CA2050334C - Iodinated non-ionic compounds, process for their preparation and contrast materials containing them - Google Patents
Iodinated non-ionic compounds, process for their preparation and contrast materials containing themInfo
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- CA2050334C CA2050334C CA002050334A CA2050334A CA2050334C CA 2050334 C CA2050334 C CA 2050334C CA 002050334 A CA002050334 A CA 002050334A CA 2050334 A CA2050334 A CA 2050334A CA 2050334 C CA2050334 C CA 2050334C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to compounds of the general formula:
(see fig. I) in which R is selected from 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl.
These compounds can be used as X ray contrast media.
(see fig. I) in which R is selected from 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl.
These compounds can be used as X ray contrast media.
Description
The present invention relates to compounds which can be used as contrast media for radiography.
lodobenzene compounds containing several iodine atoms in the benzene ring, usually 3 iodine atoms per benzene ring, and various other substituents have been used for a long time as contrast materials. 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 a tolerance sufficient for their use in the human organism.
For this purpose, non-ionic structures have been suggested, i.e. iodobenzene derivatives possessing non-ionic 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 proposed.
A compound illustrative of this class is metrizamide which has, however, proved to be of limited stability.
In the European patent 357467 A1, non-ionic compounds were suggested which are well tolerated by the human organism and which exhibit good stability in aqueous solution.
These compounds correspond to the formula:
~R~
CO
~H ~ CH20H
lodobenzene compounds containing several iodine atoms in the benzene ring, usually 3 iodine atoms per benzene ring, and various other substituents have been used for a long time as contrast materials. 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 a tolerance sufficient for their use in the human organism.
For this purpose, non-ionic structures have been suggested, i.e. iodobenzene derivatives possessing non-ionic 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 proposed.
A compound illustrative of this class is metrizamide which has, however, proved to be of limited stability.
In the European patent 357467 A1, non-ionic compounds were suggested which are well tolerated by the human organism and which exhibit good stability in aqueous solution.
These compounds correspond to the formula:
~R~
CO
~H ~ CH20H
in which R, is a group of formula -N-CO-RS
Rs RS being selected from C -C, ,~Ikyl, C -C , hydroxyalkyl or C -C , polyhydroxyalkyl, Rs being selected from hydrogen, C,-C4 alkyl, C,-C4 hydroxyalkyl or C,-C4 polyhydroxyalkyl) or a group of formula -CO-N-R~
R, being selected from C,-C4 hydroxyalkyl or C,-C4 polyhydroxyalkyl, R8 being selected from hydrogen or C,-C4 alkyl, R2 is selected from hydrogen, C,-C4 hydroxyalkyl or C,-C,, polyhydroxyalkyl, R3 is selected from hydrogen or C,-C4 alkyl, and R4 is selected from hydrogen, C,-C4 alkyl, C,-C4 hydroxyalkyl or C,-C4 polyhydroxyalkyl.
The aim of the present invention is to provide novel compounds belonging to the family of the compounds of formula I, which are characterized by both good stability and good solubility in aqueous media.
The compounds according to the invention have the following general formula:
CON-R
HO
-R
HO~
V c:H3 in which R is selected from 2,3-dihydroxypropyl or 1,3-dihydroxy-2-propyl.
Rs RS being selected from C -C, ,~Ikyl, C -C , hydroxyalkyl or C -C , polyhydroxyalkyl, Rs being selected from hydrogen, C,-C4 alkyl, C,-C4 hydroxyalkyl or C,-C4 polyhydroxyalkyl) or a group of formula -CO-N-R~
R, being selected from C,-C4 hydroxyalkyl or C,-C4 polyhydroxyalkyl, R8 being selected from hydrogen or C,-C4 alkyl, R2 is selected from hydrogen, C,-C4 hydroxyalkyl or C,-C,, polyhydroxyalkyl, R3 is selected from hydrogen or C,-C4 alkyl, and R4 is selected from hydrogen, C,-C4 alkyl, C,-C4 hydroxyalkyl or C,-C4 polyhydroxyalkyl.
