MXPA96002577A - Treatment of arterioesclerosis and xant - Google Patents

Abstract

A combination of one or more HMG-CoA reductase inhibitors (eg, pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin or atorvastatin) with one or more insulin sensitizers (eg troglitazone, pioglitazone, englitazone, BRL-49653, 5- ( 4- { 2- [1- (4-2'-pyridylphenyl) ethylideneaminooxy] et oxy] benzylthiazolidino-2,4-dione, 5-. {4- (5-methoxy-3-methylimidazo [ 5,4-b] -pyridin-2-ylme-toxy) benzyl.} Thiaz-olidino-2,4-dione or its hydrochloride, 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benz il] thiazolidino-2,4-dione, 5- [4- (1-methyl) benzimidazol-2-ylmethoxy) -benzyl] thiazo, lidino-2,4-dione and 5- [4- (5-hydroxy-1, 4-6,7-tetramethyl-benzimidazol-2-ylmethoxy) benzyl] thiazolidino-2,4-dione) exhibits a synergistic effect and is significantly better in the prevention and / or treatment of arteriosclerosis and / or xanthoma than any of the components of the combination by itself

Description

TREATMENT OF ARTERIQESCLEROSIS AND XANTOHA BACKGROUND OF THE INVENTION The present invention relates to methods and compositions for the treatment and prophylaxis of arteriosclerosis is and / or antoma. Throughout the world, in recent years, the trend for the incidence of coronary heart disease and arteriosclerosis, including atherosclerosis, has tended to increase, even in those countries where they had not prevailed so far. Among the factors involved in this increase are the changes in lifestyle, including the western diet rich in meat, and the adoption of this diet included in countries where it is not traditional, and the general increase in the average age of the population. As a result, these diseases and arteriosclerosis, in particular, are widely feared as arteries are a well-known potential cause of unexpected death, for example, due to the sequelae of arteriosclecasis or myocardial infarction. One of the main risk factors involved in these diseases is the high level of lipids in the blood plasma, particularly a level of cholesterol in the high blood plasma. Therefore, many attempts have been made to use an agent that reduces the level of cholesterol in order to avoid and cure these diseases, and many compounds have been developed which, to a greater or lesser degree, have this effect. For example, one of these compounds, which has been very successful and which is well known is pravastatin, which is a lipid regulating agent and is an inhibitor of 3-hydroxy-3-ethylglutaryl-coenzyme A reductase (hereinafter known as "HMG-CoA reductase inhibitor") which is believed to act on the calestecol biosynthesis speed determining step. It has been reported that the art coronary iosclerosis and xanoma can be avoided in rabbits receiving pravastatin, but its efficacy is still insufficient CBiochimica et Biophysica Acta 960, 29-302 (19 & ß) D. Studies to control coronary arteriosclerosis and xanthoma have been carried out using a combination of two lipid regulating agents, pravastatin and cholestyramine, which is well known as an agent to reduce lipoprotein levels, but the effectiveness of this combination also remains insufficient CAtherosclerosis, ß3, 69 - &0 (1990) 3. In the Japanese patent application Kokai No. Hei 7- < + i < It has been proposed that a specific class of insulin resistance enhancing agents, eg, troglitaone, may be effective in the treatment and prophylaxis of arteriosclerosis, particularly atherosclerosis, but again the efficacy of said compounds is not very satisfactory.

