AU617810B2

AU617810B2 - Novel iodinated non-ionic triiodobenzene compounds and contrast media containing them

Info

Publication number: AU617810B2
Application number: AU35235/89A
Authority: AU
Inventors: Didier Doucet; Maryse Dugast-Zrihen; Michel Guillemot; Dominique Meyer; Michel Schaefer
Original assignee: Guerbet SA
Current assignee: Guerbet SA
Priority date: 1988-06-02
Filing date: 1989-05-26
Publication date: 1991-12-05
Anticipated expiration: 2009-05-26
Also published as: KR0148358B1; DE68911237T2; CN1038094A; FI102745B1; HU201732B; EG19008A; FI892681A; JPH07100684B2; KR900000329A; DE68911237D1; YU104289A; DK175034B1; HRP920498A2; FI892681A0; RU1833365C; IL90326A; LV10234A; CN1021440C; ES2060800T3; NO177461B

Abstract

The invention relates to new nonionic compounds of formula <IMAGE> These compounds can be employed as contrast agents.

Description

i- 617810 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION NAME ADDRESS OF APPLICANT: Guerbet S.A.

re des Vanesses Villepinte 93420 France NAME(S) OF INVENTOR(S): Michel SCHAEFER Maryse DUGAST-ZRIHEN Michel GUILLEMOT Didier DOUCET t Dominique MEYER S ADDRESS FOR SERVICE: DAVIES COLLISON Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

SCOMPLETE SPECIFICATION FOR THE INVENTION ENTITLED: i Novel iodinated non-ionic triiodobenzene compounds and contrast media containing them SThe following statement is a full description of this invention, including the best method of Sperforming it known to me/us:- Fla la The present invention relates to compounds which can be used in contrast media for radiography.

Iodobenzene compounds containing several iodine atoms in the benzene nucleus, usually 3 iodine atoms per benzene nucleus, and various other substituents have been used for a long time as contrast medium. These other substituents are pharmacologically acceptable groups which enable the compounds to be administered to man and animals. Generally speaking, these substituents are chosen, on the one hand, in order to confer adequate solubility in water on the compound so that they can be administered in aqueous solution and, on the other, in order to confer on these compounds sufficient tolerance j for them to be tolerated by the human organism.

For this purpose, non-ionic structures have been suggested, i.e. iodobenzene derivatives possessing nonionic substituents.

Thus, in the patent FR-A-2 053 037, carbamoyl iodobenzene compounds containing a total of at least one N-hydroxy alkyl group and at least two hydroxy groups were suggested.

j A compound illustrative of this class is metrizamide which has, however, provided to be of limited stability.

The present invention aims to provided novel nonionic compounds where are well tolerated by the human K organism, exhibit an unexpected and improved stability in aqueous solution, possess a high solubility in water and a low viscosity in solution.

{To this end, the subject of the present invention is compounds of formula: 13 CO-N -R I q co I I /CH2OH

CH

in which CH 2 OH 1 N 0 t 93 l0916,dbspec.014,35235,spc,i v^l* R, is selected from a group of formula: -N CO R in which R5 selected from ClIC4 alkyl, Cl-C4

R

6 is selected from hydrogen, Cl-C 4 alkyl, Cl-C 4 hydroxyalkyl or Cl-C 4 polyhydroxyalkyl, and a group of formula:

R

-CO N -R in which R7is selected from Cl-C 4 hydroxyalkyl or Cl-C 4 po.lyhydroxyalkyl, and

R

8 is selected from hydrogen or C 1

-C

4 alkyl, R~2 is selected from hydrogen, Cl-C 4 hydroxylalkyl or Cl-C 4 polyhydroxyalkyl, Ris selected from hydrogen or CI-C 4 alkyl, and

R

4 is selected from hydrogen, Cl-C 4 alkyl, Cl-C 4 hydroxyalkyl or Cl-C0 4 polyhydroxyalkyl.

20 In the present invention by polyhydroxyalkyl group is meant a linear or branched polyhdyroxyalkyl group.

A preferred compound of the formula I is the compound of formula I in which

RI=-CO-HN-CH

2

-CH

2 OH, R 2

=-CH

2

-CH

2 OH R 3

=H

R

4

CH

2 -C11OH- CH 2

OH.

Moreover, a preferred group of the compounds of formula I is that constituted by the compounds of the symmetrical diamino type, i.e. the compounds of formula: A4V~ 910619,dbdat.066,3S235,res,2

C

r~ 3

R

i CO-N R I I 0

SR

4 -N N-R 4

I

CH OH CH OH CH

CH

CH2OH CH2OH The compounds of formula I can be prepared in a standard manner in S particular by acylation and/or alkylation reactions starting from known compounds.