The aim of the present invention is to provide novel compounds belonging to the family of the compounds of formula I, which are characterized by both good stability and good solubility in aqueous media.
The compounds according to the invention have the following general formula:
CON-R
HO
-R
HO~
V c:H3 in which R is selected from 2,3-dihydroxypropyl or 1,3-dihydroxy-2-propyl.
One of the compounds according to the invention is 5-[3-hydroxy-2-(hydroxymethyl)-propionamido]-N,N'-dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide) i.e. the compound of formula:
CON
-,H OH
(A) HO
~- OH OH
HO~
a c:H3 The other compound according to the invention is 5-[3-hydroxy-2-(hydroxymethyl)-propionamido]-N,N'-dimethyl-N,N'-bis-(1,3-dihydroxy-2-propyl)-2,4,6-triiodoisophthalamide corresponding to the formula below:
CON
OH
(B) HO OH
C ~ON
HO ~H3 OH
These formula cover not only the racemates but also all of the stereoisomers associated with the presence of asymmetric carbon and the prevention of rotation of certain bonds owing to the steric hindrance contributed by the iodine atoms.
Unexpectedly, the compound of formula A is characterized by a better solubility in aqueous medium than the compound of example 1 of the European patent application mentioned above, namely the 5-[3-hydroxy-2-(hydroxymethyl)-N-(2,3-dihydroxypropyl)propionamido]-N',N"-bis-(2-hydroxy-ethyl)-2,4,6-triiodo-isophthalamide.
CON
-,H OH
(A) HO
~- OH OH
HO~
a c:H3 The other compound according to the invention is 5-[3-hydroxy-2-(hydroxymethyl)-propionamido]-N,N'-dimethyl-N,N'-bis-(1,3-dihydroxy-2-propyl)-2,4,6-triiodoisophthalamide corresponding to the formula below:
CON
OH
(B) HO OH
C ~ON
HO ~H3 OH
These formula cover not only the racemates but also all of the stereoisomers associated with the presence of asymmetric carbon and the prevention of rotation of certain bonds owing to the steric hindrance contributed by the iodine atoms.
Unexpectedly, the compound of formula A is characterized by a better solubility in aqueous medium than the compound of example 1 of the European patent application mentioned above, namely the 5-[3-hydroxy-2-(hydroxymethyl)-N-(2,3-dihydroxypropyl)propionamido]-N',N"-bis-(2-hydroxy-ethyl)-2,4,6-triiodo-isophthalamide.
Furthermore, the compounds according to the invention possess the advantage, compared with the compound of example 1 of the patent application mentioned above, of being more easily accessible in that they do not require a final N-alkylation step which poses problems of purification at the industrial scale.
The compounds according to the invention may be obtained according to a procedure consisting of:
a) reacting a diacyl chloride of formula:
COCI
R'-U
(II) R' designating a -CH-(CH20H)2 group, the hydroxy groups of which are p rotected , with an amine selected from 1-(N-methylamino) propane-2,3-diol and 2-(N-methylamino) propane-1,3-diol, so as to produce a compound of formula:
CON-R
(III) R'- -R
U C:H3 and b) removing the protecting groups from the R' group.
The compounds of formula II are described in FR-A-2 632 304.
The present invention relates also to contrast media which contain at least one of the compounds according to the invention.
These contrast media are used in man and animals for radiological purposes.
The preferred pharmaceutical form of the contrast media according to the invention consists of aqueous solutions of the compounds.
The aqueous solutions usually contain a total of 5 to 100 g of 5 compound according to the invention per 100 ml and the injectable volume of such solutions usually varies from 1 to 1000 ml.
