WO1993014751A1

WO1993014751A1 - Pharmaceutical compositions containing as active principle associations of vanadium and/or niobium with pyrocatechol derivatives

Info

Publication number: WO1993014751A1
Application number: PCT/FR1993/000068
Authority: WO
Inventors: Jean-Claude Maurel; Renaud Kiesgen De Richter; Eric Rose
Original assignee: I.R.2.M.
Priority date: 1992-01-28
Filing date: 1993-01-22
Publication date: 1993-08-05
Also published as: FR2686512A1; FR2686512B1

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 pyro¬ catechol derivatives.

The present invention relates to pharmaceutical compositions containing as active ingredient combinations of vanana and / or niobium with catechol derivatives. It also relates to the use of said combinations as active principle for the manufacture of a medicament, useful in particular in the treatment or prevention of diabetes and of the 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 Nu mer 48), Verbindungen, Verlag Chemie-GMBH, Weinhei / 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 complexes of V5 ) and in Handbuch der anorganischen Chemie, 8 Auflage, Niobium (System Nummer 49), Teil B4, Verbindungen, VerLagChe ie-GMBH, Weinheim / Bergstrasse, 1973, in particular on pages 334-472 for organic complexes niobium.

A bibliographic review with 198 references on "The Bioinorganic Che istry of Vanadium" was recently carried out by Dieter Rehder, (Angew. 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 species in equilibrium. Thus, vanadate, where the vanadium is at oxidation state 5, depending on the pH and the concentration, can be in several ono eric forms (polycoordinated with solvent or Ligands), or polymeric, with one or more charges. Thus, with hydroxylated derivatives of the H0-R form, vanadate spontaneously forms mono-, di- and tri-esters ((R0) V0 (0H),) which coexist in equilibrium. The geometry of coordination is also very diverse, the degree of coordination generally ranging from 4 to 7 (sometimes 8) and the same ligand that can coordinate the metal in an axial or equatorial position and giving rise to tetragonal pyramids, trigonal, pentagonal or octahedral bipyramids, etc. It is the same for Vanadyle, in which the vana ^¬ dium is found at oxidation state 4, as shown in particular by J. Costa Pessoa et al., Polyhedron, 1988, 1_, 1245-1262 and Polyhedron, 1989, 8., 1173-1199, depending on the pH and the concentration if LH is noted an amino acid such as serine (alanine,

++ threonine, etc.) and M Metal (V0 in this case), one or more of the following species can co¬ exist: MLH, ML, MLH_ ₂ ,

MLH, ML H, ML ₂ H, ML ₂ , ML ₂ H_ ₁ , L ₂ H, M _ ₂ H, " ₂ ^L Z ^H 3 'and ^C "' as ^well as a few hydrolysis or hydration products.

Several authors have suggested that the biological actions of vanadate may be due to the estéπ ^'f cation Tyrosine by V (5). For example, AS Tracey and MJ Gresser, in Their article of Proc. Natl. Acad. Sci. 1986, j $ 3_, 609-613, proved that Phenol and a tyrosine derivative (N-acetyl tyrosine ethyl ester) spontaneously form vanadium esters, 1,000 to 100,000 times faster than with Les phosphates. However,

51 7

Their studies by 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 derivatives of pyrocatechol form esters with vanadate as well as with vanadyle, 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 are a good combination of vanadium and molybdenum, for example 2,3-dihydroxynaphthalene (Collext. CZech. Che. Commun. 1970, 15 _^ , 1599), or tiron (Helv. Chi. Acta , 1951, 34, 528).

Patent EP 248 506 uses tiron (4,5-dihydroxy-1,3-benzenedisulfonic acid) as ligand for the transfer of metal ions onto proteins or polypeptides having a chelating group of greater affinity than tiron for the 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 with oxidation state 4 or 5 is described in this document. Otherwise. The complexes described in this document are used as anti-tumor or anti-viral agents.

Much work has been done on the activity of vanadium in the treatment of hyperglycemia. These are mainly scientific literature documents where only mineral derivatives of vanadium are involved.

In the literature since 1985, numerous studies have described 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 M0NG0LD, September 1991, University of Montpellier I,

France.

