IE65329B1 - 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 them

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Publication number
IE65329B1
IE65329B1 IE3591A IE3591A IE65329B1 IE 65329 B1 IE65329 B1 IE 65329B1 IE 3591 A IE3591 A IE 3591A IE 3591 A IE3591 A IE 3591A IE 65329 B1 IE65329 B1 IE 65329B1
Authority
IE
Ireland
Prior art keywords
compound
ppm
preparation
contrast medium
compounds
Prior art date
Application number
IE3591A
Other versions
IE910035A1 (en
Inventor
Michel Schaefer
Maryse Dugast-Zrihen
Michel Guillemot
Didier Doucet
Dominique Meyer
Original Assignee
Guerbet Sa
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Publication date
Application filed by Guerbet Sa filed Critical Guerbet Sa
Publication of IE910035A1 publication Critical patent/IE910035A1/en
Publication of IE65329B1 publication Critical patent/IE65329B1/en

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Classifications

    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Cephalosporin Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Compounds having general formula (I), wherein R is selected among 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl groups. These compounds can be used as contrasting products for X-ray image formation.

Description

The present invention relates to compounds which can be used as contrast media for radiography. ? Iodobenzene 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 application 89 401 509.8, 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: CH OH in which R| is a group of formula - N - CO - R.
I 5 R6 Rj being selected from C^-C^ alkyl, C^-C^ hydroxyalkyl or C^-C^ polyhydroxyalkyl, Rj being selected from hydrogen, C^-C^ alkyl, Cj-C^ hydroxyalkyl or Cj-C^ polyhydroxyalkyl, or a group of formula R? being selected from C^-C^ hydroxyalkyl or C^-C^ polyhydroxyalkyl, Rg being selected from hydrogen or C^-C^ alkyl, R2 is selected from hydrogen, Cj-C^ hydroxyalkyl or Cj-C^ polyhydroxyalkyl , Rg is selected from hydrogen or Cq-C^ alkyl, and R^ is selected from hydrogen, Cq-C^ alkyl, Cq-C^ hydroxyalkyl or Cjpolyhydroxyalkyl.
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 to following general formula: CH HQ HQ cr-jH II I ./V x cor 4 — F I CH..
(I) · in which R is selected from 2,3-dihydroxypropyl or 1,3-dihydroxy-2propyl.
One of the compounds according to the invention is -/3-hydroxy-2-(hydroxymethyl)-propionamide7-N,N’-dimethyl-N,N *-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide, i.e. the compound of formula: The other compound according to the invention is 5-Z3-hydroxy2-(hydroxymethyl-propionamido/-N,N’-dimethyl-N,N’-bis-(1,3-dihydroxy2,4,6-triiodoisophthalamide corresponding to the formula below: CH.
(B) These formulae 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)propionamido7-N’,Nbis-(2-hydroxy-ethy1)-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: R’ designating a -CH-iCI^OH^ group, the hydroxy groups of which are protected, with an amine selected from l-(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.
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 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 IB - 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.
