MX2008006259A - 2,3,4,5-tetrahydroxy-6-sulfooxyhexanoic acid and its metal salts for medical use - Google Patents

Abstract

The invention relates to novel compounds of general formula I wherein M represents hydrogen, or a metallic cation, preferably an alkaline metal, or alkaline-earth metal, and n is equal to 1, 2 or 3. The present invention also comprises compounds of general formula I in their equilibrium forms, including lactonic forms, their enantiomers in pure form, or in an enriched form in one of the optical isomers, racemic mixtures, diastereomers and solvates thereof. The present invention further relates to processes for the preparation of compounds of general formula I, to pharmaceutical compositions comprising compounds of general formula I as only active ingredient, or in association with other active ingredients. Another aspect of the invention is the use of compounds of general formula I for the treatment of dyslipidemia, associated, or not, to other metabolic disorders, such as glucose intolerance syndrome and type 1 or 2 diabetes mellitus, by means of isolated administration or combined with other substances.

Description

ACID 2,3,4,5-TETRAHIDROXI-6-SULFOOXIHEXANOICO AND ITS METAL SALTS FOR MEDICAL USE FIELD OF THE INVENTION The invention relates to novel compounds of the general formula I, wherein M, represents hydrogen, or a metal cation, preferably an alkali metal, or alkaline earth metal and n is equal to 1, 2 or 3. The present invention also comprises the compounds of the general formula I, in their balanced forms, including lactone forms, their enantiomers in pure form, or in a form enriched in one of the optical isomers, the racemic mixtures, diastomers and solvates thereof. The present invention is further related to the processes for the preparation of the compounds of the general formula I, to the pharmaceutical compositions comprising the compounds of the general formula I, as the sole active ingredient, or in association with other active ingredients.

Another aspect of the invention is the use of the compounds of the general formula I, for the treatment of dyslipidemias, associated, or not, with other metabolic disorders, such as glucose intolerance syndrome and diabetes mellitus type 1 or 2, by means of administration alone or in combination with other substances.

BACKGROUND OF THE INVENTION For some decades, it has been evident that dyslipidemias are the main risk factor for the presence of cardiovascular diseases. Epidemiological studies carried out in human subjects, have made it evident that a high level LDL-C (low density lipoprotein cholesterol) associated with a reduced level of HDL-C (high density lipoprotein cholesterol), induce early atherosclerosis. On the other hand, several studies showed that the risk of coronary heart disease (CHD) can be reduced through hypocholesterolemic therapy. The Framigham Heart Study, the Multiple Risk Factor Intervention (MRFIT) and the Lipid Research Studies (LRC) found a direct relationship between the serum LDL-C concentration and the percentage of events in patients (men and women) with acute coronary disease with no history of CHD. Many studies show that the risk of coronary heart disease can be reduced due to lipid-lowering therapy. Until 1987, therapeutic strategies aimed at reducing lipids were essentially limited to a diet low in saturated fats and bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), fibrates and probucol. Unfortunately, all these treatments have limited efficacy or tolerability, or both. Only after the emergence of the HMG-CoA reductase inhibitors, such as lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, derivatives and their analogue, have physicians been able to obtain comparatively high plasma cholesterol reductions with very high few adverse effects. The administration of these compounds is associated with a reduction in the mortality rate associated with coronary heart disease, and the risk of acute myocardial infarction, coronary revascularization procedures, cerebrovascular accident and peripheral vascular disease. The most frequently reported adverse effects are muscular (myopathy) and hepatic (increased liver enzymes). Inhibitors of HMG-CoA reductase, are they indicate for patients with dyslipidemia, essentially with an increase in LDL-C, when the diet turns out to be insufficient to control the disorder. Patterns with additional risk factors, similar to coronary heart disease or equivalents, diabetes mellitus and risk factors for coronary heart disease, should be treated promptly and intensively. In these circumstances, the objective that will be reached for the serum LDL-C concentration (<; 100 mg / dl), requires higher doses of HMG-CoA inhibitors and / or association with other compounds. This therapeutic area has been the target of intense research and novel lipid-lowering agents are being studied. The present invention discloses novel compounds useful for the treatment of hypocholesterolemia and atherosclerosis, a process for preparing them and the pharmaceutical compositions containing them. It has long been known to prepare inorganic esters through the attack of an inorganic acid to an alcohol (see, for example, "Advanced Organic Chemistry, Reaction Mechanisms and Structure" 4th edition, Jerry March, Wiley Interscience 1992). Namely, this reaction is used for the industrial production of detergents and cleaning agents, when fatty alcohols are produced to react with sulfuric acid and later they become salts. However, these compounds are structurally different from the compounds of the present invention. In the prior art, no reference to the general formula I has been found, nor for the processes of its preparation, or attempts for its synthesis and, as a result, no reference has been found for possible industrial applications. The reaction using a d-1-gluconic acid substrate, or the racemic mixture, salts or lactones thereof to provide the corresponding monosulfates is novel.

