FR2686512A1 - PHARMACEUTICAL COMPOSITIONS CONTAINING AS ACTIVE INGREDIENT COMBINATIONS OF VANADIUM AND / OR NIOBIUM WITH PYROCATECHOL DERIVATIVES. - Google Patents

Abstract

The invention relates to a pharmaceutical composition containing as active principle the association of a mole of vanadium and/or niobium derivative with oxidation degree of 4 or 5 with 1 to 10 mole of pyrocatechol derivative. Said pharmaceutical composition is particularly useful for the treatment or prevention of diabetes, hypercholesterolemy, hypertriglyceridimy, hyperlipidemy as well as troubles associated with said pathologies.

Description

Pharmaceutical compositions containing as active principle combinations of vanadium and / or niobium with pyrocatechol derivatives.

 The present invention relates to pharmaceutical compositions containing as active principle combinations of vanadium and / or niobium with catechol derivatives. It also relates to the use of said combinations as active ingredient for the manufacture of a medicament, useful in particular in the treatment or prevention of diabetes and associated complications.

The synthesis of derivatives or complexes of vanadium and niobium is well known: for example it can be done according to the methods listed by Léopold Gmelins, and described in the collection Handbuch der anorganischen Chemie, Vanadium (System
Nummer 48), Verbindungen, Verlag Chemie-GMBH, Weinheim / Bergstrasse, in particular Teil B Leiferung 2, 1967, at pages 688-819 for organic complexes (pages 719-789 for complexes of V4, pages 790- 819 for V5 complexes) and in Handbuch der anorganischen Chemie, 8 Auflage, Niobium (System Nummer 49), Teil
B4, Verbindungen, VerlagChemie-GMBH, Weinheim / Bergstrasse, 1973, in particular at pages 334-472 for organic complexes of niobium.

 A bibliographic review with 198 references on "The Bioinorganic Chemistry of Vanadium" was recently carried out by Dieter Rehder, (angel. Chem. Int. Ed. Engl. 1991, 30, 148-167).

 It is known, and this emerges very particularly from the above publication, that the vanadium derivatives in aqueous solution exist in the form of several equilibrium species. Thus, vanadate, where the vanadium is at oxidation state 5, depending on the pH and the concentration, can be in several monomeric forms (polycoordinated with solvent or ligands), or polymeric, with one or more charges .

Thus, with hydroxylated derivatives of the HO-R form, vanadate spontaneously forms mono-, di- and tri-esters ((R0) xVO (OH) 3 x) which coexist in equilibrium. Geometry of coor
x 3-x dination is also very diverse, the degree of coordination generally going from 4 to 7 (sometimes 8) and the same ligand being able to coordinate the metal in axial or equatorial position and giving rise to tetragonal pyramids, trigonal bipyramides, pentagonal or octahedrals, etc.

It is the same for vanadyLe, in which vanadium is in the oxidation state 4, as shown in particular by J. Costa Pessoa et al., Polyhedron, 1988, 7, 1245-1262 and
Polyhedron, 1989, 8, 1173-1199, depending on the pH and the concentration if we note LH an amino acid like serine (alanine, threonine, etc.) and M the metal (VO in this case), it can coexist one or more of the following species: MLH, ML, MLH 2, MLH ML H2, ML2H, ML2, ML2H ~ 1 ML2H2, M2L2H, M2L2H3, etc., as well as some hydrolysis or hydration products.

Several authors have suggested that the biological actions of vanadate may be due to the esterification of tyrosine by V (5). For example, AS Tracey and MJ Gresser, in their article in Proc. Natl. Acad. Sci. 1986, 83, 609-613, have shown that phenol and a tyrosine derivative (N-acetyl tyrosine ethylester) spontaneously form vanadium esters, 1,000 to 100,000 times faster than with phosphates. However,
Their studies by 5 V NMR showed that it was necessary to use between 100 and 1500 excess of phenolic derivative, to have an almost total esterification of vanadium.

 It is also known that pyrocatechol derivatives form esters with vanadate as well as with vanadyl, even more easily than phenols. As a general rule, a stoichiometry of 1 to 2 substrates for 1 metal is sufficient. It is known that catechol derivatives complex well with vanadium and moLybdenum, for example 2,3-dihydroxynaphthalene (Collext.

CZech. Chem. Common. 1970, 35, 1599), or tiron (Helv. Chim.

Acta, 1951, 34, 528).

 Patent EP 248 506 uses tiron (4,5 dihydroxy-1,3-benzenedisulfonic acid) as a ligand for transferring metal ions onto proteins or polypeptides having a chelating group of greater affinity than tiron for metal. The product obtained serves as a diagnostic agent.

 Patent application WO 88/03805 describes organic compounds and complexes of these compounds with different metal salts. Among the compounds described in this application, there are many products derived from pyrocatechol, but no complex with vanadium or niobium in oxidation state 4 or 5 is described in this document. Furthermore, the complexes described in this document are used as antitumor or antiviral agents.

 Numerous studies have been carried out concerning the active activity of vanadium in the treatment of hyperglycemia. These are mainly scientific literature documents which deal only with mineral derivatives of vanadium.

In the literature since 1985, numerous studies describe the hypoglycemic effects of mineral derivatives of vanadate (+5) or vanadyle (+4) ions. An excellent bibliographical update can be found in the Doctoral Thesis in Pharmacy of
Jean-Jacques MONGOLD, September 1991, University of Montpellier I,
France.

