IE65719B1 - Novel carboxamide non-ionic contrast media - 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 agents for use as non-ionic contrast: media and to the preparation thereof. · Background X-ray contrast media for visualization of the cardiovascular system and body cavities must be of low viscosity, be highly water-soluble and non-toxic and have a high iodine content. Low viscosity is imperative for rapid delivery, for the temporary replacement of rapidly flowing blood, such as in cardioangiography or high-dose urography, and for contrast enhancement in computer tomography. In order to be non-toxic, the medium must be strongly hydrophilic, non-ionic and of an osmolality close to the body milieu. Although the hitherto known non-toxic monomeric contrast media are of adequate biological compatibility and usable viscosity, they are hyperosmolal compared with the body milieu. Typically, at the diagnostically useful concentration of 300 mg I/ml, they exceed substantially the physiological value of 310 mOsm. Hyperosmolality of those solutions inevitably drives water out of the cells, destroying the cell membranes, disturbing the overall electrolyte metabolism and damaging the lining of vessels or of organ cavities. Also, hyperosmolality has been shown to be a cause of vascular pain, which is invariably brought about by hyperosmolal contrast media.

Most of the non-ionic contrast media, whether monomeric * or oligomeric, are aromatic amides having one or more polyhydroxy, lower aliphatic alkyl or acyl sub-groups bonded to nitrogen. The triiodinated benzene ring contains a number of functionalities spatially closely bonded to one another. The prior art describes various hydroxyalkylamines attached as amides. The following may be mentioned as examples of those amines: serinol; 1amino-2,3-propanediol; N-methyl-l-amino-1,3-propanediol; aminotetritols; ethanolamine, diethanolamine and tromethamine .

Substitution of the carboxy groups in the 1 and 3 positions by the same hydroxyalkylamine severely restricts the structure, since the substituents available in practice are either too small to render the molecule soluble, or too large to produce a solution of low viscosity (Nycomed, U.S. 4 021 481 and 3 701 771; Schering AG, U.S. 4 547 357, Bracco, U.S. 4 001 323). For that reason, improved compounds were developed in which the two hydroxyalkylamines were different (Schering AG U.S. 4 364 921). Such compounds, however, have a complicated synthesis and are costly to produce.

Relevant Publications U.S. Patents Nos. 3 701 771, 4 001 323, 4 021 481, 364 921, 4 547 357 and co-pending U.S. Application serial No. 214 663, filed July 1, 1988, describe various compounds reported to be useful for non-ionic contrast media.

ABSTRACT Non-ionic contrast media based on an asymmetrical triiodoisophthalic diamide in which the remaining ring position is occupied by a substituted nitrogen atom, one of the carboxy groups being an unsubstituted amide and the other carboxy group being at least a mono-(hydroxyalkyl) -substituted amide. The molecule contains at least two hydroxy groups.

DESCRIPTION OF SPECIFIC EMBODIMENTS Non-ionic contrast media based on an acylamide-substituted triiodoisophthalic diamide are provided in which only one of the amide nitrogens is at least monosubstituted. The compounds may be produced inexpensively in a good yield and are obtained in a high degree of purity. The compounds forming the subject of the invention have proved to be of low osmolality but at the same time retain a moderate to low viscosity.

The compounds according to the invention correspond preferably to the following formula (I) (with the exception of 3-[N-(1,3-dihydroxyprop-2-yl)carbamoyl ]-5(2-hydroxy-1-oxopropyl)amino-2,4,6-triiodobenzamide): wherein Rj represents hydrogen, lower alkyl or hydroxyalkyl, the alkyl group containing from 1 to 3, usually 1 or 2, carbon atoms, and the hydroxyalkyl group containing at least 0.5 hydroxys per carbon atom and up to n-1 hydroxy groups, wherein n represents the number of carbon atoms, and containing from 2 to 6, usually from 2 to 4, carbon atoms; R2 is a mono- or poly-hydroxyalkyl containing from 2 to 6, usually from 2 to 4, carbon atoms that has at least one hydroxy group, and a minimum of n-2 and a maximum of n-1 hydroxy groups, n representing the number of carbon atoms; R3 represents lower alkyl, hydroxy-substituted lower alkyl or lower alkoxy-substituted lower alkyl, alkyl containing from 1 to 4 carbon atoms, usually from 1 to 3 carbon atoms, and alkoxy containing from 1 to 3, usually 1 or 2, carbon atoms, the number of oxy groups varying from 0 to n-1, with n representing the number of carbon atoms, or two R3 groups may be combined to form a bridge of from 0 to 2 carbon atoms, preferably l carbon atom; that is to say R3 represents R4 represents hydrogen, lower alkyl or mono- or polyhydroxyalkyl wherein the alkyl groups and the hydroxy groups correspond to the definitions described above for analogous groups.

The alkyl groups may be straight-chain or branched, usually straight-chain, the carbon atoms normally not being quaternary.

The alkyl radical in the mono- or poly-hydroxyalkyl groups R^ and R2 usually contains from 2 to 6 carbon 20 atoms, preferably from 2 to 4 carbon atoms. The groups * preferably have from 1 to 5, usually from 1 to 3, hydroxy groups. Those hydroxy groups may be primary, secondary or tertiary. Examples are tris-hydroxymethylmethyl, hydroxyethyl, dihydroxypropyl and trihydroxybutyl. The carbamides may be prepared using 3-amino-l, 2-propanediol, serinol or amino-tetritols, that is to say, threitol and erythritol either in D,L mixture or in optically pure forms, ethanolamine or diethanolamine or tromethamine or derivatives thereof, the hydroxy groups being reversibly protected. R3 represents hydrogen or lower alkyl, preferably hydrogen or methyl. R3 is lower alkyl or oxyalkyl containing from 1 to 6, usually from 1 to 4, carbon atoms, preferably methyl, hydroxymethyl or hydroxyethyl. There may be mentioned by way of example alkoxy groups containing from 1 to 3 carbon atoms, preferably alkoxyalkyl groups containing 1 or 2 carbon atoms and alkyl groups containing from l to 3 carbon atoms, especially methoxymethyl. Alternatively two R3 groups are combined to form a bond, methylene or ethylene, especially methylene. R4 represents hydrogen, alkyl or mono- or poly-hydroxyalkyl containing from l to 6, preferably from 1 to 4, carbon atoms, including methyl, ethyl, propyl, hydroxyethyl and dihydroxypropyl.

The monomeric compounds of interest here include 5-[N-(2hy dr oxy e thy 1) me thoxy acetamido )-2,4,6-triiodo-3- [ N- (1,3,4trihydroxybut-2-yl) ] carbamoyl benzamide; 5- [ N- (2-hydroxyethyl) hydr oxy acetamido ] -2,4,6-tr iiodo-3- [N-(2,3-dihydroxypropyl) ] carbamoyl benzamide; 5- [ N- (2,3-dihydroxypropyl ) acetamido )-2,4,6-tr i iodo-3- [N-(2,3-dihydroxypropyl) ] carbamoyl benzamide; 5- [N-(2,3-dihydroxypropyl) glycolamido-2,4,6-triiodo-3-[N-( 2-hydroxyethyl) ]carbamoyl benzamide; 5-[N-(1,3,4-trihydroxybut-2-yl) acetamido] 2,4,6—triiodo—3—[N-( 2—hydroxyethyl) ]carbamoyl benzamide; - [ N- (methyl) glycolamido ] -2,4,6-tr iiodo-3- [N-(l,3,4trihydroxyerythrobut-2-yl) carbamoyl benzamide; • and 5-[N-(hydroxyethyl)acetamido)-2,4,6-triiodo-3-[N(1,3,4-trihydroxythreobut-2-y1) ]carbamoyl benzamide.

The dimeric compounds of interest here include: malonic acid bis- [ { 3-N- ( 2,3-dihydroxypropylcarbamoy 1) -5-carbamoyl )-2,4,6-triiodo-N- (2,3-dihydroxypropyl) anilide; malonic acid bis- [ {3-N- (2,3-dihydroxypropylcarbamoyl) -5carbamoyl )-2,4,6-triiodo-N-(2-hydroxyethyl)anilide; and malonic acid bis-[ {3-N-( 1,3,4-trihydroxybut-2-ylcarbamoyl)-5-carbamoyl)-2,4,6-triiodo-N-methyl anilide.

The media forming the subject of the invention contain from 50 to 52 % iodine, usually approximately 51 %, and in a solution of 300 mg I/ml at 37*C (cps), have a viscosity in the range of 4-5 and an osmolality in mOsm in the range of approximately from 275 to 400, usually 285 to 375, for 300 mg I/ml at 37*C in aqueous solution, whereas in pharmaceutical compositions the osmolality is in the range of approximately from 300 to 400, usually 325 to 390.

The media according to the invention are prepared under conventional conditions. Customarily, the compositions will have an aqueous medium that contains a physiologically acceptable chelate-bound calcium salt, for example EDTA, and a buffer for adjusting the pH value to approximately from 6.5 to 7.5, especially about 7, which may be tris, carbonate, citrate or combinations thereof. As further additives bicarbonate, phosphate etc. may be used. The chelate-bound calcium is generally present in an amount of from 5 to 15, usually about 10 mg/100 ml, and the buffer is generally used in amounts of approximately from 2 to 10 mM.