BRIEF DESCRIPTION OF THE INVENTION It has now surprisingly been found that the application of a combination of one or more HMG-CoA reductase inhibitors with one or more insulin sensitizers shows a synergistic effect and is significantly better in the prevention and / or treatment of art iosclerosis and / or xanthoma than any of the components of the combination alone. In fact, using the new combination of the present invention, these diseases can be cured slowly but consistently. Therefore, an object of the present invention is to provide a combination of one or more HMG-CoA reductase inhibitors with one or more insulin sensitizers or insulin resistance enhancing agents. A further and more specific object of the invention is to provide a combination of this type that shows a synergistic effect. Still another object of the invention is to provide methods and compositions that use said combination for the prevention and / or treatment of arteriosclerosis and / or xanthoma. Other objects and advantages of the present invention will become apparent as the description proceeds. Therefore, in a first step, the present invention consists of a method for the prevention or treatment of arteriosclerosis or xanthoma, said method comprising administering to a patient suffering from or susceptible to undergoing arteriosclerosis or xanthoma, a first agent selected from the group consisting of HMG-CoA reductase inhibitors and a second agent selected from the group consisting of insulin sensitizers , said first and second agents being administered together or within a period to act synergistically. The invention also provides a packaged pharmaceutical formulation for the treatment or prophylaxis of arteriosclerosis or xanthoma, comprising a first agent selected from the group consisting of HMG-CoA reductase inhibitors and a second agent selected from the group consisting of insulin sensitizers, said first and second agents being mixed or packaged separately. In a further aspect, the invention provides a pharmaceutical composition for the treatment or prophylaxis of arteriosclerosis or xanthoma, comprising a first agent selected from the group consisting of inhibitors of HMG-CoA reductase and a second agent selected from the group consisting of sensitizers of insulin.

