FR2686603A1 - Organometallic complexes of niobium or vanadium with derivatives of dithiocarbamic acid and of its salts, and pharmaceutical composition containing these complexes or their constituents - Google Patents

Abstract

The invention relates to organometallic complexes of vanadium or niobium, resulting from the reaction of 1 mol of metal derivative of vanadium or niobium, where the metal is found at the 4 or 5 oxidation state, with 1 to 3 mol of a dithiocarbamic acid or derivative of dithiocarbamic or of its salts including a group where M is hydrogen, an alkali metal or an ammonium or alkylammonium group, it being possible for the said alkylammonium to contain one, two, three or four C1-C4 alkyl groups. It also relates to pharmaceutical compositions containing the said complexes as active principle.

Description

Organometallic complexes of niobium or vanadium with derivatives of dithiocarbamic acid and its salts and pharmaceutical composition containing these complexes or their constituents
The present invention relates, as new industrial products, to organometallic complexes of niobium or vanadium with derivatives of dithiocarbamic acid and its salts.

 It also relates to a process for the preparation of these complexes. It also relates to their use for the manufacture of pharmaceutical compositions containing these complexes.

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

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

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

 Japanese patent JP 2 292 217 describes an antidiabetic activity for 7 vanadyle-dioxo complexes (tartrate, gluconate, malonate, oxalate, lactate, salycilate and acetyl-acetonate), as well as for 2 vanadyle-monoamino-monothio complexes: the L complex 'methyl ester of cysteine with vanadyl and that of 2-amino-ethane-thiol.

 Furthermore, the applicant has described in its international applications W091 / 07406 and W091 / 13892 as well as in its French application not yet published and filed under number 91 06174 organometallic complexes of transition metals with porphyrin structures useful in particular in the treatment of hyperglycemia.

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

 A bibliographic review with 198 references on "The Bioinorganic Chemistry of Vanadium" was recently carried out by Dieter Rehder, (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 equilibrium species. Thus, Vanadate, or vanadium is at oxidation state 5, depending on the pH and the concentration, can be in several monomeric forms (polycoordinated with solvent or Ligands), or polymeric, with one or more charges .

Thus, with hydroxyl derivatives of the HO-R form, vanadate spontaneously forms mono-, di- and tri-esters (CR0) VO (OH) x) which coexist in equilibrium. The geometry of
x 3-x coordination is also very diverse, the degree of coordination generally going from 4 to 7 (sometimes 8) and the same ligand which can coordinate the metal in an axial or equatorial position and giving rise to tetragonal pyramids, trigonal bipyramides, pentagonal or octahedrals, etc.

It is the same for vanadyLe, in which vanadium is in oxidation state 4, as shown in particular by J. Costa Pessoa et al., Polyhedron, 1988, 7, 1245-1262 and
Polyhedron, 1989, 8, 1173-1199, depending on the pH and the concentration if we note LH an amino acid like serine (alanine, threonine, etc.) and M the metal (VO ++ in this case), it can coexist one or more of the following species: MLH, ML, MLH 2 '
MLH ML2H2, ML2H, ML2, ML2H ~ 1 t ML2H-2 'M2L2H, M2L2H3, etc., as well as some hydrolysis or hydration products.

Various organometallic derivatives of dithiocarbamates are known, as well as their applications as cytostatic, antitumor and anticancer agents. These are mainly platinum and tin salts. Particular reference is made to the following documents: V. Scarcia et al, Metal Ions in Biology and
Medicine, Ed. Ph. Collery, LA. Poirier, M. Manfait, JC Etienne,
John Libbey Eurotest, Paris, 1990, 511-513; RA Bulman,
Structure and Bonding, The Chemistry of Chelating Agents in
Medicinal Sciences, Springer-Verlag Berlin Heidelberg, no 67, 1987, 130-131.

 However, to date, no complex of vanadium or niobium with derivatives of dithiocarbamic acid has been described.