Thus, the compounds of the symmetrical diamino type (compounds of formula II) can be prepared by a) acylation of a diamino comoound of formula:

R

3 3 CON -R'2 2 IIo 4 NH 2

R

2 representing a R 2 group, the hydroxy groups of which have been protected S"I with an acid chloride of formula RCOC1 IV in which R represents CH2-OH a -CH group, the hydroxy groups of which are protected,

CH

2

-OH

b) alkylation of the compound obtained, if necessary, with an ,w i alkylating reagent of formula: R'4Z V in which R' 4 has the meanings given previously except hydrogen and Z represents a labile group such as an atom of chlorine, bromine or iodine, in the presence of a base such as sodium methylate, sodium ethylate, sodium hydride or sodium hydroxide, c) deprotection Compounds of formula III are described in the French patent application FR-A-2 614 299.

The other compounds of formula III can be prepared in an analogous manner starting in particular from an alkyl 3,5-dinitrobenzoate of formula:

COOR'

15 15

VI

1 0 N NO *4 a* 2 2 in which R' is a C -C 4 alkyl group such as methyl.

Asymmetric diamino compounds can also be prepared starting from a compound of formula VI by: a) reaction with an amine of formula: NH-R VII

R

3 so as to produce a compound of formulat 4 4 CON -R 2 0 VIII O N O2N NO2 b) reduction by means of ammonium sulfide so as to give rise to a compound of formula: R 3 CON -R 2 N 0 2 c) acylation of the compound of formula IX by an acid chloride of formula RCOCI (IV) so as to give rise to a compound of formula: R 3 CON R-CO-Hd NO 2 d) reduction and iodination of the compound of formul~a X so as to give rise to a compound of formula:

R

CO-

-R

1 1 2 e) alkylation, if required, of the compound of formula XI with an alkylating reagent of formula V so as to give rise to a compound of foz'iulal 6 R3 CO-N -R 2 RI-N

NH

4! 2 COR I f) deprotection of the compound of formula XII g) acylation of the deprotected compound obtained with an acid chloride of formula: CI,-CO-RI XIII RI representing a group R 5 the hydroxy groups of which are protected, 5 5 so as to give rise af ter deprotecqtion to a cornpourid of formula

R

g3 CO-H -R2 0 XIV RN

CO

CHI OH 2 the steps f and g may be carried out in the reverse order, and if necessary h) alkylation to give rise to a compound of formula I in whichR has thz meanings indicated except hydrogen.

Symmetrical compounds of the isophthalic type (compounds of formula I in which R -CO-N-R I2 7 can be prepared by a) acylation of an amine of formula: coc I H2 P coc 3 with an acid chloride of formula RCOCI (IV) so as to give riea to a compound of formula; coc I

II

0

XVI

R -CO-iN* COCI b) reaction of the compound of formula XVI with an amine of formula H-N-R (VII) so ns to give rise to a compound of forrnulat 1 2 hR 3 R 3 CO-N R 2 IO I R2 x VI I 3 then, if desired, either o) al',ylation of the compound of formula XVII vith an alkyilating 8 reagent of formula R' Z such as that specified previously and finally Sremoval of the protecting groups from the -CH(CHH) group, or e) removal of the protecting groups from the -CH(CH2OH) 2 group and, e) removal of the protecting groups from the -CH(CH 2

OH)

2 group and, c if desired, f) alkylation of the deprotected compound with an alkylating reagent R' Z.

i The asymmetric compounds of the isophthalic type (compounds of .S formula I in which RI -CO-N-R 7 with R R 2 and/or R8€ R 3 can be 1 7 2 8 prepared by a) acylation of an amine of formula

R

CO-N -R 2

XVIII

O RR7 H N [01 2 CON-R

I

with an acid chloride of formula RCOC1, b) alkylation, if desired, with an ,siKylating reagent of formula R' Z and 4 c) removal of the protecting groups from the -CH-(CH 2

OH)

2 group.

The compound of formula XVIII may be obtained as described in IP-O 015 867.

As an alternative, the asymmetric compounds of the isophthalic type can be prepared by a) acylation of an amine of formula! j coz H N CO-R'

XIX

0

R

8 in which R'represents a Rgroup in which the hydroxy groups are protected, with an acid chloride of formula FcCCI (IV) so as to give rise to a compound of formula: CodI

II

0 xx HN CO-N R

C

b) reaction of the compound of foxrmula XX with an amine of formula: HN -R 2

(VII)

R

3 so as to give to a compound of formula;

IR

R

3

CO-N-R~

0 xxI UN CO-N-R'

COR

R

then# if desired, either c) alkylation of the compound of formula XXI with an alkylating reagent of formula R' 4 Z such as that previously specified and finally d) removal of the protecting groups from the -CH-(011 2 0OH) 2 group, or e) removal of the protecting groups from the -CH-(CH 2 OH) 2 group, and, if desired, f) alky'lation of :!~deprotected compound With an alkylating reagent R' 4

Z'

Another subject of the present invention is contrast caiuIM, which contain at least one compound of formula I.

