WO2000000461A1 - Tetraiodoterephthalamide polyhydroxylated derivatives, preparation method and use in radiology - Google Patents

Tetraiodoterephthalamide polyhydroxylated derivatives, preparation method and use in radiology Download PDF

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Publication number
WO2000000461A1
WO2000000461A1 PCT/FR1999/001406 FR9901406W WO0000461A1 WO 2000000461 A1 WO2000000461 A1 WO 2000000461A1 FR 9901406 W FR9901406 W FR 9901406W WO 0000461 A1 WO0000461 A1 WO 0000461A1
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mixture
isomers
iodine
choh
radiology
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PCT/FR1999/001406
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French (fr)
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Myriam Petta
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Guerbet S.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/69—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton

Definitions

  • the present invention relates to an amide derived from tetraiodoterephthalic acid and from 1-deoxy 1 - [(2,3-dihydroxypropyl) amino] D-galactitol, its application as a contrast agent in medical X-ray imaging, as well as stereoisomers of this synthetic intermediate amino alcohol.
  • An iodine, non-ionic compound for imaging the cardiovascular system, the nervous system as well as the hepatobiliary or urinary zones must be administered, intravenously and / or intraarterially, which implies that it satisfies a certain number of criteria more or less contradictory: - significant opacification power (high number of iodine atoms per molecule),
  • the amides derived from tetraiodoterephthalic acid which have a large number of hydroxyl groups on the substituents of the nitrogen atoms, from 10 to 24, such as those described in EP-A-6751 05, give aqueous solutions of sufficient concentration for quality medical imaging, while exhibiting an acceptable viscosity and an osmolality, in principle, lower than that of triiodic nonionic monomers.
  • Some of these compounds may be present, given the presence of asymmetric carbon atoms, in the form of mixtures, in various proportions, of isomers which can be distinguished, in general, by high performance liquid chromatography.
  • the steric hindrance around the carboxamido groups due to the presence of 2 iodine atoms in ortho on the phenyl nucleus, hinders the rotations of the atoms around the C-CO and CO-N bonds so that the isomers
  • Corresponding conformals in solution are generally not interconvertible under ordinary temperature and pressure conditions, but also during recrystallizations of the product or final heat sterilization.
  • the product of the present invention easy to prepare, inexpensive, has properties suitable for wider diagnostic use, and this even with respect to its isomers, derived from mannitol and sorbitol. So, - Its solubility at room temperature (20 ° C) is greater than 45 g of iodine / 1 00 ml of solution whereas that of the isomers from which the pentahydroxylated chain is derived is D-glucose (example 7 in EP-A-6751 05 ), or D-mannose, is less than 30 g of iodine / 1 00 ml; in addition, at the lower temperatures that can be encountered during storage, the solubility of the product remains high, while that of the isomers drops suddenly with temperature.
  • the osmolality of its aqueous solution containing 30 g of iodine per 100 ml is approximately 2 times lower than that of the solutions of monomers derived from the triiodophenyl nucleus.
  • the invention relates to the compound, useful as a contrast agent for X-ray radiology, of formula
  • N-CH 2 - (CHOH) 4 -CH 2 OH groups have the configuration of 1-amino
  • each CH 2 -CHOH-CH 2 OH group, having an asymmetric carbon is in the form of each of the 2 enantiomers or of a mixture of the two, preferably in relative proportion between 25% and 50 % and better from 45% to 50%.
  • this compound can have several conformations whose relative percentages will depend on its structure but also, in particular, on the conditions its synthesis and purification, insofar as they are not easily interconvertible; the invention also relates to the various mixtures of these conformational isomers, the existence of which can generally be demonstrated by high pressure liquid chromatography.
  • the compound of the invention is prepared in a manner known per se, by the action of the tetraiodoterephthalic acid dichloride on the amino alcohol of appropriate configuration of formula
  • N-methylpyrrolidone and in the presence of a base, which may be a tertiary amine, a carbonate or an alkali metal hydroxide or an excess of the amino alcohol, at a temperature between 30 ° C and 100 ° C. Under these conditions, it is possible not to block the hydroxyl functions of the amino alcohol.
  • a base which may be a tertiary amine, a carbonate or an alkali metal hydroxide or an excess of the amino alcohol
  • the diamide can be purified by precipitation or by recrystallization, preferably after removal of the salts formed and of the acid and basic impurities by treatment of an aqueous solution of the crude mixture with anion and cation exchange resins.
  • Tetraiodoterephthalic acid dichloride is a known product, which can be prepared by the action of SOCI 2 in excess on the diacid, optionally in a solvent such as an aromatic hydrocarbon, a halogenated hydrocarbon, or dioxane, preferably in the presence a catalyst such as dimethylformamide, a tertiary amine or a quaternary ammonium, for example as described in Synthesis, p. 441 -442, June 1991.
  • Tetraiodoterephthalic acid can be prepared by the action of iodine on terephthalic acid in a sulfuric medium.
  • 1-deoxy 1 - [(2,3-dihydroxypropyl) amino] D-galactitol can be prepared by processes the principle of which is known, for example by the action of 3-chloropropane-1, 2-diol or glycidol on the 1 -amino 1 -deoxy D-galactitol or by action of D-galactose on 3-aminopropane-1, 2-diol in reducing medium or also by action of D-galactose on benzylamine in reducing medium to give l - ( benzylamino) 1-deoxy D-galactitol, known compound, on which reacts 3-chloropropane-1, 2-diol or glycidol to obtain the tertiary amine which is debenzylated in the usual way by the action of hydrogen.
  • the separation of the 2 diastereoisomers and / or the enrichment of the mixture with one or the other can be carried out in a known manner by recrystallization of the amino alcohol or one of its salts.
  • the invention also relates to 1-deoxy 1 - [2,3-dihydroxypropylamino] D-galactitol, a new product, a fundamental intermediate in the synthesis of the contrast product of the invention since the other known isomer, 1-deoxy 1 - [(2,3-dihydroxypropyl) amino] D-glucitol leads to a tetraiodic diamide which can only be administered in aqueous solution at a concentration of less than 300 mg of iodine / ml, whereas such a concentration is necessary for certain types of diagnostic radiology.