 European patent EP-O 264 278 describes compositions with insulin-mimetic activity containing vanadates and mineral peroxovanadates.

 By the way, the plaintiff described in its international applications WO 91/07406 and WO 91/13892 as well as in its French application not yet published and filed on May 21, 1991 under the number 91 06 174 of organo-metallic complexes of metals transition to porphyrinic structure useful in particular in the treatment of hyperglycemia.

 European patent EP-O 305 264 describes organomineral vanadyl compounds obtained from C6-C10 esters of cysteine. For the compounds described in this document, the hypoglycemic dose is 4.3 mg of vanadium / kg and the duration of action is approximately 6 h.

 Japanese patent JP 2 292 217 describes an antidiabetic activity for 7 vanadyle-dioxo complexes (tartrate, gluconate, malonate, oxalate, lactate, salycilate and acetyl-acetonate), as well as for 2 vanadyle-monoamino-monothio complexes: the L complex 'methyl ester of cysteine with vanadyl and that of 2-amino-ethane-thiol. For the complex of the methyl ester of cysteine with vanadyl, a lowering of the glycemia is described from 377 mg / dl for the controls to 318 mg / dl, for a dose of 3 mg of vanadium / kg and to 258 mg / dl for a dose of 10 mg vanadium / kg.

 The Applicants have now discovered that the complexes resulting from the reaction of a derivative of niobium or vanadium at oxidation state 4 or 5 with products derived from pyrocatechol, also known as catechol, have an increased bioavailability compared to that uncomplexed metal compound. In particular, the Applicant has established that the complexes have a largely increased effectiveness in the treatment of diabetes compared to that of the mineral derivatives of vanadium known up to now.

 By "complex" is meant the reaction product of the metal derivative with the ligand consisting of catechol or one of its derivatives. It is in fact a mixture of complexes corresponding to the fixing by bonds with 1 and / or 2 electrons of a variable number of heteroatoms according to the envisaged ligand and whose spatial arrangement around the metal and the degree of Metal coordination may vary.

 Complexes resulting from the reaction of a vanadium or niobium derivative at degree of oxidation 4 or 5 with pyrocatechol or one of its derivatives have been found to be useful as an active ingredient in medicaments for the treatment of diabetes and diseases associated.

 The above complexes having the distinction of being formed very easily by contact either in solution or in suspension of the metallic derivative and of the organic derivative, the invention covers not only pharmaceutical compositions including said already formed complexes but also pharmaceutical compositions including mixture of the two types of constituents, the complexation of which will be carried out in vivo during the administration of the pharmaceutical composition.

 The term “association” denotes both the mixture of the two types of constituents and the product of the complexation reaction.

dans laquelle R, R' et R" sont identiques ou différents et représentent ::
- de l'hydrogène,
- une channe hydrocarbonée aliphatique linéaire ou ramifiée contenant de 1 à 30 atomes de carbone, de préférence de 16 à 20, et de O à 6 insaturations, ladite channe pouvant, dans le cas de R", être rattachée par l'intermédiaire d'un -CO,
- une channe hydrocarbonée contenant jusqu'à 30 atomes de carbone, linéaire ou ramifiée et incluant au moins un cycle aromatique ou hétéroaromatique, ladite channe pouvant, dans le cas de
R", être rattachée à L'atome d'oxygène par un -CO,
- une chaîne contenant jusqu'à 50 atomes de carbone, linéaire ou ramifiée ou renfermant au moins un cycle à 3 à 8 chainons saturé, insaturé ou aromatique, ladite chaîne contenant de O à 10 insaturations et de O à 10 hétéroéléments, en particulier de Oxygène, du soufre ou de L'azote et ladite chaîne comportant 0 à 10 ramifications en C -C contenant des fonctions conférant un caractère hydrosoluble, par exemple des fonctions acide, sulfate, phosphate, alcool, amine, amide, éther,
R et R' pouvant également représenter
- un groupement OH,
- un groupement S03H,
- un groupement P03H, ledit principe actif étant incorporé dans un excipient, véhicule ou support pharmaceutiquement acceptable.According to an essential characteristic, the invention relates to a pharmaceutical composition characterized in that it contains as active principle the association of a mole of a derivative of vanadium and / or niobium with the degree of oxidation 4 or 5 with 1 10 mol of a pyrocatechol derivative corresponding to the formula:

in which R, R 'and R "are identical or different and represent:
- hydrogen,
a linear or branched aliphatic hydrocarbon chain containing from 1 to 30 carbon atoms, preferably from 16 to 20, and from O to 6 unsaturations, said chain being able, in the case of R ", to be attached via a -CO,
a hydrocarbon chain containing up to 30 carbon atoms, linear or branched and including at least one aromatic or heteroaromatic cycle, said chain being able, in the case of
R ", be attached to the oxygen atom by a -CO,
a chain containing up to 50 carbon atoms, linear or branched or containing at least one saturated, unsaturated or aromatic chain with 3 to 8 links, said chain containing from O to 10 unsaturations and from O to 10 heteroelements, in particular of Oxygen, sulfur or Nitrogen and said chain comprising 0 to 10 C -C ramifications containing functions conferring a water-soluble character, for example acid, sulfate, phosphate, alcohol, amine, amide, ether functions,
R and R 'can also represent
- an OH group,
- an S03H group,
- A PO3H group, said active ingredient being incorporated into a pharmaceutically acceptable excipient, vehicle or support.