European patent EP-0 264 278 describes compositions with insulin-mimetic activity containing vanadates and mineral peroxo-vanadates.

Furthermore, the plaintiff described in its international applications W0 91/07406 and W0 91/13892 as well as in its French application not yet published and filed May 21, 1991 under number 91 06 174 organo-metallic complexes of metals transitioning to porphyrinic structure useful in particular in the treatment of hyperglycemia.

European patent EP-0 305 264 describes organomineral vanadyl compounds obtained from C 1 -C 10 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 anti-diabetic 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 complex of the methyl ester of cysteine with vanadyle and that of 2-amino-ethane-thiol. For the complex of the methyl ester of cysteine with vanadyl, a lowering of the glycemia of 377 mg / dl is described for the controls to 318 mg / dl, for a dose of 3 mg of vanadium / kg and at 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 niobium or vanadium derivative at the oxidation state 4 or 5 with products derived from pyrocatechol, also known as catechoL, have an increased bioavailability compared to that of the uncomplexed metallic compound. In particular, the Applicant has established that the complexes have a greatly 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 constituted by catechoL or one of its derivatives. It is in fact a mixture of complexes corresponding to The fixation by Connections with 1 and / or 2 electrons of a variable number of heteroatoms according to the Ligand envisaged and of which The spatial arrangement around the metal and The degree of coordination of the metal may vary.

The complexes resulting from the reaction of a derivative of vanadium or niobium at the degree of oxidation 4 or 5 with pyro¬ catechol or one of its derivatives have been found to be useful as active principle in medicaments intended for the treatment of diabetes and associated diseases.

The above complexes having the particularity of being formed very easily by contact either in solution or in suspension of the metal derivative and of the organic derivative, the invention covers not only pharmaceutical compositions including said already formed complexes but also pharmaceutical compositions ¬ ceuticals including the mixture of the two types of constituents whose compLexation 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.

According to an essential characteristic, the invention relates to a pharmaceutical composition characterized in that it contains as active principle the association of one mole of a derivative of vanadium and / or niobium with the degree of oxidation 4 or 5 with 1 to

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 0 to 6 unsaturations, said chain being able, in the case of R ", to be attached via a -C0,

- a hydrocarbon chain containing up to 30 carbon atoms, linear or branched and including at least one aromatic or heteroaromatic ring, said chain being able, in the case of R ", to be attached to the oxygen atom by a -C0,

a chain containing up to 50 carbon atoms, linear or branched or containing at least one saturated, unsaturated or aromatic 3- to 8-membered ring, said chain containing from 0 to 10 unsaturations and from 0 to 10 heteroelements, in particular of oxygen, sulfur or nitrogen and said chain having 0 to 10 Ci-C branches. containing functions which confer a water-soluble character, for example acid, sulphate, phosphate, alcohol, amino, amide, ether, R and R ^{1 functions which} may also represent - an OH group,

- a group S0, H,

- a PO ^ H group,

Said active ingredient being incorporated into an excipient, vehicle or pharmaceutical carrier ent acceptable.

As previously seen 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 liable 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 association 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 derivative of pyro ^¬ catechol 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 hetero-aromatic cycle. By way of example, mention will be made of nordihydroguaiaretic acid. According to other variants, the groups R and R ′ can be linear or branched chains optionally including a or cycles and which may contain functions which confer in particular a certain water-soluble character to the product. These functions can, in particular, be acid, amino, ether, ester, amide functions. As an example of pyrocatechol derivatives in which R or R ′ contains an acid function, caffeic acid will be mentioned.

By way of example of pyrocatechol derivatives where R or R ′ contains an innate 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 oleylide of caffeic acid, γ-linoleate of dopamine.

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. By way of example of such products, mention will be made of La 3,4-dihydroxybenzylamine glutarate.

According to another variant, the group R or R ′ comprises both an acid function and an amino 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 S0, H or PO, H. Among the above products, the catechol derivative where R = R '= S0, H, called tiron, will advantageously be chosen. According to other variants, one of the groups R or R ′ is an OH group.

Examples of such pyrocatechol derivatives include gallates, in particular C 1 -C 4 alkyl gallates, 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 -C0 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 -C0 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 -C0.

