CA2020489C - Carboxamide non-ionic contrast media - Google Patents

Abstract

Novel triiodo 5-aminoisophthaldiamides are provided, where the amino and one of the amide nitrogens are substituted. The compounds have at least two hydroxyl groups and are found to provide low viscosity and osmolality. Procedures for preparing the compounds are provided.

Description

~U~U4~9 NOpEI. CARBO%AN(IDE NON-IONIC
CONTRAST 1~~EDIA
INTRODUCTION
Technical Field The field of the invention is methods of preparation and compositions for use as non-ionic contrast media.
Background Radiographic contrast media for~visualization of the cardiovascular system and body cavities must have low viscosity, be highly water soluble, non-toxic, and have a high iodine content. Low viscosity is imperative for rapid delivery, to momentarily replace rapidly flowing blood, such as in cardioangiography or high dose urography, or contrast enhancement in computerized tomography. To be non-toxic, the compound must be highly hydrophilic, non-ionic, and of osmolality close to the body milieu. While the non-ionic monomeric media of the prior art have a reasonable biological tolerance and useful viscosity, they are hyperosmolal vis-a-vis the body milieu.
Typically, at the diagnostically useful concentration of 300 mg I/ml, they substantially exceed the physiological value of 310 mOsm. Hyperosmolality of these solutions necessarily drives water out of cells, disrupting the cellular membranes, perturbing the

2 overall electrolytic balance, and damaging the lining of vessels or of organ cavities. Also, hyperosmalality has been shown to be one cause of vascular pain invariably elicited by hyperosmolal contrast media.
Most of the non-ionic contrast media, whether monomeric or oligomeric, are aromatic amides, with one or more polyhydroxy, lower aliphatic alkyl, and acyl subgroups bonded to nitrogen, with annular carboxamides and amino groups. The triiodinated benzene ring contains a number of functionalities in close spatial relationships. The prior art describes several hydroxyalkylamines attached as amides. Examples of these amines include: serinol; 1-amino-2,3-propanediol; N-methyl 1-amino-2,3-propanediol;
aminotetritols; ethanolamine, diethanolamine, or tromethamine.
Substitution of the carboxyl groups in the 1 and 3 positions with the same hydroxyalkylamine poses a severe limitation on the design, since the substitutents practically available are either too small to solubilize the molecule, or too large to result in a solution of low viscosity (Nycomed, U.S.
4,021,481 and 3,701,771; Schering AG, O.S. 4,547,357 Bracco, U.S. 4,001,323). For this reason, improved compounds were developed where the two hydroxyalkyl-amines were different (Schering AG O.S. 4,364,921).
Such compounds, however, have a complex synthesis and are costly to synthesize.
Relevant Literature U.S. Patent Nos. 3,701,771, 4,001,323, 4,021,481, 4,364,921, 4,547,357 and 4,954,348 are illustrative of various compounds reported as useful for non-ionic contrast media.

3 SUMMARY OF THE ~N'VENTICIN
Non-ionic contrast media are provided based on an asymmetrical triiodoisophthalic diamide, where the remaining rang position is occupied by a substituted nitrogen, one of the carboxyl groups being unsubstituted amide, and the other carboxyl. groups being at least a mono-(hydroxyalkyl) substituted amide. The molecule has at least two hydroxyl.
groups.

Non-ionic contrast media are provided based on an acylamido substituted triiodoisophthalic diamide, where only one of the amide nitrogens is at least monosubstituted. The compounds may be inexpensively synthesized in good yield and obtained in high purity..
The subject compounds have been found to provide low osmalality~ while at the same time maintaining moderate to low viscosity.
The compounds of the subject invention will for the most part have the following Formula (I):

T ~Z
R3COt~ '--r' Ct~NRIRZ

I
wherein:
R1 is hydrogen, lower alkyl or hydroxyalkyl, v~herei.n the alkyl group is from 1 to 6, preferably 1 to 3, usually ~ to 2 carbon atoms, and the hydroxyalkyl group has at least tJ.S
hydroxyls per carbon atom and up to r~~~. hydroxyl ~o~o~~~
groups, where n is the number of carbon atoms, hydroxyalkyl being from 2 to 6, usually 2 to 4 carbon atoms;
R2 is a mono- or polyhydroxyalkyl, of from 2 to 6, usually 2 to 4 carbon atoms, having at least one hydroxyl group and not less than n-2 and not more than n-1 hydroxyl groups, where n is the number of carbon atoms;
R3 is lower alkyl, hydroxy (lower alkyl), or lower alkoxy (lower alkyl), where alkyl is from 1 to 4 carbon atoms, usually of from 1 to 3 carbon atoms, and alkoxyl is of from 1 to 3, usually 1 to 2, carbon atoms, with the number of oxy groups varying from 0 to n-1, where n is the number of carbon atoms, or two Rg groups may be taken together to define a bridge of from 0 to 2 carbon atoms, preferably 1 carbon atom; i.e., R3 represents I I
-(CtI')C-2-CON CONR1R2 Rq I
R4 is hydrogen, lower alkyl, or mono- or polyhydroxyalkyl, where the alkyl groups and the hydroxyl groups come within the definitions as described above for analogous groups.
The alkyl groups may be straight chain or branched, usually straight chained where carbon atoms will normally be other than quaternary.
The alkyl residue in the mono- or polyhydroxyalkyl R1 and R2 will usually have 2 to 6 carbon atoms, usually 2 to 4 carbon atoms.
Preferably, the groups will have 1 to 5, usually 1 to 3 hydroxy groups. These hydroxy groups may be primary, secondary, or

- 4 -tertiary. Examples include trishydroxymethylmethyl, hydroxyethyl, dihydroxypropyl, and trihydroxybutyl. Carbamides may be prepared using 3-amino-1, 2-propanediol, serinol or amino-tetritols, i.e., threitol and erythritol, either in D,L mixture or optically pure forms, ethanolamine, or diethanolamine, or tromethamine, or derivatives thereof, where the hydroxyl groups are reversibly protected. R1 is hydrogen, or lower alkyl, preferably hydrogen or - 4a -~~~~~~9 , methyl. R3 is a lower alkyl or oxya:Lkyl of 1 to 6, usually 1 to 4 carbon atoms, preferably methyl, hydroxymethyl or hydroxyethyl. Also exemplified are alkoxyalkyls containing alkoxyl groups of 1 to 3 carbon

5 atoms, preferably 1 to 2 carbon atoms, and alkyls of from 1 to 3 carbon atoms, more particularly methoxymethyl. Alternatively, two R3 groups are taken together to be a bond, methylene or ethylene, particularly methylene. R4 is hydrogen, alkyl or mono-or polyhydroxyalkyl of from 1 to 6, usually 1 to 4, carbon atoms, including methyl, ethyl, propyl, hydroxyethyl, and dihydroxypropyl.
Monomeric compounds of interest include 5-[N-(2-hydroxyethyl)methoxyacetamido]-2,4,6-triiodo-3-[N-(1,3,4-trihydroxybut-2-yl)]carbamoyl benzamide; S-[N-(2-hydroxyethyl)hydroxyacetamido]-2,4,6-triiodo-3-[N-(2,3-dihydroxypropyl)]carbamoyl benzamide: 5-[N-(2,3-dihydroxypropyl)acetamido]-2,4,6-triiodo-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-trihydroxy-but-2-yl)acetamido]-2,4,6-triiodo-3-[N-(2-hydroxyethyl)]carbamoyl benzamide; 5-[N-(methyl)glycolamido]-2,4,6-triiodo-3-[N-(1,3,4-trihydroxy-erythro-but-2-yl]carbamoyl benzamide: and 5-[N-(2-hydroxyethyl)acetamido]-2,4,6-triiodo-3-[N-(1,3,4-trihydroxythreobut-2-yl)]carbamoyl benzamide.
Dimeric compounds of interest include malonic acid bis-l~3-N-(2,3-dihydroxypropyl-carbamoyl)5-carbamoylj-2~1~~6-triiodo-N-(2,3-dihydroxypropyl); malonic acid bis-~_i3-N-(2,3-dihydroxypropyl-carbamoyl)5-carbamoylJ-2,4,6-triiodo-N-(2-hydroxyethyl)anilide; and malonic acid bis-~~3-N-(~,3,4-trihydroxy-but-2-yl-carbamoyl)-5-carbamoylf-2,1l,6-triiodo-N-methyl anilide.
The compositions of the subject invention will have from about 50 to 52~ iodine, usually about 51~,

6 have a viscosity of a solution of 300 mg I/ml at 37°C
(cps) in the range of about 4 to 5, and an osmolality of 300 mg I/ml at 37°C in mOsm for an aqueous solution in the range of about 275 to 400, more usually about 285 to 375, while with a pharmaceutical formulation, it will range from about 300 to 400, more usually about 325 to about 390.
The subject compositions are formulated in accordance with conventional conditions. Usually, the formulations will comprise an aqueous medium, which includes a physiologically acceptable chelated calcium salt, e.g., EDTA, a buffer to provide a pH in the range of about 6.5 to 7.5, particularly about 7, where the buffer may include tris, carbonate, citrate, or combinations thereof. Other additives which may be included are bicarbonate, phosphate, etc. The chelated calcium will generally be present in from about 5 to 15, usually about 10 mg/100 ml, while the buffer will generally be present in the amount from about 2 to 10 mM.
Conventional reactions may be combined in a defined pathway to prepare the subject compounds.
Thus, in a subject process, the products of this invention can be prepared, for example, from the compound of Formula (II):
COX

II
where R1 and R2 are as defined previously, and X is either a lower alkyl ester or a halogen.

