FR2649698A1 - New nonionic polyiodinated derivatives having an arylsulphonamide structure and contrast agent containing them - Google Patents

Abstract

The subject of the invention is compounds of formula I in which R1 represents an group and R2 and R3, which are identical or different, are chosen from the groups These compounds can be used as contrast agents.

Description

 The present invention relates to compounds useful in contrast media for radiography.

 Iodobenzene compounds having a plurality of iodine atoms on the benzene ring have long been used as contrast agents. in general 3 iodine atoms per benzene ring, and various other substituents. These other substituents are pharmacologically acceptable groups that allow the administration of the compounds in humans and animals. These substituents are generally chosen on the one hand to give the compounds sufficient water solubility for the administration of these compounds in aqueous solution and, on the other hand, to give these compounds sufficient tolerance by the human body.

 For this purpose, non-ionic structures have been proposed. iodobenzene derivatives having non-ionic substituents.

 So. in FR-A-2 053 037 carbamoyl iodobenzene compounds containing at least one N-hydroxyalkyl group and at least two hydroxy groups have been proposed.

 A compound illustrating this class is metrizamide, which is, however, of limited stability.

 The present invention aims to provide new nonionic compounds that are well tolerated by the human body, very stable in aqueous solution. which have a high solubility in water and which in aqueous solution have a low viscosity.

dans laquelle R1 représente un groupe

dans lequel R4 et R5 identiques ou différents sont choisis parmi un atome d'hydrogène, un groupe alkyle en C1-Cs, hydroxyalkyle en C1-C6 et polyhydroxy alkyle en C1-C6 :R2 et R3 identiques ou différents sont choisis parmi- les groupes

- N - COR8 et - SO2
R9

dans lesquels
Rs, R 7' R6, R9, R10 et R11 identiques ou différents sont choisis parmi un atome d'hydrogène, un groupe alkyle en C1-C6, hydroxy-alkyle en C1-C6, polyhydroxy-alkyle en C1-C6, alkoxy(C1-C5)-alkyle en C1-C6 et hydroxy-alkoxy (C1-C5)-alkyle en C1 -C6; sous réserve que les composés de formule I contiennent au moins deux groupes hydroxy dans leur molécule.For this purpose, the subject of the present invention is compounds of formula I

in which R1 represents a group

in which R4 and R5, which are identical or different, are chosen from a hydrogen atom, a C1-C6 alkyl group, a C1-C6 hydroxyalkyl group and a polyhydroxy C1-C6 alkyl group: R2 and R3, which may be identical or different, are chosen from the groups

- N - COR8 and - SO2
R9

wherein
Rs, R 7 'R 6, R 9, R 10 and R 11, which are identical or different, are chosen from a hydrogen atom, a C 1 -C 6 alkyl group, a hydroxy C 1 -C 6 alkyl group, a polyhydroxy C 1 -C 6 alkyl group and an alkoxy group ( C1-C5) -C1-C6alkyl and -C1-C6alkoxy (C1-C5) -alkyl; provided that the compounds of formula I contain at least two hydroxy groups in their molecule.

 The alkyl, hydroxyalkyl or polyhydroxyalkyl groups may have a linear, branched or cyclic structure.

 The compounds of formula I according to the invention comprise all the isomeric forms due either to the absence of rotation of the bonds due to the steric encumbrance provided by the iodine atoms, or to the presence of asymmetric carbon atoms on the the side chains. present in racemic form, or in an optically active R or S configuration.

Preferred groups for R 1 are - NH 2, - NHCH 3, - NHCH 2 CH 2 OH

-CHOHCH2OH2-CH2OCH3 et-CHOH-CH3 et les groupes préférés pour R g sont
H,-CH3, -CH2CH2OH, -CH2CHOHCH2OH, - CH2CHOHCH2OCH3

Preferred groups for R8 are -CH3, -CH2OH

-CHOHCH2OH2-CH2OCH3 and -CHOH-CH3 and the preferred groups for R g are
H, -CH3, -CH2CH2OH, -CH2CHOHCH2OH, -CH2CHOHCH2OCH3

The groups of compounds are especially those in which
I - R1 is as defined previously and
R2 and R3 are identical and represent a group of formula

R6 and R7 being as defined above.

et R 3 représente le groupe

- - R1 is as defined above.
R2 represents the group

and R 3 represents the group

R8, Rg. R10 and R11 being as defined above.

