WO1991007406A1 - Derivatives of a transition metal having a porphyrinic structure, and use of this derivative in drug manufacturing - Google Patents

Derivatives of a transition metal having a porphyrinic structure, and use of this derivative in drug manufacturing Download PDF

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Publication number
WO1991007406A1
WO1991007406A1 PCT/FR1990/000821 FR9000821W WO9107406A1 WO 1991007406 A1 WO1991007406 A1 WO 1991007406A1 FR 9000821 W FR9000821 W FR 9000821W WO 9107406 A1 WO9107406 A1 WO 9107406A1
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Prior art keywords
derivative
transition metal
organic
chosen
pharmaceutical composition
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PCT/FR1990/000821
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French (fr)
Inventor
Jean-Pierre Masse
Original Assignee
I.R.2.M.
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Publication of WO1991007406A1 publication Critical patent/WO1991007406A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings

Definitions

  • Transitional metal derivatives with porphyrinic structure use of this derivative for the manufacture of medicaments,
  • the present invention relates essentially to a new organic derivative of transition metal with a porphyrin structure, a use of this derivative for the manufacture of medicaments, a therapeutic composition containing it, in particular hypoglycemic activity and a process for the preparation of such a composition. therapeutic.
  • the invention provides a new organic derivative of transition metal, characterized in that it consists of a derivative of a transition metal M with an organic compound with porpnyrinic structure, said derivative responding to the following general formula: in which R1., R. ,, R.5 ,, R., Ri, ->, Ro ,, Rr ,, Ro courtare independently chosen from the usual substituents of chlorophylls, in particular hydrogen, lower alkyl CC-. straight chain, branched or cyclic. These usual substituents of chlorophyll are in particular those described by Hendry and Jones in the journal Journal of Medical Genetics, 1980, 17, 1-14, and in particular in Table 1, page 5.
  • the substituents currently preferred are chosen from: hydrogen, a methyl, ethyl, propyl, isopropyl, vinyl, formyl and its esters, acetyl and its esters, propionyl and its esters, acrylyl and its esters, and cyclopentanoyl radicals.
  • the aforementioned transition metal is chosen from vanadium and molybdenum.
  • This new transition metal derivative according to the invention can be prepared synthetically from its corresponding constituents which are reacted under operating conditions well known to those skilled in the art.
  • Other easily accessible sources for the preparation of this transition metal derivative are plants which are subjected to specific extraction treatments which will be described later.
  • the particularly preferred plants serving as raw material for the isolation of this new derivative according to this invention come from the families of:
  • - Legumes in particular those which are rich in Leghemoglobins, in particular Soya, Beans, Peas, Chickpeas, Alfalfa, Oats and Cesbania from Madagascar; - Plantaged plants, in particular Plantains, sands, major, medium and Psyllium; - Crucifers, in particular rapeseed, radishes, cabbage, turnips, watercress;
  • Urticaceae in particular the nettles Urtica dio ⁇ ca and U. urens. and the gamblers;
  • the present invention relates, according to a second aspect, to a process for isolating the new organic transition metal derivative according to the invention from an appropriate plant, characterized in that it comprises:
  • extraction by appropriate extraction means of part or all of the plant either fresh or dried, in particular the aerial parts, in particular an extraction of the aqueous, alcoholic or hydroalcoholic type; and. - optionally subjecting the crude extract obtained to one or more separation steps.
  • separation steps are those of techniques well known to those skilled in the art, in particular those relating to the extraction of chlorophylls.
  • one of these separation steps comprises subjecting the crude extract to chromatography, in particular adsorption chromatography.
  • the abovementioned extraction of a part or of the whole of the plant, in particular the aerial parts takes place using as extraction solvent the following solvents:
  • the water / alcohol proportion is advantageously between 95/05 and 45/55.
  • the invention also covers a use of the above-mentioned organic transition metal derivative as active principle for the manufacture of a medicament, in particular useful in the treatment of patients suffering from disorders of blood glucose and related disorders such as 1 yperlipidartifact, including diabetic patients.
  • the present invention covers a pharmaceutical composition, characterized in that it comprises, as active principle, an organic derivative formed of a transition metal M and of an organic compound with a porphyrinic structure.
  • a pharmaceutical composition characterized in that it comprises, as active principle, an organic derivative formed of a transition metal M and of an organic compound with a porphyrinic structure.
  • Said organic derivative having the following general formula:
  • organic derivative being incorporated into a pharmaceutically acceptable excipient, vehicle, or support.
  • the concentration of transition metal derivative is between approximately 0.1 and approximately 10 g relative to the total weight of the pharmaceutical composition.
  • the metal is preferably chosen from vanadium and molybdenum.
  • the pharmaceutical composition is characterized in that it is a composition with hypoglycaemic activity, or an associated activity, in particular an antihypercholesterolageante or antihypertriglycéridropante activity.
  • This pharmaceutical composition can be formulated in any suitable galenic form well known to those skilled in the art.
  • an oral formulation can be produced, in particular under form of tablets, dragees or capsules, dosed with a content of the aforementioned transition metal of approximately 0.01 to approximately 1 mg.
  • the present invention also covers, according to another aspect, a process for preparing a pharmaceutical composition, characterized in that a new transition metal derivative is incorporated with an organic compound of porphyrinic structure, this derivative having the following general formula :
  • R-, R ? , R ,, R ,, R-., R ,, R- ,, R is chosen from vanadium and molybdenum.