7 Compounds under general Formula (II) a.re prepared by reacting an hydroxyalkylamine (NHR1,R2,) whose OH groups are protected or unprotected, with a commercially available monoester of 5-nitroisophthalic acid, followed by activation of the remaining carboxyl group. Such activation is suitably achieved when X is a halogen such as C1, Hr, I, or alkoxy with chlorine and methoxy being preferred.
The ester group of 5-nitroisophthalic acid, mono-ester is aminolyzed with the hydroxyalkylamine of general formula HNR1R2 as defined above, or aminolysis can be achieved with ammonia first. The remaining carboxyl group is then activated as described above.
If the hydroxyl groups of the residue NR1R2 are 1S unprotected and could be affected by the activation, they can suitably be protected by conventional means such as 0-acetylation or by isopropylidination.
The compound of general Formula (II) can be conveniently crystallized from water or lower alcohols.
After reaction with anhydrous ammonia or ammonium hydroxide, where the asyimnetrical isophthaldiamide is obtained, the compound is hydrogenated. triiodinated and acylated in a conventional manner to arrive at general Formula (III):

R3COHN CON' I
III

where R1, R2, and R3 are defined as above.
Reduction and iodination is typically carried

8 out by standard methods using as catalysts, palladium on carbon or Raney nickel in water or lower alcohols, and hydrogen under low or high pressure. The resulting 5-aminoisophthalic acid bisamide is then iodinated by known methods. The compound is then conveniently recovered as it crystallizes from the reaction mixture, washed, dried, and subjected to acylation, also following known methods. Thus, an activated aayl R3C0--X, where X is halo or the same acyl group to form an anhydride, and catalyzing solvents such as pyridine, DMA, or DMF may be used.
If compounds according to Formula (I), where R4 is other than hydrogen, are prepared, the alkylation is carried out by standard methods. Except for lower alkyls which are conveniently introduced at an earlier stage of the synthesis, the reaction with hydroxyalkyl residues is carried out typically as the last step.
Such an alkylation can be carried out in a high boiling glycol solvent, such as ethylene or propylene glycol, and highly basic pH achieved with sodium methoxide, sodium hydroxide, or other inorganic or organic bases.
Alternatively, it is sometimes advantageous for the purposes of purification where side products are formed which would otherwise be difficult to remove by conventional purification methods, to maintain the presence of one carboxyl group until the latter stages of the reaction sequence, so that the compound can conveniently be dissolved in water as a salt and thereafter precipitated or reprecipitated with an inorganic acid. Preferred salts include ammonium, sodium, potassium, calcium, barium or lithium.
Such alternative process is based on the reduction, iodination and acetylation of compounds of Formula (II) (where X = OH) in the manner described above to arrive at Formula (IV):

9 COON
I I

I
IV
where Rl, R2 and R3 are defined above.
The hydroxyl groups are protected prior to activation of the carboxyl group. It is also necessary to diacylate the anilide with R3C0, as this nitrogen would likewise be adversely affected during carboxyl activation. The carboxyl group will be activated as described above, with the acid chloride being preferred, although mixed anhydrides may be used, e.g., _t-butyloxycarbonyl. Compounds under Formula (IV) can conveniently be crystallized from an aprotic solvent and reacted with ammonium hydroxide or ammonia, followed by alkylation as the last step.
Effective amidation usually requires use of either an excess of amidating base as an acid acceptor or alternatively, tertiary amines, such as triethylamine, tributylamine, pyridine, or inorganic bases such as bicarbonate or carbonate.
Yet another variation of the synthetic process can be applied when undesirable side products occur.
Thus, alkylation of the anilide may be carried out prior to the amidation. Alkylation of the compounds under general Formula (IV), where Rl, R2, and R3 are as defined above may be carried out by known methods as described above.
During alkylation to introduce R4, the protecting groups R3C0 are lost, and thus the hydroxyl groups of Rl and R2 (also R4 if present) must be

10 re-protected prior to carboxyl activation and subsequent amidation with ammonia. Acetyl groups are most often employed for this purpose.
Following the final step, if hydroxyl groups are still protected, such as would be the case when alkylation is not carried out as the last step, the protecting groups may conveniently be removed by standard means such as exposure to ion exchange resins, or use of acids or bases in catalytic amounts in alcoholic or aqueous solvents.
Desalting can be accomplished by known methods. Typically, salts will be removed by ion exchange resins, either mixed-bed or in separate columns individually containing an anionic or cationic exchange resin. Alternatively, the compounds of general Formula (I) can be absorbed on a polystyrene-absorbing neutral resin and thereafter eluted.
Following 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 with activated charcoal.
The diner is conveniently prepared from the benzamide, with the amino nitrogen alkylated and the remaining carbonyl group activated, e.g., chloro-carbonyl. The dibasic acid is used in activated form, particularly as the diacyl dichloride in an organic aprotic polar solvent. The ring carbon bound chloracarbonyl is then hydroxyalkylamidated to obtain the final product.
The compounds of this invention and under general Formula (I) are stable in aqueous solutions;
they readily form supersaturated solutions which also remain stable. The solutions can be autoclaved by standard means. At diagnostically useful iodine concentrations, the compounds have osmolalities which typically are very close to the physiological values.

At the same, time, the solution viscosity is low. Thus, the objective of this invention to overcome the previously recognized mutual exclusivity o:E the two factors, i.e., low osmolality and low viscosity, has been accomplished. As a result, the novel compounds have excellent local and systemic tolerance. The compounds have good biological tolerance and high iodine content, particularly as compared to presently available non-ionic radiographic contrast media.
As examples of the properties of the benzamide class compounds, data were generated for the compounds (11) and (19). For comparison, data on prior art compounds are also shown in Table I.

- 11 -~~~~4~~
u1 L1 [j1 cn b N r a~ Ix .--i ~c o CT O I c~'1 N M

'(..;~ 1f1 r-1 r-fi11 r1 H r-1 .-I .-1 ro r-, I I I I . I
I

1-~ t0 rl N ri rr1:f~ W
p O N

~ r~i r-~ -I r-1 r-i c0 r-1 r1 4l 1~

i~

.-I
O
fll y x u O O l0 L'~
Ca v~

as ~

p, o r Wn co ~o I r C1~ QI ri rl rl (~'1ri N rl r1 ~C ri I I 1 I I
> I I

m uo v ~o fr u m a H

A .-i r.i rH

\

U
Cn H rl ,~ .~ .
ro ~

~v b s ~ n v o 0 ~ ao N
W

O fU ~O ~O C~1M
N r1 X11 m ro ~

U a ~
v H ~''~
O

, ..i rtf 1., w .G N
.a.i O

O Pa w ~ Cv O

~ 3 O .
c ~

.~ ~ ?~

.-i tA to O 1.~
~

.-1 U ro O
~
m ,- . o ~-1 m o ~
H ~ u r o O ar ~ t~ o ~o o ~ b O ~o U
O

F, ,7 l0 ~O M M M H N
r1 t0 N 51 ~

p ~

O ~C
N

rob E'' o ''' a~

ro w w w ~
..i s fJ7 j' H

., ~
W

...i m * * * w ''' ~

Q U cn n ~o .-aN u'ro ~ r.
cn ar M >.

U ~ ~O ~! it v .u aJ ~! ~r ri m b o .-r ro v~

U 0' y H .u ~ ' al N U

H
~C b ~

v ro v rox aN .~w ..~ ro R

b w o ov ao .-~~-I N ro .- ao C~

o ~r ~ v m vn ,nw a a H tr U N

a ) ar dP .C
H N

O .~.~
C

T . O
O

r rn ~ ~ b ~

e-ir~ a7 r~

.-1 a1 ~ w O

o ro ro ~o ~ ~.
m b ~ a a ro . o o ~.-~
~

v ro a o ~ ~

o, , ~ c U U U

*

~, The observed low osmolality and concurrent low toxicity was only previously achieved in non-ionic dimers, which, however, cannot be utilized in general uroangiography due to their high viscosity which, for a comparable solution concentration, is at least two times higher.
The novel compounds show an excellent general biological tolerance. Since high osmolality is the causative factor of vascular pain and a major side effect of depicting the peripheral limb vasculature (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. The novel compounds of this invention are expected to be virtually painless in such procedures. Because of their physiochemical and pharmacological properties,.the novel compounds are suitable as water-soluble contrast media for the visualization of the urine excretory and cardiovascular systems, and body cavities and for general contrast enhancement in computerized tomography. The injectable solutions of the novel compounds can be prepared by dissolution in water and adding standard physiological-compatible buffers, and stabilizers such as chelating agents. The compounds also are suitable for enteral application when formulated with carriers usually employed in the pharmacopoeias. The dimers find particular use for myelograms.
For intravascular use, the compounds of this invention contain 20%-80% weight by volume, with iodine concentrations of 150 to 400 mg/ml preferred.
The following examples are offered by way of illustration and not by way of limitation.

cwocv Tra~a~mar.