The invention furthermore relates to a process for the preparation of compounds of the general formula I which is characterised in that a) compounds of the general formula V I wherein hydroxy groups contained in and R2 are optionally protected, are converted by reaction with R3CO-X, wherein X represents halogen or an ester radical, in catalysing solvents such as, for example, pyridine, DMA or DMF, with subsequent removal of protecting groups where appropriate, into end products of the general formula I wherein R4 represents hydrogen or into intermediates of the general formula I' wherein R4 represents R3CO, and those, optionally with protected hydroxy groups, are then, if desired, converted by alkylation under basic conditions with R4-containing reagents, after subsequent removal of the protecting groups where appropriate, into end products of the general formula I in which R4 does not represent hydrogen, or b) compounds of the general formula VI COX (VI) wherein R5 represents R3 or hydrogen, Rg represents R2 or hydrogen and X represents halogen or an ester radical, are reacted with ammonia or with hydroxyalkylamines containing radicals Rj and R2 the hydroxy groups of which may be protected, and then the protecting groups are where appropriate removed.

In order to prepare the compounds according to the invention, conventional reactions may be combined to produce a defined reaction path. In accordance with one process according to the invention, the products according to .the invention may be prepared, for example, from a compound of formula (II): / CON.

\ (II) 5 wherein Rj and R2 are as defined above and X represents either a lower alkyl ester or a halogen.

Compounds of the general formula (II) are prepared by reacting a hydroxyalkylamine (NHR^,R2), the OH groups of which may be protected or unprotected, with a customary commercial monoester of 5-nitroisophthalic acid, and then activating the remaining carboxy group. That activation is suitably achieved if X is a halogen, such as Cl, Br, I, or an alkoxy, chlorine and methoxy being preferred.

The ester group of the 5-nitroisophthalic acid monoester is aminolysed with the hydroxyalkylamine of the general formula HNR]R2 according to the above definition, or the aminolysis can be effected initially with ammonia. The remaining carboxy group is then activated in the manner described above. If the hydroxy groups of the NR1R2 radical are unprotected and may be adversely affected by the activation, then they may be suitably protected in conventional manner, for. example by O-acetylation or isopropylidation.

The compound of the general formula (II) may be crystal9 lised in conventional manner from water or from lower alcohols.

After reaction with anhydrous ammonia or ammonium hydroxide, the asymmetric isophthalic diamide being produced, the compound is hydrogenated, triiodinated and acylated in conventional manner, yielding the general formula (III): CONE, I (III) wherein Rlz R2 and R3 are as defined above. Reduction and iodination are effected in known manner according to standard processes 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 known manner. The compound is then obtained in simple manner by crystallisation from the reaction mixture and is washed, dried and acylated according to processes that are also known. For example an activated acyl R3CO-X in which X is halogen or the same acyl group used for the anhydride formation, and catalysing solvents such as pyridine, DMA of DMF, may be used.

If compounds according to formula (I) wherein R4 is not hydrogen are prepared, the alkylation is carried out according to customary processes. Except for lower alkyls, which are expediently introduced at an earlier stage of the synthesis, the reaction with hydroxyalkyl radicals is typically carried out in the last step. The alkylation can be effected in a glycol Solvent having a high boiling point, for example ethylene or propylene glycol; a pH value in the high basic range is achieved using sodium methoxide, sodium hydroxide or other inorganic or organic bases.

Alternatively, where by-products are formed which would otherwise be difficult to remove by conventional purification methods, it is sometimes advantageous for the purposes of purification to maintain the presence of one carboxy group until the last stages of the reaction sequence so that the compound can readily be dissolved in water as a salt and then precipitated or re-precipitated with an inorganic acid. Preferred salts include ammonium, sodium, potassium, calcium, barium and lithium.

That alternative process is based on the above-described reduction, iodination and acetylation of compounds of formula (II) (in which X = OH), and arrives at formula (IV); R3COHN CON.

/ '\ IV wherein R1# R2 and R3 are as defined above.

The hydroxy groups are protected prior to activation of the carboxy group. Furthermore, the anilide must be diacylated with R3CO, since that nitrogen would likewise be adversely affected during carboxy activation. The carboxy group is activated as described above, preferably with acid chloride, but mixed anhydrides, such as tbutoxycarbonyl, may also be used. Compounds according to formula (IV) can readily be crystallised from an aprotic solvent, and then reacted with ammonium hydroxide or ammonia and subjected, as a final step, to alkylation.

An effective amidation normally requires either the use of an excess of an amidating base as acid acceptor, or alternatively the use of tertiary amines, such as triethylamine, tributylamine, pyridine, or inorganic bases, such as bicarbonate or carbonate.

A further variant of the synthetic process may be used if undesired by-products are formed. For example, the alkylation of the anilide may be effected before the amidation. The alkylation of the compounds of the general formula (IV), in which R1# R2 and R3 are as defined hereinbefore, may be carried out according to known processes as described above.

During the alkylation to introduce R4, the protecting groups R3CO are lost and therefore the hydroxy groups of Rj and R2 (and also R4 if present) must be protected again before carboxy activation and subsequent amidation with ammonia. Acetyl groups are generally used for that purpose.

After the last step, if the hydroxy groups are still protected, which is the case if the alkylation is not the last step, the protecting groups can readily be removed by standard means, for example by treatment with ion exchange resins or using acids or bases in catalytic amounts in alcoholic or aqueous solvents.

Salt removal can be effected according to known processes. Typically, the salts are removed by means of ion exchangers either in the mixed bed process or in separate columns that contain a non-ionic and cationic exchange resin, respectively. If desired, the compounds of the general formula (I) can also be absorbed on a polystyrene-absorbing neutral resin and then eluted.

After removal of the salts, the product can be crystallised from a number of solvents, preferably lower alcohols. Decolouring is effected by refluxing in agueous solution using activated carbon.

The dimer is advantageously prepared from the benzamide, the amino nitrogen being alkylated and the remaining carbonyl group being activated, for example, as chlorocarbonyl. The dibasic acid is used in the activated form, especially as the diacyl dichloride, in an organic, aprotic polar solvent. The chlorocarbonyl bonded to the ring carbon is then hydroxyalkylamidated to the end product.

The compounds according to the invention and the compounds according to the general formula (I) are stable in agueous solution; they readily form supersaturated solutions that are also stable. The solutions can be treated with customary agents in an autoclave. At diagnostically useful iodine concentrations, the compounds have osmolalities that typically are very close to the physiological values. At the same time, the viscosity of the solution is low. The objective of the invention is thus achieved, that is, to overcome the generally accepted fact that the reguirements of low osmolality and low viscosity are mutually exclusive. The novel compounds accordingly exhibit an excellent local and systemic tolerability. The compounds are well tolerated biologically and have a high iodine content, especially in comparison with the non-ionic X-ray contrast media currently available.

Data'for the compounds (11) (claim 5) and (19) (claim 6) have been compiled as examples of the properties of compounds from the benzamide class. Table I also shows data for compounds of the prior art for the purpose of comparison.

TABLE 1 BASIC PROPERTIES OF NON-IONIC MONOMERIC X-RAY CONTRAST MEDIA Iodine as a percentage of Molecular Weight Viscosity of 30.0 mg I/ml at 37*C Osmolality of 300 mg I/ml Solutions Approximate ranges i.v. LDeλ q I/kq (cps) Aqueous Solution (mOsm) Pharmaceutically Formulated Sol'n (mOsm) Male Mouse 16-20 g Male Rat 80-100 g Iohexol 46 6.3* 650 685 16-17 11.5-12.5 lopamidol 49 4.7* 671 704 16-18 12-13 lopromide 48 4.6* 607 630 14-16 11-12 Ioxllan 46 4.7 560 568 16-18 12-13 Compound 19 51 4.1 365 390 14-16 13-14 Compound 11 51 4.2 300 326 15.5 -16.5 15.5-17.5 Compound 41 52 3.5 314 322 16 - 17.5 15 - 17 According to literature data; other data were All solutions were pharmaceutically formulated generated in our laboratory unless stated otherwise.

The observed low osmolality and simultaneous low toxicity was achieved hitherto only with non-ionic dimers which, because of their high viscosity, which for a comparable solution concentration is at least twice as high, cannot be used in general uroangiography.

The novel compounds have an excellent biological tolerability, since high osmolality is the causative factor of vascular pain and substantial side effects in the visualization of peripheral vessels of the limbs (Sovak.

M., Current Contrast Media and Ioxilan, Comparative Evaluation of Vascular Pain by Aversion Conditioning, Investigative Radiology, September 1988 Supp). This is one of the major diagnostic procedures in vascular radiology. It is expected that it will be possible for the novel compounds according to the invention to be used in such procedures virtually pain-free. Owing to their physicochemical and pharmacological properties, the novel compounds are suitable as water-soluble contrast media for visualization of the urinary tract and the cardiovascular system, for body cavities and for general contrast enhancement in computer tomography. The injection solutions of the novel compounds can be prepared by dissolution in water and the addition of customary physiologically compatible buffers and stabilisers, such as, for example, complex formers. When formulated with carriers, as customarily used in pharmacopoeias, the compounds are suitable also for enteral administration. The dimers may be used especially in myelography.

