EP0624092A1

EP0624092A1 - Utilization of niobium derivatives as active principle of medicaments useful in the treatment and/or prevention of glucid and/or lipid metabolium troubles

Info

Publication number: EP0624092A1
Application number: EP93904111A
Authority: EP
Inventors: Jean-Claude Maurel; Renaud Kiesgen De Richter; Eric Rose
Original assignee: Ir2m
Current assignee: Ir2m
Priority date: 1992-01-28
Filing date: 1993-01-22
Publication date: 1994-11-17
Also published as: WO1993014772A1

Abstract

L'invention concerne une nouvelle utilisation des dérivés du niobium à l'état d'oxydation 4 ou 5 comme principe actif pour la fabrication de médicaments utiles dans le traitement et/ou la prévention des désordres du métabolisme des glucides et/ou des lipides. Les dérivés du niobium utiles selon l'invention sont sous forme de sels minéraux ou de sels ou complexes organométalliques. Les médicaments sont utiles pour le traitement du diabète, de l'hypercholestérolémie, de l'hyperlipidémie, de l'hypertriglycéridémie, et des complications associées à ces pathologies.The invention relates to a novel use of niobium derivatives in oxidation state 4 or 5 as an active principle for the manufacture of medicaments useful in the treatment and / or prevention of disorders of the metabolism of carbohydrates and / or lipids. The niobium derivatives useful according to the invention are in the form of inorganic salts or of organometallic salts or complexes. The drugs are useful for the treatment of diabetes, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, and complications associated with these conditions.

Description

Use of niobium derivatives as active principle of medicaments useful in the treatment and / or prevention of disorders, of carbohydrate and / or lipid metabolism.

05 The present invention relates to the use of niobium derivatives as active principle of medicaments useful in the treatment and / or prevention of disorders of the metabolism of glu¬ cides and / or lipids.

The search for new hypoglycemic derivatives for

10 treatment of diabetes is very important because, in the present state, the available substances (insulin, biguanides, chlofibrates, sulfonamides, etc.) help to control it via a ^regulators' tion in blood sugar, treat "effects" of diabetes and associated metabolic disorders, but do not treat it

15 causes mostly unknown and do not cure it. In addition, these treatments are long-lasting, generally for life, and restrictive for the individual ⁽ daily injections). They are therefore necessarily accompanied by side effects and new pathologies appear over the years (insulin-

Resistance, blindness, etc.).

With the discovery and study for several years of essential trace elements, certain metal ions have been described as having insulin-magnetic properties. This is particularly the case for the mineral salts of vanadium, as is the case.

25 comes out of the bibliographical update entitled "The bio-inorganic Chemistry of Vanadium" carried out recently by Dieter REHDER (Angew. Chem. Int. Ed. Engl. 1991, 30., 148-167) of certain derivatives of molybdenum and d other chromium ⁽ in particular a natural peptide not yet fully identified ⁽ called GTF, and a

30 derivative called dithiochrome, cf. W0 91/01738, published on 21.02.1991). In addition, many metallo- has been discovered. enzymes involving V, Cr or Mo naturally, or in replacement of another missing or deficient metal. the current assumption is that metal ions like

35 vanadate have an important biological action by analogy with phosphate ions, in particular because they have substantially the same size and the same lengths of metal-oxygen bonds.

Numerous studies have been carried out concerning 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, many studies describe the hypoglycemic effects of mineral derivatives of vanadate (+5) or vanadyle (+4) ions. An excellent bibliographic update can be found in Jean-Jacques M0NG0LD's Doctoral Thesis in Pharmacy, 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 applicant has 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 organo-metallic complexes of transition metals porphyrinic structure useful in particular in the treatment of hyperglycemia.

European patent EP-0 305 264 describes organo inorganic vanadyl compounds obtained from C, -C _1n esters of cysteine. Japanese patent JP 2 292 217 describes an anti-diabetic activity for 7 vanadyl-dioxo complexes ⁽ tartrate, gluconate, alonate, oxalate, lactate, salycilate and acetyl-acetonate), as well as for 2 vanadyl-monoamino-monothio complexes: The com ¬ Cysteine methyl ester plex with Vanadyl and that of 2-amino-ethane-thiol.

Mineral salts of niobium as well as some organic derivatives of niobium (cyclopentadienyls and isothiocyanates) have other medical uses (toothpaste, contrast agent for radiography or NMR imaging, or use in oncology). They are therefore administered to humans and their toxicity is known. For example. The Merck Index, 11 Edition, indicates that the oxovanadate chloride (VOCl, product no. 9834) has an oral lethal dose DL- ₀ = 140 g / kg for rats ⁽ which makes 41.2 mg of metal / kg), while niobium chloride (NbC product No. 6473) has an oral lethal dose DL-. = 830 mg / kg for mice (which makes 285 mg of metal / kg). It would therefore seem that niobium has less toxicity than ^' vanadium, which itself is much less toxic than chromium VI.

The synthesis of derivatives or complexes of ^niobium is well known: for example it may be done according to the methods listed by Leopold Gmelins, and described in: Handbuch der anorgani Chemie, 8 Auflage, Niobium (System Nummer 49), Teit B4 , Verbindungen, VerlagCheππe-GMBH, Weinheim / Bergstrasse, 1973, in particular on pages 334-472 with regard to organic complexes. The mineral salts of niobium can be prepared according to known procedures and described for example in the above book, niobium sulfates on page 303.

Niobium alkoxides, niobium dialkylamides and niobium aminoalkoxides can also be prepared by following, for example, the procedures described in patents EP 0 450 717 and EP 0 442 563.

