract

Novel triiodo-5-aminoisophthaldiamides are disclosed in which the amino and one of the amide nitrogen groups are substituted. The compounds have at least two hydroxyl groups and have low viscosity and osmolality. Methods for the preparation of the compounds are given {new non-ionic carboxamide contrast agents; substituted; hydroxyl groups; low, viscosity; osmolality}

Description

CONH,

CON

R

in which R ₁ and R ₂ contained hydroxy groups are optionally protected by reaction with R ₃ CO-X, wherein X is halogen or an ester radical, in catalysing solvents such as. B. pyridine, DMA or DMF and optionally subsequent cleavage of the protective groups in end products of the general formula I with R ₄ in the meaning of hydrogen or in intermediates of the general formula I with R ₄ in the meaning of R ₃ CO converted and these, optionally with protected hydroxy groups, then, if desired, by alkylation under basic conditions with R ₄ -containing reagents, optionally followed by removal of the protective groups, into end products of the general formula I, in which R _{4 is} not hydrogen, converts or

Compounds of the general formula VI COX

R CON

(Vl)

CON

R _{5 is} R ₁ or hydrogen, R _{6 is} R ₂ or hydrogen and X is halogen or an ester radical,

with Ammoniakbzw. Hydroxyalkylaminen contained withResteRT and R ₂ , whose hydroxy groups may be protected, and then optionally eliminates the protecting groups.

Field of application of the invention

The invention relates to compositions for use as nonionic contrast agents.

Characteristic of the known state of the art

X-ray contrast media for visualization of the cardiovascular system and body cavities must have low viscosity, be readily water-soluble and non-toxic and have a high iodine content. Low viscosity is for quick application, temporary replacement of fast-flowing blood, eg. As in cardioangiography or high-dose urography, or contrast enhancement in computed tomography indispensable. To be non-toxic, the agent must be highly hydrophilic, non-ionic, and osmolality, which is close to the body milieu. Although the previously known non-toxic monomeric contrast media have sufficient biocompatibility and usable viscosity, they are hyperosmolally related to the body milieu. At the diagnostically useful concentration of 300 mg I / ml, they typically significantly exceed the physiological value of 310mOsm. Hyperosmolality of these solutions inevitably drives

Water from the cells, which destroys the cell membranes, disturbs the overall electrolyte balance, and damages the lining of vessels or organ cavities. It has also been shown that hyperosmolahatate is a cause of the vascular pains caused by hyperosmolar contrast agents. Most non-ionic contrast agents , whether monomeric or oligomeric in nature, are aromatic amides having one or more nitrogen-bonded polyhydroxy, lower aliphatic alkyl or acyl subgroups. The tniodinated benzene ring contains a number of spatially closely related functionalities. The prior art describes various amide-attached hydroxyalkylamines as examples for these amines there may be mentioned serinol, 1-amino-2-propanediol, N-methyl-1-amino-2,3-propanediol, aminotetritols, ethanolamine, diethanolamine or triethamine. Substitution of the 1- and 3-membered carboxyl groups with the same hydroxyalkylamine restricts the design greatly, since the practically available substituents are either too small to solubilize the molecule, or too large to give a low viscosity solution (Nycomed, US 4 021 481 and 3 701 771, Schering AG, US 4,547,357, Bracco, US 4,001,323). For this reason, improved compounds have been developed in which the two hydroxyalkylamines were different (Schering AG ₁ US 4,364,921). However, such compounds are complex in synthesis and expensive to produce

U.S. Patent Nos. 3,701,771.4, 001, 323, 401, 481, 464, 921, 547, 357 and co-pending US Application Serial No. 214,663, filed July 1, 1988, describe various compounds which are reported to they are useful for non-ionic contrast agents

Object of the invention

The invention avoids the disadvantages of the prior art

Explanation of the essence of the invention

It is an object of the present invention to provide novel nonionic carboxamide contrast agents. Nonionic contrast agents based on an asymmetric Tniodisophthaldiamids be provided in which the remaining ring position is occupied by a substituted nitrogen atom, while one of the carboxyl groups is an unsubstituted amide and the other carboxyl group is at least one mono- (hydroxyalkyl) substituted amide. The molecule has at least two hydroxy groups

Non-ionic contrast agents based on an acylamide-substituted Tniodisophthaldiamids be provided, wherein at least one of the amide nitrogens is at least monosubstituted The compounds can be inexpensively produced in good yield and are obtained in high purity The subject of the invention forming compounds prove to be low osmolal while retaining moderate to low viscosity at the same time The compounds of the invention preferably correspond to the following formula (I)

wherein

R _{1 is} hydrogen, a lower alkyl or hydroxyalkyl, wherein the alkyl group has between 1-3, usually 1-2, carbon atoms, and the hydroxyalkyl group contains at least 0.5 hydroxyls per carbon atom and up to η - 1 hydroxyl groups, where η is the number denotes the carbon atoms, and the hydroxyalkyl has between 2-6, usually 2-4, carbon atoms,

R ₂ is a mono- or polyhydroxyalkyl having 2-6, usually 2-4, C atoms which has at least one hydroxyl group and at least n-2 and at most n-1 hydroxyl groups, where η is the number of carbon atoms, R ₃ a lower alkyl, hydroxy-substituted lower alkyl or lower alkoxyl-substituted lower alkyl, wherein the alkyl is 1-4 carbon atoms, usually 1-3 carbon atoms, and the alkoxyl is 1-3, usually 1-2, C atoms and the number of oxy groups between O and n-1, where η represents the number of C atoms, varies or two R ₃ groups can be combined to form a bridge of 0-2 C atoms, preferably 1 C atom, to form, ie R ₃ stands for

CONH ₂

-I

CONR ₁ R ₂

R ₄ is hydrogen, a lower alkyl or mono- or polyhydroxyalkyl, wherein the alkyl groups and the hydroxyl groups are as defined above for analogous groups. The alkyl groups may be straight or branched chain, usually straight chain, the C atoms normally being non-quaternary

The alkyl radical in the mono- or polyhydroxyalkyl groups R ₁ and R ₂ usually has 2-6 C atoms, preferably 2-4 C atoms. The groups preferably have 1-5, usually 1-3 hydroxy groups. These hydroxy groups may be primary, secondary or tertiary Examples are tris-hydroxymethylmethyl, hydroxyethyl, dihydroxypropyl and trihydroxybutyl. The carbamides can be prepared using 3-amino-1,2-propanediol, serinol or amino-tetritols, ie threitol and erythritol

either in D, L-blend or in optically pure forms, ethanolamine or diethanolamine, or tromethamine or derivatives thereof wherein the hydroxyl groups are protected in reversible form. R ₁ is hydrogen or a lower alkyl, preferably hydrogen or methyl. R ₃ is a lower alkyl or oxyalkyl of 1-6, usually 1-4, carbon atoms, preferably methyl, hydroxymethyl or hydroxyethyl. By way of example, alkoxyl groups having 1-3 C atoms, preferably 1-2 C atoms, alkoxyalkyl and alkyl having 1-3 C-atoms, in particular methoxymethyl, called. Alternatively, two R ₃ groups are combined to form a bond, methylene or ethylene, in particular methylene. R ₄ is hydrogen, alkyl or mono- or polyhydroxyalkyl having 1-6, preferably 1-4, C atoms, including methyl, ethyl, propyl, hydroxyethyl and dihydroxypropyl.

Among the monomeric compounds of interest here are 5- [N- (2-hydroxyethyl) methoxyacetamide] -2,4,6-triiodo-3- [N- (1,3,4-trihydroxybut-2-yl)] carbamoylbenzamide ; 5- [N- (2-hydroxyethyl) hydroxyacetamide] -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl)] carbamoyl benzamide; 5- [N- (2,3-dihydroxypropyl) -acetamide] -2,4,6-triiodo-3- [N- (2,3-dihydroxypropyl) lcarbamoyl-benzamide; 5- [N- (2,3-dihydroxypropyl ) glycolamido-2,4,6-triiodo-3- [N- (2-hydroxyethyl)] carbamoyl benzamide; 5- [N- (1,3,4-trihydroxy-but-2-yl) -acetamide] -2,4,6-triiodo-3- [N- (2-hydroxyethyl) lcarbamoyl-benzamide; 5- [N- (methyl) glycolamido-2,4,6-triiodo-3- [N- (1,3,4-trihydroxy-erythro-but-2-yl] -carbamoyl-benzamide; and 5- [N- (hydroxyethyl) acetamido] -2,4,6-triiodo-3- [N- (1,3,4-trihydroxythreobut-2-yl)] carbamoyl benzamide.

