MX2008008895A - Combination of triazine derivatives and insulin sensitisers - Google Patents

Abstract

The present invention relates to combinations of triazine derivatives and of insulin sensitisers for the treatment and/or prevention of diabetes and of pathologies associated with insulin resistance, wherein the triazine derivative is a compound of formula (I).

Description

COMBINATION OF TRIAZINE DERIVATIVES AND INSULIN SENSITIZERS FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition of triazine derivatives or their described salts acceptable for pharmaceutical use with an insulin sensitizer, for the manufacture of a medicament that can be used in the treatment of non-insulin-dependent diabetes and pathologies associated with the insulin resistance syndrome. BACKGROUND OF THE INVENTION "Diabetes melli tus" (or diabetes) is one of the most frequent diseases in the world. People suffering from diabetes have been divided into two classes, namely type I or diabetes melli your insulin dependent or type II or diabetes melli your non insulin dependent (NIDDM). Non-insulin dependent diabetes mellitus (NIDDM) accounts for approximately 90% of diabetic cases and is estimated to affect between 12 and 14 million adults in the US alone. (6.6% of the population). NIDDM is characterized by both fasting hyperglycemia and exaggerated postprandial increases in plasma glucose levels.

NIDDM is associated with a variety of long-term complications, including microvascular diseases, such as retinopathy, nephropathy, and neuropathy, as well as REF .: 193441 macrovascular diseases, such as coronary heart disease. Numerous studies in animal models show a causal relationship between long-term complications and hyperglycemia. The most recent results obtained by the "Diabetes Control and Complications Trial" (DCCT) and the "Stockholm Prospective Study" have shown for the first time This relationship in man shows that insulin dependent diabetics have a substantially lower risk of developing and increasing these complications if they are subjected to a more strict glycemic control. It is also expected that stricter control will benefit patients with NIDDM. Hyperglycaemia in the case of NIDDM is associated with two biochemical abnormalities, namely, insulin resistance and insufficiency of insulin secretion. The initial treatment of NIDDM is based on a controlled diet and controlled physical activity, given that a considerable number of diabetics are overweight or obese (~ 67%) and given that weight loss can improve insulin secretion and sensitivity to insulin and lead to normal blood glucose. Patients suffering from hyperglycaemia who can not be controlled only with diet and / or physical activity, are treated with oral antidiabetics.

Currently there are several classes of oral antidiabetics that are used in monotherapy for the treatment of NIDDM: • Insulin secretion stimulators. They are represented, firstly, by sulfonylureas (SU) and by "glinidas". As regards the SUs, mention may be made in particular of carbutamide (Glucidoral®), glibenclamide / glyburide (Daonil®, Euglucan®), glibomuride (Glutril®), gliclazide (Diamicron®), glimepiride (Amarel®) and glipizide (Glibenese®). As regards the "glinidas", repaglinide can be particularly mentioned (NovoNorm®); • agents that reduce glycogenesis, represented by the biguanides. Metformin can be particularly mentioned (Glucophage®, Stagid®); • insulin sensitizers, represented mainly by thiazolidinediones (TZD). In particular, pioglitazone (Actos®) and rosiglitazone can be mentioned (Avandia®); • alpha glucosidase inhibitors. Particularly can be mentioned acarbose (Glucor®) and miglitol (Diastabol®). However, over time monotherapy may be losing effectiveness. This phenomenon is called "secondary deficiency". It can represent up to 50% of Unsatisfactory responses after 10 years of treatment. Studies have shown that it is possible to address this problem by combining metformin with sulfonylureas or TZD in the same pharmaceutical form (EP 869 796 Bl or EP 861 666 Bl). On the other hand, the metformin + rosiglitazone combination (Avandamet®) has been marketed. However, these combinations based on metformin have side effects associated with the use of metformin, in particular intestinal symptoms, such as nausea, diarrhea and abdominal pain. In WO 01/55122, triazine derivatives having an antidiabetic effect comparable to that of metformin have been described. However, their combination has never been suggested. BRIEF DESCRIPTION OF THE INVENTION The applicant has developed a new pharmaceutical composition comprising a triazine-type antidiabetic agent, such as those described in WO 01/55122 and an insulin sensitizer. Unexpectedly, the combinations according to the invention show a synergistic activity and significantly reduce the side effects of the known combinations. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new A pharmaceutical composition comprising an insulin sensitizer and a compound of the general formula (I): R 2 H R 4 I I R 1 R 3 N 5 N R 5 R 6? wherein: R1, R2, R3 and R4 are independently selected from the following groups: "H, - (C1-C20) alkyl optionally substituted by halogen, (Cl-C5) alkyl, (C1-C5) alkoxy or ( C3-C8) cycloalkyl, - (C2-C20) alkenyl optionally substituted by halogen, (Cl-C5) alkyl or (C1-C5) alkoxy- (C2-C20) alkynyl optionally substituted by halogen, (C1-C5) alkyl or (C1-C5) - (C3-C8) alkoxycycloalkyl optionally substituted with (Cl-C5) alkyl or (C1-C5) alkoxy-hetero (C3-C8) cycloalkyl with one or more heteroatoms selected from N, O and S and optionally substituted with (C1-C5) alkyl or (C1-C5) alkoxy- (C6-C14) aryl (C1-C20) alkyl optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (Cl-) C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, - (C6-C14) aryl optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (Cl- C5) alkylthio, (C1- C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, (C1-C13) heteroaryl with one or more heteroatoms selected from N, and S and optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (Cl-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, ( C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, R1 