For intravascular administration, the compounds according to the invention contain 20-8Q % wt/vol, iodine concentrations of 150-400 mg/ml being preferred.

The following Examples are purely for the purpose of illustration and do not limit the scope of the invention.

EXPERIMENTAL SECTION EXAMPLE 1 Amidation of 5-nitroisophthalic acid monomethyl ester (1) with (threo)-2-amino-l,3,4-butanetriol to form: 5-nitro-3-(N-f1.3.4-trihvdroxvthreobut-2-vl))carbamovlbenzoic acid (2) The starting material (X, 22.5 g, 0.1 mol) was mixed with (threo)-2-amino-l,3,4-butanetriol (30.25 g, 0.25 mol) and the suspension was heated to 110-120’C for 30 minutes.

TLC indicated complete conversion to the product, and the solution was added to IN hydrochloric acid (200 ml) in order to precipitate the product. After cooling overnight, the product was filtered and washed with icecold water (20 ml x 2). Drying in vacuo yielded a white solid (2, 21.0 g, 67 % yield).

EXAMPLE 2 Esterification of 5-nitro-3-(N-(l,3,4-trihydroxythreobut-2-yl))carbamoylbenzoic acid (2) with dimethyl sulphate to form: methyl 5-nitro-3-(N(1.3.4-trihydroxvthreobut-2-vl)1carbamoyl benzoate (3) The title compound (2, 15.7 g, 0.05 mol) was dissolved in IN sodium hydroxide solution (55 ml) and the solution was cooled to <20*C. Dimethyl sulphate (9.45 g, 0.075 mol) was added over a period of 5 minutes, and the pH value wds maintained at 8-10 by the occasional addition of 5N sodium hydroxide solution. The solution was stirred at room temperature for 12 hours and then 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 (2, 11.8 g, 72 % yield).

EXAMPLE 3 Amidation of methyl 5-nitro-3-(N-(l,3,4-trihydroxythreobut-2-yl))carbamoyl benzoate (2) with ammonia to form: 5-nitro-3-(N-f1.3.4-trihvdroxvthreobut-2-vl1carbamoyl benzamide (41 The ester (2, 10.0 g, 0.0305 mol) was dissolved in methanol (50 ml) and concentrated ammonium hydroxide (20 ml, about 0.3 mol) was added. The suspension was heated to 50-60*C for 30 minutes in a sealed vessel; subsequent TLC indicated completion of the reaction. Methanol and ammonium hydroxide were removed by distillation and were replaced by H2O (50 ml). The mixture was left to cool overnight, then the insoluble product was filtered off and washed with cold water (5 ml x 2). Vacuum-drying yielded the white mixed amide (A, 7.15 g, % yield).

EXAMPLE 4 Chlorination of 5-nitroisophthalic acid monomethyl ester (2) with thionyl chloride to form: -nitroisophthalic acid monomethyl ester monoacid chloride f51 The title compound (2, 225 g, 1 mol) was dissolved in ethyl acetate (0.5 1) and Ν,Ν-dimethylformamide (0.1 ml) was added as catalyst. The solution was heated to 70*C and thionyl chloride (219 ml, 3 mol) was added over a period of 1.25 hours. The temperature was then maintained at 70’c for 2 hours.

The thionyl chloride was distilled off together with ethyl acetate (200 ml x 3) and the product was dissolved in hot ethyl acetate (250 ml) and precipitated with cyclohexane (1 1), filtered and washed with cyclohexane (200 ml x 2). Drying in vacuo at 50*C yielded a white solid (5, 216 g, 89 % yield).

EXAMPLE 5 Amidation of 5-nitroisophthalic acid monomethyl ester monoacid chloride (5) with aminodioxepan to form: methvl 5-nitro-3- (N- (trans-2^2-dimethy 1-6-hvdroxv1.3-dioxepan-5-vl))carbamoyl benzoate (61 The monoester monochloride (4, 100 g, 0.411 mol) was dissolved in dry tetrahydrofuran (1 1) and solid aminodioxepan (132.8 g, 0.825 mol) was added in portions over a period of 15 minutes, the temperature being maintained below 25'C with the aid of an ice-bath. The heterogeneous mixture was then stirred for 30 minutes at room temperature, whereupon TLC indicated the reaction was complete.

The insoluble aminohydrochloride was filtered off and the tetrahydrofuran was removed from the filtrate by distillation. The residue was dissolved in ethyl acetate (400 ml) close to the boiling point; the solution was left to stand for several days until crystallisation 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, % yield).

EXAMPLE 6 * Amidation of methyl 5-nitro-3-{N-(£Ean£-2,2-dimethyl6-hydroxy-l, 3-dioxepan-5-yl)} carbamoyl benzoate (6) with ammonium hydroxide to form: -nitro-3- (N- (trans-2.2-dimethvl-6-hydroxy1.3-dioxepan-5-vl) 1carbamoyl benzamide (71 A Parr pressure reactor (800 ml) was charged with the title compound (4., 80 g, 0.22 mol), methanol (110 ml) and 15N ammonium hydroxide (225 ml, 3.38 mol). The reaction vessel was sealed and immersed in a water bath for 2 hours at 50"c; subsequent TLC indicated complete reaction. The heterogeneous reaction mixture was mixed with water (100 ml) and then stripped as a foam. The foam was made into a slurry in water (100 ml), filtered and washed twice with 50 ml of H2O; a white’solid (7, 60.4 g, 79 % yield) was obtained.

EXAMPLE 7 Reduction and cleavage of 5-nitro-3- (N- (trans2,2-dimethyl-6-hydroxy-l, 3-dioxepan-5-yl)}carbamoyl benzamide (7) with hydrogen and palladiura-on-carbon and hydrochloric acid to form: 5-amino-(hvdrochloride)-3(N- f 1.3.4-trihvdroxvthreobut-2-vl) 1 carbamoyl benzamide 18) A Parr pressure reaction apparatus (2.0 1) was charged with the title compound (2, 58 g, 0.16 mol), IN hydrochloric acid (410 ml) and palladium-on-carbon (10 % Pd/C, .8 g, l % w/w Pd). The reaction vessel was connected to a hydrogenation apparatus and agitated for 2 hours at 50 psi (3.5 kp/cm2) under hydrogen gas; subsequent HPLC indicated 90 % conversion into the product (£.). The palladium catalyst was filtered off and the acetone formed during the deprotection was removed in vacuo at 50°C. The resulting clear solution (£, 450 ml, 90 % yield) was used directly for the iodination.

EXAMPLE 8 Iodination of 5-amino-(hydrochloride)-3-{N-(l,3,4trihydroxythreobut-2-yl) ) carbamoyl benzamide (£) with iodine monochloride to form: 5-amino-2.4.6-triiodo-3- (N(1.3.4-trihvdroxvthreobut-2-vl) Icarbamovl benzamide ( 9) The title compound (£, 0.14 mol) in IN hydrochloric acid (450 ml) was heated to 85*C and iodine monochloride (135 ml, 0.49 mol) was added. The reaction mixture was heated at 85‘C for 2 hours; subsequent HPLC indicated completion of the reaction. The reaction mixture was cooled to 25‘C and extracted with 2 x cyclohexene (200 ini), 3 x dichloromethane (300 ml) and 5 x chloroform (200 ml) until the purple colour of the aqueous phase had disappeared. The resulting light yellow solution was recirculated in a column with Duolite resin A340 (800 g) and Dowex resin 50W-X8 (266 g). The resins were rinsed with H2O (6 1) and the solution was concentrated to 300 ml, whereupon a white crystalline solid began to 10 crystallise out. After filtration of the product a white solid was obtained (9., 40 g, 0.06 mol, 43 % yield).

EXAMPLE 9 Acetylation of 5-amino-2,4,6-triiodo3- {N-1,3,4-trihydroxythreobut-2-yl)) carbamoyl 15 benzamide (*)) with acetic anhydride to form: -diacetylamino-2.4.6-triiodo-3-(N-f 1.3.4-triacetoxvthreobut-2-vl11carbamoyl benzamide (10) The title compound (2, 90 g, 0.14 mol) was mixed with acetic anhydride (500 ml, 4.95 mol) at 70*C with vigorous 20 stirring. Perchloric acid (0.36 ml, 0.004 mol) was added as catalyst, as a result of which the temperature rose to 85’C. The reaction mixture was stirred for 1 hour at 85 °C; it was then homogeneous and TLC indicated completion of the reaction. Sodium acetate (0.33 g, 0.004 mol) 25 was added to neutralise the perchloric acid, 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 was then removed. The stripping process was repeated twice; a brown foam (Afi, 113 g, 0.13 mol, 93 % 30 yield) was obtained.