 As seen above by "association", we mean complexes or mixtures of complexes obtained by reaction of the two constituents, but also the mixture of the two constituents insofar as the complex is likely to form, by reaction of the two constituents contained in said association, in the organism after administration of the pharmaceutical composition.

 According to an advantageous variant of the invention, the combination contains 1 mol of vanadium and / or niobium derivative for 1 to 4 mol of catechol or catechol derivatives as defined above.

 According to a variant of the invention, the pyrocatechol derivative is pyrocatechol itself (R "= R = R '= H).

 According to a variant, the pyrocatechol derivative is a mono- or disubstituted derivative on the cycle of an ortho dihydroxybenzene (R "= H).

 According to another variant, one of the groups R or R 'is a linear or branched alkyl chain containing 1 to 30 carbon atoms, the other group being hydrogen.

 According to another variant, one of the groups R or R ′ is a linear or branched mono or polyunsaturated chain containing 1 to 6 unsaturations and up to 30 carbon atoms, the other group being hydrogen.

 By way of example of such chains, mention will be made of linolenyl and linoleyl groups.

According to a variant of the invention, at least one of the two groups R and R ′ is hydrogen and the other is a linear or branched chain containing an optionally substituted aromatic or heteroaromatic cycle. By way of example, we will cite
Nordihydroguaiaretic acid.

 According to other variants, the groups R and R ′ may be linear or branched chains possibly including one or more rings and which may contain functions which confer in particular a certain water-soluble character to the product. These functions can, in particular, be acid, amine, ether, ester, amide functions.

 As an example of pyrocatechol derivatives in which R or R ′ contains an acid function, mention will be made of caffeic acid.

 By way of example of pyrocatechol derivatives where R or R ′ contains an amine function, mention will be made of dopamine.

 By way of example of pyrocatechol derivatives in which R or R ′ contains an amide function, mention will be made of the oleylamide of caffeic acid, the dopamine γ-linoleate.

 According to another variant of the invention, at least one of the groups R and R ′ contains both an acid function and an amide function. As an example of such products, mention will be made of 3,4- glutarate. dihydroxybenzylamine.

 According to another variant, the group R or R ′ comprises both an acid function and an amine function. Mention will be made, for example, of L-DOPA (3,4-hydroxydiphenylalanine).

 According to another variant of the invention, the two groups R and R 'are different from hydrogen and can be, in particular, identical and represent in particular SO 3 H or PO 3 H.

 Among the above products, the catechol derivative where R = R '= S03H, called tiron, will advantageously be chosen.

 According to other variants, one of the groups R or R ′ is an OH group.

By way of example of such pyrocatechol derivatives, mention will be made of gallates, in particular C1 to C1 alkyl gallates.
C30, for example octylgallate or linoleylgallate.

 According to other variants, the group R "is different from H and can be, in particular, a linear or branched alkyl chain containing from 1 to 30 carbon atoms is directly attached to the carbon atom and the pyrocatechol derivative will be a derivative of an ortho alkoxyphenol either via a group -CO and the pyrocatechol derivative is then an ortho ether derivative of phenol.

 According to other variants, R "can also be a mono- or polyunsaturated chain, linear or branched, containing from 1 to 6 unsaturations and up to 30 carbon atoms, optionally linked to the oxygen atom by a -CO .

According to other variants, R "is a linear or branched chain containing an optionally substituted aromatic or heteroaromatic cycle. This chain can be linked to
The oxygen atom by a -CO.

 According to other variants, the group R "can be a linear or branched chain optionally including one or more rings and which can contain functions which confer in particular a certain water-soluble character to the product. These functions can, in particular, be acid functions, amine, ether, ester, amide.

When the pyrocatechol derivative carrying the desired branching or heteroatom functions is not commercially available, a person skilled in the art can prepare it by following the conventional methods of synthesis, protection and deprotection of functional groups. Such methods are in particular described in Peptide Chemistry, 1988, M. BODANSZKY, Berlin Spinger as well as in Protective Goups in Organic Synthesis, TW Greene,
Wiley Interscience 1980 and in Protective Goups in Organic
Chemistry, JFW McOmie, Plenum Press, 1973).

So
a) when it is desired to obtain a derivative with a branched hydrocarbon chain, it is possible for example
- on an acid function of the substrate, carry out the coupling of a branched alcohol (such as phytol, geraniol, farnesol, etc.), or of a primary or secondary amine by means of a coupling agent such as DCC , or, in the case of fatty alcohols, by esterification in a dehydrating medium (azeotropic removal of water),
- on an amine or alcohol function of the substrate, carry out the coupling of a branched acid by means of a coupling agent such as DCC, or by reaction with an acid anhydride,
- on an amine function (or an alcohol function transformed into an alcoholate) of the substrate, perform the coupling using a branched halogenated derivative (such as farnesyl or geranyl bromide, etc.),
b) when it is desired to obtain a derivative with a chain having ether or thioether functions, it is possible, for example, to esterify an acid function of the substrate, for example by hexaethylene glycol, or to alkylate an amine function of the substrate by a chain halogenated polythioether,
c) when it is desired to obtain a derivative with a chain having alcohol functions, it is possible, for example, to hydrate in alcohol or to oxidize in diol the unsaturation (s) of an unsaturated hydrocarbon chain of the substrate, for example the double bond d 'an oleylamine derivative by H30 or by K Mn 04. -
It is also possible to couple along a) a chain containing, in addition to an alcohol, amine or free acid function, one or more OH functions protected, for example by .methoxyethoxyethyl groups. , then release the alcohol functions by Zon ions.

