MX2008008894A - Combination of triazine derivatives and insulin secretion stimulators - Google Patents

Abstract

The present patent application relates to novel combinations of a triazine derivative and of an insulin secretion stimulator.

Description

COMBINATION OF TRIAZINE DERIVATIVES AND INSULIN SECRETION STIMULATORS FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition of triazine derivatives or their pharmaceutically acceptable salts described with a stimulator of insulin secretion, for the manufacture of a medicament that can be used in the treatment of diabetes non-insulin dependent and pathologies associated with 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. : 193437 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. Hyperglycemia 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", mention may be made of particularly repaglinide (NovoNorm®); • 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®). 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. The studies have shown that it is possible to face this problem by combining in the same pharmaceutical form metformin with sulfonylureas or TZD (EP 869 796 Bl, EP 974 365 Bl, EP 861 666 Bl, WO 03/006004 A2), a series of these have been commercialized fixed combinations: • metformin + glibenclamide / glyburide (Glucovance®) • metformin + glipizide (Metaglip®) • metformin + rosiglitazone (Avandamet®). In WO 01/55122, triazine derivatives having an antidiabetic effect comparable to that of metformin have been described. BRIEF DESCRIPTION OF THE INVENTION The Applicant has demonstrated, in a totally unexpected manner, that the combination of a triazine-type antidiabetic agent, such as those described in WO 01/55122, with a stimulator of insulin secretion exhibits a synergistic effect and a strong reduction of side effects compared to combinations with metformin, especially in what it does to nausea and diarrhea. DETAILED DESCRIPTION OF THE INVENTION Therefore, the present invention relates to a new pharmaceutical composition comprising an antidiabetic agent of the triazine type (WO 01/55122) and a stimulator of insulin secretion with one or more excipients acceptable for pharmaceutical use.