  • the present invention also covers a method for the therapeutic treatment of a mammal including a human being, characterized in that this mammal is administered a therapeutically effective amount of a transition metal derivative and of an organic compound with a porphyrinic structure.
  • Said derivative having the following general formula:
  • this transition metal is chosen from vanadium and molybdenum.
  • a hypoglycemic, or cholesterol-lowering or hypotriglyceridemic treatment is carried out.
  • the invention therefore makes it possible to treat all the disturbances resulting from a dysfunction of the pancreas: hyperglycemia and associated hyperlipidemia, which makes it possible to treat patients suffering from glycemic disorders and associated disorders such as hyperlipidemia, in particular diabetic patients. .
  • Example 1 Isolation of the transition metal derivative according to the invention from nettle.
  • the liquid phase is concentrated to one-tenth of its initial volume according to a non-destructive process, then the concentration supplemented with 10 g / l of maltodextrin is subjected to lyophilization.
  • a transition metal derivative is thus obtained essentially comprising vanadium and traces of molybdenum, the determination of vanadium with a plasma torch gives 1.3 mg of vanadium per gram of lyophilisate.
  • Example 2 Chemical synthesis of the organic transition metal derivative according to the invention.
  • 1 g of sodium metavanadate is suspended with stirring in 100 ml of absolute ethanol, and the whole is brought to a boil; after distillation of 25 ml of alcohol, 3 g of hematoporphyrin IX, or 8,13-bis (1-hydroxyethyl) -3,7,12, - 17-tetramethyl-21H, 23H-porphine-2 acid, are added 18-dipropionic, in solution in 150 ml of absolute ethanol heated to 65 C; then the whole with stirring is brought to reflux for 1 h; after cooling to 25 ° C., the medium is filtered through a frit of porosity 3, and the filtrate obtained concentrated to 10 ml; the precipitate is collected on a frit, washed with 3 times 3 ml of absolute ethanol, then dried.
  • a transition metal derivative according to the invention can be prepared, the transition metal of which is molybdenum, using ammonium molybdenate, as the starting salt.
  • Example 3 Pharmaceutical composition.
  • Example 4 Pharmaceutical composition.
  • the transition metal derivative according to the invention prepared in Example 2 is packaged with the addition of pharmaceutically acceptable vehicles, supports or excipients, in 200 mg capsules at a rate of 1 mg of metal derivative of transition according to the invention by gelules, ie 0.07 mg of metal
  • Example 5 Determination of a hypoglycemic effect.
  • mice with a blood sugar level greater than or equal to 2 g are selected and subjected to treatment with the test substance.
  • the administration of the complex according to Example 2 was twice daily (8-18 h) for 3 days, then daily (18 h).
  • the glycemia control is carried out in the morning at 9 am, time of the day when the glycemia of the diabetic control or treated rats, subjected to great variations during the day, is the highest.
  • Diabetic rats receive only the excipient (physiological saline) and serve as diabetic controls.
  • the daily glycemic control did not allow us to demonstrate a hypoglycemic effect during the first 2 days of treatment.
  • a significant and significant drop in blood glucose compared to that of control rats appears from the third day and is maintained on the following days. This is accompanied by an equally significant reduction in polyphagia and polydipsia, Food and water consumption covering values tending to approach that of non-diabetic control rats.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Novel organic derivatives of a transition metal having a porphyrinic structure. This novel derivative is characterized in that it consists of a transition metal derivative with an organic compound having a porphyrinic structure, said derivative being of general formula (I): wherein R1?, R2?, R3?, R4?, R5?, R6?, R7?, R8? are selected independently among the common substituents of chlorophylls, particularly hydrogen, a straight-, branched- or ring-chain C1?-C5? lower alkyl. This derivative is hypoglycaemically active and therefore suited to therapeutical applications.

Description

Dérivés de métal de transition à structure porphyrinique, utilisation de ce dérivé pour la fabrication de médicaments,Transitional metal derivatives with porphyrinic structure, use of this derivative for the manufacture of medicaments,
La présente invention concerne essentiel Le ent un nouveau dérivé organique de métal de transition à structure porphyrinique, une utilisation de ce dérivé pour la fabrication de médicaments, une composition thérapeutique le contenant, en particulier activité hypoglycémiante et un procédé de préparation d'une telle composition thérapeutique.The present invention relates essentially to a new organic derivative of transition metal with a porphyrin structure, a use of this derivative for the manufacture of medicaments, a therapeutic composition containing it, in particular hypoglycemic activity and a process for the preparation of such a composition. therapeutic.
Dans l'état actuel de la technique, on a réalisé diverses formulations du vanadium en vue de le rendre biodisponible dans le cadre du traitement de l'hyperglycémie. Les formulations réalisées jusqu'à présent sont encore très insu fisantes par le fait que leur biodisponibilité très faible, voire inexistante- La présente invention a donc pour but de résoudre le nouveau problème technique consistant en la fourniture d'une nouvelle formulation de vanadium qui présente une excellente bio- disponibilité. De préférence, cette nouvelle formulation doit être simple à préparer et être suffisamment stable dans le temps pour permettre une utilisation thérapeutique dans les meilleures conditions. L'invention résout ce problème d'une manière extrêmement simple en fournissant une formulation d'un métal de transition qui présente de manière inattendue une biodisponibilité remarquable.In the current state of the art, various formulations of vanadium have been produced with a view to making it bioavailable in the context of the treatment of hyperglycemia. The formulations produced up to now are still very insuffi cient in that their very low bioavailability, even nonexistent. The present invention therefore aims to solve the new technical problem consisting in the supply of a new formulation of vanadium which has excellent bioavailability. Preferably, this new formulation must be simple to prepare and be sufficiently stable over time to allow therapeutic use under the best conditions. The invention solves this problem in an extremely simple manner by providing a formulation of a transition metal which unexpectedly exhibits remarkable bioavailability.