d) when it is desired to obtain a derivative with a chain having sulphate or phosphate functions, it is possible, for example, to transform an alcohol derivative obtained according to c) by means of a Cl
PO (OR) 2 or a Cl-S02 (0R), R being, for example, a Me, Et,
Benzyl,
e) when it is desired to obtain a derivative with a chain having sulfonate or phosphonate functions, it is possible, for example, to transform an alcohol or amine function of the substrate by means of CL-CH2-CH2P0 (0Na) 2 or of Cl- CH2-CH2S02 (ONa),
f) when it is desired to obtain a derivative with a chain having acid functions, it is possible, for example, to couple along a) a chain containing, in addition to an alcohol, amine or free acid function, one or more C00H functions protected in the form tert-butyl ester, then release the C00H functions in an acid medium,
g) when it is desired to obtain a derivative with a chain having amine functions, it is possible, for example, to couple along a) a chain containing, in addition to an alcohol, amine or free acid function, one or more primary amine or amine functions secondary protected, for example, by t-butyloxycarbonyl groups (BOC), then release the amine functions in an acid medium
In the case of tertiary amines these do not need to be protected, for example, EDTA (by any of its acid functions) can be coupled to an amine function of the substrate, or else make an ester of tetrakis- (2-hydroxypropyl) -ethylenediamine on an acid function of the substrate,
h) when it is desired to obtain a derivative with a chain having thiol functions, it is possible, for example, to couple along a) a chain containing, in addition to an alcohol, amine or free acid function, one or more thiol functions protected by Me3SiCH2CH2- groups, then release these SH functions by F ions
In the combinations and complexes according to the invention, vanadium or niobium is at the oxidation state 4 or 5.

 The niobium or vanadium derivative will be at the oxidation state 4 or 5 and advantageously in the form of an oxide, a halide, an oxyhalide, a sulfate, an alkali metal metallate or d ammonium, an acetate, an acetylacetonate, said derivative can be in the form of a hydrate or a complex with a solvent.

 The metal is in the oxidation state 4 or 5.

 When the metal is vanadium, it is at degree of oxidation 4 or 5, preferably at degree of oxidation 4.

 When the metal is niobium, it is at degree of oxidation 4 or 5, preferably at degree of oxidation 5.

 By way of example of metal derivatives which can be used according to the invention, mention will be made, by designating by (acac) an acetylacetonate group and by OAc an acetate group, the following derivatives VOS04, VCl4, VOCI2, VO (OAc) 2, VO (acac ) 2, VOICI3, V205, Na3V04, K3VO4, NaV03, H4NV03, NbCl4, NbCl5, Nb205, as well as their hydrates (for example VOS04,5H20) or their complexes with a solvent, for example with water, THF (by example NbCl4, THF), Ether, ethylene glycol, etc.

 An important advantage of the complexes useful according to the invention is that they are easily formed by simple contacting of the pyrocatechol or its derivatives with the metallic derivative.

 This reaction can be carried out either in solution in water or in a solvent.

 As solvent, mention may be made of hydroalcoholic mixtures, for example mixtures containing 100 to 70% of water for 0 to 30% of alcohol.

The alcohol entering into the constitution of the hydroalcoholic medium is advantageously chosen from C1-C4 alcohols
Linear or branched, preferably ethyl alcohol.

 The reaction can also be carried out in suspension in an organic agent. By way of example, mention will be made of THF, DMF and dichloromethane.

 The organometallic complexes described above are used more particularly for the preparation of medicaments useful in the treatment or prevention of diseases such as diabetes, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia as well as complications associated with these pathologies.

 Examples of associated pathologies include arterial hypertension, arteriosclerosis, heart failure, peripheral ischemia or ocular pathologies progressing to blindness.

 The present invention therefore relates to pharmaceutical compositions including the complexes described above or the mixture of the two constituents not yet complexed but capable of complexing in the body after administration of the pharmaceutical composition.

 The pharmaceutical compositions containing the complexes or associations of the invention may be in different forms. The complexes or mixtures of the invention will be incorporated into a pharmaceutically acceptable excipient, vehicle, or support.

 As pharmaceutically acceptable excipients, vehicles or carriers, any excipient, vehicle or carrier well known to those skilled in the art can be used. Mention may be made, for example, and without limitation of lactose, corn starch, glucose, gum arabic, stearic acid or magnesium stearate, dextrin, mannitol, talc or an oil of natural origin rich in essential unsaturated fatty acids, etc. In particular, if this proves to be necessary, other additives well known to those skilled in the art can be used, such as stabilizers, desiccants, binders, pH buffers, etc.

 An advantage of the complexes described above is that they can be used directly without prior purification other than the removal of the solvent, in particular when it is an organic solvent.

