WO1995032978A1 - Trivalent metal complexes with a polyol such as cis-inositol, for medical use and method of preparation - Google Patents

Trivalent metal complexes with a polyol such as cis-inositol, for medical use and method of preparation Download PDF

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Publication number
WO1995032978A1
WO1995032978A1 PCT/FR1995/000674 FR9500674W WO9532978A1 WO 1995032978 A1 WO1995032978 A1 WO 1995032978A1 FR 9500674 W FR9500674 W FR 9500674W WO 9532978 A1 WO9532978 A1 WO 9532978A1
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complex
inositol
cis
trivalent metal
ino
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PCT/FR1995/000674
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French (fr)
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Léon Odier
Lorenza Hausherr-Primo
Kaspar Hegetschweiler
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Commissariat A L'energie Atomique
Vifor (International) Ag
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Publication of WO1995032978A1 publication Critical patent/WO1995032978A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/06—Cobalt compounds
    • C07F15/065—Cobalt compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/02—Iron compounds
    • C07F15/025—Iron compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/06—Aluminium compounds
    • C07F5/069—Aluminium compounds without C-aluminium linkages

Definitions

  • the present invention relates to complexes of trivalent metals with a polyol such as cis-inositol, with a view to their use for medical purposes.
  • the present invention specifically relates to new complexes of cis-inositol which can be isolated in the form of crystalline solids, stable and soluble in an aqueous solution.
  • the complex of a trivalent metal with cis-inositol corresponds to the formula: [M 6 (ino) 6 0] A 5 , nH 2 0 in which M represents a trivalent metal atom such as Fe 111 , Co 111 or Al 111 , "ino" represents a group derived from cis-inositol by elimination of at least one proton, A represents an alkali metal atom, and n is a number from 0 to 20.
  • the alkali metal can be lithium, sodium, potassium, rubidium or cesium.
  • potassium K is used.
  • the number of water molecules linked to the complex can vary from 0 to 20, but it is generally 14.5.
  • the trivalent metal is iron.
  • the complex advantageously meets the formula:
  • the present invention also relates to a process for the preparation of a trivalent metal complex with a ligand consisting of an organic molecule belonging to the group of polyols, which makes it possible to obtain neutral complexes of this type.
  • This process comprises the following stages: a) preparing an aqueous solution comprising ions of the trivalent metal and the organic molecule serving as ligand, b) adding to the aqueous solution a neutral salt of alkali metal to compensate for the loss of positive charge due to the release of H + protons from the ligand during complexation, by alkali metal ions in order to obtain a neutral complex, and c) adjusting the pH of the aqueous solution to the precipitation pH of the complex.
  • This process is interesting because it is easy to implement and makes it possible to obtain a stable complex, in particular thanks to the addition of neutral salt.
  • the trivalent metal is introduced into the aqueous solution in the form of a salt, for example chloride.
  • a salt for example chloride.
  • the coordination of the trivalent metal to the molecules of the polyol ligand causes the deprotonation of the complexed hydroxyls originating from the polyol, which decreases the pH of the solution. It is therefore generally necessary to then raise the pH of this solution to precipitate the complex formed.
  • a + from a neutral salt so as not to simultaneously introduce anions capable of strongly modifying the pH of the solution.