EXAMPLE 10 -Deacetylation and alkylation of 5-diacetylaraino2,4,6-triiodo-3- {N- (1,3,4-triacetoxythreobut-2-yl)} carbamoyl benzamide (101 with sodium methoxide and 2-chloroethanol to form: 5-1N-(2-hydroxyethvl ace tain idol 1-2.4.6-triiodo-3-(N-( 1^3.4-trihvdroxvthreobut-2-vlUcarbamoyl benzamide ill) The title compound (10, 113 g, 0.13 mol) was dissolved in methanol (500 ml) to which 25 % sodium methoxide (55 g, 0.25 mol) was added at 50*C. After 5 hours, HPLC indicated completion of the deacetylation, and the solution was neutralised with Dowex resin 50 W-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 for 48 hours at 45*0 and then chloroethanol (4.7 ml, 0.07 mol) and sodium methoxide (14.7 g, 0.07 mol) were added thereto. After 71 hours HPLC indicated completion of the reaction. The insoluble salts (89 g) were removed by filtration and the solution was neutralised with hydrochloric acid (6N, ml). After concentration of the solution, a brown foam was obtained (XI) (94 g, 0.12 mol, 92 % yield).

EXAMPLE 11 Amidation of 5-nitroisophthalic acid monomethyl ester (X) with 3-amino-l,2-propanediol to form: 5-nitro-3-f N-f 2.3dihydroxypropyl Hcarbamovlbenzoic acid (12) The starting material (X, 225 g, 1 mol) was mixed with 3amino-1,2-propanediol (227.8 g, 2.5 mol) and the heterogeneous mixture was heated for 1 hour at 11O-12O*C. The reaction was thereby complete and the homogeneous mixture was mixed with water (1 1) and cone. HCl (170 ml). The mixture was cooled for several days in order to precipitate the product fully, and the solid was filtered off and washed with cold water (50 ml x 2). After vacuum drying, a white solid was obtained (12. 193 g, 68 % yield).

EXAMPLE 12 Reduction of 5-nitro-3-{N-(2,3-dihydroxypropyl)}carbamoylbenzoic acid (.12) with hydrogen and palladiumon-carboh to form: 5-amino-(hydrochloride)-3-(N-(2.3dihydroxypropyin carbamoylbenzoic acid. Cl3) The nitro acid (12, 180 g, 0.634 mol) was mixed with water (1 1), and concentrated HCl (60 ml) and 10 % palladium-on-carbon (18 g) were added. The suspension was hydrogenated at 2-4 atm. until constant pressure was reached, at which point HPLC and TLC indicated the end of the reaction. The palladium catalyst was removed by filtration and the homogeneous solution was used for the following reaction without the product being isolated f13. approximate yield 98 %).

/ EXAMPLE 13 Iodination of 5-amino-(hydrochloride)-3-{N-( 2,3dihydroxypropyl)}carbamoylbenzoic acid (13) with iodine monochloride to form: 5-amino-2.4.6-triiodo-3-(N(2.3-dihvdroxvpropvl)) carbamoylbenzoic acid (14) The title compound (13., approximately 0.62 mol in 1.5 1 of water) was further diluted with water to a total volume of 4 1 and heated to 85 °C. Over a period of 20 minutes, iodine monochloride (4.1 molar, 499 ml, 2.05 mol) was added and the temperature was maintained at 90‘c for 6 to 8 hours. The end of the reaction was detected by HPLC. The homogeneous mixture was cooled and extracted with 1,2-dichloroethane:cyclohexene (9:1, 500 ml x 2) and then with 1,2-dichloroethane (250 ml x 2). The aqueous phase was then concentrated to 0.9 1 by distillation and cooled for several days until the solid had been fully precipitated. After filtration, washing with cold water (100 ml x 2) and vacuum drying, the yellow-brown product (14 . 286 g, 73 % yield) was obtained .

EXAMPLE 14 Acetylation of 5-amino-2,4,6-triiodo-3-{N-(2,3-dihydroxypropyl) }carbamoylbenzoic acid (14.) with acetic anhydride to form: 5-diacetvlamino-2.4.6-triiodo-3(N- (2.3-diacetoxypropvl1)carbamovlbenzoic acid (151 The starting material (14, 100 g, 0.158 mol) was mixed with acetic anhydride (300 ml, 3.16 mol) and 70 % perchloric acid (0.2 ml) and heated at 80-90*0 for 8 hours. The mixture was neutralised with anhydrous sodium acetate (0.25 g) and the acetic anhydride and the acetic acid were removed by distillation at 70-80*0. The oily residue was azeotropically distilled with butyl acetate (100 ml x 2), 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)jcarbamoylbenzoic acid (IS) with thionyl chloride to form: 5-diacetvlamino-2.4.6triiodo-3-(N-(2.3-diacetoxvpropvl)Icarbamovlbenzovl chloride (16) At 65-70*0, thionyl chloride (57 ml, 0.78 mol) was added to the starting material (IS, approx. 0.142 mol) in ethyl acetate (225 ml); the temperature was then increased to 75-80*0 for 1 hour. Thionyl chloride and ethyl acetate were distilled off in vacuo. The residue was azeo30 tropically distilled with butyl acetate (100 ml x 2) and vacuum-dried. The brown, foam (IS, approx. 130 g, estimated yield 95 %) was used directly in the subsequent amidation step.

EXAMPLE 16 Amidation of 5-diacetylamino-2,4,6-triiodo-3{N-(2,3-diacetoxypropyl))carbamoylbenzoyl chloride (16) with ammonia to form: 5-acetylamino2.4.6-triiodo-3-(N-(2.3-diacetoxvpropyl))carbamoyl benzamide (17) The acid chloride f 16. approx. 0.135 mol) was dissolved in dry N,N-dimethylacetamide (15 ml). The solution was cooled to 0-5*C; using a dry ice/acetone condenser anhydrous ammonia (approx. 20 ml) was condensed into the mixture and the reaction mixture was kept sealed at room temperature for 24 hours. Ammonia and DMA were then removed by vacuum distillation. Using 1-pentanol (500 ml) a solid was precipitated 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)Jcarbamoyl benzamide (171 to form: 5-acetvlamino-2.4.6-triiodo-3-(N-(2.3dihvdroxypropyll1carbamoyl benzamide (181 The title compound (12, 81.2 g, 0.107 mol) was suspended in water (203 ml) and then treated by the dropwise addition of 50 % w/w sodium hydroxide in water (16.9 ml, 0.322 mol). Complete dissolution was achieved by stirring. The solution was degassed for 30 minutes In vacuo. whereupon 12M HCl (15 ml, 0.18 mol) was added. After storage at 4*C, the resulting solid precipitate was filtered, washed with ice-cold water (3 x 50 ml) and ethanol (80 ml) and dried in vacuo to yield the product f18. 54.1 g, 75 % yield).

EXAMPLE 18 Alkylation of 5-acetylamino-2,4,6-triiodo-3-{N(2,3-dihydroxypropyl) )carbamoyl benzamide (18.) to form: 5-fN-f2.3-dihYdroxvpropylIacetamido>2.4.6-triiodo-3-(N-f 2.3-dihvdroxvproPVl11carbamoyl benzamide (19) The title compound (18., 39.7 g, 0.059 mol) was dissolved in propylene glycol (16.7 ml), ethanol (120 ml) and 25 % w/w sodium methoxide (17.6 ml, 0.077 mol). Chloropropanediol (9.78 g, 0.0885 mol) was added and the mixture was stirred for 1 hour at 25*C. The reaction mixture was heated to 33"C and stirred for a further 19 hours; during that 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 H20 (200 ml) and distilled again to an aqueous solution which was deionised with Dowex resin 50 H+ resin (62 g) and Duolite resin A-340 OH (170 g). After elution of the resins with H20 and concentration 150 g of the solution were obtained, which were treated with Norit Ultra SX charcoal (1.0 g) at 60*C for 14 hours. After filtering off the charcoal an aqueous solution was obtained which was stirred for 2 hours with Dowex 50 H+ (1.0 g) and Duolite A-340 OH (4 g). The resin was filtered off and the aqueous solution was distilled to 50.3 g of an oil containing the product (22/ 32.8 g, 74 % yield) in glycerol/propylene glycol. The oil was purified in accordance with the process described in the following step.

EXAMPLE 19 Peracetylation, purification on silica gel and subsequent deacetylation of: 5-f N-(2.3-dihydroxypropyl)acetamido)-2.4,6-triiodor3-(N-(2.3dihvdroxvpropvl)1carbamoyl benzamide f19) The title compound (22/ 16.4 g, 0.022 mol) dissolved in glycerol/propylene glycol oil (total mass 25.15 g) was diluted with pyridine (1.74 g, 0.022 mol) and acetic anhydride (115 g, 1.12 mol) and then heated at 60*C for 18 hours. The reaction mixture was distilled to an oil at reduced pressure, dissolved in CHC13 (100 ml) and extracted with 0.1N HCI (2 x 50 ml) and 15 % w/v sodium chloride solution (2 x 50 ml). The CHC13 phase was dried over MgSO4, filtered and distilled to an oil. The 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 combined, distilled to a foam and then treated with methanol (30 ml) and 25 % w/w sodium methoxide in methanol (0.98 g, 0.0054 mol). After 30 minutes the solution was distilled, reconstituted with methanol (20 ml) and then stirred with Dowex resin 50 H+ (1.3 g). After the pH value had fallen from 12 to 5, the resin was filtered off and a solution was obtained which was distilled to a foam, reconstituted with H20 (25 ml) and concentrated by evaporation to the solid title compound (12, 8.12 g, 49 % yield).