 The Applicant has synthesized such complexes and found that, in particular, those in the form of substituted dithiocarbamates had remarkable bioavailability and could be used as active ingredient in pharmaceutical compositions, in particular intended for the treatment of diabetes.

 In particular, the applicant has discovered that the complexes of vanadyle and pyrrolidinecarbamadithioic acid or diethylcarbamadithioic acid are quite remarkable, in that they correct (reduce to normoglycemia) between 83 and 100% of diabetic animals treated, while the vanadium salt used to prepare them (vanadyl sulfate is a model substance in the literature) corrects only 33% at the same dose of metal and under the same conditions of biological tests in vivo.

 A particular advantage of the new complexes is their remarkable ease of synthesis which also makes it possible to envisage, for the therapeutic uses of these complexes, a formation of said complexes in vivo in the organism from a pharmaceutical composition containing the two types of constituents. in mixture.

By "complexes" in the present invention is meant the reaction products of the dithiocarbamate derivative and of the metallic derivative; these are generally mixtures since it is known that the metallic derivatives, in particular those of vanadium as has been exposed previously, lead to a mixture of complexes corresponding to the fixing by Liai sounds with 1 and / or 2 electrons d '' a variable number of heteroatoms depending on the ligand envisaged and whose spatial arrangement around the metal and
The degree of coordination of the metal can vary.

où M est de l'hydrogène, un métal alcalin, un groupement ammonium ou alkylammonium, Ledit alkylammonium pouvant être un mono-, di-, tri- ou tétraalkyl en
C1-C4.According to an essential characteristic of the invention, it relates, as new industrial products, organometallic complexes of vanadium or niobium characterized in that they result from the reaction of 1 mole of vanadium or niobium derivative where the metal is at the oxidation state 4 or 5 with 1 to 3 moles of a derivative of dithiocarbamic acid or of its salts including a group

where M is hydrogen, an alkali metal, an ammonium or alkylammonium group, said alkylammonium possibly being a mono-, di-, tri- or tetraalkyl in
C1-C4.

 The term “derivatives of dithiocarbamic acid and of dithiocarbamates” means derivatives in which one or both of the hydrogen atoms carried by the nitrogen atom have been substituted by independent groups as well as products in which 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.

ou

ou: -M est de L'hydrogène, un métal alcalin, un groupement ammonium ou mono-, di-, tri- ou tétraalkylammonium en C1-C4.According to another variant, they will be in the form of an ammonium or alkylammonium salt, in particular of mono-, di-, triou tetraalkylammonium, the allyl being advantageously an alkyl in
C1 to C
According to an advantageous variant of the invention, the derivatives of dithiocarbamic acid giving complexes according to
The invention will take one of the following forms:

or

or: -M is hydrogen, an alkali metal, an ammonium or mono-, di-, tri- or tetraalkylammonium group in C1-C4.

 -n is an integer between 1 and 3.

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

-R and R 'are
- hydrogen,
- a linear aliphatic hydrocarbon chain or
branched containing from 1 to 30 carbon atoms,
preferably 16 to 20 and containing from 0 to 6 unsatura
tions,
- a hydrocarbon chain containing up to 30 atoms
carbon and including at least one aromatic ring or
heteroaromatic,
or - a chain containing up to 50 carbon atoms,
linear, branched or containing at least one cycle and
containing O to 10 heteroelements, in particular of
oxygen, sulfur or nitrogen and O to 10 ramifica
containing functions conferring a character
water-soluble, for example acid, sulfate functions,
phosphate, alcohol, amine, ether, amide.

 According to a variant, the dithiocarbamic derivative is a product of family I.

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

By way of example of such products, mention will be made
Diisobutylcarbamadithioic acid, the sodium salt of Dioctylcarbamadithioic acid.

 The nitrogen atom can also carry one or two mono- or polyunsaturated chains, mention will be made, for example, of mono oleylcarbamadithioic acid.

 The groups carried by the nitrogen atom of the dithiocarbamate or of the derivative of dithiocarbamic acid can also comprise an aromatic or heteroaromatic cycle.