  • the pH is adjusted to the desired value in order to obtain the precipitation of the complex.
  • this pH is around 5-6 and it can be obtained by adding a strong base such as KOH.
  • the method preferably comprises an additional step of recrystallization of the precipitated complex.
  • the precipitated complex can be dissolved in a basic aqueous solution, for example using a strong base such as KOH in concentrated solution, then cover the aqueous solution with a layer of ethanol and thus crystallize the complex by slow diffusion of the two liquids one inside the other.
  • a pure, neutral complex is thus obtained, in crystallized form, soluble in water and capable of releasing the trivalent metal which it contains.
  • the polyol type organic ligands which can be used in the process of the invention can be of different types. Generally, they belong to the group of sugars and cyclitols. Preferably, cis-inositol is used as ligand, since its configuration promotes the formation of the complex.
  • Cis-inositol can be prepared in particular by the process described in EP-A-0 524 082.
  • the complexes of the invention are particularly advantageous for medical use, for example for combating conditions resulting from an iron deficiency, such as anemia.
  • the complexes of the invention link reversibly and selectively ions of trivalent metals such as iron, to an organic molecule of biological interest such as cis-inositol, makes it possible to transport these metal ions in solution in the biological medium, for example in the human organism.
  • the cis-inositol complexes obtained in accordance with the invention are particularly advantageous for these medical applications, because they are soluble in water at room temperature and at a pH close to neutrality, that is to say in conditions compatible with their introduction into a biological medium.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a complex of Fe * 11 with cis-inositol having the characteristics developed above.
  • FIG. 1 represents the central unit of the complex formed by six Fe 11 ions linked together by oxygen atoms coming from cis-inositol,
  • FIGS. 2, 3, 4, 5 and 6 represent the different bonding modes between the iron atoms and the cis-inositol
  • Example 1 Preparation of an iron-cis-inositol complex A 429 mg of a 1 mol / 1 aqueous solution of FeCl ⁇ , 0.5 HCl, having a density of 1.1325 g / ml, which is equivalent to 0 , 38 mol of iron, 150 mg (0.83 mmol) of cis-inositol dissolved in 1 ml of water are added. To the solution thus obtained, 126 mg (1.25 mmol) of KNO3 are added, then slowly a 0.1 mol / l solution of KOH until the product precipitates, that is to say until at a pH of the solution of 5-6. The suspension obtained is then kept at 4 ° C for 3 hours.
  • Example 2 Preparation of an Fe-cis-inositol complex.
  • FIG. 1 there is shown the central unit of the complex obtained in these examples.
  • This unit is formed by six Fe 111 ⁇ "ions numbered from 1 to 6, which are linked together by oxygen atoms coming from cis-inositol. Three Fe 111 ions are linked to an additional oxygen atom from a molecule in the KOH base, which later stabilizes this unit.
  • One of the six iron atoms (Fe (l)) has five coordinated oxygen atoms, while the other five iron atoms have six.
  • the distances between the iron atoms of the complex are as follows o
  • Fe (3) -Fe (6) 2.804 A
  • Fe (4) -Fe (6) 3.138 A
  • the lengths of the bonds between the iron atoms and the oxygen atoms to which they are bonded, o are shown in the figure 1 in A.
  • the iron atoms can be arranged according to a triaxial arrangement, the iron being linked with three axial hydroxyls of cis-inositol, or according to "axial-equatorial-axial" arrangements, the iron being linked with two axial hydroxyls and an equatorial hydroxyl.
  • the central unit of the complex is represented, that is to say the atoms of iron, ⁇ of oxygen ⁇ and of carbon without the five potassium ions and water.

