MX2008008887A - Combination of triazine derivatives and hmg- coa reductase inhibitors for the treatment of diabetes - Google Patents

Abstract

The present patent application relates to combinations of a triazine derivative with an HMG-CoA reductase inhibitor.

Description

COMBINATION OF TRIAZINE DERIVATIVES AND INHIBITORS OF THE HMG-CoA REDUCTASE 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 HMG-CoA reductase inhibitor, for the manufacture of a drug 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 REFs. : 193438 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 this relationship for the first time in men by showing 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: • stimulators of insulin secretion. 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 "glinides", repaglinide (NovoNorm®) can be particularly mentioned; • agents that reduce glycogenesis, represented by the biguanides. Particular mention may be made of metformin (Glucophage®, Stagid®); • insulin sensitizers, represented mainly by thiazolidinediones (TZD). Particular mention may be made of pioglitazone (Actos®) and rosiglitazone (Avandia®); • alpha glucosidase inhibitors. Acarbose (Glucor®) and miglitol can be particularly mentioned.

(Diastabol®). In WO 01/55122, triazine derivatives having an antidiabetic effect comparable to that of metformin have been described. In addition, it is known that diabetic patients are a population at risk in terms of the development of pathologies cardiovascular diseases, particularly arteriosclerosis and atherosclerosis. In part, this is due to an increased susceptibility to factors such as hyperlipidemia or hypercholesterolemia. Consequently, it is recommended to maintain a low level of low density lipoprotein (LDL) in the serum of diabetics. In particular, this goal will be achieved through an adequate diet and treatments that use therapeutic agents. A particular class of active compounds as agents for reducing the level of LDL cholesterol in serum is that of the inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Inhibitors of HMG-CoA reductase act in general in a limiting step in the regulation of cholesterol biosynthesis and, as a result, reduce the total amount of cholesterol that is formed in the body. The most commonly used compounds in the class of HMG-CoA reductase inhibitors are statins. The use of statins for the treatment of diabetics has been studied. For example, U.S. Patent No. 5,130,333 relates to a method for reducing the risk of type II diabetes (NIDDM) by administering to a patient a hypocholesterolemic, such as mevastatin, lovastatin, pravastatin or velostatin. Various combinations of compounds or various treatment methods have been developed using combinations of compounds For example, U.S. Patent Nos. 5,798,375 and 6,159,997 relate to methods for the prevention or treatment of arteriosclerosis or xanthoma by administration to a patient of a combination of HMG inhibitors. -CoA reductase and insulin sensitizers, such as thiazolidendiones. Preferred HMG-CoA reductase inhibitors are, in particular, pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin and atorvastatin. A treatment that combines a reduction of blood glucose in parallel with a reduction of lipid factors and, in particular, of LDL cholesterol, is then desirable to lead to a better control of the risk factors in the case of patients suffering from non-insulin-dependent diabetes and related pathologies, such as macrovascular and microvascular complications, obesity and insulin resistance. Unexpectedly, the combinations according to the invention significantly reduce the side effects. BRIEF DESCRIPTION OF THE INVENTION The applicant has developed a novel pharmaceutical composition to synergistically reduce the glycemic and lipid parameters of patients suffering from non-insulin-dependent diabetes, comprising the combination of an antidiabetic agent of the triazine type, such as those described in WO 01/55122, with an inhibitor of HMG-CoA reductase. Said pharmaceutical composition has not been described to date. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new pharmaceutical composition comprising an HMG-CoA reductase inhibitor and a compound of the general formula (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) (C2-C20) alkynyl 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 , 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 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, 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, R1 and R2, on the one hand, and R3 and R, on the other hand, can form with the nitrogen atom a n-member ring (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-C1) 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, (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 by 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, - (C2-C20) alkynyl optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C1) aryloxy, (C6-C1) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, - (C3-) C8) cycloalkyl 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, - 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, tri-fluoromethyl, carboxyl, carboxymethyl or carboxyethyl, (C6-C14) aryl optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C1) aryloxy, (C6-C1) 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-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, R5 and R6 can form with the carbon atom to which a ring of m members are attached (m is between 3 and 8) that contains or optionally one or more heteroatoms selected from N, O and S and may be 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, or can form with the carbon atom a C10-C30 polycyclic residue 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, 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 (Cl- C5) alkyl, (C3-C8) cycloalkyl group (C6-) C14) aryl, (C6-C14) aryl (C1-C5) alkyl or (Cl-C) acyl, and also the racemic forms, tautomers, enantiomers, diastereoisomers, epimers and mixtures thereof, and their pharmaceutically acceptable salts , and one or more acceptable excipients for pharmaceutical use. The term "ring of m members formed by R 5 and R 6" 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.