R 6 et R7 étant tels que définis précédemment.III - R1 is as defined previously and
R2 and R3 are identical and represent the group

R 6 and R 7 being as defined above.

et R3 représente le groupe

IV - R1 is as defined previously, R2 represents the group

and R3 represents the group

R6, R7, R8 and R9 being as defined above.

 V - R1 is as defined above.

et
R3 représente le groupe

R2 represents the group

and
R3 represents the group

R6, R7, R10 and R11 being as previously defined.

VI - R1 is as defined previously and
R2 and R3 are identical and represent the group -N-COR8, R8 and R9 being as defined above.

R9
The compound of formula I in which R 1 represents the group -NH-CH 2 -CHOH-CH 2 OH is particularly preferred and R 2 and R 3 are identical and represent the group -CO-NH-CH 2 -CHOH-CH 2 OH (triiodo-2,4, 6, N- (2,3-dihydroxypropyl) sulfonamoyl-5-bis-N ', N "- (2,3-dihydroxypropyl) -1,3 isophthalamide).

Other compounds according to the invention are in particular the compounds of formula I in which - R 1 represents the group -NH-CH 2 -CH 2 OH and R 2 and R 3
are identical and represent the group -CO-NH-
CH2-CHOH-CH2OH (2,4,6-triiodo-N- (2-hydroxyethyl)
sulfonamoyl-6 bis-N, N "- (2'-dihydroxy, 3'-propyl)
-1,3 isophthalamide) - R 1 represents the group -NH-CH 2 -CHOH-CH 2 OH and R 2 and
R3 are identical and represent the group
-SO2-NH-CH2-CHOH-CH2OH (triiodo-2.4.6 tris N, N 'N "-
(2,3-dihydroxypropyl) 1,3,5-sulfonamoyl benzene.

R1 represents the group -NH-CH2-CHOH-CH2OH, R2
represents the group -SO2-NH-CH2-CHOH-CH2OH, and
R3 represents the group -CO-NH-CH2-CHOH-CH2OH
(2,4,6-triiodo-N, N '- (2,3-dihydroxy propyl) sulphate
1,3-fonamoyl N- (2,3-dihydroxypropyl) -5-benzamide).

- R1 represents the group -NH-CH2-CH2OH, R; represent
the group -CO-NH-CH2-CH2OH and R3 represents the group
p -N-CO-CH- (CH 2 OH) 2 (triiodo-2,4,6- / N- (dihydroxy)
CH2-CHOH-CH2OH
-2.3 propyl) N-di (hydroxymethyl) -acetylamino / -5
N '- (2-hydroxyethyl) -3-sulfonamoyl N "- (2-hydroxy)
ethyl) benzamide).

R1 represents a group -NH-CH2-CH2OH, R2 represents
a group -SO2-NH-CH2-CH2OH and R3 represents a
group -N-CO-CH- (CH 2 OH) 2 (2,4,6-triido-N- (dihydro CH 2 -CHOH-CH 2 OH
xy-2.3 propyl) N-di (hydroxymethyl) acetyl aminol-5
bis N '.N "- (2-hydroxyethyl) 1,3-sulfonamoyl ben
zene).

 The compounds of formula I are obtained by a process consisting of reactive oxidation, acylation and / or alkylation ions.

Rt, R6 et R7 étant tels que définis précédemment peuvent être obtenus par un procédé consistant
a1) à faire réagir un composé de formule II

dans laquelle R 1 et R"1 sont choisis parmi les groupes -OH et

Compounds of formula I wherein R2 and R3 represent a group of formula

Rt, R6 and R7 being as defined above can be obtained by a process consisting of
a1) reacting a compound of formula II

wherein R 1 and R "1 are selected from -OH groups and

R6 and R7 being as defined above with the optionally protected hydroxy groups. with NaNO 2 in an aqueous solution of hydrochloric or sulfuric acid so as to obtain a compound of formula III

b1) reacting the compound of formula III with Na2S, S or SO2, CuCl in a solvent such as water or acetic acid so as to obtain a sulfenic compound of formula IV