The dimeric compounds of interest include bis - [{3-N- (2,3-dihydroxypropylcarbamoyl) -5-carbamoyl} -2,4,6-triiodo-N- (2,3-dihydroxypropyl) -malonic acid; bis - [{3-N- (2,3-dihydroxypropylcarbamoyl) 5-carbamoyl} -2,4,6-triiodo-N- (2-hydroxyethyldisilide-malonic acid; and bis-KS-Nd ^^ - trihydroxy- but ^ -yl-carbamoyDS-carbamoyl ^ Ae-triiodo-N-methylanilide-malonic acid.

The agents forming the subject invention contain between 50 and 52% iodine, usually about 51%, in a solution of 300 mg l / ml at 37 ° C (cps) have a viscosity in the range of 4-5 and an osmolality in mOsm in Range of about 275-400, usually about 285-375, for 300 mg / ml at 37 ° C in aqueous solution, while in pharmaceutical preparations it is between about 300-400, usually between 325-390.

The compositions of the invention are prepared under conventional conditions. Usually, the preparations will comprise an aqueous medium containing a physiologically acceptable chelated calcium salt, e.g. B. EDTA, and a buffer for adjusting to a pH between about 6.5 and 7.5, in particular about 7, which may be tris, carbonate, citrate or combinations thereof. As further additives bicarbonate, phosphate etc. can be used.

The chelated calcium is generally present in an amount of 5-15, usually about 10 mg / 100 ml, and the buffer is generally used in amounts between about 2-10 mM.

The invention further relates to a process for the preparation of compounds of general formula I, characterized in that

a) compounds of general formula V

CONH "

R.

CON

R

in which R ₁ and R ₂ contained hydroxy groups are optionally protected by reaction with R ₃ CO-X, wherein X is halogen or an ester radical, in catalysing solvents such as. B. pyridine, DMA or DMF and optionally subsequent cleavage of the protective groups in end products of the general formula I with R ₄ in the meaning of hydrogen or in intermediates of the general formula I with R ₄ in the meaning of R ₃ CO converted and these, optionally with protected hydroxy groups, then, if desired, by alkylation under basic conditions with R ₄ -containing reagents, optionally after the following removal of the protective groups, into end products of general formula I in which R _{4 is} not hydrogen, or b) compounds of general formula Vl

COX

R CON

(Vl)

CON

R _{5 is} R ₁ or hydrogen, R _{6 is} R ₂ or hydrogen and X is halogen or an ester radical,

with hydroxyalkylamines containing hydroxyalkyl groups which may be protected with ammonia or with radicals R ₁ and R ₂ , and if appropriate subsequently cleaving off the protective groups.

For the preparation of the compounds according to the invention, conventional reactions can be combined into a defined reaction route. By a process according to the invention, the products according to the invention can be prepared, for example, from the compound of the formula (II):

COX

CON,

wherein

Rt and R ₂ are as defined above and X is either a lower alkyl ester or a halogen.

Compounds of the general formula (II) are prepared by reacting a hydroxyalkylamine (NHR ₁ , Rj), whose OH groups may be protected or unprotected, with a commercial monoester of 5-nitroisophthalic acid and then activating the remaining carboxyl group. This activation is suitably achieved when X is a halogen such as Cl, Br, I, or an alkoxy, with chlorine and methoxy being preferred.

The ester group of the 5-nitroisophthalic acid monoester is amino-aminolysed with the hydroxyalkylamine of the general formula HNR ₁ R ₂ as defined above, or the aminolysis can first be achieved with ammonia. The remaining carboxyl group is then activated as described above. If the hydroxyl groups of the NR ₁ R ₂ -ResStS are unprotected and can be affected by the activation, they can be suitably protected in a conventional manner, for example O-acetylation or isopropylidation.

The compound of the general formula (II) can be crystallized in a conventional manner from water or lower alcohols.

After reaction with anhydrous ammonia or ammonium hydroxide to give the asymmetric isophthalamide, the compound is hydrogenated, triiodinated and acylated in a conventional manner to give the general formula (III):

COKH.

R ₃ COHN

CON,

wherein

R ₁ , R ₂ and R _{3 have} the abovementioned meaning. Reduction and iodination are carried out in a known manner by standard methods using a catalyst, palladium on carbon or Raney nickel in water or lower alcohols, and hydrogen under low or high pressure. The resulting 5-aminoisophthalic acid diamide is then iodinated in a known manner. The compound is then obtained in a simple manner by crystallization from the reaction mixture, washed, dried and acylated according to also known methods. Thus, an activated acyl R ₃ CO-X with X as the halogen or the like used for anhydride formation acyl group, and catalyzing solvents such as pyridine, DMA or DMF can be used.

When compounds of formula (I) wherein R4 is not hydrogen are prepared, alkylation is by conventional methods. Reaction with hydroxyalkyl groups occurs except for the lower alkyls which are conveniently introduced in an earlier step in the synthesis, typically in the last step. The alkylation can be carried out in a high boiling point glycol solvent, e.g. Ethylene or propylene glycol; a pH in the high basic range is achieved with sodium methoxide, sodium hydroxide or other inorganic or organic bases.

On the other hand, if byproducts are formed which would otherwise be difficult to remove by conventional purification methods, it is sometimes advantageous to maintain the presence of a carboxyl group until the last stages of the reaction sequence for purification so as to easily dissolve the compound as a salt in water and then precipitated with an inorganic acid or can be precipitated again. The preferred salts include ammonium, sodium, potassium, calcium, barium or lithium.

This alternative process is based on the above-described reduction, iodination and acetylation of compounds of the formula (III) (in which X = OH), which leads to the formula (IV):

COOH

R ₃ COHN

IV

CON

R ₁ , R ₂ and R _{3 have} the meaning given above.

The hydroxyl groups are protected from activation of the carboxyl group. In addition, the anilide must be diacylated with R ₃ CO, since this nitrogen would also be impaired in the carboxyl activation. The carboxyl group is activated as described above, preferably with acid chloride, but mixed anhydrides such as t-butyloxycarbonyl may also be used.

Compounds of formula (IV) are readily crystallized from an aprotic solvent, then allowed to react with ammonium hydroxide or ammonia and subjected to alkylation as the last step.

Effective amidation normally requires that either an excess of an amidating base be used as the acid acceptor or, alternatively, tertiary amines such as triethylamine, tributylamine, pyridine, or inorganic bases such as bicarbonate or carbonate.

Another variant of the synthesis method can be used when undesirable by-products occur. Thus, the alkylation of the anilide can take place before the amidation. The alkylation of the compounds of the general formula (IV) in which R ₁ , R ₂ and R _{3 have} the abovementioned meaning can be carried out by known processes as described above.

In the alkylation to introduce R ₄ , the protecting groups R ₃ CO are lost and therefore the hydroxyl groups of R 1 and R ₂ (if present also R ₄ ) must be newly protected from carboxyl activation and subsequent amidation with ammonia. Acetyl groups are mostly used for this purpose.

After the last step, if the hydroxyl groups are still protected, as is the case if the alkylation is not the last step, the protecting groups can be easily removed by standard means, e.g. by treatment with ion exchange resins or use of acids or bases in catalytic amounts in alcoholic or aqueous solvents.

By known methods, desalting can be achieved. Typically, the salts are removed by means of ion exchangers either in the mixed bed process or in separate columns, each containing a nonionic or cationic exchange resin. Alternatively, the compounds of general formula (I) may also be absorbed on a polystyrene-absorbing neutral resin and then eluted.

After removal of the salts, the product can now be crystallized from a variety of solvents, preferably lower alcohols. Decolorization is achieved by refluxing in aqueous solution over activated charcoal.