The aqueous solutions of the compounds according to the invention may also contain certain additives such as:
- sodium chloride at concentrations between 0.1 and 10 mM
- disodium EDTA at concentrations between 0.1 and 2 mM
- sodium citrate at concentrations between 0.1 and 10 mM
- heparin at doses 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 materials. Thus they may be administered by the enteral or parenteral route (intravenous or intra-arterial route, opacification of the cavities) and in particular into the subarachnoid space.
An example of the composition according to the present invention will be given below.
Composition Compound A according to the invention 65 g Water for injectable preparation QS 100 ml The following examples illustrate the preparation of the compounds according to the invention.
Preparation of 5-[3-hydrox<r-2-(hyd_roy methyly-I r~opionamidol~
N.N'-dimethyl-N.N'-bis-( .2 3dihyrdrox~pyly-2.x,6-triiodoisophthalamide.
The compounds according to the invention may be obtained according to a procedure consisting of:
a) reacting a diacyl chloride of formula:
COCI
R'-U
(II) R' designating a -CH-(CH20H)2 group, the hydroxy groups of which are p rotected , with an amine selected from 1-(N-methylamino) propane-2,3-diol and 2-(N-methylamino) propane-1,3-diol, so as to produce a compound of formula:
CON-R
(III) R'- -R
U C:H3 and b) removing the protecting groups from the R' group.
The compounds of formula II are described in FR-A-2 632 304.
The present invention relates also to contrast media which contain at least one of the compounds according to the invention.
These contrast media are used in man and animals for radiological purposes.
The preferred pharmaceutical form of the contrast media according to the invention consists of aqueous solutions of the compounds.
The aqueous solutions usually contain a total of 5 to 100 g of 5 compound according to the invention per 100 ml and the injectable volume of such solutions usually varies from 1 to 1000 ml.
The aqueous solutions of the compounds according to the invention may also contain certain additives such as:
- sodium chloride at concentrations between 0.1 and 10 mM
- disodium EDTA at concentrations between 0.1 and 2 mM
- sodium citrate at concentrations between 0.1 and 10 mM
- heparin at doses 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 materials. Thus they may be administered by the enteral or parenteral route (intravenous or intra-arterial route, opacification of the cavities) and in particular into the subarachnoid space.
An example of the composition according to the present invention will be given below.
Composition Compound A according to the invention 65 g Water for injectable preparation QS 100 ml The following examples illustrate the preparation of the compounds according to the invention.
Preparation of 5-[3-hydrox<r-2-(hyd_roy methyly-I r~opionamidol~
N.N'-dimethyl-N.N'-bis-( .2 3dihyrdrox~pyly-2.x,6-triiodoisophthalamide.
a) Preparation of [2-isopropyl-1,3-dioxane-5-carboxamido]-N,N'-dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.
74 g (98 mmoles) of 5-[2-isopropyl-1,3-dioxane-5-carboxamido]-2,4,6-triiodo-isophthaloyl dichloride are suspended in 300 ml of isopropanol containing 41 ml (294 mmoles) of triethylamine. 31 g (295 mmoles) of N-methyl-aminopropane-2,3-diol are added dropwise. Stirring is maintained for 12 h at room temperature. The triethylamine hydrochloride is removed by filtration.
The filtrate is evaporated to dryness, the residue is taken up in water and eluted from OH resin IRA 67T"".
After evaporation, the product is purified by passage through silanized silica (KieseIgeIT"' 60 Merck) with water as eluant.
After evaporation to dryness, 60 g of a white powder are recovered in a yield of 68.5%.
Iodine determination: 96.4%
HPLC Ruritv: 97% HypersilT"" CB 25cm 5 ,um NaH2P04 0.01 M 60 Methanol 40 TLC Si02, Rf. 0.12 0.25 0.30 0.36 Eluant CHC23 55, MeOH 30, NH3H20 10 NMR (DMSO)'H 200 MHz 0.9 ppm (doublet) CH3 (6H); 2.8 ppm (singlet) N-CH3 (3H); 3 ppm (singlet) N
CH3 (3H); 3.3 ppm (multiplet) N-CHZ and CH (5H); 3.5-3.9 ppm (multiplet) CHZ and CH (8H); 4.3 ppm (quadruplet) CH (3H); 4.6 ppm (triplet) OH (2H);
4.7 ppm (doublet) OH (2H); 10.2 ppm (enlarged multiplet) NH (1 H).
b) Preparation of 5-[3-hydroxy-2-(hydroxymethyl)-propionamido]-N,N'-dimethyl-N,N'-bis-(2;3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.