VThese contrast medi a are used in man and animals for radiological purposes.

The preferred pharmaceutical form of the contrast materials according to the invention consists of aqueous solutions of the compounds.

The aqueous solutions usually contain a total of from 5 to 100 g of compounds of formula I per 100 ml and the volume of such solution to be injected usually varies from I to 1000 ml.

The aqueous solution of the compounds of formula I may also contain certain additives such as: sodium chloride at concentrations included between 0.,1 and 10 mfl/l disodium EDTA at concentrations included between 0. 1 and 2 mM sodium citrate at concentrations included between 0. 1 and 10 mM A~ heparin at doses included between 10 and 100 Units per 100 ml of solution.

These compounds may be administered by all routes conventionally used for iodinated non-ionic contrast medium Thus, they may be administered by the enteral route or the parenteral route (intravenous route, intra-arterial route, opacification of the civities) and in particular into the subaraohnoid space.

An example of the composition according to the present invention will be given below.

Composition 245 Composition of example 1 65 g Water for injectable preparation QS too ml.

The following examples illustrate the preparation of the compounds of formula 1.

EXAMPLE I Preparation of 5--f3-hydroxty-2-(hydroxymethyl,)--N-(2.3-.

dihydroxypropyl)propionanidoJ-N'.,NH 'bis-(C2-hydroxyethyl)-2 4.6,-triiodoisonhthalamide, a) Ugmoaration of 5-(2-isoprop4l1,3-dioxane-5-carboxamido1-2.4.6-, triiodo-isophtheloyl dichloride, 137 g of 5-amtno-2,4,6-trtiodoisiophthaloyI chloride (0.23 mole) are iiiT -ii h dissolved in 460 ml of DMAC to which are adcad 110 g (0.57 mole) of 2isopropyl-1,3-dioxane-5-carboxylic acid chloride. The reaction mixture is stirred under argon at ambient temperature for 4 days. The DMAC is removed in a vacuum. The oil obtained is extracted with 3 1 of ethyl acetate and washed twice with 1 1 of ice-cold water, The organic phase is dried and concentrated to dryness. The product is crystallized from 200 mi of CH Cl2 After filtration, 110 g of solid are obtained: 2 2' Yield: 64.

STLC: Si02 CH2 2 Rf Q,13 2 22 (60 F 254) Si0 ether/petroleum ether 50/50 Rf 0.52 b) Preparation of 5-E2-isopropyl-1,3-dioxane-5-carboxamiol-N',Nbis-(2-hydroxyethyl)-2,4,6-triiodo-isphthalamide, 130 g of the product obtained in a (0.173 mole) are dissolved in a solution of 750 mi of DMAC and 75 mi (0,534 mole) of triethylamine.

33,7 g of ethanolamine (0.552 mole) are added dropwise to the reaction mixture. The reaction mixture is then stirred for 3 hours at ambient temperature. The triethylamine hydrochloride is removed by filtration and the DMAC is removed in a vacuum The oil obtained is crystallized from I liter of water, The product is filtered off and dried in a vacuum Yield 1 TLC SO2 Rf 0.25 CH2 Cl 2/methanol 9/1 (60F254) SiO Rf 1 0.67 CH2 2C /methanol 8/2 V. I -45,6 (found) 47,6 (theory) Hypersil 0C8 Sp 15 m HPLC purity 97% 0,01 NaH2P0 L 2 4 Methanol 4 c) Preparation of 5-(3-hydroxy-2-hydroRymethyl-N-(2,3dihydroxypropyl)propionamidol N-bis- (2-hydroxyethyl) 4,6-triiodoisophthalamide To a suspension of 100 g of the product obtained in 1 (0,125 mole) in 350 mil of ethylene glycol are added dropwiee 125 ml (0,5 mole) of 4 N methylate at 60*C folloed by 65 g (04625 mcole) of i-choro-2i3propanediol, After I hour at 600C the mass of the reaction mixture has increased. 100 mi (0.4 mole) of 4 N methylate and 55,2 g (0,5 mole) of 12 i-chloro-2,3-propanediol are added. The mixture is maintained overnight at 600C. A further addition of 31 ml 125 mole) of 4 N methylate and 20.7 g of i-chloro-2,3-propanediol is made. Stirring is maintained for 4 hours at 604C, The mineral salts arp removed by filtration. The ethylene glycol is evaporated in a vacuum.

