FR2654620A1 - NOVEL ORGANIC TRANSITION METAL WITH PORPHYRINIC STRUCTURE AND THERAPEUTIC COMPOSITION CONTAINING SAME, IN PARTICULAR HYPOGLYCEMIC ACTIVITY. - Google Patents

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

The present invention essentially relates 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 therapeutic composition.
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 so far are still very insufficient by the fact that their bioavailability is very low, or even non-existent.

 The present invention therefore aims to solve the new technical problem consisting in the supply of a new vanadium formulation 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.

dans laquelle R1 R2 R3, R41 R51 R6, R7, 8 sont choisis indépendamment parmi les substituants usuels des chlorophylles, en particulier lrhydrogène, un alkyle inférieur en C 1-C5 à chaine droite, ramifiée ou cyclique.Ces substituants usuels de la chlorophylle sont en particulier ceux décrits par Hendry et Jones dans la revue Journal of Medical Genetics, 1980, 17, 1-14, et en particulier au tableau 1, page 5. Les substituants actuellement préférés sont choisis parmi : l'hydrogène, un radical méthyle, éthyle, propyle, isopropyle, vinyle, formyle et ses esters, acétyle et ses esters, propionyle et ses esters, acrylyle et ses esters, et cyclopentanoyles.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 porphyrinic structure, said derivative responding to the formula generated the following:

in which R1 R2 R3, R41 R51 R6, R7, 8 are independently selected from the usual substituents of chlorophylls, in particular hydrogen, a lower C 1 -C 5 alkyl, 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 radical, ethyl, propyl, isopropyl, vinyl, formyl and its esters, acetyl and its esters, propionyl and its esters, acrylyl and its esters, and cyclopentanoyles.

 Preferably, 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 leghemo
globins, especially soybeans, broad beans, peas, Peas
chick, alfalfa, Oats and cesbania from Madagascar; - Plantaged plants, in particular plantains, sands, major,
medium and Psyllium; - Crucifers, in particular rapeseed, radish, cabbage,
turnips, watercress; - Salsolaceae, especially spinach; - Urticaceae, in particular the nettles Urtica diolca and U. urens.

 and the gamblers; - Algae, in particular ULva latissima.

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 means of appropriate extraction of a part
or the whole plant, either fresh or dried, notam
The aerial parts, in particular an extraction of the type
aqueous, alcoholic or hydroalcoholic; and - possibly the submission of the raw extract obtained to one or
several stages of separation. These separation steps are
those of techniques well known to those skilled in the art, in particular
those relating to the extraction of chlorophylls.

 Advantageously, one of these separation steps comprises subjecting the crude extract to chromatography, in particular adsorption chromatography.

 According to a particular embodiment, the aforementioned extraction of part or all of the plant, in particular the aerial parts, takes place using as extraction solvent the following solvents: - water plus methanol, - water plus ethanol , - water plus propanots, - water plus butanols.

 In the context of a hydroalcoholic solvent, the water / alcohol proportion is advantageously between 95/05 and 45/55.

 According to a third aspect, the invention also covers a use of the above-mentioned organic transition metal derivative as an active principle for the manufacture of a medicament, in particular useful in the treatment of patients suffering from glycemia disorders and disorders associates such as hyperlipidemia, especially diabetic patients.

dans LaqueLLe R1, R2, R3, R4, R5, R6, R7, R8 sont tels que précédemment définis, ledit dérivé organique étant incorporé dans un excipient, véhicule, ou support pharmaceutiquement acceptable.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 porphyrinic structure, said organic derivative having the formula generated the following

In LaqueLLe R1, R2, R3, R4, R5, R6, R7, R8 are as previously defined, said organic derivative being incorporated in a pharmaceutically acceptable excipient, vehicle, or support.

 According to an alternative embodiment, the concentration of transition metal derivative is between approximately 0.1 and approximately 10 mg relative to the total weight of the pharmaceutical composition.

 The metal is preferably chosen from vanadium and molybdenum.

 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.

 This pharmaceutical composition can be formulated in any suitable dosage form well known to those skilled in the art. In particular, an oral formulation can be produced, in particular in the form of tablets, dragees or capsules, dosed with a content of the aforementioned transition metal of approximately 0.01 to approximately 1 mg.

dans LaqueLLe R1, R2, R3, R4, R5, R6, R7 R8 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.The present invention also covers, according to another aspect, a process for the preparation of 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 :

in LaqueLLe R1, R2, R3, R4, R5, R6, R7 R8 being as previously defined, in a pharmaceutically acceptable vehicle, support or excipient. Preferably, the aforementioned transition metal is chosen from vanadium and molybdenum.

dans laquelle R1, R2, R3, R4, R5, R6 R7, R8 sont teLs que précédemmment définis.The present invention also covers a method for the therapeutic treatment of a mammal including a human being, characterized in that a mammally effective amount of a transition metal derivative and an organic compound with a porphyrinic structure is administered to this mammal , said derivative having the following formula:

in which R1, R2, R3, R4, R5, R6 R7, R8 are such as previously defined.