DETAILED DESCRIPTION OF THE INVENTION Currently, experimental evidence seems to suggest that the synergistic effect arises from an interaction between the modes of action of the two classes of compounds, the HMG-CoA reductase inhibitors and the insulin sensitizers, so it is believed that the structure The chemistry of the compounds is of less importance than their activities. Accordingly, any compound having HMG-CoA reductase inhibitory activity can be used as the first agent, while any compound containing insulin sensitizing activity can be used as the second agent. HMG-CaA reductase inhibitors are commonly used for the treatment or prophylaxis of hyperlipidemia, and may comprise substances that occur in nature that are involved in the metabolism of microorganisms, semi-synthetic substances derived therefrom and totally synthetic substances. Of those compounds, examples of preferred compounds include pravastatin, lovastatin, if vastatin, fluvastatin, rivastatin and atorvastatin. Pravastatin is described in Japanese Patent Publication No. Sho 61-13699 and in the U.S. Patents. Nos. «+ 3 < +6 227 and M + 9 979, and its formula (as the sodium salt) is 1, 2.6, 7, &, a-hexahydro-6, fl-tetrahydroxy-2-methyl-l-naf sodium alenoheptanate. Lovastatin is described in Japanese Patent Application Kokai No. Sho 56-16-S75 and in European Patent No. 22? + 7A, and its formula is 6-IF2-C1, 2.6, 7,6,6a- hexahydro-γ- (2- and ilbutyryl) -2,6-di and yl-l-naphthiyl-1-tetrahydro-hydroxy-2H-pyran-2-one. Sinvastatin is described in Japanese Patent Application Kokai No. Hei 1-1 6 and in European Patent No. 33 536, and its formula is 6-C2-C1, 2.6, 7.6,6a-hexahiriro- 6- (2-met Jbut iryl i) -2,6-di et i 1-1-naft ill til > -tetrahydro-4-hydroxy-2H-pyran-2-one. Fluvastatin is described in Japanese Patent Publication No. Hei 2 46031 and in the patent of E.U.A. No. 4 739 073, and its formula (as the sodium salt) is 7-C3- (4-fluoro-phenyl) -l-methyl-1-yl) -JH-indol-2-yl) -3,5-dihydroxy -6-sodium heptanoate. Rivastatin is described in Japanese Patent Application Kokai No. Hei 1-216974 and in the U.S. Patents. No. 5 006 530, 5 169 657 and 5 401 746, and its formula (as the sodium salt) is 7- (4-p-phenylphenyl) -2,6-di isoprc? Pil-5-methoxy ethylpyridin-3-i 1) -3, 5-d hydroxy-6-heptanoate sodium. Atocvastat in is described in the Kokai application of Japanese Patent No. Hei 3-56967 and in the patent of E.U.A. No. 5,273,995, and its form is 2- (4-f luoraphenyl) -5- < I-Ile il) -3-phe-il-4- (phenylcarbamoyl) -lH-pyrrole-i- (2,4-dihydroxyhoxanoic). The insulin sensitizer, the other active ingredient of the invention, can also be considered as an insulin resistance enhancing agent, and was originally used for the prevention and / or treatment of diabetes. The term encompasses a wide variety of compounds, typically thiazolidinedione compounds, oxazolidinedione compounds and oxathiadiazole compounds. These compounds are described, for example, in the Japanese patent applications Kakai Nos. Hei 4-69363 and Hei 7-330726, W0 69/06651, W0 91/07107, W0 92/02520, W0 94/01433 and patent E.U.A. Nos. 4 267 200, 4 340 605, 4 436 141, 4 444 779, 4 461 902, 4 572 912, 4 667 777, 4 703 052, 4 725 610, 4 673 255, 4 697 393, 4 697 405, 4 916 091, 4 946 900, 5 002 953, 5 061 717, 5 120 754, 5 132 317, 5 194 443, 5 223 522, 5 232 925, 5 260 445, and European Patent No. 676 396, etc. Of these, examples of preferred compounds include troglitazone, pioglitazone, englitazone, BRL-49653, 5- (4-C2-. {L- (4-2'-pyridylphepiDetyl itineaminooxyethoxy.) Ncyl) -thiazolidine-2, -dione (hereinafter "Compound A"), 5-. {4- (5-methoxy-3-me i 1 imidazo C5,4-b pyridin-2-i-eai) benzyl &thiazolidine-2 , 4-dione (preferably as its hydrochloride), 5-C4- (6-methoxy-l-methylbenzimidazol-2-ylmethyl) benzylthiazolidine-2,4-dione, 5-C4- (i- methybenzimidazole-2-ylmeto i) benzyl t-azolidine-2,4-dione and 5-C - (5-hydroxy, 4,6, 7-tetramethyl-benzimidazol-2-ylmethyl) -benzyl-3-thiazilidin-2, 4-dione Troglitazone is described in Japanese Patent Publication No. Hei 2-31079 and US Patent No. 4 572 912, and its formula is 5-C4-C (6-hydroxy-2,5,7). , 6-tetramethyl-chroman-2-i 1) methoxy-3-benzyl >; -2,4-t i zolid no-diona. Pioglitazone is described in Japanese Patent Publication No. Sho 62-42903 and No. Hei 5-66956 and in the U.S. Patents. Nos. 4 267 200, 4 340 605, 4 436 141, 4 444 779 and 4 725 610 and its formula is 5-. { 4-C2- (5-ethylpyridin-2-yl) ethoxy-3-benzyl > -2,4-thiazolidinedione. Englitazone is described in Japanese Patent Publication No. Hei 5-66953 and in the US patent. No. 4,703,052, and its formula is 5-C3,4-dihydro-2- (phenylmethoxy) -2H-benzo-pi ran-6-yl et i 1 2, 4-thiazole i- & dinodiona. BRL-49653 is disclosed in Japanese Patent Application Kokai No. Hei 1-131169 and in US Patents. Nos. 5 002 953, 5 194 443, 5 232 925 and 5 260 445, and its formula is 5-C4-C2-met i l-2- (pyridin-2-ylamino) ethoxy-3-benzyl > -2,4-t iazo-lidinadiona. Compound A is described in European Patent No. 706 096. 5- < 4- (5-methoxy-3-methylimidazoC5,4-b3pyridin-2-ylmethaxy) benzyl} -thiazolidin-2,4-dione (and its hydrochloride) are disclosed in Japanese Patent Application No. Hei 7-330726 and in European Patent No. 676 396. The above compounds are prepared as described in the prior art to the one that was referenced before. 5-C4- (6-methoxy-l-methyl-1-benzyl-imidazol-2-yl) i) benzyl-3-thiazolidin-2,4-diopane, 5-C4- (1-methyl-1-ylbenzyl-dazol-2-ylmethoxy) benzyl-3-thiazolidin-2,4 -dione and 5-C4- (5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmeto i) benzyl-iazolidin-2,4-dione are described in European Patent Application No.96303940.9, and can be prepared as described later. The active ingredients used in the present invention comprise, first, one or more HMG-CoA reductase inhibitors and, second, one or more insulin sensitizers or insulin resistance enhancing agents. According to the invention, a combination of the HMG-CoA reductase inhibitor and the insulin sensitizer shows a synergistic effect compared to the application of the respective components alone, as shown below. Interestingly, such synergism seems to occur even when the compounds of the two classes do not always exist simultaneously in the body. That is, the synergistic effect can be observed even when the concentration of one of the compounds of the two classes in the blood is less than that required by the blood to show an appreciable effect. Although it is simply a conjecture, it is thought that, when a compound of one of the two classes is received in the body and transported to a receiver, it triggers a "switch" in vivo. After a certain time, the level of the compound in the blood may have decreased to a value at which it seems that no additional effect would be observed, but the "switch" can still be activated, thus maintaining the preventive and / or therapeutic effect. for arteriosclerosis and / or xanthoma inherent in the compounds of that class. When a compound of the other class is administered to a patient in this state, the effect of the prevention and / or treatment of arteriosclerosis and / or xanthoma can be combined with the effect resulting from the previous administration of the other compound, and The effects of the two compounds operate together