FR2720398A1 - New tri:valent metal cis-inositol complexes - Google Patents
New tri:valent metal cis-inositol complexes Download PDFInfo
- Publication number
- FR2720398A1 FR2720398A1 FR9406389A FR9406389A FR2720398A1 FR 2720398 A1 FR2720398 A1 FR 2720398A1 FR 9406389 A FR9406389 A FR 9406389A FR 9406389 A FR9406389 A FR 9406389A FR 2720398 A1 FR2720398 A1 FR 2720398A1
- Authority
- FR
- France
- Prior art keywords
- complex
- inositol
- cis
- trivalent metal
- ino
- 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.)
- Granted
Links
- CDAISMWEOUEBRE-JMVOWJSSSA-N cis-inositol Chemical class O[C@@H]1[C@H](O)[C@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-JMVOWJSSSA-N 0.000 title claims abstract description 28
- 229910052751 metal Inorganic materials 0.000 title claims abstract description 22
- 239000002184 metal Substances 0.000 title claims abstract description 22
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 13
- -1 cis-inositol Chemical class 0.000 claims abstract description 10
- 229920005862 polyol Polymers 0.000 claims abstract description 9
- 150000003077 polyols Chemical class 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 239000003446 ligand Substances 0.000 claims description 10
- 230000007935 neutral effect Effects 0.000 claims description 10
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 229910002553 FeIII Inorganic materials 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 150000001340 alkali metals Chemical group 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims description 2
- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 2
- 238000010668 complexation reaction Methods 0.000 claims description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims 2
- 229910002651 NO3 Inorganic materials 0.000 claims 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate group Chemical group [N+](=O)([O-])[O-] NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims 1
- 235000011164 potassium chloride Nutrition 0.000 claims 1
- 239000001103 potassium chloride Substances 0.000 claims 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 abstract description 40
- 229910052742 iron Inorganic materials 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 4
- 229910052700 potassium Inorganic materials 0.000 abstract description 3
- 208000007502 anemia Diseases 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- 150000001768 cations Chemical class 0.000 description 4
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000003999 cyclitols Chemical class 0.000 description 2
- 230000005595 deprotonation Effects 0.000 description 2
- 238000010537 deprotonation reaction Methods 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 235000010333 potassium nitrate Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022971 Iron Deficiencies Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- JAWGVVJVYSANRY-UHFFFAOYSA-N cobalt(3+) Chemical compound [Co+3] JAWGVVJVYSANRY-UHFFFAOYSA-N 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004698 iron complex Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 101150013507 mt:CoIII gene Proteins 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
Description
COMPLEXES DE ME TAUX TRIVALENTS AVEC UN POLYOL TEL QUE
LE CIS-INOSITOL, UTILISABLES A DES FINS MEDICALES ET
LEUR PROCEDE DE PREPARATION
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.COMPLEXES OF MY TRIVALENT RATE WITH A POLYOL SUCH AS
CIS-INOSITOL, USED FOR MEDICAL AND
THEIR PREPARATION PROCESS
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 precisely, it relates to the production of complexes of this type in the form of crystalline 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 Haworth Memorial Lecture,
Chemical Society Reviews, vol. 9, nO 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 ability to complex cations in aqueous solution. Studies of the formation of such complexes have been published by Angyal in Tetrahedron, vol. 30, 1974, pages 1695-1702 and in Haworth Memorial Lecture,
Chemical Society Reviews, vol. 9, No. 4, 1980, pages 415-428. In these publications, it is stated that cis-inositol exhibits a greater ability to complex metal cations than that of other sugars due to its configuration, that is to say the presence of three syn- hydroxyl groups. 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, in the pure state, in the form of crystalline solids have never been isolated heretofore.
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 novel 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)6O] A51 nH2O dans laquelle M représente un atome de métal trivalent tel que Fe1111 CoIII ou ALIBI, "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 O à 20.According to the invention, the complex of a trivalent metal with cis-inositol corresponds to the formula
[M6 (ino) 6O] A51 nH2O in which M represents a trivalent metal atom such as Fe1111 CoIII or ALIBI, "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.
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 the alkali metal, which makes it possible to obtain a neutral complex , stable and easily crystallizable.
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.
Le nombre de molécules d'eau liées au complexe peut varier de O à 20, mais il est généralement de 14,5. The number of water molecules bound to the complex can vary from 0 to 20, but it is usually 14.5.