74 g (98 mmoles) of 5-[2-isopropyl-1,3-dioxane-5-carboxamido]-2,4,6-triiodo-isophthaloyl dichloride are suspended in 300 ml of isopropanol containing 41 ml (294 mmoles) of triethylamine. 31 g (295 mmoles) of N-methyl-aminopropane-2,3-diol are added dropwise. Stirring is maintained for 12 h at room temperature. The triethylamine hydrochloride is removed by filtration.
The filtrate is evaporated to dryness, the residue is taken up in water and eluted from OH resin IRA 67T"".
After evaporation, the product is purified by passage through silanized silica (KieseIgeIT"' 60 Merck) with water as eluant.
After evaporation to dryness, 60 g of a white powder are recovered in a yield of 68.5%.
Iodine determination: 96.4%
HPLC Ruritv: 97% HypersilT"" CB 25cm 5 ,um NaH2P04 0.01 M 60 Methanol 40 TLC Si02, Rf. 0.12 0.25 0.30 0.36 Eluant CHC23 55, MeOH 30, NH3H20 10 NMR (DMSO)'H 200 MHz 0.9 ppm (doublet) CH3 (6H); 2.8 ppm (singlet) N-CH3 (3H); 3 ppm (singlet) N
CH3 (3H); 3.3 ppm (multiplet) N-CHZ and CH (5H); 3.5-3.9 ppm (multiplet) CHZ and CH (8H); 4.3 ppm (quadruplet) CH (3H); 4.6 ppm (triplet) OH (2H);
4.7 ppm (doublet) OH (2H); 10.2 ppm (enlarged multiplet) NH (1 H).
b) Preparation of 5-[3-hydroxy-2-(hydroxymethyl)-propionamido]-N,N'-dimethyl-N,N'-bis-(2;3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.
45 g (50.6 mmole) of the compound described in a) are dissolved in 101 ml (10 eq.) of 5 N hydrochloric acid. Stirring is maintained for 12 h at room temperature. The solution is filtered and evaporated to dryness. The solid obtained is taken up in 100 ml of ethyl ether, then filtered off and eluted from silanized silica (KieseIgeITM 60 Merck) with water. After evaporation to dryness, 38 g of a white powder are recovered.
Yield = 90%
Iodine determination: 98.3%
HPLC uritv 98% HypersilTM C8 25 cm 5 ,u NaH2P04 0.01 M 95 MeOH 5 TLC Si02 Rf 0.56 0.63 0.67 Eluant CHCQ3 55, MeOH 30, NH3H20 10 NMR (DMSO)'H 200 MHz 2.7 pm (multiplet) CH (1 H); 2.85 ppm (enlarged singlet) N-CH3 (3H);
3.08 (poorly resolved doublet) N-CH3 (3H); 3.10-3.35 ppm (multiplet) N-CH2;
3.45 ppm (quadruplet) CH2 (4H); 3.6-4 ppm (multiplet) OH (6H); 9.9 ppm (multiplet) NH (1 H).
Preaaration of 5-[3-hyrdroxVr-2-(hyrdrox\rmethyrl)-~roaionamido]~
N.N'-dimethyrl-N.N'-bis-(1.3-dihydroxy-2-propyll-2.4.6-triiodois~~hthalamide).
a) Preparation of (2-isopropyl-1,3-dioxane-6-carboxamido) N,N'-dimethyl-N,N'-bis-(1,3-dihydroxy-2-propyl)-2,4,6-triiodoisophthalamide.