EXAMPLE 1 Preparation of 5-/3-hydroxy-2-(hydroxymethyl)-propionamido7N,N'-dimethyl-N,N *-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. a) Preparation of /2-isopropyl-l,3-dioxane-5-carboxamido7-N,N’dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide. g (98 mmoles) of 5-£2-isopropyl-l,3-dioxane-5-carboxamido72,4,6-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 67.
After evaporation, the product is purified by passage through silanized silica (Kieselgel 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 purity : 97% Hypersil CB 25 cm 5 um NaH2P04 0.01 M 60 Methanol 40 TLC SiOp, Rf. 0.12 0.25 0.30 0.36 Eluant CHC13 55, MeOH 30, NH^O 10 NMR (DMSO) XH 200 MHz 0.9 ppm (doublet) CH^ (6H); 2.8 ppm (singlet) N-CH^ (3H); 3 ppm (singlet) N-CH^ (3H); 3.3 ppm (multiplet) N-CH2 and CH (5H); 3.5-3.9 ppm (multiplet) CH2 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 (IH). b) Preparation of 5-Z3-hydroxy-2-(hydroxymethyl)propionamido7-N,N’-dimethyl-N,N’-bis-(2,3-dihydroxypropyl)-2,4,6triiodoisophthalamide. 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 .silicg (Kieselgel 60 Merck) with water. After evaporation to dryness, 38 g of a white powder are recovered.
Yield » 90% Iodine determination: 98.3% HPLC purity 98% Hypersil C8 25 cm 5 μ NaH2P04 0.01 Μ 95 MeOH 5 TLC SiO2 Rf 0.56 0.63 0.67 Eluant CHC13 55, MeOH 30. NH^O 10 NMR (DMSO) XH 200 MHz 2.7 pm (multiplet) CH (IH); 2.85 ppm (enlarged singlet) N-CH^ (3H); 3.08 (poorly resolved doublet) N-CH^ (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 (IH).
EXAMPLE 2 Preparation of 5-/3-hydroxy-2-(hydroxymethyl)-propionamidQ7N,N'-dimethyl-N,N *-bis-(1,3-dihydroxy-2-propyl)-2,4,6-triiodoisophthalamide). a) Preparation of (2-isopropyl-l,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 Ν,Ν-dimethylacetamide and 2 ml (114.4 mmole) of triethylamine. 3.5 g (4.65 mmole) of 5-(2-isopropyl-l,3-dioxane-5-carboxamido)-2,46-triiodoisophthaloyl 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%.
TLC SiOn Rf 0.16 0.28 Eluant toluene 60 - methyl-ethyl-ketone 35 - formic acid .
NMR (DMSO) TH : 200 MHz. 0.9 ppm (doublet) CH3 (6H); 1.7 ppm (multiplet) CH (IH); 2.7 ppm (singlet) N-CH3 (3H) Z isomer; 2.99 ppm (singlet) N-CH^ (3H) E isomer; 3.4-4 ppm (multiplet) CH, CH2 (15H); 4.8 ppm (multiplet) CH20H (4H); .2 ppm (multiplet) NH (IH). b) Preparation of -/3-hydroxy-2-(hydroxyImethyl-propionamido7N,N’-dimethy1-N,N’-bis(1,3-dihydroxy-2-propy1)-2,4,6-triiodoisophthalamide. 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 H+ resin (IRN 77) and a 0H~ resin (IRA 68).
After evaporation to dryness, 1.7 g of a white powder are recovered in a yield of 60.7%.
Iodine purity: 98.4% TLC Si02 Rf 0.26 0.33 0.45 Eluant butanol 50, water 25, acetic acid 11.
NMR (DMSO) XH 200 MHz. 2.7 ppm (enlarged singlet) N-CH^ (3H), Z isomer; 3 ppm (enlarged singlet) N-CH^ (3H), E isomer; 3.3-4.05 ppm (poorly resolved multiplet) CH, CI^OH (15H); 4.45 ppm (poorly resolved multiplet) CHjOH (6H); 9.8 ppm (multiplet) NH (IH).
NMR (DMSO)13 C 200 MHz. 170.6 ppm (2 C); 172 ppm (1C); 149 ppm (C. -C); II II ftr 11 0 0 145 ppm (CA1-NH); 100-98-90 ppm (CAr-I); 61-57-52 ppm (C-H); 59.1-59.9 ppm (CH2-0H); 32.8-30.1 ppm (CH3-N).