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  • Organic Chemistry (AREA)

Abstract

Trivalent metal complexes with a polyol such as cis-inositol, for medical use and method of preparation. The trivalent metal complexes with cis-inositol are of formula (I): [M6(ino)6O] A5, nH2O in which M is a trivalent metal atom, for example FeIII, 'ino' is a group derived from cis-inositol, A is an alkaline metal atom such as K and n is a number from 1 to 20. These complexes can be used in pharmaceutical compositions for administering iron to a patient suffering from anemia.

Description

COMPLEXES DE METAUX TRIVALENTS AVEC UN POLYOL TEL QUE TRIVALENT METAL COMPLEXES WITH A POLYOL SUCH AS
LE CIS-INOSITOL, UTILISABLES A DES FINS MEDICALES ETCIS-INOSITOL, USEFUL FOR MEDICAL PURPOSES AND
LEUR PROCEDE DE PREPARATIONTHEIR PREPARATION PROCESS
La présente invention a pour objet des complexes de métaux trivalents avec un polyol tel que le cis-inositol, en vue de leur utilisation à des fins médicales.The present invention relates to complexes of trivalent metals with a polyol such as cis-inositol, with a view to their use for medical purposes.
De façon plus précise, elle concerne la réalisation de complexes de ce type sous la forme de solides cristallisés, stables, solubles en solution aqueuse.More specifically, it relates to the production of complexes of this type in the form of crystallized solids, stable, soluble in aqueous solution.
On sait que de nombreux polyols tels que les cyclitols et les sucres, ont la capacité de complexer des cations en solution aqueuse. Des études portant sur la formation de tels complexes ont été publiées par Angyal dans Tetrahedron, vol. 30, 1974, pages 1695 à 1702 et dans Ha orth Mémorial Lecture, Chemical Society Reviews, vol. 9, n° 4, 1980, pages 415-428. Dans ces publications, il est indiqué que le cis-inositol présente une aptitude à complexer des cations métalliques plus importante que celle d'autres sucres en raison de sa configuration, c'est-à-dire de la présence de trois groupes hydroxyles syn-axiaux.It is known that many polyols, such as cyclitols and sugars, have the capacity to complex cations in aqueous solution. Studies of the formation of such complexes have been published by Angyal in Tetrahedron, vol. 30, 1974, pages 1695 to 1702 and in Ha orth Mémorial Lecture, Chemical Society Reviews, vol. 9, n ° 4, 1980, pages 415-428. In these publications, it is indicated that cis-inositol has a greater ability to complex metal cations than that of other sugars due to its configuration, that is to say the presence of three hydroxyl groups syn- axial.
Toutefois, on n'a jamais isolé jusqu'à présent de complexes de ce type, à l'état pur, sous la forme de solides cristallisés.However, complexes of this type have never been isolated in the pure state in the form of crystalline solids.
La présente invention a précisément pour objet des nouveaux complexes du cis-inositol qui peuvent être isolés sous la forme de solides cristallisés, stables et solubles dans une solution aqueuse.The present invention specifically relates to new complexes of cis-inositol which can be isolated in the form of crystalline solids, stable and soluble in an aqueous solution.
Selon l'invention, le complexe d'un métal trivalent avec le cis-inositol répond à la formule : [M6(ino)60] A5, nH20 dans laquelle M représente un atome de métal trivalent tel que Fe111, Co111 ou Al111, "ino" représente un groupe dérivé du cis-inositol par élimination d'au moins un proton, A représente un atome de métal alcalin, et n est un nombre allant de 0 à 20.According to the invention, the complex of a trivalent metal with cis-inositol corresponds to the formula: [M 6 (ino) 6 0] A 5 , nH 2 0 in which M represents a trivalent metal atom such as Fe 111 , Co 111 or Al 111 , "ino" represents a group derived from cis-inositol by elimination of at least one proton, A represents an alkali metal atom, and n is a number from 0 to 20.
Dans ce complexe, la coordination du métal trivalent au cis-inositol a provoqué la déprotonation des hydroxyles complexés, mais cette perte de charges positives est compensée par les charges positives provenant des cations A+ de métal alcalin, ce qui permet d'obtenir un complexe neutre, stable et facilement cristallisable.In this complex, the coordination of the trivalent metal with cis-inositol caused the deprotonation of the complexed hydroxyls, but this loss of positive charges is compensated by the positive charges coming from the A + cations of alkali metal, which makes it possible to obtain a complex neutral, stable and easily crystallized.
