EP0656884A1 - Nouveaux composes poly-iodes, procede de preparation, produit de contraste les contenant - Google Patents

Nouveaux composes poly-iodes, procede de preparation, produit de contraste les contenant

Info

Publication number
EP0656884A1
EP0656884A1 EP93919397A EP93919397A EP0656884A1 EP 0656884 A1 EP0656884 A1 EP 0656884A1 EP 93919397 A EP93919397 A EP 93919397A EP 93919397 A EP93919397 A EP 93919397A EP 0656884 A1 EP0656884 A1 EP 0656884A1
Authority
EP
European Patent Office
Prior art keywords
group
represent
formula
groups
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP93919397A
Other languages
German (de)
English (en)
French (fr)
Inventor
Maryse Dugast-Zrihen
Dominique Meyer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guerbet SA
Original Assignee
Guerbet SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guerbet SA filed Critical Guerbet SA
Publication of EP0656884A1 publication Critical patent/EP0656884A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent

Definitions

  • the present invention relates to new polyiodinated compounds which can be used in contrast products for radiography.
  • the invention also relates to a process for the preparation of these compounds and to the contrast products containing them.
  • the subject of the invention is therefore poly-iodinated compounds of formula:
  • R 1 and R 2 which are identical or different from each other, represent a group of formula
  • R 3 , R 4 identical or different from each other, represent a group of formula
  • R 5 and R 6 , R 7 and R 8 which are identical or different from each other represent a hydrogen atom, a linear or branched C 1 -C 6 alkyl group, a hydroxy- or polyhydroxy-C 1 alkyl group - Linear or branched C 6 , optionally also comprising one or more C 1 -C 6 alkoxy groups, in particular methoxy or ethoxy, a C 1 -C 6 alkoxy group, linear or branched C 1 -C 6 alkyl or a hydroxy- or polyhydroxy-alkoxy- (C 1 -C 6 ) linear or branched C 1 -C 6 alkyl, said substituents R 1 , R 2 , R 3 , R 4 comprising in total at least ten hydroxy groups.
  • R 5 , R 6 and R 8 are chosen from -CH 3 , -CH 2 OH, -CH 2 -CH 2 OH,
  • R 5 represents the group
  • R 6 is chosen from -CH 3 , -CH 2 -CH 2 OH, and .
  • R 7 is as defined above
  • R 8 is chosen from -CH 3 , -CH 2 OH,, -CHOH-CH 2 OH and
  • the preferred compounds of the present invention are those in which:
  • R 1 and R 2 represent the group
  • R 3 and R 4 represent the group -NH-CO-CHOH-CH 2 OH (compound No. 1); - R 1 and R 2 represent the group
  • R 3 and R 4 represent the group
  • R 1 and R 2 represent the group
  • R 3 and R 4 represent the group -NH-CO-CH 3 (compound No. 3);
  • R 1 and R 2 represent the group
  • R 3 and R 4 represent the group
  • R 1 and R 2 represent the group
  • R 3 and R 4 represent the group
  • R 1 and R 2 represent the group and R 3 and R 4 represent the group
  • R 1 and R 2 represent the group
  • R 3 and R 4 represent the group
  • R 1 and R 2 represent the group
  • R 3 and R 4 represent the group
  • R 1 and R 2 represent the group
  • R 3 and R 4 represent the group
  • R 1 and R 2 represent the group
  • R 3 and R 4 represent the group
  • R 1 and R 2 represent the group
  • R 3 and R 4 represent the group
  • R 1 and R 2 represent the group
  • R 3 and R 4 represent the group
  • the compounds of general formula (I) of the present invention can be prepared by alkylation and / or acylation reactions.
  • the compounds of general formula (I) of the present invention can in particular be prepared by a process comprising the following stages:
  • X being chosen from chlorine, bromine and iodine and
  • R ' 1 , R' 2 represent the group -CO 2 R with R representing a C 1 -C 6 alkyl group, and R ' 3 , R' 4 represent the group -NO 2 so as to obtain a compound of formula IV:
  • R ' 1 , R' 2 , R ' 3 and R' 4 are as defined above.
  • R 5 and R 6 being defined as above;
  • step a) deprotection of the protected hydroxy groups and optionally alkylation of the amido groups by a reagent of formula ZR 7 , Z being a labile group such as Cl, Br or I and R 7 being as defined above.
  • the reaction of step a) preferably takes place in an appropriate solvent such as xylene, nitrobenzene, nitrotoluene, DMF or pyridine, in the presence of a metal catalyst such as copper according to the method of Ullman (E. FANTA, Chem. Rev. 64, 613, 1964).
  • step c) is a catalytic reduction by hydrogen on palladium carbon or on Ranney nickel or a chemical reduction.
  • step d) takes place under usual conditions, such as by aqueous ICI or I 2 , in the presence of K1 / ethylamine at temperatures between 0 ° C and 100 ° C.
  • acylation and alkylation reactions of steps f) and g) are carried out under conventional conditions, in the presence of a strong base.
  • the compounds of formula (I) of the present invention can also be prepared by a process comprising the following steps:
  • R 5 and R 6 being as defined above;
  • the compounds of formula I of the present invention can also be prepared by a process comprising the following stages:
  • X being chosen from chlorine, bromine and iodine and R ' 1 , R' 2 representing the group -CO 2 R with R representing H or a C 1 -C 6 alkyl group, and R ' 3 , R' 4 representing the group -NO 2 so as to obtain a compound of formula IV:
  • R ' 1 , R' 2 , R ' 3 and R' 4 are as defined above;
  • amine alcohols used to obtain the preferred compounds of the present invention can be prepared in the following manner: Preparation of the amine alcohol n ° 1 a) Preparation of the compound of formula
  • the compound is prepared according to the method described above.
  • butene 1,4-diol (commercially available from the company Aldrich-Strasbourg), butene 3,4-diol is prepared according to the method of rearrangement described in US Patent 4,661,646.
  • the invention encompasses not only the compounds of formula (I) in the form of a racemic mixture but also the stereoisomers such as enantiomers, diastereoisomers, atropoisomers, SYN-ANTI, ENDO-EXO, EZ isomers, linked to the presence asymmetric carbon atoms and / or rotation impediments due to steric hindrance provided by iodine atoms and / or by the substituents R 1 to R 4 of the compounds of formula (I).
  • the present invention also relates to contrast products which comprise at least one compound of formula (I).
  • contrast media are used in humans and animals for radiological purposes.
  • the preferred pharmaceutical form of the contrast agents according to the invention consists of aqueous solutions of the compounds.
  • the compounds are encapsulated inside liposomes.
  • the aqueous solutions generally contain a total of 5 to 100 g of compounds per 100 ml and the injectable amount of such solutions can generally vary from 1 to 1000 ml.
  • the solutions can also contain additives such as a sodium salt including sodium citrate, heparin and sodium EDTA calcium.
  • compositions can be administered by any of the routes conventionally used for iodinated nonionic contrast media.
  • routes conventionally used for iodinated nonionic contrast media can be administered by enteral or parenteral route (intravenous, intraarterial, opacification of the cavities) and in particular in the subarachnoid space.
  • the residual paste is washed with 2 ⁇ 500 ml of petroleum ether, then taken up in ether.
  • the brown precipitate formed is drained and then purified by chromatography on silica. After evaporation, 20 g of brown crystals are obtained.
  • step a) To the solution obtained in step a) are added dropwise 4.35 ml (0.024 mole) of a 70% IC1 solution. When the addition is complete, the reaction mixture is brought to 80 ° C. for 18 h and then left for 12 h at room temperature. The brown solution obtained is evaporated and then returned to iodization with 1.45 ml of 70% IC1 in 20 ml of MeOH. After 10 h at 80 ° the solvent is evaporated and the paste washed with acetone. The product is taken up in ether, then dried. 2.1 g of white crystals are obtained.
  • the slightly concentrated reaction medium is poured onto 200 cm 3 of ice-cold H 2 O. After filtration of the precipitate, 10 g of a cream solid are obtained.
  • Example 1 12.5 g (0.0376 mol) of the compound obtained in 4) of Example 1 are added to a solution of 100 ml of SOCl 2 and 0.1 ml of DMF. The solution is brought to reflux for 5 hours. After distillation of SOCl 2 , the paste obtained is dissolved in CH 2 Cl 2 and poured dropwise at 20 ° C in a solution containing 20.5 g (0.105 mole) of N-2,3 propanediol-N, 2,3 , 4-trihydroxybutylamine and 14.6 ml (0.105 mole) of triethylamine dissolved in 80 ml of DMAC. After addition, the mixture is stirred for 4 hours at room temperature. After filtration of the triethylamine hydrochloride, the solvent is evaporated. The paste obtained is purified by passage over H + resin. After evaporation of the solvent, 33 g of brown oil are obtained.
  • step a) To the solution obtained in step a) are added dropwise 54 ml (0.3 mole) of a 70% ICl solution. When the addition is complete, the reaction mixture is left at room temperature for 12 hours. The solution is poured into 2000 ml of ether, the precipitate obtained is filtered and then washed with ether. After drying, the product obtained is returned to iodization with 54 ml (0.3 mole) of 70% IC1 in 500 ml of MeOH. After 12 hours at 50 ° C the same treatment as above is applied to the solution. The precipitate obtained is returned a third time to iodization with 27 ml of IC1 (0.15 mole) in 300 ml of MeOH.
  • the paste obtained is purified by passage over H + resin. After evaporation of the solvent, 150 g of brown oil are obtained.
  • step a) To the solution obtained in step a) are added dropwise 62 ml (0.353 mole) of a 10% ICl solution. When the addition is complete, the reaction mixture is left at room temperature for 12 hours. The solution is poured into 2000 ml of ether, the precipitate obtained is filtered, then washed with ether. After drying, the product obtained is returned to iodization with 31 ml of 70% IC1 (0.17 mole) in 300 ml of MeOH. After 12 hours at 50 ° C, the same treatment as above is applied to the solution. Cream crystals are obtained.