According to other variants. The group R "may be a linear or branched chain optionally including one or more rings and which may contain functions which confer in particular a certain water-soluble character to the product. These functions may, in particular, be acid, amino, ether, ester, When the pyrocatechol derivative carrying the desired branching or heteroatom functions is not commercially available, those skilled in the art can prepare it by following the conventional methods of synthesis, protection and protection of functional groups. in particular described in Peptide Che istry, 1988, M. BODANSZKY, Berlin Spinger as well as in Protective Goups in Organic Synthesis, TW Greene, Wi Ley Interscience 1980 and in Protective Goups in Organic Chemistry, JFW McOmie, Plénum Press, 1973). : 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 cou¬ range of a branched alcohol (such as phytoL, géranioL, farnesoL, etc.), or a primary or secondary amine using 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 amino or alcohol function of the substrate, perform the coupling of a branched acid using a coupling agent such as DCC, or by reaction with an acid anhydride. - on an amino function (or an alcohol function transformed into an alcoholate) of the substrate, carry out the coupling using a branched halogen derivative (such as farnesyl or geranyl bromide, etc.), b) when wishes 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 hexa-ethylene glycol, or to alkylate an amino function of the substrate by a halogenated polythioether chain , 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 of an oleylamine derivative by H, 0 or by K Mn 0. It is also possible to couple according to a) a chain containing, in addition to an alcohol, amino or free acid function, one or more protected OH functions, for example by gro methoxyethoxyethyl, then release the alcohol functions by Zn 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- P0 (0R) _? or of a Cl-S0_ (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, transform an alcohol or amino function of the substrate by means of CL-CH ₂ ~ CH PO (ONa) or of Cl-CH -CH SO ^ ONa), f) when it is desired to obtain a derivative with a chain having acid functions , one can, for example, couple along a) a chain containing, in addition to an alcohol, amino or free acid function, one or more COOH functions protected in the form of tert-butyl ester, then release the COOH functions in acid medium, g ) when it is desired to obtain a derivative with a chain having amino functions, it is possible, for example, to couple according to a ⁾ a chain containing, in addition to an alcohol, amino or free acid function, one or more primary innate or secondary amino functions protected, for example, by t-butyloxycarbonyl groups (BOC), then Liberating the amino 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 amino function of the substrate, or else make an ester of tetrakis- (2-hydroxypropyl) -ethylene-diamine 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 according to a) a chain containing, in addition to an alcohol, amino or free acid function, one or more thiol functions protected by Me, SiCH _? CH_-, then release these SH functions with 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 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 in the oxidation state 4 or 5, preferably in the oxidation state 4.

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

By way of example of metal derivatives which can be used according to the invention, mention will be made, designating by (acac) an acetylacetonate group and by OAc an acetate group The following derivatives: V0S0 ₄ , VCL, V0CL ₂ , V0 (0Ac ⁾ ₂ , V0 (acac) ₂ , VOCL ,, V 0, Na VO,

K..V0., NaVO ,, H.NV0 ₇ , NbCl., NbC, Nb_0, -, 3 4 _5 4 J __) <__. __) as well as their hydrates (for example V0S0,, 5H-, 0) or their complexes with a solvent, for example with water, THF (for example NbCl., THF), ether, L ' ethylene glycol, etc. An important advantage of useful complexes according to the inven tion is ^¬ they are easily formed by simply contacting pyrocatechol or its derivatives with the metal derivative.

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

By way of solvent, mention may be made of hydro ^¬ alcoholic mixtures, for example mixtures containing 100 to 70% of water for 0 to 30% of alcohol.

The alcohol used in the constitution of the hydroalcoholic medium is advantageously chosen from C 1 -C alcohols, linear or branched, advantageously the 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 as well as the mixtures of their constituents which are not yet complexed but which are capable of complexing in the organism are used more particularly for the preparation of medicaments useful in the treatment or prevention of diseases such as diabetes, 'hypercholesterolemia, Hypertriglyceridemia, Hyper Lipidemia 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 complexes described above as well as the mixture of their constituents not yet complexed but capable of complexing to form the complexes described above are also used for the preparation of medicaments useful for the treatment and / or prevention of insulin resistance that this insulin resistance is associated or not with a form of diabetes.