 Examples include dibenzyLcarbamadithioic acid and its salts.

 The groups carried by the nitrogen atom of the dithiocarbamate can also contain heteroelements or carry functions conferring a certain water-soluble character.

As we saw earlier, in other variants of
The invention, the two hydrogens of dithiocarbamic acid or dithiocarbamate are substituted by two groups together forming a ring.

où n est compris entre 1 et 3 et où Z est de l'oxygène, du soufre ou un groupement -NR ou -CHR dans lequel R est constitué d'hydrogène,
d'une chaîne hydrocarbonée aliphatique linéaire ou
ramifiée contenant de 1 à 30 atomes de carbone, de
préférence 16 à 20 et contenant de O à 6 insaturations,
d'une chaîne hydrocarbonée contenant jusqu'à 30 atomes
de carbone et incluant au moins un cycle aromatique ou hété roa romati que,
ou . d'une chaine contenant jusqu'à 50 atomes de carbone,
linéaire, ramifiée ou renfermant au moins un cycle et
renfermant de O à 10 hétéroéléments, en particulier de
l'oxygène, du soufre ou de L'azote et de O à 10 rami
fications contenant des fonctions conférant un carac
tère hydrosoluble, par exemple des fonctions acide,
sulfate, phosphate, alcool, ou amine, éther, amide.Among the derivatives cited above, advantageously will be used to prepare complexes according to the invention those in which the cycle comprises 5 to 7 links and very particularly those of the following form

where n is between 1 and 3 and where Z is oxygen, sulfur or a group -NR or -CHR in which R consists of hydrogen,
a linear aliphatic hydrocarbon chain or
branched 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 atoms
of carbon and including at least one aromatic or hetero ring roa romati que,
or . a chain containing up to 50 carbon atoms,
linear, branched or containing at least one cycle and
containing from O to 10 heteroelements, in particular from
oxygen, sulfur or nitrogen and O to 10 rummy
fications containing functions conferring a charac
water-soluble tere, for example acid functions,
sulfate, phosphate, alcohol, or amine, ether, amide.

 When the two substituents on the nitrogen together form a ring, it is preferably a ring of the morpholino, thiomorpholino, pyrrolidinyl, piperazinyl or homopiperazinyl type.

 According to a variant of the present invention, the ratio in number of moles of the dithiocarbamic or dithio-carbamate type derivative to the metal derivative is 2.

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

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

 According to a second object, the present invention relates to the preparation of the complexes previously defined.

 The dithiocarbamate or dithiocarbamic derivatives previously defined, when they are not commercial, are easily synthesized by methods known to those skilled in the art, one of the preferred synthesis methods being the reaction of a primary or secondary, linear amine. or cyclic on carbon disulfide (CS2) in the middle place.

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

So :
a) when it is desired to obtain a derivative with a branched hydrocarbon chain, it is possible for example
- on an acid function of the substrate, carry out the coupling of a branched alcohol (such as phytol, geraniol, farnesol, etc.), or of a primary or secondary amine by means of a coupling agent such as DCC , or, in the case of fatty alcohols, by esterification in a dehydrating medium (azeotropic removal of water),
- on an amine or alcohol function of the substrate, carry out the coupling of a branched acid by means of a coupling agent such as DCC, or by reaction with an acid anhydride,
- on an amine function (or an alcohol function transformed into an alcoholate) of the substrate, perform the coupling using a branched halogenated derivative (such as farnesyl or geranyl bromide, etc.),
b) when it is desired to obtain a derivative with a chain having ether or thioether functions, it is possible, for example, to esterify an acid function of the substrate, for example by hexaethylene glycol, or to alkylate an amine function of the substrate by a chain halogenated polythioether,
c) when it is desired to obtain a derivative with a chain having alcohol functions, it is possible, for example, to hydrate in alcohol or to oxidize in diol the or the unsaturations of an unsaturated hydrocarbon chain of the substrate, for example the double bond d 'an oleylamine derivative by H30 or by KMnO4.