1.46 g (13.9 mmole) of N-methyl-aminopropane-1,3-diol (synthesized according to the European patent application EP-A-025 083 filed by EPROVA A.G.) is dissolved in a mixture composed of 20 ml of N,N-dimethylacetamide and 2 ml (114.4 mmole) of triethylamine. 3.5 g (4.65 mmole of 5-(2-isopropyl-1,3-dioxane-5-carboxamido)-2,4-6-triiodoi-sophthaloyl dichloride are added in portions. Stirring is maintained for 3 hours at 30°C, then for 12 hours at room temperature.
The triethylamine hydrochloride is removed by filtration.
The filtrate is evaporated to dryness and the residue is crystallized in a mixture composed of 20 ml of isopropanol and 200 ml of ethyl ether.
After filtration and drying, 3.6 g of a white powder are recovered in a yield of 87%.
I~GSi02Rf0.16 0.28 Eluant toluene 60 - methyl-ethyl-ketone 35 - formic acid 25.
~ (DMSO)'H : 200 MHz.
0.9 ppm (doublet) CH3 (6H); 1.7 ppm (multiplet) CH (1 H); 2.7 ppm (singlet) N-CH3 (3H) Z isomer; 2.99 ppm (singlet) N-CH3 (3H) E isomer; 3.4-4 ppm (multiplet) CH, CH2 (15H); 4.8 ppm (multiplet) CH ~H (4H); 10.2 ppm (multiplet) NH (1 H).
b) Preparation of 5-[3-hydroxy-2-(hydroxylmethyl-propionamido]N,N'-dimethyl-N,N'-bis-(1,3-dihydroxy-2-propyl)-2,4,6-triiodoisophthalamide.
3 g (3.4 mmole) of the compound described in a) are dissolved in 10 ml (15 eq.) of 5N hydrochloric acid. Stirring is maintained for 3 hours at 45°C, then for 12 hours at room temperature. The solution is evaporated to dryness. The residue obtained is taken up in 50 ml of ethyl ether, filtered off, then dissolved in 50 ml of water before being eluted from a HT"" resin (IRN 77)TMand a OH resin (IRA 68)T"".
After evaporation to dryness, 1.7 g of a white powder are recovered in a yield of 60.7%.
Iodine purity: 98.4%
~ Si02 Rf 0.26 0.33 0.45 Eluant butanol 50, water 25, acetic acid 11.
NMR (DMSO)'H 200 MHz.
2.7 ppm (enlarged singlet) N-CH3 (3H), Z isomer; 3 ppm (enlarged singlet) N-CH3 (3H), E isomer; 3.3-4.05 ppm (poorly resolved multiplet) CH, C,~-120H
(15H); 4.45 ppm (poorly resolved multiplet) CH20,~ (6H); 9.8 ppm (multiplet) NH (1 H).
NMR (DMSO)'3 C 200 MHz.
170.6 ppm (2 C); 172 ppm (1 C); 149 ppm (C~-C);
O O O
145 ppm (CA,-NH); 100-98-90 ppm (CAS I); 61-57-52 ppm (C-H); 59.1-59.9 ppm (CH2-OH); 32.8-30.1 ppm (CH3-N).
Yield = 90%
Iodine determination: 98.3%
HPLC uritv 98% HypersilTM C8 25 cm 5 ,u NaH2P04 0.01 M 95 MeOH 5 TLC Si02 Rf 0.56 0.63 0.67 Eluant CHCQ3 55, MeOH 30, NH3H20 10 NMR (DMSO)'H 200 MHz 2.7 pm (multiplet) CH (1 H); 2.85 ppm (enlarged singlet) N-CH3 (3H);
3.08 (poorly resolved doublet) N-CH3 (3H); 3.10-3.35 ppm (multiplet) N-CH2;
3.45 ppm (quadruplet) CH2 (4H); 3.6-4 ppm (multiplet) OH (6H); 9.9 ppm (multiplet) NH (1 H).