The present invention therefore relates to pharmaceutical compositions including the complexes described above or the mixture of the two constituents not yet complexed but likely to complex 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 support 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 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, mucous (oral, nasal, ocular) route. They can also be in injectable form and intended for subcutaneous, intramuscular or intravenous injection.

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

The organo-metal associations advantageously represent from 5 to 80% by weight relative to the total weight of the pharmaceutical preparation, and are 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 contain advantageously 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 material 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 highlight 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 g) are dissolved in acetone, 5.1 mmol of K 2 are added thereto _. C0, dissolved in a minimum of water, the coloration becomes slightly black, translucent, then 5 mmol of vanadyl sulphate dissolved in water are added and the coloration of the solution becomes very dark 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:

The procedure described in the article by SR C00PER et al. ⁽ J. Am. Chem. Soc, 1982, 104, p. 5092-5102) is followed. 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 Na, V0,) dissolved in water are added. The coloring of the solu¬ tion becomes opaque black. The solvents are then evaporated under vacuum at 50 ° C.

Example 4 Complexation of Vanadate with Caffeic Acid:

Is dissolved 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 Na, V0.) Dissolved in is added. water, The coloring of the solution becomes opaque black. The solvents are then evaporated under vacuum at 50 C.

Example 5

Complexation of vanadyle by Caffeic acid:

10 mmol of trans 3,4-dihydroxycinnamic acid (1.8 g) are dissolved in a degassed solution of water-acetone in a degassed solution of water-acetone, then 5.25 ml of K-, C0, are added. Then under a stream of nitrogen, we add

5 mmol of vanadyl sulphate (1.265 g V0S0., 5H-, 0) dissolved in

H ά water, the coloring of the solution becomes black and a release of C0_ is observed. 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 NEt. Then under a current of nitrogen, 2.5 mmol of niobium pentachloride (0.675 g NbCl, - ^{) are added} and the mixture is heated at reflux for 8 h. Then the solvent is evaporated under vacuum. Example 7

Complexation of niobium by dopamine:

5 mmol of 3-hydroxytyramine acid chloride (0.948 g) are dissolved in anhydrous THF (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 NbCl.rTHF) and the mixture is heated at reflux for 12 h. Then the solvent is evaporated under vacuum.

EXAMPLE 8 Complexation of Niobium by 3-Pentadecycatcatol:

Under a stream of nitrogen, 2 mmol of 3-pentadecylcatechol (0.64 g) and 1 mmol of niobium pentaethoxide (0.32 g (Et0), - Nb) 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 NaHCO 2 are dissolved in a water-acetone mixture, then 1 mmol of vanadyl sulphate (0.253 g VSO, 0.5H0) is added beforehand. water, and then the solvents are evaporated under vacuum at 60 C.

Example 10

Complexion of vanadium by nordihydroguaïaretic acid: 1 mmol of nordihydroguaïaretic acid (0.3 g) is dissolved in a THF-alcohol mixture 100, then 0.5 mmol of vanadium oxide (0.091 g V-, 0 ,.) and 1 mmol of potassium hydroxide and then heated to 60 C for 4 h, then the solvents are evaporated in vacuo.

Example 11

Complexation of vanadium by octylqallate:

10 mmol of octyl gallate (2.82 g) are dissolved in a water-alcohol mixture, then 5 mmol of vanadyl sulphate (1.265 g VSO4.5H 2 O), previously dissolved in water, is added, followed by evaporation. pore solvents under vacuum at 45 C. Free on 12

Complexion of vanadium by oleyLamide from caffeic acid:

1 g (5.55 mL) of 3,4-dihydroxycinnamic acid is dissolved in a mixture of DMF-CH-CL- with 2 equivalents (11.2 mmol, 3 g) of oleylamine and 5.6 mmol of DCC (1.155 g of dicyclohexylcarbodiimide) and the mixture is 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) is added.

V0S0,, 5H _? 0) previously dissolved in water, then the solvents are evaporated under vacuum at 45 C.