De préférence dans ce complexe, le métal trivalent est le fer. Dans ce cas, le complexe répond avantageusement à la formule
[Fe6(ino)6O] Kg, 14,5 H2O dans laquelle "ino" a la signification donnée ci-dessus.Preferably in this complex, the trivalent metal is iron. In this case, the complex advantageously corresponds to the formula
[Fe6 (ino) 6O] Kg, 14.5 H2O in which "ino" has the meaning given above.
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. A subject of the present invention is also a process for preparing a complex of trivalent metal 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.
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.This process includes the following steps
a) preparing an aqueous solution comprising ions of the trivalent metal and the organic molecule serving as a ligand,
b) adding to the aqueous solution a neutral alkali metal salt 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 gracie à l'adjonction du sel neutre. This process is interesting because it is easy to carry out and makes it possible to obtain a stable complex, in particular thanks to the addition of the 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. In this process, the trivalent metal is introduced into the aqueous solution in the form of a salt, for example a chloride. In this solution, the coordination of the trivalent metal with the molecules of the polyol ligand causes the deprotonation of the complexed hydroxyls from the polyol, which decreases the pH of the solution. It is therefore generally necessary to then increase the pH of this solution in order to precipitate the complex formed.
Toutefois, on préfère ajouter les cations
A+ à partir d'un sel neutre pour ne pas introduire simultanément des anions susceptibles de modifier fortement le pH de la solution.However, we prefer to add the cations
A + from a neutral salt so as not to simultaneously introduce anions liable to greatly modify the pH of the solution.
A titre d'exemples de sels utilisable, on peut citer les nitrates et les chlorures tels que KNO3 et KCl. As examples of salts which can be used, mention may be made of nitrates and chlorides such as KNO3 and KCl.
Après cette étape de neutralisation des charges du complexe, on ajuste le pH à la valeur voulue pour obtenir la précipitation du complexe. After this step of neutralizing the charges of the complex, the pH is adjusted to the desired value in order to obtain precipitation of the complex.
Généralement, ce pH est d'environ 5-6 et il peut être obtenu par addition d'une base forte telle que KOH.Usually 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. After precipitation of the complex, the process preferably comprises an additional step of recrystallization of the precipitated complex.
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. To carry out this recrystallization, one can dissolve the precipitated complex 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 into each 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 crystalline 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 organic ligands of the polyol type 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-O 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 Fe1111 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 Fe1111 complexes, are of particular interest for medical use, for example for combating conditions resulting from iron deficiency, such as anemia.
En effet, la possibilité donnée par les complexes de l'invention de lier réversiblement 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 of reversibly and selectively binding 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, since 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 FeIII avec le cis-inositol présentant les caractéristiques développées ci-dessus. Also, a subject of the invention is also a pharmaceutical composition comprising a complex of FeIII with cis-inositol exhibiting the characteristics developed above.
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
- la figure 1 représente l'unité centrale du complexe formé par six ions FeIII liés entre eux par des atomes d'oxygène provenant du 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, et
- la figure 7 représente la structure du complexe de fer sans les ions potassium et l'eau.Other characteristics and advantages of the invention will appear better on reading the following examples, given of course by way of illustration and not limiting, with reference to the appended drawings in which
- Figure 1 shows the central unit of the complex formed by six FeIII ions linked together by oxygen atoms from cis-inositol,
- Figures 2, 3, 4, 5 and 6 represent the different modes of bonding between the iron atoms and cis-inositol, and
- Figure 7 shows the structure of the iron complex without potassium ions and water.
Exemple 1 : Préparation d'un complexe fer-cis-inositol
A 429 mg d'une solution aqueuse à 1 mol/l de FeCl3, 0,5 HCl, ayant une densité de 1,1325 g/ml, ce qui équivaut à 0,38 mmol 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/l 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 40C pendant 3 heures.Example 1: Preparation of an iron-cis-inositol complex
To 429 mg of a 1 mol / l aqueous solution of FeCl3, 0.5 HCl, having a density of 1.1325 g / ml, which is equivalent to 0.38 mmol of iron, 150 mg (0, 83 mmol) of cis-inositol dissolved in 1 ml of water. 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 solution pH of 5-6. The suspension obtained is then maintained at 40C 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 C6H14 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. The suspension is then filtered and the separated solid product is dissolved in very little water using very concentrated KOH. This gives a total volume of 5 ml. A few drops of C6H14 hexane are deposited on the surface of the aqueous solution, then a layer of C2H5OH ethanol without stirring. The complex which is insoluble in ethanol crystallizes as it diffuses into the aqueous solution.