R'1 and R "1 being as defined above,
c1) oxidizing the compound of formula IV with an oxidizing agent selected from KMnO4, peracids such as metachloroperbenzoic acid or acid or peracetic acid, nitric acid or iodine in the presence of sodium periodate to obtain a compound of formula V

d1) reacting on the compound of formula
V a chlorination reagent such as PCl5, SOCl2, POC13, PCl3. ClCOCOCl in solvents such as toluene, chlorobenzene, DMF, dioxane, DMAC to obtain a compound of formula VI

un atome de chlore, R6 et R7 étant tels que définis précédemment avec les groupes hydroxy protégés sous forme d'acétals cycliques ou d'esters, et soit
e1) à amidifier le composé de formule VI par un exces supérieur à 3 équivalents d'une amine de formule

R'1 and R "1 representing a group

a chlorine atom, R6 and R7 being as defined above with protected hydroxy groups in the form of cyclic acetals or esters, and
e1) amidifying the compound of formula VI with an excess greater than 3 equivalents of an amine of formula

R4 and R5 being as defined above to obtain a compound of formula I in which R1, R2 and R3 represent a group

X representing CO or a single bond. f1) to amidify the compound of formula
VI by 2 equivalents of an amine of formula

et amidifier le composé de formule VII par 1 équivalent d'une amine de formule

R and R7 being as previously defined so as to obtain a compound of formula VIT

and amidifying the compound of formula VII with 1 equivalent of an amine of formula

91) et -soit à déprotéger les groupes hydroxy

R4 and R being as previously defined so as to obtain a compound of asymmetric formula I in which the group R1 is different from the group

91) and / or to deprotect the hydroxyl groups

<tb><SEP> R
<tb> of the <SEP> group <SEP> N <SEP> and <SEP> amidify <SEP> the <SEP> compound <SEP> of <SEP> formula
<tb><SEP> R7 <SEP> R
<tb><SEP> R7 <SEP> / R4
<tb> VI <SEP> with <SEP> 1 <SEP> equivalent <SEP> of a <SEP> amine <SEP> of <SEP> formula <SEP> HN <SEP>, <SEP> R4
<tb><SEP> R5
<tb> and R5 being as defined previously,
or to amidify the compound of formula
VI with 1 equivalent of an amine of formula

de manière à obtenir également un composé de formule.I dissymétrique dans laquelle le groupe R1 est différent du groupe

R4 and R5 being as defined above, and to deprotect the hydroxyl groups of the group

to also obtain a compound of asymmetric formula.I in which the group R1 is different from the group

The compounds of formula I in which R2 represents the group

et R1, R8, R9, R10 et R étant tels que definis précédemment peuvent être obtenus par un procédé consistant
a2) à ioder un composé de formule VIII

n étant égal à 0,2 ou 3 dans des conditions classiques, notamment en présence de KI/éthylamine à des températures comprises entre O-C et 100 C ou ICl ou KICl2 de manière à obtenir le composé triiodé de formule IX

CO - R8 and R3 represents the group - S02

and R1, R8, R9, R10 and R being as defined above can be obtained by a process consisting of
a2) to iodose a compound of formula VIII

n being equal to 0.2 or 3 under standard conditions, in particular in the presence of KI / ethylamine at temperatures of between 0 ° C. and 100 ° C. or IC1 or KIC12, so as to obtain the triiodinated compound of formula IX

b2) optionally to oxidize the compound of formula IX as described previously in step c1),
c2) reacting the compound thus obtained with a chlorination reagent as described above in step d1) so as to obtain a bis-chlorosulfonyl compound.

d2) amidifying the compound obtained in c2) by means of an amine of formula

R4 and R5 being as defined above with the protected or non-protected hydroxy groups,
f2) to acylate the compound obtained by R8-CO-Cl,
R8 being as previously defined with the protected hydroxy groups, and
92) optionally alkylating the amide thus obtained in the presence of a base with an alkylating reagent of formula Z-Rg, Z being a leaving group chosen from chlorine, bromine and iodine and R 1 being as defined above, and deprotecting the R8 group and optionally the R4 and R5 groups.

h) either to unprotect the group R8 and possibly
R4 and R5 and alkylate the amide obtained in the presence of a base with an alkylating reagent of formula Z-R9. Z being a leaving group selected from chlorine, bromine and iodine and R1 being as defined above.