It is also possible to couple according to a) a chain containing, in addition to an alcohol, amine or free acid function, one or more OH functions protected, for example by groups (methoxyethoxyethyl), then liberating 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-
PO (OR) 2 or a CL-SO2 (OR), R being, for example, a Me, Et,
Benzyl,
e) when it is desired to obtain a derivative with a chain having sulfonate or phosphonate functions, it is possible, for example, to transform an alcohol or amine function of the substrate by means of CL-CH2-CH2PO (ONa) 2 or of CL- CH2-CH2SO2 (ONa),
f) when it is desired to obtain a derivative with a chain having acid functions, it is possible, for example, to couple along a) a chain containing, in addition to an alcohol, amine or free acid function, one or more COOH functions protected in the form of tert-butyl ester, then release the COOH functions in mid acid place.

 g) when it is desired to obtain a derivative with a chain having amine functions, it is possible, for example, to couple along a) a chain containing, in addition to an alcohol, amine or free acid function, one or more primary amine or amine functions secondary protected, for example, by t-butyloxy carbonyl (BOC) groups, then release the amine functions in mid acidic place.

In the case of tertiary amines these do not need to be protected, for example, one can couple ENTA (by any one of its acid functions) to an amine 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 along a) a chain containing, in addition to an alcohol, amine or free acid function), one or more thiol functions protected by Me3SiCH2CH2- groups, then release these SH functions by F ions
The complexes which are the subject of the present invention are easily prepared by simple contacting of the dithiocarbamic or dithiocarbamate type derivatives defined above with the metal derivatives either in solution or in the solid state or dispersed in an organic solvent.

 The complexation reaction will advantageously be carried out in a common solvent for the two reactants, advantageously in water or a hydroalcoholic mixture when the two reactants are soluble in such a medium.

 It is therefore advantageously possible, if the metal derivative and the dithiocarbamic or dithiocarbamate type derivative are soluble in such a medium, carry out the reaction in water or an hydroalcoholic mixture, for example a mixture containing from 100 to 70% of water for O to 30 X alcohol. The alcohol used in the constitution of the alcoholic environment will be a C1 to C4 alcohol, linear or branched, advantageously ethyl alcohol.

 The metallic derivative can also be reacted with a suspension of the dithiocarbamoqie or dithiocarbamate type derivative in an organic agent.

 As an example of organic agents which can be used to suspend the dithiocarbamic or dithiocarbamate type suspension, THF, ethers, C5-C81 alkanes, DMF, advantageously THF or DMF, will be chosen.

 The metallic derivative will advantageously be an oxide, a halide, an oxyhalide, a sulphate, or a metallate, for example an alkali metal or ammonium metallate of the metal considered, an acetylacetonate, an acetate or a hydrate or a complex with a solvent. of these metal derivatives.

By way of examples of metal derivatives used for the preparation of the complexes according to the invention, mention will be made by designating by acac an acetylacetonate group and by OAc the acetate group VOS04, VCl4, VOCl2, VO (OAc) 2, VO (acac) 2, VOCl3, V205,
Na3VO4, K3V04, NaV03, H4NV03, NbCl4, NbCl5, Nb205, as well as their hydrates, for example VOSO415H2O, or Their complexes with a solvent, for example with water, THF, for example NbCl4, THF, Ether, ethylene glycol, and etc.

 The proportions between the metal derivative and the dithiocarbamic or dithiocarbamate type derivative are those set out above, that is to say from 1 to 3 moles of dithiocarbamic or dithiocarbamate type derivative per mole of metal derivative, advantageously 2 moles of derivative of dithiocarbamic or dithiocarbamate type per mole of metal derivative.

 According to another object, the invention relates to pharmaceutical compositions containing the complexes described above as active ingredient.

 As we have seen previously, and as is apparent from the examples which follow, these complexes are very easily formed.