Niobium complexes with hydroxy acids ⁽ such as tartaric, lactic, glycolic and malic acids ⁾ can be prepared by following for example the procedures described by E. RUZDIC and N. BRNICEVIC in Inorganica Chimica Acta, 1984, _^ 88, 99 -103.

Peroxo niobium complexes with organic derivatives such as tartaric, lactic, glycolic, dipicolinic and malic acids can be prepared by following for example the procedures described by A.C. Dengel and W.P. Griffith, Polyhedron, 1989,, 1371-1377.

At present, niobium is not considered to be an essential trace element and is not used for the prevention or treatment of disorders of the metabolism of carbohydrates and / or lipids. Furthermore, the analogy with phosphate ions which can be made, as we saw above in the case of vanadium, is by no means justified in the case of niobium.

Therefore, there was no evidence that niobium would exhibit a therapeutic activity similar to that of vanadium in the treatment of diabetes and related diseases.

Now, the Applicant has now discovered that niobium derivatives with a degree of oxidation 4 or 5 had an activity comparable to that of vanadyls and vanadates in the treatment of diabetes and more broadly proved to be active for the treatment and the prevention of disorders of the metabolism of carbohydrates and / or lipids and of the complications associated with these pathologies.

The Applicant has discovered that this activity could be further significantly increased by complexing said derivatives with different organic ligands.

Generally speaking, the term “complex according to the invention” will be understood to mean the reaction product of a niobium derivative at degree of oxidation 4 or 5 with an organic ligand. They are, in general, mixtures of complexes corresponding to the fixation by bonds with 1 and / or 2 electrons of a variable number of heteroatoms according to the ligand used whose spatial arrangement around the metal and the degree of coordination metal may vary

Since the above complexes have the particularity of being formed very easily by contact, either in solution or in suspension, of a niobium derivative at oxidation state 4 or 5 with an organic ligand, the invention does not cover only the use of said complexes already formed as active principle for the manufacture of a medicament useful in the treatment and prevention of disorders of the metabolism of carbohydrates and / or lipids, but also the use of the mixture of the two types of constituents ⁽ derivative of niobium with the degree of oxidation 4 or 5 and organic ligand) 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 com¬ pLexation reaction. Thus, according to an essential characteristic, the. The present invention relates to a new use of niobium derivatives in oxidation state 4 or 5 as active ingredient for obtaining a medicament useful in the treatment of disorders of the metabolism of carbohydrates and / or lipids.

Among the diseases whose treatment or prevention is particularly targeted in the context of the present invention, mention will first of all be made of diabetes but also hypercholesterolemia, hyperglyceridemia, hyperlipidemia as well as the diseases associated with these pathologies.

Examples of associated pathologies include arterial hypertension, arteriosclerosis, heart failure, peripheral ischemia or ocular pathologies progressing to blindness. According to a first variant of the invention, the niobium is in the form of an inorganic derivative.

Advantageously, this mineral derivative is soluble in water.

One will preferably choose among these salts, salts giving solutions of pH ranging between 3 and 9, preferably close to normality.

Examples of mineral derivatives which can be used include oxides, sulfates, halides, hydrochlorides, metallates of alkali or ammonium salts, as well as their hydrates or their complexes with a solvent.

By way of oxide, particular mention will be made of Nb_0, -. As chloride, mention will be made of NbCl, and NbCl, -. Among the preferred sulphates, mention will be made very particularly of that corresponding to the formula (NH,), Nb (SO,),. As a complex of these mineral derivatives with a solvent, there may be mentioned, for example, the complex between NbCl and THF.

The organic derivatives which can be used according to the invention are very particularly in the form of salts or complexes in which the niobium is in the oxidation state 4 or 5. Among the organic sets or complexes with niobium, mention will be made very particularly of those with organic derivatives containing at least one hetero atom or an electron donor function capable of giving one or two electrons.

By way of hetero atom of an electron-donor nature, mention may be made of oxygen, nitrogen and sulfur. As functions of an electro-donor nature, mention may be made of carboxylic acid, sulfuric acid, phosphoric acid, amino, alcohol, thiol, ether, ^• thioether functions.

As preferred organic derivatives, mention will be made of niobium complexes with ligands comprising at least one free electronic doublet, preferably several, that is to say with organic derivatives called polydentates, and in particular bidentates, tridentates and tetradentates. .

As a family of preferred complexes, there may be mentioned, without being limiting, the complexes of niobium with amines, polya ines, alcohols, polyols, sugars, sugar polymers, nucleotides, thioLs, amino -acids, amino alcohols, guanines, oxymes, diketones-1, 3, carboxylic, phosphoric, sulfuric, carboxydithioic, carbamadithioic acids, phenols, catechols, Schiff bases, proteins, peptides, polyfunctional derivatives containing heteroatoms such as oxygen, sulfur, nitrogen, rings containing these heteroatoms.

These organic and complex derivatives have the advantage of being easily formed by contact of said ligand with an inorganic derivative or an organic niobium salt in the oxidation state 4 or 5 either in solution or in suspension in a solvent. Reference will be made to the examples of synthesis given by way of illustrative examples highlighting the simplicity of formation of organic complexes and salts of niobium where the niobium is a degree of oxidation 4 or 5, useful according to the invention.

As niobium derivative useful for the preparation of complexes or combinations useful according to the present invention, mention will be made of oxides, halides, in particular chloride, oxy-halides, sulphate, alkali metal or ammonium etalate, acetate, acetylacetonate and also their derivatives as hydrate or complex with a solvent. Examples of salts and complexes which can be used according to the invention include oxalate, tartrate, alcoholate, .catecholate.