Landscapes

  • 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)
EP93919397A 1992-08-25 1993-08-24 Nouveaux composes poly-iodes, procede de preparation, produit de contraste les contenant Withdrawn EP0656884A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9210270 1992-08-25
FR9210270A FR2695125B1 (fr) 1992-08-25 1992-08-25 Nouveaux composés poly-iodés, procédé de préparation, produit de contraste les contenant.
PCT/FR1993/000824 WO1994004488A1 (fr) 1992-08-25 1993-08-24 Nouveaux composes poly-iodes, procede de preparation, produit de contraste les contenant

Publications (1)

Publication Number Publication Date
EP0656884A1 true EP0656884A1 (fr) 1995-06-14

Family

ID=9433015

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93919397A Withdrawn EP0656884A1 (fr) 1992-08-25 1993-08-24 Nouveaux composes poly-iodes, procede de preparation, produit de contraste les contenant

Country Status (15)

Country Link
US (1) US5618977A (fi)
EP (1) EP0656884A1 (fi)
JP (1) JPH08500355A (fi)
CN (1) CN1090572A (fi)
AU (1) AU4964493A (fi)
CA (1) CA2142986A1 (fi)
FI (1) FI950874A (fi)
FR (1) FR2695125B1 (fi)
HU (1) HUT70943A (fi)
IL (1) IL106768A0 (fi)
NO (1) NO950665L (fi)
PL (1) PL307587A1 (fi)
TR (1) TR26907A (fi)
WO (1) WO1994004488A1 (fi)
ZA (1) ZA936188B (fi)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6310243B1 (en) 1994-09-23 2001-10-30 Nycomed Imaging As Iodinated x-ray contrast media
GB9419206D0 (en) * 1994-09-23 1994-11-09 Nycomed Innovation Ab Contrast media
GB9419203D0 (en) * 1994-09-23 1994-11-09 Nycomed Innovation Ab Contrast media
IT1271134B (it) * 1994-12-01 1997-05-26 Bracco Spa Derivati iodurati del bifenile e loro impiego diagnostico
US6265610B1 (en) * 1999-01-12 2001-07-24 The University Of North Carolina At Chapel Hill Contrast media for angiography
US8926945B2 (en) 2005-10-07 2015-01-06 Guerbet Compounds comprising a biological target recognizing part, coupled to a signal part capable of complexing gallium
WO2017165841A1 (en) 2016-03-25 2017-09-28 Nanoprobes, Inc. Iodine-based particles

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3429949A1 (de) * 1984-08-10 1986-02-20 Schering AG, 1000 Berlin und 4709 Bergkamen Neue nicht -ionische 2,4,6-trijod-isophthalsaeure-bis-amide, verfahren zu ihrer herstellung und ihre verwendung als roentgenkontrastmittel
DE3731542A1 (de) * 1987-09-17 1989-03-30 Schering Ag Neue dicarbonsaeure-bis(3,5-dicarbamoyl-2,4,6-triiod-anilide), verfahren zu deren herstellung sowie diese enthaltende roentgenkontrastmittel
IL90326A (en) * 1988-06-02 1993-05-13 Guerbet Sa Non-ionic triiodobenzene compounds and contrast media containing them

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9404488A1 *

Also Published As

Publication number Publication date
PL307587A1 (en) 1995-05-29
ZA936188B (en) 1994-06-24
WO1994004488A1 (fr) 1994-03-03
FI950874A0 (fi) 1995-02-24
FI950874A (fi) 1995-02-24
NO950665D0 (no) 1995-02-22
US5618977A (en) 1997-04-08
CN1090572A (zh) 1994-08-10
AU4964493A (en) 1994-03-15
CA2142986A1 (en) 1994-03-03
FR2695125B1 (fr) 1994-12-23
IL106768A0 (en) 1993-12-08
NO950665L (no) 1995-04-24
FR2695125A1 (fr) 1994-03-04
HUT70943A (en) 1995-11-28
JPH08500355A (ja) 1996-01-16
TR26907A (tr) 1994-08-22
HU9500578D0 (en) 1995-04-28

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