Le métal alcalin peut être le lithium, le sodium, le potassium, le rubidium ou le césium. De préférence, on utilise le potassium K.The alkali metal can be lithium, sodium, potassium, rubidium or cesium. Preferably, potassium K is used.
Le nombre de molécules d'eau liées au complexe peut varier de 0 à 20, mais il est généralement de 14,5.The number of water molecules linked to the complex can vary from 0 to 20, but it is generally 14.5.
De préférence dans ce complexe, le métal trivalent est le fer. Dans ce cas, le complexe répond avantageusement à la formule :Preferably in this complex, the trivalent metal is iron. In this case, the complex advantageously meets the formula:
[Fe6(ino)60] K5, 14,5 H20 dans laquelle "ino" a la signification donnée ci-dessus. La présente invention a également pour objet un procédé de préparation d'un complexe de métal trivalent avec un ligand constitué par une molécule organique appartenant au groupe des polyols, qui permet d'obtenir des complexes neutres de ce type. Ce procédé comprend les étapes suivantes : a) préparer une solution aqueuse comprenant des ions du métal trivalent et la molécule organique servant de ligand, b) ajouter à la solution aqueuse un sel neutre de métal alcalin pour compenser la perte de charge positive due à la libération de protons H+ provenant du ligand lors de la complexation, par des ions de métal alcalin afin d'obtenir un complexe neutre, et c) ajuster le pH de la solution aqueuse au pH de précipitation du complexe.[Fe 6 (ino) 6 0] K 5 , 14.5 H 2 0 in which "ino" has the meaning given above. The present invention also relates to a process for the preparation of a trivalent metal complex with a ligand consisting of an organic molecule belonging to the group of polyols, which makes it possible to obtain neutral complexes of this type. This process comprises the following stages: a) preparing an aqueous solution comprising ions of the trivalent metal and the organic molecule serving as ligand, b) adding to the aqueous solution a neutral salt of alkali metal to compensate for the loss of positive charge due to the release of H + protons from the ligand during complexation, by alkali metal ions in order to obtain a neutral complex, and c) adjusting the pH of the aqueous solution to the precipitation pH of the complex.
Ce procédé est intéressant, car il est facile à mettre en oeuvre et permet d'obtenir un complexe stable, en particulier grâce à l'adjonction du sel neutre.This process is interesting because it is easy to implement and makes it possible to obtain a stable complex, in particular thanks to the addition of neutral salt.
Dans ce procédé, on introduit le métal trivalent dans la solution aqueuse sous la forme de sel, par exemple de chlorure. Dans cette solution, la coordination du métal trivalent aux molécules du ligand polyol provoque la déprotonation des hydroxyles complexés provenant du polyol, ce qui diminue le pH de la solution. Il est donc généralement nécessaire de rehausser ensuite le pH de cette solution pour précipiter le complexe, formé. Toutefois, on préfère ajouter les cationsIn this process, the trivalent metal is introduced into the aqueous solution in the form of a salt, for example chloride. In this solution, the coordination of the trivalent metal to the molecules of the polyol ligand causes the deprotonation of the complexed hydroxyls originating from the polyol, which decreases the pH of the solution. It is therefore generally necessary to then raise the pH of this solution to precipitate the complex formed. However, we prefer to add the cations
A+ à partir d'un sel neutre pour ne pas introduire simultanément des anions susceptibles de modifier fortement le pH de la solution.A + from a neutral salt so as not to simultaneously introduce anions capable of strongly modifying the pH of the solution.
A titre d'exemples de sels utilisable, on peut citer les nitrates et les chlorures tels que KNO3 et KC1.As examples of salts which can be used, mention may be made of nitrates and chlorides such as KNO3 and KC1.