The distillation residue is taken up in 800 ml of 10 N HCi and the solution i6 stirred overnight at ambient temperature. The reaction mixture is co-ncentrated dryness and the residue is taken up in 300 ml of ethanol. The mineral salts are removed by filtration. The ethanol is evaporated in a vacuum and the residue is crystal lit. I from I liter of isopropyl alcohol. The precipitate is filtered off and purified by HPLC (RP 18) (elution with water), Total yield (alkylation-deprotection-purification) :52% 1) TLC (silica 60F254) ICH 2

CI

2 /methanol 7/3 Rf :0.4 2) HPLC Hypersil C8 5p 15 cm Buffer 0.01 M1 NaH 2 PO 4 .97 methanol 3 Purity t97% 3) I :45.8 (found) 46.4 (theory) 4) NflR (DIIO) Poorly resolved multiplet centered at 3.5 ppm (i8H); multiplet centered at 4.5 ppm (OH) exchangeable with D 20 (6 H)e4 broad peak at, 8.4 ppm (NH) exchangeable with D 2 0 (2 H).

EXAMIPLE 2 Pyreparation of 5-qlycolamido-3-C3-hYdroxy-2hydroxymethyl-N-(2.3-dihydroxypropyl)propionamido2-2, 4,6-triiodo-Nhydroxyethyl benzamide a) Preparation of 3,5-dinitro-N-(2-hydroxyethyl)benzamidL 750 g (3.32 moles) of methyl 3,5-dInitro benzoate are suspended in, 2 liters of methanol in the presence of 222.7 g (3.65 moles) of ethai&"iamine, The reaction mixture is refluxed for 48 hours until the eater has disappeared. After 4 hours at room temperature, the crystalline product is filtered off, washed with 500 cm 3of methylene chloride, then dried in an oven at GOOC in a vacuum lov' 4 hours. This procedure leads to the recovery of 718 g of product in a yield of elting point: 140,,C.

TLC (toluene/methyl ethyl ketone/formic acid (60/25/25) Rf b Preparation of 3-nitro 5-amino-N- (2-hydroxyethyl )benzamide.

To a suspension of 25.5 g (0.5 mole) of 3,5-dinitro-N-(2-hydroxy ethyl)benzamide in 135 cm 3of water are added at 700C 12.25 g (0.18 mole) of ammonium sulfide, At the end of the addition the mixture is homogenous but rc-precipitation occurs after 1/2 hour at 700 C. The reaction mixture is allowed to cool to anibient temperature and stirring is continued for 2 hours. The precipitate is filtered off, washed with methanol (70 cm 3 then dried in an oven (600 C).

Mass obtained 5 il g yield 67%.

TLC (toluene/methyl ethyl ketone/formic acid 60/25/25). Rf :0.3 H NMR (DM60) t3.4 ppm (multiplet; 4H,QH aliphatics); 4.65 ppm (multiplet, H exchangeable with D 0, NH 5.9 ppm (singlet, H exchangeable with D 2 0, ORj); 7.4 7.7 ppm (2 multiplets; 3H, aromatic-, protons); 8.6 ppm (multiplet, IH, NIAD.

c) Preparation of 3-nitro-5-[2-isopropyl-l. carboxamJdo)-N-hydroxyethyl benzamide g (0.177 mole) of 3- nitro- 5 -amino- N hydroxyethyl) benzami de are dissolved in 400 cm 3of DMAC, The addition of 74.9 g (0,389, mole) of 2-isopropyl-1,3-dioxane-5-carboxylic acid chloride in the presence of triethylamine (54.6 cm 3) gives rise to an exothermic reaction, The reaction mixture is maintained under argon for 18 hours at ambient temperature. The mixture is filtered and the filtrate is diluted with water and extracted with ethyl acetate. The residlue obtained ter evaporation of the solvent is treated with potassium carbonate (12 g) in 300 cm 3of methanol. After being stirred at ambient temperature for 48 hours, the mixture is concentrated, then extracted with ethyl acetate. The crude product obtained after treatment is recrystallized from a mixture of ether/ethyl acetate 80/20.

37.8 g of product are isolated in a yield of 56%.

TLC (ethyl acetate Rf 0.48).

HPLC Hypersil C8 5p 15 cm.

Buffer: 0.01 M1 NaH 2 PO 4 MeOH Purity: 94%.

33 d) Preparation of S -amino E2- isooropyl -1.3-dioxane-5carboxamldoJ 4.6-triiodo-N-hvdroxyethyl-benzamide.

14 A methanolic solution (1.4 1) of 40 g of 3-nitro-5-(2-isopropylbenzamide is stirred under an 5 atmosphere of hydrogen (5.10 Pa) for 5 hours at 5OOC in the presence of 4 g of pailadized charcoal. The catalyst is then filtered off and the filtrate is evaporated undev' reduced pressure. The resulting compound is suspended in 950 cm 3of water. The mixture is made homogenous by the addition of 20 cm 3 of 2 N hydrochloric acid. 63 cm 3 of iodine chloride in iodine) are then added dropwise with vigorous stirring. After 24 hours at ambient temperature, the precipitate is filtered off, washed with water, taken up in, ether, After drying, 32 g of product are obtained in a yield of 42%.