Claims (13)

1. Compounds corresponding to the general formula: ch 3 in which R is chosen from 2,3-dihydroxypropyl and 1,3dihydroxy-2-propyl groups.
2. 5 - [3 -Hydroxy-2 - (hydroxymethyl) propionamido] -N, Ν' dimethyl-Ν,Ν' -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. Process for the preparation of a compound according to Claim 1, consisting in a) reacting a diacyl chloride of formula: R' denoting a -CH-(CH 2 OH) 2 group in which the hydroxyl groups are protected, with an amine chosen from 1-(N-methylamino) -propane-2,3- ‘ diol and 2-(N-methylamino) -propane-1,3-diol, so as to obtain a compound of formula and b) removing the protecting groups of the group R' .
5. Contrast medium, characterized in that it contains at least one compound according to Claim 1. 5
6. Contrast medium, characterized in that it contains at least the compound of Claim 2.
7. Contrast medium, characterized in that it contains at least the compound of Claim 3.
8. Contrast medium according to Claim 6, charac10 terized in that it consists of an aqueous solution of the compound.
9. Contrast medium according to Claim 7, characterized in that it consists of an aqueous solution of the compound. 15
10. A compound as claimed in Claim 1 substantially as hereinbefore described with reference to the examples.
11. Process for the preparation of a compound as claimed in Claim 1, substantially as hereinbefore 20 described.
12. A compound as claimed in Claim 1, whenever prepared by a process claimed in a preceding claim.
13. A contrast medium as claimed in any one of Claims 5-7, substantially as hereinbefore described.
IE3591A 1990-01-05 1991-01-04 Iodinated non-ionic compounds process for their preparation and contrast materials containing them IE65329B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR9000106A FR2656865B1 (en) 1990-01-05 1990-01-05 NON-IONIC IODINE COMPOUND, PROCESS FOR PREPARING THE SAME, AND CONTRAST PRODUCT CONTAINING THE SAME.

Publications (2)

Publication Number Publication Date
IE910035A1 IE910035A1 (en) 1991-07-17
IE65329B1 true IE65329B1 (en) 1995-10-18

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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) FI102746B (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)
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Families Citing this family (6)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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

Also Published As

Publication number Publication date
DE69014581T2 (en) 1995-06-08
EP0437144A1 (en) 1991-07-17
HK1006019A1 (en) 1999-02-05
HUT59079A (en) 1992-04-28
HU912860D0 (en) 1992-02-28
NO180297B (en) 1996-12-16
IE910035A1 (en) 1991-07-17
FR2656865A1 (en) 1991-07-12
AU7057491A (en) 1991-07-24
NO913403D0 (en) 1991-08-30
IL96812A (en) 1995-05-26
NZ236675A (en) 1992-08-26
KR920701132A (en) 1992-08-11
AU641212B2 (en) 1993-09-16
CA2050334A1 (en) 1991-07-06
WO1991009836A1 (en) 1991-07-11
JPH05132455A (en) 1993-05-28
ES2067710T3 (en) 1995-04-01
DE69014581D1 (en) 1995-01-12
TR24944A (en) 1992-07-01
PL165683B1 (en) 1995-01-31
NO180297C (en) 1997-03-26
DK0437144T3 (en) 1995-01-23
KR100194506B1 (en) 1999-06-15
IL96812A0 (en) 1991-09-16
PT96410B (en) 1998-06-30
CS648290A3 (en) 1992-02-19
ATE114639T1 (en) 1994-12-15
SK279646B6 (en) 1999-01-11
ZA9173B (en) 1992-08-26
JP2529032B2 (en) 1996-08-28
PL288603A1 (en) 1992-04-06
NO913403L (en) 1991-08-30
FI102746B1 (en) 1999-02-15
GR3015183T3 (en) 1995-05-31
CA2050334C (en) 1999-09-07
EP0437144B1 (en) 1994-11-30
FI914114A0 (en) 1991-09-02
CZ283986B6 (en) 1998-07-15
FI102746B (en) 1999-02-15
PT96410A (en) 1991-10-15
RO108559B1 (en) 1994-06-30
FR2656865B1 (en) 1993-03-26
FI914114A (en) 1992-06-29

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