HK1006019B - Non-ionic iodinated compounds, procedure for their preparation and contrast agents containing them - Google Patents
Non-ionic iodinated compounds, procedure for their preparation and contrast agents containing them Download PDFInfo
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- HK1006019B HK1006019B HK98105100.9A HK98105100A HK1006019B HK 1006019 B HK1006019 B HK 1006019B HK 98105100 A HK98105100 A HK 98105100A HK 1006019 B HK1006019 B HK 1006019B
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Description
The present invention relates to compounds which can be used in contrast products for radiography.
Iodobenzene compounds with several iodine atoms on the benzene nucleus, usually 3 iodine atoms per benzene nucleus, and various other substituents have long been used as contrast agents. These other substituents are pharmacologically acceptable groups that allow the administration of the compounds to 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, i.e. iodobenzene derivatives with non-ionic substituents, have been proposed.
Thus, in patent FR-A-2 053 037, carbamoyl iodobenzene compounds containing a total of at least one N-hydroxy alcohol group and at least two hydroxy groups were proposed.
An example of this class is metrisamide, which has been shown to be limited in stability.
In European patent application 89 401 509.8 non-ionic compounds are proposed which are well tolerated by the human body and which have good stability in aqueous solution.
These compounds have the formula:
in which
R1 represents a group of formula
- What?
R5 representing an alkyl group at C1-C4, an alkyl hydroxy group at C1-C4 or a polyhydroxyalkyl group at C1-C4,
R6 representing a hydrogen atom, an alkyl group in C1-C4, a hydroxyalkyl group in C1-C4 or a polyhydroxyalkyl group in C1-C4,
or a group of formula
- What?
R7 representing a hydroxyalkyl group in C1-C4 or a polyhydroxyalkyl group in C1-C4
R8 representing a hydrogen atom or an alkyl group in C1-C4
R2 is a hydrogen atom, a hydroxyalkyl group in C1-C4 or a polyhydroxyalkyl group in C1-C4,
R3 is a hydrogen atom or an alkyl group in C1-C4, and
R4 represents a hydrogen atom, an alkyl group in C1-C4, a hydroxyalkyl group in C1-C4 or a polyhydroxyalkyl group in C1-C4.
The present invention is intended to provide new compounds belonging to the family of formula I compounds, which are characterized by both good stability and good solubility in aqueous media.
The compounds of the invention have the following general formula:
- What?
where R is the 2,3-dihydroxypropyl group or the 1,3-dihydroxy-2-propyl group.
One of the compounds of the invention is 5-[3-hydroxy-2- ((hydroxymethyl) -propionamide]-N,N'-dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophtalamide, i.e. the compound with the formula
- What?
The other compound according to the invention is 5-[3-hydroxy-2- ((hydroxymethyl-propionamide]-N,N'-dimethyl-N,N'-bis-(1,3-dihydroxy-2-propyl)-2,4,6-triiodoisophtalamide with the following formula:
These formulas cover not only racemics but also all stereoisomers associated with the presence of asymmetric carbon and the inhibition of rotation of certain bonds due to steric congestion by iodine atoms.
Unsurprisingly, the compound of formula A has a better solubility in aqueous media than the compound in example 1 of the European patent application cited above, namely 5-[3-hydroxy-2-(hydroxymethyl) -N-(2,3-dihydroxypropyl) propionamide]-N'-N'-bis-(2-hydroxy-ethyl)-2,4,6-triiodo-isophthallamide.
In addition, the compounds of the invention have the advantage of being more readily available than the compound in example 1 of the above patent application in that they do not require a final N-alkylation stage which poses industrial purification problems.
The compounds of the invention may be obtained by a process consisting of:
(a) react an acid dichloride of formula: R' denoting a -CH-(CH2OH) 2 group whose hydroxy groups are protected,
with an amine chosen from l- ((N-methylamino) propane-2,3-diol and 2- ((N-methylamino) propane-1,3-diol, to obtain a compound with the formula
(b) eliminate the protective groups from group R'.