Ainsi, selon un premier aspect, l'invention fournit un nouveau dérivé organique de métal de transition, caractérisé en ce qu'il est constitué par un dérivé d'un métal de transition M avec un composé organique à structure porpnyrinique, ledit dérivé répondant à la formule générale suivante :
Figure imgf000004_0001
dans Laquelle R1., R.,, R.5,, R., Ri,->, Ro,, R-r,, Ro„ sont choisis indépendamment parmi Les substituants usuels des chlorophylles, en particulier L'hydrogène, un alkyle inférieur en C--C-. à chaîne droite, ramifiée ou cyclique. Ces substituants usuels de la chloro¬ phylle sont en particulier ceux décrits par Hendry et Jones dans la revue Journal of Médical Genetics, 1980, 17, 1-14, et en particu¬ lier au tableau 1, page 5. Les substituants actuellement préférés sont choisis parmi : l'hydrogène, un radical méthyle, éthyle, pro- pyle, isopropyle, vinyle, formyle et ses esters, acétyle et ses esters, propionyle et ses esters, acrylyle et ses esters, et cyclo- pentanoyles.Thus, according to a first aspect, the invention provides a new organic derivative of transition metal, characterized in that it consists of a derivative of a transition metal M with an organic compound with porpnyrinic structure, said derivative responding to the following general formula:
Figure imgf000004_0001
in which R1., R. ,, R.5 ,, R., Ri, ->, Ro ,, Rr ,, Ro „are independently chosen from the usual substituents of chlorophylls, in particular hydrogen, lower alkyl CC-. straight chain, branched or cyclic. These usual substituents of chlorophyll are in particular those described by Hendry and Jones in the journal Journal of Medical Genetics, 1980, 17, 1-14, and in particular in Table 1, page 5. The substituents currently preferred are chosen from: hydrogen, a methyl, ethyl, propyl, isopropyl, vinyl, formyl and its esters, acetyl and its esters, propionyl and its esters, acrylyl and its esters, and cyclopentanoyl radicals.
De préférence, Le métal de transition précité est choisi parmi Le vanadium et le molybdène.Preferably, the aforementioned transition metal is chosen from vanadium and molybdenum.
Ce nouveau dérivé de métal de transition selon L'invention peut être préparé par voie de synthèse à partir de ses constituants correspondants que L'on fait réagir dans des conditions opératoires bien connues à L'homme de L'art. D'autres sources aisément accessibles pour La préparation de ce dérivé de métal de transition sont constituées par des plantes que l'on soumet à des traitements d'extraction spécifiques qui seront décrits plus Loin.This new transition metal derivative according to the invention can be prepared synthetically from its corresponding constituents which are reacted under operating conditions well known to those skilled in the art. Other easily accessible sources for the preparation of this transition metal derivative are plants which are subjected to specific extraction treatments which will be described later.
Les plantes particulièrement préférées servant de matière première à L'isolement de ce nouveau dérivé selon cette invention sont issues des familles des :The particularly preferred plants serving as raw material for the isolation of this new derivative according to this invention come from the families of:
- Légumineuses, en particulier celles qui sont riches en Leghémo- globines, en particulier Le soja, La fève, Le pois, Le pois chiche, La Luzerne, L'avoine et le cesbania de Madagascar ; - Plantaginées, en particulier Les plantains, des sables, majeur, moyen et Psyllium ; - Crucifères, en particulier Le colza, le radis, Les choux, Les navets, le cresson ;- Legumes, in particular those which are rich in Leghemoglobins, in particular Soya, Beans, Peas, Chickpeas, Alfalfa, Oats and Cesbania from Madagascar; - Plantaged plants, in particular Plantains, sands, major, medium and Psyllium; - Crucifers, in particular rapeseed, radishes, cabbage, turnips, watercress;
- Salsolacées, en particulier Les épinards ;- Salsolaceae, in particular spinach;
- Urticacées, en particulier les orties Urtica dioïca et U. urens. et les pariétaires ;- Urticaceae, in particular the nettles Urtica dioïca and U. urens. and the gamblers;
- Algues, en particulier Ulva latissima.- Algae, in particular Ulva latissima.
La présente invention concerne, selon un deuxième aspect, un procédé d'isolement du nouveau dérivé organique de métal de transition selon l'invention à partir d'une plante appropriée, caractérisé en ce qu'il comprend :The present invention relates, according to a second aspect, to a process for isolating the new organic transition metal derivative according to the invention from an appropriate plant, characterized in that it comprises:
- L'extraction par des moyens d'extraction appropriés d'une partie ou de la totalité de La plante, soit fraîche, soit séchée, notam¬ ment Les parties aériennes, en particulier une extraction de type aqueux, alcoolique ou hydroalcoolique ; et . - éventuellement la soumission de l'extrait brut obtenu à une ou plusieurs étapes de séparation. Ces étapes de séparation sont celles des techniques bien connues à L'homme de l'art, notamment celles se rapportant à L'extraction des chlorophylles.- Extraction by appropriate extraction means of part or all of the plant, either fresh or dried, in particular the aerial parts, in particular an extraction of the aqueous, alcoholic or hydroalcoholic type; and. - optionally subjecting the crude extract obtained to one or more separation steps. These separation steps are those of techniques well known to those skilled in the art, in particular those relating to the extraction of chlorophylls.