EXAMPLE 20 Deacetylation of 5-diacetylamino-2,4,6-triiodo-3-(N(2,3-diacetoxypropyl)}carbamoylbenzoic acid (15) to form: 5-acetvlamino-2.4.6-triiodo-3-(Ν-Γ2.3dihydroxypropyl))carbamoylbenzoic acid (20) The title compound (15. 720 g, 0.9 mol) was dissolved in 50 ml of methanol, and 25 % w/w sodium methoxide in methanol (345 ml, 1.5 mol) was added. After 4 hours at 45-50 °C, the reaction mixture was distilled at reduced pressure and acidified with 12M HCI (124 ml, 1.5 mol); the salts were filtered off. The filtrate was distilled at reduced pressure to yield an oil which was diluted with n-propanol (680 ml). After crystallisation at 4*C, the resulting solid product (22) was filtered off, washed with n-propanol (2 x 300 ml) 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 form: 5-(N-f2.3-dihydroxypropy 1)acetamido 1 2.4.6-triiodo-3-(N-(2.3-dihvdroxvpropvl)) carbamovlbenzoic acid sodium salt (21) The title compound (20. 100 g, 0.148 mol) was dissolved in 400 ml of methanol. There were added dropwise thereto solid Na3PO4.12 H2O (140.6 g, 0.37 mol) and then chloropropanediol (32.7 g, 0.296 mol) and 25 % w/w sodium methoxide in methanol (24.1 g, 0.111 mol). The reaction mixture was heated at 40'C for 10 hours, a further 25 % sodium methoxide (8.0 g, 0.0368 mol) being added in portions. The salts were filtered off and the methanol filtrate was acidified with 12M HCl (3.5 ml), concentrated in vacuo to a viscous oily product (21) and used directly in the next reaction step.

EXAMPLE 22 Acetylation of the sodium salt of 5-{N-(2,3-dihydroxypropyl) acetamido )-2 ,4,6-triiodo-3-{N-(2,3-dihydroxypropyl) ) carbamoy lbenzoic acid (21) to form: - (N- f 2.3-diacetoxvpropyl) acetamido )-2.4.6-triiodo-3(N-(2.3-diacetoxvpropvincarbamovlbenzoic acid (22) The title compound (21. 114 g, 0.148 mol) in the form of an oil was diluted with pyridine (11.7 g, 0.148 mol) and acetic anhydride (605 g, 5.92 mol) and stirred for 2 hours at 65-70°C. The reaction mixture was concentrated to an oil, a zeo tropica lly distilled with butyl acetate (2 x 100 ml) and partitioned between water (300 ml) and 3:1 toluene/ethyl acetate (200 ml). The agueous phase was extracted with 3:1 toluene/ethyl acetate (3 x 100 ml) and acidified with HCl (22.5 ml) in the presence of ethyl acetate (300 ml). The acidified H2O phase was separated and extracted twice with ethyl acetate (100 ml). The last three ethyl acetate extracts were combined, dried over MgSO4, filtered and concentrated by evaporation to a 5 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 form: 5- (N- (2.3-diacetoxvpropvl) acetamido )-2.4.6-triiodo-3(N—f2.3—diacetoxypropvl)Icarbamoylbenzoyl chloride (23) The title compound f 22. 113.6 g, 0.124 mol) was dissolved at 55eC in ethyl acetate (100 ml); thionyl chloride (44 g, 0.37 mol) was added dropwise thereto and the mixture was heated for 2 hours under reflux, concentrated in vacuo to an oil and then azeotropically distilled with butyl acetate (2 x 50 ml) to a foam, which was dissolved in chloroform (200 ml) and extracted with 0.2M phosphate buffer pH 6.7 (100 ml). The organic phase was dried over MgSO4, filtered and concentrated by evaporation 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-diacetoxy25 propyl) }carbamoylbenzoyl chloride (22) to form: - (N- (2.3-diacetoxypropyl) acetamido )-2.4.6-triiodo-3(N-(2.3-diacetoxypropvl) )carbamoyl benzamide (24) The title compound f 23. 105 g, 0.111 mol) was dissolved in acetonitrile (400 ml) and, using a dry-ice condenser, anhydrous ammonia was added at 25*C. The reaction was complete after 3 hours' NH3 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-tr iiodo-3 - (N- (2,3-diacetoxypropyl))carbamoyl benzamide (24) to form: -{K- (2 ,-3~dihydrQxyprQpyJ) aggstamidp )72,4^ 1N- (2.3-dihvdroxvpropyl) 1 carbamoyl benzamide f 19) The title compound (24/ 98.7 q, 0.106 mol) was dissolved in methanol (250 ml) and, at 25*C, 25 % w/w sodium methoxide in methanol (2.30 g, 0.0106 mol) was added. After 15 minutes the solution was concentrated in vacuo to an oil, reconstituted with methanol (200 ml) and then stirred with Dowex resin 50 H+ (6.0 g) until the pH value had fallen from 12 to 6. The resin was filtered off and a solution was obtained which was distilled to a foam, reconstituted with water (320 ml) and Norit SX charcoal (3.0 g), heated under reflux for 7 hours, filtered, deionised by stirring with Dowex resin 50 H+ (3 g) and Dowex resin XUS-40123 OH (12 g), filtered and concentrated by evaporation to the solid (19. 79.2 g, 96 % yield).

EXAMPLE 26 Methoxyacetylation of 5-amino-2,4,6-triiodo-3{N- (1,3,4-trihydroxythreobut-2-yl)) carbamoyl benzamide (9) with methoxyacetyl chloride to form: 5-methoxyacetylamino-2.4.6-triiodo-3-{N-( 1.3.4trihydroxythreobut-2-vl)) carbamoyl benzamide 125) The title compound (£, 100 g, 0.15 mol) was suspended at 25*C in N,N-dimethylacetamide (250 ml) and over a period of 30 minutes methoxyacetyl chloride (68 ml, 0.75 mol) was added. The reaction mixture was stirred for 5 hours at 35*C; HPLC indicated the end of the reaction. The reaction mixture was quenched with sodium methoxide (97 g, 0.45 mol) and stirred for 2 hours at 40’C. The solution was neutralised with Dowex resin 50W-X4, filtered and diluted with n-butanol (700 ml). Directly a white precipitate was formed which was filtered to yield a whitish solid (25. 80.6 g, 0.11 mol, 73 % yield).

EXAMPLE 27 Alkylation of ioxithalamic acid (25) to form: -(N-(2.3-dihvdroxvpropvl)acetamido)-2.4.6-triiodo-3-(N-f 2-hvdroxvethvl11carbamoyl sodium benzoate (271 Ioxithalamic acid (25, 966 g, 1.5 mol) was dissolved at room temperature in IN sodium hydroxide (1.5 1), heated to 75*C and, over a period of 1.25 hours, 3-chloro-l,2propanediol (223.8 g, 2.03 mol) and 5N sodium hydroxide (approx. 0.4 1) were added simultaneously. The reaction mixture was heated for a further 2.5 hours at 80-90°C, whereupon HPLC indicated completion of the reaction (approx. 90 % conversion into the product).

The reaction mixture was neutralised with concentrated hydrochloric acid (approx. 3 ml) and concentrated by evaporation. Approximately half the foamy residue was taken up in water (0.4 1). On cooling, a white crystalline solid was deposited, which was filtered and washed with ice-cold water. After drying, the crystalline product was obtained (22, 249 g).