  • the invention also includes the compositions for medical X-ray imaging, containing the contrast product of formula I previously defined, and a pharmaceutically acceptable vehicle.
  • These compositions will, depending on the type of imaging, be administered at the usual doses parenterally or intravascularly.
  • the composition is in the form of an aqueous solution with a concentration of between 200 mg of iodine / ml to 350 mg of iodine / ml and better still of approximately 300 mg of iodine / ml; the solution may contain the usual adjuvants of iodinated contrast agents, such as buffers, ions of the blood plasma (Na + , Ca + + , Mg + + , K + ), oxygen, or stabilizers, such than EDTA.
  • iodinated contrast agents such as buffers, ions of the blood plasma (Na + , Ca + + + , Mg + + , K + ), oxygen, or stabilizers, such than EDTA.
  • compositions can be used as the nonionic iodine contrast agents currently on the market, in particular for visualizing the vascular compartment, the nervous system, the gastrointestinal region, the lung, the kidneys, or other parts of the body. They can therefore find an application, in particular, in cerebral angiography or peripheral, in urography, in myelography, or in arthrography and hysterosalpingography.
  • the unit doses (volume and iodine concentration of the solutions) will be of the same order as those currently used in practice, depending on the size and age of the patient and obviously on the type of imaging performed.
  • 0.25 liters of 65% oleum is introduced dropwise at 40 ° C in 500 ml of concentrated sulfuric acid, then at 70 ° C, 170 g of iodine are introduced. 62.5 g of terephthalic acid are added at 80 ° C. then the reaction medium is brought, within 2 hours, to 125 ° C., a temperature which is then maintained for 36 hours.
  • the mixture After returning to room temperature, the mixture is poured slowly into 3 liters of water; 5 ml of 5 M aqueous NaHSO 3 solution are added before filtering off the precipitate.
  • the amino alcohol is a practically 50/50 mixture of the two diastereoisomers.
  • the mixture can be enriched in one or other of the isomers.
  • Each diastereoisomer can also be obtained by condensing D-galactose on the pure enantiomer of aminopropanediol or by the action of the enantiomers of glycidol on N- (2,3,4,5,6-pentahydroxyhexyl) benzylamide as follows: a ) N-benzyl N- (2,3,4,5,6-pentahydroxyhexyl) amine 29 g of D-galactose, 1 7 ml of benzylamine are dissolved in 230 ml of methanol and the mixture is kept at 50 ° C. for 7 hours under a hydrogen pressure of 8 ⁇ 10 5 Pa, after addition of 5 g of 5% palladium on carbon.
  • an aqueous solution of hydrochloric acid up to acidic pH is introduced at 40 ° C. into the reaction medium.
  • the mixture is filtered on celite® at room temperature to remove the catalyst, and after partial concentration, an aqueous solution of 5N NaOH is introduced until basic pH.
  • the precipitate formed is isolated and recrystallized from ethanol.
  • the mixture is kept stirring for 3 days at this temperature and then poured into 3 liters of ethyl acetate.
  • the solid is isolated by filtration then it is dissolved in the minimum of water (20 ml) and this solution is poured into 1 liter of isopropanol.
  • the precipitate formed is dissolved in 200 ml of water and the solution is chromatographed on a cation exchange resin in acid form (1 50 ml of IMAC HP 1 1 0 NA) then of weakly basic anions (1 20 ml of Amberlite® IRA 67).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

The invention concerns an amide, derived from tetraiodoterephthalic acid and from amino 1-deoxy D-galactitol of formula (I). The invention is useful as contrasting product in X-ray radiology.

Description

Dérivé polyhydroxylé du tétraiodotéréphtalamide , son procédé de préparation et son utilisation en radiologie . Polyhydroxylated derivative of tetraiodoterephthalamide, its preparation process and its use in radiology.
La présente invention concerne un amide dérivé de l'acide tétraiodotéréphtalique et du 1 -déoxy 1 -[(2,3-dihydroxypropyl)amino] D-galactitol, son application comme produit de contraste en imagerie médicale par rayons X, ainsi que les stéréoisomères de cet aminoalcool intermédiaire de synthèse. Un composé iodé, non ionique, pour l'imagerie du système cardiovasculaire, du système nerveux comme des zones hépatobiliaires ou urinaires, doit être administré, par voie intraveineuse et/ou intraartérielle, ce qui implique qu'il satisfasse un certain nombre de critères plus ou moins contradictoires: - pouvoir d'opacification important (nombre d'atomes d'iode par molécule élevé),The present invention relates to an amide derived from tetraiodoterephthalic acid and from 1-deoxy 1 - [(2,3-dihydroxypropyl) amino] D-galactitol, its application as a contrast agent in medical X-ray imaging, as well as stereoisomers of this synthetic intermediate amino alcohol. An iodine, non-ionic compound for imaging the cardiovascular system, the nervous system as well as the hepatobiliary or urinary zones must be administered, intravenously and / or intraarterially, which implies that it satisfies a certain number of criteria more or less contradictory: - significant opacification power (high number of iodine atoms per molecule),
- solubilité aqueuse élevée (concentration exprimée en grammes d 'iode/litre) ,- high aqueous solubility (concentration expressed in grams of iodine / liter),
- stabilité lors de la stérilisation des solutions et pendant leur conservation,- stability during the sterilization of the solutions and during their conservation,
- viscosité de la solution diagnostique compatible avec une injection rapide et osmolalité voisine de celle du sang pour limiter l'hémodilution et l'inconfort du patient,- viscosity of the diagnostic solution compatible with rapid injection and osmolality close to that of blood to limit hemodilution and patient discomfort,
- pas ou peu d'effets indésirables in vivo (une faible lipophilie limite les interactions néfastes avec des bio-molécules),- no or few undesirable effects in vivo (low lipophilicity limits harmful interactions with biomolecules),
-_ élimination du corps rapide et totale, sans formation de métabolites toxiques.-_ rapid and total elimination from the body, without the formation of toxic metabolites.
Ces conditions sont développées notamment, dans l'ouvrage Contrast Media: Biologie effects and clinical application - 1(3) - Zaheer Parvez - CRC Press ( 1 987).These conditions are developed in particular in the book Contrast Media: Biologie effects and clinical application - 1 (3) - Zaheer Parvez - CRC Press (1 987).