The dimer is conveniently prepared from the benzamide wherein the amino nitrogen is alkylated and the remaining carbonyl group, e.g. B. as chlorocarbonyl is activated. The dibasic acid is used in the activated form, especially as the diacyl dichloride in an organic aprotic polar solvent. The chlorocarbonyl attached to the ring carbon is then hydroxyalkylamidated to the final product.

The compounds of the invention and the compounds of general formula (I) are stable in aqueous solution; they readily form supersaturated solutions that are also stable. The solutions can be autoclaved by conventional means. For diagnostically useful iodine concentrations, the compounds have osmolalities that are typically very close to physiological levels. At the same time the viscosity of the solution is low. The object of the invention, namely to overcome the well-known fact of the mutually exclusive requirements for a low osmolality and low viscosity, is thus achieved. As a result, the novel compounds have excellent local and systemic compatibility. The compounds are biologically well tolerated and have a high iodine content, especially when compared to currently available non-ionic X-ray contrast agents.

As examples of the properties of the compounds of the class of the benzamides, data for the compounds (11) (claim 5) and (19) (claim 6) have been compiled. Table I also shows data for compounds of the prior art for comparison.

Table 1 Basic properties of non-ionic monomeric X-ray contrast agents

Iodine in% of Viscosity of Osmolity of 300 mg l / ml pharmaceutical Approximate range gl / kg molecular weight 300 mg l / ml solutions formul. solution Lv ₁ LD ₅₀ : male rat at 37 ^° C aqueous (MOsm) male mouse 80-10Og solution 685 16-2Og (MOsm) 704 11.5 to 12.5 46.4 (Cps) 650 630 16-17 12-13 iohexol 49 6.3 » 671 588 16-18 11-12 iopamidol 48 4.7 » 607 390 14-16 12-13 iopromide 48 4.6 * 560 326 16-18 13-14 loxilan 51 4.7 365 14-16 14.5 to 15 Connection 19 51 4.1 300 14-16 Connection 11 4.2

* According to the literature; the other data were determined in our laboratory

 All solutions were formulated pharmaceutically unless otherwise indicated.

The observed low osmolality and at the same time low toxicity has hitherto only been achieved in non-ionic dimers, which, however, can not be used in general uro-angiography because of their high viscosity, which is at least twice that at a comparable solution concentration.

The novel compounds have excellent biocompatibility, since high osmolality is the causative factor of vascular pain and has significant side effects in presenting the peripheral vessels of the limbs. (Sovak, M., Current Contrast Media and Toxilan, Comparative Evaluation of Vascular Pain by Aversion Conditioning, Investigative Radiology, September 1988 Supp). This is one of the major diagnostic methods of vascular radiography. It is expected that the novel compounds according to the invention can be used practically painlessly in these methods. Because of their physiochemical and pharmacological properties, the new compounds are useful as water-soluble contrast agents for the imaging of the urinary tract and the cardiovascular system, for body cavities and for general contrast enhancement in computed tomography. The injection solutions of the novel compounds can be prepared by dissolving in water and adding conventional physiologically compatible buffers and stabilizers, e.g. Complexing agent, produce. When formulated with excipients commonly used in pharmacopoeias, the compounds are also suitable for enteral use. The dimers find particular application in myelography.

For intravascular use, the compounds of the invention contain 20-80 w / v%, with iodine concentrations of 150-400 mg / ml being preferred

 The following examples are merely illustrative and do not limit the scope of the invention.

Experimental part

example 1

Amidation of 5-nitroisophthalic acid monomethyl ester (1) with (threo) -2-amino-1,3,4-butanetriol to: 5-nitro-3 {N- (1,3,4-trihydroxythreo-but-2-yl )} - carbamoyl-benzoic acid (2)

The starting material (1.22.5 g, 0.1 mol) was mixed with (threo) -2-amino-1,3,4-butanetriol (30.25 g, 0.25 mol) and the suspension was allowed to stand for 30 minutes 110-120 ⁰ C heated. The DSC showed complete conversion to the product and the solution was added to 1 N hydrochloric acid (200 mL) to precipitate the product. After cooling overnight, the product was filtered and washed with ice-water (20 ml χ 2). Drying in vacuo gave a white solid (2.21.0 g, 67% yield).

Example 2

Esterification of 5-nitro-3- {N- (1,3,4-trihydroxy-threo-but-2-yl)} carbamoylbenzoic acid (2) with dimethyl sulfate to give: 5-nitro-3- {N- (1 , 3,4-trihydroxy-threo-but-2-yl)} carbamoyl-methylbenzoate (3)

The title compound (2,15,7g, 0.05 mol) was dissolved in 1 η sodium hydroxide solution (55ml) and the solution cooled to <20 ⁰ C.

Dimethyl sulfate (9.45g, 0.075 mol) was added over 5 minutes, and the pH was kept at 8-10 by occasional addition of 5N sodium hydroxide solution. The solution was stirred for 12 h at room temperature, after which the insoluble solid was filtered off. The pasty solid was washed with cold water (50 ml x 2) and dried in vacuo to a powder (3.11.8 g, 72% yield).

Example 3

Amidation of 5-nitro-3- {N- (1,3,4-trihydroxy-threo-but-2-yl)} carbamoyl methyl benzoate (3) with ammonia to give: 5-nitro-3- {N- (1 , 3,4-trihydroxy-threo-but-2-yl) carbamoyl-benzamide (4)

The ester (3.10.0 g, 0.0305 mol) was dissolved in methanol (50 ml) and treated with concentrated ammonium hydroxide (20 ml, ca. 0.3 ml). The suspension was heated in a closed vessel for 30 minutes at 50-60 ⁰ C; the subsequent DSC indicated the completion of the reaction. Methanol and ammonium hydroxide were removed by distillation and replaced with H ₂ O (50 ml).

The mixture was allowed to cool overnight, then the insoluble product was filtered off and washed with cold water (5 mL χ 2). Vacuum drying gave the white, mixed amide (4,7,15g, 75% yield).

Example 4

Chlorination of 5-nitroisophthalic acid monomethyl ester (1) with thionyl chloride to: 5-nitroisophthalic acid monomethyl ester monosilicic chloride (5)

The title compound (1.225 g, 1 mol) was dissolved in ethyl acetate (0.5 L) and added with N, N-dimethylformamide (0.1 mL) as a catalyst. The solution was heated to 7O ⁰ C and treated with thionyl chloride (219ml, 3 mol) was added over 1.25H. The temperature was then maintained at 70 ⁰ C for 2 hours.

The thionyl chloride was distilled off together with ethyl acetate (200 ml × 3) and the product was dissolved in hot ethyl acetate (250 ml) and precipitated with cyclohexane (11), filtered and washed with cyclohexane (200 ml × 2). Drying in vacuo at 50 ⁰ C gave a white solid (5,216g, 89% yield).

Example 5

Amidation of 5-nitroisophthalic acid monomethyl ester monoacid chloride (5) with aminodioxepane to give: 5-nitro-3- {N- (trans-2,2-dimethyl-6-hydroxy-1,3-dioxepan-5-yl)} carbamoyl -Methylbenzoate (6)

The monoester monochloride (5.00 g, 0.411 mol) was dissolved in dry tetrahydrofuran (11) and spiked with solid aminodioxepane (132.8 g, 0.825 mol) portionwise over 15 minutes, keeping the temperature below 25 ° C using an ice bath , Subsequently, the heterogeneous mixture was stirred for 30 minutes at room temperature, whereupon the DSC indicated the end of the reaction.

The insoluble amino hydrochloride was filtered off and the tetrahydrofuran was removed by distillation from the filtrate. The residue was dissolved in ethyl acetate (400 ml) near the boiling point; The solution was allowed to stand for several days until crystallization of the product was complete. The solid was filtered off, washed with cold ethyl acetate (50 ml x 2) and dried in a vacuum oven; a whitish product was obtained (6.82.4 g, 55% yield).