 The compositions of the invention can be administered in various ways, in particular by the oral, permucosal (lingual, nasal, ocular) route. They can also be in injectable form and intended for subcutaneous, intramuscular or intravenous injection.

They can also be used in application
Local, for example in the form of patches.

 The organometallic associations advantageously represent from 5 to 80% by weight relative to the total weight of the pharmaceutical preparation, and are found incorporated in an acceptable excipient, vehicle or pharmaceutical support compatible with the mode of administration envisaged.

 The pharmaceutical compositions according to the invention when they are intended for oral administration advantageously contain from 10 to 5000 nanomoles of metal derivative per dose.

 The compositions in the form of injectable formulations advantageously contain from 20 to 10,000 nanomoles of metal derivative per injectable dose of 1 to 10 ml.

 The compositions intended for local application, in particular in the form of a patch, advantageously contain from 0.1 to 100 micromoles of metal derivative per applicable dose.

 According to another aspect, the invention relates to the use of the complexes described above as active ingredient of a medicament useful for the treatment of diabetes and associated diseases.

 The following examples are given purely by way of illustration and in no way limit the invention. They demonstrate the ease of preparation of the complexes, their use for preparing pharmaceutical compositions and the effectiveness of the active ingredient.

Example 1
Complexation of vanadyle by catechol:
10 mmol of pyrocatechol (1.1 9) are dissolved in acetone, 5.1 mmol of K2CO3 dissolved in a minimum of water are added thereto, the coloration becomes slightly black, translucent, then 5 mmol of sulfate is added. vanadyle dissolved in water and the color of the solution becomes very dark or opaque blue. The solvents are then evaporated under vacuum at 50 C.

Example 2
Complexation of 1 equivalent of vanadyle with 3 equivalents of pyrocatechol
We follow the procedure described in the article by
SR COOPER et al., (J. Am. Chem. Soc., 1982, 104, p. 5092-5102).

Example 3
Complexation of vanadate by Le catéchol
10 mmol of pyrocatechol (1.1 g) are dissolved in acetone, then 5 mmol of sodium ortho vanadate (0.919 g Na3VO4) dissolved in water is added, the coloring of the solution becomes opaque black. The solvents are then evaporated under vacuum at SO0C.

Example 4
Complexation of vanadate by Caffeic acid
Solubilized in a water-acetone solution 10 mmol of trans 3,4-dihydroxycinnamic acid (1.8 g), then 5 mmol of sodium ortho vanadate (0.919 g Na3VO4) dissolved in water is added. coloration of the solution becomes opaque black. We eva
o then pore the solvents under vacuum at 50 C.

Example 5
Complexation of vanadyle by Caffeic acid
Solubilized in a degassed solution of water-acetone 10 mmol of trans 3,4-dihydroxycinnamic acid (1.8 g), then 5.25 mmol of K2CO3 is added. Then under a stream of nitrogen, 5 mmol of vanadyl sulphate (1.265 g VOS04.5H20) dissolved in water is added, the coloring of the solution becomes black and a
o release of C02. The solvents are then evaporated under vacuum at 45 C.

Example 6
Complexation of niobium by caffeic acid
5 mmol of trans 3,4-dihydroxycinnamic acid (0.9 g) are dissolved in anhydrous THF (0.9 g) with 0.5 ml of NEt3. Then under a stream of nitrogen, 2.5 mmol of niobium pentachloride (0.675 g NbCl5) is added and the mixture is heated under reflux for 8 h. Then the solvent is evaporated under vacuum.

Example 7
Complexing of niobium by dopamine
Solubilized in anhydrous THF 5 mmol of 3-hydroxytyramine acid chloride (0.948 g) with 0.3 ml of pyridine.

Then under a stream of nitrogen, 2.5 mmol of the THF complex is added with niobium tetrachloride (0.947 g NbCl4: THF) and the mixture is heated at reflux for 12 h. Then the solvent is evaporated under vacuum.

Example 8
Complexation of niobium by 3-pentadecylcatechol
Under a stream of nitrogen, 2 mmol of 3pentadecylcatechol (0.64 g) and 1 mmol of niobium pentaethoxide (0.32 g (EtO) 5Nb) are placed in THF and heated under reflux for 72 h. Then the solvents are evaporated under vacuum.

Example 9
Complexation of vanadium by 3-pentadecylcatechol
2 mmol of 3-pentadecylcatechol (0.64 g) and 2 mmol of NaHC03 are dissolved in a water-acetone mixture, then 1 mmol of vanadyl sulfate (0.253 g VOS04.5H20) is dissolved beforehand.
o in water, and then the solvents are evaporated under vacuum at 600CI
Example 10
Complexation of vanadium by nordihydroguaiaretic acid o
Dissolve in a THF-alcohol 100 mixture 1 mmol of nordihydroguaiaretic acid (0.3 g), then add 0.5 mmol of vanadium oxide (0.091 g V205) and 1 mmol of potassium hydroxide and then heat
o at 60 C for 4 h, then the solvents are evaporated under vacuum.

Example II
Complexation of vanadium by octylgallate:
10 mmol of octylgallate (2.82 g) are dissolved in a water-alcohol mixture, then 5 mmol of vanadyl sulfate (1.265 g VOSO4.5H2O) previously dissolved in water is added, then eva
o pore solvents under vacuum at 45 C.