Pour augmenter le pouvoir d 'opacification par molécule et donc diminuer l'osmolalité des solutions de concentration en iode donnée, ce n'est que récemment qu'on a proposé des composés comportant un noyau phényle tétraiodé comme produits de contraste non ioniques, alors que de très nombreux dérivés du noyau phényle triiodé ont été étudiés et que tous les produits commercialisés comportent ce groupe. Même si la présence de 4 atomes d'iode par molécule pouvait suggérer une bonne opacification associée à une faible osmolalité, on estimait, en effet, que ce noyau polyiodé particulièrement volumineux et hydrophobe donnerait des produits peu solubles et toxiques. On sait maintenant que les amides dérivés de l'acide tétraiodotéréphtalique, qui comportent un grand nombre de groupes hydroxyles sur les substituants des atomes d'azote, de 1 0 à 24, tels que ceux décrits dans EP-A-6751 05, donnent des solutions aqueuses de concentration suffisante pour une imagerie médicale de qualité, tout en présentant une viscosité acceptable et une osmolalité, en principe, inférieure à celle des monomères non ioniques triiodés.To increase the opacification power per molecule and therefore decrease the osmolality of the solutions with given iodine concentration, it is only recently that compounds comprising a tetraiodinated phenyl nucleus have been proposed as nonionic contrast agents, whereas very many derivatives of the triiodinated phenyl nucleus have been studied and that all the products sold contain this group. Even if the presence of 4 iodine atoms per molecule could suggest a good opacification associated with a low osmolality, it was estimated, in fact, that this particularly voluminous and hydrophobic polyiodic nucleus would give poorly soluble and toxic products. It is now known that the amides derived from tetraiodoterephthalic acid, which have a large number of hydroxyl groups on the substituents of the nitrogen atoms, from 10 to 24, such as those described in EP-A-6751 05, give aqueous solutions of sufficient concentration for quality medical imaging, while exhibiting an acceptable viscosity and an osmolality, in principle, lower than that of triiodic nonionic monomers.
Certains de ces composés peuvent se présenter, étant donné la présence des atomes de carbone asymétriques, sous forme de mélanges, en proportions diverses, d'isomères que l'on peut distinguer, en général, par chromatographie liquide haute performance. En outre, l'encombrement stérique autour des groupes carboxamido, dû à la présence de 2 atomes d'iode en ortho sur le noyau phényle, gêne les rotations des atomes autour des liaisons C-CO et CO-N de telle sorte que les isomères conformationnels correspondants en solution ne sont en général pas interconvertibles dans les conditions de température et pression ordinaires, mais aussi lors des recristallisations du produit ou de la stérilisation finale à la chaleur.Some of these compounds may be present, given the presence of asymmetric carbon atoms, in the form of mixtures, in various proportions, of isomers which can be distinguished, in general, by high performance liquid chromatography. In addition, the steric hindrance around the carboxamido groups, due to the presence of 2 iodine atoms in ortho on the phenyl nucleus, hinders the rotations of the atoms around the C-CO and CO-N bonds so that the isomers Corresponding conformals in solution are generally not interconvertible under ordinary temperature and pressure conditions, but also during recrystallizations of the product or final heat sterilization.
Le présent inventeur a constaté que malgré leurs propriétés intéressantes, les composés antérieurs répondant à la formule mentionnée dans EP-A-6751 05, ne pouvaient, compte-tenu des critères précédemment cités, être comparés favorablement aux produits de contraste de type monomère ou dimère non ioniques actuellement commercialisés dans tous les domaines de la radiologie médicale, notamment à cause de leur solubilité aqueuse insuffisante.The present inventor has found that, despite their advantageous properties, the prior compounds corresponding to the formula mentioned in EP-A-6751 05, could not, in view of the criteria mentioned above, be compared favorably with contrast agents of monomer or dimer type non-ionic currently marketed in all areas of medical radiology, especially because of their insufficient aqueous solubility.
Aussi il est surprenant que le produit de la présente invention, facile à préparer, peu coûteux, ait des propriétés convenant à une utilisation diagnostique élargie, et cela même vis-à-vis de ses isomères, dérivés du mannitol et du sorbitol. Ainsi, - sa solubilité à température ambiante (20°C) est supérieure à 45 g d'iode/1 00 ml de solution alors que celle des isomères dont la chaîne pentahydroxylée dérive soit du D-glucose (exemple 7 dans EP-A-6751 05), soit du D-mannose, est inférieure à 30 g d'iode/1 00 ml; en outre, aux températures plus basses que l'on peut rencontrer en cours de stockage, la solubilité du produit reste élevée, alors que celle des isomères chute brutalement avec la température.Also it is surprising that the product of the present invention, easy to prepare, inexpensive, has properties suitable for wider diagnostic use, and this even with respect to its isomers, derived from mannitol and sorbitol. So, - Its solubility at room temperature (20 ° C) is greater than 45 g of iodine / 1 00 ml of solution whereas that of the isomers from which the pentahydroxylated chain is derived is D-glucose (example 7 in EP-A-6751 05 ), or D-mannose, is less than 30 g of iodine / 1 00 ml; in addition, at the lower temperatures that can be encountered during storage, the solubility of the product remains high, while that of the isomers drops suddenly with temperature.
- son coefficient de partage (octanol/eau) est inférieur à celui des composés à noyau triiodophényle commercialisés;- its partition coefficient (octanol / water) is lower than that of commercial triiodophenyl ring compounds;
- l'osmolalité de sa solution aqueuse à 30 g d'iode pour 1 00 ml est d'environ 2 fois plus faible que celle des solutions de monomères dérivés du noyau triiodophényle.- the osmolality of its aqueous solution containing 30 g of iodine per 100 ml is approximately 2 times lower than that of the solutions of monomers derived from the triiodophenyl nucleus.