Among the families of complexes or associations preferred according to the invention, there will be mentioned: a) the complexes or associations of niobium in the oxidation state 4 or 5 with inositol, an inositot phosphate or one of their derivatives:

More specifically, these complexes or associations are obtained by mixing or reacting from 0.1 to 6 moles, preferably 1 to 3 moles of a niobium derivative with oxidation state 4 or 5 as defined above for -1 mole of an inositot derivative corresponding to the formula:

where R, R_, R .., R ,, R,., R are identical or different and represent:

- Hydrogen, - a linear or branched atiphatic hydrocarbon chain containing from 1 to 30 carbon atoms, preferably 16 to 20 and containing from 0 to 6 unsaturations, said chain being linked to an oxygen of the inositol ring by a group - CH_ or a carbonyl group -C0, - a linear or branched hydrocarbon chain containing up to 30 carbon atoms and including at least one aromatic or heteroaromatic ring, Said chain being linked to an oxygen of the inositol ring by a group -CH _? or a carbonyl group -C0,

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

1 o hydrosoluble character, for example acid, sulfate, phosphate, alcohol, amino, amide, ether functions,

0 0Y. il / ¹ - a group -P in which Y ₁ and Y_ are identical or

^ OY ₂ different:. Hydrogen,

. an alkali metal,. an NH group.,

. Y ₁ and Y- together form a phenylene group,. a linear or branched aliphatic hydrocarbon chain containing from 1 to 30 carbon atoms, preferably 16 to 20 and containing 0 to 6 unsaturations,. a hydrocarbon chain containing up to 30 carbon atoms and including at least one aromatic or heteroaromatic ring,

. a chain containing up to 50 carbon atoms, linear or branched or containing at least one 3- to 8-membered ring saturated, unsaturated or aromatic, said chain containing from 0 to

10 unsaturations and from 0 to 10 heteroelements, in particular of

Oxygen, sulfur or nitrogen and said chain comprising

0 to 10 branches in C _j -C, containing functions conferring a water-soluble character, for example acid, sulphate, phosphate, alcohol, amino, amide, ether functions, b) complexes or associations of niobium at the oxidation state 4 or 5 with the amino acids and their derivatives, in particular their derivatives in the form of a tertiary or secondary ide or amine:

More specifically, these complexes or associations are obtained by mixing or reacting a mole of nobium derivative at the oxidation state 4 or 5 and 1 to 100, preferably 2 to 5, moles of amino acid L or D containing a side chain of a natural amino acid or a derivative of such an amino acid, said derivative being an alkali metal salt, a hydrochloride, a hydroxamate or a derivative containing at least one secondary or tertiary amide, ester or amine function resulting from the transformation of at least one of the acid and / or amino functions of said amino acid, said active principle being incorporated in a pharmaceutically acceptable excipient or carrier.

According to a variant, the ratio of the number of moles of amino acid or of amino acid derivative to the number of moles of the metal derivative will advantageously be between -2 and 5.

The niobium 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 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. The amino acid is advantageously chosen from natural amino acids.

According to an advantageous variant, the amino acid is chosen from natural amino acids having a side chain containing heteroatoms. Thus, the amino acid will advantageously be chosen from the group consisting of tryptophan, lysine, tyrosine, serine, threonine, arginine, aspartic acid, glutamine, asparagine, glutamate, aspartate. These amino acids can therefore coordinate or count either a second metal ion or the same.

Among the amino acids advantageously chosen, there is also proline.

The amino acid derivatives useful according to the invention are the amino acid derivatives in the form of esters, amides or hydroxamates, that is to say amino acid derivatives in which at least a carboxylic acid or free inene function has been transformed by reactions well known to those skilled in the art. The amino acid derivatives used to form the nobium complexes useful according to the invention are advantageously found in one of the following forms: 0 R

Il l R "- C - NH - CH - COYR '(I) or

R "'N - CH - COYR' (i:

R 'or

R "

where Y is 0 or -NH,

R is an amino acid side chain, R ', R "and R"' are independently:

- hydrogen, or - a linear or branched aliphatic hydrocarbon chain containing 1 to 30 carbon atoms, preferably 16 to 20 and containing 0 to 6 unsaturations and which may contain amino, alcohol, thioL, phosphate, acid functions , ether, amide, or - a linear or branched hydrocarbon chain containing up to 30 carbon atoms and containing at least one aromatic or heteroaromatic ring,

R 'can also be a sugar or a polyalcohol.

According to a variant of the invention, in the derivatives of formulas I, II or III above, R '= R "= R'" = H and The derivative is the amino acid itself. According to another variant, the amino acid derivative is a monoester. In formulas I, II or III above, Y = 0 and R "= R" '= H.

R ′ is then advantageously an alkyl, mono- or polyunsaturated or arylalkyl group at C.-C, - ,. By way of a pThe exe of such groups, mention may be made of methyl, ethyl, tinoleyl, gamma-tinolenyl, oleyl, phenyl, benzyl, ricinoleyte groups.

According to another variant, the amino acid derivative is in the form of a monoamide and one of the groups R ′ or R ″ or

R "'is a C.sub.1-C.sub.1, _n , ac.-C.sub.4, _n , arytatkyl or alkylaryte group or an oleyl, linoteyl, gamma-linotenyte, ricinoleyte group.

According to another variant, the derivative of amino acid is a sugar ester, mention will be made, for example, of the esters obtained by condensation of a glucose or of a fructose on the acid function of an inoacid.

According to another variant of the invention, the amino acid derivative is in the form of a hydroxamate. ^'According to another variant, the amino acid derivative is a secondary or tertiary amine. Among these secondary or tertiary amines, particular mention will be made of those for which

R "and / or R" 'are linear or branched hydrocarbon chains containing 1 to 30 carbon atoms, in particular alkyl chains, or chains comprising from 1 to 6 unsaturations or alkylaryte chains.