Example 12
Complexion of vanadium by oleylamide of caffeic acid
1 g (5.55 mmol) of 3,4-dihydroxycinnamic acid is dissolved in a mixture of DMF-CH2Cl2 with 2 equivalents (11.2 mmol, 3 g) of oleylamine and 5.6 mmol of DCC (1.155 g dicyclohexylcarbodiimide) and stirred at room temperature for 72 h.

The solution is filtered, then the solvents are evaporated under vacuum. The amide obtained is purified by chromatography on a silica column.

 3 mmol of the product obtained are dissolved in a water-alcohol mixture, then 1.5 mmol of vanadyl sulfate (0.38 g VOSO4.5H20) previously dissolved in water is added, then the solvents are evaporated under vacuum at 450C .

Example 13
Complexation of vanadium by dopamine y-linolenate
It is dissolved in OOC and under nitrogen in an anhydrous mixture of hexane-CH2Cl2 0.5 g (1.8 mmol) of y-linolenic acid, then 5 equivalents (9 mmol) of oxalyl chloride are added and the mixture is stirred at room temperature for 3 h. The solvents are evaporated cold in vacuo of the vane pump, then redissolved under nitrogen in THF at OOC the chloride of α-linolenic acid and there is added a solution in TMF containing 4 mmol of Et3N and 1.8 mmol of 3
o hydroxytyramine. The solution is slowly heated to 20 ° C., then the solvents are evaporated in vacuo. The amide obtained is purified by chromatography on a silica column.

1 mmol of the product obtained is dissolved in a water-alcohol mixture, then 0.5 mmol of vanadyl sulphate (0.1265 g VOSO4, SH2O) previously dissolved in water is added, then the
o solvents under vacuum at 20 C.

Example 14
Complexation of vanadate by L-DOPA
10 mmol of the sodium salt of 3,4-dihydroxyphenylalanine (2.19 g) are dissolved in water, then 5 mmol of sodium meta vanadate (0.61 g NaV03) dissolved in water are added. The coloring of the solution becomes black. We then evaporate the soil
o under vacuum at 40 C.

Example 15
Complexation of vanadyle by tiron:
10 mmol (3.32 g) of 4.5 dihydroxy-1,3-benzenedisulfonic acid are dissolved in water, then 10 mmol of vanadyl sulphate (2.53 g VOSO4.5H20) dissolved in 1 is added 'water. The solvent is then evaporated under vacuum at 600C.

Example 16
Complexation of vanadyl by 3,4-dihydroxybenzylamine glutarate
1 g (4.54 mmol) of 3,4-dihydroxybenzylamine hydrobromide is dissolved in 0.5 ml of triethylamine and 50 ml of anhydrous DMF, then 4.6 mmol of glutaric anhydride is added and the mixture is heated to 7O0C for 2 , 5 a.m. A CCM plate shows that any
o
The starting amine has disappeared. Then added at 25 C 0.5 equivalent of vanadyl sulfate (0.575 g VOS04.5H20) dissolved in DMF. We
o then evaporates the solvent under vacuum at 65 C.

Example 17
Complexes of V5 and an orthomethoxyphenol derivative
1 mmol of vanillomandelic acid is dissolved in water, then 0.5 mmol of sodium orthovanadate, previously dissolved in water, is added. The solution becomes very dark. We eva
o then pore the water under vacuum at 50 C.

Example 18
Complexes of V4 and a vanillin derivative
2.5 mmol of the Shiff base obtained by reaction of pyridoxalamine on vanillin are complexed with 1.25 mmol of vanadyl sulfate in a 90-10 solution of water-ethanol.

Example 19
Niobium and guaiacol complexes
8 mmol of guaiacol are dissolved in THF with 8 mmol of tri ethyl laminate and 2 mmol of NbCl 4: THF are added thereto, then the mixture is brought to reflux for 1 h. The products obtained are brought to dryness by evaporation of the solvent under vacuum from the water pump.

Example 20
Complexes of V4 and a pyrocatechol monoester
The catechol monosuccinate obtained by reacting 20 mmol of pyrocatechol with 20 mmol of succinic anhydride is com plexed with 0.5 equivalent of vanadyl sulphate in aqueous solution.

Example 21
V4 and syringic acid complexes
It is dissolved in an aqueous solution containing 10 mmol of sodium hydroxide 10 mmol of syringic acid, then 5 mmol of vanadyl sulfate in aqueous solution is added. The water is then evaporated at 500C under vacuum from the water pump.

Example 22
V4 and 3-benzyloxy 4-hydroxyacetophenone complexes
2 mmol of 3-benzyloxy 4-hydroxyacetophenone are dissolved in a water-alcohol-acetone mixture, then 1 mmol of vanadyl sulphate previously dissolved in water is added thereto. We evaporate
o then the solvents under vacuum at 45 C.