and R2, on the one hand, and R3 and R4, on the other hand, can form a ring with the nitrogen atom of n members (n is between 3 and 8) optionally containing one or more heteroatoms selected from N, O and S and may be substituted by one or more of the following groups: amino, hydroxyl, thio, halogen, (C1-C5) ) alkyl, (C1-C5) ) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (Cl-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, R5 and R6 are independently selected from the following groups: -H, - (C1-C20) alkyl optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (Cl- C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1- C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, - (C2-C20) alkenyl optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (Cl- C5) alkoxy, (C1-C5) ) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, - (C2-C20) alkynyl optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (Cl- C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl ( C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, - (C3-C8) cycloalkyl optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (Cl- C5) alkoxy, (C1 -C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carbox ilo, carboxymethyl or carboxyethyl, -hetero (C3-C8) cycloalkyl with one or more heteroatoms selected from N, O and S and optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C1) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, (C6-C14) aryl optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (Cl-C5) alkoxy, (C1 -C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, (C1-C13) heteroaryl with one or more heteroatoms selected from N, O and S and optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (Cl-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy , (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, (C6-C14) aryl (C1-C5) alkyl optionally substituted with amino, hydroxyl, thio, halogen, (C1- C5) alkyl, (Cl-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C1) aryl (C1-C5) alkoxy, cyano, trifluo-romethyl , carboxyl, carboxymethyl or carboxyethyl, 5 and R6 can form with the carbon atom to which they are attached a ring of m members (m is between 3 and 8) which optionally contains one or more heteroatoms selected from N, 0 and S and may be substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1 -C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, or can form a polycyclic C10-C30 residue with the carbon atom optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C1) ) aryl (C1-C5) -alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, R5 and R6 together can also represent the group = 0 or = S, the nitrogen atom of a heterocycloalkyl or heteroaryl group can be substituted with a group (Cl-C5) alkyl, (C3-C8) cycloalkyl, (C6-C14) aryl, (C6-C14) aryl (Cl-C5) alkyl or (Cl-C) acyl, and also the racemic forms, tautomers, enantiomers, diastereoi somers, epimers and mixtures thereof, and their salts acceptable for pharmaceutical use. A particular group of the invention relates to the pharmaceutical compositions according to the invention wherein the triazine derivatives are compounds of the formula (I) wherein R5 is hydrogen.

Another particular group of the invention relates to the pharmaceutical compositions according to the invention wherein the triazine derivatives are compounds of the formula (I) wherein R5 and R6 form with the carbon atom to which a ring of m is attached. members (m is between 3 and 8) optionally containing one or more heteroatoms selected from N, O and S and may be substituted by one or more of the following groups: (C1-C5) alkyl, amino, hydroxyl, (Cl-) C5) alkylamino, (C1-C5) alkoxy, (C1-C5) alkylthio, (C6-C14) aryl, (C6-C1) aryl (C1-C5) alkoxy, or form with the carbon atom a polycyclic residue of C10 -C30 optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C1) aryloxy, (C6) -C14) aryl (C1-C5) -alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl. Another particular group of the invention relates to the pharmaceutical compositions according to the invention wherein the triazine derivatives are compounds of the formula (I) wherein R5 and R6 are independently selected from the following groups: -groups (C1) -C20) alkyl optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (Cl-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) -aryloxy , (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl. Preferably, R1, R2, R3 and R4 are independently selected from H and (C1-C20) alkyl groups optionally substituted by halogen, (C1-C5) alkyl, (C1-C5) alkoxy or (C3-C8) cycloalkyl; more preferably, R1 = R2 = H and R3 = R4 = (Cl-C20) alkyl optionally substituted with halogen, (Cl-C5) alkyl, (C1-C5) alkoxy, (C3-C8) cycloalkyl or vice versa. Preferably, R5 and R6 are independently selected from H and (C1-C20) alkyl groups optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C 1 -C 5) alkylamino, (C 6 -C 14) aryloxy, (C 6 -C 14) aryl (C 1 -C 5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; more preferably, R5 = H and R6 = (C1-C20) alkyl optionally substituted with amino, hydroxyl, thio, halogen, (Cl-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (Cl-) C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl or vice versa. A more particular group of the invention relates to the pharmaceutical compositions according to the invention wherein the triazine derivatives are compounds of the formula (I) wherein R 1 and R 2 are a methyl group and R 3 and R 4 represent a hydrogen. The term "ring of m members formed by R5 and R6" is refers in particular to a saturated ring, such as a cyclohexyl, piperidyl or tetrahydropyranyl group. The term "polycyclic group consisting of R5 and R6" refers to a polycyclic group on the basis of optionally substituted carbon and in particular a spheroidal residue. The following compounds of formula (I) can be mentioned especially: and more preferably the compound of Example 18. According to another preferred embodiment, the invention in more particular form relates to pharmaceutical compositions which are