Example 13 Complexation of Vanadium with γ-LinoLenate de-Dopamine:

Is dissolved at 0 C and under nitrogen in an anhydrous mixture of hexane-CH _? CL _? 0.5 g (1.8 mmol) of γ-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 under cold vacuum of the vane pump, then redissolved under nitrogen in THF at 0 C γ-linolenic acid chloride and a solution in THF containing 4 mmol of Et, N and 1.8 mmol of 3-hydroxytyramine. The solution is slowly heated to 20 ° C., then the solvents are evaporated under vacuum. 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 VSO5, 5H-, 0) previously dissolved in water is added, then the solvents are evaporated. under vacuum at 20 C.

Example 14

Complexation of vanadate by L-DOPA:

10 mmol of the sodium salt of La are dissolved in water

3,4-dihydroxyphenylalanine (2.19 g), then 5 mmoL of sodium meta vanadate (0.61 g NaVO,) dissolved in water is added. The coloration of the solution becomes black. The solvents are then evaporated under vacuum at 40 C.

EXAMPLE 15 Complexation of Vanadyle by Le Tiron:

Are dissolved in water 10 mmol (3.32 g) acid 4,5-dihydroxy-1,3-benzenedisulfonic then added 10 mmol of vanadyl sulfate (2.53 g V0S0,, _5H? 0) dissolved in water. The solvent is then evaporated under vacuum at 60 C.

Example 16

Complexation of vanadyl by 3,4-dihydroxybenzylamine glutarate:

Dissolve in 0.5 ml of triethylamine and 50 ml of anhydrous DMF 1 g (4.54 mmol) of 3,4-dihydroxybenzylamine hydrobromide, then 4.6 mmol of glutaric anhydride are added and the mixture is heated to 70 C for 2.5 h. A CCM plate shows that all the starting amine has disappeared. Then added at 25 ° C. 0.5 equivalent of vanadyl sulfate (0.575 g VSO5. 5H 2 O) dissolved in DMF. We

4 c then evaporates the solvent under vacuum at 65 C.

Example 17

Complexes of V5 and a derivative of OrthomethoxyphenoL:

1 mmol of vanilomandelic acid is dissolved in water, then 0.5 mmol of sodium orthovanadate, dissolved beforehand, is added. The solution becomes very dark. The water is then evaporated 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 sul¬ fate 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 triethylamine and 2 mmol of NbCL.rTHF 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 reaction of

20 mmol of pyrocatechol on 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:

Dissolve in an aqueous solution containing 10 mmol of sodium hydroxide 10 mmol of syringic acid, then add 5 mmol of sulphate ddee vvaannaaddyyllee eenn ssoolluuttiioonn aaqquueeuse. The water is then evaporated at 50 ° C. 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 sul¬ fate previously dissolved in water is added thereto. The solvents are then evaporated under vacuum at 45 C.

Example 23 Formulation in any acceptable pharmaceutical 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 quantities to make a 100 ml Ligrammes tablet, which is then coated with arabic gum and sorbitan monosterate. Advantageously, gastro-resistant 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 from 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 the physiological serum (pH 7.4 and 9 g / l), by acids, bases or mineral salts made up of elements found in the blood, preferably

+ - +. - rence H, H0, 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 an emulsion of water, glycerol, mono-, di- and triglycerides of fatty acids, and fatty alcohols.

Example 24

Determination of a hyperglycemic effect:

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

a) Protocol

The tests were carried out on male rats of Wistar strain ⁽ 6 per batch), coming from the breeding center of La Faculté de Pharmacie de 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 aç_ {libitum and are subjected to a temperature between 21 and 23 C and a day / dark cycle of 12 h.

In all tests. Diabetes was induced by injection of streptozotocin SIGMA in citrate buffer at pH 4.5.

Animals with an average weight of 180 g are anesthetized with Ether. An intravenous injection of streptozotocin is practiced in the vein of the penis; a control glycemia is carried out 72 h after the 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 / kg were administered twice a day the first two days and doses corresponding to 2 mg of metal / kg were administered, once a day The 13 days following,

- For niobium derivatives, doses corresponding to 120 micromoles of metal / kg were administered the first two days and 60 micromoles / kg the following 13 days. 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 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 consumption of water and food.

b) Results The daily glycemic control did not allow us to highlight the hypoglycemic effect during the first two first 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 glycaemia 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 decrease 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.