L'invention concerne le composé, utile comme produit de contraste pour la radiologie X, de formuleThe invention relates to the compound, useful as a contrast agent for X-ray radiology, of formula
Figure imgf000005_0001
dans laquelle les groupes N-CH2-(CHOH)4-CH2OH ont la configuration du 1 -amino
Figure imgf000005_0001
in which the N-CH 2 - (CHOH) 4 -CH 2 OH groups have the configuration of 1-amino
1 -déoxy D-galactitol et chaque groupe CH2-CHOH-CH2OH, ayant un carbone asymétrique, est sous forme de chacun des 2 énantiomères ou d'un mélange des deux, de préférence en proportion relative comprise entre 25% et 50% et mieux de 45% à 50%. Etant donné l'encombrement stérique autour du groupe amido, dû à la présence des 2 atomes d 'iode en ortho sur le noyau phényle, ce composé peut présenter plusieurs conformations dont les pourcentages relatifs seront fonction de sa structure mais aussi, notamment, des conditions de sa synthèse et de sa purification, dans la mesure où elles ne sont pas aisément interconvertibles; l'invention concerne aussi les différents mélanges de ces isomères conformationnels, dont l'existence peut en général être mise en évidence par chromatographie liquide haute pression. Le composé de l'invention est préparé de façon connue en soi, par action du dichlorure de l'acide tétraiodotéréphtalique sur l'aminoalcool de configuration appropriée de formule1 -deoxy D-galactitol and each CH 2 -CHOH-CH 2 OH group, having an asymmetric carbon, is in the form of each of the 2 enantiomers or of a mixture of the two, preferably in relative proportion between 25% and 50 % and better from 45% to 50%. Given the steric hindrance around the amido group, due to the presence of the 2 atoms of iodine in ortho on the phenyl nucleus, this compound can have several conformations whose relative percentages will depend on its structure but also, in particular, on the conditions its synthesis and purification, insofar as they are not easily interconvertible; the invention also relates to the various mixtures of these conformational isomers, the existence of which can generally be demonstrated by high pressure liquid chromatography. The compound of the invention is prepared in a manner known per se, by the action of the tetraiodoterephthalic acid dichloride on the amino alcohol of appropriate configuration of formula
CH2-CHOH-CH2OHCH 2 -CHOH-CH 2 OH
H-NH-N
^CH2(CHOH)4-CH2OH en solution dans un solvant aprotique polaire, tel que le diméthylacétamide ou la^ CH 2 (CHOH) 4 -CH 2 OH in solution in a polar aprotic solvent, such as dimethylacetamide or
N-méthylpyrrolidone, et en présence d'une base, qui peut être une aminé tertiaire, un carbonate ou un hydroxyde de métal alcalin ou un excès de l'aminoalcool, à une température comprise entre 30°C et 100°C. Dans ces conditions, il est possible de ne pas bloquer les fonctions hydroxyles de l'aminoalcool.N-methylpyrrolidone, and in the presence of a base, which may be a tertiary amine, a carbonate or an alkali metal hydroxide or an excess of the amino alcohol, at a temperature between 30 ° C and 100 ° C. Under these conditions, it is possible not to block the hydroxyl functions of the amino alcohol.
Le diamide peut être purifié par précipitation ou par recristallisation, de préférence après élimination des sels formés et des impuretés acides et basiques par traitement d'une solution aqueuse du mélange brut avec des résines échangeuses d'anions et de cations. Le dichlorure d'acide tétraiodotéréphtalique est un produit connu, qui peut être préparé par action de SOCI2 en excès sur le diacide, éventuellement, dans un solvant tel qu'un hydrocarbure aromatique, un hydrocarbure halogène, ou le dioxanne, de préférence en présence d'un catalyseur tel que le diméthylformamide, une aminé tertiaire ou un ammonium quaternaire, par exemple comme décrit dans Synthesis, p. 441 -442, Juin 1991.The diamide can be purified by precipitation or by recrystallization, preferably after removal of the salts formed and of the acid and basic impurities by treatment of an aqueous solution of the crude mixture with anion and cation exchange resins. Tetraiodoterephthalic acid dichloride is a known product, which can be prepared by the action of SOCI 2 in excess on the diacid, optionally in a solvent such as an aromatic hydrocarbon, a halogenated hydrocarbon, or dioxane, preferably in the presence a catalyst such as dimethylformamide, a tertiary amine or a quaternary ammonium, for example as described in Synthesis, p. 441 -442, June 1991.
L'acide tétraiodotéréphtalique peut être préparé par action de l'iode sur l'acide téréphtalique en milieu sulfurique.Tetraiodoterephthalic acid can be prepared by the action of iodine on terephthalic acid in a sulfuric medium.
Le 1 -déoxy 1 -[(2,3-dihydroxypropyl)amino] D-galactitol peut être préparé par des procédés dont le principe est connu, par exemple par action du 3-chloropropane-1 ,2-diol ou du glycidol sur le 1 -amino 1 -déoxy D-galactitol ou par action du D-galactose sur le 3-aminopropane-1 ,2-diol en milieu réducteur ou encore par action du D-galactose sur la benzylamine en milieu réducteur pour donner le l -(benzylamino) 1 -déoxy D-galactitol, composé connu, sur lequel on fait réagir le 3-chloropropane-1 ,2-diol ou le glycidol pour obtenir l'aminé tertiaire que l'on débenzyle de façon habituelle par action de l'hydrogène.1-deoxy 1 - [(2,3-dihydroxypropyl) amino] D-galactitol can be prepared by processes the principle of which is known, for example by the action of 3-chloropropane-1, 2-diol or glycidol on the 1 -amino 1 -deoxy D-galactitol or by action of D-galactose on 3-aminopropane-1, 2-diol in reducing medium or also by action of D-galactose on benzylamine in reducing medium to give l - ( benzylamino) 1-deoxy D-galactitol, known compound, on which reacts 3-chloropropane-1, 2-diol or glycidol to obtain the tertiary amine which is debenzylated in the usual way by the action of hydrogen.
La séparation des 2 diastéréoisomères et/ou l'enrichissement du mélange en l'un ou l'autre peuvent être effectués de façon connue par recristallisation de l'aminoalcool ou d'un de ses sels.The separation of the 2 diastereoisomers and / or the enrichment of the mixture with one or the other can be carried out in a known manner by recrystallization of the amino alcohol or one of its salts.