Avantageusement, L'une de ces étapes de séparation comprend La soumission de l'extrait brut à une chromatographie, en particulier une chromatographie d'adsorption.Advantageously, one of these separation steps comprises subjecting the crude extract to chromatography, in particular adsorption chromatography.
Selon un mode de réalisation particulier, l'extraction précitée d'une partie ou de la totalité de la plante, notamment les parties aériennes, a Lieu en utilisant comme solvant d'extraction les solvants suivants :According to a particular embodiment, the abovementioned extraction of a part or of the whole of the plant, in particular the aerial parts, takes place using as extraction solvent the following solvents:
- eau plus méthanol,- water plus methanol,
- eau plus éthanol,- water plus ethanol,
- eau plus propanols,- water plus propanols,
- eau plus butanols. Dans le cadre d'un solvant hydroalcoolique, la proportion eau/alcool est avantageusement comprise entre 95/05 et 45/55.- water plus butanols. In the context of a hydroalcoholic solvent, the water / alcohol proportion is advantageously between 95/05 and 45/55.
Selon un troisième aspect, l'invention couvre encore une L'utilisation du dérivé organique de métal de transition précité comme principe actif pour la fabrication d'un médicament, en particulier utile dans Le traitement de malades souffrant de troubles de La glycémie et de troubles associés tels que l1 yperlipidémie, notamment des malades diabétiques.According to a third aspect, the invention also covers a use of the above-mentioned organic transition metal derivative as active principle for the manufacture of a medicament, in particular useful in the treatment of patients suffering from disorders of blood glucose and related disorders such as 1 yperlipidémie, including diabetic patients.
Selon un quatrième aspect, La présente invention couvre une composition pharmaceutique, caractérisée en ce qu'elle comprend à titre de principe actif un dérivé organique formé d'un métal de transition M et d'un composé organique à structure porphyrinique. Ledit dérivé organique ayant La formule générale suivante :According to a fourth aspect, the present invention covers a pharmaceutical composition, characterized in that it comprises, as active principle, an organic derivative formed of a transition metal M and of an organic compound with a porphyrinic structure. Said organic derivative having the following general formula:
Figure imgf000006_0001
dans Laquelle R sont tels que précédemment définis,
Figure imgf000006_0001
in which R are as previously defined,
Ledit dérivé organique étant incorporé dans un excipient, véhicule, ou support pharmaceutiquement acceptable.Said organic derivative being incorporated into a pharmaceutically acceptable excipient, vehicle, or support.
Selon une variante de réalisation, la concentration en dérivé de métal de transition est comprise entre environ 0,1 et environ 10 g par rapport au poids total de la composition pharmaceutique.According to an alternative embodiment, the concentration of transition metal derivative is between approximately 0.1 and approximately 10 g relative to the total weight of the pharmaceutical composition.
Le métal est de préférence choisi parmi Le vanadium et Le molybdène.The metal is preferably chosen from vanadium and molybdenum.
Selon un mode de réalisation particulier à L'invention, La composition pharmaceutique est caractérisée en ce qu'il s'agit d'une composition à activité hypoglycémiante, ou une activité associée, en particulier une activité antihypercholestérolémiante ou antihypertriglycéridémiante.According to an embodiment particular to the invention, the pharmaceutical composition is characterized in that it is a composition with hypoglycaemic activity, or an associated activity, in particular an antihypercholesterolémiante or antihypertriglycéridémiante activity.
Cette composition pharmaceutique peut être formulée sous toute forme gaLénique appropriée bien connue à l'homme de L'art. En particulier, on peut réaliser une formulation orale, notamment sous forme de comprimés, dragées ou gélules, dosée à une teneur en métal de transition précité d environ 0,01 à environ 1 mg.This pharmaceutical composition can be formulated in any suitable galenic form well known to those skilled in the art. In particular, an oral formulation can be produced, in particular under form of tablets, dragees or capsules, dosed with a content of the aforementioned transition metal of approximately 0.01 to approximately 1 mg.
La présente invention couvre encore, selon un autre aspect, un procédé de préparation d'une composition pharmaceutique, caractérisé en ce qu'on incorpore un nouveau dérivé de métal de transition avec un composé organique de structure porphyrinique, ce dérivé ayant la formule générale suivante :The present invention also covers, according to another aspect, a process for preparing a pharmaceutical composition, characterized in that a new transition metal derivative is incorporated with an organic compound of porphyrinic structure, this derivative having the following general formula :
Figure imgf000007_0001
Figure imgf000007_0001
dans Laquelle R- , R?, R,, R,, R-., R,, R-,, R„ étant tels que précédemment définis, dans un véhicule, support ou excipient pharmaceutiquement acceptable. De préférence, le métal de transition précité est choisi parmi le vanadium et le molybdène.in which R-, R ? , R ,, R ,, R-., R ,, R- ,, R „being as defined above, in a pharmaceutically acceptable vehicle, support or excipient. Preferably, the aforementioned transition metal is chosen from vanadium and molybdenum.