Amidation of 5-nitroisoph~thalic acid, monomethyl ester (1) with (threo)-2-amino-1,3,4-butanetriol into: 5-nitro-3{N-(1,3.4-trihydroxy-threo-but-2~r1)~carbamo~l benzoic acid (2) The starting material (1, 22.5 g, 0.1 mole) was mixed with (threo)-2-amino-1,3,4-butanetriol (30.25 g, 0.25 moles) and the suspension heated to 110-120°C
for 30 min. Complete conversion to the product was seen by TLC and the solution was poured into 1 N
hydrochloric acid (200 ml) to precipitate the product.
After cooling overnight. the product was filtered and washed with ice-cold water (20 ml x 2). Drying in vacuo gave a white solid (2, 21.0 g, 67t yield).

Esterification of 5-nitro-3{N-(1,3,4-trihydroxy-threo-but-2-yl)}carbamoyl benzoic acid (2) with dimethyl sulfate into:
methyl 5-nitro-3{N-(1,3,4-trihydroxy-_threo-but-2-yl)}carbamoyl benzoate (3) The title compound (2, 15.7 g. 0.05 moles) was dissolved in 1 N sodium hydroxide solution (55 ml) and the solution cooled to < 20°C. Dimethylsulfate (9.45 g, 0.075 moles) was added over 5 min and the pH was maintained between 8-10 by the occasional addition of 5 N sodium hydroxide solution. The solution was stirred for ca. 12 hr at room temperature after which the insoluble solid was filtered off. The pasty solid was washed with cold water (50 ml x 2) and was dried in vacuo to give a powder (3, 11.8 g, 72~ yield).

E~A~PLE 3 Amidation of methyl 5-nitro-3-j,N-(1,3,4-trihydroxy-threo-but-2-yl)}carbamoyl benzoate (3) with ammonia into: 5-nitro-3-{N-(1,3,4-trihydroxy-threo-but-2-yl~}carbamoy:L benzamide (4) The ester (3, 10.0 g, 0.0305 moles) was dissolved in methanol (50 ml) and concentrated ammonium hydroxide (20 ml, ca. 0.3 moles) was added. The suspension was heated in a sealed vessel at 50-60°C for 30 min when TLC indicated reaction completion. The methanol and ammonium hydroxide were removed by distillation, and were replaced by H20 (50 ml). The mixture was cooled overnight, after which the insoluble product was filtered, and washed with cold water (5 ml x 2). Vacuum drying gave the white mixed amide (4, 7.15 g, 75% yield).
E%AKPLS 4 Chlorination of 5-nitroisophthalic acid, monomethyl ester (1) with thionyl chloride into: 5-nitroiso~hthalic acid, monomethyl ester, monoacid chloride (5) 'The title compound (1, 225 g, 1 mole) was dissolved in ethyl acetate (0.5 L) and N,N-dioethyl-formamide (0.1 ml) added as a catalyst. The solution was heated to 70°C and thionyl chloride (219 al, 3 moles) added over 1.25 hr. The temperature was subsequently maintained at 70°C for 2 hr.
The thionyl chloride was codistilled with ethyl acetate (200 ml x 3) and the product dissolved in hot ethyl acetate (250 ml) and precipitated with cyclohexane (1 L), filtered, and washed with cyclohexane (200 ml x 2). Drying at 50°C under vacuum gave a white solid (5, 216g, 89% yield).

~~?~~~..~~

EXA~'LE 5 Amidation of 5-nitroisophthalic acid, monomethyl ester mono acid chloride (5) with aminodioxepan into: methyl 5-vitro-3-{N-(trans--2,2-dimethyl-6 hydroxy-1,3-dioxepan-5-yl)}carbamoyl benzoate (6) The monoester, monoehloride (5. 100 g, 0.411 moles) was dissolved in dry tetrahydrofuran (1 L) and the solid aminodioxepan (132.8 g, 0.825 moles) was added in portions over 15 min, keeping the temperature below 25°C with the aid of an ice bath. Thereafter, the heterogenous mixture was allowed to stir for 30 min at room temperature, when TLC showed reaction completion.
The insoluble amine hydrochloride was filtered off and the tetrahydrofuran was removed from the filtrate by distillation. The residue was dissolved in ethyl acetate (400 ml) near the boiling point, and the solution 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, giving an off-white product (6, 82.4 g, 55~ yield).
ERAlSPLE 6 Amidation of methyl 5-vitro-3-{N-(traps-2r2-dimethyl-6-hydroxy-1,3-dioxepan-5-yl)}-carbamoyl benzoate (6) with ammonium hydroxide into: 5-vitro-3-{N-(traps-2,2-dimethyl-6-_~~~droxy-1,3-dioxepan-5-yl)}carbamoyl benzamide (7) A Parr pressure reactor (800 ml) was charged with the title compound (6, 80 g, 0.22 moles), methanol (110 ml) and 15 N ammonium hydroxide (225 ml, 3.38 moles). The reaction vessel was sealed and submerged in a water bath at 50°C for 2 hr, when TLC indicated complete reaction. The heterogeneous reaction mixture was mixed with H20 (100 ml) and then stripped to a foam. The foam was slurried in H20 (100 ml), filtered ~~~~~3~

and washed two times with 50 ml H20 to obtain a white solid (7, 60.4 g, 79% yield).
E~4PLE 7 Reduction and deprotection of 5-~nitro-3-{N-(traps-2,2-dimethyl-6-hydroxy-1,3-dioxepan-5-yl)}carbamoyl benzamide (7) with hydrogen and palladium on carbon and hydrochloric acid into:
5-amino-(hydrochloride)-3-{N-(1,3,4-trihydroxy-threo-but-2-yl)}carbamoyl benzamide (8) A Parr pressure reactor (2.0 L) was charged with the title compound (7, 58 g, 0.16 moles). 1 N
hydrochloric acid (410 ml) and palladium-on-carbon (10%
Pd/C, 5.8 g, 1% Pd w/w). The reaction vessel was connected to a hydrogenator and shaken under 50 psi hydrogen gas for 2 hr, when HPLC indicated 90%
conversion to product (8). The palladium catalyst was filtered and the acetone formed during deprotection was removed in vacuo at 50°C. The resulting clear solution (8, 450 ml, 90% yield) was taken directly to iodination.
EZAI~PLE 8 Iodination of 5-amino-(hydrochloride)-3-{N
(1,3,4-trihydroxy-threo-but-2-yl)}carbamoyl benzamide (8) with iodine monochloride into:
5-amino-2,4,6-triiodo-3-{N-(1,3,4-trihydroxy _threo-but-2-yl)}carbamoyl benzamide (9) The title compound (8, 0.14 moles) in 1 N
hydrochloric acid (450 ml) was heated to 85°C and iodine monochloride (135 ml, 0.49 moles) was added.
The reaction mixture was heated at 85°C for 2 hr, when HPLC indicated that the reaction was done. The reaction mixture was cooled to 25°C and extracted 2 x cyclohexene (200 ml), 3 x dichloromethane (300 ml), and 5 x chloroform (200 ml) until all the purple color was removed from the aqueous layer. The resulting light yellow solution was recirculated on a column containing Duolite-A340 (800 g) and Dowex 50W-X8 (266 g) resins.
The resins were flushed with H20 (6 L) and the solution was concentrated to 300 ml when a white crystalline solid began crystallizing. The product was filtered to obtain a white solid (9, 40 g, 0.06 moles, 43% yield).

Acetylation of 5-amino-2,4,6-triiodo-3-{N
(1,3,4-trihydroxy-threo-but-2-yl)}carbamoyl benzamide (9) with acetic anhydride into:
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 moles) was mixed with acetic anhydride (500 ml, 4.95 moles) at 70°C, with vigorous stirring. Perchloric acid (0.36 ml, 0.004 moles) catalyst was added, causing the temperature to rise to 85°C. The reaction mixture was stirred at 85°C for 1 hz, when it became homogenous and TLC indicated reaction completion. Sodium acetate (0.33 g, 0.004 moles) was added to neutralize the perchloric acid, and the solvent was removed to obtain a thick brown oil. The oil was diluted with butyl acetate (200 ml) at 70°C, followed by solvent removal. The stripping procedure was repeated two times to obtain a brown foam (10, 113 g, 0.13 moles, 93% yield).
E%A~1PLE 10 Deacetylation and alkylation of 5-diacetylamino-2,4,6-triiodo-3{N-(1,3,4-triacetoxy-threo-but-2-yl)}carbamoyl benzamide (10) with sodium methoxide and 2-chloroethanol into: 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, 113 g, 0.13 moles) was dissolved in methanol (500m1) to whit:h was added 25~
sodium methoxide (55 g, 0.25 moles) at 50°C. After 5 hr, HPLC indicated the deacetylation was complete and the solution was neutralized with Dowex 50 W-X4 resin (10 g). The resin was filtered and the filtrate was concentrated to 400 ml. The neutral methanolic solution was warmed to 45°C and charged with trisodium phosphate dodecahydrate (129 g, 0.34 moles) and 2-chloroethanol (18.2 ml, 0.272 moles). The reaction was stirred at 45°C for 48 hr, when chloroethanol (4.7 ml, 0.07 moles) and sodium methoxide (14.7 g, 0.07 moles) was added. After 71 hr, HPLC indicated the reaction had gone to completion. The insoluble salts (89 g) were removed by filtration and the solution neutralized with hydroxhloric acid (6 N, 7 ml). The solution was concentrated to obtain a brown foam (11) (94 g, 0.12 moles, 92~ yield).
E~AI~LB 11 Amidation of 5-nitroisophthalic acid, monomethyl ester (1) with 3-amino-1,2-propanediol into: 5-vitro-3-(N-(2,3-dihydroxypropyl)}carbamoyl benzoic acid (12) The starting material (1, 225 g, 1 mole) was mixed with 3-amino-1,2-propanediol (227.8 g, 2.5 moles) and the heterogeneous mixture was heated to 110-120°C
for 1 hr. At this point, the reaction was complete, and the homogeneous mixture was mixed with water (1 L), and concentrated HC1 (170 ml). The mixture was cooled for several days to fully precipitate the product, and the solid was filtered off and washed with cold water (50 ml x 2). Vacuum drying gave a white solid (12, 193 g, 68~ yield).