selected from: • (+) -2-amino-3,6-dihydro-4-dimethylamino hydrochloride - 6-methyl-1,3,5-triazine and rosiglitazone; • (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride, and troglitazone; • (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride and pioglitazone; • (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride, and muraglitazar. The term "insulin sensitizer" means any compound capable of increasing tissue sensitivity to insulin. Insulin sensitizers include, e.g., tyrosine phosphatase inhibitors (PTP inhibitors), GSK-3 inhibitors, retinoid X receptor agonists (RXR agonists), glitazones (TZD), TZD agonists no PPAR ?, double PPARoí / PPARy agonists, agonists based on compounds containing vanadium and biguanides, e.g., metformin. The insulin sensitizers may also be in the form of salts suitable for pharmaceutical use, such as, without limitation, the hydrochloride, hydrobromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate or acetate, the sodium ion, the potassium ion , the calcium ion or the magnesium ion .. The term "glitazones" includes, without limitation, englitazone, darglitazone, ciglitazone, DRF2189, BM-13.1246, AY-31637, YM268, AD-5075, DN-108, rosiglitazone, pioglitazone, troglitazone, MCC555, T-174 and KRP297. The term "PPAR agonist, not TZD" more particularly includes analogues of N- (2-benzoylphenyl) -L-tyrosine, such as, without limitation, GI-262570 and JTT501. The term "double PPARa / PPAR agonist?" includes, without limitation, compounds such as: NNC-61-4655, TZD18, LY-510929, LY-465608, LSN862, GW-409544, Muraglitazar, Ragaglitazar, Tesaglitazar, and also the compounds described in WO 03/011819 (Example 8) and WO 00/039113 (Example 16b where oxeglitazar is described). The compounds of the invention of the formula (I) as defined, which contain a sufficiently basic function, or both, may include the corresponding salts of organic or mineral acids acceptable for pharmaceutical use.

For the purposes of the present invention, the term "corresponding salts of organic or mineral acids acceptable for pharmaceutical use" means any salt prepared from any non-toxic organic or inorganic acid acceptable for pharmaceutical use. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, citric acid, carbonic acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, lactic acid, mandelic acid, malic acid, maleic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, tartaric acid and para-toluenesulfonic acid. It is advantageous to use hydrochloric acid. The invention also relates to the chiral salts of the compounds of the formula (I) which are used for the racemate separation of the compounds of the formula (I). By way of example, the following chiral acids are used: (+) - D-di-O-benzoyltartaric acid, (-) - L-di-O-benzoyltartaric acid, (-) - L-di-O, O acid '-p-toluyl-L-tartaric acid (+) -D-di-O, O' -p-toluyl-L-tartaric acid, (R) - (+) - magic, acid (S) - (- ) -malic, acid- (+) -Canphanic, (-) - cananic acid, R- (-) -1, 1'-β-2-hydrophthalene-2-dihydro-phosphonic acid, (+) - caphoric acid, (-) acid ) -Canoric acid (S) - (+) -2-phenylpropionic acid, (R) - (+) -2-phenylpropionic acid, D- (-) -mandelic acid, L- (+) - mandelic acid, D-tartaric acid, L-tartaric acid, or a mixture of two or more thereof. The compounds of the formula (I) above also include the prodrugs of these compounds. The term "prodrugs" refers to compounds that, when administered to the patient, are converted by chemical or biological processes within the living organism to compounds of the formula (I). In the present specification, the terms used have, unless otherwise indicated, the following meanings: the term "(C1-C20) alkyl" denotes an alkyl radical, linear or branched, containing between 1 and 20 carbon atoms. Among the C1-C20 alkyl radicals which can be mentioned especially, without limitation, are the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl, dodecyl, hexadecyl radicals and octadecyl; - the term "(C1-C20) alkenyl" denotes a linear or branched radical based on hydrocarbons containing one or more unsaturations in the form of double bonds. As alkylene radicals containing between 1 and 20 carbon atoms, there can be mentioned, without limitation, the radicals ethenyl, prop-2-enyl, but-2-enyl, but-3-enyl, pent-2-enyl, pent 3-enyl and pent-4-enyl; - the term "(C1-C20) alkynyl" denotes a linear or branched radical based on hydrocarbons containing one or more unsaturations in the form of triple bonds. As alkylene radicals containing between 1 and 20 carbon atoms, there can be mentioned, without limitation, the ethynyl, prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, pent radicals -3-ynyl and pent-4-ynyl; - the term "alkoxy" refers to the term "alkyl-oxy"; the term "halogen" refers, without limitation, to fluorine, chlorine or bromine; - the term "(C6-C14) aryl (C1-C20) alkyl" refers to the corresponding -alkylaryl groups. Particular mention may be made of the benzyl and phenethyl groups; - the term "(C6-C14) aryl" refers to an aromatic group containing between 6 and 14 carbon atoms in which at least one of the rings has a conjugated pi electron system, and which includes biaryls, which can be optionally replaced. Mention may be made in particular of the radicals, in particular biphenyl, phenyl, naphthyl, anthryl and phenanthryl; - the term "hetero (C6-C14) aryl" refers to a 6-14 membered aromatic heterocycle containing 1-4 heteroatoms, the remaining atoms being carbon atoms. Among the heteroatoms, oxygen, sulfur and nitrogen can be particularly mentioned. Among the heteroaryl radicals, Mention may be made in particular of furyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, oxazolyl, oxadiazolyl, isoxazolyl, quinolyl and thiazolyl radicals; - the term "(C3-C8) cycloalkyl" refers to a saturated ring based on hydrocarbons and containing monocyclic, bicyclic and polycyclic radicals containing between 3 and 8 carbon atoms. The cyclopropyl and cyclobutyl radicals can be mentioned, without limitation. It will be appreciated that the compounds that are useful in accordance with the present invention may contain asymmetric centers.