Example 6

Amidation of S-nitro-S-iN-itrans ^^ -dimethyl-e-hydroxy-IS-dioxepan-6-yD-carbamoyl-methylbenzoate (6) with ammonium hydroxide to give: 5-nitro-3- {N- (trans-2, 2-dimethyl-6-hydroxy-1,3-dioxepan-5-yl) -carbamoyl-benzamide (7) A Parr pressure reactor (800 ml) was added with the title compound (6.80 g, 0.22 mol), methanol (110 mL) and 15 N ammonium hydroxide (225 mL, 3.38 mol). The reaction vessel was closed and immersed for 2 hours in a water bath at 50 ⁰ C; the subsequent DSC showed complete implementation. The heterogeneous reaction mixture was mixed with water (100 ml) and then stripped as a foam. The foam was slurried in water (100ml), filtered and washed twice with 50ml H ₂ O; a white solid was obtained (7,60,4g, 79% yield).

Example 7

Reduction and cleavage 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 to: S-amino- (hydroxychloride) -3- {N- (1,3- _> 4-trihydroxy-threo-but-2-yl)} carbamoylbenzamide (8)

A Parr pressure reactor (2.0 L) was charged with the title compound (7.58 g, 0.16 mol), 1 N hydrochloric acid (410 mL) and palladium on carbon (10% Pd / C, 5.8 g, 1% w / w). Weight Pd). The reaction vessel was connected to a hydrogenation apparatus and shaken under hydrogen gas at 50 psi (3.5 kp / cm ² ) for 2 hours; the subsequent HPLC showed 90% conversion into the product (8). The palladium catalyst was filtered off and the acetone formed upon deprotection was removed in vacuo at 50 ° C. The resulting clear solution (8.450 ml, 90% yield) was used directly for iodination.

Example 8

iodination of 5-amino- (hydrochloride) -3- {N- (1,3,4-trihydroxy-threo-but-2-yl)} carbamoylbenzamide (8) with iodine monochloride to give 5-amino-2,4 _> 6-triiodo-3- {N- (1 ^, 4-trihydroxy-threo-but-2-yl)} carbamoylbenzamide (9) The title compound (8,0,14 mol) in 1N hydrochloric acid (450 ml) was heated to 85 ⁰ C and treated with iodine monochloride (135ml, 0.49 mol). The reaction mixture was heated to 85 ° C for 2 hours; the subsequent HPLC indicated the completion of the reaction. The reaction mixture was cooled to 25 ° C and extracted with 2x cyclohexane (200ml), 3x dichloromethane (300ml) and 5x chloroform (200ml) until the purple color of the aqueous phase disappeared. The resulting light yellow solution was recirculated in a column of Duolite resin A340 (800g) and Dowex resin 50W-X8 (266g). The resins were rinsed with H ₂ O (6I) and the solution was concentrated to 300 ml, whereupon a white, crystalline solid began to crystallize out. Filtration of the product gave a white solid (9.40g, 0.06 mol), 43% yield).

Example 9

Acetylation of 5-amino-2,4,6-triiodo-3- {N- (1,3,4-trihydroxy-threo-but-2-yl)} carbamoyl-benzamide (9) with acetic anhydride to give: 5-diacetylamino -2,4,6-triiodo-3- {N- (1,3,4-triacetoxy-threo-but-2-yl)} carbamoyl-benzamide (10) The title compound (9.90 g, 0.14 mol) was mixed with acetic anhydride (500 ml, 4.95 mol) at 70 ⁰ C with vigorous stirring. As catalyst, perchloric acid (0.36 ml, 0.004 mol) was added, whereby the temperature rose to 85 ⁰ C. The reaction mixture was stirred at 85 ° C for 1 h; it then became homogeneous and the DSC indicated the completion of the reaction. To neutralize the perchloric acid, sodium acetate (0.33 g, 0.004 mol) was added, the solvent was removed, and a viscous, brown oil was obtained. The oil was diluted at 70 ° C with butyl acetate (200 mL) and the solvent then removed. The stripping process was repeated twice; This gave a brown foam (10.113 g, 0.13 mol, 93% yield).

Example 10

Deacetylation and alkylation of S-diacetylamino ^^, e-triiodo-SiN-dS ^ -triacetoxy-threo-buty-yD-carbamoyl-benzamide (10) with sodium methoxide and 2-chloroethanol to: 5- {N- (2-hydroxyethylacetamido) "2,4,6-triiodo-3- {N- (1,3,4-trihydroxy-threo-but-2-yl)} carbamoyl-benzamide (11)

The title compound (10,113g, 0.13 mol) was dissolved (500 ml) in methanol, the strength at 50 ⁰ C with 25% sodium methoxide (55g, 0.25 mol) was added. After 5 h, HPLC indicated completion of deacetylation and the solution was neutralized with Dowex resin 50W-X4 (10 g). The resin was filtered off and the filtrate was concentrated to 400 ml. The neutral methanolic solution was heated to 45 ° C and trisodium phosphate dodecahydrate (129 g, 0.34 mol) and 2-chloroethanol (18.2 mL, 0.272 mol) were added. The reaction mixture was stirred at 45 ° C for 48 h, then chloroethanol (4.7 mL, 0.07 mol) and sodium methoxide (14.7 g, 0.07 mol) were added. After 71 h, HPLC indicated the completion of the reaction. The insoluble salts (89 g) were removed by filtration and the solution was neutralized with hydrochloric acid (6N, 7 mL). Concentration of the solution gave a brown foam (11) (94 g, 0.12 mol, 92% yield).

Example 11

Amidation of 5-nitroisophthalic acid monomethyl ester (1) with 3-amino-1,2-propanediol to: 5-nitro-3- {N- (2,3-dihydroxypropyl)} carbamoylbenzoic acid {12}

The starting material (1.225 g, 1 mol) was mixed with 3-amino-1,2-propanediol (227.8 g, 2.5 mol) and the heterogeneous mixture was heated at 110-120 ° C for 1 h and the homogeneous mixture was mixed with water (11) and conc. HCl (170 mL) The mixture was cooled for several days to precipitate the product completely, the solid was filtered off and washed with cold water (50 mL χ 2) After vacuum drying, a white solid was obtained (12.193 g, 68% yield).

Example 12

Reduction of S-nitro-S-iN - ^. S-dihydroxypropyl-1-carbamoylbenzoic acid (12) with hydrogen and palladium on carbon to give: 5-amino- (hydrochloride) -3- {N- (2,3-dihydroxy-propyl) } -carbamoylbenzoic acid (13) The nitro acid (12.180 g, 0.634 mol) was mixed with water (11) and treated with concentrated HCl (60 mL) and 10% palladium on carbon (18 g). The suspension was at 2-4 atm. hydrogenated to constant pressure at which time HPLC and DSC indicate the end of the reaction. The palladium catalyst was removed by filtration and the homogeneous solution was used for the following reaction (13, approximate yield 98%) without isolating the product.

Example 13

iodination of 5-amino- (hydrochloride) -3- {N- (2,3-dihydroxy-propyl)} carbamoylbenzoic acid (13) with iodine chloride to give: 5-amino-2,4,6-triiodo-3 { N (2,3-dihydroxypropyl) -carbamoylbenzoic acid (14) The title compound (13, ca. 0.62 mol in 1.51 water) was further diluted with water to a total volume of 41 and to 85 ° C heated. During 20 minutes (4.1 molar, 499 mL, 2.05 mol) iodine monochloride was added and the temperature was maintained at 90 ⁰ C 6-8h. The end of the reaction was detected by HPLC. The homogeneous mixture was cooled, extracted with 1,2-dichloroethane: cyclohexene (9: 1,500 ml χ 2) and then with 1,2-dichloroethane (250 ml χ 2). The aqueous phase was then concentrated by distillation to 0.91 and cooled for several days until complete precipitation of the solid. After filtration, washing with cold water (100 ml χ 2) and vacuum drying gave the yellow-brown product (14, 286g, 73% yield).