Exemple 2 : Préparation d'un complexe Fe-cis-inositol.Example 2: Preparation of an Fe-cis-inositol complex.
A 577 mg d'une solution aqueuse à 1 mol/l de FeCl3 , 0,5 HCl 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 KCl (2,75 mmol), puis une solution à 1 mol/l de KOH jusqu'à ce que le produit précipite (pH de la solution 10-11). To 577 mg of a 1 mol / l aqueous solution of FeCl3, 0.5 HCl having a density of 1.1325 g / ml, which is equivalent to 0.51 mmol of iron, is added 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, followed by a 1 mol / l solution of KOH until the product precipitates (pH of the 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. The suspension is maintained 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 applied. on the surface of the solution obtained, and a layer of ethanol without stirring, a complex is thus crystallized as above.
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)6O] K5, 14,5 H2O
Sur la figure 1, on a représenté l'unité centrale du complexe obtenu dans ces exemples. Cette unité est formée de six ions FeIII
numérotés de 1 à 6, qui sont liés entre eux par des atomes d'oxygène
provenant du cis-inositol. Trois ions FeIII 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(1)) 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
Fe(l)-Fe(2) = 2,983 A.The structure of the complex obtained in these two examples was determined using X-ray diffraction diagrams. It corresponds to the formula
[Fe6 (ino) 6O] K5, 14.5 H2O
FIG. 1 shows the central unit of the complex obtained in these examples. This unit is made up of six FeIII ions
numbered 1 to 6, which are linked together by oxygen atoms
from cis-inositol. Three FeIII ions are bonded to an additional oxygen atom from a base KOH molecule, which subsequently stabilizes this unit. One of the six iron atoms (Fe (1)) has five coordinated oxygen, while the other five iron atoms have six. The distances between the iron atoms of the complex are as follows
Fe (l) -Fe (2) = 2.983 A.
Fe(1)-Fe(3) = 3,505 A
Fe(1)-Fe(4) = 3,670 A
Fe(1)-Fe(6) = 3,504 A
Fe(2)-Fe(5) = 3,242 A
Fe(3)-Fe(5) = 3,108 A
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, sont indiquées sur la figure 1 en A.Fe (1) -Fe (3) = 3.505 A
Fe (1) -Fe (4) = 3.670 A
Fe (1) -Fe (6) = 3.504 A
Fe (2) -Fe (5) = 3.242 A
Fe (3) -Fe (5) = 3.108 A
Fe (3) -Fe (6) = 2.804 A
Fe (4) -Fe (6) = 3.138 A
The bond lengths between iron atoms and the oxygen atoms to which they are bonded are shown in Figure 1 in A.
Ce complexe cristallise dans le système triclinique, groupe d'espace P-1 avec les paramètres de réseau suivants
a = 12,730 A
b = 13,850 A
c = 19,743 A
a = 90,65 ss = 93,29
y = 112,34
Les indices finaux R sont les suivants
R = 4,71 %
RW = 5,20 %
Sur les figures 2 à 6, on a représenté les modes de liaison entre les atomes de fer
et les atomes d'oxygène
du cis-inositol. Les atomes de carbone du cis-inositol sont représentés par
a = 12.730 A
b = 13.850 A
c = 19.743 A
a = 90.65 ss = 93.29
y = 112.34
The final indices R are as follows
R = 4.71%
RW = 5.20%
In Figures 2 to 6, there is shown the bonding modes between the iron atoms
and oxygen atoms
cis-inositol. The carbon atoms of cis-inositol are represented by
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. In these figures, it can be seen that the iron atoms can be arranged in a triaxial arrangement, the iron being linked with three axial hydroxyls of cis-inositol, or in "axial-equatorial-axial" arrangements, the iron being linked with two axial hydroxyls and an equatorial hydroxyl.
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 FIG. 3, the central unit of the complex is represented, that is to say the iron atoms,
oxygen
and carbon
without the five potassium ions and water.