TLC (dichloromethane/methanol 90/1,Q) Rf :0.8.

e) Preparation of 5-amino-3-CN-(2, 3-dihydroxypropyl)-2-isopropyl- 1, 3-dioxane-5-carboxamidoJ 6-triiodo-N-hydroxyethyl benzamide, To a solution of the compound obtained in d) (20g, 0.027 mole) in a mixture of ethylene glycol-dimethylformanide v/v (160 ml) are added dropwise 84 cm 3(0.337 mole) of 4N sodium methy'latLe. The mixturc is 3 heated at 60CC for 1/2 hour and 36,1 cm (0.432 mole) of l-chlos~o-2,3propanediol are added at this temperature. The reaction mixture is maintained at 60CC under nitrogen for 60 hours. The mineral salts are removed by filtz-ation. The ethylene glycol and the DI'IP are evaporated in a varnuum. The crude product obtained is purified on siln~iized silica (elution with water, followed by water/methanol 50/50). M65 g of produot are isolated. Yield 76%.

TLC (dichloromethane/methanol 80/20), Rf 0.8.

f) Preparation of 5-amino 3-(3-hydroxy-2(hydroxymethyl)-N-(2,3dohydroxypropyl)propionamidoJ-2. 4,6-triiodo-.N-hydroxyethyl benzamide.

16g (0.02 mole) of the product obtained in e0 are deprotected in the presence of 80 cm 3of 10 N hydrochlor:Ic acid for 48 hours at ambient temperature. After neutralization and evaporation under reduced pressure, the residue is precipitated with a mixture of methanol-ether f,4ltered off then purified by IJPLC (RP 18) (elution with water then with water/methanol 90/10).

4g of product are isolated it! an overall yield (deprotection, purification) of TLC (dichloromethane/methanol 80/20). Rf :0.25.

HPLC Hypersil C8 5p 15 cm.

Buffer: 0.01 M NaH PO 2 4 MeOH Purity: 97%.

g Preparation of 5-N-qlycolamido-3-13-hydrc,,xy-2(hydroxymethyl)-N- (2,3-dihydroxypropyl)propionamidol-2.4,6-triiodo-N-hydroxyethyl benzamide.

g of 0-acetylated glycolic acid chloride (0.04 mole) are added dropvise at ambient temperature to a solution of 3 g of the compound obtained in step f (0.004 mole) in 30 cm of anhydrous DMAC. The reaction mixture is heated at 406C for 12 hours, then poured into 250 cm 3 of ice-cold water. The precipitate obtained is filtered off then extracted with ethyl acetate. After treatment followed by evaporation, the 3 product obtained dissolved in 50 cm of methanol is deprotected in the 3 presence of 10 cm of I N sodium hydroxide. The solution is stirred at ambient temperature for 14 hours, then desalted by successive passages through H (IRN77) and OH (1RN78) resins4 After evaporation to dryness, the residue is taken up in ethyl ether, filtered then dried.

Mass obtained: 1.5 g. Overall yield: 47%, Purity in iodine: 99%.

TLC (ethyl acetate/methanol/ammonia 60/40/1V.

Rf 0.25.

HPLC Hypersil 08 53 15 cm.

Buffer: 0,01 M NaH2PO 2 4 NS Me OH Purity 89% EXAMPLE 3 Preparation of 3,5-bis-(3-hydroxy-2-hydroxymethylpropionamido)-2, 4, 6-triiodo-N-(2, 3-dihvdroxypropyl)benzamide a) Preparation of 3 5-diamino-2,4.6-triiodo-N-(2,3diacetoxypropyl)benzamide 301.5 g (0.5 mole) of 3,5-diamino-2,3,6-triiodo-N-(2,3dihydroxypropyl)benzamide are suspended in 1 I of anhydrous pyridine cooled to 15aC. After the addition of 2450 mi of ncetic anhydride, the solution is stirred for 18 h at ambient temperature, then poured into acidulated water. After extraction with ethyl acotate, drying of the organic phase and evaporation, 270 g of product *re obtained in a yield 16 'ii of 78.5%.

Purity in iodine 98.3%.

TLC toluene/methylethylketone/HCOOH 60/25/35. Rf: 0.70.

b) Preparation of 3,5-bis(2-isopropyl-1,3-dioxane-5carboxamido)2,4,6-triiodo-N-(2,3-diacetoxypropyl) benzamide 114.5 g (0.166 mole) of the compound obtained in a) are dissolved in 350 ml of anhydrous DMAC. The addition of 128 g (0.66 mole) of 2isopropyl-1,3-dioxane-5-carboxylic acid chloride is carried out at 0'C.