The compounds of formula II are described in FR-A-2 632 304.
The present invention also covers contrast products which include at least the compounds of the invention.
These contrast agents are used in humans and animals for radiological purposes.
The preferred pharmaceutical form of the contrast agents of the invention is aqueous solutions of the compound.
The aqueous solutions generally contain a total of 5 to 100 g of the compound of the invention per 100 ml and the injectable quantity of such solutions may generally vary from 1 to 1000 ml.
The aqueous solutions of the compounds of 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, and heparin at doses between 10 and 100 units per 100 ml of solution.
These compositions can be administered by all the routes normally used for iodized non-ionic contrast agents, and may be administered entera or parenterally (intravenous, intra-arterial, cavity opacification) and in particular into the subarachnoid space.
An example of composition according to the present invention is given below.
- What?
The following examples illustrate the preparation of the compounds according to the invention.
(a) Preparation of [2-isopropyl-1,3-dioxane-5-carboxamide]-N,N'-dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisoftalamide.
74 g (98 mO) of 5-[2-iso-propyl-1,3-dioxane-5-carboxamide]-2,4,6-triiodoisophtaloyl dichloride is suspended in 300 ml of isopropanol containing 41 ml (294 mO) of triethylamine. 31 g (295 mO) of N-methyl-aminopropane-2,3-diol is added by drip. The agitation is maintained for 12 h at room temperature. Triethylamine hydrochloride is removed by filtration.
The filtrate is evaporated dry, taken up with water and electrolytically treated on OH− IRA 67 resin.
After evaporation, the product is purified by passing on silanized silica (Kieselgel 60 Merck) with water as the electrolyte.
After dry evaporation, 60 g of white powder is collected with an efficiency of 68.5%.- What?
The following is added to the list of substances:
The following shall be reported:
The following substances are to be used in the preparation of the product: (a) N-CH3 (6H); (b) N-CH3 (3H); (c) N-CH3 (3H); (d) N-CH3 (3H); (e) N-CH3 (3H); (f) N-CH2 (3H); (g) N-CH3 (3H); (h) N-CH3 (3H); (g) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) N-CH3 (3H); (h) (3H); N-CH3 (3H); N-CH3 (3H); N-CH3 (3H); N-CH3 (3H); N-CH3 (3H); N-CH3 (3H); N-CH3 (3H); N-CH3 (3H); N-CH3 (3H); N-CH3 (3H); N-CH3 (3H); N-CH3 (h); N-CH3 (h) (3H); N-CH3 (h); N-CH3 (h) (3H); N-CH3 (h); N-CH3 (h) (3H); N-CH3 (h); N-CH3H); 3,5 -3, N-CH3 (h) (3H); N-CH3 (h) (3H); N-CH3 (h) (3H); N-CH3H); N-CH3H); N-CH3 (h) (3H); N-CH (8H); 4, N-CH3H); 4, N-CH3H; 4, 4, 4,
45 g (50.6 mmole) of the compound described in (a) are dissolved in 101 ml (10 eq) of hydrochloric acid 5 N. The agitation is maintained for 12 h at room temperature. The solution is filtered and evaporated dry. The resulting solid is taken up into 100 cm3 of ethyl ether and then filtered and eluted on silanized silica (Kieselgel 60 Merck) with water.After dry evaporation, 38 g of white powder is collected.
The following is added to the list of substances:
The following shall be reported:
The test chemical is used to determine the concentration of the active substance in the test medium.
(a) Preparation of (2-isopropyl-1,3-dioxane-6-carboxamide) -N,N'-dimethyl-N,N'-bis- ((1,3-dihydroxy-2-propyl) --2,4,6-triiodoisoftalamide. The preparation of the product is based on the following formula:
1.46 g (13.9 mmole) of N-methyl-aminopropane -1.3-diol (synthesised according to European patent application EP-A-025 083 filed by EPROVA A.G.) is dissolved in a mixture consisting of 20 cm3 of N-N-dimethylacetamide and 2 cm3 (14.4 mmole) of triethylamine. 3.5 g (4.65 mmole) of 5-(2-isopropyl-1,3-dioxane-5-carboxamide dichloride)-2,4,6-triiodoisophtaloyl is added per serving. The agitation is maintained for 3 hours at 30°C, 12 hours at room temperature. The triethylamine hydrochloride is removed by filtration.