SUMMARY OF THE INVENTION In one aspect, the present invention relates to novel compounds of the general formula I, wherein M, represents hydrogen, or a metal cation, preferably an alkali metal, or alkaline earth metal and n is equal to 1, 2 or 3. The present invention also comprises the compounds of the formula General I, in its balanced forms, including lactone forms, its enantiomers in pure form, or in a form enriched in one of the optical isomers, racemic mixtures, diastomers and solvates thereof. The present invention is further related to the processes for the preparation of the compounds of the general formula I, to the pharmaceutical compositions comprising the compounds of the general formula I, as the sole active ingredient, or in association with other active ingredients, and its use for the treatment of hypocholesterolemia and atherosclerosis.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 illustrates a 1 H-NMR spectrum in D20 (300 MHz) of the calcium salt of 2,3,3,5-tetrahydroxy-6-sulfooxyhexanoic acid. Figure 2 illustrates an average mass spectrum of the calcium salt of 2, 3, 5-tetrahydroxy-6-sulfooxyhexanoic acid. An electrospray ionization source (ESI) was used with a voltage source of 4.5 kV, a capillary voltage of -24 V and an ion trap.

DETAILED DESCRIPTION OF THE INVENTION Monosulfate esters could be expected of compounds with polyalcoholic functions using sulfuric acid may not be interesting for synthetic purposes, due to the formation of mixtures comprising olefin monosulfate esters, saturated and unsaturated polysulphated esters and products for the dehydration of polyhydroxyalcohols. Despite the low yield, surprisingly, it was found that the reaction between the d-1-gluconic acid, or the racemic mixture, of its lactone, or the salts thereof, in the absence or presence of an organic base, or amino acids, originated the products of the general formula I, with a low contamination of by-products of dehydration and other sulfates. In another aspect, the present invention discloses the processes for the production of compounds of the general formula I. These processes comprise the cooling of an aqueous solution of d-1-gluconic acid 50%, or a racemic mixture, or lactone thereof in an ice bath and the slow addition of sulfuric acid, keeping the temperature below 40 ° C. ° C. It is also possible to add an organic base, or an amino acid, such as, glycine, dimethylglycine, alanine, serine, cysteine, methanolamine, ethanolamine, or analogs thereof, preferably dimethylglycine, to an aqueous solution of d-1-gluconic acid 50%, or a racemic mixture, or lactone thereof and add the mixture until complete dissolution, at a temperature between 30- 70 ° C. The mixture is placed in a bath with ice and concentrated sulfuric acid is added slowly, keeping the temperature below 40 ° C. The mixture is further stirred for 3 hours at 40 ° C, or at a slightly lower temperature. The water is removed by distillation under vacuum at a solids content of 75-78% and the reaction mixture is allowed to stand overnight at 40 ° C. Again the water is extracted by distillation under vacuum to a solids content of 81-82%. The mixture is neutralized when adding, slowly under agitation while continuing to cool, an excess amount of an aqueous suspension of a base, such as, alkali metal hydroxides, alkali metal carbonates, alkaline earth metal hydroxides, alkaline earth metal carbonates, until a stable pH is reached in the variation of 4.5-9.0. The sulfates are removed by filtration and the precipitate is washed with water. The washings and the filtrate are combined and a salt of the freshly prepared 2,3,4,5-tetrahydroxy-6-sulfoxy-hexanoic acid is precipitated by the addition of an agent for precipitation, such as a lower alcohol, preferably methanol or ethanol . Lower alcohol means an alcohol with 1 to 4 carbon atoms straight or branched chain, such as methanol, ethanol, isopropanol, butanol. The precipitate is removed by filtration and if desired, it is placed in a vacuum oven to dry. The conversion of the salt of 2,3,4,5-tetrahydroxy-6-sulfooxyhexanoic acid into the acid is carried out by usual processes, well known to those skilled in the art. The freshly prepared reaction product contains, among other substances, the unreacted qluconic acid in salt form and the unconverted organic base, or amino acids, when used in the reaction. An aspect of the invention is also the purification of the salt of 2,3,3,5-tetrahydroxy-6-sulfooxyhexanoic acid by nanofiltration. This technology is a pressure induced process to separate large solutes from aqueous solutions through a semipermeable membrane. The variation in pressure used is typically