Compounds of formula I wherein R2 and R3 are - SO2-N R6, R1, R6 and R7
R7 being as defined above can be obtained by a process consisting of
a3) reacting the compound of formula IX as defined previously with NaNO2 as described in step a1),
b3) reacting the compound thus obtained with Na2S, S or SO2, CuCl in a solvent such as water or acetic acid so as to obtain the corresponding sulfenic compound,
c3) to oxidize the compound thus obtained as described in step c1) so as to obtain a compound of formula X

d3) reacting the compound thus obtained with a chlorination reagent as described in step d1), and
e3) amidating the compound obtained in step d3) as described in step e1).

The compounds of formula I in which R2 and R3 respectively represent the groups -N-COR8
R

dans laquelle n est égal à 0,2 ou 3 comme décrit à l'étape a2) pour obtenir un composé triiodé de formule
XII

n étant tel que défini précédemment,
b4) éventuellement à oxyder le composé obtenu comme décrit précédemment à l'étape c1) de manière à obtenir un compose de formule XII dans laquelle n est égal à 3,
c4) à faire réagir sur le composé obtenuj à l'étape b4) un réactif de chloruration comme decrit à l'étape d1), et
d4) à amidifier le composé ainsi obtenu comme décrit à l'étape e1),
e4) à acyler le composé ainsi obtenu par
R8-CO-Cl, R6 étant tel que défini précédemment avec les groupes hydroxy protégés, comme décrit à l'étape f2), et
f4) soit éventuellement à alkyler l'amide ainsi obtenu par un réactif alkylant de formule Z-Rg, comme décrit à l'étape 92) et déprotéger le groupe R8,
g4) soit à déprotéger le groupe R8 et alkyler l'amide obtenu par un réactif alkylant de formule
Z-Rg, comme decrit à l'étape g2).R1, R6, R7, R8 and R9 being as defined above can be obtained by a process consisting of
a4) iodizing a compound of formula XI

wherein n is 0.2 or 3 as described in step a2) to obtain a triiodinated compound of formula
XII

n being as defined above,
b4) optionally to oxidize the compound obtained as described above in step c1) so as to obtain a compound of formula XII in which n is equal to 3,
c4) reacting the compound obtained in step b4) with a chlorination reagent as described in step d1), and
d4) amidifying the compound thus obtained as described in step e1),
e4) to acylate the compound thus obtained by
R8-CO-Cl, R6 being as previously defined with the protected hydroxy groups, as described in step f2), and
f4) or optionally alkylating the amide thus obtained with an alkylating reagent of formula Z-Rg, as described in step 92) and deprotecting the R8 group,
g4) either to deprotect the R8 group and to alkylate the amide obtained by an alkylating reagent of formula
Z-Rg, as described in step g2).

The compounds of formula I in which R2 and R3 respectively represent the groups
R10 R -SO2-N and -CO-N R1, R6, R7, R10 and R11
R 11 R 7 being as defined above can be obtained by a process consisting of
a5) reacting a compound of formula XII wherein n is 3, obtained previously in step b4) with NaNO2 as described in step a1) so as to obtain the corresponding diazonium compound
b5) reacting the compound obtained with
Na2S, S or SO2, CuCl as described in step b1) so as to obtain the corresponding sulfenic compound,
c5) oxidizing the compound obtained as described in step c1) so as to obtain a compound of formula XIII

d5) reacting on the compound of formula
XIII a chlorination reagent as described in step d1) so as to transform the groups -SO3H and -COOH respectively into groups -SO2Cl and -COCl, and
e5) amidifying the compound thus obtained as described in step e1).

COR8. R1, R8 et R9 étant tels que définis précédement peuvent être obtenus par un procédé consistant
a6) à faire réagir un composé diaminotriiodo benzamide de formule XIV

avec un réactif d'acylation de formule R8-CO-Cl, R8 étant tel que défini précédemment, avec les groupes hydroxy protégés, comme indiqué à l'étape f2),
b6) à obtenir le composé de formule XV

par réarrangement d' HOFFMANN en série iodée, selon la méthode décrite dans FR 2 571 367
c6) à faire réagir le composé obtenu avec
NaNO2 comme décrit à l'étape a1),
d6) à faire réagir le composé obtenu à l'étape précédente avec NaS, S ou SO2, CuCl comme décrit à l'étape b1),
e6) à oxyder le composé obtenu à l'étape précédente de manière à transformer le groupe -SOH en -SO3H comme décrit à l'étape c1),
f6) à faire réagir sur le composé obtenu à l'étape précédente un réactif de chloruration comme décrit à l'étape d1) de manière à obtenir le composé chlorosulfonyle correspondant,
g6) soit à amidifier le composé obtenu à l'étape f6) comme décrit à l'étape e1) avec une amine de formule