Example 14

Acetylation of 5-amino-2,4,6-triiodo-3- {N- (2,3-dihydroxypropyl)} carbamoylbenzoic acid (14) with acetic anhydride to give: 5-diacetylamino-2,4,6-triiodo-3 - {N- (2,3-diacetoxypropyl)} - carbamoylbenzoic acid (15) The starting material (14.100 g, 0.158 mol) was treated with acetic anhydride (300 ml, 3.16 mol) and 70% perchloric acid (0.2 ml). mixed and heated to 80-90 "C for 8 h. the mixture was neutralized with anhydrous sodium acetate (0.25 g), and the acetic anhydride and acetic acid were removed by distillation at 70-80 ⁰ C. the oily residue was (with butyl acetate 100 ml x 2) azeotropically, then dissolved in ethyl acetate (250 ml) and used directly for the chlorination (15, approximate yield 90%).

Example 15

Chlorination of 5-diacetylamino-2,4,6-triiodo-3- {N- (2,3-diacetoxypropyl)} carbamoylbenzoic acid (15) with thionyl chloride to give: 5-diacetylamino-2,4,6-triiodo-3 - {N- (2,3-diacetoxypropyl)} - carbamoyl-benzoyl chloride (16) The starting material (15, ca. 0.142 mol) in ethyl acetate (225ml) was added at 65-7O ⁰ C with thionyl chloride (57 ml, 0.78 mol); then the temperature was increased to 75-80 ⁰ C for 1 h. Thionyl chloride and ethyl acetate were distilled off under vacuum. The residue was azeotroped with butyl acetate (100 ml χ 2) and vacuum dried. The brown foam (16, ca. 130 g, estimated yield 95%) was taken directly into the subsequent amidation step.

Example 16

Amidation of 5-diacetylamino-2,4,6-triiodo-3- {N- (2,3-diacetoxypropyl) -carbamoyl-benzoyl chloride (16) with ammonia:

5-Acetylamino-2,4,6-triiodo-3- {N- (2,3-diacetoxypropyl)} carbamoylbenzamide (17) The acid chloride (16, ca. 0.135 mol) was dissolved in dry Ν, Ν-dimethylacetamide (15ml) solved. This solution was cooled to 0-5 ° C, using a dry ice / acetone condenser, anhydrous ammonia (about 20 ml) was condensed into the mixture, and the reaction mixture was kept closed at room temperature for 24 hours. Ammonia and DMA were removed by vacuum distillation. A solid was deposited with 1-pentanol (500 ml), which was filtered off and washed with 1-pentanol (150 ml x 2). After drying in vacuo, a yellow-brown solid was obtained (17.82 g, 80.2% yield).

Example 17

Deacetylation of 5-acetylamino-2,4,6-triiodo-3- {N- (2,3-diacetoxypropyl)} carbamoylbenzamide (17) to: 5-acetylamino-2,4,6-triiodo-3 { N- (2,3-dihydroxy-propyl) -carbamoyl-benzamide (18)

The title compound (17.81.2 g, 0.107 mol) was suspended in water (203 ml) and then added by dropwise addition of 50% w / w. Sodium hydroxide in water (16.9ml, 0.322mol). With stirring, a complete solution was achieved. The solution was degassed in vacuo for 30 minutes whereupon 12M HCl (15 mL, 0.18 mol) was added. After storage at 4 ⁰ C, the resulting solid precipitate was filtered, washed with ice water (3x 50 ml) and ethanol (80ml) and dried in vacuo to product (18,54,1 g, 75% yield).

Example 18

Alkylation of 5-acetylamino-2,4,6-triiodo-3- {N- (2,3-dihydroxypropyl)} carbamoylbenzamide (18) to: 5- {N- (2,3-dihydroxypropyl) acetamido} - 2,4,6-triiodo-3- {N- (2,3-dihydroxypropyl)} carbamoylbenzamide (19) The title compound (18.39.7 g, 0.059 mol) was dissolved in propylene glycol (16.7 mL), ethanol ( 120ml), and 25% w / w. Sodium methoxide (17.6 ml, 0.077 mol) dissolved. Chloropropanediol (9.78 g, 0.0885 mol) was added and the mixture was stirred for 1 h at 25 ° C. The reaction mixture was warmed to 33 ° C and stirred for another 19h; During this time, 25% w / w sodium methoxide (3.4 ml, 0.015 mol) was added. The reaction mixture was quenched with 12M HCl, distilled in vacuo, reconstituted with H ₂ O (200 mL) and redistilled to an aqueous solution containing Dowex resin 50H ⁺ resin (62 g) and Duolite resin A-340 OH "(170 g). was deionized. After elution of the resin with H ₂ O and concentration to obtain 150 g of the solution with Norit Ultra SX charcoal (1.0 g) was treated at 60 ⁰ C 14h. After filtering off the charcoal to give an aqueous solution containing 2 h with Dowex 50H ⁺ (1.0g) and Duolite A-340OH "(4g) was stirred. The resin was filtered off and the aqueous solution was distilled to 50.3 g of oils containing the product (19.32.8 g, 74% yield) in glycerol / propylene glycol. This oil was purified by the method described in the following step.

Example 19

Peracetylation, purification over silica gel and subsequent deacetylation of: 5- {N- (2,3-dihydroxypropyl) acetamido} -2,4,6-triiodo-3- {N- (2,3-dihydroxypropyl)} carbamoylbenzamide ( 19)

The title compound (19.16.4g, 0.022 mol) dissolved in glycerol / propylene glycol oil {total mass 25.15g) was diluted with pyridine (1.74g, 0.022mol) and acetic anhydride (115g, 1.12mol) and then 60h for 18h ° C heated. The reaction mixture was distilled under reduced pressure to an oil, dissolved in CHCl ₃ (100 ml) and treated with 0.1 N HCl (2 × 50 ml) and 15% w / v. Brine (2x 50 ml) extracted. The CHCl ₃ phase was dried over MgSO ₄ , filtered, and distilled to an oil. This oil was purified on 900 g of silica gel using a solvent gradient which ran from 5% acetic acid / 95% chloroform to 5% acetic acid / 4% methanol / 91% chloroform. The purified fractions were pooled, distilled to a foam and then washed with methanol (30 ml) and 25% w / w. Sodium methoxide in methanol (0.98 g, 0.0054 mol) treated. After 30 minutes the solution was distilled, reconstituted with methanol (20ml) and then stirred with Dowex resin 50H ⁺ (1.3g). Upon lowering the pH from 12 to 5, the resin was filtered off to give a solution which was distilled to a foam, reconstituted with H2O (25 mL) and added to the solid title compound (19.8.12 g, 49% yield). was evaporated.

Example 20

Deacetylation of 5-diacetylamino-2,4,6-triiodo-3- {N- (2,3-diacetoxypropyl)} carbamoylbenzoic acid (15) to: 5-acetylamino-2,4,6-triiodo-3 { N- (2,3-dihydroxypropYI)} carbamoylbenzoic acid (20)

The title compound (15.720 g, 0.9 mol) was dissolved in 50 mL of methanol and treated with 25% w / w. Sodium methoxide in methanol (345 ml, 1.5 mol) was added. After ⁴ h at 45-50 ° C., the reaction mixture was distilled under reduced pressure and acidified with 12 M HCl (124 ml, 1.5 mol); the salts were filtered off. The filtrate was distilled under reduced pressure to give an oil which was diluted with n-propanol (680 ml). After crystallization at 4 ° C, the resulting solid product (20) was filtered off, washed with n-propanol (2x 300ml) and dried in vacuo. The yield was 391 g (64%).

Example 21

Alkylation of 5-acetylamino-2,4,6-triiodo-3- {N- (2,3-dihydroxypropyl)} carbamoylbenzoic acid (20) to: 5- {N- (2,3-dihydroxypropyl) acetamido) - 2,4,6-triiodo-3- {N- (2,3-dihydroxypropyl)} carbamoylbenzoic acid sodium salt (21) The title compound (20.100 g, 0.148 mol) was dissolved in 400 ml of methanol. Solid Na ₃ PO ₄ .12H ₂ O (140.6 g, 0.37 mol) was added followed by chloropropanediol (32.7 g, 0.296 mol) and 25% w / w. Sodium methoxide in methanol (24.1 g, 0.111 mol) added dropwise. The reaction mixture was heated to 40 ° C for 10h with further 25% sodium methoxide (8.0g, 0.0368 mol) added portionwise. The salts were filtered off and the methanol filtrate was acidified with 12 M HCl (3.5 mL), concentrated in vacuo to a viscous, oily product (21) and taken directly to the next reaction step.