in a favorable synergistic manner. Of course, it is obvious that it may be convenient to administer the two compounds simultaneously in clinical practice. Therefore, the HMG-CaA reductase inhibitor and the insulin sensitizer can be administered together in the form of a combined preparation. Alternatively it is difficult to mix the two, either because there is some incompatibility between them or for some other reason, for example, problems in the mixing process, the two active agents can be administered separately in the form of a single dose. As described above, since the compounds of the two classes show a synergistic effect to each other, they can be administered almost simultaneously or at suitable intervals. The maximum acceptable range for administering the compounds of the two classes so that they achieve the synergistic effect of the present invention can be confirmed by clinical practice or by animal experiments. The HMG-CoA reductase inhibitors and insulin sensitizers of the present invention can generally be admixed orally. Accordingly, the compounds of the two classes can be prepared separately as two unit dose forms or can be physically mixed to give a single unit dose form. Examples of such formulations include, for example, powders, granules, tablets or capsules. These pharmaceutical formulations can be produced by conventional means well known in the pharmaceutical field. In the present invention, the individual dose of HMG-CoA reductase inhibitors and insulin sensitizers and the ratio of the amounts of HMG-CoA reductase inhibitors and insulin sensitizers can vary widely, depending on the activity of each compound and other factors, such as the condition, age and body weight of the patient. For example, in the case of insulin sensitizer, the potency of BRL-49653 is approximately 100 times greater than that of traglitazone in vivo in a diabetic animal model, allowing the dose of these two compounds to differ theoretically in approximately two orders of magnitude and in practice differ approximately one order of magnitude. The dose of each of the HMG-CoA reductase inhibitors and insulin sensitizers, where they are used in the treatment of arteriosclerosis and xanthoma, would normally be expected to be lower than that used when the two compounds are used separately. for its original uses, that is to say, as antidihiperl ipidéico and antidiabetic agents. Their doses are reduced to a certain degree by the synergistic effect due to the combination of the compounds of the two classes. For example, where pravastatin and troglitazone are used according to the invention, their daily doses are preferably within the range of 1 mg to 40 mg and 1 mg to 500 mg, respectively, compared to the doses from 5 mg to 60 mg and from 10 mg to 100 mg, respectively, wherein the compounds are used for their original uses as antihyperlipidemic and antidiabetic agents. Very generally, although as indicated in marked form, the dose of the HMG-CoA reductase inhibitors and the insulin sensitizers according to the invention can vary widely, the daily dose is usually within the range of 0.01 mg to 40 mg , preferably from 1 mg to 40 mg and from 0.05 mg to 500 mg, preferably from 1 mg to 500 mg respectively. The relationship between the compounds of these two classes can also vary widely-; however, it is preferred that the ratio of the HMG-CoA reductase inhibitor to the insulin sensitizer be within the range of HMG-CoA reductase by weight, preferably from 1: 200 to 200: 1 by weight, preferably from 1: 100. at 10: 1 and most preferably from 1:50 to 5: 1 by weight. The HMG-CoA reductase inhibitor and the insulin sensitizer according to the invention are preferably administered simultaneously or almost simultaneously at a daily dose as described above, and may be administered as a single dose or co or divided doses. The compounds and compositions of the present invention can be administered in various forms, depending on the disease or disorder to be treated and the age, condition and body weight of the patient, as is well known in the art. For example, wherein the compounds or compositions are to be administered orally, they can be formulated as tablets, capsules, granules, powders or syrups; or parenterally, they can be formulated as injections (intravenous, intramuscular or subcutaneous), preparations of infusion of drops or supposito ios. For application via the ophthalmic mucous membrane, they can be formulated as eye drops or eye ointments. These formulations can be prepared by conventional means and if desired, the active ingredient can be mixed with any conventional additive such as an excipient, a binder, a disintegrating agent, a lubricant, a concealer, a solubilizing agent, a suspension aid. , an emulsifying agent or a coating agent. Examples of vehicles that can be employed include: organic vehicles including sugar derivatives, such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives, such as corn starch, potato starch, < x-starch, dextrin and carboxy et ilal ideal; cellulose derivatives, such as crystalline cellulose, low substituted hydroxypropyl cellulose, hiriroxypropylmethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose and sodium carbo-imethylcellulose with internal bridge; gum arabic; dextranof pullulan; and inorganic vehicles including silicate derivatives, such as light silicic anhydride, synthetic aluminum silicate? metallic magnesium aluminate silicate; phosphates, such as calcium phosphate; carbonates, such as calcium carbonate; and sulfates, such as calcium sulfate. Examples of lubricants that may be employed include: stearic acid; metal stearates, such as calcium stearate and magnesium stearate; talcum powder; colloidal silica; waxes, such as beeswax and whalewax wax; boric acid; adipic acid; sulfates, such as sodium sulfate; glycol; fumaric acid, sodium benzoate; DL-Jeucina; sodium salts of fatty acid; lauryl sulfates, such as lauryl sodium sulfate and magnesium lauryl sulfate; silicates, such as silicic anhydrides and hydrated silicic acid; and the aforementioned starch derivatives. Examples of binders that may be employed include: polyvinyl 3 pyrrolidone; acrogol; and the same compounds as mentioned above for the vehicles. Examples of disintegrants that may be employed include: the same compounds as mentioned above for vehicles; and chemically modified and cellulosic starches, such as sodium elose, carboxy and sodium starch and bridged polyolide bridge. Examples of stabilizers that may be employed include: parao? Ibenzoates, such as or methylparabe and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and fepiletide alcohol; benzalkonium chloride; phenols, such as phenol and cresol; erosive dehydroacetic acid; and sorbic acid. Examples of editors that may be employed include: sweetening agents, acidifying agents and species. The present invention is further illustrated by the following examples, which demonstrate the increased activity achieved by the synergistic combination of the present invention. In addition, the subsequent formulations illustrate the pharmaceutical formulations that can be prepared and the preparations illustrate the preparation of some of the insulin sensitizers used in the present invention.