A particular group of the invention The pharmaceutical compositions according to the invention are related in which the triazine derivatives are compounds of the formula (1) 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 members are attached (m is between 3 and 8) optionally containing one or more heteroatoms selected from N, 0 and S and can 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-C14) aryl (C1-C5) alkoxy, or 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-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: - (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. 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, (Cl-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; more preferably, R5 = H and R6 = (C1-C20) alkyl 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 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 R1 and R2 are a methyl group and R3 and R4 represent a hydrogen. The following compounds of formula (I) can be mentioned especially: 15 20 and more preferably the compound of Example 18. The term "HMG-CoA reductase inhibitor" means any inhibitor of HMG-CoA reductase commonly used in human or veterinary therapy. Preferably, the HMG-CoA reductase inhibitor is a statin; more preferably, it is selected, without limitation, between simvastatin (Zocor®), atorvastatin (Lipitor®), fluvastatin (Lescol®), lovastatin (Mevacor®), pravastatin (Pravachol®), rosuvastatin (Crestor®), velostatin, itavastatin , sinvinoline and pitivastatin. The statins may also be in the form of pharmaceutically acceptable salts, such as, but not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, citrate, methane sulfonate, trifluoroacetate or acetate, the sodium ion, the potassium ion, calcium ion or magnesium ion. According to another preferred embodiment, the invention relates more particularly between the pharmaceutical compositions selected from: • (+) -2-amino-3,6-dihydro-4-dimethylamino-methyl-1,3,5-hydrochloride. triazine and simvastatin • (+) -2-amino-3,6-dihydro-4-dimethylamino-methyl-1,3,5-triazine hydrochloride and atorvastatin • (+) -2-amino-3,6 hydrochloride -dihydro-4-dimethylamino- 6-methyl-1,3,5-triazine and fluvastatin • (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride and lovastatin • hydrochloride , (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine and pravastatin • (+) -2-amino-3,6-dihydro-4 hydrochloride -dimethylamino-6-methyl-l, 3, 5-triazine and rosuvastatin. The invention also relates to the racemic, tautomeric, enantiomeric, diastereomeric and epimeric forms, and mixtures thereof, of the compounds of the general formula (I). 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-0-acid '-p-toluyl-L-tartaric, (+) - D-di-0'-p-toluyl-L-tartaric acid, (R) - (+) - málico acid, (S) - (-) acid ) -malic, (+) -Canphanic acid, (-) - 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- acid 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 in compounds of the formula (I). It will be appreciated that the compounds that are useful in accordance with the present invention they 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, P-ex. chromatographic techniques or recrystallization techniques, or they can be prepared separately from suitable isomers of their intermediates. The enantiomers of the compounds according to the invention and the process for the preparation are those specially described in the 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 others 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 Prepare as follows: Approximately 3 g of 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 Brüker 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 normalized by vectorization in the spectral range 4000-400 cm-1 as an absorption spectrum. The following preset was made: - 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) CuKal radiation at 1.5406 Á (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 (), 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 (w), 521 +/- 1.5 (), 478 + / - 1,5 (w) FT-Raman bands (in cm "1): 3217 +/- 1,5 (), 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 (w), 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 (w), 603 +/- 1,5 (w), 573 +/- 1,5 (w), 549 +/- 1,5 (), 527 +/- 1,5 (w) For this document, it is understood that tautomeric forms are included when mentioning a given group, for example thio / mercapto or oxo / hydroxy. 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" 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 may be optionally substituted. Mention may be made in particular of the radicals, in particular biphenyl, phenyl, naphthyl, anthryl and phenanthryl; - 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 "hetero (C6-C14) aryl" refers to a 6-14 membered aromatic heterocycle containing 1-4 heteroatoms, with the remaining atoms being carbon atoms. Among the heteroatoms, oxygen, sulfur and nitrogen can be particularly mentioned. Among the heteroaryl radicals, more particularly, furyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, oxazolyl, oxadiazolyl, isoxazolyl, quinolyl and thiazolyl radicals may be mentioned; - the term "(C3-C8) cycloalkyl" refers to a saturated ring based on hydrocarbons and contains monocyclic, bicyclic and polycyclic radicals containing between 3 and 8 carbon atoms. The cyclopropyl and cyclobutyl radicals can be mentioned, without limitation. 