ExP~9PLE 12 Reduction of 5-nitro-3-{N-(2,3-dihydroxy propyl)}carbamoyl benzoic acid (12) with hydrogen and palladium-on-carbon into: 5-amino-(hydrochloride)-3-{N-(2,3-dihydroxypropyl)}carbamoyl benzoic acid (13~
The vitro acid (12, 180 g, 0.634 moles) was mixed with water (1 L), and concentrated HCl (60 ml) and 10% palladium-on-carbon (18 g) were added. The suspension was hydrogenated at 2-4 atmospheres until the pressure remained constant, by which time HPLC and TLC indicated reaction completion. The palladium-on-carbon was removed by filtration and the homogeneous solution was used without product isolation for the following reaction (13, approximate yield 98%).
EgAMPLE 13 Iodination of 5-amino-(hydrochloride)-3-{N
(2,3-dihydroxypropyl)}carbamoyl benzoic acid (13) with iodine monochloride into: 5-amino 2,4,6-triiodo-3-{N-(2,3-dihydroxy-propyl)}carbamoyl benzoic acid (14) The title compound (13, ca. 0.62 moles in 1.5 L water) was further diluted with water to a total volume of 4 L and heated to 85°C. Over 20 minutes, iodine monochloride (4.1 molar, 499 ml, 2.05 moles) was added and the temperature maintained at 90°C for 6-8 hr. HPLC indicated reaction completion. The homogeneous mixture was cooled, extracted with 1,2-dichloroethane:cycloheYene (9:1, 500 ml x 1), followed by 1,2-dichloroethane (250 ml x 2). The aqueous layer was then concentrated by distillation to 0.9 L, and cooled for several days to complete the precipitation of the solid. Filtration, washing with cold water (100 ml x 2) and vacuum drying gave the tan product (14, 286 g, 73% yield).

Acetylation of 5-amino-2,4,6-triiodo-3 {N-(2,3-dihydroxypropyl)}carbamoyl benzoic acid (14) with acetic anhydride into:
5-diacetylamino-2,4,6-triiodo-3-{N-(2,3-diacetoxypropyl)}carbamoyl benzoic acid (15) The starting material (14, 100 g, 0.158 moles) was mixed with acetic anhydride (300 ml, 3.16 moles) and 70% perchloric acid (0.2 ml), and heated to BO-90°C
for 8 hr. The mixture was neutralized with anhydrous sodium acetate (0.25 g) and the acetic anhydride and acetic acid removed by distillation at 70-80°C. The oily residue was azeotroped with butyl acetate (100 ml x 2), then dissolved in ethyl acetate (250 ml), and taken directly into chlorination (15, approximate yield 90%).

Chlorination of 5-diacetylamino-2,4,6-triiodo-3-{N-(2,3-diacetozypropyl)}-carbamoyl benzoic acid (15) with thionyl chloride into: 5-diacetylamino-2,4,6-trifodo -3-{N-(2,3-diacetoxypropyl)}carbamoyl benzoyl chloride (16) To the starting material (15, ca. 0.142 moles) in ethyl acetate (225 ml) was added thionyl chloride (5? ml, 0.78 moles) at 65-70°C, and the temperature increased afterwards to ?5-80°C for 1 hr. Thionyl chloride and ethyl acetate were vacuum distilled. The residue was azeotroped with butyl acetate (100 ml z 2), and vacuum dried. The brown foam (16, ca. 130 g, estimated yield 95%) was taken directly into the subsequent amidation step.