The triazine derivative is preferably represented by the general formula (I): R2 H R4 III R1 ^ (Y R3 NN R5 R6 where: 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 by halogen, (C1-C5) alkyl or (C1-C5) alkoxy- (C3-C8) cycloalkyl optionally substituted by (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) alkoxy- (C6-C14) aryl (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, (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 of n members with the nitrogen atom (n is between 3 and 8) optionally containing one or more heteroatoms selected from N, 0 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) a ryloxy, (C6-C14) aryl (C1-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-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, (Cl-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, (C1-C5) alkoxy, (Cl-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, 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 optionally substituted with amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (Cl-C5) alkylthio, (C1-C5) alkylamino, (C6-C1) 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, (Cl-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 Rβ can form with the carbon atom to which they are united a ring of m members (m is between 3 and 8) which optionally contains one or more se heteroatoms cited between N, 0 and S and can 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 C10-C30 polycyclic residue optionally substituted with amino, hydroxyl , uncle, 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 together may 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, (C6-C14) aryl, (C6-C14) -aryl (Cl-C5) group ) alkyl or (Cl-Cβ) acyl, and also the racemic, tautomeric, enantiomeric, diastereomeric, epimeric and mixtures thereof, and their pharmaceutically acceptable salts. 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 relates to the pharmaceutical compositions according to the invention wherein the triazine derivatives are compounds of the formula (I) where 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, 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-) 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 (Cl-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 H and -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 with halogen, (C1-C5) alkyl, (C1-C5) alkoxy or (C3-) C8) cycloalkyl; more preferably, R1 = R2 = H and R3 = R4 = (C1-C20) alkyl optionally substituted by halogen, (C1-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) "to the chyle, (Cl-C5) alkoxy, (Cl-) C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C1) 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, (Cl-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkyl thio, (C1-C5) -alkylamino , (C6-C1) aryloxy, (C6-C14) aryl (Cl-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. These of formula (I): and more preferably the compound of Example 18. The term "insulin secretion stimulator" means any agent commonly used in human or veterinary therapy to stimulate the insulin secretor in the case of a patient in need thereof. Preferred especially sulfonylureas, glinides, glucagon receptor antagonists, incretin hormones, in particular glucagon-type-peptide-1 (GLP-1) or GLP-1 agonists, and DPP-IV inhibitors. The term "glucagon receptor antagonist" in particular includes the compounds described in WO 98/04528, in particular in BAY27-9955, and also those described in Bioorg. Med. Chem. Lett. 1992, 2, 915-918 and more particularly in CP-99,711, those described in J. Med. Chem. 1998, 41, 5150-5157 and in particular NNC92-1687, those described in J. Biol. Chem. , 1999, 274, 8694-8697 and in particular L-168,049, and those described in US 5 880 139, WO 99/01423, US 5 776 954, WO 98/22109, WO 98/22108, WO 98/21957 and WO 97/16442. The term "sulfonylureas" relates compounds that activate the secretion of insulin by beta cells of the pancreas by transmitting a signal via the sulfonylurea receptors located in the membrane. This includes (without limitation) tolbutamide, chlorpropamide, tolazamide, acetoxamide, glycopyramide, gliben-chlamide / glyburide, gliclazide, l-butyl-3-methanediylurea, carbutamide, glibomuride, glipizide, gliquidone, glisoxepide, glibutiazole, glibuzol, glihexamide, glimidine, glipinamide , fenbutamide, tolyl cyclamide and glimepiride, more preferably glibenclamide / glyburide, gliclazide, glimepiride and glipizide. The term "glinida" in particular means repaglinide. The term "glucagon receptor agonist" in particular includes compounds, such as GLP-1 (7-37), wherein the terminal amide of Arg36 is displaced with Gli to position 37 of GLP-1 (7-36) H2 and also variants and analogues, such as GLN9-GLP-1 (7-37), D-GLN9-GLP-1 (7-37), acetyl LYS9-GLP-K7-37), LYS18-GLP-1 (7- 37) and, in particular, GLP-1 (7-37) OH, VAL8-GLP-1 (7-37), GLI8-GLP-1 (7-37), THR8-GLP-1 (7-37), MET8-GLP-1 (7-37) and 4-imidazopropionyl-GLP-1. A particular preference is also given to the GLP agonist known as exendin-4, described by Greig et al. in Diabetology, 1999, 42, 45-50. The term "DPP-IV inhibitor" in particular includes compounds, such as, but not limited to, those described in WO 97/40832, WO 98/19998, DE 196 16 486 A1, WO 00/34241, WO 95/15309, WO 01/47514 and WO 01/52825, WO 2005/033099, WO 2005/058849 and WO 2005/075426. Preferred compounds are l- (2 - [(5-cyanopyridin-2-yl) amino] ethylamino) acetyl-2 (S) -cyanopyrrolidine dihydrochloride (Example 3 of WO 98/19998), (S) 1- [( 3-hydroxy-l-adamantyl) amino] acetyl-2-cyanopyrrolidine (Example 1 of WO 0034241), LAF-237, MK-0431, PSN-9301, BMS-477118, GW-825964, T-6666, SYR-322 , PHX-1149, LC-15-0133, FE-99901, GRC-8200, KF- 81364, SSR-162369, CP-867534-01 and TP-8211. According to another preferred embodiment, the invention in more particular form relates to pharmaceutical compositions comprising combinations selected from: • (+) -2-amino-3,6-dihydro-4-dimethylamino-methyl-1,3-hydrochloride. , 5-triazine, and glibenclamide; • (+) -2-amino-3,6-dihydro-4-dimethylamino-methyl-1,3,5-triazine hydrochloride, and glimepiride; • (+) -2-amino-3,6-dihydro-4-dimethylamino-methyl-1,3,5-triazine hydrochloride and glipizide; • (+) -2-amino-3,6-dihydro-4-dimethylamino-methyl-l, 3,5-triazine hydrochloride, and gliclazide. The invention also relates to the racemic, tautomeric, enantiomeric, diastereomeric and epimeric forms, and mixtures thereof, and also the pharmaceutically acceptable salts and esters of the compounds of the general formula (I). The compounds of the formula (I) according to the invention 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 acceptable organic or mineral acids" 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, 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 acid para-toluenesulfonic 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). , the following chiral acids are used: (+) - D-di-O-benzoyltartaric acid, (-) - L-di-O-benzoiltar acid Tárico, (-) - L-acid di-O, O '-p-toluil-L-tartaric, acid (+) - D-di-0,0' -p-toluil-L-tartaric, acid (R) - (+) - mica, (S) - (-) - málico acid, (+) - canfánico acid, (-) - canfánico acid, R- (-) -1, 1 '-bibftalen-2, 2' acid -dihydro-hydrogen phosphonic acid, (+) - caphoric acid, (-) - camphoric acid, (S) - (+) -2-phenylpropionic acid, (R) - (+) -2-phenylpropionic acid, D- (-) - acid mandelic acid, L- (+) - mandelic acid, D-tartaric acid, L-tartaric acid, or a mixture of two or more thereof.