These asymmetric centers can have, independently, R or S configuration. Those skilled in the art will clearly appreciate that certain compounds that are useful according to the invention can also exhibit geometric isomerism. It is understood that the present invention includes individual isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of the above formula (I). Isomers of this type can be separated from their mixtures by the application or adaptation of known processes, for example chromatographic techniques or recrystallization techniques, or they can be prepared separately from suitable isomers of their intermediates. The enantiomers of the compounds according to invention and the process for the preparation are those specially described in patent application WO 2004/089917, the content of which is incorporated herein by reference. The present patent application also relates to the polymorphic forms of the compounds, obtained in accordance with patent application WO 2004/089917, for example the polymorphic form Al of the hydrochloride salt of (+) - 2-amino-3, 6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine. The present invention also relates to the other polymorphic forms of the compounds, such as the polymorphic form Hl of the hydrochloride salt of (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1, 3, 5-triazine, which can be prepared as follows: Approximately 3 g of the form Al of Example 18 are dissolved in 50 ml of 1 mol / 1 HCl at room temperature. The clear solution obtained is allowed to evaporate at room temperature, in a container without a lid, until a solid residue crystallizes. The characterization is done by: • FT-IR spectroscopy: - Vector Brü er 22 - 2 cm-1 spectral resolution - 32 scans - KBR disks (analogous to method AA21505) To evaluate the intensity of the IR bands, the IR spectra were normalized by vectorization in the spectral range 4000-400 cm "1 as an absorption spectrum The following presetting was performed: - s: A> 0.05 - m: 0.01 < A < 0.05 - w: A < 0, 01. • FT-Raman spectroscopy: - Brüker RFS-100 - excitation: 1064 nm - spectral resolution: 1 cm-1 - 1000 mW - 1000 sweeps - focused - aluminum crucible (analogous to the method RA AA21505) - To evaluate the intensity of the Raman bands, the Raman spectra were normalized by vectorization in the spectral range 3600-200 cm-1 The following presetting was performed: - s : A> 0.05 m: 0.01 <A> 0.05 w: A <0.01 • X-ray powder diffraction (XRD) "D5000 diffractometer (Brüker AXS) radiation from CuKal at 1.5406 A (U = 30 kV, A = 40 mA) Transmission mode Detector in sensitive position Primary monochromator Range of angles: 3-65 ° 2? Stage width: 0.05 ° 2? Measuring time / stage: 1.4 s The XRD equipment is set to 2? ± 0.1 °.

Results Form Al: XRD: FT / IR bands (in cm "1): 3384 +/- 1.5 (m), 3199 +/- 1.5 (m), 3163 +/- 1.5 (m), 3107 +/- 1, 5 (m), 2993 +/- 1.5 (m), 2983 +/- 1.5 (m), 1652 +/- 1.5 (s), 1606 +/- 1.5 (s), 1576 +/- 1.5 (s), 1557 +/- 1.5 (s), 1505 +/- 1.5 (s), 1449 +/- 1, 5 (m), 1427 +/- 1.5 (m), 1405 +/- 1.5 (m), 1383 +/- 1.5 (m), 1348 +/- 1.5 (m), 1306 +/- 1.5 (m), 1263 +/- 1.5 (w), 1235 +/- 1, 5 (w), 1185 +/- 1.5 (w), 1096 +/- 1.5 (w), 1068 +/- 1.5 (w), 980 +/- 1.5 (w), 946 +/- 1.5 (w), 868 +/- 1.5 (w), 761 +/- 1, 5 (w), 687 +/- 1.5 (m), 655 +/- 1.5 (m), 558 +/- 1.5 (), 521 +/- 1.5 (w), 478 + / - 1.5 (w) FT-Raman bands (in cm "1): 3217 +/- 1.5 (w), 2994 +/- 1.5 (m), 2983 +/- 1.5 (m) ), 2936 +/- 1.5 (s), 2883 +/- 1.5 (m), 1645 +/- 1.5 (w), 1602 +/- 1.5 (m), 1554 +/- 1.5 (m), 1453 +/- 1.5 (m), 1428 +/- 1.5 (m), 1349 +/- 1.5 (w), 1308 +/- 1, 5 (w), 979 +/- 1.5 (m), 866 +/- 1.5 (w), 761 +/- 1.5 (), 686 +/- 1.5 (s), 583 + / - 1.5 (m), 555 +/- 1.5 (s), 525 +/- 1.5 (m), 479 +/- 1.5 (m), 410 +/- 1.5 (m), 401 +/- 1.5 (m), 307 + / - 1.5 (m) Form Hl XRD: FT / IR bands (in cm "1): 3386 +/- 1.5 (m), 3080 +/- 3 (m), 1706 +/- 1.5 (s), 1691 +/- 1.5 ( s), 1634 +/- 1.5 (m), 1513 +/- 1.5 (m), 1445 +/- 1.5 (w), 1241 +/- 1.5 (w), 1079 +/- 1.5 (w), 989 +/- 1.5 (w), 940 +/- 1.5 (w), 861 +/- 1, 5 (w), 823 +/- 1.5 (w), 675 +/- 1,5 (), 603 +/- 1,5 (), 573 +/- 1,5 (w), 549 +/- 1,5 (w), 527 +/- 1,5 (w) For this document, it is understood that tautomeric forms are included by mentioning a given group, for example thio / mercapto or oxo / hydroxy. The pharmaceutical compositions according to the present invention are useful in the treatment of pathologies associated with the syndrome of insulin resistance (syndrome X). Insulin resistance is characterized by a reduction of the action of insulin (see Presse Medícale, 1997, 26 (No. 14), 671-677) and appears in a large number of pathological conditions, such as' diabetes and more particularly, in non-insulin-dependent diabetes (type II diabetes or NIDDM), dyslipidemia, obesity and arterial hypertension, as well as in certain