Amidation of S-diacetylamino-2,4,6-triiodo 3-(N-(2,3-diacetoxypropyl)}carbamoyl benzoyl chloride ( _16) with ammonia into: S-acetylamino 2,4,6-triiodo-3-{N-(2,3-diacet_oxy-propyl)}carbamoyl benzamide (17) The acid chloride (16, ca. 0.135 moles), was dissolved in dry N,N-dimethylacetamide (150 ml). This solution was cooled to 0-5°C, anhydrous ammonia (ca. 20 ml) was condensed into the mixture using a dry ice/acetone condenser and the reaction mixture was kept sealed at room temperature for 24 hr. The ammonia and DMA were removed by vacuum distillation. 1-pentanol (S00 ml) precipitated a solid which was filtered and washed with 1-pentanol (150 ml x 2). Vacuum drying gave a tan solid (17, 82 g, 80.2; yield).
B~L$ 17 Deacetylation of 5-acetylamino-2,4,6 triiodo-3-{N-(2,3-diacetoxypropyl)}carbamoyl benzamide (17) into: 5-acetylamino-2,4,6-triiodo-3-{N-(2,3-dihydroxypropyl)}
carbamoyl benzamide (18) The title compound (17, 81.2 g, 0.107 moles) was suspended in water (203 ml) and then treated with the dropwise addition of 50t w/w sodium hydroxide in water (16.9 ml, 0.322 moles). With stirring, total solution was obtained. The solution was degassed under vacuum for 30 min at which time 12 M HCl (15 ml, 0.18 moles) was added. After storage at 4°C, the resulting precipitated solid was filtered, washed with ice water (3 x 50 ml), ethanol (80 ml), and vacuum dried to the product (18, 54.1 g, 75~ yield).

~~~~~~9 Alkylation of 5-acetylamino-2,4,ti-triiodo-3 {N-(2,3-dihydroxypropyl)}carbamoyl benzamide (18) into: 5-{N-(2,3-dihydroxypropyl) acetamido}-2,4,6-triiodo-3-{N-(2,3-dihydroxypropyl)}carbamoyl benzamide (19) The title compound (18), 39.7 g, 0.059 moles) was dissolved in propylene glycol (16.7 ml), ethanol (120 ml), and 25~ w/w sodium methoxide (17.6 ml, 0.077 moles). Chloropropanediol (9.78 g, 0.0885 moles) was added and the mixture was stirred at 25°C for 1 hr.
The reaction was warmed to 33°C and stirred for another 19 hr during which time 25% w/w sodium methoxide (3.4 ml, 0.015 moles) was added. The reaction was quenched with 12 M HC1, distilled under vacuum, reconstituted with H20 (200 ml), and disttilled again to give an aqueous solution that was deionized with Dowex 50 H+
resin (62 g) and Duolite A-340 OH- resin (140 g).
Elution of the resins with H20 and concentration gave a 150 g solution that was treated with Norit Ultra S%
charcoal (1.00 g) at 60°C for 14 hr. The charcoal was filtered giving an aqueous solution that was stirred for 2 hr with Dowex 50 H+ (1.0 g) and Duolite A-340 OH
(4 g). The resin was filtered and the aqueous solution was distilled to 50.3 g of an oil containing the product (19, 32.8 g, 74% yield) in a glycerol/propylene glycol base. This oil was purified as described in the following step.
EgA~PLB 19 Peracetylation, silica column purification, and subsequent deacetylation of: 5- N-(2,3-dihydroxypropyl)acetamido}-2,4,6-triiodo-3-{N-(2,3-dihydrox ro yl)}
carbamoyl benzamide (19) The title compound (19, 16.4 g, 0.022 moles) dissolved in glycerol/propylene glycol oil (total mass, 25.15 g) was diluted with pyridine (1.74 g, 0.022 moles) and acetic anhydride (115 g, 1.,12 moles), and then warmed to 60°C for 18 hr. The reaction was distilled under reduced pressure to an oil, dissolved in CHC13 (100 ml) and extracted with 0.1 N HC1 (2 x 50 ml) and 15% w/v brine (2 x 50 ml). The CHC13 layer was dried over MgS04, filtered, and distilled to an oil.
This oil was purified on a 900 g silica column utilizing a solvent gradient which ran from 5% acetic acid, 95% chloroform to 5% acetic acid, 4% methanol, 91% chloroform. 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 moles). After 30 min, the solution was distilled, reconstituted with methanol (20 ml), and then stirred with Dowex 50 H+ resin (1.3 g). After the pH decreased from 12 to 5, the resin was filtered off, giving a solution that was distilled to a foam, reconstituted with H20 (25 ml), and evaporated to the solid title compound (19, 8.12 g, 49% yield).

Deacetylation of 5-diacetylamino-2,4,6-triiodo-3-{N-(2,3-diacetoxypropyl)}carbamoyl-benzoic acid (15) into: 5-acetylamino 2,4,6-triiodo-3 ~ N-(2,3-dihydroxypropyl)}
carbamoyl benzoic acid (20) The title compound (15, 720 g, 0.9 moles) was dissolved in 500 ml methanol, and 25% w/w sodium methoxide in methanol (345 ml, 1.5 moles) was added.
After 4 hr at 45-50°C the reaction was distilled under reduced pressure, acidified with 12 M HC1 (124 ml, 1.5 moles), and the salts filtered off. The filtrate was distilled under reduced pressure to give an oil which was diluted with n-propanol (680 ml). After crystallizing at 4°C, the resulting solid product (20) was filtered off, washed with n-propanol (2 x 300 ml), ?Q~~~j~
z5 and dried in vacuo. Yield was 391 g (64%).
~xAMPL~ 21 Alkylation of 5-acetylamino-2,4,6-triiodo -3-{N-(2,3-dihydroxypropyl)}carbamoyl benzoic acid (20) into: 5-{N-(2,3-dihydroxypropyl) acetamido}-2,4,6-triiodo-3-{N-)2,3-dihydroxypropyl)}carbamoyl benzoic _acid, sodium salt (21) The title compound (20, 100 g, 0.148 moles) was dissolved in 400 ml methanol. Solid Na3P04~12 H20 (140.6 g, 0.37 moles) was added, followed by chloropropanediol (32.7 g, 0.296 moles) and 25% w/w sodium methoxide in methanol (24.1 g, 0.111 moles), added dropwise. The reaction mixture was warmed to 40°C for 10 hr during which more 25% sodium methoxide (8.0 g, 0.0368 moles) was added in portions. Salts were filtered off and the methanol filtrate was acidified with 12 M HC1 (3.5 ml), rotavaped to a thick oily product (21) and carried directly into the next reaction.
.s 2z Acetylation of the sodium salt of 5-{N-(2,3-dihydroxypropyl)acetamido}-2,4,6-triiodo-3-{N-(2,3-dihydroxypropyl)}carbamoyl benzoic acid (21) into: 5-{N-(2,3-diacetoxypropyl) acetamido}-2,4,6-triiodo-3-{N-(2,3-d_iacetoxypropyl)}carbamoyl benzoic acid (22) The title compound (21, 114 g. 0.148 moles) oil, was diluted with pyridine (11.7 g, 0.148 moles) and acetic anhydride (605 g, 5.92 moles) and stirred at 65-70°C for 2 hr. The reaction was distilled 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 water layer was extracted with 3:1 toluene:ethyl acetate (3 x 100 ml) and acidified with HC1 (22.5 ml) in the presence of ethyl acetate (300 ml). The acidified H20 layer was separated and extracted twice with ethyl acetate (100 ml). The three latter ethyl acetate extracts were combined, dried over MgS04, filtered. and evaporated to a solid product (22, 118 g, 87% yield).

Chlorination of 5-{N-(2,3-diacetoxypropyl)-acetamido}-2,4,6-triiodo-3-{N-(2,3-diacetoxy-propyl)}carbamoyl benzoic acid (22) into:
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 moles) was dissolved in ethyl acetate (100 ml) at 55°C;
thionyl chloride (44 g, 0.37 moles) was added dropwise and the mixture was refluxed for 2 hr, rotavaped to an oil, and then azeotroped with butyl acetate (2 x 50 ml) to give a foam which was dissolved in chloroform (200 ml) and extracted with 0.2 M pH 6.7 phosphate buffer (100 ml). The organic layer was dried over MgS04, filtered, and evaporated to a solid product (23, 115 g, 98% yield).
EBAMPL$ 24 Amidation of 5-{N-(2,3-diacetoxypropyl)-acetamido}-2,4,6-triiodo-3-{N-(2,3-diacetoxypropyl)}carbamoyl benzoyl chloride (23) into: 5-{N-(2,3-diacetoxy-~ro~yl)acetamido}-2,4,6-triiodo-3-{N-(2,3-_diacetoxypropyl)}carbamoyl benzamide (24) The title compound (23, 105 g, 0.111 moles) was dissolved in acetonitrile (400 ml) to which anhydrous ammonia was added by utilizing a dry ice condenser at 25°C. After 3 hr of NH3 reflux, the reaction was complete. Salts were filtered off, and evaporation yielded a solid product (24, 98.8 g, 96%
yield).
EXAlIPLE 25 S Deacetylation of 5-{N-(2,3-diacetoxypropyl) acetamido}-2,4,6-triiodo-3-{N-(2,3-diacetoxypropyl)}carbamoyl benzamide (24) into: 5-{N-X2,3-dihydroxypropyl)acetamido}
-2,4,6-triiodo-3-{N ,2,3-dihydroxypropyl)}
carbamoyl benzamide (19) The title compound (24, 98.7 g, 0.106 moles) was dissolved in methanol (250 ml) to which 25% w/w sodium methoxide in methanol (2.30 g, 0.0106 moles) was added at 25°C. After 15 min, the solution was distilled under vacuum to an oil, reconstituted with methanol (200 ml) and then stirred with Dowex 50 H+
resin (6.0 g) until the pH decreased from 12 to 6. The resin was filtered off to produce a solution that was distilled to a foam, reconstituted With water (320 ml) and Norit SX charcoal (3.0 g), reflwced for 7 hr, filtered, deionized by stirring with DoweY 50 H+ resin (3 g) and Dowex XUS-40123 OH- resin (12 g), filtered, and evaporated to the solid product (19, 79.2 g, 96%
yield).

Methoxyacetylation of 5-amino-2,4,6-triiodo -3-{N-(1,3,4-trihydroxy-threo-but-2-yl)}
carbamoyl benzamide (9) with methoxyacetyl chloride into: 5-methoxyacetylamino-2,4,6 triiodo-3-{N- X1,3,4-trihydroxy-threo but-2-yl)}carbamoyl benzamide (25) The title compound (9, 100 g, 0.15 moles) was suspended in N,N-dimethylacetamide (250 ml) at 25°C to which was added methoxyacetyl chloride (68 ml, 0.75 moles) over 30 min. The reaction mixture was stirred at 35°C for 5 hr, when HPLC indicated that the reaction ~~~~a~:
z8 was complete. The reaction mixture was quenched with sodium methoxide (97 g, 0.45 moles) and the mixture was stirred at 40°C Eor 2 hr. The solution was neutralized with Dowex 50W-X4 resin, filtered and diluted with n-butanol (700 ml). A white precipitate formed immediately and was filtered to obtain an off-white solid (25, 80.6 g, 0.11 moles, 73% yield).

Alkylation of Ioxithalamic Acid (26) to:
5-{N-(2,3-dihydroxypropyl)acetamido}-2,4,6-triiodo-3-{N-(2-hydroxyethyl)}carbamoyl sodium benzoate (27) Ioxithalamic acid (26, 966 g, 1.5 moles) was dissolved in 1 N sodium hydroxide (1.5 L) at room temperature, warmed to 75°C, and 3-chloro-1,2-propan-ediol (223.8 g, 2.03 moles) and 5 N sodium hydroxide (approximately 0.4 L) were added simultaneously over 1.25 hours. The reaction was heated at 80-90°C for a further 2.5 hours, at which point HPLC showed completion of the reaction (ca. 90% conversion to product).