As, in some cases, one or two animals in the Lot are not corrected, these averages are slightly higher than the corresponding parameters of healthy subjects.

Furthermore, 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 i L is prolonged in the majority of cases after discontinuation of treatment.

In addition, it should be noted that observation of subjective parameters, such as the appearance of 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, hypertπ ^' glyceridemia ...) as well as pathologies such as hyper¬ blood pressure, arteriosclerosis, heart failure, peripheral ischemia, or even eye pathologies evolving towards blindness. It has been shown that in treated rats which have become normoglycemic, the disorders and complications described above do not appear.

Claims

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 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 0 to 6 unsaturations, said chain being able in the case of R "to be attached via a -C0 , - a hydrocarbon chain containing up to 30 carbon atoms, linear or branched and including at least one aromatic or heteroaromatic cycle, said chain possibly in the case of R "being attached to the oxygen atom by a - C0,

- a chain containing up to 50 carbon atoms, linear or branched or containing at least one ring with 3 to

8 saturated, unsaturated or aromatic links, said chain containing 0 to 10 unsaturations and from 0 to 10 heteroelements, in particular oxygen, sulfur or nitrogen and said chain comprising from 0 to 10 branchings in C.-C , containing functions conferring a water-soluble character, for example acid, sulphate, phosphate, alcohol, α ine, amide, ether, R and R ′ functions which may also represent

- a 0H group,

- a group S0..H, - a group PO, H, Said active ingredient being incorporated in an aceutically acceptable excipient, vehicle or carrier.

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 degree of oxidation 4 or 5 is in the form of an oxide, a halide, d an oxyhalide, a sulfate, an alkali metal or ammonium metallate, an acetate, an acetylacetonate. Said derivative which may be in the form of a hydrate or a co pLex 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 with an oxidation state of 5.

6. Pharmaceutical composition according to one of claims 1 to 5, characterized in that one of the groups R or R ¹ is hydrogen and the other is an alkyl or mono- or polyunsaturated chain, linear or branched containing 1 to 30 carbon atoms.

7. Composition according to one of claims 1 to 5, characterized in that one of the groups R or R ¹ is hydrogen and the other is a linear or branched chain containing an aromatic or heteroaromatic cycle, 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 possibly including a cycle and which may include functions which confer a certain character water soluble.

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 gallate at C „to C ,, -, preferably C ,, - C_. polyunsaturated.

I _5U lo -V

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 -C0,

- 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 -C0, - a chain containing up to '' with 50 carbon atoms,

Linear or branched or containing at least one cycle at 3 to

8 saturated, unsaturated or aromatic links, said chain containing

0 to 10 unsaturations and from 0 to 10 heteroelements, in particular oxygen, sulfur or nitrogen and the said chain comprising from 0 to 10 branchings in C.-C, containing functions conferring a

1 6 water-soluble character, for example acid, sulfate, phosphate, alcohol, amino, 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 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 application local cation, in particular in a patch, and contains 0.1 to 100 micromoles of metal derivative per applicable dose.

16. Pharmaceutical composition according to one of claims 1 to 15, characterized in that it is useful for the treatment or prevention of diabetes, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia as well as complications associated with these pathologies, as well as for the treatment and / or prevention of insulin resistance.

17. Pharmaceutical composition according to one of claims 1 to 16, characterized in that it is useful for the treatment of diabetes.

18. Use of complexes or mixtures of complexes resulting from the reaction of one mole of vanadium and / or niobium derivative at oxidation state 4 or 5 with 1 to 10 moles of pyrocatechol or one of its corresponding derivatives- to the formula (I) defined in Claim 1 as active principle for the preparation of a medicament useful for the treatment or prevention of diabetes, hypercholesterolemia, hypertriglycé¬ ridemia, hyperlipidemia as well only complications associated with these pathologies and insulin resistance.

19. Use of mixtures of one mole of vanadium and / or niobium derivative with an oxidation state of 4 or 5 and from 1 to 10 moles of pyrocatechol or one of its derivatives corresponding to formula (I) defined in Claim 1 as active ingredient for the preparation of a medicament useful for the treatment or prevention of diabetes, hyperchoLesterol, ie hypertriglyceridemia, hyperlipidemia as well as complications associated with these pathologies and insulin resistance.