Example 22

Acetylation of the sodium salt of 5- {N- (2,3-dihydroxy-propyl) acetamido} -2,4,6-triiodo-3- {N- (2,3-dihydroxypropyl)} carbamoylbenzoic acid (21) to: 5- {N- (2,3-diacetoxypropyl) acetamido} -2,4,6-triiodo-3- {N- (2,3-diacetoxypropyl) carbamoyl} benzoic acid (22)

The title compound (21,114g, 0.148 mol) as an oil was treated with pyridine (11.7 g, 0.148 mol) and acetic anhydride (605g, 5.92 mol) and stirred for 2 h diluted bei65-70 ⁰ C. The reaction mixture was concentrated to an oil, azeotroped with butyl acetate (2 x 100 mL) and partitioned between water (300 mL) and 3: 1 toluene / ethyl acetate (200 mL). The aqueous phase was extracted with 3: 1 toluene / ethyl acetate (3x 100ml) and acidified with HCl (22.5ml) in the presence of ethyl acetate (300ml). The acidified H ₂ O phase was separated and extracted twice with ethyl acetate (100 ml). The last three ethyl acetate extracts were combined, dried over MgSO ₄ , filtered and evaporated to a solid product (22.118 g, 87% yield).

Example 23

Chlorination of 5- {N- (2,3-diacetoxypropyl) -acetamido} -2,4,6-triiodo-3- {N- (2,3-diacetoxypropyl)} carbamoylbenzoic acid (22) to: 5- { N- (2,3-diacetoxypropyl) acetamido-2,4,6-triiodo-3- {N- (2,3-diacetoxypropyl) -carbamoyl-benzoyl chloride (23) The title compound (22.113.6 g, 0.124 mol) was dissolved in ethyl acetate (100 ml) at 55 ° C; Thionyl chloride (44g, 0.37mol) was added dropwise and the mixture refluxed for 2h, concentrated to an oil in vacuo, and then azeotroped with butyl acetate (2x50ml) to a foam which was dissolved in chloroform (200ml) and extracted with 0.2M phosphate buffer pH 6.7 (100 ml). The organic phase was dried over MgSO ₄ , filtered and evaporated to a solid product (23.115 g, 98% yield).

Example 24

Amidation of 5- {N- (2,3-diacetoxypropyl) -acetamido} -2,4,6-triiodo-3- {N- (2,3-diacetoxypropyl)} carbamoyl-benzoyl chloride (23) to: 5- {N - (2,3-Diacetoxypropyl) acetamido} -2,4,6-triiodo-3- {N- (2,3-diacetoxy-propyl)} carbamoyl-benzamide (24) The title compound (23.105 g, 0.111 mol). was dissolved in acetonitrile (400 ml) and mixed with anhydrous ammonia using a dry ice cooler at 25 ° C. The reaction was complete after ₃ h NH ₃ reflux. The salts were filtered off and, after evaporation, a solid was obtained (24.98.8 g, 96% yield).

Example 25

Deacetylation of 5- {N- (2,3-diacetoxypropyl) -acetamido} -2,4,6-triiodo-3- {N- (2 ^ -diacetoxypropyl)} - carbamoylbenzamide (24) to: 5- { N- (2,3-dihydroxypropyl) acetamido) -2,4,6-triiodo-3- {N- (2,3-dihydroxypropyl)} 4: arbamoylbenzamide (19) The title compound (24.98.7 g , 0.106 mol) was dissolved in methanol (250 ml), which at 25 ° C with 25% w / w. Sodium methoxide in methanol (2.30 g, 0.0106 mol) had been added. After 15 minutes, the solution was concentrated in vacuo to an oil, reconstituted with methanol (200 mL) and then stirred with Dowex resin 50H ⁺ (6.0 g) until the pH dropped from 12 to 6. The

Resin was filtered off to give a solution which distilled to a foam, reconstituted with water (320ml) and Norit SX charcoal (3.0g), refluxed for 7h, filtered by stirring with Dowex resin 50H ⁺ (3g). and Dowex resin XUS-40123 OH "(12g) was deionized, filtered, and evaporated to the solid (19.79.2g, 96% yield).

Example 26

Methoxyacetylation of 5-amino-2,4,6-triiodo-3- {N- (1,3,4-trihydroxy-threo-but-2-yl)} carbamoyl-benzamide (9) with methoxyacetyl chloride to: 5-methoxyacetylamino -2,4,6-triiodo-3- {N- (1,3,4-trihydroxy-threo-but-2-yl)} carbamoyl-benzamide (25) The title compound (9.100 g, 0.15 mol) was added Suspended at 25 ° C in Ν, Ν-dimethylacetamide (250ml) and treated with methoxyacetyl chloride (68ml, 0.75mol) over 30 minutes. The reaction mixture was stirred at 35 ° C for 5 hours; HPLC indicated the end of the reaction. The reaction mixture was treated with sodium methoxide (97g, 0,45mol) quenched and stirred at 40 ⁰ C for 2 h. The solution was neutralized with Dowex resin 50W-X4, filtered and diluted with n-butanol (700 ml). Immediately a white precipitate formed, which was filtered to a whitish solid (25.80.6 g, 0.11 mol, 73% yield).

Example 27

Alkylation of loxthalic acid (26) to: 5- {N- (2,3-dihydroxypropyl) acetamido} -2,4,6-triiodo-3- {N- (2-hydroxyethyl)} carbamoyl sodium benzoate (27)

loxithalamic acid (26.966 g, 1.5 mol) was dissolved at room temperature in 1 η sodium hydroxide (1.5 L), heated to 75 ° C and treated simultaneously with 3-chloro-1,2-propanediol (223.8 g, 2, 03mol) and 5η sodium hydroxide (about 0.4I). The reaction mixture was heated to 80-90 ° C for a further 2.5 h, whereupon HPLC indicated completion of the reaction (about 90% conversion to the product).

The reaction mixture was neutralized with concentrated hydrochloric acid (about 3 ml) and evaporated. About half of the foamy residue was taken up in water (0.4 L). Upon cooling, a white, crystalline solid was precipitated, which was filtered and washed with ice-water. After drying, the crystalline product (27.249 g) was obtained.

Example 28

Acetylation of 5- {N- (2,3-dihydroxypropyl) acetamido} -2,4,6-triiodo-3- {N- (2-hydroxyethyl)} carbamoyl sodium benzoate (27) to: 5- {N- (2,3-diacetoxypropyl) acetamido} -2,4,6-triiodo-3- {N- (2-acetoxyethyl) carbamoyl} benzoic acid (28) The title compound (27,50g, 0,067mol) was added at 25 ⁰ C in acetic anhydride (102ml, 1.080mol, 16.0Äqu.) stirred. Pyridine (5.4 mL, 0.067 mol, 1.0 equiv.) Was added and the temperature raised to 85 ° C for 1 h: the subsequent DSC indicated the completion of the reaction. The homogeneous reaction mixture was evaporated in vacuo to a viscous oil, dissolved in butyl acetate (50 ml) and evaporated several times. The oil was dissolved in H ₂ O (260 mL) and extracted with toluene / ethyl acetate (2: 1, 4 x 100 mL). The aqueous phase was acidified with 12N hydrochloric acid (11 ml) and extracted with ethyl acetate (3 × 50 ml). The organic phase was dried over magnesium sulfate, evaporated to a foam (28) and taken directly to the next reaction step (55 g, 0.065 mol, 97% yield).

Example 29

Chlorination of 5- {N- (2,3-diacetoxypropyl) acetamido} -2,4,6-triiodo-3- {N- (2-acetoxyethyl)} carbamoylbenzoic acid (28) to: 5- {N- ( 2,3-diacetoxypropyl) acetamido} -2,4,6-triiodo-3- {N- (2-acetoxyethyl)} carbamoylbenzoyl chloride (29) The title compound (28.55 g, 0.065 mol) was dissolved in 1,2- Dissolved dichloroethane (170ml) and heated to 85 ⁰ C. Thionyl chloride (9.8 mL, 0.134 mol, 2.0 eq) was added and the reaction was confirmed by DSC to be complete after 3 h. The reaction mixture was evaporated in vacuo to an oil, redissolved in butyl acetate (50 ml) and evaporated several times. The product was isolated as a yellow foam (29.51.9 g, 0.060 mol, 92% yield).