Après cette étape de neutralisation des charges du complexe, on ajuste le pH à la valeur voulue pour obtenir la précipitation du complexe. Généralement, ce pH est d'environ 5-6 et il peut être obtenu par addition d'une base forte telle que KOH.After this step of neutralizing the charges of the complex, the pH is adjusted to the desired value in order to obtain the precipitation of the complex. Generally, this pH is around 5-6 and it can be obtained by adding a strong base such as KOH.
Après précipitation du complexe, le procédé comprend de préférence une étape complémentaire de recristallisation du complexe précipité. Pour effectuer cette recristallisation, on peut dissoudre le complexe précipité dans une solution aqueuse basique, par exemple à l'aide d'une base forte telle que KOH en solution concentrée, puis recouvrir la solution aqueuse d'une couche d'éthanol et cristalliser ainsi le complexe par diffusion lente des deux liquides l'un dans l'autre.After precipitation of the complex, the method preferably comprises an additional step of recrystallization of the precipitated complex. To carry out this recrystallization, the precipitated complex can be dissolved in a basic aqueous solution, for example using a strong base such as KOH in concentrated solution, then cover the aqueous solution with a layer of ethanol and thus crystallize the complex by slow diffusion of the two liquids one inside the other.
On obtient ainsi un complexe pur, neutre, sous forme cristallisée, soluble dans l'eau et capable de libérer le métal trivalent qu'il contient.A pure, neutral complex is thus obtained, in crystallized form, soluble in water and capable of releasing the trivalent metal which it contains.
Les ligands organiques du type polyol utilisables dans le procédé de l'invention peuvent être de différents types. Généralement, ils appartiennent au groupe des sucres et des cyclitols. De préférence, on utilise comme ligand le cis-inositol, car sa configuration favorise la formation du complexe.The polyol type organic ligands which can be used in the process of the invention can be of different types. Generally, they belong to the group of sugars and cyclitols. Preferably, cis-inositol is used as ligand, since its configuration promotes the formation of the complex.
Le cis-inositol peut être préparé en particulier par le procédé décrit dans EP-A-0 524 082.Cis-inositol can be prepared in particular by the process described in EP-A-0 524 082.
Les complexes de l'invention, en particulier les complexes de Fe111, sont particulièrement intéressants pour une utilisation médicale, par exemple pour lutter contre des affections résultant d'une déficience en fer, telles que l'anémie.The complexes of the invention, in particular the complexes of Fe 111 , are particularly advantageous for medical use, for example for combating conditions resulting from an iron deficiency, such as anemia.
En effet, la possibilité donnée par les complexes de l'invention de lier reversiblement et sélectivement des ions de métaux trivalents tels que le fer, à une molécule organique d'intérêt biologique telle que le cis-inositol, permet de transporter ces ions métalliques en solution dans le milieu biologique, par exemple dans l'organisme humain. Les complexes de cis-inositol obtenus conformément à l'invention sont particulièrement intéressants pour ces applications médicales, car ils sont solubles dans l'eau à la température ambiante et à un pH voisin de la neutralité, c'est-à-dire dans des conditions compatibles avec leur introduction dans un milieu biologique.Indeed, the possibility given by the complexes of the invention to link reversibly and selectively ions of trivalent metals such as iron, to an organic molecule of biological interest such as cis-inositol, makes it possible to transport these metal ions in solution in the biological medium, for example in the human organism. The cis-inositol complexes obtained in accordance with the invention are particularly advantageous for these medical applications, because they are soluble in water at room temperature and at a pH close to neutrality, that is to say in conditions compatible with their introduction into a biological medium.
Aussi, l'invention a encore pour objet une composition pharmaceutique comprenant un complexe de Fe*11 avec le cis-inositol présentant les caractéristiques développées ci-dessus.Also, the invention also relates to a pharmaceutical composition comprising a complex of Fe * 11 with cis-inositol having the characteristics developed above.