La présente invention couvre encore un procédé de traitement thérapeutique d'un mammifère incluant un être humain, caractérisé en ce qu'on administre à ce mammifère une quantité thérapeutiquement efficace d'un dérivé de métal de transition et d'un composé organique à structure porphyrinique, Ledit dérivé ayant La formule générale suivante : The present invention also covers a method for the therapeutic treatment of a mammal including a human being, characterized in that this mammal is administered a therapeutically effective amount of a transition metal derivative and of an organic compound with a porphyrinic structure. , Said derivative having the following general formula:
Figure imgf000008_0001
dans Laquelle R., R , R._, R., Rc, R., R_,, R„ sont tels que I c 5 H J o ( o précédemmment définis.
Figure imgf000008_0001
in which R., R, R._, R., R c , R., R_ ,, R „are such that I c 5 HJ o (o previously defined.
De préférence, ce métal de transition est choisi parmi le vanadium et le molybdène.Preferably, this transition metal is chosen from vanadium and molybdenum.
Selon une variante de réalisation préférée de ce procédé de traitement thérapeutique, on réalise un traitement hypo- glycémiant, ou hypocholestérolémiant ou hypotriglycéridémiant.According to a preferred embodiment variant of this therapeutic treatment method, a hypoglycemic, or cholesterol-lowering or hypotriglyceridemic treatment is carried out.
Selon l'invention, on a découvert de manière totalement inattendue que le nouveau dérivé organique de métal de transition précédemment défini présente une action similaire à L'insuline.According to the invention, it has been discovered completely unexpectedly that the new organic derivative of transition metal previously defined has an action similar to Insulin.
L'invention permet donc de traiter toutes Les perturbations résultant d'un disfonctionnement du pancréas : hyperglycémie et hyperlipidémie associées, ce qui permet de traiter des malades souffrant de troubles de la glycémie et de troubles associés tels que L' hyperlipidémie, notamment des malades diabétiques.The invention therefore makes it possible to treat all the disturbances resulting from a dysfunction of the pancreas: hyperglycemia and associated hyperlipidemia, which makes it possible to treat patients suffering from glycemic disorders and associated disorders such as hyperlipidemia, in particular diabetic patients. .
La présente invention sera maintenant illustrée à partir de plusieurs exemples de réalisation de L'invention, donnés simplement à titre d'illustration et que ne sauraient donc en aucune façon limiter la portée de L'invention. Dans Les exemples, comme dans Le texte, tous Les pourcentages sont donnés en poids, sauf indication contraire.The present invention will now be illustrated on the basis of several exemplary embodiments of the invention, given simply by way of illustration and which therefore cannot in any way limit the scope of the invention. In the examples, as in the text, all the percentages are given by weight, unless otherwise indicated.
Exemple 1 - Isolement du dérivé de métal de transition selon L'invention à partir d'ortie.Example 1 - Isolation of the transition metal derivative according to the invention from nettle.
Les parties aériennes de L'ortie dioîque - Urtica dioïca L - sont soumises à une extraction par un mélange hydro- alcoolique (proportion eau/alcooL = 75/25 volume/volume) en propor¬ tion de 10/1 en poids/poids de plante, suivie d'une expression du solvant d'inhibition. La phase liquide est concentrée au dixième de son volume initial selon un procédé non destructif, puis le concen- trat additionné de 10 g/l de maltodextrine est soumis à une Lyophi¬ lisation.The aerial parts of the nettle dioïc - Urtica dioïca L - are subjected to an extraction by a hydro- alcoholic (water / alcohol ratio = 75/25 volume / volume) in proportion of 10/1 by weight / weight of plant, followed by expression of the inhibiting solvent. The liquid phase is concentrated to one-tenth of its initial volume according to a non-destructive process, then the concentration supplemented with 10 g / l of maltodextrin is subjected to lyophilization.
On obtient ainsi un dérivé de métal de transition comprenant essentiellement le vanadium et des traces de molybdène, le dosage du vanadium à la torche à plasma, donne 1,3 mg de vana- dium par gramme de Lyophilisât.A transition metal derivative is thus obtained essentially comprising vanadium and traces of molybdenum, the determination of vanadium with a plasma torch gives 1.3 mg of vanadium per gram of lyophilisate.
Exemple 2 - Synthèse chimique du dérivé organique de métal de transition selon L'invention.Example 2 - Chemical synthesis of the organic transition metal derivative according to the invention.
1 g de metavanadate de sodium est mis en suspension sous agitation dans 100 ml d'éthanol absolu, et l'ensemble est porté à ébullition ; après distillation de 25 ml d'alcool, sont ajoutés 3 g d'hematoporphyrine IX, ou acide 8,13-bis(1-hydroxyéthyl)-3,7,12,- 17-tétraméthyl-21H,23H-porphine-2,18-dipropionique, en solution dans 150 ml d'éthanol absolu chauffé à 65 C ; puis l'ensemble sous agitation est porté au reflux durant 1 h ; après refroidissement à 25 C, le milieu est filtré sur fritte de porosité 3, et le filtrat obtenu concentré à 10 ml ; le précipité est recueilli sur fritte, lavé avec 3 fois 3 ml d'éthanol absolu, puis séché.1 g of sodium metavanadate is suspended with stirring in 100 ml of absolute ethanol, and the whole is brought to a boil; after distillation of 25 ml of alcohol, 3 g of hematoporphyrin IX, or 8,13-bis (1-hydroxyethyl) -3,7,12, - 17-tetramethyl-21H, 23H-porphine-2 acid, are added 18-dipropionic, in solution in 150 ml of absolute ethanol heated to 65 C; then the whole with stirring is brought to reflux for 1 h; after cooling to 25 ° C., the medium is filtered through a frit of porosity 3, and the filtrate obtained concentrated to 10 ml; the precipitate is collected on a frit, washed with 3 times 3 ml of absolute ethanol, then dried.