After being stirred overnqht the reaction mass is poured into a mixture of ice-water. The precipitate is filtered off, washed with water then dried in a vacuum at 500C.

c) Preparation of 3,5-bis(2-isopropyl-1,3-dioxane-5-carboxamido)- 2,4,6-triiodo-N(2,3-dihydroyprop pyl) benzamide 175 g of the compound obtained in b) suspended in 2,5 1 of methanol are stirred at ambient temperature in the presence of 45 g of potassium carbonate overnight. After evaporation of the reaction mixture, the product crystallizes from water. After filtration and drying, the crystals obtained in 85% yield are used directly in the next step, d) Preparation of 3,5-bis(3-hydroxy-2-hydroxymethyl propionamido)- 2,4,6-triiodo-N-(2,3 -dihydroxypropyl)benzamide.

The compound obtained in c) is dissolved in 2 1 of 5 N HCI1 at After being stirred for 18 h, the suspension obtained is filtered. The filtrate is concentrated in a vacuum and the residue is taken up in isopropanol.

108 g of crystalline product are obtained in 2 crops in a yield cof 94%, TLC SIO2 Butanol 60, water 25, CH 3 C0OOH 11 Rf 0,2, The product is purified by preparative HPLC on SiO 2 RP8 15,25 u with water as eluant in a yield of 47%.

Purity in iodine: 99.6%.

HPLC purity: 99.1% (Hypersil C8 5p 15 cm 0.01 M NaH2PO 95, MeOH H NMR 200 MHz (DMSQ) ppm (m,H exchangeable with D 2 0, 0-CONH) 9.9 ppm (t,2H exchangeable with 020, 0-N -C0) 4.6 ppm (m,6H exchangeable, OH) 3-4 ppm 13H, CH) 2.7 ppm 2H, NH-CH -2 EXAMIPLE 4 Preparation. of 5-(3-hydroxy-2-(hydr-oxymethyl)-N-(2hydroxyethyl)pro-oionam~ido-N-(2-hydroxyethyl)-N'-(2. 3-dihydroxypropyl)-_ 2, 4, 6-triiodo-isophtiAlamide.

a Preparatioan of 5-(2-isopropyl-l. 3-dioxane-5-carboxamido)-2, 4,6triiodo-3-N'-(2-acetoxyethyl) carbamoyl-benzoyl chloride.

5.36 g of 2-isopropyl-i,3-dioxane-5-carbox.lic acid (0,0308 mole) are dissolved in 18 ml of DMAC. The reaction mixture is cooled to 5o C and 2.55 -ml (0,.0350 mole) of SOCI are added dropwise such that the 2 temperature remains below l5aC. When the addition is complete, the reaction mixture is left for 3 hours at ambient temperature.

Then 6.0 g (0.00906 mole) of 5-amino-2,4,6-triiodo-3-(N-2acetoxyethyl) carbamoyl-benzoyl chloride are added. The reaction mixture is maintained under argon for 4 days at ambient temperature.

The DM'AC is removed in a vacuum. The oil obtairied is taken up in ethyl acetate; the organic phase is washed wiu'i water, dried and concentrated to dryness. The product is crystallized from 100 ml of ether.

After being filtered off and dried, 1, 8 g of product are obtained in a yield of 24Y/.

TLC (silica GOF 254): ethyl acetate/petroleum ether 80/20 Rf Q.83.

b) Preparation of 5-.(2-.isopropyl-l. 3-dioxane-5-caroxamido) -2,4,6triiodo-N-(2-acetoxyethyl)-N'-(2, 3-dihydroxypropyl)isophthalamide I g (0,00122 mole) of the product obtained in g. is dissolved tn 100 ml of DIIAC, then 0.26 ml of triethylamine (0.00189 mole) are added.

0.18 g (0.00196 mole) of 3-amino-,2-propanediol are added dropwise to the reaction mixture. After the addition is complete, the reaction mixture is stirred under argon at ambient temperature for 24 hours.

The triethylamine hydrochloride is fil~tered off, then the DMAC is evaporated. The oil thus obtained is crystallized from 20 ml of ether.

After being filtered off nd dried, 0.8 g of product are obtained in a yield of 75.5%.

TLC (silica 60F254) CHCI 3 eOH NH H 53 30 Rf =0.77.

c) Preparation of 5-C3-hydroxy-2-(hydroxymethyl)-ki-(2-, hydroxyethyl)propionamido)-li-(2-hydroxyethyl)-N'-(2. 3-dihydroxypropyl)- 2, 4, 6-triiodoisophthalamide 18 0.4 g (0.000458 mole) of the product obtained in b are dissolved in 0.7 ml of ethylene glycol and 0.69 ml (0.00275 mole) of a 4 N solution of sodium methylate. To this solution is added 0.18 ml (0.00275 mole) of chloroethanol. The reaction mixture is heated at for 5 hours. 0.34 ml of 4 N sodium methylate and 0.1 ml of chlorethanol are addedi.