The compounds of formula I in which R2 and R3 represent the group

COR 8. R1, R8 and R9 being as previously defined can be obtained by a process consisting of
a6) reacting a diaminotriiodo benzamide compound of formula XIV

with an acylation reagent of formula R8-CO-Cl, R8 being as defined above, with protected hydroxy groups, as indicated in step f2),
b6) to obtain the compound of formula XV

by rearrangement of HOFFMANN in iodinated series, according to the method described in FR 2 571 367
c6) reacting the compound obtained with
NaNO2 as described in step a1),
d6) reacting the compound obtained in the preceding step with NaS, S or SO2, CuCl as described in step b1),
e6) oxidizing the compound obtained in the preceding step so as to convert the -SOH group to -SO3H as described in step c1),
f6) reacting the compound obtained in the preceding step with a chlorination reagent as described in step d1) so as to obtain the corresponding chlorosulfonyl compound,
g6) to amidify the compound obtained in step f6) as described in step e1) with an amine of formula

R4 and R5 being as defined above, and deprotecting the R8 group so as to obtain a compound of formula XVI

h6) either to deprotect the R8 group and to amidify the compound obtained in step f6) as described in step e1) with an amine of formula

R4 and R5 being as defined above, so as to obtain a compound of formula XVI described above,
i6) and, optionally, to alkylate the compound of formula XVI by means of a compound of formula Rg-Z,
Z being a leaving group selected from chlorine, bromine and iodine and Rg being as defined above.

The compounds of formula II, VIII, XI, XII,
XIV used in the processes described above are compounds known and described in particular in 3. Chem.

Soc. 1933, p. 1373; by Madhavlal S. and Chinubhai T.

(compound n XI), Bd XIV, S. 1924 (compound n VIII) and
FR-2 571 367 (compounds II and XIV).

 The present invention also relates to contrast products which comprise at least one compound of formula I.

 These contrast agents are used in humans and animals for radiological purposes.

 The preferred pharmaceutical form of the contrast products according to the invention is aqueous solutions of the compounds.

 Aqueous solutions generally contain a total of 5 to 100 g of compounds per 100 ml and the injectable amount of such solutions may vary generally from 1 to 1000 ml.

Aqueous solutions of the compounds of formula I may also contain certain additives such as
sodium chloride at concentrations of between 0.1 and 10 mM / l
disodium EDTA at concentrations of between 0.1 and 2 mMIl
sodium citrate at concentrations of between 0.1 and 10 mM / l
heparin at doses of between 10 and 100 units per 100 ml of solution.

 These compositions may be administered by any of the methods conventionally used for iodinated nonionic contrast media. Thus they can be administered enterally or parenterally (intravenously, intraarterially, opacification of cavities) and in particular in the subarachnoid space.

An example of a composition according to the present invention, Comnosition, will be given below.
Compound of Example 1 77 g
Water for injection
OSP 100 ml
EXAMPLE 1
Preparation of triiodo-2,4,6-N- (2,3-dihydroxypropyl) -5-sulfonamyl-bis (N, N "- (dihydroxy-2 ', 3'-propyl) -1,3-isophthalamide.

1) Prearing of 2,4,6-triiodo-5-sulfenoisophthalic acid
44 g (1.1 moles) of pelletized sodium hydroxide are added to a suspension of 448 g (0.8 mole) of 2,4,6-triiodo-5-isophthalic acid in 4000 ml of water.