Example 30

Amidation of 5- {N- (2,3-diacetoxypropyl) acetamido} -2,4,6-triiodo-3- {N- (2-acetoxyethyl)} carbamoylbenzoyl chloride (29) to:

5- {N- (2,3-Diacetoxypropyl) acetamido} -2,4,6-triiodo-3- {N- (2-acetoxyethyl)} carbamoylbenzamide (30) The title compound (29.51.9 g, 0.060 mol) was dissolved in acetonitrile (200 ml) and treated at 10 ⁰ C with anhydrous ammonia (excess). After 4 hours the DSC indicated completion of the reaction. The reaction mixture was filtered to remove the ammonium chloride salts and, after removal of the solvent, gave a yellow oil (30.47 g, 0.056 mol, 93% yield).

Example 31

Deacetylation of 5- {N- (2,3-diacetoxypropyl) acetamido} -2,4,6-triiodo-3- {N- (2-acetoxyethyl)} carbamoylbenzamide (30) to: 5- {N- ( 2,3-Dihydroxypropyl) acetamido} -2,4,6-triiodo-3- {N- (2-hydroxyethyl)} carbamoylbenzamide (31) The title compound (30.47g, 0.056mol) was dissolved in methanol (240mL ) and to increase the pH to about 12 with 25% sodium methoxide (3.9 g, 0.3 Äqu.). The solution was stirred for 1 h at 25 ° C, whereupon the completion of the deacetylation was indicated by HPLC. The reaction mixture was neutralized with 1 N HCl (10 mL) and, after removal of the solvent, gave a whitish foam (31.39 g, 0.054 mol, 97% yield, 98% purity) prepared from heated methanol (5 g in 15 mL, with vaccination) was recrystallized.

Example 32

Amidation of 5-amino-2,4,6-triiodoisophthaloyl chloride (32) to: 5-amino-2,4,6-triiodo-3-chlorocarbonyl-benzamide (33) The starting material (32.300 g, 0.503 mol ) was dissolved in tetrahydrofuran (900 ml) and the homogeneous solution was cooled to 5-10 ° C. in ice. Concentrated ammonium hydroxide (92.3 mL, 1.38 mol) was added over 10 minutes; the temperature rose to 30 ⁰ C.

The reaction mixture was stirred at room temperature for a total of 90 hours while further adding ammonium hydroxide (total 25.2 mL, 0.38 mol); then cooled and the insoluble salts were removed by filtration. The filtrate was washed with saturated NaCl (200 ml x 2).

Evaporation of the tetrafuran gave a viscous oil. A yellow-brown solid was precipitated with ethyl acetate (800 ml), filtered, washed with ethyl acetate (100 ml × 2) and dried; to give (33.193 g, 66.5% yield).

Example 33

Dimerization of S-amino ^ Ae-triiodo-S-chlorocarbonyl-benzamide (33) to: bis - {(3-chlorocarbonyl-5-carbamoyl) -2,4,6-triiodanilide} -malonic acid (34)

The title compound (33.20g, 34.7mM) was dissolved in dry tetrahydrofuran (100ml), heated to 45 ° C and treated with malonyl dichloride (2.53ml, 26mM) over 3 minutes to give a heterogeneous mixture. Dry THF (100 mL) was added and the suspension was allowed to stir for 1 h whereupon the DSC indicated that the reaction was complete. The mixture was diluted with butyl acetate (150ml), the solid was filtered, washed with butyl acetate (50ml χ 2) and dried in vacuo to give the product (34.13.18g, 62% yield).

Example 34

Amidation of bis - {(3-chlorocarbonyl-5-carbamoyl) -2,4,6-triiodanilide} -malonic acid (34) to: bis - [{3-N- (1,3,4-trihydroxy-threobut-2 -yl-carbamoyl-5-carbamoyl} -2,4,6-triiodanilide] -malonic acid (35)

The title compound (34,8,0g, 6,56mM) was dissolved in dry Ν, Ν-dimethylacetamide (10 ml), treated with triethylamine (1,83ml, 13.12 mM) was added and the solution cooled to 20 ⁰ C. Trans-5-amino-2,2-dimethyl-6-hydroxy-1,3-dioxepane (2.64g, 16.4mM) was added over 3 minutes, and the homogeneous mixture was stirred at room temperature for 6 hours whereupon the DSC was allowed to terminate the implementation indicated. The solvent was evaporated, water (50 ml) added and the mixture heated to 75 ° C for 15 minutes to cleave the acetonides. Evaporation and precipitation with isopropanol (100 ml) gave the product. The solid was filtered, washed with isopropanol (20 ml χ 2) and dried. This gave 8.6 g (35.94% yield).

Example 35

Amidation of S-N-methylamino ^ Ae-triiodoisophthaloyl chloride (36) to: S-N-methylamino ^ Ae-triiodo-S-chlorocarbonyl-benzamide (37)

The starting material (36.305 g, 0.5 mol) was dissolved in tetrahydrofuran (11) and cooled to 10 ° C. Concentrated ammonium hydroxide (100 ml, 1.5 mol) was added over 5 minutes; the temperature rose to about 25 ° C.

The reaction mixture was stirred at room temperature for 65 hours, after which additional concentrated NH ₄ OH was added after 20 hours (3.5 ml) and 44 hours (3.5 ml).

After cooling, the insoluble salts and bis-amides were filtered off and the THF filtrate was washed with saturated sodium chloride solution (100 ml x 2).

The THF was evaporated and the product precipitated from the viscous oil with ethyl acetate (500 ml). Filtration, washing with ethyl acetate and drying gave (37.132.1 g, 45% yield).

Example 36

Dimerization of SN-methylamino ^ Ae-triiodo-S-chlorocarbonyl-benzamide (37) to: Ві5 - {(3-СпІогсагЬопуІ-5-сагЬатоуІ) -2,4,6 · triiodo-N-methyl-anilide} -malonic acid ( 38)

The Titelyerbindung (37,25g, 42,3mM) was dissolved in dry tetrahydrofuran (100ml) and heated the homogeneous solution to 5O ⁰ C. Malonyl dichloride (3.05 mL, 31.3 mmol) was added over 2 minutes followed by further tetrahydrofuran (50 mL) and the suspension was heated for 1 h whereupon the DSC indicated completion of the reaction.

After dilution with butyl acetate (50 ml), the product was filtered, washed with butyl acetate (25 ml x 2) and dried; a whitish solid was obtained (38.15.24 g, 58% yield).

Example 37

Conversion of bis - {(3-chlorocarbonyl-5-carbamoyl) -2,4,6-triiodo-N-methyl-anilide} -malonic acid (38) into: bis - [{3-N- (1,3,4 -Trihydroxy-threo-but-1-yl-carbamoyl-S-carbamoyl-1-triiodo-N-methyl-anilide-malonic acid (39) The starting material (38.10 g, 8 mmol) was dissolved in dry Ν, Ν-dimethylacetamide (15 ml For 5 minutes, trans -5-amino-2,2-dimethyl-6-hydroxy-1,3-dioxepane (aminodioxepane) (3.22 g, 20 mmol) was added, and., triethylamine (2.23 ml, 16 mmol) was added the homogeneous mixture was stirred for 8 h, whereupon it was detected by DSC that the reaction was complete

The DMA was removed by distillation in vacuo and the Isopropylidene were digested at 5O ⁰ C with aqueous hydrochloric acid. The water was removed on a rotary evaporator and isopropanol was added to precipitate the product.

Filtration, washing with isopropanol (10 ml x 3) and drying gave the dimer (39.9.86 g, 87% yield).

Example 38

Conversion of 5-N- (methyl) amino-2,4,6-triiodo-3-chloro-carbonyl-benzamide (36) into: 5- {N- (methyl) -2-acetoxyacetamido} -2,4,6 triiodo-3-chlorocarbonyl-benzamide (40)

The starting material (36.25 g, 42.3 mmol) was dissolved in Ν, Ν-dimethylacetamide (50 ml) at room temperature. 2-Acetoxyacetyl chloride (6.83ml, 63.5mM) was added and allowed to stir overnight; the subsequent DSC indicated the completion of the reaction.