On peut aussi faire réagir l'énantiomère R ou l'énantiomère S du glycidol, produits commercialisés, sur le l -(benzylamino) 1 -déoxy D-galactitol pour obtenir après débenzylation chacun des diastéréoisomères de l'aminoalcool. L'invention concerne aussi le 1 -déoxy 1 -[2,3-dihydroxypropylamino] D-galactitol, produit nouveau, intermédiaire fondamental dans la synthèse du produit de contraste de l'invention puisque l'autre isomère connu, le 1 -déoxy 1 -[(2,3-dihydroxypropyl)amino] D-glucitol conduit à un diamide tétraiodé ne pouvant être administré en solution aqueuse qu'à une concentration inférieure à 300 mg d'iode/ml, alors qu'une telle concentration est nécessaire pour certains types de radiologie diagnostique.It is also possible to react the R enantiomer or the S enantiomer of glycidol, marketed products, on l - (benzylamino) 1-deoxy D-galactitol to obtain, after debenzylation, each of the diastereoisomers of the amino alcohol. The invention also relates to 1-deoxy 1 - [2,3-dihydroxypropylamino] D-galactitol, a new product, a fundamental intermediate in the synthesis of the contrast product of the invention since the other known isomer, 1-deoxy 1 - [(2,3-dihydroxypropyl) amino] D-glucitol leads to a tetraiodic diamide which can only be administered in aqueous solution at a concentration of less than 300 mg of iodine / ml, whereas such a concentration is necessary for certain types of diagnostic radiology.
L'invention comprend aussi les compositions pour l'imagerie médicale par rayons X, contenant le produit de contraste de formule I précédemment défini, et un véhicule pharmaceutiquement acceptable. Ces compositions seront, selon le type d'imagerie, administrées aux doses usuelles par voie parentérale ou intravasculaire. Dans ce cas, on préfère que la composition se présente sous forme d'une solution aqueuse de concentration comprise entre 200 mg d'iode/ml à 350 mg d'iode/ml et mieux d'environ 300 mg d'iode/ml; la solution peut contenir les adjuvants habituels des produits de contraste iodés, tels que des tampons, des ions du plasma sanguin (Na + , Ca+ + , Mg+ + , K + ), de l'oxygène, ou encore des stabilisants, tel que I' EDTA.The invention also includes the compositions for medical X-ray imaging, containing the contrast product of formula I previously defined, and a pharmaceutically acceptable vehicle. These compositions will, depending on the type of imaging, be administered at the usual doses parenterally or intravascularly. In this case, it is preferred that the composition is in the form of an aqueous solution with a concentration of between 200 mg of iodine / ml to 350 mg of iodine / ml and better still of approximately 300 mg of iodine / ml; the solution may contain the usual adjuvants of iodinated contrast agents, such as buffers, ions of the blood plasma (Na + , Ca + + , Mg + + , K + ), oxygen, or stabilizers, such than EDTA.
Ces compositions pourront être utilisées comme les produits de contraste iodés non ioniques actuellement commercialisés, notamment pour visualiser le compartiment vasculaire, le système nerveux, la région gastrointestinale, le poumon, les reins, ou d'autre parties du corps. Elles peuvent donc trouver une application, notamment, en angiographie cérébrale ou périphérique, en urographie, en myélographie, ou en arthrographie et hysterosalpingographie.These compositions can be used as the nonionic iodine contrast agents currently on the market, in particular for visualizing the vascular compartment, the nervous system, the gastrointestinal region, the lung, the kidneys, or other parts of the body. They can therefore find an application, in particular, in cerebral angiography or peripheral, in urography, in myelography, or in arthrography and hysterosalpingography.
Les doses unitaires (volume et concentration en iode des solutions) seront du même ordre que celles actuellement utilisées en pratique, fonction de la taille et de l'âge du patient et évidemment du type d'imagerie pratiquée.The unit doses (volume and iodine concentration of the solutions) will be of the same order as those currently used in practice, depending on the size and age of the patient and obviously on the type of imaging performed.
Dans ce qui suit, on décrit des exemples de la préparation du composé de l'invention, étant entendu que d'autres méthodes de synthèse, mettant en oeuvre des principes connus ou des variantes des conditions opératoires décrites ci-dessus donneront aussi le composé de l'invention, éventuellement contenant des proportions différentes des nombreux isomères.In the following, examples of the preparation of the compound of the invention are described, it being understood that other synthetic methods, using known principles or variants of the operating conditions described above will also give the compound of the invention, possibly containing different proportions of the numerous isomers.
1 . Préparation du dichlorure de l'acide 2,3,5,6-tétraiodotéréphtalique a) lodation de l'acide téréphtalique:1. Preparation of 2,3,5,6-tetraiodoterephthalic acid dichloride a) lodation of terephthalic acid:
On introduit goutte à goutte, à 40°C, 0,25 litres d'oléum à 65% dans 500 ml d'acide sulfurique concentré, puis à 70°C, on introduit 1 70 g d'iode. 62,5 g d'acide téréphtalique sont ajoutés à 80°C puis le milieu réactionnel est porté, en 2 heures, jusqu'à 1 25°C, température qui est ensuite maintenue pendant 36 heures.0.25 liters of 65% oleum is introduced dropwise at 40 ° C in 500 ml of concentrated sulfuric acid, then at 70 ° C, 170 g of iodine are introduced. 62.5 g of terephthalic acid are added at 80 ° C. then the reaction medium is brought, within 2 hours, to 125 ° C., a temperature which is then maintained for 36 hours.
Après retour à température ambiante, le mélange est versé lentement dans 3 litres d'eau; on ajoute 5 ml de solution aqueuse 5 M de NaHSO3 avant de filtrer le précipité.After returning to room temperature, the mixture is poured slowly into 3 liters of water; 5 ml of 5 M aqueous NaHSO 3 solution are added before filtering off the precipitate.