 Thus, according to a variant of the invention, it also relates to pharmaceutical compositions containing the mixture of metallic derivative and dithiocarbamic or dithiocarbamate derivative in the proportions in which they form the complexes according to the invention, said complexes then forming in vivo in the organism during the administration of the pharmaceutical composition.

 According to another object, the present invention relates to the use of the complexes defined above for the manufacture of medicaments useful in particular for the treatment and prevention of metabolic diseases.

 Among these diseases, mention will be made more particularly of diabetes, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia and the complications associated with these pathologies.

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

 According to an advantageous variant of the invention, the vanadium is at the oxidation state 4.

 According to another advantageous variant of the invention, niobium has an oxidation state of 5.

 According to another variant, the compositions contain a mixture of vanadium and niobium complexes.

 The pharmaceutical compositions containing the complexes of the invention may be in different forms.

 The complexes of the invention will be incorporated into a pharmaceutically acceptable excipient, vehicle or support.

 As pharmaceutically acceptable excipients, vehicles or supports, 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: lactose, corn starch, glucose, gum arabic, stearic acid or magnesium stearate, dextrin, mannitol, talc, oils of natural origin rich in essential unsaturated fatty acids, etc. In particular, if this proves to be necessary, it is possible to use other additives well known to those skilled in the art such as stabilizers, desiccants, binders, pH buffers, etc.

 An advantage of the complexes according to the invention is that they can be used directly without prior purification other than the removal of the solvent.

 The compositions of the invention can be administered in various ways, 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 the form of patches.

 The organometallic complexes according to the invention advantageously represent from 5 to 80% relative to the total weight of the pharmaceutical preparation, which corresponds to a total metal content of 10 to 10,000 nanomoles per dose.

 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 examples which follow are given by way of illustration and in no way limit the invention. They illustrate the synthesis of the complexes of the invention, the preparation of pharmaceutical compositions comprising them and the biological effect of these derivatives,
Examples
Example l
Preparation of a V4 derivative with dimethylcarbamadi thionic acid:
2.5 mmol of vanadyl sulfate is dissolved in water, and an aqueous solution containing 5 mmol of the sodium salt of dimethylcarbamadithioic acid is added to it. The water is then evaporated at 50 ° C. under vacuum.

Example 2
Preparation of a V4 derivative with diethylcarbamadi thioic acid:
5 mmol of vanadyl sulfate are dissolved in water, and an aqueous solution containing 10 mmol of the sodium salt of diethylcarbamadithioic acid is added to it. The water is then evaporated at 50 ° C. under vacuum.

Example 3
Preparation of a V4 derivative with dibenzylcarbamadi thionic acid:
2.5 mmol of vanadyl acetate (VO (OCOMe) 2) are dissolved in water, and an aqueous solution containing 5 mmol of the sodium salt of dibenzylcarbamadithioic acid is added to it. The water is then evaporated at 500C under vacuum.

Example 4
Preparation of a V4 derivative with 4-morpholinocarbama dithiolque acid
2.5 mmol of vanadyl sulfate is dissolved in water, and a morpholine solution containing 5 mmol of the lithium salt of 4-morpholinocarbamadithioic acid is added to it. The solvents are then evaporated at 600C under vacuum.

Example 5
Preparation of a V4 derivative with 4-thiomorpholinocarbama dithioic acid
1 mmol of vanadyl sulfate is dissolved in water, and a morpholine solution containing 2 mmol of the potassium salt of 4-thiomorphoiinocarbamadithioic acid is added to it. The solvents are then evaporated at 65 ° C. under vacuum.

Example 6
Preparation of a V4 derivative with pyrrolidinecarbama dithioic acid
5 mmol of vanadyl sulfate are dissolved in water, and an aqueous solution containing 10 mmol of the ammonium salt of pyrrolidinecarbamadithioic acid is added thereto. The solvents are then evaporated at 60 ° C. under vacuum.