The reaction mixture was neutralized with concentrated hydrochloric acid (ca. 3 ml) and evaporated. About half of the foamy residue was taken up in water (0.4 L). On cooling, a white, crystalline solid precipitated, which was filtered and washed with ice cold water. Drying gave the crystalline product (27, 249 g).
S~AMpLE 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-diacetoxy ropyl)acetamido}-2,4,6-triiodo-3-{N-(2-acetoxyethyl)}carbamoyl-benzoic acid (28) The title compound (27), 50 g, 0.067 moles) was added to stirred acetic anhydride (102 ml, 1.080 ~~~~4~9 moles, 16.0 eq.) at 25°C Pyridine (5.4 ml, 0.067 moles, 1.0 eq.) was added and the temperatures was raised to 85°C for 1 hour when TLC indicated the' reaction had gone to completion. The homogeneous reaction mixture was evaporated in vacuo to a thick oil, dissolved in butyl acetate (50 ml) and repeatedly evaporated. The oil was dissolved in H20 (260 ml) and extracted with toluene: ethyl acetate (2:1; 4 x 100 ml). The aqueous layer was acidified with 12 N hydrochloric acid (11 ml) and extracted with ethyl acetate (3 x 50 ml). The organic layer was dried over magnesium sulfate, evaporated to a foam (28) and taken directly to the next step (55 g, 0.065 moles, 97% yield).

Chlorination of 5-{N-(2,3-diacetoxypropyl) acetamido}-2,4,6-triiodo-3-{N-(2-acetoxy ethyl)}carbamoyl-benzoic acid (28) to:
5-~N-(2,3-diacetoxypropyl)acetamido}-2,4,6-triiado-3-{N-(2-acetoxyethyl)}carbamo~l-benzoyl chloride (29) The title compound (28, 55 g, 0.065 moles) was dissolved in 1,2-dichloroethane (170 ml) and heated to 85°C. Thionyl chloride (9.8 ml, 0.134 moles, 2.0 eq.) was added and TLC indicated the reaction had reached completion after 3 hours. The reaction mixture was evaporated in vacuo to an oil, redissolved in butyl acetate (50 ml) and repeatedly evaporated. The product was isolated as a yellow foam (29), 51.9 g, 0.060 moles, 92% yield).
EXAI~PLS 30 Amidation of 5-{N-(2,3-diacetoxypropyl) acetamido}-2,4,6-triiodo-3-{N-(2-acetoxyethyl)}
carbamoyl-benzoyl chloride (29) to:
5-{N-(2,3-diacetoxypcopyl)acetamido}-2,4,6-triiodo-. 3-~N-(2-acetoxvethyl)}carbamoyl-benzamide (30) The title compound (29, 51.9 g, 0.060 moles) x was dissolved in acetonitrile (200 ml) and anhydrous ammonia (excess) was added at 10°C. After 4 hours, TLC
indicated the reaction was complete. The reaction mixture was filtered to remove ammonium chloride salts 5 and the solvent was removed to give a yellow oil (30, 47 g, 0.056 moles, 93% yield).

Deacetylation of 5-{N-(2,3-diacetoxypropyl) 10 acetamido}-2,4,6-triiodo-3-{N-(2-acetoxy ethyl)}carbamoyl-benzamide (30) to:
5-{N-(2,3-dihydroxypropylacetamido)}-2,4,6-triiodo 3-{N-(2-hydroxyethyl)}carbamoyl-benzamide (31) The title compound (30, 47 g, 0.056 moles) was 15 dissolved in methanol (240 ml) and 25% sodium methoxide (3.9 g, 0.3 eq.) was added to raise the pH to ca. 12.
The solution was stirred at 25°C for 1 hour when HPLC
indicated the deacetylation was complete. The reaction mixture was neutralized with 1 N HC1 (10 ml) and 20 solvent removal gave an off-white foam (31, 39 g, 0.054 moles, 97% yield, 98% pure), which was recrystallized from hot methanol (5 g in 15 ml, with seeding).
E%AlsPLE 32 25 Amidation of 5-amino-2,4,6-triiodo-isophthaloyl chloride (32) into:
_5-amino-2,4,6-triiodo-3-chlorocarbonyl-benzamide (33) The starting material (32, 300 g, 0.503 moles) was dissolved in tetrahydrofuran (900 ml) and the 30 homogeneous solution cooled in ice to 5-10°C.
Concentrated ammonium hydroxide (92.3 ml, 1.38 moles) was added over 10 minutes; the temperature rose to 30°C.
The reaction mixture was stirred at room temperature for a total of 90 hours, with further additions of ammonium hydroxide (total 25.2 ml, 0.38 moles), then it was cooled and the insoluble salts removed by filtration. The filtrate was washed with saturated NaCl (a00 ml x 2).
The tetrahydrofuran was evaporated to give a viscous oil. Ethyl acetate (800 ml) precipitated a tan solid which was filtered, washed with ethyl acetate (100 ml x 2) and dried to give (33, 153 g, 66.5%
yield).

Dimerization of 5-amino-2,4,6-triiodo-3-chlorocarbonyl-benzamide (33) into:
Malonic Acid-bis-{(3-chlorocarbonyl-5-carbamoyl)-2,4,6-triidodanilide} (34) The title compound (33, 20.0 g, 34.7 mM) was dissolved in dzy tetrahydrofuran (100 ml), heated to 45°C, and malonyl dichloride (2.53 ml, 26 mM) was added over 3 minutes to give a heterogeneous mixture. Dry THF (100 ml) was added, and the suspension stirred~for 1 hour when TLC showed the reaction to be 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 give the product (34, 13.18 g, 62% yield).
2 5 ExAbIPLg 34 Amidation of Malonic Acid-bis-{(3-chlorocarbonyl S-carbamoyl)-2,4,6-triiodoanilide} (34) into:
Malonic Acid-bis-({3-N-(1,3,4-trihydroxy-threo-but-2 yl-carbamoyl-5-carbamoyl}-2,4,6-triiodoanilide] (35) The title compound (34, 8.0 g, 6.56 mM) was dissolved in dry N,N-dimethyl-acetamide (10 ml), triethylamine (1.83 ml, 13.12 mM) was added and the solution was cooled to 20°C. Traps-S-amino-2,2-dimethyl-6-hydroxy-1,3-dioxepan (2.64g, 16.4 mM) was added over 3 minutes, and the homogeneous mixture was stirred at room temperature for 6 hours, when TLC
indicated the reaction was complete. The solvent was evaporated, water (50 ml) was added, and the mixture was heated at 75°C for 15 minutes to cleave the acetonides. The product was obtained by evaporation and precipitation with isopropanol (7.00 ml). The solid was filtered, washed with isopropanol. (20 ml x 2) and dried to give 8.6 g (35, 94% yield).

Amidation of 5-N-methylamino-2,4,6-triiodo-isophthaloyl-chloride (36) to:
5-N-methylamino-2,4,6-triiodo-3-chlorocarbonyl-benzamide (37) The starting material (36, 305 g, 0.5 moles) was dissolved in tetrahydrofuran (1 L) and cooled to 10°C. Concentrated ammonium hydroxide (100 ml, 1.5 moles) was added over 5 minutes; the temperature rose to ca. 25°C.
The reaction mixture was stirred at room temperature for 65 hours, with additional portions of concentrated NH40H added at 20 hours (3.5 ml) and 44 hours (3.5 ml).
Upon cooling, the insoluble salts and bis-amide were filtered and the THF filtrate washed with saturated sodium chloride solution (100 ml x 2).
The THF was evaporated and the product precipated from the thick oil by ethyl acetate (500 ml). Filtration, washing with ethyl acetate and drying gave (37, 132.1 g, 45% yield).
EBAI~PLE 36 Dimerization of 5-N-methylamino-2,4,6-triiodo-3-chlorocarbonyl-benzamide (37) into:
Malonic Acid-bis-((3-chlorocarbonyl-5-carbamoYl)-2,4,6-triiodo-N-methyl 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. Malonyl ~)~~y~ ~~~( dichloride (3.05 ml, 31.3 mM) was added over 2 minutes, followed by additional tetrahydrofuran (50 ml) and the suspension was heated far one hour, when TLC showed the reaction was complete.
Upon dilution with butyl acetate (50 ml), the product was filtered, washed with butyl acetate (25 ml x 2) and dried to give an off-white solid (38, 15.24 g, 58~ yield).

Transformation of Malonic Acid-bis-{(3-chlorocarbonyl 5-carbamoyl)-2,4,6-triiodo-N-methyl anilide} (38) into:
Malonic Acid-bis-[~3-N-(1,3,4-trihydroxy-threo but-2-yl-carbamoyl) 5-carbamoyl}-2,4,6-triiodo N-methyl anilide] (39) The starting material (38, 10 g, 8 mM) was dissolved in dry N,N-dimethyl-acetamide (15 ml) and triethylamine (2.23 ml, 16 mM). Trans-5-amino-2,2-dimethyl-6-hydroxy-1,3-dioxepan (aatinodioxepan) (3.22 g, 20 mM) was added over S minutes, and the homogeneous mixture was stirred for 8 hours, when TLC showed the reaction to be complete.
The DMA was removed by vacuum distillation and the isopropylidenes were cleaved with aqueous hydro-chloric acid at 50°C. The water was removed on the rotary evaporator and isopropanol added to precipitate the product. Filtration, washing with isopropanol (10 ml x 3), and drying gave the dimer (39, 9.86 g, 87%
yield).

5-N-(methyl)amino-2,4,6-triiodo-3-chlorocarbonyl-benzamide (36) into:
5-{N-(methyl)-2-acetoxyacetamido}-2,4,6-_triiodo-3-chlorocarbonyl-benzamide (40) The starting material (36, 25 g, 42.3 mM) was dissolved in dry N,N-dimethyl-acetamide (50 ml) at room temperature. 2-Acetoxyacetyl chloride (6.83 ml, 63.5 mM) was added, and after stirring overnight, TLC
indicated the reaction was complete.
The product was precipitated by the addition of ice-cold water (200 ml) and filtered. After dashing with water the solid was dissolved in tetrahydrofuran (200 ml), and the solution extracted with saturated NaCl:saturated NaHC03 (3:1, 250 ml), followed by saturated NaCl (100 ml). The organic layer was dried (MgS04) and the solvent removed to give a foam (40, 22.1 g, 77.2 yield).
ExAMPLE 39 Amidation and Deprotection of 5-{N-(methyl)-2-acetoxyacetamido}-2,4,6-triiodo-3-chlorocarbonyl-benzamide (40) into:
5-~N-(methyl)-2-hydroxyacetamido}-2,4,6-triiodo 3-{N-(1,3,4-trihydroxy-threo-but-2-yl)}
carbamoyl-benzamide (41) The title compound (40, 7.0 g, 10.35 mM)' was dissolved in a mixture of tetrahydrofuran (40 ml) and triethylamine (1.44 mlr 10.35 mM) and cooled to 10°C.
Solid aminodioxepan (2.0 g, 12.41 mM) was added, the cooling was removed and the reaction was allowed to stir at 25°C. By 18 hours, TLC indicated reaction completion. The reaction mixture was diluted with tetrahydrofuran (40 ml) and saturated NaCl:saturated NaHC03 (3:1, 50 ml) and the layers were separated. The organic layer was washed with saturated NaCl (40 ml x 2), dried (MgS04) and the solvent evaporated to give a foam (6.9 g, 823 yield).
The foam was dissolved in methanol (50 ml) and 4.6 formal NaOMe solution (0.5 ml) added. The solution was stripped at 50°C to yield an oil which was subsequently mixed with water (50 ml) and Dowex 50 H~
resin (10 g). Heating at 60°C for 30 minutes eventually gave a homogeneous solution, and HPLC