microvascular and macrovascular complications, for example, atherosclerosis, retinopathy and neuropathy. In this regard, reference will be made, e.g., to Diabetes, vol. 37, 1988, 1595-1607; Journal of Diabetes and i ts Complications, 1998, 12, 110-119 or Horm. Res. , 1992, 38, 28-32. The object of the present invention is to propose a pharmaceutical composition for significantly improving the condition of diabetics. The pharmaceutical compositions of the invention possess especially hypoglycaemic activity. Therefore, the compounds of the formula (I) are useful in the treatment of pathologies associated with hyperglycemia. The pharmaceutical composition comprising the triazine compound of the formula (I) in combination with an insulin sensitizer can be prepared by mixing the various active ingredients, either by mixing all at once or independently with a carrier, an excipient, a binder , a diluent, etc., suitable for physiological use. It is then administered orally or non-orally, for example by parenteral, intravenous, cutaneous, nasal or rectal. If the active ingredients are formulated independently, the corresponding formulations can be mixed together extemporaneously using a diluent and administered in this way or they can be administered independently of one another, both sequentially and sequentially. The pharmaceutical compositions of the invention include formulations such as granules, powders, tablets, gel capsules, syrups, emulsions and suspensions, and also forms used for non-oral administration, for example injections, vaporizers or suppositories. The dosage forms can be prepared by conventional known techniques. The preparation of a solid dosage form for oral administration will be carried out according to the following process: an excipient (eg lactose, sucrose, starch, mannitol, etc.), a disintegrant (eg, carbonate calcium, calcium carboxymethylcellulose, alginic acid, sodium carboxymethylcellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, aluminum magnesium silicate, microcrystalline cellulose, cellulose powder, pregelatinized starch, sodium alginate, starch glycolate, etc.) , a binder (eg alpha starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, alginic acid, carbomer, dextrin, ethylcellulose, sodium alginate, maltodextrin, liquid glucose, aluminum magnesium silicate, methylcellulose, guar gum, etc.) and a lubricant (eg talcum, magnesium stearate, polyethylene 6000, etc.) are added to, for example, active ingredients and the obtained mixture is then pressed into tablets. If necessary, the tablet can be coated with known techniques in order to mask the taste (eg with cocoa powder, mint, borneol, cinnamon powder, etc.) or to allow enteric dissolution or release sustained of the active principles. The products that can be used for the coating are, for example, ethylcellulose, hydroxymethylcellulose, polyoxyethylene glycol, cellulose acetophthalate, hydroxypropylmethylcellulose phthalate and Eudragit® (methacrylic acid copolymer with acrylic acid), Opadry® (hydroxypropylmethylcellulose + macrogol + oxide) titanium + lactose monohydrate). Dyes suitable for pharmaceutical use can be added (eg yellow iron oxide, red iron oxide, quinoline yellow lake, etc.). For oral administration, pharmaceutical forms such as tablets, powders, sachets and gel capsules can be used. Liquid dosage forms for oral administration include solutions, suspensions and emulsions. Aqueous solutions can be obtained by dissolving the active principles in water, followed by the addition of flavorings, dyes, stabilizers and thickeners, when necessary. To increase the solubility, ethanol, propylene glycol or other non-aqueous solvents suitable for pharmaceutical use can be added. Aqueous suspensions for oral use can be obtained by dispersing the finely divided active ingredients in water with a viscous product, such as natural or synthetic gums, resins, methylcellulose or sodium carboxymethylcellulose. The pharmaceutical forms for injection can be obtained, for example, by the following process. The active ingredient (s) are dissolved, suspended or emulsified in an aqueous medium (eg distilled water, physiological solution, Ringer's solution, etc.) or in an oily medium (for example a vegetable oil, such as olive oil, sesame oil, cottonseed oil, corn oil, etc., or propylene glycol), with a dispersant (for example Tween 80, HCO 60 (Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), a preservative (for example methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol, chlorobutanol, phenol, etc.), an agent for isotonia (for example sodium chloride, glycerol, sorbitol, glucose, etc.) and also other additives, such as, if desired, a solubilizing agent (e.g., sodium salicylate, sodium acetate, etc.) or a stabilizer (e.g., human serum albumin).