By way of free amino acid derivatives in the form of secondary or tertiary amine, there may be mentioned in particular for example N-otéyLproline, N-benzylproline. c) complexes or associations of niobium with oxidation state 4 or 5 with organic compounds containing a ring containing at least two nitrogen atoms.

Examples of such organic compounds include imidazole, pyrazole, purine base, pyrimidine base derivatives or derivatives containing a polydentate macrocycle containing 6 to 30 atoms including at least 3 heteroatoms.

The complexes or associations between a niobium derivative with oxidation state 4 or 5 and an organic compound containing a ring containing at least two nitrogen atoms are obtained from a mole of niobium derivative with oxidation state 4 or 5 and from 0.25 to 20 moles of organic compound comprising a ring containing at least two nitrogen atoms.

As organic compound containing a cycle containing at least two nitrogen atoms, one will advantageously choose an imidazole derivative, pyrazole, of purine or pyrimide base or a polydentate cycle containing 6 to 30 atoms including at least three hetero elements.

When the organic compound is an imidazole derivative, it is advantageously of the form:

or in the form of a benzimidazole derivative

where R and R 'are independently of Hydrogen, a linear or branched aliphatic hydrocarbon chain containing 1 to 30 carbon atoms, preferably 16 to 20 and containing 0 to 6 unsaturations which may contain a ine, alcohol, thiol, phosphate functions , acid, ether, amide or a hydrocarbon chain containing up to 30 carbon atoms and containing at least one aromatic or heteroaromatic ring, R can also be a guanidinium group.

By way of example of an organic derivative of the imidazole type, mention will be made of the imidazole itself, the alkyl-2-imidazole, the alkenyl-2-imidazole, the benzimidazole, the 2-guanidinobenzimidazole.

When the organic compound is a derivative of pyrazole, it corresponds to the formula:

in which :

Y is 0 or NH,

R, R ', R "are independent

- hydrogen,

- An aliphatic hydrocarbon chain, linear or branched containing 1 to 30 carbon atoms, preferably 16 to 20 and containing 0 to 6 unsaturations and which can carry amine, alcohol, thiol, phosphate, acid, ether, amide, or

- a linear or branched hydrocarbon chain containing up to 30 carbon atoms and containing at least one aromatic or heteroaromatic cycle.

By way of example of pyrazole derivatives, mention will be made of pyrazole itself, dialkyl-3,5-pyrazoles, diesters of dicarboxylic acid-3,5-pyrazole, more particularly alkyl diesters and your diesters phytol or linoleol. According to another advantageous variant of the invention, the organic derivative containing a cyle containing at least two nitrogen atoms will be a purine base, a pyrimidine base or a derivative of such a base.

Among the purine and pyriidic bases, adenine, guanine, thymine, cytosine, t'uπ ^' dine will be mentioned.

Among the derivatives of these bases, mention will be made of derivatives of bases exhibiting NH _? free, namely derivatives of adenine, guanine and cytosine in which NH- has been transformed into a secondary amine or into an amide. Thus the purine and pyrimidine bases as well as their preferred derivatives correspond to the following formulas:

where Z denotes -CH _? , -C0 or H and where R is either:

- Hydrogen,

- An aliphatic, linear or branched hydrocarbon chain containing 1 to 30 carbon atoms, preferably 16 to 20 and containing 0 to 6 unsaturations and which can carry amine, alcohol, thiol, phosphate, acid, ether, amide functions.

According to another variant, the organic compound containing a ring containing at least two nitrogen atoms is a polydentate ring containing 6 to 30 atoms and at least a third heteroato consisting of nitrogen or oxygen, each nitrogen atom of the cycle which can carry a substituent R which can be:

- hydrogen,

- An aliphatic hydrocarbon chain, linear or branched containing 1 to 30 carbon atoms, preferably 16 to 20 and containing 0 to 6 unsaturations and which can carry amine, alcohol, thiol, phosphate, acid, ether, amide functions. - A linear or branched hydrocarbon chain containing up to 30 carbon atoms and containing at least one aromatic or heteroaromatic cycle.

By way of example of the above organic compounds, mention will be made of:

- The derivatives of ta 1, 3,5-triazine:

./ \.

for example La tribenzy 1-1, 3,5-t riazine,

- derivatives of, 4,8,11-tetraazacyc lotetradecane

in particular your mono- and dia lkyl-1, 4,8,11-tetraazacyclotetra-decane,

- derivatives of 1, 4,10-trioxa-7,13-diazacyclopentadécane

in particular 1, 4,10-trioxa-7,13-diazacyclopentadécane (R = H), d) complexes or associations of niobium with oxidation state 4 or 5 with derivatives of dithiocarbamic acid and its salts (dithiocarbamates):

More specifically, the complexes or associations between a niobium derivative with an oxidation state of 4 or 5 and a derivative of dithiocarbamic acid or its salts are obtained by mixing or compounding reaction between 1 mole of a niobium derivative where the metal is in the oxidation state 4 or 5 and 1 to 3 moles of an acid derivative dithiocarbamic acid or one of its salts S including a group NC 'where M is hydrogen, a metal

MS alkaline, an ammonium or alkylammonium group, said alkylammonium possibly being a mono-, di-, tri- or tetraalkyl in cc ₄ .

By derivatives of dithiocarbamic acid and of dithiocarbamates, are meant the derivatives in which one or both hydrogen atoms carried by the nitrogen atom have been substituted by independent groups as well as products where the two atoms of hydrogen have been substituted by two groups together forming a ring including the nitrogen atom.