The mixture is maintained at 40 0 C overni±ght.

The pH of the reaction mixture i~s brought to 7.00 by the addition of dilute hydrochloric acid.

A The ethylene glycol is evaporated in a vacuum.

The residue after distillation is taken up to 6 ml of water and 5 ml of concentrated hydrochloric acid, then stirred overnight at ambient temperature.

4 15 by The reaction mixture is concentrated then purified bpreparative HPLC (RP 18, elution with water). After evaporation and drying, 0,1 g of product is obtained in ;~2an overall yield (alkylation purification) of 27%.

TLC (silica 60F254) CH 2 Cl 2 /methanol/7/3/ -Rf 0.33.

HPLC column of Hypersi]. C8 5p 25 cm Buffer: 0.01l M NaH 2

PO

4 MeOH 95/5 Purity IH NMR (Bruker 200 MHz) in DMSO :inconformity with the expected structure.

EXAMPLE 5 Preparation of 5-r3-hydroxy-2- (hvdroxvmethvl )-propionamidol N"-dimethyl-NI. N"-bis- -di-.hydroxvpropyl 6-triiodoisophtalamide a) Preparation of [2-isopropYl-l carboxamidol-N' .N"-dimethyl-N' ,N"-bis-(2,_3 dihydroxypropyl 6-triiodoisophtalamide 74 g (98 mmoles) of 5-[2-iospropyl-l,3-dioxanne-5carboxamido] 6-triiodoisophtaloyl dichloride are suspended in 300 ml of iospropanol containing 41 ml (294 mmoles) of triethyilamine. 31 g (295 mmoles) of N-methylaminopropane-.2,3-diol are added dropwise. Stirring is maintained 12 h at room temperature. Triethylamine 91916,dbspe.0 14, 5 335.speC, 18 -18ahydrocililoride is removed by filtration.

The filtrate is evaporated to dryness, taken up in water and eluted on resin OH IRA 67.

After evaporation, the product is purified on silanized silica (JKieselgel 60 Merck) with water as eluent.

After evaporation to dryness, 60 g of white powder is obtained with a yield of 68.5%.

Purity in iodine 96.4% Purity HPLC :97% Hypersil CB 25 cm NaH 2

PO

4 0.01 Mv Methanol TLC SiO 2 Rf 0.12 0.25 150.30 0.36 Eluent CHC1 3 55, MeOH 30, NH 3 H2O NMR (DMSO) 1 H 200 MHz 0.9 ppm CH- 3 2.8. ppm N-CH 3 3 ppm (s)

N-CH

3 3.3 ppm (in) N-CH 2 and CH 3.5-3.9 pjpi (broad signal CH 2 et CH 4.3 ppm CH 4.6 ppm OH 4.7 ppm OH 10.2 ppm (broadened signal) HN (1H).

b) Prernaration of 5-r3-hydroxy-2-hydroxymethyl)propionamidol-N'.,N"-dimethvl-N' dihydroxypropyl .4.6-triiodoisophtalamide g (50.6 inmole) of the compound disclosed in a) are dissolved in 101 ml (10 eq) of hydrochloric acid 5 N.

Stirring is maintained 12 h at room temperature. The solution is filtered and evaporated to dryness. The resulting product is taken up in 100 ml of ethyl ether and then filtered and eluted on silanized silica (Kieselgel 60 Merck) with water. After evaporation to dryness, 38 g of white powder is obtained.

Yield Purity in iodine -98.3% Purity HPLC 98% Hypersil C8 25 cm 5 u NaH 2

PO

4 0.01 M f:~910916,dbspc.014,35235speL 1 19 181 MeOH TLC SiG 2 Rf 0.56 0.63 0.67 Eluent CHC1 3 55, MeOH 30, NH 3

H

2 0 NMR (DMSO) 1H 200 MHz 2,7 ppm (broad signal) CH 2.85 ppm (broadened singlet) N-CH 3 3.08 ppm'(badly resolved doublet) N-

CH

3 3.10-3.35 ppm (in) N-CH 2 3.45 ppm CH 2 (4H); 3.6-4 ppm (broad signal) OH 9.9 ppm (broad signal) NH (1H).

COMPARATIVE EXAMPLE The following compounds have been compared.