A pharmaceutical form for external use can be obtained from a solid, semi-solid or liquid composition containing the active ingredient (s). For example, in order to obtain a solid form, the active ingredient (s) are treated, separately or in mixtures, with excipients (eg lactose, mannitol, starch, microcrystalline cellulose, sucrose, etc.) and a thickener (e.g. natural gums, cellulose derivatives, acrylic polymers, etc.) in order to convert them into powder. The liquid pharmaceutical compositions are prepared in substantially the same manner as the forms for injection, as indicated above. The semi-solid dosage forms are preferably in the form of aqueous or oily gels or in the form of an ointment. Optionally, these compositions may contain a pH regulator (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.) and a preservative agent (eg esters of p-hydroxybenzoic acid, chlorobutanol, benzalkonium chloride, etc.) and also other additives. The daily doses of insulin sensitizers are between 0.5 mg and 50 mg. More particularly, if rosiglitazone is used in the present invention, the daily dose is between 1 mg and 8 mg, more preferably 4 mg. Pioglitazone is used, the daily dose is between 15 mg and 45 mg. If muraglitazar is used, Daily dose is between 0.5 mg and 20 mg, preferably 5 mg. The daily doses of the compounds of the formula (I) are between 200 mg and 2000 mg. The relative proportion of the constituents of the pharmaceutical compositions of the present invention takes into account the recommended doses of the respective active ingredients. Therefore, these relative proportions of insulin sensitizers, or their pharmaceutically acceptable salts, and of the compounds of the formula (I), or of their pharmaceutically acceptable salts, vary accordingly. Preferably, the weight ratio between the insulin sensitizer and the compound of the formula (I) is between 1/2 and 1/2000, more particularly between H and 1/2000 and especially between 1/5 and 1/2000 . The preferred administration frequency of the compounds of the invention is between one and two administrations per day. In cases where the doses of the compounds of the formula (I) require more than one daily administration, the amounts of the insulin secretion stimulator and the insulin secretion / compound ratio of the formula (I) are will adjust accordingly. It is also an object of the present invention to propose a method of treatment by means of the co-administration of an effective amount of a compound of the formula (I) and of an insulin sensitizer, and also of sets of elements to allow this co-administration. The present invention also relates to sets of elements that are suitable for treatment with the methods described above. These sets of elements comprise a composition containing the compound of the formula (I) in the doses indicated above and a second composition containing the sensitizers of the secretion of insulin in the doses indicated above, for a simultaneous, separate or consecutive administration, in effective amounts according to the invention. The term "co-administration" means the simultaneous, separate or consecutive administration of one or more compounds to the same patient during a period that can be up to 2 hours or even up to 12 hours. For example, the term "co-administration" includes (1) a simultaneous administration of two compounds, (2) an administration of the first, followed 2 hours later by the administration of the second compound, (3) an administration of the first, followed 12 hours later by the administration of the first. administration of the second compound. The following examples of compositions according to the invention are presented by way of non-limiting illustrations.

EXAMPLES The quantities are expressed on a weight basis. Formulation Example 1: (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride: 1000 mg rosiglitazone: 4 mg microcrystalline cellulose: 114 mg croscarmellose: 28 mg polyvinylpyrrolidone: 40 mg magnesium stearate: 14 mg Opadry: 24 mg Formulation example 2: (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-hydrochloride -triazine: 1000 mg pioglitazone: 25 mg microcrystalline cellulose: 115.5 mg croscarmellose: 28 mg polyvinyl pyrrolidone: 40 mg magnesium stearate: 9 mg Opadry®: 24 mg Formulation example 3: (+) -2-amino-hydrochloride 3, 6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine: 750 mg rosiglitazone: 2 mg microcrystalline cellulose: 110 mg croscarmellose: 21 mg polyvinyl pyrrolidone: 30 mg magnesium stearate: 10.5 mg Opadry®: 18 mg Formulation example 4: (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl- hydrochloride 1, 3, 5-triazine: 1000 mg muraglitazar: 5 mg microcrystalline cellulose: 150 mg croscarmellose: 24 mg polyvinyl pyrrolidone: 44 mg magnesium stearate: 8 mg Eudragit®: 24 mg Biological test: Modulation of glucose levels with combinations of the invention with insulin sensitizers The ability of the compounds of the invention in combination with insulin-sensitive antidiabetic compounds to modify insulin levels. Blood glucose is evaluated in vivo in diabetic GK rats. Alone or in combination, the antidiabetic agents are administered twice a day (bid) to the GK rats for 4 days. The oral glucose tolerance test (OGTT) is performed after the last day of treatment.

The OGTT is performed in the morning, after 3 hours of fasting, orally administering a glucose load of 2 g / kg of body weight. Blood samples are drawn from the caudal vein at 0; 10; twenty; 30; Four. Five; 60; 90 and 120 minutes to determine glucose levels. Results of the combinations according to the invention The combination of rosiglitazone and the hydrochloride salt of (+) -2-amino-3,6-dihydro-4-dimethyl-ylamino-6-met-il-1, 3, 5- t ria zina was examined as detailed below. The two compounds were administered alone and combined. The doses of hydrochloride salt of (+) -2-amino-3,6-dihydro-4-dimetholamino-6-met i 1-1, 3, 5-triazine were 50 and 100 mg / kg PO twice a day for 4 days. For rosiglitazone, the doses used were 1 and 5 mg / kg PO twice a day for 4 days. The following combination was tested: - (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1, 3, 5-triazine hydrochloride salt: 100 mg / kg and rosiglitazone: 5 mg / kg PO twice a day for 4 days.