Example 7
Preparation of a V4 derivative with methyl-4-piperazinylcar bamadithioic acid
2.5 mmol of vanadyl sulfate is dissolved in water, and an ethanolic solution containing 5 mmol of the sodium salt of 4-methyl-piperazinylcarbamadithioic acid is added thereto. The solvents are then evaporated at 50 ° C. under vacuum.

Example 8
Preparation of a V4 derivative with Madithioic 4-homopiperazinylcarba acid
An aqueous solution containing 1 mmol of VOS04.5H20 is added to a hydroalcoholic solution containing 2 mmol of the diethylammonium salt of 4-homopiperazinylcarbamadi thionic acid, then heated to 40 ° C. for 1 h, and finally placed under vacuum.

Example 9
Preparation of a niobium derivative with diethylcarbamadithioic acid
1.25 mmol of Nb205 is reacted with 5 mmol of
Et2NCS2NH4 and 2.5 mmol of Na2CO3 in 100 ml of water at reflux for 12 h, then the solvent is evaporated in vacuo. The compound obtained is dried at 400C under vacuum of the vane pump.

Example 10
Preparation of a V5 derivative with diethylcarbamadi thioic acid
10 mmol of sodium salt of diethylcarbamadithioic acid are dissolved in anhydrous DMF with 10 mmol of Et3N, then 5 mmol of VOCAL3 at -1OOC is added, the solution is stirred for 2 h while allowing the temperature to rise slowly. The solvent is then evaporated under vacuum at 55 C.

Example 11
Preparation of a carbamadithioic derivative of oleylamine, then preparation of the V4 salt
An ethanolic solution of 25 mmol of oleylamine is stirred for 12 h with 50 mmol of CS2 and an excess of potassium hydroxide. An isopropanol-hexane mixture is added. The solution is filtered, and the solvents and excess CS2 are then evaporated in vacuo. The potassium salt of oleylcarbamadithiolic acid thus obtained is then complexed with vanadyl sulfate in hydroalcoholic solution.

Example 12
Preparation of a niobium IV derivative with dibenzylcarbamadithioic acid
1.25 mmol NbCl4: THF is reacted with 2.5 mmol of (C6H5-CH2) 2NCS2Na in 100 ml of acetonitrile for 12 h, then the solvent is evaporated under vacuum. The compound obtained is dried at 400C under vacuum of the vane pump.

Example 13
Formulation in any pharmaceutically acceptable diluent or excipient a) Example of composition for oral administration
A metal complex prepared according to any one of Examples 1 to 12 is mixed in a mill, in an amount of 10 to 5000 nanomoles of metal (preferably from 20 to 250 nanomoles), with a sugar polymer, for example dextran or cellulose, with zinc stereate, in sufficient amounts to make a 100 milligram tablet, which is then coated with gum arabic and sorbitan monosterate. Advantageously, gastro-resistant gel capsules based on gelatin, titanium dioxide and cellulose ester can be prepared.

b) Example of composition for administration by injection
A metal complex prepared according to any one of Examples 1 to 12 and which is soluble in water, is dissolved in an amount of 20 to 10,000 nanomoles of metal (preferably 50 to 500 nanomoles), in 1 to 10 milliliters of sterile deionized water (preferably 2 to 4 milliliters), then it is adjusted in pH and mineral salts so as to be as close as possible to the physio serum
Logic (pH 7.4 and 9 g / l), with base acids, or mineral salts made up of elements found in the blood, preferably H, HO, Na, Cl c) Example of composition for local application
A metal complex prepared according to any one of the preceding examples 1 to 12 is emulsified, micronized or suspended in an amount of 0.1 to 100 micromoles of metal (preferably from 1 to 20 micromoles), in a water emulsion, glycerol, mono-, diet triglycerides of fatty acids, and fatty alcohols.

Example 14
Determination of a hypoglycemic effect:
The injection of 60 mg / kg of streptozotocin intravenously into the rat causes, within 24 hours of the injection, the induction of stable, irreversible and insulin sensitive diabetes mellitus. Subsequent hyperglycemia can be reduced by the administration of substances with hypoglycaemic properties.