~~~Q~~~
indicated that ester and isopropylidene~ cleavage was complete.
The resin was filtered, and the solution cycled through sequential Duolite A 340 OH-/Dowex SO H+
5 columns until deionization was completE~. The compound was eluted from the columns with water and subsequently treated with Norit Ultra S-X carbon (0.4 g). After 1 hour at 70°C, the carbon was filtered and the water evaporated to yield a white foam (41, 3.8 g, 50~ yield 10 from 40).

Acetoxyacetylation of 5-amino-2,4,6-triiodo-3-chlorocarbonyl benzamide (33) unto 5-acetoxyacetylamino-2,4,6-triiodo-3-chlorocarbonyl benzamide (42) The starting material (33, 200 g, 0.347 moles) in 1200 ml dioxane was heated to 60oC. Acetoxyacetyl chloride (142 g, 1.041 moles) was added dropwise over 15 minutes at which time the reaction was heated to 90oC and held there for 6.5 hours. After cooling to lSoC the solid product (42) was filtered, washed with 4 x 100 ml ZO dioxane and vacuum dried to a weight of 200.5 g (yield 85~).

Amidation of 5-acetoxyacetylamino-2,4,6-triiodo-3-chlorocarbonyl benzamide (42) into 5-acetoxyacetylamino-2,4,6-triiodo-3-{N-(2,3-dihydroxypropyl)}-carbamoyl benzamide (43) The starting material (42, 118 g, 0.174 moles) was added to a flask containing N,N-dimethyl acetamide (180 ml), 3-amino-1,2-propanediol (24.2 g, 0.266 moles) and triethylamine (18.0 g, 0.177 moles). The reaction was held at 25°C for 4 hours and was then diluted by the dropwise addition of n-pentanol (1080 m1) during vigorous mechanical stirring. The resulting precipitate (43) was filtered, washed with 4 x 100 ml n-pentanol, and vacuum dried to a weight of 124.9 g (crude yield 98~).

Deacetylation of 5-acetoxyacetylamino-2,4,6-triiodo-3-{N-(2,3-dihyroxypropyl)}-carbamoyl benzamide (43) into 5-hydroxyacetylamino-2,4,6-triiodo-3-{N-(2,3-dihydroxypropyl)}-carbamoyl benzamide (44) - 35a -The starting material (43, 124.8 g, 0.170 moles) was dissolved in methanol (1.5L) and water (0.5L) and then treated with Dowex 50 H+ and Biorex 5 OH ion exchange resins. The resins were removed with a sieve after 20 hours of stirring and the resulting mixture was distilled under reduced pressure to a solid residue.
Methanol (400 ml) and 25~ w/w sodium methoxide in methanol (36.9 g, 0.17 moles) were added to the residue to produce a solution which was filtered, distilled under pressure to remove methyl acetate, diluted with methanol, neutralized with concentrated HC1 and then distilled under reduced pressure to a solid consisting of 9.9 g NaCl and 94.0 g of the product (44). The yield was 80~.

Protection of 5-hydroxyacetylamino-2,4,6-triiodo-3-{N-(2,3-dihydroxypropyl)}-carbamoyl benzamide (44) with 3,4-dihydro-2H-pyran into 5-(2-tetrahydropyranyloxy)acetylamino-2,4,6-triiodo-3 {N-(2,3-tetrahydropyranyloxy)propyl}carbamoyl benzamide (45) The starting material (44, 3.44 g, 5mmoles) was mixed with dioxane (15 ml) and methanesulfonic acid (29.6 mg = 0.31 mmoles).
3,4-Dihydro-2Hpyran (3.36 g, 40 mmole) was added and the mixture was stirred at 25°C for 4 days. The reaction was filtered, basified with triethylamine (62 mg, 0.62 mmole), distilled under reduced pressure to an oil, reconstituted with methanol, and distilled under reduced pressure to a product residue (45) which was carried directly into alkylation.

Alkylation and Deprotection of 5-(2-terthydropyranyloxy)acetylamino-2,4,6-triiodo-3-{N-(2,3-tetrahydropyranyloxy)propyl}carbamoyl benzamide (45) into 5-{N-(2-hydroxyethyl)hydroxyacetamido}-2,4,6-triiodo-3-{N-(2,3-dihydroxypropyl)}carbamoyl benzamide (46) - 35b -The starting material (45, 50. mmole). a semisolid residue from the previous step, was mixed with methanol (18 ml), trisodium phosphate dodecahydrate (4.75 g, 12,.5 mmoles) and chloroethanol (805 mg, 10 mmoles). The resulting suspension was stirred at 40-45oC for 31 hours, filtered and diluted with 0.5 ml concentrated HC1. The acidified filtrate was distilled under reduced pressure to an oil and reconstituted with 0.01 N HCl (20 ml) and methanol (20 ml). After repeating this twice more, the acidic solution was finally distilled under reduced pressure to solid product (46) weighing 3.50 g, yield 95~.

Alkylation of 3,5-diacetylamino-2,4,6-triiodobenzoic acid (diatrizoic acid, 47) into Sodium 3,5-{N, N'-(2,3-dihydroxypropyl)diacetamido}-2,4,6-triodobenzoate (48) To a suspension of the starting material (47, 50 g, 0.079 moles) in methanol (300 ml) was added trisodium phosphate dodecahydrate (149 g, 0.393 moles) and 3-chloro-1,2-propanediol (35 g, 0.314 moles) and the reaction was heated at 40°C for 24 hours.
Insoluble salts were removed by vacuum filtration, the filtrate was neutralized with HC1 and evaporated to a white foam (4~, ca.
59 g, yield 94~ including 10~ ester byproduct). The foam was taken directly into acetylation.

Acetylation of Sodium 3,5-{N, N'-(2,3-dihydroxypropyl) diacetamido}-2,4,6-triiodobenzoata (48) into: 3,5-{N, N'-(2,3-diacetoxypropyl)diacetamido}-2,4,6-triiodobenzoic acid (49) The starting material (48, 59 g, 0.075 moles) was mixed with acetic anhydride (150 ml, 1.58 moles) and pyridine (6 ml, 0.075 moles) and heated to 85oC for 1 hour. The acetic anhydride, acetic acid and pyridine were removed by distillation at 70-80oC, - 35c -and the yellow foam was azet roped with butyl acetate (50 ml x x2).
The product (sodium salt of 49) was dissolved in water (300 ml) and extracted with a 2:1 mixture of toluene and ethyl acetate (150 ml x 3) to remove the ester byproduct from the previous alkylation step. The aqueous solution was acidified with concentrated HC1 to pH 2.5 and the white precipitate was extracted with ethyl acetate (75 ml x 2). The combined organic extracts were dried over magnesium sulfate and the solvant removed to give a yellow oil (49, ca. 58 g, 83~ yield overall from 47). the product was taken directly into chlorination.

Chlorination of 3,5-{N,N'-(2,3-diacetoxypropyl)diacetamido}-2,4,6-triiodibenzoic acid (49) into 3,5-{N, N'-(2,3-diacetoxypropyl)diacetamido-2,4,6-triiodobenzoyl chloride (50) To the starting material (49, ca. 0.062 moles) in ethyl acetate (125 ml) was added thionyl chloride (23 ml, 0.32 moles) at 65-70°C, and the temperature increased to 75-80°C for 1 hour. TLC
indicated that the reaction was complete and thionyl chloride and ethyl acetate were removed under vacuum. The residue was azeptroped with butyl acetate (150 ml x 2) and the resultant solid dried. The tan foam (50, ca. 56 g, yield 95~) was taken directly into the subsequent amidation step.

Amidation of 3,5-{N,N'-(2,3-diacetoxypropyl)diacetamido}-2,4,6-triiodobenzoyl chloride (50) into 3,5-{N, N'-(2,3-diacetoxypropyl)diacetamido}-2,4,6-triiodo-bensamide (51) To the starting material (50, ca. 0.059 moles) in acetonitrile (200 ml) was added anhydrous ammonia (excess) at 10°C, and the - 35d -~;~~2~t~n temperature was increased to 25oC for 5 hours. The reaction was complete by TLC and the ammonium chloride was removed by filtration. The filtrate was evaporated to a yellow foam (51, 53 g, estimated yield 97~). The foam was taken directly to deacetylation.