After four days of treatment (placebo), the glycemic control of diabetic GK rats did not change or increase significantly. At the doses of 5 mg / kg of rosiglitazone and 100 mg / kg of the hydrochloride salt of (+) - 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine , these agents induced a decrease in fasting plasma glucose level. However, better tolerance was observed to glucose with the hydrochloride salt of (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine as with rosiglitazone. In combination, rosiglitazone 5 mg / kg and the hydrochloride salt of (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine 100 mg / kg showed much more effective than each compound per individual. The combination of an insulin sensitizer, such as rosiglitazone and a compound, such as the hydrochloride salt of (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1, 3, 5 -triazine generates a better activity in the tolerance of glucose and in the level of plasma glucose than each of the compounds. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (30)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Pharmaceutical composition characterized in that it comprises, as active principle: i) an insulin sensitizer, ii) a compound of the formula (I) in combination with one or more acceptable excipients for pharmaceutical use
2. (I) wherein: R1, R2, R3 and R4 are independently selected from the following groups: -H, - (C1-C20) alkyl optionally substituted with halogen, (C1-C5) alkyl, (C1-C5) alkoxy or (C3-C8) cycloalkyl, - (C2-C20) alkenyl optionally substituted with halogen, (C1-C5) alkyl or (C1-C5) alkoxy- (C2-C20) alkynyl optionally substituted with halogen, (C1-C5) ) alkyl or (C1-C5) alkoxy- (C3-C8) cycloalkyl optionally substituted with (Cl-C5) alkyl or (C1-C5) alkoxy -hetero (C3-C8) cycloalkyl with one or more heteroatoms selected from N, 0 and S and optionally substituted by (Cl-C5) alkyl or (C1-C5) alkoxy- (C6-C14) aryl (C1-C20) alkyl optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (Cl-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) ) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, (C6-C14) aryl optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (Cl-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, (C1-C13) heteroaryl with one or more heteroatoms selected from N, O and S and optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (Cl-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carbox ilo, carboxymethyl or carboxyethyl, Rl and R2, on the one hand, and R3 and R4, on the other hand, can form with the nitrogen atom a ring of n members (n is between 3 and 8) optionally containing one or more heteroatoms selected from N, O and S and can be substituted by one or more of the following groups: amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio,
3. (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (Cl-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, R5 and R6 are independently selected from the following groups: -H, - (C1-C20) alkyl optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (Cl-C5) alkylthio, (C1-C5) alkylamino, ( C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, - (C2-C20) alkenyl optionally substituted with amino, hydroxyl, thio, halogen, (C1- C5) alkyl, (C1-C5) alkoxy, (Cl-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl , carboxymethyl or carboxyethyl, - (C2-C20) alkynyl optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (Cl- C5) alkylthio, (C1-C5) alkylamino , (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carbox ilo, carboxymethyl or carboxyethyl, - (C3-C8) cycloalkyl optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (Cl- C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, car- boxymethyl or carboxyethyl, -hetero (C3-C8) cycloalkyl with one or more heteroatoms selected from N, 0 and S and optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (Cl-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) -aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, - (C6-C14) ) aryl optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (Cl-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano , trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, - (C1-C13) heteroaryl with one or more heteroatoms selected from N, 0 and S and optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (Cl-) C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) -aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, - (C6-C14) aryl (C1-C5) alkyl optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (Cl-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino , (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, - R5 and R6 can form with the carbon atom to which they are attached a ring of m members (m is between 3 and 8) that optionally contains one or more heteroatoms selected from N, 0 and S and may be substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (Cl-C5) alkylthio, (C1- C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, or can form with the carbon atom a polycyclic C10-C30 residue optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C1) aryl (C1-C5) -alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, R5 and R6 together can also represent the group = 0 or = S, the nitrogen atom of a heterocycloalkyl or heteroaryl group can be substituted with a group (Cl-C5) alkyl, (C3-C8) cycloalkyl, (C6-C14) aryl, (C6-C14) aryl (Cl-C5) alkyl or (Cl-C6) acyl, and also the racemic forms, tautomers, enantiomers , diastereoisom eros, epimers and polymorphs, and mixtures thereof, and their salts acceptable for pharmaceutical use. 2. Pharmaceutical composition according to claim 1, characterized in that it comprises a compound of the formula (I) wherein R5 is hydrogen. 3. Pharmaceutical composition according to claim 1 or 2, characterized in that it comprises a compound of the formula (I) wherein R5 and R6 are independently selected from H and (C1-C20) alkyl groups optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (Cl-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl.
4. 4. Pharmaceutical composition according to any of the preceding claims, characterized in that R1, R2, R3 and R4 are independently selected from H and (C1-C20) alkyl groups optionally substituted by halogen, (C1-C5) alkyl, ( C1-C5) alkoxy or (C3-C8) cycloalkyl.