Dithiocarbamates will denote the substituted or unsubstituted derivatives in the form of salts.

The dithiocarbamates previously defined will advantageously be in the form of an alkali metal salt, in particular sodium or potassium.

According to another variant, they will be in the form of an ammonium or alkylammonium salt, in particular of mono-, di-, tri- or tetraalkylammonium, the alkyl advantageously being a C ₁ to C ₄ alkyl.

According to an advantageous variant, the dithiocarbamic acid derivatives giving complexes will be in one of the following forms:

N - C ^* (IV) '^ SM or

where: -M is hydrogen, an alkali metal, an ammo¬ nium or mono-, di-, tri- or tetraalkylammonium group in C - C ,.

-n is an integer between 1 and 3.

-Z is oxygen, sulfur, an -NR or -CHR group.

-R and R 'are:

- hydrogen,

- a linear hydrocarbon chain atiphatique ^'or branched containing from 1 to 30 carbon atoms, preferably from 16 to 20 and containing from 0- to 6. unsaturation tions,

- a hydrocarbon chain containing up to 30 carbon atoms and including at least one aromatic or heteroaromatic ring, or - a chain containing up to 50 carbon atoms, linear, branched or containing at least one ring and containing 0 to 10 heteroelements , in particular oxygen, sulfur or nitrogen and 0 to 10 ramifica¬ tions containing functions conferring a water-soluble character, for example acid, sulfate, phosphate, alcohol, amino, ether, amide functions. According to a variant, the dithiocarbamic derivative is a product of the family (IV).

At least one of the groups R and R ¹ , advantageously both, can then be linear or branched alkyl chains containing 1 to 30 carbon atoms.

Examples of such products include: di isobutylcarbamadithioic acid, sodium set of dioctyIcarbamadithioic acid.

The nitrogen atom can also carry one or two mono- or polyunsaturated chains, mention will be made, for example, of monoleolecarbamadithioic acid. The groups carried by the nitrogen atom of the dithiocarbate or of the derivative of dithiocarbamic acid can also comprise an aromatic or heteroaromatic ring.

Mention will be made, for example, of dibenzylcarbamadithioic acid and its salts.

The groups carried by the nitrogen atom of dithiocai-bamate can also contain heteroelements or carry functions which confer a certain water-soluble character.

As seen previously, in other variants of the invention, the two hydrogens of dithiocarbamic acid or of dithiocarbamate are substituted by two groups which together form a ring.

Among the derivatives mentioned above, advantageously used to prepare complexes or associations useful according to the invention are those in which the cycle comprises 5 to 7 links and very particularly those of the following form:

where π is between 1 and 3 and where Z is oxygen, sulfur or a group -NR or -CHR in which R is made up:. hydrogen,. a linear or branched aliphatic hydrocarbon chain containing from 1 to 30 carbon atoms, preferably 16 to 20 and containing from 0 to 6 unsaturations,. a hydrocarbon chain containing up to 30 carbon atoms and including at least one aromatic or heteroaromatic ring, or. of a chain containing up to 50 carbon atoms, linear, branched or containing at least one ring and containing from 0 to 10 heteroelements, in particular of Oxygen, sulfur or nitrogen and from 0 to 10 rami¬ fications containing functions conferring a water-soluble character, for example free from acid, sulfate, phosphate, alcohol, or amino, ether, amide functions. When the two substituents on the nitrogen together form a ring, it is preferably a ring of morpholino, thiomorpholino, pyrrolidinyl, piperazinyl or homopiperazinyl type.

According to an advantageous variant, the ratio in number of moles of the metal derivative to the derivative of dithiocarbamic or dithiocarbamate type is 2.

Niobium is preferably at the oxidation state 5. e) complexes or associations of niobium at the oxidation state 4 or 5 with pyrocatechol derivatives: These complexes or associations advantageously result from the mixture or the reaction of a mole a niobium derivative with an oxidation state of 4 or 5 with 1 to 10 moles of a pyrocatechol derivative corresponding to your 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,

20

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 comprising C with 10 branches in C - C containing functions conferring a

'of water-soluble nature, for example acid, sulphate, phosphate, alcohol, amino, amide, ether, R and R functions' which may also represent - an OH group,

- a group SO ^ H,

- a P0-.H group,

Said active principle being incorporated in a pharmaceutically acceptable excipient, vehicle or support. 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 likely to form, by reaction of the two constituents contained in said association, in the body after administration of your pharmaceutical composition. According to an advantageous variant of the invention, the association contains 1 mole of niobium derivative for 1 to 4 moles of pyrocatechol or of pyrocathéchoL derivatives as defined previously. According to a variant of the invention, the pyro¬ catechol derivative is pyrocatechol itself (R "= R = R ¹ = H).

According to one 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 an alkyl chain linear or branched 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 is hydrogen. By way of example of such chains, mention will be made of linotenyl and linoleyl groups.

According to a variant, at least one of the two groups R and R ′ is hydrogen and the other is a linear or branched sequence containing an aromatic or heteroaromatic cycle which is evenly substituted. By way of example, mention will be made of nordihydroguaiaretic acid.

According to other variants, the R. and R ^{1 groups} may be linear or branched chains optionally including one or more rings and which may contain functions which confer in particular a certain water-soluble character on 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 ¹ contains an amino 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 γ-dopamine 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. By way of example of such products, mention will be made of ta 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-hydroxydiphenytalanine).

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 derivative of catechoL 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 that may be mentioned include gallates, in particular C 1 to C alkyl gallates, for example octylgallate or linoleylgallate.