IL est à noter que, en suivant essentiellement Le même procédé, on peut préparer un dérivé de métal de transition selon l'invention dont Le métal de transition est le molybdène, en utilisant le molybdènate d'ammonium, comme sel de départ. Exemple 3 - Composition pharmaceutique.It should be noted that, by essentially following the same process, a transition metal derivative according to the invention can be prepared, the transition metal of which is molybdenum, using ammonium molybdenate, as the starting salt. Example 3 - Pharmaceutical composition.
Le lyophilisât selon l'exemple 1 est conditionné avec L'adjonction d'excipients pharmaceutiquement acceptables, en comprimés de 150 mg dosés à 10 mg de lyophilisât, le dosage en métal (vanadium) de ce dernier étant Lui-même de 0,1%. Exemple 4 - Composition pharmaceutique.The lyophilisate according to Example 1 is packaged with the addition of pharmaceutically acceptable excipients, in 150 mg tablets dosed with 10 mg of lyophilisate, the metal (vanadium) dosage of the latter itself being 0.1%. . Example 4 - Pharmaceutical composition.
Le dérivé de métal de transition selon l'invention préparé à L'exemple 2 est conditionné avec l'adjonction de véhicules, supports ou excipients pharmaceutiquement acceptables, en gélules de 200 mg à raison de 1 mg de dérivé de métal de transition selon l'invention par géluLes, soit 0,07 mg de métalThe transition metal derivative according to the invention prepared in Example 2 is packaged with the addition of pharmaceutically acceptable vehicles, supports or excipients, in 200 mg capsules at a rate of 1 mg of metal derivative of transition according to the invention by gelules, ie 0.07 mg of metal
(vanadium) .(vanadium).
Exemple 5 - Détermination d'un effet hypogLycémiant.Example 5 - Determination of a hypoglycemic effect.
1 - Animaux Des rats mâles de souche istar (12 par Lot), provenant du centre d'élevage de Montpellier ont été utilisés dans cette étude. Les animaux sont maintenus en observation pendant 4 j avant Le début des essais. En début d'essai. Les animaux pèsent en moyenne 140 g. Pendant La période d'observation les animaux, répartis par cage de 5, reçoivent nourriture et eau de boisson ad Libitum et sont soumis à une température comprise entre 21 et 23 C et à un cycle jour/obscurité de 12 h.1 - Animals Male rats of the istar strain (12 per Lot), from the Montpellier breeding center were used in this study. The animals are kept under observation for 4 days before the start of the tests. At the start of the test. The animals weigh on average 140 g. During the observation period, the animals, divided into cages of 5, receive food and drinking water ad Libitum and are subjected to a temperature between 21 and 23 C and a day / dark cycle of 12 h.
2 - Produits2 - Products
- Complexe porphyrinométallique selon L'exemple n 2 - Streptozotocine- Porphyrinometallic complex according to Example 2 - Streptozotocin
- Excipients - tampon citrate pH 4,5- Excipients - citrate buffer pH 4.5
- sérum physiologique- physiological serum
3 - Protocole3 - Protocol
10 animaux d'un poids moyen de 220 g sont anesthésiés à l'éther. Une injection intraveineuse de streptozotocine est pratiquée au niveau de la veine du pénis ; une glycémie de contrôle est effectuée 48 h après l'administration de La streptozotocine.10 animals with an average weight of 220 g are anesthetized with ether. An intravenous injection of streptozotocin is performed in the vein of the penis; a control glycemia is carried out 48 h after the administration of streptozotocin.
Seuls les animaux présentant une glycémie supérieure ou égale à 2 g sont sélectionnés et soumis au traitement par La substance testée. L'administration du complexe selon l'exemple 2 a été biquotidienne (8-18 h) pendant 3 j, puis quotidienne (18 h). Le contrôle de La glycémie est effectué Le matin à 9 h, moment de La journée où La glycémie des rats diabétiques témoins ou traités, soumise à de grandes variations durant La journée, est La plus élevée. Des rats diabétiques ne reçoivent que L'excipient (sérum physiologique) et servent de témoins diabétiques.Only animals with a blood sugar level greater than or equal to 2 g are selected and subjected to treatment with the test substance. The administration of the complex according to Example 2 was twice daily (8-18 h) for 3 days, then daily (18 h). The glycemia control is carried out in the morning at 9 am, time of the day when the glycemia of the diabetic control or treated rats, subjected to great variations during the day, is the highest. Diabetic rats receive only the excipient (physiological saline) and serve as diabetic controls.
Enfin, des rats "témoins blancs" de même poids, n'ayant pas reçu d'injection de streptozotocine sont conservés à fin de comparaison des consommations d'eau et de nourriture. RESULTATSFinally, "white control" rats of the same weight, which have not received an injection of streptozotocin, are kept at the end of the comparison of consumption of water and food. RESULTS
Le contrôle quotidien de la glycémie ne nous a pas permis de mettre en évidence d'effet hypoglycémiant durant Les 2 premiers jours du traitement. Une chute importante et significative de La glycémie par rapport à celle des rats témoins apparaît dès Le troisième jour et se maintient Les jours suivants. Celle-ci est accompagnée d'une réduction également significative de la polyphagie et de la polydipsie, Les consommations de nourriture et d'eau recouvrant des valeurs tendant à se rapprocher de celle des rats témoins non diabétiques.The daily glycemic control did not allow us to demonstrate a hypoglycemic effect during the first 2 days of treatment. A significant and significant drop in blood glucose compared to that of control rats appears from the third day and is maintained on the following days. This is accompanied by an equally significant reduction in polyphagia and polydipsia, Food and water consumption covering values tending to approach that of non-diabetic control rats.