Elle concerne aussi l'utilisation de complexes ferriques conformes à l'invention pour la fabrication de médicaments destinés au traitement d'états sidéropéniques.It also relates to the use of ferric complexes in accordance with the invention for the manufacture of medicaments intended for the treatment of sideropenic states.
D'autres caractéristiques et avantages de l'invention apparaîtront mieux à la lecture des exemples suivants, donnés bien entendu à titre illustratif et non limitatif, en référence aux dessins annexés sur lesquels :Other characteristics and advantages of the invention will appear better on reading the following examples, which are of course given by way of illustration and not limitation, with reference to the appended drawings in which:
- la figure 1 représente l'unité centrale du complexe formé par six ions Fe11 liés entre eux par des atomes d'oxygène provenant du cis-inositol,FIG. 1 represents the central unit of the complex formed by six Fe 11 ions linked together by oxygen atoms coming from cis-inositol,
- les figures 2, 3, 4, 5 et 6 représentent les différents modes de liaison entre les atomes de fer et -le cis-inositol, etFIGS. 2, 3, 4, 5 and 6 represent the different bonding modes between the iron atoms and the cis-inositol, and
- la figure 7 représente la structure du complexe de fer sans les ions potassium et l'eau. Exemple 1 : Préparation d'un complexe fer-cis-inositol A 429 mg d'une solution aqueuse à 1 mol/1 de FeClβ, 0,5 HCl, ayant une densité de 1,1325 g/ml, ce qui équivaut à 0,38 mol de fer, on ajoute 150 mg (0,83 mmol) de cis-inositol dissous dans 1 ml d'eau. A la solution ainsi obtenue, on ajoute 126 mg (1,25 mmol) de KNO3, puis lentement une solution à 0,1 mol/1 de KOH jusqu'à ce que le produit précipite, c'est-à-dire jusqu'à un pH de la solution de 5-6. On maintient ensuite la suspension obtenue à 4°C pendant 3 heures.- Figure 7 shows the structure of the iron complex without potassium ions and water. Example 1 Preparation of an iron-cis-inositol complex A 429 mg of a 1 mol / 1 aqueous solution of FeClβ, 0.5 HCl, having a density of 1.1325 g / ml, which is equivalent to 0 , 38 mol of iron, 150 mg (0.83 mmol) of cis-inositol dissolved in 1 ml of water are added. To the solution thus obtained, 126 mg (1.25 mmol) of KNO3 are added, then slowly a 0.1 mol / l solution of KOH until the product precipitates, that is to say until at a pH of the solution of 5-6. The suspension obtained is then kept at 4 ° C for 3 hours.
On filtre alors la suspension et on dissout le produit solide séparé, dans très peu d'eau à l'aide de KOH très concentré. On obtient ainsi un volume total de 5 ml. On dépose quelques gouttes d'hexane C5H1 à la surface de la solution aqueuse, puis une couche d'éthanol C2H5OH sans agiter. Le complexe qui est insoluble dans l'éthanol cristallise au fur et à mesure que celui-ci diffuse dans la solution aqueuse. Exemple 2 : Préparation d'un complexe Fe-cis-inositol.The suspension is then filtered and the separated solid product is dissolved in very little water using very concentrated KOH. A total volume of 5 ml is thus obtained. A few drops of hexane C5H1 are deposited on the surface of the aqueous solution, then a layer of ethanol C2H5OH without stirring. The complex which is insoluble in ethanol crystallizes as it diffuses into the aqueous solution. Example 2: Preparation of an Fe-cis-inositol complex.
A 577 mg d'une solution aqueuse à 1 mol/1 de FeCl3 , 0,5 HC1 ayant une densité de 1,1325 g/ml, ce qui équivaut à 0,51 mmol de fer, on ajoute 100 mg (0,55 mmol) de cis-inositol dissous dans 1 ml d'eau. On ajoute à cette solution 205 mg de KC1 (2,75 mmol), puis une solution à 1 mol/1 de KOH jusqu'à ce que le produit précipite (pH de la solution 10-11) . On maintient la suspension pendant 2 jours à 4°C, puis on sépare le précipité de la suspension par filtration. On redissout le précipité dans le minimum d'eau à l'aide de KOH très concentré, puis on dépose quelques gouttes d'hexane à la surface de la solution obtenue, et une couche d'éthanol sans agiter. On cristallise ainsi un complexe comme précédemment.To 577 mg of a 1 mol / l aqueous solution of FeCl3, 0.5 HC1 having a density of 1.1325 g / ml, which is equivalent to 0.51 mmol of iron, 100 mg (0.55 mmol) of cis-inositol dissolved in 1 ml of water. 205 mg of KCl (2.75 mmol) are added to this solution, then a 1 mol / l solution of KOH until the product precipitates (pH of the solution 10-11). The suspension is kept for 2 days at 4 ° C., then the precipitate is separated from the suspension by filtration. The precipitate is redissolved in the minimum amount of water using very concentrated KOH, then a few drops of hexane are deposited on the surface of the solution obtained, and a layer of ethanol without stirring. A complex is thus crystallized as before.