The filtrate is evaporated dry, and the residue is crystallized in a mixture of 20 cm3 isopropanol and 200 cm3 ethyl ether.
After filtration and drying,The test chemical is a white powder with an efficiency of 87%.
The frequency range of the radio spectrum shall be specified.
The following substances are to be classified in the same category as the active substance:
3 g (3.4 mmole) of the compound described in (a) are dissolved in 10 cm3 (15 eq) of 5N hydrochloric acid.The resulting residue is then picked up by 50 cm3 of ethyl ether, filtered, then dissolved in 50 cm3 of water, before being electrolytically treated on H+ (IRN 77) and OH− (IRA 68) resins.
After dry evaporation, 1.7 g of white powder is collected with an efficiency of 60.7%.
The solute is butanol 50, water 25, acetic acid 11.
The frequency range is specified in the Annex to this Regulation.
The following is a list of the chemical compounds of the isomer Z:The test chemical is a chemical compound with a specific chemical activity.
The frequency range is from 0 to 100 MHz.
The total number of samples shall be calculated by adding the following data:
Claims (9)
- Process for the preparation of a compound corresponding to the general formula: in which R is chosen from 2,3-dihyroxypropyl and 1,3-dihydroxy-2-propyl groups, consisting ina) reacting a diacyl chloride of formula: R' denoting a -CH-(CH₂OH)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 andb) removing the protecting groups of the group R'.
- Process for the preparation of a contrast medium, characterized in that a compound of formula I as defined in Claim 1 is placed in a form which may be administered.
- Process according to Claim 2, characterized in that the compound is placed in the form of an aqueous solution.
Applications Claiming Priority (2)
| 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. |
| FR9000106 | 1990-01-05 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1006019B true HK1006019B (en) | 1999-02-05 |
| HK1006019A1 HK1006019A1 (en) | 1999-02-05 |
Family
ID=9392557
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HK98105100A HK1006019A1 (en) | 1990-01-05 | 1998-06-10 | Non-ionic iodinated compounds, procedure for their preparation and contrast agents 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 DK DK90403770.2T patent/DK0437144T3/en active
- 1990-12-26 DE DE69014581T patent/DE69014581T2/en not_active Expired - Lifetime
- 1990-12-26 EP EP90403770A patent/EP0437144B1/en not_active Expired - Lifetime
- 1990-12-26 ES ES90403770T patent/ES2067710T3/en not_active Expired - Lifetime
- 1990-12-26 AT AT90403770T patent/ATE114639T1/en not_active IP Right Cessation
- 1990-12-27 IL IL9681290A patent/IL96812A/en not_active IP Right Cessation
- 1990-12-28 KR KR1019910701024A patent/KR100194506B1/en not_active Expired - Lifetime
- 1990-12-28 RO RO148263A patent/RO108559B1/en unknown
- 1990-12-28 HU HU912860A patent/HUT59079A/en unknown
- 1990-12-28 WO PCT/FR1990/000969 patent/WO1991009836A1/en not_active Ceased
- 1990-12-28 CA CA002050334A patent/CA2050334C/en not_active Expired - Lifetime
-
1991
- 1991-01-03 PT PT96410A patent/PT96410B/en not_active IP Right Cessation
- 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 JP JP3052354A patent/JP2529032B2/en not_active Expired - Lifetime
- 1991-01-04 IE IE3591A patent/IE65329B1/en not_active IP Right Cessation
- 1991-01-04 NZ NZ236675A patent/NZ236675A/en unknown
- 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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