- 1/EvoLution de la glycémie des animaux témoins et des animaux traités durant Les 12 j de traitement (mg/100 ml).- 1 / Evolution of the glycemia of the control animals and of the animals treated during the 12 days of treatment (mg / 100 ml).
JOURS J1 J2 J3 J4 J5 J6 J8 J12 TEMOINS 390 400 398 >400 >400 >400 >400 >400 TRAITES 225 217 95 156 159 124 108 135DAYS D1 D2 D3 D4 D5 D6 D8 D12 WITNESSES 390 400 398> 400> 400> 400> 400> 400 TREATED 225 217 95 156 159 124 108 135
- 2/Consommation moyenne de nourriture (g).- 2 / Average food consumption (g).
JOURS J5 J8 J12 TEMOINS 34,16 39,16 46,25DAYS D5 D8 D12 WITNESSES 34.16 39.16 46.25
TRAITES 20,8 22,16 25TREATIES 20.8 22.16 25
- 3/Consommation moyenne d'eau de boisson (ml).- 3 / Average consumption of drinking water (ml).
JOURS J5 J8 J12 TEMOINS 250 250 275DAYS D5 D8 D12 WITNESSES 250 250 275
TRAITES 125 100 100TREATIES 125 100 100
En regard des trois paramètres objectifs ci-dessus, ainsi qu'en regard des paramètres subjectifs, tels L'aspect et Le comportement des animaux, il apparaît que Le traitement, dans Les conditions opératoires retenues, a eu un effet hypoglycémiant, et que celui-ci est majeur. Il a pu également être observé un effet thérapeutique rémanent même après L'arrêt du traitement. With regard to the three objective parameters above, as well as with regard to the subjective parameters, such as the appearance and behavior of the animals, it appears that the treatment, under the operating conditions adopted, had a hypoglycemic effect, and that that -this is major. A residual therapeutic effect could also be observed even after the treatment was stopped.

Claims

REVENDICATIONS
1. Dérivé organique de métal de transition, caractérisé en ce qu'il est constitué par un dérivé d'un métal de transition (M) avec un composé organique à structure porphyrinique, ledit dérivé répondant à La formule générale suivante :1. Organic derivative of transition metal, characterized in that it consists of a derivative of a transition metal (M) with an organic compound with a porphyrinic structure, said derivative corresponding to the following general formula:
Figure imgf000012_0001
Figure imgf000012_0001
dans laquelle R-, R^, R,, R., Rc, R., R.,, R_ sont choisisin which R-, R ^, R ,, R., R c , R., R. ,, R_ are chosen
I d _5 D O f O indépendamment parmi les substituants usuels des chlorophylles, en particulier l'hydrogène, un alkyle inférieur en C.-C-. à chaîne droite, ramifiée ou cyclique ; les substituants préférés étant choisis parmi L'hydrogène, un radical méthyle, éthyle, propyle, isopropyle, vinyle, formyle et ses esters, acétyle et ses esters, propionyle et ses esters, acrylyles et ses esters, et cycLo- pentanoyles.I d _5 D O f O independently among the usual substituents of chlorophylls, in particular hydrogen, lower C 1 -C alkyl. straight chain, branched or cyclic; the preferred substituents being chosen from hydrogen, a methyl, ethyl, propyl, isopropyl, vinyl, formyl radical and its esters, acetyl and its esters, propionyl and its esters, acrylyl and its esters, and cycLopentanoyl.
2. Dérivé organique selon La revendication 1, caractérisé en ce que Le métal de transition est choisi parmi Le vanadium et Le molybdène.2. Organic derivative according to claim 1, characterized in that the transition metal is chosen from vanadium and molybdenum.
3. Dérivé organique selon la revendication 1 ou 2, caractérisé en ce qu'il est d'origine naturelle et obtenu par extraction à partir de la plante de La famille des légumineuses, en particulier ceLLes qui sont riches en Leghemoglobines, comme Le soja, La fève. Le pois, Le poids chiche, La luzerne, l'avoine et Le cesbania de Madagascar ; les plantaginées, en particulier les plan- tains, Les sables, majeur, moyen et Psyllium ; les crucifères, en particulier le colza, le radis. Les choux. Les navets, Le cresson, Les Salsolacées, en particulier les épinards, les Urticacées, en particulier Les orties Urtica dioîca et U. urens et les parié- taires ; les algues, en particulier Ulva Latissima.3. Organic derivative according to claim 1 or 2, characterized in that it is of natural origin and obtained by extraction from the plant of the legume family, in particular those which are rich in Leghemoglobins, such as soybeans, The bean. Peas, Chickpeas, Alfalfa, oats and Cesbania from Madagascar; planted crops, especially plantings tains, Sands, middle, middle and Psyllium; crucifers, especially rapeseed, radish. Cabbage. Turnips, Watercress, Salsolaceae, in particular spinach, Urticaceae, in particular Nettle Urtica dioîca and U. urens and its partners; algae, especially Ulva Latissima.
4. Dérivé organique selon l'une des revendications 1 à 3, caractérisé en ce qu'il est obtenu par extraction à partir de l'ortie Urtica dioîca.4. Organic derivative according to one of claims 1 to 3, characterized in that it is obtained by extraction from the nettle Urtica dioîca.