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 in 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 hypertension, as well as in certain microvascular and macrovascular complications, for example, atherosclerosis, retinopathy and neuropathy. In this regard, reference will be made, for example, 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 a statin can be prepared by mixing the various active ingredients, either by mixing all at once or independently with a vehicle, an excipient, a binder, a diluent, etc., suitable for physiological use. It is then administered orally or non-orally, for example parenterally, intravenously, cutaneously, nasally or rectally. 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, either successively or at intervals. The pharmaceutical compositions of the invention include formulations such as granules, powders, primers, 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 (for example lactose, sucrose, starch, mannitol, etc.), a disintegrant (for example calcium carbonate, 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 examples include 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 (e.g. talc, magnesium stearate, polyethylene 6000, etc.) for example, are added to the active ingredient (s) and the The obtained one is then pressed into tablets. If necessary, the tablet can be coated with the known techniques in order to mask the taste (for example with cocoa powder, mint, borneol, cinnamon powder, etc.) or to allow enteric dissolution or sustained release of the active ingredients. The products that can be used for the Coating are, for example, ethyl cellulose, hydroxymethyl cellulose, polyoxyethylene glycol, cellulose acetophthalate, hydroxypropylmethyl cellulose phthalate and Eudragit® (methacrylic acid copolymer with acrylic acid), Opadry® (hydroxypropylmethylcellulose + macrogol + titanium oxide + lactose monohydrate). Dyes suitable for pharmaceutical use can be added (for example 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 ingredients in water, followed by the addition of flavorings, colorants, 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. He or she active ingredients are dissolved, suspended or emulsified in an aqueous medium (for example distilled water, physiological solution, Ringer's solution, etc.) or in an oily medium (for example a vegetable oil, such as olive oil, sesame oil, cotton 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-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 (for example lactose, mannitol, starch, microcrystalline cellulose, sucrose, etc.) and a thickener (for example 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 de 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, etc.) and also other additives. More particularly, if lovastatin is used in the present invention, the daily dose is between 10 mg and 40 mg, more preferably 20 mg. If fluvastatin is used, the daily dose is between 20 mg and 40 mg. If atorvastatin is used, the daily dose is between 10 mg and 80 mg and preferably between 10 mg and 40 mg. If simvastatin is used, the daily dose is between 5 mg and 50 mg and preferably between 5 mg and 20 mg. If cerivastatin is used, the daily dose is between 0.1 mg and 0.8 mg and preferably between 0.1 mg and 0.3 mg. If pravastatin is used, the daily dose is between 10 mg and 40 mg, preferably 20 mg. If atavastatin is used, the daily dose is between 1 mg and 20 mg and preferably between 2 mg and 20 mg. If rosuvastatin is used, the daily dose is between 4 mg and 80 mg and preferably between 10 mg and 20 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 HMG-CoA reductase inhibitors, or of their pharmaceutically acceptable salts, and of the compounds of the formula (I), or of their pharmaceutically acceptable salts, vary accordingly. Preferably, the weight ratio of the HMG-CoA reductase inhibitor and the compound of the formula (I) is between 1/2 and 1/20 000, 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 compounds of the formula (I) require more than one daily administration, the amounts of HMG-CoA reductase inhibitors and the inhibitory ratio of the HMG-CoA reductase / compound of the formula (I) ratios will be adjusted accordingly. It is also an object of the present invention to propose a method of treatment by means of the co-administration of effective doses of a compound of the formula (I) and an inhibitor of the HMG-CoA reductase, 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 HMG-CoA reductase inhibitors in the doses indicated above, for 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 which may be up to 2 hours or even up to 12 hours. For example, the term co-administration includes: (1) a simultaneous administration of the 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 for the 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-hydrochloride methyl-1, 3, 5-triazine: 1000 mg atorvastatin: 10 mg microcrystalline cellulose: 110 mg croscarmellose: 28 mg polyvinyl pyrrolidone: 40 mg magnesium stearate: 14 mg Opadry: 24 mg Formulation example 2: (+) - hydrochloride 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine: 1000 mg fluvastatin: 20 mg microcrystalline cellulose: 115.5 mg croscarmellose: 28 mg polyvinylpyrrolidone: 40 mg magnesium stearate : 9 mg Opadry®: 24 mg Formulation example 3: (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride: 750 mg pravastatin: 10 mg microcrystalline cellulose: 89 mg croscarmellose: 21 mg polyvinyl pyrrolidone: 30 mg magnesium stearate: 10.5 mg Opadry®: 18 mg Formulation Example: (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride: 