La structure du complexe obtenu dans ces deux exemples a été déterminée à l'aide de diagrammes de diffraction des rayons X. Il répond à la formule : [Fe6(ino)60] K5, 14,5 H20The structure of the complex obtained in these two examples was determined using X-ray diffraction diagrams. It corresponds to the formula: [Fe 6 (ino) 6 0] K 5 , 14.5 H 2 0
Sur la figure 1, on a représenté l'unité centrale du complexe obtenu dans ces exemples. Cette unité est formée de six ions Fe111 κ« numérotés de 1 à 6, qui sont liés entre eux par des atomes d'oxygène provenant du cis-inositol. Trois ions Fe111 sont liés à un atome d'oxygène supplémentaire provenant d'une molécule de la base KOH, ce qui stabilise ultérieurement cette unité. Un des six atomes de fer (Fe(l)) a cinq oxygènes coordinés, alors que les cinq autres atomes de fer en ont six. Les distances entre les atomes de fer du complexe sont les suivantes oIn Figure 1, there is shown the central unit of the complex obtained in these examples. This unit is formed by six Fe 111 κ "ions numbered from 1 to 6, which are linked together by oxygen atoms coming from cis-inositol. Three Fe 111 ions are linked to an additional oxygen atom from a molecule in the KOH base, which later stabilizes this unit. One of the six iron atoms (Fe (l)) has five coordinated oxygen atoms, while the other five iron atoms have six. The distances between the iron atoms of the complex are as follows o
Fe(l)-Fe(2) = 2,983 A. oFe (l) -Fe (2) = 2.983 A. o
Fe(l)-Fe(3) = 3,505 A oFe (l) -Fe (3) = 3.505 A o
Fe(l)-Fe(4) = 3,670 A o Fe(l)-Fe(6) = 3,504 A oFe (l) -Fe (4) = 3,670 A o Fe (l) -Fe (6) = 3,504 A o
Fe(2)-Fe(5) = 3,242 A oFe (2) -Fe (5) = 3.242 A o
Fe(3)-Fe(5) = 3,108 A oFe (3) -Fe (5) = 3.108 A o
Fe(3)-Fe(6) = 2,804 A Fe(4)-Fe(6) = 3,138 A Les longueurs des liaisons entre les atomes de fer et les atomes d'oxygène auxquels ils sont liés, o sont indiquées sur la figure 1 en A .Fe (3) -Fe (6) = 2.804 A Fe (4) -Fe (6) = 3.138 A The lengths of the bonds between the iron atoms and the oxygen atoms to which they are bonded, o are shown in the figure 1 in A.
Ce complexe cristallise dans le système triclinique, groupe d'espace P-l avec les paramètres de réseau suivants : a = 12,730 A o b = 13,850 A o c = 19,743 A α ≈ 90,65 ° β = 93,29 ° γ = 112,34 °This complex crystallizes in the triclinical system, space group P-l with the following network parameters: a = 12,730 A o b = 13,850 A o c = 19,743 A α ≈ 90.65 ° β = 93.29 ° γ = 112.34 °
Les indices finaux R sont les suivants :The final indices R are as follows:
R = 4,71 %R = 4.71%
RW = 5,20 % Sur les figures 2 à 6, on a représenté les modes de liaison entre les atomes de fer fê& et les atomes d'oxygène y du cis-inositol. Les atomes de carbone du cis-inositol sont représentés par ORW = 5.20% In FIGS. 2 to 6, the bonding modes between the iron atoms f & and the oxygen atoms y of the cis-inositol are shown. The carbon atoms of cis-inositol are represented by O
Sur ces figures, on remarque que les atomes de fer peuvent être disposés suivant un arrangement triaxial, le fer étant lié avec trois hydroxyles axiaux du cis-inositol, ou selon des arrangements "axial-équatorial-axial", le fer étant lié avec deux hydroxyles axiaux et un hydroxyle équatorial. Sur la figure 3, on a représenté l'unité centrale du complexe, c'est-à-dire les atomes de fer, ^^ d'oxygène ^^ et de carbone sans les cinq ions potassium et l'eau. In these figures, we note that the iron atoms can be arranged according to a triaxial arrangement, the iron being linked with three axial hydroxyls of cis-inositol, or according to "axial-equatorial-axial" arrangements, the iron being linked with two axial hydroxyls and an equatorial hydroxyl. In FIG. 3, the central unit of the complex is represented, that is to say the atoms of iron, ^^ of oxygen ^^ and of carbon without the five potassium ions and water.