According to other variants, the group R "is different from H and can be, in particular, an 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-aIcoxyphenoL 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, possibly 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 In the preceding examples of preferred complexes or mixtures which are useful according to the invention, the organic compounds intended to be complexed with a niobium derivative in certain cases comprise at least one linear or branched chain optionally including one or cycles 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, amide functions.

When such organic derivatives carrying the branching or heteroatom functions are not commercially available, the skilled person can prepare them 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 McO ie, Plénum Press, 1973 ). Thus: 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> perform the coupling of a branched alcohol (such as phytot, geraniol, farnesol, etc.), or of a primary or secondary amine by means of a coupling agent such as your 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, effect the coupling of a branched acid by means of '' 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 by means of 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 or The unsaturations of an unsaturated hydrocarbon chain of the substrate, for example the double bond of an oleyl derivative ine 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 function, an innate or free acid, one or more OH functions protected, for example by methoxyethoxyethyl groups, then Releasing 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) ₂ or of a CL-S0 ₂ (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 a function alcohol or amino of the substrate by means of Cl-CH ₂ "CH ₂ P0 0Na) ₂ or of CL-CH ₂ " CH ₂ S0 ₂ (0Na), f) When it is desired to obtain a derivative with a chain having functions acids, one can, for example, couple along a) a chain containing, in addition to an alcohol, amino or free acid function, one or more C00H functions protected in the form of tert-butyl ester, then Release The C00H 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 along a) a chain co Now, in addition to an alcohol, amino or free acid function, one or more primary amine or secondary amino functions protected, for example, by t-butyloxycarbononyL (BOC) groups, then release 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, an innate or free acid function, one or more thiol functions protected by groups Me, SîCH-, CH ₂ -, then liberating these SH functions by F ions. An important advantage of the complexes useful according to the invention is that they are generally formed easily by simple contacting of the organic ligand with the niobium derivative at the oxidation state 4 or 5. This reaction is most often carried out at room temperature or at a moderate temperature, generally less than 50 ° C.

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

As solvent, - your hydro-alcoholic mixtures will be mentioned, 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 C-C alcohols, ι 4 linear or branched, advantageously ethyl alcohol.

The reaction can also be carried out in suspension in an organic agent. For example, the THF may be mentioned, DMF, ^'the dichloro ethane. The organo-metallic complexes described above are used for the preparation of medicaments useful in the treatment or prevention of diseases such as diabetes, hypercholesterolemia, ypertriglyceridemia, "hyperlipidemia as well as complications associated with these pathologies. These complexes are also useful for the treatment and / or prevention of insulin resistance whether or not associated with any form of diabetes.

As mentioned above, niobium is found in oxidation state 4 or 5 in the mineral or organometallic derivatives useful according to the invention.

According to a particularly advantageous variant, it is found there in the oxidation state 5.

Furthermore, the Applicant has found, quite surprisingly, that the use of a mixture of a mineral derivative or of a niobium complex useful according to the invention with a mineral derivative or a complex of a derivative of vanadium in the oxidation state 4 or 5 made it possible to obtain antidiabetic effects at doses lower than what one might expect given the activity of each of the two derivatives or complexes. The invention therefore also relates to the use of a mixture of a niobium salt or complex with a degree of oxidation of 4 or 5 and a salt or corn- vanadium plex of oxidation state 4 or 5, as active material for the manufacture of a medicament useful for the treatment or prevention of disorders of the metabolism of carbohydrates and / or lipids, in particular of diabetes. As a synergistic mixture, mention may be made, for example, of the mixture of the niobium and vanadium complexes with proline, more particularly that of a mixture of a pro¬ line complex with te vanadium 4 and a complex of proline with nio¬ bium 5. The present invention therefore relates to the use of the complexes described above or to the mixture of their two constituents not yet complexed but capable of being added to the body after administration of the pharmaceutical composition for preparing a drug useful in the treatment and / or prevention of diabetes, hypercholesterolemia, hyper lipid and the complications associated with these pathologies as well as insulin resistance associated or not with a form of diabetes.

The pharmaceutical compositions containing the complexes or associations of the invention may be found in different forms. The niobium derivatives, in the form of salts, complexes or mixtures of the invention will be incorporated into an excipient, vehicle, or pharmaceutically acceptable carrier.

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 in a nonlimiting manner, 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 removal of the solvent, particularly when it is an organic solvent.

The pharmaceutical compositions can be administered in various manners, in particular by 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 local application, for example in the form of patches. Organo-metal tick associations advantageously represent from 5 to 80% by weight relative to the total weight of the pharmaceutical preparation, and are incorporated into an acceptable excipient, vehicle or pharmaceutical carrier compatible with the mode of administration. considered. 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. 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 salts and complexes useful according to the invention, the use of the different niobium derivatives for preparing pharmaceutical compositions and the effectiveness of the active material.

Example 1

Preparation of niobium oxalate:

A concentrated aqueous solution of Nb., 0, - is prepared, to which a saturated and hot solution of sodium monooxalate NaHC_0, is added. On cooling it precipitates monooxalate from sodium that is filtered. This solution is then left under the extractor hood until about two-thirds of the water has evaporated. The colorless crystals which appear are filtered, washed with alcohol and dried under vacuum.

Example 2

Preparation of niobium tartrate:

An aqueous solution of Nb ^ O _t - is prepared, to which a solution of ammonium monotartrate C, H _g 0, N is added. This solution is then heated to 85 ° C. for 2 h while allowing the water to evaporate. When cooling by a water-ice bath nothing precipitates. The solution is then concentrated under vacuum to approximately 10 ml, and precipitated by addition of alcohol. The precipitate is filtered and washed with alcohol, then dried under vacuum.

Example 3

Preparation of a niobium alcoholate:.