within the range of 3.45 kPa-31.04 kPa. This process is carried out by passing a flow of the solution through the membrane under pressure. Therefore, the driving force of the separation process is the difference in pressure between the feed (concentrated aqueous protein solution) and the filtrate (impregnation) on the membrane separation surface. Rejection of the membrane is influenced by the size, structure and charge of the components in solution. Water and monovalent ions pass freely through the membrane, they retain the multivalent salts. Due to the logarithmic decrease in the flow magnitude of the impregnation, when the concentration increases, it is necessary to dilute the concentrated aqueous protein solution with demineralized water and let the nanofiltration process run again. By applying the so-called diafiltration step, it is possible to achieve a greater concentration in the desired products. In the present invention, when the compound of the general formula I is in the form of a monovalent salt, the nanofiltration step is used to separate the organic base, or amino acids, from the reaction mixture, when used. The selection of a membrane with a suitable molecular weight cutoff value is possible to recover the organic base, or amino acid, in the concentrated aqueous protein solution and reuse it in the chemical reaction. Preferably, the nanofiltration process is used when the compounds of the general formula I are in the form of multivalent salts and, more preferably, in the form of divalent salts, because not only the organic base, or the amino acid , it is separated from the reaction mixture, but also the unconverted gluconic acid is partially extracted, allowing the desired compound to be further concentrated in the concentrated aqueous protein solution. If desired, you can obtain an additional increase in the degree of concentration, through the addition of a monovalent salt, such as, for example, sodium sulfate. An increased amount of the gluconate anion will pass through the membrane, for example, in the form of sodium gluconate. Therefore, it will be possible to increase the amount of the compound to be concentrated in the concentrated aqueous protein solution. The nanofiltration is carried out at a temperature that varies from 20 ° C-40 ° C. Examples 2-4 explain in more detail the manner in which the nanofiltration step of the present invention was carried out. Finally, the product is subjected to high performance liquid chromatography (PHPLC), using as eluent acetic acid: water: 1-butanol (25:25:50), using a silica gel in stationary phase, or hydrophilic interaction chromatography (HILIC, for its acronym in English). In another aspect, the present invention provides the pharmaceutical compositions comprising the compounds of the general formula I, as the sole active ingredient or in association with other active ingredients. Compounds of the general formula I, can be combined, for example, with at least one normolipidemic selected from the HMG-CoA reductase inhibitors, aqonists of the receptors activated by the peroxisome proliferator (PPAR, for its siqlas in English) or ion exchange resins. As examples of the HMG-CoA reductase inhibitors, Lovastatin, Atorvastatin, Pravastatin, Simvastatin, Rosuvastatin, Pitavastatin, Mevastatin or Fluvastatin are indicated. PPAR agonists can be of the subtype PPARa, PPAR? or double PPARa and PPAR ?, which will be selected from Bezafibrate, Ciprofibrate, Etofibrate, Fenofibrate, Gemfibrozil, Troqlitazone, Rosiqlitazone, Pioglitazone or Muraglitazar. From the group of ion exchange resins, Colestipol or Cholestyramine can be selected. The pharmaceutical composition can be presented in the form of tablets, granules, coated tablets or granules coated with a sugar film or with an enteric coating, capsules, suspension, solution, emulsion, etc. These compositions can be prepared as a medicament for oral, parenteral, rectal, transdermal, buccal or nasal administration. They may comprise the addition to the active ingredient of one or several compounds selected from suitable diluent carriers, fillers, solvents, lubricants, aggregates, disintegrants, preservatives, emulsifiers, etc.

Another aspect of the invention is the use of the compounds of the general formula I, for the treatment of dyslipidemias, associated or not with other metabolic disorders, such as the syndrome of glucose intolerance and diabetes mellitus type 1 or 2, by administration alone or in combination with other active substances, such as those mentioned above. The invention will be described later in greater detail through the following non-limiting examples of the scope of the present invention.