Après lavage à l'eau et séchage, le produit brut est maintenu 4 heures dans 480 ml de méthanol au reflux contenant 8,5 ml d'acide sulfurique concentré. Il peut ensuite être purifié par dissolution dans une solution aqueuse de NaOH (pH 6) et reprécipitation en milieu acide. Le produit pur est obtenu avec 45% de rendement. b) Dichlorure de l'acide tétraiodotéréphtalique:After washing with water and drying, the crude product is kept for 4 hours in 480 ml of methanol at reflux containing 8.5 ml of concentrated sulfuric acid. It can then be purified by dissolving in an aqueous NaOH solution (pH 6) and reprecipitation in an acid medium. The pure product is obtained with 45% yield. b) Tetraiodoterephthalic acid dichloride:
On ajoute 4,5 ml de SOCI2 à une suspension de 13,5 g du diacide préparé à l'étape a) et 0,4 g de chlorure de tricaprylméthylammonium dans 25 ml de toluène et le mélange est maintenu durant 18 heures à 80°C. Les produits volatils sont éliminés par distillation sous pression réduite vers 30°C, et on introduit 25 ml d'oxyde de diisopropyle dans le milieu. Le précipité de chlorure d'acide est alors isolé. Rendement : 95 %.4.5 ml of SOCI 2 are added to a suspension of 13.5 g of the diacid prepared in step a) and 0.4 g of tricaprylmethylammonium chloride in 25 ml of toluene and the mixture is maintained for 18 hours at 80 ° C. The volatile products are removed by distillation under reduced pressure around 30 ° C, and are introduced 25 ml of diisopropyl ether in the medium. The acid chloride precipitate is then isolated. Yield: 95%.
2. Préparation du 1 -déoxy 1 -[(2,3-dihydroxypropyl)amino] D-galactitol:2. Preparation of 1-deoxy 1 - [(2,3-dihydroxypropyl) amino] D-galactitol:
On maintient 27 g de 3-aminopropane-1 ,2-diol et 50 g de D-galactose dans 1 40 ml de méthanol sous agitation à 40 °C pendant 1 6 heures. On ajoute alors 60 ml d'eau et on effectue, en présence de 7 g de paladium sur charbon (à27 g of 3-aminopropane-1, 2-diol and 50 g of D-galactose are maintained in 1 40 ml of methanol with stirring at 40 ° C for 1 6 hours. 60 ml of water are then added and, in the presence of 7 g of paladium on carbon (
10%) l'hydrogénation de l'imine durant 7 heures à 60°C sous une pression de10%) hydrogenation of the imine for 7 hours at 60 ° C under a pressure of
20 x 1 05 Pa d'hydrogène.20 x 1 0 5 Pa of hydrogen.
Le catalyseur est alors séparé par filtration sur Célite®. Après élimination du solvant sous pression réduite, le résidu, dissous dans le minimum d'eau (50 ml), est introduit lentement dans 600 ml d'isopropanol. Le précipité formé est isolé. F = 1 32° C, rendement 90%.The catalyst is then separated by filtration on Celite®. After removing the solvent under reduced pressure, the residue, dissolved in a minimum of water (50 ml), is slowly introduced into 600 ml of isopropanol. The precipitate formed is isolated. M = 132 ° C., yield 90%.
On peut aussi avant la précipitation dans l'isopropanol, chromatographier le produit brut, en solution dans 200 ml d'eau sur 500 ml d'une résine échangeuse d'ions sous forme acide sulfonique. (IMAC HP 1 1 0 NA, commercialisé par Rohm et Haas), en éluant par une solution aqueuse de NH4OH dilué.It is also possible, before precipitation in isopropanol, to chromatograph the crude product, in solution in 200 ml of water on 500 ml of an ion-exchange resin in the form of sulphonic acid. (IMAC HP 1 1 0 NA, marketed by Rohm and Haas), eluting with a dilute aqueous NH 4 OH solution.
Dans ces conditions, l'aminoalcool est un mélange pratiquement 50/50 des deux diastéréoisomères. Par recristallisation, précipitation fractionnée ou mise en suspension, on peut enrichir le mélange en l'un ou l'autre des isomères.Under these conditions, the amino alcohol is a practically 50/50 mixture of the two diastereoisomers. By recrystallization, fractional precipitation or suspension, the mixture can be enriched in one or other of the isomers.
Ainsi, par traitement au méthanol à sa température de reflux (25 g de l'aminoalcool dans 500 ml du solvant) on obtient un mélange qui contient un excès de l'un des isomères (65% de l'isomère ayant le plus grand temps de rétention d'après les surfaces mesurées sur les chromatogrammes obtenus dans les conditions suivantes):Thus, by treatment with methanol at its reflux temperature (25 g of the amino alcohol in 500 ml of the solvent) a mixture is obtained which contains an excess of one of the isomers (65% of the isomer having the longest time retention based on the surfaces measured on the chromatograms obtained under the following conditions):
Chromatographie en phase gazeuse (dérivé totalement trifluoroacétylé par action de l'anhydride trifluoroacétique à 60° C) Appareil: Varian Star 3400 Colonne: DB 1 701 de J & W (0,25 μm - 30 m x 0,25 mm)Gas chromatography (fully trifluoroacetylated derivative by action of trifluoroacetic anhydride at 60 ° C) Device: Varian Star 3400 Column: DB 1 701 from J & W (0.25 μm - 30 m x 0.25 mm)
Gaz vecteur He - T injecteur (split 1 /40e) = 290° C T colonne = 1 50°C à 280°C (5 °C/mn) - Volume: 1 μlCarrier gas He - T injector (split 1/40 e ) = 290 ° C T column = 1 50 ° C to 280 ° C (5 ° C / min) - Volume: 1 μl
Temps de rétention: 1 4,5 et 1 4,9 minutes (5,6 mn pour l'aminopropanediol de départ)Retention time: 1 4.5 and 1 4.9 minutes (5.6 minutes for the starting aminopropanediol)
- RMN 1 3C (200 MHz - DMSO d6 - Réf DMSO - T = 30°C) δ (ppm): 71 ,7; 71 ,6; 70,5; 70, 1 ; 69,5; 68,5; 68,2 - (CHOH) 64,6; 63,2;- 1 3 C NMR (200 MHz - DMSO d6 - Ref DMSO - T = 30 ° C) δ (ppm): 71, 7; 71, 6; 70.5; 70, 1; 69.5; 68.5; 68.2 - (CHOH) 64.6; 63.2;
(CH2OH) - 53,4; 53; 52,9 (NCH2).(CH 2 OH) - 53.4; 53; 52.9 (NCH 2 ).