The compounds used for 'the comparison are of general

R

formula: 4 N R 3 Co CON R 1 3 The compared, compounds are the following;l Compound RR2R 3

R

-CH-

2

-CH

2 0H -CH 2 f- -CH 2

-CHOH-CH

2 0H B -CH 2

CHOH-CH

2 OH -CH-CH 2 OH -CR 2

-CH

2 OH -H

OH

CH

2 0H Compound -CH 2

CH-OH-CH

2 OH -C -CH 2

-CH

2 OH of Ex. 1

CH

2 0H Compound H-CH -CH 2

-CH-CI

2 OH -CH- 3 Of EX. 5 CH001iv1~~ i 3 18c Compound A is loversol, a prior art compound disclosed in US-4 396 598.

Compound B is disclosed in EP-0 345 163 filed by the Applicant.

Compound B is a closer compound, especially with respect to compound Example 1 than the prior art compound loversol.

The stabilities of the compounds have been compared by measuring the percentage of degradation on a HPLC apparatus after 3 months in an aqueous solution buffered at pH 9, respectively at 25 0 C and 50 0

C.

The following results have been obtained: Compound of degradation measured by HPLC t after 3 months in an aqueous solution buffered at pH9 Values at 0 C 50°C t 0 I A 3 21 <0,1 B 40 100 <0,1 Ex. 1 1,4 3,2 <0,1 Ex. 5 <0,1 1,5 <0,1 SThese results show that the compound of Example 1

CH

2 0H bearing a radical of the formula -CH

CH

2

OH

has an unexpected and improved stability than the compound of prior art bearing a -CH20H radical; and a more improved stability than the closest compound bearing a radical of formula -CHOH-CH 2 0H.

This improved activity is also exhibited by the S910916,dbspec.0135235.spec21 18Sd compound of Example Thus, the introduction of a group of the formula

CH

2 0H -CH C2H in the acylamide group results in the compounds of the invention having an unexpected and improved stability over the prior art compounds.

S

I

.55555 S U

'U

'555 I S I S I

'I

555* S A

U

SI S S S I I .5

I

9 10 16dbscc.0 14,3523S&spodj2Z

Claims

1. A compound of the formula: R 13 CO-N -R 2 0 R 4 -N I Co I CH 2 OH CC2D ~CH O01 in which R 1 io selected from a group of formula: N c-CO -R in which R5 selected from C 1 -0 4 alkyl, CI-C 4 hydroxyalkyl or Q,-C 4 polyhydroxyalkyl, and RG is selecteO ',Om hydrogen, C 1 -C 4 alkyl,, C-C 4 hydroxyalkyl o polyhydroxyalkyl, and a group of formuida; CO N in which R7 is selected from C 1 -C 4 hydoxyalkyl or C -C 4 polyhydroxyalkyl, and R 8 is selected from hydrogen or C'-C 4 alkyl, R 2 is selected from hydrogen, C 1 -C 4 hydroxylalkyl or C 1 C 4 polyhydroyalkyl i R 3 is selected from hydrogen and C 1 -C 4 alkyl, and R 4 is selected from hydrogen, C 1 -C 4 alkyi, C 1 -C 4 hydroxyalkyl and C 1 -C 4 polyhydroxyalkyl.

2. A compound according to Claim 1, having the, formua:. 9 IO4 9,bML O66bS25e ,rc d :0-N -R 2 R4- N N-R 4 C C 1,CH 2OH ICoC OH CH 1 2 H 1, ~CH 2 OH 1CH2O in which R 2 R~3 and R 4 have the meanings given in Claim 1.

3, A compound according to Claim 1 which is hydroxy-2- (hydroxymethy.) (2,3- dihydroxypropyl)propionamido] hydroxyethyl 4, 6-triiodoisophthalamide,

4. A compound according to Claim 1 which is gJlyco2amido-3- [3-hydroxy-2- (hydroxymethy.) 3- dihyd,*'oQypr'opyl )propionamidoi 6-tr-iiodo-N- hydroxyethy. benzamide.

A compound according to Claim 1 which is 3,5-bis-(3- hydroxy-2-hydroxymethyl.-pzopionamido-2,4, 6-triiodo-N- (2,3-dihydiroxypiropyl)benzami de.

6, A compound according to Claim 1 which is 5-[3- hycroxy-2- Chydroxymethyl (2-hydz'oxyethyl) propionamidol-N- (2-hydroxyethyl)N' dihydroxypropyl) 6-tri iodo-isophthalamide.

7. A contrast medium comprising an ef footive amount of a compound accordirq to any one of the Claims I. to 6, together with the pharmaceutically acceptable carrier'.

8. A contrast meoium according to Claim 7, comprising an aqueous solution of the compound(s). ~1O6,clbd4t.O~S23$t~,2O 2 1 21

9. Compounds of formula 1, methods for their manufac-,ure or contrast media containing them substantially as hereinbefore described with reference to the Examples (exccluding Example 5 and the Comparative Example). DATED this 16th day of September, 1991 Guerbet .A. By Its Patent Attorneys DAVIES COLT 4 ISON M49" 910916,dbspec,014,35235.sped,21 L