A solution of 5 mmol of NbCL,: THF is poured into anhydrous THF under nitrogen, onto a suspension in hexane, of 20 mmol of the lithium alcoholate of the phytol, alcoholate prepared in situ will precede by addition to 0 C of 20 mmol of nBuLi on 20 mmol of phytol. This solution is then heated to 45 ° C. for 2 h. The solvents are then evaporated under vacuum and the product is dried at 40 ° C. with a vane pump.

Example 4

Preparation of a mixed complex of niobium ethanolate and pro- linol:

A solution of 2 mmol of Nb (OEt), - in toluene is prepared, to which a solution of 4 mmol of 2-pyrroLidine methanoL in toluene is added. This solution is then heated to 85 ° C. for 5 h. When cooling by a water-ice bath nothing precipitates. The solution is then evaporated in vacuo at this temperature. Example 5

Preparation of a niobium catechotate:

A solution of 2.5 mmol of NbCl 2 in anhydrous toluene is heated to reflux under nitrogen, then 20 mmol of recrystallized catechot are added thereto. This solution is then heated to 85 ° C. for 16 h. While cooling it precipitates red needles. The whole is placed in the cold (+ 6 ° C.) for 48 h, then the precipitate is filtered, which is washed with hexane, then dried under vacuum.

Example 6

Preparation of a niobium and pyridine complex:

An excess of pyridine is added to a solution of 5 mmol of NbCl 3: THF in absolute ethanol. The mixture is left to stir overnight, then it is cooled to 0 ° C. and the red precipitate which forms is filtered. This precipitate is dried under vacuum at 30 C.

Example 7

Preparation of a niobium derivative with diethylcarbamadithioic acid: 1.25 mmol NbCl 3: THF is reacted with 5 mmol of

And _? NCS-, Na in 35 ml of acetonitrile for 2 h, then the solvent is evaporated in vacuo. The dark purple compound obtained is dried at 50 ° C. under vacuum of the vane pump.

Example 8

Preparation of a niobium and diethylamine complex:

4 equivalents of diethylamine are added to an aqueous solution of Nb_0 _ς (freshly prepared ⁾ . The mixture is left under agitation for 4 hours, then the water is evaporated at 70 ° C. on a rotary evaporator.

Example 9

Preparation of a niobium and oteylamine complex:

2 equivalents of an alcoholic solution of oteylamine are added to an aqueous solution of Nb_0, -. The mixture is left to stir overnight, then the water is evaporated at 45 ° C. under vacuum. Example 10

Preparation of a niobium derivative with an aminodiol:

2 equivalents of an aqueous solution of 2,3-hydroxypropylamine are reacted with an aqueous solution of Nb_0--. The mixture is brought to reflux overnight, then the water is evaporated at 60 ° C. under vacuum from the water pump. The compound obtained is then dried at 55 ° C. under vacuum of the vane pump.

Example 11 Preparation of a proline complex with niobium 5:

In a solution of anhydrous THF and under nitrogen, 25 millimoles of L-proline (2.875 g ^{) are} suspended, then 5 millimoles of NbC (1.35 g ⁾ are added all at once. The resulting yellow solution becomes darker and darker very quickly (orange, then red, then brown, then black with blue reflections) as the proline dissolves. Then it discolours very quickly until it becomes very slightly yellow. A little methanol is added, then the solvents are evaporated in vacuo (water pump) while heating to 40 C. The vacuum drying of the vane pump is perfect, at 75 C. This results in a very fine yellow film- clear on the ball, practically unstuck. To recover the product, it is dissolved in 50 ml of water and it is transferred to a bottle, where it solidifies into a kind of white gelatin.

Example 12

Preparation of a proline salt with niobium 4:

20 millimoles of L-proline (2.3 g) are suspended in a solution of anhydrous THF and under nitrogen, and then 5 millimoles of the complex of niobium chloride with THF, ie NbCL.rTHF, are added all at once. 1.895 g). The resulting red-ocher solution quickly becomes darker (brown-black with yellow-green reflections). A little methanol is added, then the solvents are evaporated under vacuum (water pump) while heating to 40 C. This results in a very hygroscopic dark gummy product. Example 13

Preparation of pyrazole complexes with niobium 5:

2.5 mmol (0.675 g) of NbCl- is added. dissolved in 15 ml of THF in a solution of anhydrous THF under nitrogen containing 0.851 g ⁽ 12.5 mmol) of pyrazole. The mixture obtained turns dark yellow very quickly. After 2 h of stirring, the solvent is evaporated, then dried with a vane pump at 45 ° C. for 3 h.

Example 14 Preparation of cytosine complexes with niobium 5:

5 mmol of cytosine (0.556 g) are suspended in 20 ml of anhydrous THF under nitrogen, then 15 ml of a - THF solution containing 2.5 mmol of NbCl, - (0.675 g) are added. All white precipitate in suspension gradually becomes yellow. After 3 h, methanol is added, the mixture is then transformed into a white gel.

Example 15

Preparation of 1/1 complexes of inositot hexaphosphate (acid, phytic) and niobium:

2.5 mmol of niobium pentobloride Nb (Cl) - are added to 10 ml of anhydrous THF in which 2.5 mmol of the sodium salt of phytic acid is suspended. (0.675 g ⁾ dissolved in 15 ml of THF. The yellow solution turns white and a white powder remains in suspension. After 2 h of stirring, 15 ml of MeOH are added. Then evaporate your solvents on a rotary evaporator.