Example 23
Formulation in any pharmaceutically acceptable diluent or excipient a) Example of composition for oral administration
A metal complex prepared according to any one of Examples 1 to 22 is mixed in a grinder, at a rate of 10 to 5000 nanomoles of metal (preferably from 20 to 250 nanomoles), with a sugar polymer, for example dextran or cellulose, with zinc stereate, in sufficient amounts to make a 100 milligram tablet, which is then coated with gum arabic and sorbitan monosterate. Advantageously, gastro-resistant gel capsules based on gelatin, titanium dioxide and cellulose ester can be prepared.

b) Example of composition for administration by injection
A metal complex prepared according to any one of Examples 1 to 22 and which is soluble in water, is dissolved in an amount of 20 to 10,000 nanomoles of metal (preferably 50 to 500 nanomoles), in 1 to 10 milliliters of sterile deionized water (preferably 2 to 4 milliliters), then it is adjusted in pH and in mineral salts so as to be as close as possible to physiological saline (pH 7.4 and 9 g / l), with acids, bases or mineral salts made up of elements found in the blood, preferably + - + - rence H, HO, Na, Cl - c) Example of composition for local application
A metal complex prepared according to any one of the preceding examples 1 to 22 is emulsified, micronized or suspended in an amount of 0.1 to 100 micromoles of metal (preferably from 1 to 20 micromoles), in a water emulsion, glycerol, mono-, diet triglycerides of fatty acids, and fatty alcohols.

Example 24
Determination of a hypoglycemic effect:
The injection of 60 mg / kg of streptozotocin intravenously into the rat causes, within 24 hours of the injection, the induction of stable, irreversible and insulin sensitive diabetes mellitus. Subsequent hyperglycemia can be reduced by the administration of substances with hypoglycaemic properties.

a) Protocol
The tests were carried out on male rats of the Wistar strain (6 per batch), coming from the breeding center of the
Faculty of Pharmacy of Montpellier.

 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 180 g. During the observation period, the animals, divided into cages of 3, receive food and drinking water ad o libitum and are subjected to a temperature between 21 and 23 C and a day / dark cycle of 12 h.

 In all trials, diabetes was induced by injection of streptozotocin SIGMA in citrate buffer at pH 4.5.

 The animals with an average weight of 180 g are anesthetized with Ether. An intravenous injection of streptozotocin is performed in the vein of the penis; a control blood sugar level is carried out 72 hours after Administration of streptozotocin only animals with a blood sugar level greater than or equal to 3 g / l (on average 3.8 g / l) are selected and subjected to treatment with the test substance.

The complexes tested were administered under the following injection conditions
- for vanadium derivatives, doses corresponding to 2 mg of metal were administered twice a day for the first two days and doses corresponding to 2 mg of metal were administered, once a day for the following 13 days,
- For niobium derivatives, doses corresponding to 120 micromoles of metal were administered the first two days and 60 micromoles the following 13 days.

 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 in order to compare the consumption of water and food.

b) Results
The daily glycemic control did not allow us to highlight the hypoglycemic effect during the first two days of treatment. A significant and significant drop in blood sugar compared to that of control rats appears from the following days and is maintained in most cases even after treatment is stopped. This is accompanied by an equally significant reduction in polyphagia and polydipsia, which they manifest from the first days. Food and water consumption cover values tending to approach those of non-diabetic control rats.

 The figures in the appendix show the water and food consumption and the evolution of the glycemia of the rats treated with the complexes of examples 1, 5, 6, 10 and 12.

 The results are represented, for each example, in the form of a bar diagram; the black bar corresponding to the results obtained with the diabetic controls and the hatched bar corresponding to the results obtained with the rats treated with the complexes according to the invention.

 FIGS. 1a, 1b and 1c respectively represent the variations in consumption of water, food and the variations in the blood sugar level over time for a batch of diabetic rats treated with the product of Example 1 in comparison with the results. obtained for a batch of untreated diabetic rats.

 FIGS. 2a, 2b and 2c respectively represent the variations in consumption of water, food and the variations in the blood sugar level over time for a batch of diabetic rats treated with the product of Example 5 in comparison with the results. obtained for a batch of untreated diabetic rats.

 FIGS. 3a, 3b and 3c respectively represent the variations in consumption of water, food and the variations in the blood sugar level over time for a batch of diabetic rats treated with the product of Example 6 in comparison with the results. obtained for a batch of untreated diabetic rats.

 FIGS. 4a, 4b and 4c respectively represent the variations in consumption of water, food and the variations in the blood sugar level over time for a batch of diabetic rats treated with the product of Example 10 in comparison with the results. obtained for a batch of untreated diabetic rats.

FIGS. 5a, 5b and 5c respectively represent the variations in consumption of water, food and the variations in the blood sugar level over time for a batch of diabetic rats treated with the product of Example 12 in comparison with
The results obtained for a batch of untreated diabetic rats.

 There has been a marked reduction in the consumption of water and food accompanied by a significant drop in blood sugar.

 Note that the values given in these figures are averages obtained for the whole of a lot.

 Since, in some cases, one or two animals in the batch are not corrected, these means are slightly higher than the corresponding parameters of healthy subjects.

 In addition, the weight development as well as that of the food consumption / weight gain ratio clearly show a hypoglycemic effect that no current treatment for diabetes provides since, in particular, it is prolonged in the majority of cases after stopping the treatment.

 Furthermore, it should be noted that the observation of subjective parameters, such as the appearance of the animals and their behavior, also shows the positive effect of the treatment.

 Measuring cholesterol and triglyceride levels also shows a return to normal levels.

 Like humans, diabetic rats develop metabolic disorders (hypercholesterolemia, hyperlipidemia, hypertriglyceridemia ...) as well as pathologies such as arterial hypertension, atherosclerosis, heart failure, peripheral ischemia, or even ocular pathologies progressing to blindness. .