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

 The animals are kept under observation for 4 days before the start of the tests. At the start of the test, the animals weigh on average 180 g. During the observation period, the animals, divided into cages of 3, receive food and drinking water ad libitum and are subjected to a temperature between 21 and 230C and to a day / dark cycle of 12 h.

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

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

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

The glycemia control is carried out in the morning at 9 a.m., the time of the day when the glycemia of the diabetic control or treated rats, subjected to large variations during the day, is the highest. Diabetic rats receive only the excipient (physiological saline) and serve as diabetic controls; Finally, "white control" rats of the same weight, which have not received an injection of streptozotocin are kept in order to compare the consumption of water and food. b) Results
The daily glycemic control did not allow us to highlight the hypoglycemic effect during the first two days of treatment. A significant and significant drop in blood sugar compared to that of control rats appears from the following days and is maintained in most cases even after treatment is stopped, which is accompanied by an equally significant reduction in polyphagia and polydipsia, which they manifest from the first days. Consumption of food and water overlaps tending to approach that of non-diabetic control rats.

 The consumption of water, food and the evolution of the glycaemia of the rats treated with the complexes of examples 2, 3, 6, 7, 9 are given here.

 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 2 in comparison with the results. obtained for a batch of untreated diabetic rats.

FIGS. 2a, 2b, 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 3 in comparison with the results. obtained for a batch of untreated diabetic rats
FIGS. 3a, 3b, 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 ss in comparison with the results. obtained for a batch of untreated diabetic rats
FIGS. 4a, 4b, 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 7 in comparison with the results. obtained for a batch of untreated diabetic rats
FIGS. 5a, 5b, 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 9 in comparison with the results. obtained for a batch of untreated diabetic rats
There has been a marked decrease in food and water consumption accompanied by a significant drop in
Glycemia.

 It will be noted that the values given in the examples are averages obtained for the whole of a lot.

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

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

 Furthermore, it should be noted that 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.

 Like humans, diabetic rats developing metabolic disorders (hypercholesterolemia, hyperlipidemia, hypertriglyceridemia ...) as well as pathologies such as hypertension, arteriosclerosis, heart failure, peripheral ischemia, or even eye pathologies progressing to blindness.

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

Claims (17)

 1. Organometallic complexes of vanadium or niobium, characterized in that they result from the reaction of 1 mole of metal derivative of vanadium or niobium where the metal is in the oxidation state 4 or 5 with 1 to 3 moles d 'a dithiocarbamic acid or derived from Dithiocarbamic acid or its salts including a group

 where M is hydrogen, an alkali metal, an ammonium or alkylammonium group, said alkylammonium can be a mono-, di-, tri- or tetraalkyl C1-C4.  2. Complexes according to claim 1, characterized in that the nitrogen atom of the derivative of dithiocarbamic acid or of its salts carries two groups R and R 'which are identical or different representing independently  hydrogen,  a linear or branched aliphatic hydrocarbon chain  containing 1 to 30 carbon atoms, preferably  rence 16 to 20 and containing from O to 6 unsaturations,  - a hydrocarbon chain containing up to 30 atoms of  carbon and including at least one aromatic cycle or  heteroaromatic,  I a chain containing up to 50 carbon atoms,  linear, branched or containing at least one cycle and  containing O to 10 heteroelements, in particular of  oxygen, sulfur or nitrogen and O to 10 ramifica  containing functions conferring a character  water-soluble, for example acid, sulfate functions,  phosphate, alcohol, amine, ether, amide.  3. Complexes according to claim 2, characterized in that the groups R and R 'are identical or different and each represents a linear or branched aliphatic hydrocarbon chain containing from 1 to 30 carbon atoms and having from 0 to 6 unsaturations.  4. Complexes according to claim 2, characterized in that the groups R and R 'are identical or different and each represent a hydrocarbon chain containing from 1 to 30 carbon atoms and including at least one aromatic or heteroaromatic ring.  5. Complexes according to claim 1, characterized in that the nitrogen atom of the derivative of dithiocarbamic acid or its salts is included in a cycle comprising 5 to 7 members optionally including a heteroatom consisting of oxygen, sulfur or nitrogen.  6. Complexes according to claim 5, characterized in that the dithioacarbamate is a salt of thionic pyrrolidinocarbamadi acid.  7. Complexes according to claim 5, characterized in that the dithiocarbamate corresponds to the formula