On peut aussi obtenir chaque diastéréoisomère en condensant le D-galactose sur l'énantiomère pur de l'aminopropanediol ou par action des énantiomères du glycidol sur la N-(2,3,4,5,6-pentahydroxyhexyl)benzylamide comme suit: a) N-benzyl N-(2,3,4,5,6-pentahydroxyhexyl)amine On dissout dans 230 ml de méthanol 29 g de D-galactose, 1 7 ml de benzylamine et on maintient le mélange à 50° C pendant 7 heures sous une pression d'hydrogène de 8 x 1 05 Pa, après addition de 5 g de charbon palladié à 5 % .Each diastereoisomer can also be obtained by condensing D-galactose on the pure enantiomer of aminopropanediol or by the action of the enantiomers of glycidol on N- (2,3,4,5,6-pentahydroxyhexyl) benzylamide as follows: a ) N-benzyl N- (2,3,4,5,6-pentahydroxyhexyl) amine 29 g of D-galactose, 1 7 ml of benzylamine are dissolved in 230 ml of methanol and the mixture is kept at 50 ° C. for 7 hours under a hydrogen pressure of 8 × 10 5 Pa, after addition of 5 g of 5% palladium on carbon.
Après l'hydrogénation, on introduit à 40°C, une solution aqueuse d'acide chlorhydrique jusqu'à pH acide dans le milieu réactionnel.After the hydrogenation, an aqueous solution of hydrochloric acid up to acidic pH is introduced at 40 ° C. into the reaction medium.
On filtre le mélange sur célite® à température ambiante pour éliminer le catalyseur, et après concentration partielle, on introduit une solution aqueuse de NaOH 5N jusqu'à pH basique. Le précipité formé est isolé et recristallisé dans l'éthanol.The mixture is filtered on celite® at room temperature to remove the catalyst, and after partial concentration, an aqueous solution of 5N NaOH is introduced until basic pH. The precipitate formed is isolated and recrystallized from ethanol.
- RMN 13C (200 MHz - DMSO d6 - Réf DMSO - T = 30°C) δ (ppm): 140,8 (£ CH2N) - 1 28,8; 1 28,4; 1 26,9 (phényl) - 72; 70,6; 69,9; 68,8; (CHOH) - 63,2 (CH2OH) - 53, 1 ; 52,4 (CH2NH). b)N-benzyl N-(2,3-dihydroxypropyl)(2,3,4,5,6-pentahydroxyhexyl)amine- 13 C NMR (200 MHz - DMSO d6 - Ref DMSO - T = 30 ° C) δ (ppm): 140.8 (£ CH 2 N) - 1 28.8; 1 28.4; 1 26.9 (phenyl) - 72; 70.6; 69.9; 68.8; (CHOH) - 63.2 (CH 2 OH) - 53.1; 52.4 (CH 2 NH). b) N-benzyl N- (2,3-dihydroxypropyl) (2,3,4,5,6-pentahydroxyhexyl) amine
On dissout 6,5 g de l'aminé secondaire obtenue dans l'étape précédente dans 200 ml de méthanol à 60°C, puis on introduit dans la solution à cette température 2,5 g de glycidol (racémique ou énantiomère pur) et on maintient le mélange sous agitation 24 heures. On élimine ensuite le solvant par distillation sous pression réduite, et on chromatographie le résidu après dissolution dans 200 ml d'eau sur une colonne de résine IMAC 1 10 sous forme H + en éluant avec une solution aqueuse de NH4OH diluée (0, 1 %). On obtient ainsi 5,5 g de l'aminé. c) N-(2,3-dihydroxypropyl) N-(2,3,4,5,6-pentahydroxyhexyl)amine6.5 g of the secondary amine obtained in the previous step are dissolved in 200 ml of methanol at 60 ° C., then 2.5 g of glycidol (racemic or pure enantiomer) are introduced into the solution and keeps the mixture stirred for 24 hours. The solvent is then removed by distillation under reduced pressure, and the residue is chromatographed after dissolving in 200 ml of water on a column of IMAC 1 resin 10 in the form H + , eluting with a dilute aqueous NH 4 OH solution (0.1%). 5.5 g of the amine are thus obtained. c) N- (2,3-dihydroxypropyl) N- (2,3,4,5,6-pentahydroxyhexyl) amine
2 g de l'aminé tertiaire obtenue dans l'étape précédente en solution dans 30 ml d'eau sont hydrogénés à 45 ° C sous pression d'hydrogène de 1 0 x2 g of the tertiary amine obtained in the previous step dissolved in 30 ml of water are hydrogenated at 45 ° C under hydrogen pressure of 10 x
1 0 Pa pendant 5 heures en présence de O,6 g de charbon palladié à 1 0%. La solution est ensuite filtrée sur célite® pour éliminer le catalyseur et concentrée sous pression réduite. Le résidu peut être recristallisé dans l'éthanol.10 Pa for 5 hours in the presence of 0.6 g of 10% palladium on carbon. The solution is then filtered through Celite® to remove the catalyst and concentrated under reduced pressure. The residue can be recrystallized from ethanol.
Lorsque l'on condense le (S)-glycidol on obtient l'aminoalcool diastéréoisomère dont le temps de rétention dans les conditions de la chromatographie en phase gazeuse précédente est le plus long.When the (S) -glycidol is condensed, the diastereoisomeric amino alcohol is obtained, the retention time of which under the conditions of the preceding gas chromatography is the longest.
ExempleExample
N,N'-bis(2,3-dihydroxypropyl)(2, 3,4,5, 6-pentahydroxyhexyl)-2, 3,5,6- tétraiodotéréphtalamide (stéréoisomères dérivés du D-galactitol). On dissout, à 70°C, 9,2 g du 1 -déoxy 1 -[(2,3-dihydroxypropyl)amino]N, N'-bis (2,3-dihydroxypropyl) (2,3,4,5,6-pentahydroxyhexyl) -2,3,5,6- tetraiodoterephthalamide (stereoisomers derived from D-galactitol). 9.2 g of 1-deoxy 1 - [(2,3-dihydroxypropyl) amino] are dissolved at 70 ° C.