Example 1 Preparation of the calcium salt of 2,3,4,5-tetrahydroxy-6-sulfooxyhexanoic acid A solution of 643.2 g of dimethylglycine hydrochloride and 1224 ml of a 50% aqueous solution of a solution of d-gluconic acid, they were stirred in a 3 liter flask until total dissolution at a temperature of 40 ° C. The mixture was placed in a bath with ice and 385 ml of concentrated sulfuric acid were added slowly, keeping the temperature below 40 ° C. The mixture was further stirred for 3 hours at 40 ° C, or at a slightly lower temperature. The water was removed by distillation under vacuum to a solids content of about 75-78% and the reaction mixture was left stand overnight at 40 ° C. The water was removed by distillation under vacuum again at a solids content of 81-82%. The mixture was neutralized by adding, plus stirring, an excess amount of calcium hydroxide to a stable pH value in the 4.5-9.0 variation. The calcium sulfate was removed by filtration and the precipitate was washed with water. The washings and the filtrate were combined and the calcium salt of 2, 3, 5-tetrahydroxy-6-sulfooxyhexanoic acid was precipitated by the addition of about 9 liters of ethanol. The precipitate was removed by filtration and, if desired, the resulting product is placed in a vacuum oven to dry.

Example 2 Nanofiltration of the freshly prepared reaction product The nanofiltration was carried out with a Desal-5 thin-film membrane with a molecular weight cut-off of 160-300 Daltons for uncharged organic molecules.

Amount of the reaction mixture for nanofiltration: 1.5 kg Concentration of the reaction mixture in the container for concentrated aqueous protein solution at the start of the operation: 100 g / 1 Osmotic pressure: 14.71 kg / cm2 (15 bar) Column temperature during nanofiltration: 20-25 ° C Mass percentage of dimethylglycine in the reaction mixture: 14.88% Mass percentage of calcium gluconate in the reaction mixture: 21.14% Mass percentage of the calcium salt of 2,3,4,5-tetrahydroxy-6-sulfoxy-hexanoic acid in the reaction mixture: 13.27% Water for dialfiltration: 180 1 Mass percentage of dimethylglycine after nanofiltration: 0% Mass percentage of calcium gluconate after nanofiltration: 22% Mass percentage of the calcium salt of 2,3,4,5-tetrahydroxy-6-sulfooxy-hexane acid after nanofiltration: 22% Example 3 The nanofiltration product obtained according to the procedure described in Example 2 was subjected to three additional nanofiltration processes according to Example 2. The composition of the product obtained after a total of four nanofiltration processes is as follows: Mass percentage of dimethylglycine after nanofiltration: 0% Mass percentage of calcium gluconate after nanofiltration: 26% Mass percentage of the calcium salt of 2,3,4,5-tetrahydroxy-6-sulfooxy-hexane acid after nanofiltration: 50% Example 4 Nanofiltration of the reaction product freshly prepared The nanofiltration was carried out with a thin-film membrane Desal-5 with a molecular weight cutoff of 160-300 Daltons for organic molecules without change.

Amount of the reaction mixture for nanofiltration: 1.5 kg Concentration of the reaction mixture in the container for concentrated aqueous protein solution at the start of the operation: 100 g / 1 Amount of sodium sulfate added to the reaction mixture: 99 g Osmotic pressure: 14.71 kg / cm2 (15 bar) Column temperature during nanofiltration: 20-25 ° C Mass percentage of dimethylglycine in the reaction mixture: 14.88% Mass percentage of calcium gluconate in the reaction mixture: 21.14% Mass percentage of the calcium salt of 2,3,4,5-tetrahydroxy-6-sulfoxy-hexanoic acid in the reaction mixture: 13.27% Water for dialfiltration: 180 1 Mass percentage of dimethylglycine after nanofiltration: 0% Mass percentage of calcium gluconate after nanofiltration: 22% Mass percentage of the calcium salt of 2,3,4,5-tetrahydroxy-6-sulfooxy-hexane acid after nanofiltration: 40% Example 5 The product obtained after the nanofiltration was subjected to preparative high-performance liquid phase chromatography, using as eluent acetic acid: water: 1-butanol (25:25:50), and using a silica gel in stationary phase . Calcium salt of 2, 3, 4, 5, 5-tetrahydroxy-6-sulfooxyhexanoic acid was obtained in the form of white powder. Figures 1 and 2 show, respectively, 1 H-NMR in D20 (300 MHz) and mass spectra (ESI).