Preaaration of 5-[3-hyrdroxVr-2-(hyrdrox\rmethyrl)-~roaionamido]~
N.N'-dimethyrl-N.N'-bis-(1.3-dihydroxy-2-propyll-2.4.6-triiodois~~hthalamide).
a) Preparation of (2-isopropyl-1,3-dioxane-6-carboxamido) N,N'-dimethyl-N,N'-bis-(1,3-dihydroxy-2-propyl)-2,4,6-triiodoisophthalamide.
1.46 g (13.9 mmole) of N-methyl-aminopropane-1,3-diol (synthesized according to the European patent application EP-A-025 083 filed by EPROVA A.G.) is dissolved in a mixture composed of 20 ml of N,N-dimethylacetamide and 2 ml (114.4 mmole) of triethylamine. 3.5 g (4.65 mmole of 5-(2-isopropyl-1,3-dioxane-5-carboxamido)-2,4-6-triiodoi-sophthaloyl dichloride are added in portions. Stirring is maintained for 3 hours at 30°C, then for 12 hours at room temperature.
The triethylamine hydrochloride is removed by filtration.
The filtrate is evaporated to dryness and the residue is crystallized in a mixture composed of 20 ml of isopropanol and 200 ml of ethyl ether.
After filtration and drying, 3.6 g of a white powder are recovered in a yield of 87%.
I~GSi02Rf0.16 0.28 Eluant toluene 60 - methyl-ethyl-ketone 35 - formic acid 25.
~ (DMSO)'H : 200 MHz.
0.9 ppm (doublet) CH3 (6H); 1.7 ppm (multiplet) CH (1 H); 2.7 ppm (singlet) N-CH3 (3H) Z isomer; 2.99 ppm (singlet) N-CH3 (3H) E isomer; 3.4-4 ppm (multiplet) CH, CH2 (15H); 4.8 ppm (multiplet) CH ~H (4H); 10.2 ppm (multiplet) NH (1 H).
b) Preparation of 5-[3-hydroxy-2-(hydroxylmethyl-propionamido]N,N'-dimethyl-N,N'-bis-(1,3-dihydroxy-2-propyl)-2,4,6-triiodoisophthalamide.
3 g (3.4 mmole) of the compound described in a) are dissolved in 10 ml (15 eq.) of 5N hydrochloric acid. Stirring is maintained for 3 hours at 45°C, then for 12 hours at room temperature. The solution is evaporated to dryness. The residue obtained is taken up in 50 ml of ethyl ether, filtered off, then dissolved in 50 ml of water before being eluted from a HT"" resin (IRN 77)TMand a OH resin (IRA 68)T"".
After evaporation to dryness, 1.7 g of a white powder are recovered in a yield of 60.7%.
Iodine purity: 98.4%
~ Si02 Rf 0.26 0.33 0.45 Eluant butanol 50, water 25, acetic acid 11.
NMR (DMSO)'H 200 MHz.
2.7 ppm (enlarged singlet) N-CH3 (3H), Z isomer; 3 ppm (enlarged singlet) N-CH3 (3H), E isomer; 3.3-4.05 ppm (poorly resolved multiplet) CH, C,~-120H
(15H); 4.45 ppm (poorly resolved multiplet) CH20,~ (6H); 9.8 ppm (multiplet) NH (1 H).
NMR (DMSO)'3 C 200 MHz.
170.6 ppm (2 C); 172 ppm (1 C); 149 ppm (C~-C);
O O O
145 ppm (CA,-NH); 100-98-90 ppm (CAS I); 61-57-52 ppm (C-H); 59.1-59.9 ppm (CH2-OH); 32.8-30.1 ppm (CH3-N).
Claims (9)
1. A compound of the formula:
in which R is selected from 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl.
in which R is selected from 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl.