EXAMPLE 28 Acetylation of 5-{N-(2,3-dihydroxypropyl)acetamido)-2,4,6-triiodo-3-{N-(2-hydroxyethyl)}carbamoyl sodium benzoate (22) to form: -f N-(2.3-diacetoxypropyl1acetamido1-2.4.6-triiodo-3(N-(2-acetoxyethy111carbamovlbenzoic acid (281 The title compound (22, 50 g, 0.067 mol) was stirred at 25°C into acetic anhydride (102 ml, 1.080 mol, 16.0 eq.). Pyridine (5.4 ml, 0.067 mol, 1.0 eq.) was added and the temperature was increased to 85C for one hour: subsequent TLC indicated completion of the reaction. The homogeneous reaction mixture was concentrated by evaporation in vacuo to yield a viscous oil, dissolved in butyl acetate (50 ml) and repeatedly concentrated by evaporation. The oil was dissolved in H20 (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 x 50 ml). The organic phase was dried over magnesium sulphate, concentrated by evaporation to a foam (28) and used directly in 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 (25.) to form: - (N- f 2.3-diacetoxvpropvl) acetamido )-2.4. β-triiodo-31N-(2-acetoxyethvl) )carbamoylbenzoyl chloride (29) The title compound (25, 55 g, 0.065 mol) was dissolved in 1,2-dichloroethane (170 ml) and heated to 85C. Thionyl chloride (9.8 ml, 0.134 mol, 2.0 eq.) was added, and TLC indicated that the reaction was complete after 3 hours. The reaction mixture was concentrated by evaporation in vacuo to an oil, dissolved again in butyl acetate (50 ml) and repeatedly concentrated by evaporation. The product was isolated in the form of a yellow foam (25, 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 (25) to form: -( N- (2.3-diacetoxypropvl 1 acetamido )-2.4. β-tri iodo-3(N-f 2-acetoxyethvl))carbamoyl-benzamide (30) The title compound (29. 51.9 g, 0.060 mol) was dissolved in acetonitrile (200 ml) and, at 10'c, anhydrous ammonia (excess) was added. After 4 hours, TLC indicated completion of the reaction. The reaction mixture was filtered in order to remove the ammonium chloride salts, and after, removal of the solvent a yellow oil was obtained (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)}carbamoyl benzamide (22) to form: -(N-f 2.3-dihvdroxvpropvl)acetamido)-2.4.6-triiodo-3fN-f2-hvdroxvethyl)>carbamoyl Jbenzamide (31) 10 The title compound (22/ 47 g, 0.056 mol) was dissolved in methanol (240 ml) and 25 % sodium methoxide (3.9 g, 0.3 eq.) was added to increase the pH value to approximately 12. The solution was stirred at 25*C for 1 hour, whereupon HPLC indicated completion of the deacetylation 15 The reaction mixture was neutralised with IN HCl (10 ml) and, after removal of the solvent, a whitish foam was obtained (21, 39 g, 0.054 mol, 97 % yield, 98 % purity), which was recrystallised from heated methanol (5 g in 15 ml, with inoculation).

EXAMPLE 32 Amidation of 5-amino-2,4,6-triiodoisophthaloyl chloride (22) to form: 5-amino-2.4.6-triiodo3-chlorocarbonvl benzamide (33) The starting material (32. 300 9/ 0.503 mol) was dis25 solved in tetrahydrofuran (900 ml) and the homogeneous solution was cooled in ice to 5-10*C. Over a period of 10 minutes, concentrated ammonium hydroxide (92.3 ml, 1.38 mol) was added; the temperature rose to 30*C.

The reaction mixture was stirred at room temperature for 10 a total of 90 hours, during the course of which further ammonium hydroxide (a total of 25.2 ml, 0.38 mol) was added; the mixture was then cooled and the insoluble salts were removed by filtration. The filtrate was washed with saturated NaCl (200 ml x 2).

After evaporation of the tetrahydrofuran, a viscous oil was obtained. A yellow-brown solid was precipitated with ethyl acetate (800 ml), filtered, washed with ethyl acetate (100 ml x 2) and dried; (22., 193 9, 66.5 % yield) was obtained.

EXAMPLE 33 Dimerisation of 5-amino-2,4,6-triiodo-3chlorocarbonyl benzamide (33) to form: malonic acid bis- ((3-chlorocarbonvl-5-carbanioyl) -2.4.6triiodoanilide) (34) The title compound (22, 20.0 g, 34.7 mM) was dissolved in dry tetrahydrofuran (100 ml) and heated to 45 °C and, over a period of 3 minutes, malonyl dichloride (2.53 ml, 26 mM) were added, a heterogeneous mixture thereby being obtained. Dry THF (100 ml) was added and the suspension was stirred for 1 hour, whereupon TLC indicated that the reaction was complete. The mixture was diluted with butyl acetate (150 ml), and the solid was filtered, washed with butyl acetate (50 ml x 2) and dried in vacuo to yield the product (34. 13.18 g, 62 % yield).

EXAMPLE 34 Amidation of malonic acid bis-{(3-chlorocarbonyl-5carbamoyl)-2,4,6-triiodoanilide} (24.) to form: malonic acid bis-Γ(3-N-(1.3.4-trihvdroxvthreobut2-vlcarbamoyl-5-carbamovl )-2.4.6-triiodoanilide) (35) The title compound (34. 0.0 g, 6.56 mM) was dissolved in (fry Ν,Ν-dimethylacetamide (10 ml), triethylamine (1.83 ml, 13.12 mM) was added and the solution was cooled to 20°C. Over a period of 3 minutes, trans-5-amino-2.2dimethyl-6-hydroxy-l,3-dioxepan (2.64 g, 16.4 mM) was added and the homogeneous mixture was stirred for 6 hours at room temperature, whereupon TLC indicated completion of the reaction. The solvent was evaporated, water (50 ml) was added, and the mixture was heated to 75°C for minutes in order to remove the acetonides. After concentration by evaporation and precipitation with isopropanol (100 ml) the product was obtained. The solid was filtered, washed with isopropanol (20 ml x 2) and dried. 8.6 g (35. 94 % yield) were obtained.

EXAMPLE 35 Amidation of 5-N-methylamino-2,4,6-triiodoisophthaloyl chloride (36) to form: 5-N-methvlamino2.4.6-triiodo-3-chlorocarbonYl benzamide (37) The starting material (36. 305 g, 0.5 mol) was dissolved in tetrahydrofuran (1 1) and cooled to 10’C. Over a period of 5 minutes, concentrated ammonium hydroxide (100 ml, 1.5 mol) was added thereto; the temperature rose to approx. 25*C.

The reaction mixture was stirred at room temperature for 65 hours, further concentrated NH4OH being 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 was precipitated from the viscous oil with ethyl acetate (500 ml). After filtration, washing with ethyl acetate and drying, (37. 132.1 g, 45 % yield) was obtained.

EXAMPLE 36 Dimerisation of 5-N-methylamino-2,4,6-triiodo-3chlorocarbonyl benzamide (37) to form: malonic acid bis- ((3-chlorocarbonvl-5-carbamovl )-2.4.6triiodo-N-methvl anilide) (38) The title compound (37. 25 g, 42.3 mM) was dissolved in dry tetrahydrofuran (100 ml) and the homogeneous solution was heated to 50*C. Over a period of 2 minutes, malonyl dichloride (3.05 ml, 31.3 mM) and then further tetrahydrofuran (50 ml) were added and the suspension was heated for 1 hour, whereupon TLC 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 malonic acid bis-((3-chlorocarbonyl-5carbamoyl)-2,4,6-triiodo-N-methyl anilide} (38) to: malonic acid bis-Γ(3-N-(1.3.4-trihydroxythreobut-2-ylcarbamoyl1-5-carbamovl)-2.4.6-triiodo-N-roethyl anilide1 (391 The starting material (38. 10 g, 8 mM) was dissolved in dry N,N-dimethylacetamide (15 ml) and triethylamine (2.23 ml, 16 mM). Over a period of 5 minutes, trans-5amino-2,2-dimethyl-6-hydroxy-l, 3-dioxepan (aminodioxepan) (3.22 g, 20 mM) was added and the homogeneous mixture was stirred for 8 hours, whereupon TLC indicated that the reaction was complete.

The DMA was removed by distillation in vacuo. and the isopropylidene was cleaved at 50°C with aqueous hydrochloric acid. The water was removed using a rotary evaporator, and isopropanol was added to precipitate the product. After filtration, washing with isopropanol (10 ml x 3) and drying, the diner was obtained (59, 9^86 g, 87 % yield).

EXAMPLE 38 Conversion of 5-N-(methyl)amino-2,4,6-triiodo3-chlorocarbonyl benzamide (36) to: 5-(N-fmethvl)-2acetoxyacetamido 1-2.4.6-triiodo-3-chlorocarbonvl benzamide (40) The starting material (36, 25 g, 42.3 mM) was dissolved at room temperature in Ν,Ν-dimethylacetamide (50 ml). 2Acetoxyacetyl chloride (6.83 ml, 63.5 mM) was added and the mixture was stirred overnight; subsequent TLC indicated completion of the reaction.

The product was precipitated by the addition of ice-cold water (200 ml) and filtered. After washing with water, the solid was dissolved in tetrahydrofuran (200 ml) and the solution was extracted with saturated NaCl:saturated NaHCO3 (3:1, 250 ml) and again with saturated NaCl (100 ml). The organic phase was dried (MgSO4) and the solvent was removed; a foam (40, 22.1 g, 77.2 % yield) was obtained.