Example 6 A clinical trial with a duration of 12 weeks in approximately 60 patients with hypocholesterolemia and the indication for pharmacological lipid-lowering therapy with inhibitors of the coenzyme A reductase of hydroxymethylglutaryl was carried out (HMG-CoA reductase), according to the criteria of the National Cholesterol Education Program - Adult Treatment Panel III (NCEP-ATP III). First, the clinical trial evaluated the efficiency of an experimental intervention that consisted of the combined treatment of a compound of the group of inhibitors of the reductase HMG-CoA and a compound of the general formula I, (Group II), compared to the treatment isolated with a composed of the group of HMG-CoA reductase inhibitors (Group I). The variable was mainly the average variation between the final values and the initial values of the plasma concentration of LDL-C (lipoprotein-low density cholesterol). After the experimental intervention, in Group II an average reduction of 54.30 mg / dl was observed, while the reduction in Group II was 34.30 mg / dl. Subsequently, the same comparison was made for the average variation of total plasma cholesterol concentration (-67.20 mg / dl versus -50.25 mg / dl), without HDL (high density lipoprotein) cholesterol (-95.80 mg / dl versus -54.50 mg / dl) and triglycerides (-151 mg / dl versus -123.0 mg / dl). Referring to the average variation of the plasma concentration of HDL-C (high density lipoprotein cholesterol), its increase is associated with the reduction of cardiovascular risk and the variation observed in the clinical test was +8.67 mg / dl (Group II ) against +4.25 mg / dL (Group I). thus, the clinical test showed that the combination of a compound of the reductase inhibitor group HMG-CoA and a compound of the general formula I, is more effective in the treatment of dyslipidemia than the isolated administration of a compound of the reductase inhibitor group HMG -CoA. In this clinical trial, patients were included who suffer from metabolic disorders, such as glucose intolerance and diabetes mellitus type 1 or 2.

Example 7 A clinical trial was performed in patients suffering from diabetes mellitus and dyslipidemia associated with diabetes mellitus, with indication of pharmacological lipid-lowering therapy with HMG-CoA reductase inhibitors, according to the criteria of the National Cholesterol Education Program - Adult Treatment Panel III (NCEP-ATP III). First, the clinical trial evaluated the efficiency of the combined treatment of a compound of the statin group and a compound of the general formula I (Group II), compared to the isolated treatment with a compound of the statin group (Group I), after a treatment period of 12 weeks, under a plasma concentration of LDL-C. Subsequently, the same comparison was made for the total plasma concentration of cholesterol, HDL-C and triglycerides.