2. 5-[3-hydroxy-2-(hydroxymethyl)-propionamido]-N,N~-dimethyl-N,N~-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.
3. 5-[3-hydroxy-2-(hydroxymethyl)-propionamido]-N,N~-dimethyl-N,N~-bis (1,3-dihydroxy-2-propyl)-2,4,6-triiodoisophthalamide.
4. A contrast media, which comprises at least one compound according to claim 1.
5. A contrast media, which comprises the compound of claim 2.
6. A contrast media, which comprises the compound of claim 3.
7. A contrast media according to claim 5, which is constituted by an aqueous solution of the compound.
8. A contrast media according to claim 6, which is constituted by an aqueous solution of the compound.
9. Process for the preparation of a compound of the formula:
in which R is selected from 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl, comprising:
a) reacting an acyl dichloride of formula:
R' designating a -CH-(CH2OH)2 group, the hydroxy groups of which are protected, with an amine selected from 1-(N-methylamino) propane-2,3-diol and 2-(N-methylamino) propane-1,3-diol) so as to produce a compound of formula:
and b) removing the protecting groups from the R' group.
in which R is selected from 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl, comprising:
a) reacting an acyl dichloride of formula:
R' designating a -CH-(CH2OH)2 group, the hydroxy groups of which are protected, with an amine selected from 1-(N-methylamino) propane-2,3-diol and 2-(N-methylamino) propane-1,3-diol) so as to produce a compound of formula:
and b) removing the protecting groups from the R' group.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9000106 | 1990-01-05 | ||
| FR9000106A FR2656865B1 (en) | 1990-01-05 | 1990-01-05 | NON-IONIC IODINE COMPOUND, PROCESS FOR PREPARING THE SAME, AND CONTRAST PRODUCT CONTAINING THE SAME. |
| PCT/FR1990/000969 WO1991009836A1 (en) | 1990-01-05 | 1990-12-28 | Nonionic iodinated compounds, method for preparing them, and contrast products containing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2050334A1 CA2050334A1 (en) | 1991-07-06 |
| CA2050334C true CA2050334C (en) | 1999-09-07 |
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ID=9392557
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002050334A Expired - Lifetime CA2050334C (en) | 1990-01-05 | 1990-12-28 | Iodinated non-ionic compounds, process for their preparation and contrast materials containing them |
Country Status (25)
| Country | Link |
|---|---|
| EP (1) | EP0437144B1 (en) |
| JP (1) | JP2529032B2 (en) |
| KR (1) | KR100194506B1 (en) |
| AT (1) | ATE114639T1 (en) |
| CA (1) | CA2050334C (en) |
| CZ (1) | CZ283986B6 (en) |
| DE (1) | DE69014581T2 (en) |
| DK (1) | DK0437144T3 (en) |
| ES (1) | ES2067710T3 (en) |
| FI (1) | FI102746B1 (en) |
| FR (1) | FR2656865B1 (en) |
| GR (1) | GR3015183T3 (en) |
| HK (1) | HK1006019A1 (en) |
| HU (1) | HUT59079A (en) |
| IE (1) | IE65329B1 (en) |
| IL (1) | IL96812A (en) |
| NO (1) | NO180297C (en) |
| NZ (1) | NZ236675A (en) |
| PL (1) | PL165683B1 (en) |
| PT (1) | PT96410B (en) |
| RO (1) | RO108559B1 (en) |
| SK (1) | SK279646B6 (en) |
| TR (1) | TR24944A (en) |
| WO (1) | WO1991009836A1 (en) |