D-galactitol dans 200 ml de diméthylacétamide et 5 ml de triéthylamine, puis à 45 ° C, on introduit, par portions, 1 0 g de dichlorure d'acide 2,3,5,6- tétraiodotéréphtalique.D-galactitol in 200 ml of dimethylacetamide and 5 ml of triethylamine, then at 45 ° C., 10 g of 2,3,5,6-tetraiodoterephthalic acid dichloride are introduced in portions.
Le mélange est maintenu 3 jours sous agitation à cette température puis versé dans 3 litres d'acétate d'éthyle.The mixture is kept stirring for 3 days at this temperature and then poured into 3 liters of ethyl acetate.
LE solide est isolé par filtration puis il est dissout dans le minimum d'eau (20 ml) et cette solution est versée dans 1 litre d'isopropanol. Le précipité formé est dissous dans 200 ml d'eau et la solution est chromatographiee sur une résine échangeuse de cations sous forme acide ( 1 50 ml d'IMAC HP 1 1 0 NA) puis d'anions faiblement basique ( 1 20 ml d'Amberlite® IRA 67).The solid is isolated by filtration then it is dissolved in the minimum of water (20 ml) and this solution is poured into 1 liter of isopropanol. The precipitate formed is dissolved in 200 ml of water and the solution is chromatographed on a cation exchange resin in acid form (1 50 ml of IMAC HP 1 1 0 NA) then of weakly basic anions (1 20 ml of Amberlite® IRA 67).
Le résidu est purifié par précipitation dans l'isopropanol à partir de sa solution aqueuse concentrée. Rendement: 50%.The residue is purified by precipitation in isopropanol from its concentrated aqueous solution. Yield: 50%.
- Chromatographie sur couches minces: plaque gel de silice 60 F 254 (Merck) - Eluant CH2CI2/CH3OH (5/5 - V/V) - rf = 0, 1 - Chromatographie liquide haute pression:- Chromatography on thin layers: silica gel plate 60 F 254 (Merck) - Eluent CH 2 CI 2 / CH 3 OH (5/5 - V / V) - rf = 0, 1 - High pressure liquid chromatography:
Appareil: HP 1 090 (Hewlett Packard) Colonne: Lichrospher® 100RP1 8 - 5 μm ( 1 2,5 x 4 mm) MerckDevice: HP 1 090 (Hewlett Packard) Column: Lichrospher® 100RP1 8 - 5 μm (1 2.5 x 4 mm) Merck
Eluant: H20/CH3CN (V/V - 95/5 à 70/30 en 15 min) 1 ml/m - T = 25 °CEluent: H 2 0 / CH 3 CN (V / V - 95/5 to 70/30 in 15 min) 1 ml / m - T = 25 ° C
Temps de rétention: 2,9 - 3,2 - 3,9 - 4,7 minutes massifs (2, 10 mn pour l'iopamidol)Retention time: 2.9 - 3.2 - 3.9 - 4.7 massive minutes (2, 10 mins for iopamidol)
- RMN 13C (200 MHz - DMSO d6 - Réf. DMSO - T = 30°C) - δ (ppm) 171 ,5 (CO); 148,8 (£-CO) - 1 10,9 (C-l); 70,7 ; 70,3; 69,4; 68; 67,3; 66,8 (CHOH); 64,5; 63,7; 63,2 (CH2OH) - 53,2 (m); 50,0 (m) (CH2N). - 13 C NMR (200 MHz - DMSO d 6 - Ref. DMSO - T = 30 ° C) - δ (ppm) 171, 5 (CO); 148.8 (£ -CO) - 1 10.9 (Cl); 70.7; 70.3; 69.4; 68; 67.3; 66.8 (CHOH); 64.5; 63.7; 63.2 (CH 2 OH) - 53.2 (m); 50.0 (m) (CH 2 N).

Claims

Revendications claims
1 . Mélange d'isomères du composé de formule1. Mixture of isomers of the compound of formula
Figure imgf000013_0001
dont la configuration du groupe N-CH2-(CHOH)4-CH2OH est celle du 1 -amino 1 -déoxy D-galactitol et chaque groupe CH2-CHOH-CH2OH est sous forme de chacun de ses 2 énantiomères ou d'un mélange de ceux-ci.
Figure imgf000013_0001
whose configuration of the N-CH 2 - (CHOH) 4 -CH 2 OH group is that of 1-amino 1 -deoxy D-galactitol and each CH 2 -CHOH-CH 2 OH group is in the form of each of its 2 enantiomers or a mixture of these.
2. Mélange des isomères de formule I selon la revendication 1 qui contient les deux énantiomères de chaque groupe N-CH2-CHOH-CH2OH en proportion relative comprise entre 25 à 50%. 2. Mixture of isomers of formula I according to claim 1 which contains the two enantiomers of each N-CH 2 -CHOH-CH 2 OH group in relative proportion between 25 to 50%.
3. Mélange des isomères de formule I selon la revendication 1 qui contient les deux énantiomères de chaque groupe N-CH2-CHOH-CH2OH en proportion relative comprise entre 45 à 50%.3. Mixture of isomers of formula I according to claim 1 which contains the two enantiomers of each group N-CH 2 -CHOH-CH 2 OH in relative proportion between 45 to 50%.
4. Composition utile comme produit de contraste pour l'imagerie médicale par rayons X caractérisée en ce qu'elle contient ' un mélange des isomères selon l'une des revendications 1 à 3, associé à un véhicule pharmaceutiquement acceptable. 4. A composition useful as a contrast agent for medical imaging by X-rays characterized in that it contains a mixture of isomers according to one of claims 1 to 3, associated with a pharmaceutically acceptable carrier.
PCT/FR1999/001406 1998-06-30 1999-06-14 Tetraiodoterephthalamide polyhydroxylated derivatives, preparation method and use in radiology WO2000000461A1 (en)

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EP0675105A1 (en) * 1994-03-22 1995-10-04 Guerbet S.A. Polyiodinated compounds, process for their preparation and diagnostic composition

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* Cited by examiner, † Cited by third party
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EP0675105A1 (en) * 1994-03-22 1995-10-04 Guerbet S.A. Polyiodinated compounds, process for their preparation and diagnostic composition

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