The enantiomers of the compounds according to the invention and the process for separating them are described in particular 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 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: - Brüker Vector 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 -: 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 RA AA21505 method) - 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 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 20 ± 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 (w), 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 (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 (), 603 +/- 1.5 (w), 573 +/- 1,5 (w), 549 +/- 1,5 (w), 527 +/- 1,5 (w) 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" 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 "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, furyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, oxazolyl, oxadiazolyl, isoxazolyl, quinolyl and thiazolyl radicals may be mentioned more particularly.; - the term "(C3-C8) cycloalkyl" refers to a saturated ring based on hydrocarbons and includes monocyclic, bicyclic and polycyclic radicals containing between 3 and 8 carbon atoms. Mention may be made, without limitation, of cyclopropyl and cyclobutyl radicals; - 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. 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. For this document, it is understood that tautomeric forms are included when 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 in the action of insulin (see Presse Médicale, 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 (diabetes type II 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 Compli ca tions, 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 and, more particularly, to optimize the use of glucose. 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 secretion stimulator 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 may be mixed together extemporaneously using a diluent and administered in this manner, or they may be administered independently of one another, both successively and consecutively. 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 (for example lactose, sucrose, starch, mannitol, etc.), a disintegrant (for example calcium carbonate, calcium carboxymethyl cellulose, alginic acid, sodium carboxymethylcellulose, colloidal silicon dio, 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 (for example talcum, magnesium stearate, polyethylene 6000, etc.) for example, are added to the active ingredient (s) and the mixture obtained 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, ethylcellulose, hydroxymethylcellulose, polyoxyethylene glycol, cellulose acetophthalate, hydroxypropylmethylcellulose phthalate and Eudragit® (copolymer of methacrylic acid 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 be 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 oxymethylcellulose. 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, oxymethylcellulose, sodium alginate, etc.), a preservative (eg methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol, chlorobutanol, phenol, etc.), an isotonic agent (eg, sodium, glycerol, sorbitol, glucose, etc.) and also other additives, such as, if desired, a solubilizing agent (for example sodium salicylate, sodium acetate, etc.) or a stabilizer (for example human serum albumin). A pharmaceutical form can be obtained for external use 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 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, onic 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. 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, the relationships between the respective amounts of the insulin secretion stimulator and the compound of the formula (I) vary accordingly. The weight ratio between the secretion stimulator of insulin and the compound of the formula (I) is preferably between 1/1000 and particularly from 4/100 and especially from 1/500 to 4/100 or, more preferably, from 1/300 to 4/100. The doses will depend on those usually used for the active ingredients. Therefore, for the stimulator of insulin secretion, the doses are between 1 and 6 mg / day for glimepiride, from 1.5 to 15 mg / day for glibenclamide, from 30 to 120 mg / day for gliclazide and from 2.5 to 20 mg / day for glipizide. For the compound of the formula (I), the daily doses are between 200 mg and 2000 mg. 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 a stimulator of the secretion of insulin, and also of sets of elements to allow this co-administration The present invention also concerns 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 stimulator of insulin secretion 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 by 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-methyl-1,3,5-triazine hydrochloride: 1000 mg glibenclamide: 5 mg microcrystalline cellulose: 113 mg croscarmellose: 28 mg polyvinyl pyrrolidone: 40 mg magnesium stearate: 14 mg Opadry: 24 mg Formulation example 2: (+) -2-amino-3,6-dihydro-4- hydrochloride dimethylamino-6-methyl-1,3,5-triazine: 1000 mg glibenclamide: 2.5 mg microcrystalline cellulose: 115.5 mg croscarmellose: 28 mg polyvinylpyrrolidone: 40 mg magnesium stearate: 9 mg Opadry®: 24 mg Example Formulation 3: (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride: 750 mg glibenclamide: 5 mg microcrystalline cellulose: 89 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-1,3,5-triazine hydrochloride: 1000 mg gliclazide: 30 mg microcrystalline cellulose: 150 mg croscarmellose: 24 mg polyvinyl pyrrolidone: 44 mg magnesium stearate: 8 mg Eudragit®: 24 mg Formulation example 5: (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3-hydrochloride, 5-triazine: 1000 mg glimepiride: 1 mg Silicon dioxide: 4 mg croscarmellose: 25 mg polyvinyl pyrrolidone: 40 mg magnesium stearate: 8 mg Opadry®: 10 mg Biological test: Modulation of glucose levels with the combinations of the invention with insulin secretion stimulators The ability of the compounds of the invention in combination with anti-diabetic compounds to stimulate insulin secretion to modify blood glucose levels 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, administering orally 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. 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 (29)