 Preferably, this transition metal is chosen from vanadium and molybdenum.

 According to a preferred embodiment variant of this therapeutic treatment method, a hypoglycemic, or cholesterol-lowering or hypotriglyceridemic treatment is carried out.

 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.

 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 blood sugar disorders and associated disorders such as hyperlipidemia, in particular diabetic patients.

 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.

Example 1 - Isolation of the transition metal derivative according to
The invention from nettle.

 The aerial parts of Dioecious nettle - Urtica dioica L - are subjected to an extraction with a hydroalcoholic mixture (water / alcohol ratio = 75/25 volume / volume) in proportion to 10/1 by weight / weight of plant, followed 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 concentrate added 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 distilling 25 ml of alcohol, are added 3 g of hematoporphyrin IX, or 8,13-bis (1-hydroxyethyl) -3,7,12,17-tetramethyl-21H, 23H-porphine-2.18 acid -dipropionic, in solution o 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 sinter 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.

It should be noted that, by essentially following the same process, a transition metal derivative can be prepared according to
The invention, the transition metal of which is molybdenum, using ammonium molybdenate, as the starting salt.

Example 3 - Pharmaceutical composition.

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.

 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 the rate of 1 mg of transition metal derivative according to L ' invention per capsule, i.e. 0.07 mg of metal (vanadium).

Example 5 - Determination of a hypoglycemic effect.

1 - Animals
Male rats of Wistar strain (12 per batch), coming 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 an average of 140 g. During the observation period, the animals, distributed in cages of 5, receive food and drinking water ad libitum and are subjected to a temperature between 21 and 230C and to a day / dark cycle of 12 h.

2 - Products
o
- Porphyrinometallic complex according to Example 2
- Streptozotocin
- Excipients - citrate buffer pH 4.5
- physiological serum 3 - Protocol
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.

 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 a.m., the time of the day when the glycemia of the diabetic control or treated rats, subjected to large variations during the day, is the highest. Diabetic rats receive only the excipient (physiological saline) and serve as diabetic controls.

 Finally, "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
The daily glycemic control did not allow us to demonstrate any 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 of the glycemia of the control animals and of the animals treated during the 12 days of treatment (mg / 100 ml).

DAYS 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 / Average food consumption (g).

DAYS D5 D8 D12
WITNESSES 34.16 39.16 46.25
TREATED 20.8 22.16 25 - 3 / Average consumption of drinking water (ml).

DAYS D5 D8 D12
WITNESSES 250 250 275
TREATIES 125 100 100
With regard to the three objective parameters above, as well as with regard to the subjective parameters, such as the appearance and behavior of animals, it appears that the treatment, under the operating conditions selected, 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 (11)

 1. Organic transition metal derivative, characterized in that it consists of a derivative of a transition metal (M) with an organic compound with porphyrinic structure, said derivative corresponding to the following general formula

 in which R1, R2, R3, R4, R5, R6, R7 R8 are independently selected from the usual substituents of chlorophylls, in particular hydrogen, a lower C1-C5 straight chain, branched or cyclic alkyl; the preferred substituents being 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.  2. Organic derivative according to claim 1, characterized in that the transition metal is chosen from vanadium and molybdenum.  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, broad beans, peas, chickpeas, alfalfa, oats and cesbania from Madagascar; planted plants, in particular flat, sand, major, medium and Psyllium; crucifers, in particular rapeseed, radishes, cabbage, turnips, watercress, Salsolaceae, in particular spinach, Urticaceae, in particular nettles Urtica dioica and U. urens and parietarians; algae, especially Ulva latissima.  4. Organic derivative according to one of claims 1 to 3, characterized in that it is obtained by extraction from Nettle Urtica dio7ca.  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. 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

 in which R1, R2, R3, R4, R5, R6, R7, R8 are as defined in claim 1, said organic derivative being incorporated in a pharmaceutically acceptable excipient, vehicle or carrier.  7. Therapeutic composition according to claim 6, characterized in that it is hypoglycemic, or antihypercholesterolemic, or antihypertriglyceridemic.  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. Pharmaceutical composition according to one of claims 6 and 8, characterized in that the transition metal is chosen from vanadium and molybdenum.  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. 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

 in which R1, R2, R3, R4, R5, R6, R7, R8 are as defined in claim 1, in a pharmaceutically acceptable vehicle, support or excipient, the transition metal preferably being chosen from vanadium and molybdenum .