 It has been shown that in treated rats, which have become normoglycemic, the disorders and complications described above do not appear.

Claims (16)

 1. Pharmaceutical composition, characterized in that it contains as active principle the association of one mole of a vanadium and / or niobium derivative at the oxidation state 4 or 5 with 1 to 10 mol of a derivative pyrocatechol with the formula

 in which R, R 'and R "are identical or different and represent:  - hydrogen,  a linear or branched aliphatic hydrocarbon chain containing from 1 to 30 carbon atoms, preferably from 16 to 20 and from O to 6 unsaturations, said chain being able in the case of R "to be attached via a -CO ,  a hydrocarbon chain containing up to 30 carbon atoms, linear or branched and including at least one aromatic or heteroaromatic ring, said chain possibly in the case of R "being attached to the oxygen atom by a -CO,  - a chain containing up to 50 carbon atoms, linear or branched or containing at least one 3- to 8-membered saturated, unsaturated or aromatic ring, said chain containing O to 10 unsaturations and from O to 10 heteroelements, in particular oxygen, sulfur or nitrogen and said chain comprising from O to 10 branches in C1-C6 containing functions conferring a water-soluble character, for example functions acid, sulfate, phosphate, alcohol, amine, amide, ether, R and R 'can also represent  - an OH group,  - an S03H group,  - A PO3H group, said active principle being incorporated in a pharmaceutically acceptable excipient, vehicle or support.  2. Pharmaceutical composition according to claim 1, characterized in that said combination contains 1 mol of metal derivative for 1 to 4 mol of catechol derivative.  3. Pharmaceutical composition according to one of claims 1 or 2, characterized in that the derivative of vanadium or niobium in the oxidation state 4 or 5 is in the form of an oxide, a halide, a oxyhalide, a sulfate, an alkali metal or ammonium metallate, an acetate, an acetylacetonate, said derivative being able to be in the form of a hydrate or of a complex with a solvent.  4. Pharmaceutical composition according to one of claims 1 to 3, characterized in that the metal derivative is a derivative of vanadium in the oxidation state 4.  5. Pharmaceutical composition according to claims 1 to 3, characterized in that the metal derivative is a niobium derivative at the degree of oxidation 5.  6. Pharmaceutical composition according to one of claims 1 to 5, characterized in that one of the groups R or R ′ is hydrogen and the other is an alkyl or mono- or polyunsaturated chain, linear or branched containing I to 30 carbon atoms.  7. Composition according to one of claims 1 to 5, characterized in that one of the groups R or R 'is hydrogen and the other is a linear or branched chain containing an aromatic or heteroaromatic ring, optionally substituted .  8. Pharmaceutical composition according to one of claims 1 to 5, characterized in that at least one of the groups R or R ′ is a linear or branched chain optionally including a ring and which may include functions conferring a certain water-soluble character.  9. Pharmaceutical composition according to one of claims 1 to 5, characterized in that the pyrocatechol derivative is tiron.  10. Pharmaceutical composition according to one of claims 1 to 5, characterized in that the pyrocatechol derivative is a galate C1 to C30, preferably C16-C20 polyunsaturated.  11. Pharmaceutical composition according to one of claims 1 to 9, characterized in that the group R "is:  - hydrogen,  a linear or branched aliphatic hydrocarbon chain containing from 1 to 30 carbon atoms, preferably from 16 to 20 and from 0 to 6 unsaturations, said chain possibly being attached via a -CO,  - a hydrocarbon chain containing up to 30 carbon atoms, linear or branched and including at least one aromatic or heteroaromatic ring, said chain possibly being attached to The oxygen atom by a -CO,  - a chain containing up to 50 carbon atoms, linear or branched or containing at least one 3- to 8-membered saturated, unsaturated or aromatic ring, said chain containing O to 10 unsaturations and from O to 10 heteroelements, in particular oxygen, sulfur or nitrogen and said chain comprising from O to 10 branches in C 1-C6 containing functions conferring a water-soluble character, for example acid, sulfate, phosphate, alcohol, amine, amide, ether functions.  12. Pharmaceutical composition according to one of claims 1 to 10, characterized in that said association is in the form of a mixture of complexes resulting from the reaction of said metal derivative with pyrocatechol or one of its derivatives.  13. Pharmaceutical composition according to one of claims 1 to 11, characterized in that it is produced for an oral formulation and contains 10 to 5000 nanomoles of metal derivative per dose.  14. Pharmaceutical composition according to one of claims 1 to 11, characterized in that it is produced for an injectable formulation and contains 20 to 10,000 nanomoles of metal derivative per injectable dose of 1 to 10 ml.  15. Pharmaceutical composition according to one of claims 1 to 11, characterized in that it is formulated for local application in particular in a patch and contains, 1 to 100 micromoles of metal derivative per applicable dose.  16. Use of mixtures resulting from the complexation of one mole of vanadium and / or niobium derivative at degree of oxidation 4 or 5 or of a mixture of vanadium and niobium derivatives where niobium and / or vanadium are at the oxidation state 4 or 5 with 1 to 10 mol of pyrocatechol or one of its derivatives corresponding to the formula (I) defined in claim 1 as active ingredient for the preparation of a medicament useful for the treatment or prevention of diabetes, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia as well as complications associated with these pathologies.