The resulting solution having a pH of about 3.2 is cooled to 5 C and 80 g (1.2 moles) of sodium nitrite are added. The pH is then brought to 2.0 with 18N sulfuric acid. The temperature is maintained at 5 ° C. for 3 hours. The pH of the suspension is adjusted to 6.0 by addition of a 10N sodium hydroxide solution. The orange-yellow solution obtained is poured into a solution of 416 g (1.76 moles) of sodium sulphide and 53.6 g of sodium sulphide. g (1.68 moles) of sulfur in 240 ml of water at 50 ° C. The reaction mixture is maintained at 50 ° C. for one hour after the end of the addition.

then left at room temperature. 3000 ml of ethyl acetate are added to the brown solution thus obtained and the pH adjusted to 1.0. After settling. the solution is extracted twice with 1000 ml of ethyl acetate. All the organic phases are dried over magnesium sulphate and evaporated to dryness. The residue is stirred in 1500 ml of dichloromethane until crystallization and then filtered. The precipitate is washed again with stirring with 1000 ml of dichloromethane. After filtration and drying, 400 g of crude product are obtained. Stirring of the crude product with 600 ml of water gives a solution which is allowed to crystallize slowly. The solid is filtered, washed with a minimum of water. After drying 252 g of the expected product are obtained (Yield: 53X1.

Analvses:
TLC: eluent: toluene / methyl ethyl ketone / formic acid: 60/25/25 Rf = 0.6
Acidity: Dosage in return with H2S04 0,1N, 99,5% of purity for three acidities
IR:: (KBr pellet) 1680, 1125 cm (COOH)
1135 cm-1 (S - O from SOH)
NMR: 13C DMSO d-6 (ppm) attribution

<tb> 92
<tb><SEP> C <SEP> - <SEP> I
<tb> 104
<tb> 146 C - COOH 150 C - SOH 169

OH
Mass spectrum: (I +: NH4 +) m / z = 609 (M + NH4)
base peak 100% m / z = 592 (M +) 2) Prenaration of triiodo-2.4.6 sulfo-5 isoohtaliou acid
A solution of 252 g (0.426 mol) of 2,4,6-triiodo-5-sulfenoisophthalic acid in 1000 ml of dioxane is cooled to 10 ° C. 441 g (2.56 mol) of metachloroperbenzoic acid are then added to the mixture. fractions keeping the temperature at 10 ° C during the addition and another two hours after. using ice water bath. After returning and keeping at room temperature, the reaction mixture is left for 16 hours at this temperature for crystallization to take place. The precipitate is filtered off, washed twice with 500 ml of ethyl ether and then dried in an oven. The 210 g of product obtained are taken up in 2000 ml of a 1: 1 ethanol-water mixture and then heated under reflux for 20 hours. . The solution is then treated with activated charcoal for 1 hour under reflux and then filtered and evaporated to dryness. The residue is washed with 600 ml of toluene. Vacuum oven drying gives 173 g of the title compound (yield: 59%).

Analyzes
TLC: eluent: toluene / methyl-ethyl-ketone / formic acid: 60/25/25 Rf: 0.2 Acidite: Back titration with H2SO4 O, îN
Purity: 102.3% for three acidities.

IR: (KBr pellet) 1650, 1710 cm COOH
1060, 1190, 1350 cm SO3H
NMR: 1H (DMSO-d6) = 10.3 ppm. exchangeable protons in OQ
C (DMSO-d6) (ppm) attribution

<tb> 88.0
<tb><SEP> C <SEP> - <SEP> I
<tb> 88.4
<tb> 150.7 C - COOH 151.6 C - SO3H 170.3 # - OH
Mass spectrum: FAB negative mode m / z: 623 (MH) 3) Preparation of triiodo-2.4.6-sulfo-5-iso-dhthalamic acid trichloride:
150 g (0.22 mole) of 2,4,6-triiodo-5,5-sulfo-isophthalic acid are added little by little to 440 g (2.11 mol) of phosphorus pentachloride with stirring. The mixture is then refluxed for 6 hours. The solution is evaporated under vacuum and the residue obtained is taken up in 2500 ml of dichloromethane.

The solution is poured with stirring onto 1 kg of crushed ice. After 15 minutes, the mixture is decanted; the organic phase is washed with 500 ml of water and then dried over magnesium sulfate. After evaporation to dryness, the residue is taken up in 200 ml of cyclohexane with stirring and then filtered after half an hour. Drying under vacuum gives 103 g of white powder of the expected product (Yield: 69Z).