5. 5. Pharmaceutical composition according to any of the preceding claims, characterized in that R5 and R6 are independently selected from H and (C1-C20) alkyl groups optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, ( C1-C5) alkoxy, (Cl-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl.
6. 6. Pharmaceutical composition according to any of the preceding claims, characterized in that it comprises a compound of the formula (I) wherein R1 and R2 are a methyl group and R3 and R4 represent a hydrogen.
7. 7. Pharmaceutical composition in accordance with Any one of the preceding claims, characterized in that the triazine derivative used is 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, or its salts acceptable for pharmaceutical use.
8. 8. Pharmaceutical composition according to any of claims 1 to 6, characterized in that the triazine derivative used is (-) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5. -triazine, or its salts acceptable for pharmaceutical use.
9. 9. Pharmaceutical composition according to any of claims 1 to 6, characterized in that the triazine derivative used is (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1, 3, 5 -triazine, or its salts acceptable for pharmaceutical use.
10. 10. Pharmaceutical composition according to any of the preceding claims, characterized in that the compound of the formula (i) is in the hydrochloride form.
11. 11. Pharmaceutical composition according to any of the preceding claims, characterized in that the insulin sensitizer is selected from tyrosine phosphatase inhibitors (ptp inhibitors), inhibitors of gsk-3, retinoid receptor agonists x (rxr agonists), glitazones (tzd), ppar agonists? no tzd, double agonists of ppara / ppar ?, agonists based on compounds containing vanadium and biguanides, for example, metformin.
12. 12. Pharmaceutical composition according to any of the preceding claims, characterized in that the insulin sensitizer is glitazone (tzd).
13. 13. Pharmaceutical composition according to claim 12, characterized in that the insulin sensitizer is glitazone (tzd) selected from rosiglitazone, pioglitazone and troglitazone.
14. 14. Pharmaceutical composition according to any of claims 1 to 11, characterized in that the insulin sensitizer is a double ppara / ppary agonist. selected between muraglitazar, tesaglitazar and resaglitazar.
15. 15. Pharmaceutical composition according to any of the preceding claims, characterized in that the insulin sensitizers are in the form of an acceptable salt for pharmaceutical use.
16. 16. Pharmaceutical composition according to any of the preceding claims, characterized in that it contains between 0.5 mg and 50 mg of insulin sensitizer.
17. 17. Pharmaceutical composition according to any of the preceding claims, characterized in that it contains between 200 mg and 2000 mg of the compound of the formula (i).
18. 18. Pharmaceutical composition according to any of the preceding claims, characterized in that the weight ratio of insulin sensitizer to the compound of the formula (i) is between 1/2 and 1/2000.
19. 19. Pharmaceutical composition according to any of the preceding claims, characterized in that the insulin sensitizer is rosiglitazone and the compound of the formula (i) is (+) -2-amino-3,6-dihydro-4-dimethylamino-6. -methyl-1,3,5-triazine, preferably in the form of a hydrochloride.
20. 20. Pharmaceutical composition according to any of claims 1 to 18, characterized in that the insulin sensitizer is pioglitazone and the compound of the formula (i) is (+) -2-amino-3,6-dihydro-4-dimethylamino. -6-methyl-1,3,5-triazine, preferably in the form of a hydrochloride.
21. 21. Pharmaceutical composition according to any of claims 1 to 18, characterized in that the insulin sensitizer is troglitazone and the compound of the formula (i) is (+) -2-amino-3,6-dihydro-4-dimethylamino. -6-methyl-1,3,5-triazine, preferably in the form of a hydrochloride.
22. 22. Pharmaceutical composition according to any of claims 1 to 18, characterized because the insulin sensitizer is muraglitazar and the compound of the formula (i) is (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, preferably in the form of a hydrochloride.
23. 23. Pharmaceutical composition according to any of the preceding claims, suitable for oral administration, characterized in that the pharmaceutical composition is powder, tablets, gel capsules, sachet, solution, suspension or emulsion.
24. 24. Use of an insulin sensitizer in combination with a compound of the formula (i) according to any of claims 1 to 10, for the preparation of a medicinal combination for the treatment and / or prevention of diabetes.
25. 25. Use according to claim 24, for the preparation of a medicinal combination for the treatment and / or prevention of non-dependent insulin diabetes.
26. 26. Use of an insulin sensitizer in combination with a compound of the formula (i) according to any of claims 1 to 10, for the preparation of a medicinal combination for the treatment of at least one of the pathologies associated with the insulin resistance syndrome, selected between dyslipidemia, obesity, hypertension, and microvascular and macrovascular complications, for example atherosclerosis, retinopathy, Nephropathy and neuropathy.
27. 27. Use according to any of claims 24 to 26, wherein the insulin sensitizer is as defined in accordance with any of claims 11 to 14.
28. 28. Use according to any of claims 24 to 27, wherein the combination is as defined according to one of claims 18 to 22.
29. 29. Use according to any of claims 24 to 28, wherein the administration of the compound (i) and that of the insulin sensitizer are simultaneous, separate or sequential.
30. 30. A set of elements characterized in that it comprises a compound of the formula (i) as defined according to any of claims 1 to 10 and an insulin sensitizer as defined according to any of claims 11 to 14, for the simultaneous, separate or sequential administration.