Deacetylation of 3,5-{N,N'-(2,3-diacetoxypropyl)diacetamido)-2,3,6-triiodobenzamidc (51) into 3,5-{N, N'-(2,3-dihydroxypropyl)diacetamido}-2,4,6-triiodobenzamide (52) A solution of the starting material (51, ca 0.057 moles) in methanol (250 ml) was mixed with sodium methoxide (4.6 moles, 5.0 g, 0.023 moles) and was stirred at room temperature for 30 minutes. HPLC showed that the deacetylation was complete and the reaction mixture was neutralized with concentrated HCl. The insoluble sodium chloride was removed by filtration and the filtrate was evaporated to a yellow foam (52, 43 g, yield 97~, purity 98~ by HPLC).
- 35e -~~~~J

Injection solutions containin 5-{N- 2,3--dih drox-yprop ly )acetamido -2,4,6 -tri~.o 0-3- N-(2,3-di.hydro;K ro 1 carbamoyl enzami'~e (19) Iodine Content of Injection Composition of 100 ml Solution in mg/ml Aliquots of Solution 300 350 400 Compound (g) 58.87 68.68 78.49 Disodium, calcium salt of ethylenediaminetetraacetic acid (mg) 10 10 10 Tris-(hydroxymethyl)amino-methane (mg) 121 121 121 Water for injection to volume (ml) 100 100 100 Osmolality (mOsm/kg) 399 473 510 Viscosity @ 37C

(centipoise) 4.1 6.6 106 Procedure: The sodium-calcium salt of ethylenediamine-tetraacetic acid, tris-(hydroxymethyl)aminomethane, and the contrast media were dissolved in water for injection and adjusted to pH 7.0 by the addition of 1 N
hydrochloric acid. Solutions were QS'd to 100 ml with water for injection, filtered through a 0.22 micron membrane into glass vials, capped, and autoclaved for 20 min at 121°C.

~d Injections solutions containing 5-{N-(2-hydroxyethyl)acetamido}-2,4,6-triiodo-3-{N-(1,3,4-trihydroxy-threo-but-2-yl)}carbamoyl benzamide (11) Iodine Content of Injection Composition of 100 ml Solution in mg/ml Aliquots of Solution 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 for injection to volume (ml) 100 100 100 Osmolality (mOsm/kg) 301 337 370 Viscosity at 37°C
(centipoise) 4.2 6.6 13.1 Procedure: The calcium-disodium salt of ethylenediaminetetraacetic acid, trisodium citrate, and the contrast media were dissolved in water for injection and adjusted to pH 5.0 to 6.0 with sodium carbonate and carbon dioxide. Solutions were QS'd to 100 ml with water for injection, filtered through a 0.22 micron membrane into glass vials, capped and autoclaved for 20 minutes at 121°C.
It is evident from the above results, that novel non-ionic contrast media are provided having substantially superior properties to compounds presently available. Because of the improvement in the physical characteristics, particularly as to osmolality and viscosity, a broad range of body regions may be diagnosed while providing for easy administration and lower pain. Despite the large number of compounds which have been synthesized and tested, the subject compounds are found to be superior to previously disclosed compounds. By providing for three different nitrogens in the molecule, only two of which are substituted, 'the novel properties are achieved. In addition, synthetic routes are provided which are efficient and provide for high yields, while allowing for the use of readily available materials.

Claims (25)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A non-ionic contrast medium compound of formula I:
having at least two hydroxyl groups; and wherein:
R1 is hydrogen, or alkyl or hydroxyalkyl, each of from 1 to 6 carbon atoms;
R2 is hydroxyalkyl of from 2 to 6 carbon atoms having from 1 to n-1 hydroxyl groups, wherein n is the number of carbon atoms;
R3 is alkyl, hydroxyalkyl or alkoxyalkyl, each of from 1 to 6 carbon atoms;
or R3 is a bridge of from 0 to 2 carbon atoms terminating in a group of the formula R4 is hydrogen, or alkyl of from 1 to 6 carbon atoms having from 0 to n-1 hydroxyl groups, wherein n is the number of carbon atoms;

with the proviso that said compound is not S-(-)-3-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodoisophthalamic acid amide.

2. A contrast medium compound of claim 1, wherein R2 is hydroxyalkyl having 1 to 4 hydroxyl groups.

3. A contrast medium compound of claim 2, wherein R2 is hydroxyalkyl having 1 to 3 hydroxyl groups.

4. A contrast medium compound of claim 1, 2 or 3, wherein R3 is hydroxyalkyl or alkoxyalkyl.

5. A contrast medium compound according to claim 1, wherein: R2 is of four carbon atoms and three hydroxyl groups; R3 is alkyl, hydroxyalkyl or alkoxyalkyl, each of from 1 to 6 carbon atoms; and R4 is of from two to three carbon atoms and has at least one hydroxyl group.

6. A contrast medium compound according to claim 1, wherein: R2 is of three carbon atoms and two hydroxyl groups; R3 is alkyl, hydroxyalkyl or alkoxyalkyl; each of from 1 to 6 carbon atoms; and R4 is of three carbon atoms and two hydroxyl groups.

7. A contrast medium compound according to claim 6, wherein R2 and R4 are the same.

8. A contrast medium compound according to claim 1, 2 or 3, wherein R3 is a bridge of from 0 to 2 carbon atoms terminating in a group of the formula

9. A contrast medium according to any one of claims 1 to 8, wherein R1 is hydrogen, or alkyl of 1 to 3 carbon atoms, or hydroxyalkyl of 2 to 6 carbon atoms.

10. A contrast medium compound according to claim 1, wherein R1 is H, C1-3-alkyl or C2-6-hydroxyalkyl; R2 is C2-4-hydroxyalkyl; R3 is C1-3-alkyl, C1-4-hydroxyalkyl or C1-3-alkoxy-C1-3-alkyl; and R4 is H, C1-4-alkyl or C1-4-hydroxyalkyl.

11. A compound of formula I as defined in claim 1, which is malonic acid bis[{3-N-(2,3-dihydroxypropyl-carbamoyl) 5-carbamoyl}-2,4,6-triiodo-N-(2,3-hydroxypropyl)]anilide.

12. A compound of formula I as defined in claim 1, which is malonic acid bis[{3-N-(2,3-dihydroxypropyl-carbamoyl) 5-carbamoyl}-2,4,6-triiodo-N-(2-hydroxyethyl)]anilide.

13. A compound of formula I as defined in claim 1, which is malonic acid bis[{3-N-(1,3,4-trihydroxybut-2-yl-carbamoyl) 5-carbamoyl}-2,4,6-triiodo-N-methyl] anilide.

14. A compound of formula I as defined in claim 1, which is 5-{N-(2-hydroxyethyl) acetamido}-2,4,6-triiodo-3-(N-(1,3,4-trihydroxy-threo-but-2-yl)}carbamoyl benzamide.

15. A compound of formula I as defined in claim 1, which is 5-{N-(2,3-dihydroxypropyl)acetamido)-2,4,6-triiodo-3-{N-(2,3dihrdroxypropyl)}carbamoyl benzamide.

16. A compound of formula I as defined in claim 1, which is 5-{N-(2,3-dihydroxypropyl)acetamido}-2,4,6-triiodo-3-{N-(2-hydroxyethyl)}carbamoyl benzamide.

17. A compound of formula I as defined in claim 1, which is 5-{N-(methyl)-2-hydroxyethylacetamido}-2,4,6-triiodo-3-{N(1,3,4-trihydroxy-threo-but-2-yl)}carbamoyl benzamide.

18. A compound of formula I as defined in claim 1, which is malonic acid-bis-[3-{N-(1,3,4-trihydroxy)-threo-but-2-yl}carbamoyl-5-carbamoyl]-2,4,6-triiodo-N-(methyl)-anilide.

19. A compound of formula I as defined in claim 1, which is 5-{N-(2-hydroxyethyl)hydroxyacetamido)-2,4,6-triiodo-3-{N-(2,3-dihydroxypropyl)}carbomoyl benzamide.

42

21. A compound of formula I as defined in claim 1, which is 3,5-{N,N'-(2,3-dihydroxypropyl)diacetamido}-2,4,6-triiodobenzamide.

22. In a method for taking a non-invasive determination of a physiologic state using irradiation and a non-ionic contrast medium; the improvement which comprises employing a non-ionic contrast medium containing a compound as defined in any one of claims 1 to 21.

23. A radiologic formulation comprising a compound as defined in any one of claims 1 to 21, in a physiologically-acceptable carrier.

24. A process for producing a compound having the general formula I:

wherein R1, R2, R3 and R4 are as defined in one of claims 1 to 21, the process comprising either:
(a) reacting a compound of general formula V

wherein R1 and R2 are as defined in the said one of claims 1 to 21, and wherein hydroxyl groups in R1 and R2 are protected when required, with a compound R3CO-X, wherein R3 is as defined in the said one of claims 1 to 21 and X is a halogen or an ester radical, in a catalyzing solvent;
and, if required, subsequently cleaving protecting groups to produce a compound of formula I, in which R4 is hydrogen, which is as defined in the said one of claims 1 to 21, or converting the reaction product to an intermediate compound of formula I in which R4 is R3CO, and subsequently converting the intermediate compound into a compound of formula I in which R4, as defined in the said one of claims 1 to 21, does not represent hydrogen, the converting being carried out by alkylation under basic conditions with reagents containing R4 as defined above, and subsequently cleaving protecting groups, when required; or (b) reacting a compound of general formula VI
wherein R3 and R4 are as defined in the said one of claims 1 to 21, R5 is hydrogen or is R2 as defined in the said one of claims 1 to 21, R6 is hydrogen or is R2 as defined in the said one of claims 1 to 21, and X is a halogen or an ester radical, with ammonia or with hydroxyalkyl amines containing radicals R1 and R2 as defined above and having hydroxyl groups protected, and subsequently cleaving protecting groups, when required.

25. The process according to claim 24, wherein the catalyzing solvent comprises pyridine, DMA or DMF.