EXAMPLE 1 Rabbits WHHL 1.2-3 months old, the hyperlipidae rabbit inherited from Watanabe described in Biochimica et Biophysica Acta, 294-302 (1966) 3 were randomly assigned to a control group (7 animals, group A), a group receiving pravastatin alone (5 animals, group B) a group receiving troglitazone alone (7 animals, group O, and one group receiving a combination of both active substances (6 animals, group D). Pravastatin was administered orally by forced feeding to a dose of 50 mg / kg per day once a day and troglitazsna was given in the diet, containing 100 mg / g of the substance for 32 weeks.The amount ingested was limited to 120 g per rabbit daily. animal immediately after the start of the study and 4, 6, 16, 24, 26 and 32 weeks after starting the study and the total cholesterol values (.) were determined for each blood sample.The levels were reported as a percentage <) of the measured levels immediately before starting the study. The results are shown in table 1. Animals were sacrificed and necropsied at week 32 to examine (a) the percent lesion area (%) in total, thoracic or abdominal portion of the aorta; (b) stenosis (%) of the coronary arteries and (c) the incidence () of xanthoma in the joints of the fingers. The results are shown in Table 2, Table 3 and Table 4. The currently measured values are represented as co or an average value with a standard error + in those tables.

TABLE 1 * volume (mg / dl) actually measured, TABLE 2 Area of injury IX) * p < 0.05 significantly different against the control group according to the Mann-Whitney test.