Claims (20)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property: 1. Compounds of the general formula I: their balanced forms, including lactone forms, their enantiomers in pure form, or in an optically enriched form, racemic mixtures, diastomers thereof and solvates thereof, characterized in that M represents a metal cation, preferably an alkali metal, or an alkaline earth metal including the barium salt or the potassium salt, and n can be 1, 2 or 3.
2. 2. The compounds of the general formula I, according to claim 1, characterized in that they are the calcium salt of acid 2, 3, 4, 5-tetrahydroxy-6-sulfooxyhexanoic acid as well as the balanced forms thereof, including the lactone forms, their enantiomers in pure form or in a form enriched in one of the optical isomers, racemic mixtures, diastomers and solvates thereof.
3. 3. A process for the preparation of the compounds of the general formula I, their balanced forms, including the lactone forms, their enantiomers in pure form, or in an optically enriched form, racemic mixtures, diastomers thereof and solvates of the mimes , characterized in that the 1-gluconic acid or the racemic mixture, the salts thereof or the lactones thereof are reacted with sulfuric acid in the presence or absence of an organic base, or an amino acid.
4. 4. The process for the preparation of the compounds of the general formula I, according to claim 3, characterized in that the organic base or the amino acid is qylin, dimethylqycin, alanine, serine, cystine, methanolamine, ethanolamine or the like thereof .
5. 5. The process for the preparation of the compounds of the general formula I, according to claim 3, characterized in that the reaction is carried out at temperatures in the range of 30-70 ° C.
6. 6. The process for the preparation of the compounds of the general formula I, according to claim 3, characterized in that the mixture of The reaction is concentrated and subsequently neutralized by the addition of an aqueous suspension of a base, such as alkali metal hydroxides, alkali metal carbonates, alkaline earth metal hydroxides, alkaline earth metal carbonates, until a stable pH is reached in the 4.5-9.0 variation.
7. 7. The process for the preparation of the compounds of the general formula I, according to claim 3, characterized in that the freshly prepared product is precipitated by the addition of an agent for precipitation, such as an alcohol in C? -C4 , similar to methanol, ethanol, isopropanol or butanol.
8. 8. The process for the preparation of the compounds of the general formula I, according to claims 3 to 7, characterized in that it further comprises a nanofiltration step after the chemical reaction according to claim 3, to remove the organic base or amino acid, when used, and to concentrate the reaction mixture in the desired product.
9. 9. The process for the preparation of the compounds of the general formula I, according to claims 3 to 8, characterized in that it comprises a final purification by high performance liquid phase chromatography (HPLC).
10. 10. The process for the preparation of the compounds of the general formula I, according to claim 9, characterized in that the stationary phase used in high efficiency liquid chromatography is that of silica or a stationary phase of liquid chromatography with hydrophilic interaction with the stationary phase.
11. 11. A pharmaceutical composition characterized in that it comprises the compounds of the general formula I, their balanced forms, including the lactone forms, their enantiomers in pure form, or in an optically enriched form, racemic mixtures, diastomers thereof and solvates thereof, and one or more substances in pharmaceutically acceptable vehicles.
12. 12. A pharmaceutical composition characterized in that it comprises the compounds of the general formula I, their balanced forms, including the lactone forms, their enantiomers in pure form, or in an optically enriched form, racemic mixtures, diastomers thereof and solvates thereof , in combination with at least one normolipidemia, selected from the reductase inhibitor HMG-CoA, a PPAR aqonist or ion exchange resins, and one or more substances in pharmaceutically acceptable vehicles.
13. 13. The pharmaceutical composition in accordance with claim 12, characterized in that it comprises the compounds of the general formula I, in combination with a reductase inhibitor HMG-CoA, a PPAR agonist and an ion exchange resin, and one or more substances in pharmaceutically acceptable vehicles.
14. 14. The pharmaceutical composition according to claim 12 or 13, characterized in that the reductase inhibitor HMG-CoA is Lovastatin, Atorvastatin, Pravastatin, Simvastatin, Rosuvastatin, Pitavastatin, Mevastatin or Fluvastatin.
15. 15. The pharmaceutical composition according to claim 12 or 13, characterized in that the PPAR agonist is Bezafibrate, Ciprofibrate, Etofibrate, Fenofibrate, Gemfibrozil, Troglitazone, Rosiglitazone, Pioglitazone or Muraglitazar.
16. 16. The pharmaceutical composition according to claim 12 or 13, characterized in that the ion exchange resin is Colestipol or Cholestyramine.
17. 17. The use of the compounds of the general formula I, their balanced forms, including the lactone forms, their enantiomers in pure form, or in an optically enriched form, racemic mixtures, diastomers thereof and solvates thereof, in the preparation of a medicine.
18. 18. The use of the compounds of the formula General I, its balanced forms, including the lactone forms, its enantiomers in pure form, or in an optically enriched form, racemic mixtures, diastomers thereof and solvates thereof, in the preparation of a medicine for the treatment of associated dyslipidemias or not with other metabolic disorders, such as, glucose intolerance syndrome and diabetes mellitus type 1 or 2.
19. 19. The use of the compounds of the general formula I, their balanced forms, including the lactone forms, their enantiomers in the form pure, or in an optically enriched form, racemic mixtures, diastomers thereof and solvates thereof, in combination with at least one normolipidemic selected from the HMG-CoA reductase inhibitors, PPAR agonists or ion exchange resins, in the preparation of a medicine, which will be destined to the treatment of dyslipidemias associated or not with other metabolic disorders, such as glucose intolerance and diabetes mellitus type 1 or 2. The use of the compounds of the general formula I, their balanced forms, including the lactone forms, their enantiomers in pure form, or in an optically enriched form, racemic mixtures, diastomers thereof and solvates thereof, in combination with a reductase inhibitor HMG-CoA, a PPAR agonist or a ion exchange resin, for the preparation of a medicine for the treatment of dyslipidemias associated or not with other metabolic disorders, such as, glucose intolerance syndrome and diabetes mellitus type 1 or 2.