 in which n is between 1 and 3 and where Z is oxygen, sulfur, or a group -NR, -CHR in which R represents  hydrogen,  a linear aliphatic hydrocarbon chain or  branched containing from 1 to 30 carbon atoms,  preferably from 16 to 20 and containing from 0 to 6 unsatura  tions,  a hydrocarbon chain containing up to 30 atoms of  carbon and including at least one aromatic cycle or  heteroaromatic,  or . a chain containing up to 50 carbon atoms,  linear, branched or containing at least one cycle and  containing from O to 10 heteroelements, in particular from  oxygen, sulfur or nitrogen and O to 10 rummy  fications containing functions conferring a charac  water-soluble tere, for example acid functions,  sulfate, phosphate, alcohol, amine, ether, amide.  8. Complexes according to claim 7, characterized in that the group R represents hydrogen or a linear or branched hydrocarbon chain containing from 1 to 30 carbon atoms and including from O to 6 double bonds or a hydrocarbon chain containing up to with 30 carbon atoms and including an aromatic or heteroaromatic ring.  9. Complexes according to one of claims 1 to 8, characterized in that they result from the reaction of 2 moles of derivative of dithiocarbamic acid or its salts with one mole of metallic derivative.  10. Complexes according to one of claims 1 to 9, characterized in that the metallic derivative of vanadium or niobium is in the oxidation state 4 or 5 and belongs to the family of halides, sulfates, oxyhalides, acetates , acetylacetonates, sodium, potassium or ammonium metallates and hydrates or complexes of these derivatives with a solvent.  11. Process for the preparation of compLexes according to one of claims 1 to 10, characterized in that it consists in reacting the metal derivative and the derivative of dithiocarbami acid that or its salts is in a common solvent, or suspended in an organic solvent and to remove the solvent or the suspending agent.  12. Use of the complexes according to one of claims 1 to 10 or resulting from the process of claim 11, as active ingredient, for preparing a medicament useful in particular in the treatment or prevention of diabetes, high cholesterol, hypertriglyceridemia, hyperlipidemia and complications associated with these pathologies.  13. Pharmaceutical composition characterized in that it contains, as active principle, a complex according to one of claims 1 to 10 or resulting from the process of claim 11, said complex being incorporated in a pharmaceutically acceptable excipient, vehicle or support.  14. Pharmaceutical composition according to claim 13, characterized in that it is produced for an oral formulation and contains 10 to 5000 nmol of the metal derivative per dose.  15. Pharmaceutical composition according to claim 13, characterized in that it is produced for an injectable formulation and contains 20 to 10,000 nmol of metal derivative per injectable dose of 1 to 10 ml.  16. Pharmaceutical composition according to claim 13, characterized in that it is formulated for local application in particular in a patch and contains 0.1 to 100 micromoles of metal derivative per applicable dose.  17. Pharmaceutical composition, characterized in that it comprises as active principle a mixture of 1 mole of a vanadium or niobium derivative with an oxidation state of 4 or 5 for 1 to 3 moles of an acid derivative carbamadithioic acid or its salts including a group

 where M is hydrogen, an alkali metal, an ammonium or alkylammonium group, said alkylammonium being a mono-, di-, tri- or tetraalkyl C1 to C4, said mixture transforming in vivo into a complex or mixture of complexes as defined in claims 1 to 10, said active principle being incorporated in a pharmaceutically acceptable excipient, support or vehicle.