1000 mg atorvastatin: 30 mg microcrystalline cellulose: 150 mg croscarmellose: 24 mg polyvinylpyrrolidone: 44 mg magnesium stearate: 8 mg Eudragit®: 24 mg Formulation example 5: (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-hydrochloride -triazine: 1000 mg lovastatin: 20 mg silicon dioxide: 4 mg croscarmellose: 25 mg polyvinyl pyrrolidone: 40 mg magnesium stearate: 8 mg Opadry®: 10 mg Biological results of the combinations according to the invention The synergistic action of the combinations according to the invention is demonstrated using an animal model. Obese rats (obese Zucker (fa / fa)) are used to simulate non-insulin-dependent diabetes (NIDDM). The action of lovastatin alone and of the compound. { +) -2- amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, hydrochloride salt, alone and the combination of these two agents is evaluated in terms of triglycerides, total cholesterol, high density lipoprotein C (HDL C), glucose and insulin. The rats received the treatment for 5 consecutive days. The blood samples are taken 3 days before and 5 days after the start of the treatments to measure the levels of triglycerides, total cholesterol, HDL C, glucose and insulin. The following procedure is adopted. Four groups of eight rats are formed: - a "vehicle" group; a group that receives a dose of 1 mg / kg / day of oral lovastatin; - a group receiving a dose of 50 mg / kg or 100 mg / kg twice a day (bid) of (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1, 3 , 5-triazine, hydrochloride salt, oral; a group receiving a dose of 1 mg / kg / day of lovastatin + 50 mg / kg or 100 mg / kg twice a day (bid) of (+) -2-amino-3,6-dihydro-4-dimethylamino -6-methyl-l, 3, 5-triazine, hydrochloride salt, oral. The statistical analysis consists of an analysis of variance for a classification criterion, followed by multiple comparisons versus the vehicle group (Dunnett's test). To evaluate the meaning of the results obtained, the values are expressed as mean ± ESM. A difference is considered significant for p < 0.05. The results are expressed in millimoles per liter (mM) or in nanomoles per liter (nM). 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 (31)

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 an active principle: i) an inhibitor of HMG-CoA reductase, ii) a triazine derivative of formula (I)
2. (I) wherein: R1, R2, R3 and R4 are independently selected from the following groups: H, (C1-C20) alkyl optionally substituted with halogen,
3. (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,
4. (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 (C1-C5) alkyl or (C1-C5) (C6-C14) alkoxy (C1-C20) alkyl 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, - (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, (C1-C5) alkoxy,
5. (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy,
6. (C6-C1) 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 with the nitrogen atom a ring of n members (n is between 3 and 8) optionally containing one or more heteroatoms selected from N, 0 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, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) aryl (Cl-)
7. 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, (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, (C1-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, (C1-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 and 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, 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,
8. (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-C1) ) 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) optionally containing one or more heteroatoms selected from N, 0 and S and may be 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, or can form with the carbon atom a C10-C30 polycyclic residue optionally 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, 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 (C1-C5) alkyl or (Cl-C6) acyl, and also the racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures of the same, and their salts acceptable for pharmaceutical use, and one or more excipients 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-C1) aryloxy, (C6-C14) aryl (C1-C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl. 4. Pharmaceutical composition according to any of the preceding claims, characterized in that it comprises a compound of the formula (I) wherein R1, R2, R3 and R4 are independently selected from H and optionally substituted groups (Cl-C20) alkyl with halogen, (Cl-C5) alkyl, (C1-C5) alkoxy or (C3-C8) cycloalkyl. 5. Pharmaceutical composition according to any of the preceding claims, characterized in that it comprises a compound of the formula (I) wherein R5 and R6 are independently selected from H and (Cl-C20) alkyl groups optionally substituted with amino, hydroxyl , thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (Cl-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C1) aryl (C1-C5) ) alkoxy, cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl. 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. Pharmaceutical composition according to any of the preceding claims, characterized in that the compound of the formula (i) is 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine. 8. Pharmaceutical composition according to any of claims 1 to 6, characterized in that the compound of the formula (i) is (-) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1, 3, 5-triazine.