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) a stimulator of insulin secretion, ii) a triazine derivative of the formula (I) (l) 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 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, 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 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, 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) which optionally contains 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, (C1-C5) alkylamino, (C6-C14) aryloxy, ( C6-C14) aryl (Cl-
2. C5) alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, R5 and R6 are independently selected from the following groups: -H, - (C1-C20) alkyl 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, - (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, carboxyl, carboxymethyl or carboxyethyl, - (C3-C8) cycloalkyl uyl 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, -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) optionally substituted aryl 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, - (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 between N, O and S and can 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-C14) aryl (Cl-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 (C1-C6) acyl, and also the racemic, tautomeric, enantiomeric, diastereomeric, epimeric and polymorphic forms, and mixtures thereof, 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. 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 by amino, hydroxyl, thio, halogen, (Cl-C5) alkyl, (C1-C5) alkoxy, (C 1 -C 5) 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.
4. 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. 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-C14) -aryl (C1- C5) lcoxy, 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 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, and also the racemic, tautomeric, enantiomeric, diastereoisomeric, epimeric and mixtures thereof, and their pharmaceutically acceptable salts.
8. 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, and also the racemic, tautomeric, enantiomeric, diastereoisomeric, epimeric and mixtures thereof, and their pharmaceutically acceptable salts.
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, and also the racemic, tautomeric, enantiomeric, diastereoisomeric, epimeric and mixtures thereof, and their pharmaceutically acceptable salts.
10. 10. Pharmaceutical composition according to any of the preceding claims, characterized in that the compound of the formula (I) is in the form of hydrochloride.
11. 11. Pharmaceutical composition according to any of the preceding claims, characterized in that these pharmaceutical compositions contain between 1 mg and 120 mg of stimulator of insulin secretion.
12. 12. Pharmaceutical composition according to any of the preceding claims, characterized in that these pharmaceutical compositions contain between 200 mg and 2000 mg of the compound of the formula (I).
13. 13. Pharmaceutical composition according to any of the preceding claims, characterized in that the weight ratio of a stimulator of insulin secretion to the compound of formula (I) is between 1/1000 and 1/100.
14. 14. Pharmaceutical composition according to any of the preceding claims, characterized in that the weight ratio of a stimulator of insulin secretion to the compound of formula (I) is between 1/300 and 1/100.
15. 15. Pharmaceutical composition according to any of the preceding claims, characterized in that the stimulator of insulin secretion is selected from among glucagon receptor antagonists, incretin hormones, DPP-IV inhibitors, sulfonylureas and glinides.
16. 16. Pharmaceutical composition according to claim 15, characterized in that the sulfonylurea is selected from tolbutamide, chlorpropamide, tolazamide, acetoxamide, glycopyramide, glibenclamide / glyburide, gliclazide, l-butyl-3-methanylylurea, carbutamide, glibomuride, glipizide, gliquidone, glisoxepide, glibutiazol, glibuzol, glihexamida, glimidina, glipinamida, fenbutamida, tolilciclamida and glimepirida.
17. 17. Pharmaceutical composition according to claim 15 or 16, characterized in that the sulfonylurea is glibenclamide, gliclazide, glimepiride or glipizide.
18. 18. Pharmaceutical composition according to any of the preceding claims, characterized in that the stimulator of insulin secretion is glibenclamide 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 to 17, characterized in that the stimulator of insulin secretion is gliclazide 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 to 17, characterized because the stimulator of insulin secretion is glipizide and the compound of formula (I) is (+) -2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, advantageously in the form of a hydrochloride.
21. 21. Pharmaceutical composition according to any of claims 1 to 17, characterized in that the stimulator of insulin secretion is glimepiride and the derivative of triazine 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 the preceding claims, characterized in that it is suitable for oral administration, wherein the pharmaceutical composition is a powder, a coated tablet, a gel capsule, a sachet, a solution, a suspension or an emulsion .
23. 23. The use of an insulin secretion stimulator in combination with a compound of the formula (I) according to any of claims 1 to 10, which is for the preparation of a medicinal combination for the treatment and / or the prevention of diabetes.
24. 24. The use according to claim 23, which is for the preparation of a medicinal combination for the treatment and / or prevention of non-insulin-dependent diabetes.
25. 25. The use of an insulin secretion stimulator in combination with a compound of the formula (I) according to any of claims 1 to 10, which is for the preparation of a medicinal combination for the treatment of at least one of the pathologies associated with the syndrome of insulin resistance, which is chosen between dyslipidemia, obesity, arterial hypertension and microvascular and macrovascular complications, p. ex. , atherosclerosis, retinopathy, nephropathy and neuropathy.
26. 26. The use according to claims 23 to 25, wherein the insulin secretion stimulator is defined in accordance with claims 15 to 17.
27. 27. The use according to any of claims 23 to 26, wherein the combination is that defined in claims 18 to 21.
28. 28. The use according to any of claims 23 to 27, wherein the administration of the compound ( I) and that of the stimulator of insulin secretion is done simultaneously, separately or consecutively.
29. 29. 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 insulin secretion stimulator, according to any of claims 15 to 17, which is for simultaneous, separate or consecutive administration.