Claims

REVENDICATIONS
1. Complexe d'un métal trivalent avec le cis-inositol répondant à la formule :1. Complex of a trivalent metal with cis-inositol corresponding to the formula:
[M6(ino)60] A5, nH20 5 dans laquelle M représente un atome de métal trivalent, "ino" représente un groupe dérivé du cis-inositol par élimination d'au moins un proton, A représente un atome de métal alcalin et n est un nombre allant de 0 à 20.[M 6 (ino) 6 0] A 5 , nH 2 0 5 in which M represents a trivalent metal atom, "ino" represents a group derived from cis-inositol by elimination of at least one proton, A represents an atom of alkali metal and n is a number from 0 to 20.
2. Complexe selon la revendication 1, 10. caractérisé en ce que M est Fe111, Al111 ou Co11*.2. Complex according to claim 1, 10. characterized in that M is Fe 111 , Al 111 or Co 11 *.
3. Complexe selon la revendication 1, caractérisé en ce que A est K.3. Complex according to claim 1, characterized in that A is K.
4. Complexe selon l'une quelconque des revendications 1 à 3, caractérisé en ce que n est égal4. Complex according to any one of claims 1 to 3, characterized in that n is equal
15 à 14,5.15 to 14.5.
5. Complexe de formule : [Fe6(ino)60] K5, 14,5 H20 dans laquelle "ino" représente un ligand dérivé du cis-inositol. 20 6. Procédé de préparation d'un complexe de métal trivalent avec un ligand constitué par une molécule organique appartenant au groupe des polyols, caractérisé en ce qu'il comprend les étapes suivantes : a) préparer une solution aqueuse comprenant 25 des ions du métal trivalent et la molécule organique servant de ligand, b) ajouter à la solution aqueuse un sel neutre de métal alcalin pour compenser la perte de charges positives due à la libération de protons H+ 5. Complex of formula: [Fe 6 (ino) 6 0] K 5 , 14.5 H 2 0 in which "ino" represents a ligand derived from cis-inositol. 6. Method for preparing a trivalent metal complex with a ligand constituted by an organic molecule belonging to the group of polyols, characterized in that it comprises the following stages: a) preparing an aqueous solution comprising ions of the metal trivalent and the organic molecule serving as ligand, b) adding a neutral alkali metal salt to the aqueous solution to compensate for the loss of positive charges due to the release of H + protons
30 provenant du ligand lors de la complexation par des ions de métal alcalin afin d'obtenir un complexe neutre, et c) ajuster le pH de la solution aqueuse au pH de précipitation du complexe. 30 originating from the ligand during complexing with alkali metal ions in order to obtain a neutral complex, and c) adjusting the pH of the aqueous solution to the precipitation pH of the complex.
7. Procédé selon la revendication 6, caractérisé en ce qu'il comprend une étape complémentaire d) de recristallisation du complexe précipité dans l'étape c) . 7. Method according to claim 6, characterized in that it comprises a complementary step d) of recrystallization of the complex precipitated in step c).
8. Procédé selon l'une quelconque des revendications 6 et 7, caractérisé en ce que le ligand est le cis-inositol.8. Method according to any one of claims 6 and 7, characterized in that the ligand is cis-inositol.
9. Procédé selon la revendication 8, caractérisé en ce que le sel neutre est du nitrate ou du chlorure de potassium.9. Method according to claim 8, characterized in that the neutral salt is nitrate or potassium chloride.
10. Procédé selon l'une quelconque des revendications 8 et 9, caractérisé en ce que l'on ajuste le pH dans l'étape c) à une valeur de 5-6.10. Method according to any one of claims 8 and 9, characterized in that the pH is adjusted in step c) to a value of 5-6.
11. Procédé selon la revendication 10, caractérisé en ce que .l'on ajuste le pH par addition de11. Method according to claim 10, characterized in that. The pH is adjusted by adding
KOH.KOH.
12. Procédé selon l'une quelconque des revendications 6 à 11, caractérisé en ce que le métal trivalent est Fe111. 12. Method according to any one of claims 6 to 11, characterized in that the trivalent metal is Fe 111 .
13. Composition pharmaceutique, caractérisée en ce qu'elle comprend un complexe de Fe111 selon l'une quelconque des revendications 2 à 5.13. Pharmaceutical composition, characterized in that it comprises an Fe 111 complex according to any one of claims 2 to 5.
14. Utilisation d'un complexe ferrique selon l'une quelconque des revendications 2 et 5 pour la fabrication de médicaments destinés au traitement d'états sidéropéniques. 14. Use of a ferric complex according to any one of claims 2 and 5 for the manufacture of medicaments intended for the treatment of sideropenic states.
PCT/FR1995/000674 1994-05-26 1995-05-23 Trivalent metal complexes with a polyol such as cis-inositol, for medical use and method of preparation WO1995032978A1 (en)

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FR9406389A FR2720398B1 (en) 1994-05-26 1994-05-26 Trivalent metal complexes with a polyol such as cis-inositol, usable for medical purposes and their preparation process.
FR94/06389 1994-05-26

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RU2007117147A (en) * 2004-10-08 2008-11-20 Юнилевер Н.В. (Nl) IRON COMPLEX

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10249552A1 (en) * 2002-10-23 2004-05-13 Vifor (International) Ag Water-soluble iron-carbohydrate complexes, their preparation and medicaments containing them
US9376505B2 (en) 2002-10-23 2016-06-28 Vifor (International) Ag. Aqueous iron carbohydrate complexes, their production and medicaments containing them
US10519252B2 (en) 2002-10-23 2019-12-31 Vifor (International) Ag. Aqueous iron carbohydrate complexes, their production and medicaments containing them
US11123321B2 (en) 2002-10-23 2021-09-21 Vifor (International) Ag Aqueous iron carbohydrate complexes, their production and medicaments containing them
US11291645B2 (en) 2002-10-23 2022-04-05 Vifor (International) Ag Aqueous iron carbohydrate complexes, their production and medicaments containing them
US11590097B2 (en) 2002-10-23 2023-02-28 Vifor (International) Ag Aqueous iron carbohydrate complexes, their production and medicaments containing them

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