| ZA (1) | ZA9173B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2687669B1 (en) * | 1992-02-24 | 1997-12-19 | Guerbet Sa | COMPOUNDS FOR USE IN CONTRAST PRODUCTS FOR RADIOGRAPHY. |
| IT1256163B (en) * | 1992-10-27 | 1995-11-29 | Zambon Spa | PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF THE ORGANIC SYNTHESIS |
| IT1283319B1 (en) * | 1996-03-29 | 1998-04-16 | Zambon Spa | PROCESS FOR THE PREPARATION OF A USEFUL INTERMEDIATE IN THE SYNTHESIS OF HYDURATED CONTRAST MEDIA |
| PT108524B (en) | 2015-06-02 | 2017-12-15 | Hovione Farmaciência S A | PROCESS FOR THE PREPARATION OF USEFUL INTERMEDIARIES IN THE PREPARATION OF NON-IONIC CONTRACTING AGENTS |
| CN108947959B (en) * | 2017-05-27 | 2022-09-20 | 正大天晴药业集团股份有限公司 | Preparation method of non-ionic iodine contrast agent intermediate |
| CN110903275A (en) * | 2018-09-14 | 2020-03-24 | 苏州科伦药物研究有限公司 | Process for producing iobitridol, intermediate therefor, and process for producing the same |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2909439A1 (en) * | 1979-03-08 | 1980-09-18 | Schering Ag | NEW NON-ionic x-ray contrast agents |
| DE3429949A1 (en) * | 1984-08-10 | 1986-02-20 | Schering AG, 1000 Berlin und 4709 Bergkamen | Novel non-ionic 2,4,6-triiodoisophthalic acid bisamides, process for the preparation thereof and the use thereof as X-ray contrast media |
| IL90326A (en) * | 1988-06-02 | 1993-05-13 | Guerbet Sa | Non-ionic triiodobenzene compounds and contrast media containing them |
-
1990
- 1990-01-05 FR FR9000106A patent/FR2656865B1/en not_active Expired - Fee Related
- 1990-12-20 SK SK6482-90A patent/SK279646B6/en unknown
- 1990-12-20 CZ CS906482A patent/CZ283986B6/en not_active IP Right Cessation
- 1990-12-26 EP EP90403770A patent/EP0437144B1/en not_active Expired - Lifetime
- 1990-12-26 AT AT90403770T patent/ATE114639T1/en not_active IP Right Cessation
- 1990-12-26 DK DK90403770.2T patent/DK0437144T3/en active
- 1990-12-26 ES ES90403770T patent/ES2067710T3/en not_active Expired - Lifetime
- 1990-12-26 DE DE69014581T patent/DE69014581T2/en not_active Expired - Lifetime
- 1990-12-27 IL IL9681290A patent/IL96812A/en not_active IP Right Cessation
- 1990-12-28 HU HU912860A patent/HUT59079A/en unknown
- 1990-12-28 CA CA002050334A patent/CA2050334C/en not_active Expired - Lifetime
- 1990-12-28 KR KR1019910701024A patent/KR100194506B1/en not_active IP Right Cessation
- 1990-12-28 WO PCT/FR1990/000969 patent/WO1991009836A1/en active IP Right Grant
- 1990-12-28 RO RO148263A patent/RO108559B1/en unknown
-
1991
- 1991-01-03 PT PT96410A patent/PT96410B/en not_active IP Right Cessation
- 1991-01-04 NZ NZ236675A patent/NZ236675A/en unknown
- 1991-01-04 JP JP3052354A patent/JP2529032B2/en not_active Expired - Lifetime
- 1991-01-04 PL PL91288603A patent/PL165683B1/en not_active IP Right Cessation
- 1991-01-04 ZA ZA9173A patent/ZA9173B/en unknown
- 1991-01-04 IE IE3591A patent/IE65329B1/en not_active IP Right Cessation
- 1991-01-18 TR TR91/0009A patent/TR24944A/en unknown
- 1991-08-30 NO NO913403A patent/NO180297C/en not_active IP Right Cessation
- 1991-09-02 FI FI914114A patent/FI102746B1/en active
-
1995
- 1995-02-27 GR GR940403887T patent/GR3015183T3/en unknown
-
1998
- 1998-06-10 HK HK98105100A patent/HK1006019A1/en not_active IP Right Cessation
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