The product was precipitated by adding ice-water (200 ml) and filtered. After washing with water, the solid was dissolved in tetrahydrofuran (200 ml) and the solution extracted with saturated NaCH saturated NaHCO ₃ (3: 1.250 ml) and again with saturated NaCl (100 ml). The organic phase was dried (MgSO ₄ ) and the solvent removed; A foam was obtained (40.22.1 g, 77.2% yield).

Example 39

Amidation and cleavage of 5- {N- (methyl) -2-acetoxyacetamido} -2 _/ 4,6-triiodo-3-chlorocarbonyl-benzamide (40) to: 5- {N- (methyl) -2-hydroxy-acetamido} - 2.4 _> 6-Triiodo-3- {N- (1,3,4-trihydroxy-threo-but-2-yl)} - carbamoyl-Benzamide (41) The title compound (40.7g, 10.35mM) dissolved in a mixture of tetrahydrofuran (40 ml) and triethylamine (1.44 ml, 10.35 mM) and cooled to 10 ⁰ C. Solid amino dioxepane (2.0 g, 12.41 mM) was added, cooling was stopped, and the reaction was allowed to stir at 25 ° C. After 18 h, the DSC indicated the completion of the implementation. The reaction mixture was diluted with tetrahydrofuran (40 mL) and saturated NaCl saturated NaHCO ₃ (3: 1.50 mL) and the phases separated. The organic phase was washed with saturated NaCl (40 ml χ 2), dried and the solvent

evaporated; This gave a foam (6.9 g 82% yield).

The foam was added to methanol (50 ml) and 4.6 normal NaOMe solution (0.5 ml). The solution was stripped at 50 ⁰ C; An oil was obtained which was then mixed with water (50 ml) and Dowex resin 50 H ⁺ (10 g). After heating at 60 ° C. for 30 minutes, a homogeneous solution was finally obtained, and HPLC showed that the ester and isopropylidene

Splitting was completed.

The resin was filtered off and the solution was added sequentially through Duolite A 340 OH ~ / Dowex 50 H ⁺ columns until deionization was complete. The compound was eluted from the columns with water and then treated with Norit Ultra SX charcoal (0.4 m). After 1 h at 70 ⁰ C, the carbon was filtered off and the water evaporated; one received a white one

Foam (41.3.8g, 50% yield of 40).

Example 40

Injection solutions containing 5- {N- (2,3-dihydroxypropyl) acetamido} -2,4,6-triiodo-3- {N- (2,3-dihydroxypropyl)} carbamoyl

Benzamide (19)

Composition of 100ml aliquot of the solution

Yield content of the solution for injection in mg / ml 300 350 400

Compound (g)

Dinatrtum, calcium salt of ethylenediaminetetraacetic acid (mg) tris (hydroxymethyl) aminomethane (mg) water, injectable, for refilling (ml) osmolality (mOsm / kg) viscosity at 37 ° C (centipoise)

58.87 68.68 78.49 10 10 10 121 121 121 100 100 100 399 473 510 4.1 6.6 10.6

Procedure: The sodium-calcium salt of ethylenediaminetetraacetic acid, tris- (hydroxymethyl) aminomethane and the contrast agent were dissolved in injection-pure water and adjusted to pH 7.0 by addition of 1 N hydrochloric acid. The solutions were made up to 100 ml with injection-pure water, filtered through an O, 22 pm membrane in glass ampoules, sealed and autoclaved at 121 ° C. for 20 minutes.

Example 41

Injection solutions containing 5- {N- (2-hydroxyethyl) acetamido} -2,4,6-triiodo-3- {N- (1,3,4-trihydroxy-threo-but-2-

yl)} carbamoylbenzamide (11)

Composition of 100ml aliquot of the solution

Yield content of the solution for injection in mg / ml 300 350 400

Compound (g)

Disodium, calcium salt of ethylenediaminetetraacetic acid (mg) Trisodium citrate (mg) Water, injectable, for refilling (ml) Osmolality (mOsm / kg) Viscosity at 37 ° C (centipoise)

58.87 68.68 78.49 56 56 56 77 77 77 100 100 100 301 337 370 4.2 6.6 13.1

Procedure: The calcium disodium salt of ethylenediaminetetraacetic acid, trisodium citrate and the contrast agent were dissolved in injection pure water and adjusted to pH 5.0 to 6.0 by adding sodium carbonate and carbonic acid. The solutions were made up to 100 ml with injection-pure water, filtered through an O, 22 pm membrane in glass ampoules, sealed and autoclaved at 121 ^° C. for 20 minutes.

The above results clearly show that novel non-ionic contrast agents are provided which have substantially improved properties over the compounds currently available. Due to the improvement in physical properties, especially osmolality and viscosity, a wide range of body regions can be studied with ease of administration and greater freedom from pain. Despite the large number of compounds that have been prepared and tested, it has been found that the compounds of the present invention are superior to those disclosed hitherto. The novel properties are achieved by providing three different nitrogen groups in the molecule, of which only two are substituted. In addition, effective and high yields yielding synthetic routes are given, with readily available substances can be used. Although the foregoing invention has been described in considerable detail for purposes of clarity of explanation and examples, it will be apparent to those of ordinary skill in the art having the benefit of the benefit of the invention that certain changes and modifications are possible without departing from the spirit or scope of the appended claims ,

Claims (12)

claims: 1. Non-ionic contrast agent of the formula CONH- -I R ₃ CON CONR ₁ R ₂ with at least two hydroxy groups; wherein R _{1 represents} hydrogen, a lower alkyl or hydroxy-substituted lower alkyl, wherein the alkyl group has between ₁ and 6 carbon atoms; R ₂ is a hydroxyalkyl of 2-6 carbon atoms having 1 to n-1 hydroxyl groups, where η is the number of carbon atoms; R ₃ is a lower alkyl, hydroxy-substituted lower alkyl or alkoxy-substituted lower alkyl having 1-6 C atoms, or two R ₃ groups may be taken together to form a bridge of 0-2 C atoms; ie R ₃ stands for CONH- -I - (CH ₂ ) ₀ _ ₂ -C0N CONR ₁ R ₂ R ₄ is hydrogen or an alkyl of 1-6 C atoms which has 0 to η-1 hydroxyl groups, where η is the number of carbon atoms; 2. Non-ionic contrast agent according to claim 1, characterized in that R _{2 has} 4 C atoms and three hydroxyl groups, the R _{3 are} not combined to form a bridge and R _{4 has} 2-3 C-atoms and at least one hydroxyl group. 3. Non-ionic contrast agent according to claim 1, characterized in that R _{2 has} 3 C atoms and 2 hydroxyl groups, the R _{3 are} not combined to form a bridge and R _{4 has} 3 carbon atoms and 2 hydroxyl groups. 4. Non-ionic contrast agent according to claim 3, characterized in that R ₂ and R _{4 are the} same. 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-triiodo-3- {N- (2-hydroxyethyl)} carbamoylbenzamide. 8. 5- {N- (Methyl) -2-hydroxyacetamido} -2,4,6-triiodo-3- {N- (1,3,4-trihydroxy-threo-but-2-yl)} carbamoylbenzamide , 9. Bis-p-iN-O, -S.sup.-trihydroxybthreo-but-1-ylcarbamoyl-.alpha.-carbamoyl-Y.sub.a-triiodo-N- (methyl) -anilide-malonic acid. A radiographic agent consisting of a non-ionic contrast agent according to claim 1 in a physiologically acceptable carrier. A radiographic agent consisting of a non-ionic contrast agent according to claim 5 in a physiologically acceptable carrier. 12. A radiographic agent consisting of a non-ionic contrast agent according to claim 6 in a physiologically acceptable carrier. 13. A method for non-invasive determination of a physiological state using radiation and a non-ionic contrast agent, characterized in that one uses a non-ionic contrast agent according to claim 1. 14. A process for the preparation of compounds of general formula I, characterized in that a) compounds of general formula V