Claims (13)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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. |
| PCT/FR1995/000674 WO1995032978A1 (en) | 1994-05-26 | 1995-05-23 | Trivalent metal complexes with a polyol such as cis-inositol, for medical use and method of preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2720398A1 true FR2720398A1 (en) | 1995-12-01 |
| FR2720398B1 FR2720398B1 (en) | 1996-07-05 |
Family
ID=9463531
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR9406389A Expired - Fee Related 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. |
Country Status (2)
| Country | Link |
|---|---|
| FR (1) | FR2720398B1 (en) |
| WO (1) | WO1995032978A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006037449A2 (en) * | 2004-10-08 | 2006-04-13 | Unilever N.V. | Iron complex for use in the treatment and/or prevention of nutritional disorders |
Families Citing this family (1)
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2503781A (en) * | 1946-04-09 | 1950-04-11 | Reed & Carnrick | Organic iron alkali metal complexes |
| US3686397A (en) * | 1970-05-18 | 1972-08-22 | Mueller Arthur | Parenteral iron preparations |
-
1994
- 1994-05-26 FR FR9406389A patent/FR2720398B1/en not_active Expired - Fee Related
-
1995
- 1995-05-23 WO PCT/FR1995/000674 patent/WO1995032978A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2503781A (en) * | 1946-04-09 | 1950-04-11 | Reed & Carnrick | Organic iron alkali metal complexes |
| US3686397A (en) * | 1970-05-18 | 1972-08-22 | Mueller Arthur | Parenteral iron preparations |
Non-Patent Citations (1)
| Title |
|---|
| ANGYAL, S.J.: "COMPLEXING OF POLYOLS WITH CATIONS", TETRAHEDRON, vol. 30, 1974, pages 1695 - 1702 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006037449A2 (en) * | 2004-10-08 | 2006-04-13 | Unilever N.V. | Iron complex for use in the treatment and/or prevention of nutritional disorders |
| WO2006037449A3 (en) * | 2004-10-08 | 2006-06-15 | Unilever Nv | Iron complex for use in the treatment and/or prevention of nutritional disorders |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995032978A1 (en) | 1995-12-07 |
| FR2720398B1 (en) | 1996-07-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0618184B1 (en) | Process for the preparation of carboxylic acids or corresponding esters in presence of a catalyst based on iridium | |
| EP2203487B1 (en) | Method for preparing polymer materials doped with metal elements and resulting materials | |
| CA2894741A1 (en) | Ruthenium complexes comprising an asymmetrical unsaturated n-heterocyclic diaminocarbene | |
| JPS6245226B2 (en) | ||
| FR2619382A1 (en) | VANADYL ORGANO-MINERAL COMPOUND, PROCESS FOR OBTAINING SUCH A COMPOUND, PHARMACEUTICAL COMPOSITION CONTAINING THE ORGANO-MINERAL COMPOUND | |
| EP2491047B1 (en) | Novel organic/inorganic hybrid material ihm-2, and methods for manufacturing same | |
| EP0537242A1 (en) | Process for the preparation of transition metal nitrido complexes. | |
| US7872150B2 (en) | Process for the preparation of an oxaliplatin | |
| Miroslavov et al. | Water-soluble carbonyl complexes of 99Tc (I) and Re (I) with adamantane-cage aminophosphines PTA and CAP | |
| FR2720398A1 (en) | New tri:valent metal cis-inositol complexes | |
| CA2520157A1 (en) | Method for the enantioselective preparation of sulphoxide derivatives | |
| WO2014195416A1 (en) | Chelates of lead (ii) and bismuth (iii) based on trans-di-n-picolinate tetraazacycloalkanes | |
| JP2001335405A (en) | Antibacterial/antifungal agent | |
| CN111228276B (en) | Bromooxamide binuclear copper complex with antibacterial activity and composition thereof | |
| EP0991670B1 (en) | Method for fixing or separating ions, in particular of lead, using per(3,6-anhydro) cyclodextrin derivatives | |
| FR2612803A1 (en) | HYDROGENATION RHODIUM CATALYSTS, THEIR PREPARATION AND APPLICATION | |
| FR2459247A1 (en) | PLATINUM (II) AMINE CIS-ASCORBATE COMPLEX | |
| JPS632270B2 (en) | ||
| EA017521B1 (en) | Platinum complex compound and utilization of the same | |
| BE1000435A3 (en) | Containing rhodium catalyst, preparation and application. | |
| WO2021079069A1 (en) | Energetic amino acid salts with high oxygen balance | |
| WO1988007048A1 (en) | Phosphorous-containing organic macrocycles, process for their production and application | |
| FR2859724A1 (en) | New stable, crystalline epipodophyllotoxin 4'-demethyl-4'-phosphate glucoside compound used as anticancer agent, e.g. for treating small cell lung cancer, neuroblastoma and lymphoma | |
| KR830002844B1 (en) | Method for preparing a water soluble cholesterol derivative | |
| FR2563524A1 (en) | Mixed carboxylatoplatinum(II) complexes and process for the preparation of said complexes |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| ST | Notification of lapse |