5. Utilisation du dérivé organique selon l'une des revendications 1 à 4, comme principe actif pour la fabrication d'un médicament, en particulier utile dans le traitement de malades souffrant de troubles de La glycémie et de troubles associés tels que L' hyperlipidémie, notamment des malades diabétiques.5. Use of the organic derivative according to one of claims 1 to 4, as active ingredient for the manufacture of a medicament, in particular useful in the treatment of patients suffering from glycemia disorders and associated disorders such as hyperlipidemia , especially diabetic patients.
6. Composition pharmaceutique, caractérisée en ce qu'elle comprend à titre de principe actif, un dérivé organique formé d'un métal de transition M et d'un composé organique de structure porphyrinique. Ledit dérivé ayant la formule générale suivante :6. Pharmaceutical composition, characterized in that it comprises, as active principle, an organic derivative formed of a transition metal M and an organic compound of porphyrinic structure. Said derivative having the following general formula:
dans laquelle R., R?, R,, R,, R-., R,, R-,, R„ sont tels que définis dans la revendication 1,in which R., R ? , R ,, R ,, R-., R ,, R- ,, R „are as defined in claim 1,
Ledit dérivé organique étant incorporé dans un excipient, véhicule ou support pharmaceutiquement acceptable.Said organic derivative being incorporated into a pharmaceutically acceptable excipient, vehicle or support.
7. Composition thérapeutique selon la revendication 6, caractérisée en ce qu'elle est à activité hypoglycémiante, ou antihypercholestérolémiante, ou antihypertriglycéridémiante. 7. Therapeutic composition according to claim 6, characterized in that it is hypoglycemic, or antihypercholesterolemic, or antihypertriglyceridemic.
8. Composition pharmaceutique selon la revendication 6, caractérisée en ce qu'elle comprend une teneur en métal de transition d'environ 0,01 à environ 1 mg par dose unitaire.8. Pharmaceutical composition according to claim 6, characterized in that it comprises a transition metal content of approximately 0.01 to approximately 1 mg per unit dose.
9. Composition pharmaceutique selon l'une des revendications 6 et 8, caractérisée en ce que le métal de transition est choisi parmi le vanadium et Le molybdène.9. Pharmaceutical composition according to one of claims 6 and 8, characterized in that the transition metal is chosen from vanadium and molybdenum.
10. Composition pharmaceutique selon l'une des revendications 6, 8 ou 9, caractérisé en ce qu'elle est réalisée pour une formulation orale, notamment sous forme de comprimés, dragées ou gélules.10. Pharmaceutical composition according to one of claims 6, 8 or 9, characterized in that it is produced for an oral formulation, in particular in the form of tablets, dragees or capsules.
11. Préparation d'une composition pharmaceutique, caractérisée en ce qu'on incorpore un dérivé de métal de transition avec un composé organique de structure porphyrinique, ledit dérivé ayant la formule générale suivante :11. Preparation of a pharmaceutical composition, characterized in that a transition metal derivative is incorporated with an organic compound of porphyrinic structure, said derivative having the following general formula:
Figure imgf000014_0001
Figure imgf000014_0001
dans laquelle R^ , R-,, R,, R^, R^, R,, R.,, Rg sont tels que définis à La revendication 1, dans un véhicule, support ou excipient pharmaceutiquement acceptabLe, le métal de transition étant de préférence choisi parmi Le vanadium et Le molybdène. wherein R ^, R- ,, R ,, R ^, R ^ , R ,, R. ,, R g are as defined in claim 1, in a pharmaceutically acceptable vehicle, support or excipient, the transition metal preferably being chosen from vanadium and molybdenum.
PCT/FR1990/000821 1989-11-21 1990-11-16 Derivatives of a transition metal having a porphyrinic structure, and use of this derivative in drug manufacturing WO1991007406A1 (en)

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FR8915276A FR2654620B1 (en) 1989-11-21 1989-11-21 NOVEL ORGANIC TRANSITION METAL DERIVATIVES WITH PORPHYRINIC STRUCTURE AND THERAPEUTIC COMPOSITION CONTAINING THE SAME, IN PARTICULAR HYPOGLYCEMIC ACTIVITY.
FR89/15276 1989-11-21

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US5252730A (en) * 1992-04-10 1993-10-12 Northrop Corporation Polymer composition having intense magnetic properties and method for preparation thereof
WO2000009111A2 (en) * 1998-08-11 2000-02-24 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Inhibitors of amyloid formation

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GB2030564A (en) * 1978-09-05 1980-04-10 British Petroleum Co Isolation of vanadyl porphyrins from a mixture thereof with hydrocarbons and/or heterohydrocarbons
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US2867626A (en) * 1956-05-18 1959-01-06 Gulf Research Development Co Synthesis of porphyrin vanadium complexes
DE1181846B (en) * 1960-10-10 1964-11-19 British Petroleum Co Process for reducing the metal content of petroleum fractions boiling above 250μ
FR1321013A (en) * 1962-03-13 1963-03-15 Blood Plasma Corp Of Japan Process for preparing a cobaltiprotoporphyrin
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WO2000009111A2 (en) * 1998-08-11 2000-02-24 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Inhibitors of amyloid formation
WO2000009111A3 (en) * 1998-08-11 2000-11-23 Us Gov Health & Human Serv Inhibitors of amyloid formation
US6632808B1 (en) 1998-08-11 2003-10-14 The United States Of America As Represented By The Department Of Health And Human Services Inhibitors of amyloid formation

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