EXAMPLE 39 Amidation and cleavage of 5-.{N-(methyl)-2acetoxyacetamido)-2,4,6-triiodo-3-chlorocarbonyl benzamide (40) to form: 5-(N-(methyl)-2-hydroxvacetamido)-2.4.6-triiodo-3-(N-(1.3.4-trihvdroxvthreobut-2-yl))carbamoyl benzamide (41) The title compound (IQ, 7.0 g, 10.35 mM) was dissolved in a mixture of tetrahydrofuran (40 ml) and triethylamine (1.44 ml, 10.35 mM) and cooled to 10*C. Solid aminodioxepan (2.0 g, 12.41 mM) was added, the cooling was terminated and the reaction mixture was stirred at 25*C. After 18 hours, TLC indicated completion of the reaction. The reaction mixture was diluted with tetrahydrofuran (40 ml) and saturated NaCl:saturated NaHCO3 (3:1, 50 ml) and the phases were separated. The organic phase was washed with saturated NaCl (40 ml x 2), dried and the solvent was evaporated; a foam was obtained (6.9 g, 82 % yield). 4.6N NaOMe solution (0.5 ml) was added to the foam in methanol (50 ml). The solution was stripped at 50*C; an oil was obtained which was then mixed with water (50 ml) and Dowex resin 50 H+ (10 g). After heating for 30 minutes at 60*C, a homogeneous solution was obtained and HPLC indicated that the ester and isopropylidene cleavage was complete.

The resin was filtered off and the solution was passed in succession over Duolite A 340 0H"/Dowex 50 H+ columns until deionisation was complete. The compound was eluted from the columns with water and then treated with Norit Ultra S-X carbon (0.4 m). After 1 hour at 70 *C, the carbon was filtered off and the water was evaporated; a white foam was obtained (41, 3.8 g, 50 % yield of 40).

Example 40 Acetoxyacetylation of 5-amino-2,4,6-triiodo-3-chlorocarbonyl benzamide (22) to form: -acetoxyacetylamino-2,4,6-triiodo-3-chlorocarbonyl benzamide (42) The starting material (22, 200 g, 0.347 mol) was heated in 1200 ml of dioxan to 60*C. Acetoxyacetyl chloride (142 g, 1.041 mol) was added dropwise over a period of 15 minutes, during which the reaction temperature was ifrcreased to 90*C. That temperature was maintained for 6.5 hours. After cooling to 15*C, the solid (42) was filtered off, washed 4 times with 100 ml of dioxan and dried in vacuo (yield 200.5 g, 85 %).

Example 41 Amidation of 5-acetoxyacetylamino-2,4,6-triiodo-3chlorocarbonyl benzamide f 42) to form 5-acetoxyacetylamino-2,4,6-triiodo-3-[N-(2,3-dihydroxypropyl)]carbamoyl benzamide f43) The starting material (42, 118 g, 0.174 mol) was added to N, N-dimethylacetamide (180 ml), 3-amino-l,2-propanediol (24.2 g, 0.266 mol) and triethylamine (18.0 g, O. 177 mol). The reaction mixture was maintained at 25°C for 24 hours and then diluted by the dropwise addition of n-pentanol (1080 ml) with vigorous stirring. The resulting precipitate (43) was filtered off, washed 4 times with 100 ml of n-pentanol and dried in vacuo. 124.9 g were obtained (crude yield 98 %).

Example 42 Deacetylation of 5-acetoxyacetylamino-2,4,6-triiodo-3-[N(2,3-dihydroxypropyl) ]carbamoyl benzamide (43.) to form 5hydroxyacetylamino-2,4,6-triiodo-3-[N-(2,3-dihydroxypropyl ) ] carbamoyl benzamide (44) The starting material (42» 124.8 g, 0.170 mol) was dissolved in methanol (1.5 1) and water (0.5 1) and then treated with Dowex 50 H+ and Biorex 5 0H" ion exchange resins. The resins were removed by a sieve after 20 * hours' stirring and the resulting mixture was distilled uhder reduced pressure to yield a solid. Methanol (400-ml) and 25 % w/w sodium methoxide in methanol (36.9 g, 0.17 mol) were added to the residue. The resulting solution was then filtered and the methyl acetate was distilled off. The residue was diluted with methanol, neutralised with cone. HCl and distilled under reduced pressure to obtain a solid, which consisted of 9.9 g of NaCl and 94.9 g of the product (44). The yield was 80 .%.

Example 43 Conversion of 5-hydroxyacetylamino-2,4,6-triiodo-3-[N(2,3—dihydroxypropyl)]carbamoyl benzamide (44) with 3,4dihydro-2H-pyran to 5-(2-tetrahydropyranyloxy)acetylamino-2 ,4,6-triiodo-3-[N-(2,3-tetrahydropyranyloxy)propyl]carbamoyl benzamide (45) The starting material (Air 3.44 g, 5 mmol) was mixed with dioxan (15 ml) and methanesulphonic acid (29.6 mg, 0.31 mmol). 3,4-dihydro-2H-pyran (3.36 g, 40 mmol) was added and the mixture was stirred for 4 days at 25°C.

The reaction solution was filtered, triethylamine (62 mg, 0.62 mmol) was added and the mixture was distilled under reduced pressure to an oil, which was taken up in methanol and distilled under reduced pressure to yield a solid (45) , which was used directly in the subsequent alkylation.

Example 44 Alkylation and cleavage of 5-(2-tetrahydropyranyloxy)acetylamino-2,4,6-triiodo-3- [ N- (2,3-tetrahydropyranyloxy) propyl ] carbamoyl benzamide (45) to form 5-[N-(2hydroxyethyl) hydroxyacetamido ] -2,4,6-triiodo-3- [ N- ( 2,3• dihydroxypropyl)) carbamoyl benzamide (46) The starting material (45. 5.0 mmol), a semi-solid residue from the preceding reaction step, was mixed with methanol (18 ml), trisodium phosphate dodecahydrate (4.75 g, 12.5 mmol) and chloroethanol (805 mg, 10 mmol). The resulting suspension was stirred at 40 to 45 *C for 31 hours and then filtered, and 0.5 ml of cone. HCl was added. The acidified filtrate was concentrated under reduced pressure to an oil and taken up again in OiOlN HCl (20 ml) and methanol (20 ml). After repeating that procedure twice, the acidic solution was concentrated under reduced pressure to a solid (46, 3.50 g, yield 95 %).

Example 45 Alkylation of 3,5-diacetylamino-2,4,6-triiodobenzoic acid (diatrizoic acid, 47) to form sodium 3,5-[N,N'-(2,3dihydroxypropyl)diacetamido]-2,4,6-triiodobenzoate (48) Trisodium phosphate dodecahydrate (149 g, 0.393 mol) and 3-chloro-l,2-propanediol (35 g, 0.314 mol) were added to a suspension of the starting material (42, 50 g, 0.079 mol) in methanol (300 ml), and the reaction mixture was heated at 40c for 24 hours. Insoluble salts were removed by vacuum filtration, and the filtrate was neutralised with HCl and concentrated to a white foam f48. approx. 59 g, yield 94 % including 10 % ester byproduct). The product was used directly in the subsequent acetylation.

Example 46 Acetylation of sodium 3,5-[N,N*-(2,3-dihydroxypropyl )diacetamido]-2,4,6-triiodobenzoate (4S.) to form 3,5-[N,N'(2,3-diacetoxypropyl )diacetamido ] -2,4,6-triiodobenzoic acid (49) The starting material (4fi, 59 g, 0.075 mol) was mixed with acetic anhydride (150 ml, 1.58 mol) and pyridine (6 ml, 0.075 mol) and heated at 85’c for 1 hour. Acetic anhydride, acetic acid and pyridine were removed by distillation at 70 to 80*C. The yellow foam was azeo41 tropically distilled with butyl acetate (50 ml x 2). The product (sodium salt of 42) was dissolved in water (300 ml) and extracted with a 2:1 mixture of toluene and ethyl acetate (150 ml x 3) in order to remove the ester by-product of the preceding alkylation step. The aqueous solution was acidified to pH 2.5 with cone. HCI. The white precipitate was extracted with ethyl acetate (75 ml x 2). The combined organic extracts were dried over magnesium sulphate. The solvent was removed. A yellow oil was obtained (42/ approx. 58 g, 83 % total yield of 47), which was used directly in the subsequent chlorination.

Example 47 Chlorination of 3,5-[Ν, Ν'-(2,3-diacetoxypropyl) diacetamido]-2,4,6-tri iodobenzoic acid (42) to form 3,5-[N,N'(2,3-diacetoxypropyl) diacetamido ] -2,4,6-triiodobenzoyl chloride (50) Thionyl chloride (23 ml, 0.32 mol) was added at 65 to 70°C to the starting material (42, approx. 0.062 mol) dissolved in ethyl acetate (125 ml). The temperature was increased to 75 to 80°C for one hour. TLC indicated that the reaction was complete, so thionyl chloride and ethyl acetate were removed in vacuo. The residue was azeotropically distilled with butyl acetate (150 ml x 2) and the resulting solid was dried. The yellow-brown foam * (52/ approx. 56 g, yield 95 %) was used directly in the subsequent amidation step.

Example 48 Amidation of 3,5-[N,N'-(2,3-diacetoxypropyl)diacetamido]2,4,6-triiodobenzoyl chloride (SH) to form 3,5-[N,N#(2,3-diacetoxypropyl) di acetamido]-2,4,6-triiodobenzamide (51) Anhydrous ammonia (excess) was added at 10*C to the starting material (50, approx. 0.059 mol) dissolved in acetonitrile (200 ml). The temperature was increased to 25*c for 5 hours. The reaction was then complete according to TLC. The ammonium chloride was removed by filtration and the filtrate was concentrated to a yellow foam (51, 53 g, estimated yield 97 %). The foam was used directly in the subsequent acetylation.