9. 9. Pharmaceutical composition according to any of claims 1 to 6, characterized in that the compound of the formula (i) is (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1, 3, 5-triazine.
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 inhibitor of hmg-coa reductase is a statin.
12. 12. Pharmaceutical composition according to claim 11, characterized in that the statins are in the form of a salt selected from hydrochloride, hydrobromide, iodide, sulfate, nitrate, phosphate, citrate, methane sulfonate, trifluoroacetate and acetate, the sodium ion, the ion potassium, the calcium ion and the magnesium ion.
13. 13. Pharmaceutical composition according to any of the preceding claims, characterized in that these pharmaceutical compositions contain between 0.1 mg and 80 mg of hmg-coa reductase inhibitor.
14. 14. Pharmaceutical composition according to any of the preceding claims, characterized in that these pharmaceutical compositions contain between 200 mg and 2000 mg of a compound of the formula (i).
15. 15. Pharmaceutical composition according to any of the preceding claims, characterized in that the weight ratio between the inhibitor of hmg-coa reductase and the compound of the formula (i) is between 1/2 and 1/20 000.
16. 16. Pharmaceutical composition according to any of the preceding claims, characterized in that the statin is selected from simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, velostatin, itavastatin, sivinoline and pitivastatin.
17. 17. Pharmaceutical composition according to any of the preceding claims, characterized in that the statin is simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin or rosuvastatin.
18. 18. Pharmaceutical composition in accordance with Any of the preceding claims, characterized in that the statin is simvastatin and the compound of the formula (i) is (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5- triazine, optionally in the form of a hydrochloride.
19. 19. Pharmaceutical composition according to any of claims 1 and 17, characterized in that the statin is atorvastatin and the compound of the formula (i) is (+) -2-amino-3,6-dihydro-4-dimethylamino-6. -methyl-1,3,5-triazine, optionally in the form of a hydrochloride.
20. 20. Pharmaceutical composition according to any of claims 1 and 17, characterized in that the statin is fluvastatin and the compound of the formula (i) is (+) -2-amino-3,6-dihydro-4-dimethylamino-6. -methyl-1,3,5-triazine, optionally in the form of a hydrochloride.
21. 21. Pharmaceutical composition according to any of claims 1 and 17, characterized in that the statin is lovastatin and the compound of the formula (i) is (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, optionally in the form of a hydrochloride.
22. 22. Pharmaceutical composition according to any of claims 1 and 17, characterized in that the statin is pravastatin and the compound of the formula (i) is (+) -2-amino-3,6-dihydro-4-dimethylamino-6. -methyl-1,3,5-triazine, optionally in the form of a hydrochloride.
23. 23. Pharmaceutical composition in accordance with any of claims 1 and 17, characterized in that the statin is rosuvastatin and the triazine derivative is (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, optionally in the form of a hydrochloride.
24. 24. Pharmaceutical composition according to any of the preceding claims, which is suitable for oral administration, characterized in that the pharmaceutical composition is powder, tablets, gel capsules, sachet, solution, suspension or emulsion.
25. 25. Use of an inhibitor of hmg-coa reductase 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 .
26. 26. Use according to claim 23, for the preparation of a medicinal combination for the treatment and / or prevention of non-dependent insulin diabetes.
27. 27. Use of an inhibitor of hmg-coa reductase 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 insulin resistance syndrome, selected from dyslipidemia, obesity, hypertension, and microvascular and macrovascular complications, for example atherosclerosis, retinopathy, nephropathy and neuropathy.
28. 28. Use according to claim 25, 26 or 27, wherein the HMG-CoA reductase inhibitor according to claim 16 or 17.
29. 29. Use according to any of claims 27 or 28, wherein the combination is according to claims 18 to 23.
30. 30. Use according to any of claims 25 to 29, wherein the administration of the compound (I) and wherein the HMG-CoA reductase inhibitor are simultaneous, separate or consecutive.
31. 31. A set of elements characterized in that it comprises a compound of the formula (I) according to any of claims 1 to 10 and an inhibitor of the HMG-CoA reductase according to claim 16 or 17, for simultaneous, separate administration or at intervals.