Analvses:
TLC: eluent: toluene / methyl ethyl ketone / formic acid: 60/25/25 Rf = 0.98
eluent: toluene Rf = 0.9
IR: (KBr pellet) 1760, 1730 cm COCl
1380, 1170 cm-1 SO2Cl
Organic Chlorine Dosage: Theory 5.19Z
Found 15.66%
Purity = 97%
4) Preparation of 2,4,6-triiodo, N- (2'-dihydroxy)
propyl) sulfonamoyl-5. bis-N '.N "- (dihydroxv-2, 3'oro-
Dvl) -1.3 isoohtalamide
102 g (0.150 moles) of acid trichloride
triiodo-2,4,6-sulfo-5-isophthalic acid are added to
a mixture of 99.5 g (1.09 moles) of amino propane
2,3-diol in 200 ml of dimethylacetamide
temperature at 20-C with a gla bath
this. the solution is stirred for 16 hours at room temperature
then added with 50 ml of water. PH is
brought to 7.0 with 5N hydrochloric acid and
mixture is evaporated to dryness. The oily residue obtained
is washed with 200 ml of dichloromethane and then evaporated
under vacuum, the 242 g of crude product are purified by
Preparative HPLC- PR18 Merck phase by elution to
water (UV detection: 254-280nm)
80 g of the title compound are obtained
Yield = 63%.

Analyzes :
TLC: eluent: butanol / water / acetic acid: 50/25/11
Rf = 0.3
IR: KBr lozenge 3300 cm -OH
2920. 2860 cm CH2 and CH
1640 cm 1 CONH
1310 cm SO2NH
NMR: - 1H DMSO-d6
(ppm) attribution
2.7 - 3.8 massive CH2 and OH (protons not
exchangeable with D2O)
-4.4 - 5 massive OH (exchangeable protons
with D20)
8.5 and 8.25 triplets -NH (exchangeable protons
with D2O)
13C DMSO-d6
(ppm) attribution
42.7 CH2-N 45.9 CH2-N
63.7 CH2-OH
64.1 gH2-OH
70.0 CH-OH
97.0 and 92.7 CI
144.3 C-SO2
152 CC
o
170 CN
0
Mass Siectre: FAB positive m / z: 844 (M + H)
Microanalysis
CHINOS
Calculated 24.21 2.87 45.16 4.98 18.98 3.80
Found 24.07 2.90 44.02 4.89 18.98 3.74

Claims (10)

 in which R4 and R5, which are identical or different, are chosen from a hydrogen atom and a C1-C6 alkyl group.

 in which R1 represents a group

 1. Compounds of formula I C1-C6 and hydroxy (C1-C5) alkoxy-C1-C6alkyl, with the proviso that the compounds of formula I contain at least two hydroxy groups in their molecule.  in which R 8, R 7, R 8, R 10 and R 11, which are identical or different, are chosen from a hydrogen atom. C1-C6alkyl, hydroxy-C1-C6alkyl, polyhydroxy-C1-C6alkyl, (C1-C5alkoxy) -alkyl-

 R9  - N - COR8 and - SO2

R2 and R3, which are identical or different, are chosen from groups C1-C6 hydroxyalkyl and C1-C6 polyhydroxyalkyl,  Compounds of formula I according to claim 1, wherein R 1 is as defined in claim 1 and R 2 and R 3 are the same and represent a group of formula

 R 6 and R 7 being as defined in claim 1.  Compounds of formula I according to claim 1, wherein R 1 is as defined in claim 1, R2 is the group

 and R3 represents the group

R11 being as defined in claim 1. R8, R9, R10 and  Compounds of formula I according to claim 1, wherein R 1 is as defined in claim 1 and R 2 and R 3 are the same and represent the group

 R and R7 being as defined in claim 1.  Compounds of formula I according to claim 1, wherein R 1 is as defined in claim 1, R2 represents the group

 and R3 represents the group

 R7, R10 and R11 being as defined in claim 1.  6. -Compounds of formula I according to claim 1, wherein R1 is as defined in claim 1, R2 represents the group

R3 represents the group R6, R7, R10 and R11 being as defined in claim 1.  Compounds of formula I according to claim 1, wherein R1 is as defined in claim 1, R2 and R3 are #, R8 and R9 being as defined  R9 dication 1.  8. Compound of formula I according to claims 1 or 2 which is triiodo-2,4,6 N- (2,3-dihydroxy-propyl) sulfonamoyl-5-bis-N ', N "- (2,3-dihydroxypropyl) -1, 3 isophthalamide.  9. Contrast medium, characterized in that it contains at least one compound according to any one of claims 1 to 8.  10. Contrast medium according to claim 9, characterized in that it consists of an aqueous solution of the compound or compounds.