Example 49 Deacetylation of 3,5-[N,N'-(2,3-diacetoxypropyl)diacetamido]-2,4,6-triiodobenzamide (51) to form 3,5-[N,N'(2,3-dihydroxypropy 1 )diacetamido]-2,4,6-triiodobenzamide (52) A solution of the starting material (51, approx. 0.057 mol) in methanol (250 ml) was mixed with sodium methoxide (4.6 molar, 5.0 g, 0.023 mol) and stirred at room temperature for 30 minutes. HPLC indicated after that that the deacetylation was complete. The reaction • mixture was neutralised with cone. HCl. The insoluble sodium chloride was removed by filtration and the filtrate was concentrated to a yellow foam (52, 43 g, yield 97 %, purity 98 % according to HPLC).

EXAMPLE 50 Injection solutions comprising -f N-(2.3-dihydroxypropvl1acetamido)-2.4.6-triiodo-3(N- (2.3-dihydroxypropvl11carbamov! benzamide (191 Composition of 100 ml aliquots of the solution Iodine content of the injection solution in mg/ml 300 350 400 Compound (g) disodium, calcium salt of ethylenediaminetetraacetic acid (mg) tris-(hydroxymethyl)aminomethane (mg) water, injection-pure, to make up to (ml) osmolality (mOsm/kg) viscosity at 37 °C (centipoise) 58.87 121 100 399 4.1 68.68 121 100 473 6.6 78.49 121 100 510 .6 Procedure: the sodium-calcium salt of ethylenediaminetetraacetic acid, tris-(hydroxymethyl)aminomethane and the contrast medium were dissolved in injection-pure water, and adjusted to pH 7.0 by the addition of IN hydrochloric acid. The solutions were made up to 100 ml with injection-pure water, filtered through a 0.22 pm membrane into glass ampoules, sealed and autoclaved for 20 minutes at 121°C.

EXAMPLE 51 Injection solutions comprising -(N-(2-hvdroxvethyl)acetamido )-2.4.6-triiodo-3(N-(1.3.4-trihydroxythreobut-2-vl))carbamoyl benzamide fill Composition of 100 ml Iodine content of the aliquots of the solution injection solution in mg/ml 300 350 400 Compound (g) 58.87 68.68 78.49 disodium, calcium salt of ethylenediaminetetraacetic acid (mg) 56 56 56 trisodium citrate (mg) 77 77 77 water, injection-pure, to make up to (ml) 100 100 100 osmolality (mOsm/kg) 301 337 370 viscosity at 37c (centipoise) 4.2 6.6 13.1 Procedure: the calcium-disodium salt of ethylenediaminetetraacetic acid, trisodium citrate and the contrast medium were dissolved in injection-pure water, and adjusted to pH 5.0 to 6.0 by the addition of sodium carbonate and carbonic acid. The solutions were made up to 100 ml with injection-pure water, filtered through a 0.22 μτα membrane into glass ampoules, sealed and autoclaved for 20 minutes at 121‘c.

The above results indicate clearly that novel non-ionic contrast media are available that have substantially improved properties compared with the compounds currently obtainable. Because of the improvement in the physical properties, especially in the osmolality and the viscosity, a wide range of body areas can be examined with simple administration and with greater freedom from pain. In spite of the large number of compounds that have already been manufactured and tested, the compounds according to the invention have proved to be superior to the hitherto disclosed compounds. The novel properties are achieved by the provision of three different nitrogen groups in the molecule of which only two are substituted.

In addition, synthetic routes that are effective and deliver high yields are provided, in which readily available materials can be used.

Although the present invention has, for the purpose of a better understanding, been described in some detail by means of the illustrations and Examples, it is clear to any person of normal skill in the art, in the light of the teaching contained in this invention, that certain alterations and modifications are possible without going beyond the contents or scope of the accompanying patent claims.

Claims (10)

1. Non-ionic contrast medium of formula I having at least two hydroxy groups; wherein Rl represents hydrogen, lower alkyl or hydroxy-substituted lower alkyl, the alkyl group containing from 1 to 6 carbon atoms; R 2 represents hydroxyalkyl containing from 2 to 6 carbon atoms that has from 1 to n-1 hydroxy groups, q representing the number of carbon atoms; R 3 represents lower alkyl, hydroxy-substituted lower alkyl or alkoxy-substituted lower alkyl containing from 1 to 6 carbon atoms, or a radical of formula II and R 4 represents hydrogen or alkyl carbon atoms that has from 0 n representing the number of containing from 1 to 6 to n-1 hydroxy groups, carbon atoms, with the exception of 3-[N-(l,3-dihydroxyprop-2-yl)carbamoyl ] -5- (2-hydroxy-1-oxopropyl) amino-2,4,6-triiodobenzamide.

2. - Non-ionic contrast medium according to claim 1, characterised in that R 2 contains 4 carbon atoms and three hydroxy groups, R 3 does not represent a radical of formula II and R 4 contains 2 or 3 carbon atoms and at least one hydroxy group. 3. ,5-[N,N # -(2,3-dihydroxypropyl) diacetamido ] -2,4,6triiodobenzamide, IO

3. Non-ionic contrast medium according to claim l, characterised in that R 2 contains 3 carbon atoms and 2 hydroxy groups, R 3 does not represent a radical of formula II and R 4 contains 3 carbon atoms and 2 hydroxy groups.

4. Non-ionic contrast medium according to claim 3, characterised in that R 2 and R 4 are the same. 5. 13. A process substantially as hereinbefore described reference to the Examples. with with with Dated this 28th day of June, 1990 CRUICKSHANK & CO. Agents for the Applicant 5- [ N- (2-hydroxyethyl) hydroxyacetamido ]-2,4,6triiodo-3-[N-(2,3-dihydroxypropyl) ]carbamoyl benzamide, 5-{N- (methyl) -2-hydroxyacetamido)-2,4,6-triiodo-3{N-(1,3,4-trihydroxythreobut-2-yl))carbamoyl benzamide, malonic acid bis-[3-{N-(l,3,4-trihydroxy)threobut-2yl )carbamoyl-5-carbamoyl )-2,4,6-triiodo-N- (methyl) anilide, malonic acid bis-[{3-N-(2,3-dihydroxypropylcarbamoyl) -5-carbamoyl )-2,4,6-triiodo-N- (2,3-dihydroxypropyl )-anilide, malonic acid bis-[{3-N-(2,3-dihydroxypropylcarbamoyl) -5-carbamoyl )-2,4,6-triiodo-N- (2-hydroxyethy1)-ani1ide, 5-(N-(2,3-dihydroxypropyl)acetamido)-2,4,6-triiodo3-{N-(2-hydroxyethyl))carbamoyl benzamide, 5-{N-(2,3-dihydroxypropyl)acetamido)-2,4,6-triiodo3-(N-(2,3-dihydroxypropyl)}carbamoyl benzamide,

5. 5-(N-(2-hydroxyethyl)acetamido))-2,4,6-triiodo-3-(N(1,3,4-trihydroxythreobut-2-yl))carbamoyl benzamide,

6. An X-ray contrast medium comprising a non-ionic contrast medium according to claim 1 in a physiologically acceptable carrier.

7. An X-ray contrast medium comprising a non-ionic contrast medium according to claim 5 in a physiologically acceptable carrier.

8. An X-ray contrast medium comprising a non-ionic contrast medium according to claim 6 in a physiologically acceptable carrier.

9. A method for the non-invasive determination of a physiological condition using irradiation and a non-ionic contrast medium, characterised in that a non-ionic contrast medium according to claim 1 is used. 10. A process for the preparation of compounds of the general formula I, characterised in that a) compounds of the general formula V I / R 1 CON \ (V) wherein hydroxy groups contained in R 3 and R 2 are optionally protected, are converted by reaction with R 3 CO-X, wherein X represents halogen or an ester radical, in catalysing solvents such as, for example, pyridine, DMA or DMF, with subsequent removal of protecting groups where appropriate, into end products of the general formula I wherein R 4 represents hydrogen or into intermediates of the general formula I 7 wherein R 4 represents R 3 CO, and those, optionally with protected hydroxy groups, are then if desired converted by alkylation under basic conditions with R 4 -containing reagents, after subsequent removal of the protecting groups where appropriate, into end products of the general formula I in which R 4 does not represent hydrogen, or b) compounds of the general formula VI COX I CON / R 5 (VI) wherein R 5 represents R 3 or hydrogen, R 6 represents R 2 or hydrogen and X represents halogen or an ester radical, are reacted with ammonia or with hydroxyalkylamines containing radicals R 3 and R 2 the hydroxy groups of which may -be protected, and then the protecting groups are where appropriate removed. 'f -soli. A compound substantially as hereinbefore described reference to the Examples. 12. A method substantially as hereinbefore described reference to the Examples.

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