Example 16

Formulation in any pharmaceutically acceptable diluent or excipient: a) Free of composition for oral administration:

A metal complex prepared according to any one of Examples 1 to 15 is mixed in a grinder at a rate of 10 to

5,000 nanomoles of metal (preferably 20 to 250 nanomoles), to a sugar polymer, for example dextran or cellulose, with zinc stereate, in amounts sufficient to achieve a 100 milligram tablet, which is then coated with gum arabic 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 15 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 mi LLi liters), 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 base acids, or mineral salts made up of elements found in the blood, preferably 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 15 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 17 Determination of a hypoglycemic effect:

The injection of 60 mg / kg of streptozotocin intravenously into the rat causes, within 24 hours of the injection. Induction of a 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 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 your observation period, your animals, divided into 3 cages, receive food and drinking water a_d_ libitum and are subjected to a temperature between 21 and 23 C and a day / dark cycle of 12 h.

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

Animals weighing an average 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 niobium derivatives and complexes were administered under the following injection conditions: rats were administered doses corresponding to 120 micromoles of niobium per kg the first two days and 60 micromoles per kg the following 13 days.

The glycemia control is carried out in the morning at 9 a.m., the time of your day when your glycemia of 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 days of treatment. A significant and significant drop in blood glucose 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 equal reduction noticeably significant of polyphagia and polydipsia, which are manifested from the first days. Food and water consumption cover values tending to approach those of non-diabetic control rats. The figures appended in the appendix give the consumption of water, food and the evolution of the glycemia of rats treated with different derivatives of niobium.

The results are represented, for each derivative, 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 derivatives useful 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 niobium sulphate corresponding to the formula (NH ,), Nb (S0,), and referenced "sulfate" in the figures, 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 4 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 rate of blood sugar over time for a batch of diabetic rats treated with the product of Example 7 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 11 in comparison with the results obtained for a batch of untreated diabetic rats. Figures 5a, 5b and 5c respectively show the variations in water, food consumption and the variations of the blood sugar level over time for a batch of diabetic rats treated with the product of Example 13 in comparison with the results obtained for a batch of untreated diabetic rats.

FIGS. 6a, 6b and 6c 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 14 in comparison with the results obtained for a batch of untreated diabetic rats.

FIGS. 7a, 7b and 7c 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 free from you in comparison with The results obtained for a batch of untreated diabetic rats.

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.

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

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, 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 animals and their behavior, also shows the positive effect of the treatment. Measuring cholesterol and triglyceride levels also shows improvement.

Like humans, diabetic rats develop metabolic disorders (hypercholesterolemia, hyperlipid ie, hypertriglyceridemia ...) as well as pathologies such as hypertension, arteriosclerosis, heart failure, peripheral ischemia, or ocular pathologies progressing towards blindness.

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

Claims

1. Use of niobium derivatives in the oxidation state 4 or 5 as active principle for the manufacture of medicaments useful in the treatment and / or prevention of disorders of the metabolism of carbohydrates and / or lipids.

2. Use according to claim 1, characterized in that the niobium derivative in the oxidation state 4 or 5 is an inorganic derivative.

3. Use according to claim 2, characterized in that said mineral derivative is soluble in water.

4. Use according to claim 3, characterized in that the mineral derivative soluble in water leads to solutions of pH between 3 and 9, preferably close to 7.

5. Use according to claim 1, characterized in that the niobium is in the form of an organic derivative where the niobium is in the oxidation state 4 or 5, ^' said derivative being an organic set or an organic complex.

6. Use according to claim 5, characterized in that said organic derivative contains at least one hetero atom or an electro-donor function.

7. Use according to claim 5 or 6, characterized in that the organic derivative is a complex with a ligand carrying at least one free electronic doublet.

8. Use according to one of claims 5 to 7, characterized in that the niobium derivative is a salt or a complex with an organic product belonging to the family of amines, polya ines, alcohols, polyols, sugars, polymers sugars, nucleotides, thiols, amino acids, amino alcohols, guanines, oxymes, 1,3-diketones, carboxylic, phosphoric, sulfuric, carboxydithioic, carbamadithioic, phenols, catechols, Schiff bases, proteins, peptides, polyfunctional derivatives containing hetero atoms like Oxygen, Sulfur, nitrogen, rings containing these hetero atoms.

9. Use according to claim 1, characterized in that the niobium derivative is complexed with an organic ligand or mixed with such a ligand, said mixture being capable of being counted in the body after administration of the drug.

10. Use according to claim 9, characterized in that the ligand is inositoL, an inositoL phosphate or one of their derivatives.

11. Use according to claim 9, characterized in that Ligand is an amino acid or an amino acid derivative.

12. Use according to claim 9, characterized in that the ligand is an organic compound containing a ring containing at least two nitrogen atoms.

13. Use according to claim 9, characterized in that the Ligand is pyrocatechol or one of its derivatives.

14. Use according to claim 9, characterized in that the ligand is a derivative of dithiocarbamic acid or its salts.

15. Use according to one of claims 1 to 14, characterized in that the niobium derivative is mixed with a salt or complex of vanadium is at the oxidation state 4 or 5.

16. Use of a mixture of niobium complexes with degree of oxidation 4 or 5 with proline and complexes of vana¬ dium with degree of oxidation 4 or 5 with proline as active ingredient for the manufacture of a medicament useful for the treatment of diabetes.

17. Use according to one of claims 1 to 16, characterized in that said medicament is useful for the treatment of diabetes.

18. Use according to one of claims 1 to 16, characterized in that said drug is useful for the treatment or prevention of diabetes, hyperchoLesteroLemie, hyperlipidemia or ¹ hypertriglycerideππ ^' e complications associated with these pathologies.

19. Use according to one of claims 1 to 16, characterized in that said medicament is useful for the treatment and / or prevention of insulin resistance.

20. Use according to one of claims 1 to 19, characterized in that the niobium is at the oxidation state 5.