TABLE 3 Coronary stenosis < * > MLC: Main Left Coronary Artery CMR: Right Main Coronary Artery LAD: Left Anterior Descending Artery LCX: Left Circumflex Artery RCA: Right Coronary Artery LSP: Left Septal Artery TABLE 4 Incidence of xanthoma (*) The values in parentheses indicate the number of legs damaged / the number of legs examined. As can be seen from the previous example, no significant differences were observed in the change of plasma cholesterol levels at 32 weeks after administration between group D (which received a combination of both agents) and group B (who received pravastatin alone). Conversely, evident synergism was observed in the percentage of injury area ratio (lesion area / total artery area in) preparing group D (combination treatment) with groups B and C (treatment with a single agent) as shown previously. Synergism was observed in the prevention of coronary stenosis with respect to the left anterior descending artery, left circumflex artery and right coronary artery. The development of? Antoma in the joints of the fingers was completely avoided in group D, thus demonstrating an obvious synergism. Therefore, although plasma cholesterol levels revealed that there was no significant difference when comparing groups administered a combination of an HMG-CoA reductase inhibitor and an insulin sensitizer with the groups to which an active agent was administered, the combination of both active agents synergistically prevented the advance of arteriosclerosis, particularly of the thoracic aorta. These results could not be imagined in the prior art.

EXAMPLE 2 Male WHHL rabbits (2-3 months old), which showed almost no arterial lesions were randomly assigned to a control group (7 animals, group A), to a group submitted to oral administration of pravatsitin alone (6 animals, 50 mg / kg, group B), to a group submitted to oral administration of pioglitazone alone (7 animals, 20 mg / kg group C), to a group submitted to oral administration of 5- (4-y2-Cl- (4, 2'-pyridylphenyl) and ilideneaminoo? Ethoylbenzyl) thiazolidine-2,4-dione (hereinafter compound A, as described in EP 706 096. Seven animals, 10 mg / kg, group D), a group submitted to oral administration of a combination of pravastatin and pioglitazana (6 animals, 50 + 20 mg / kg, group E), and to a group submitted to oral administration of combination of pravastatin and compound A (7 animals, 50-10 mg / kg, group F).

Each test compound was administered for 6 months to the rabbits in the form of an aqueous suspension (0.5% carboxymethylcellulose added). In the control group, only 0.5% carboxymethylcellulose solution was administered. One month after the start of the administration, and later it was observed that the serum cholesterol in groups B, E and F was maintained at a lower level than that of the control group, and a reduction of 22 to 34% of the Cholestecol levels in the serum were observed in this group. However, no reduction in serum cholesterol levels was observed in groups C and D. The percentage of the area covered by lesions in the aortic arch and throughout the aorta are shown in table 5.

TABLE 5 Injury area (%) The values actually measured are represented by the average value plus or minus standard error. The numbers in parentheses represent the percentage of injury area against the control group. * p < 0.05, significant difference against the control group according to the Mann-Whitney U test. A significant difference was observed (p <0.05) between groups B and F, between groups C and E and between groups D and F in the aortic arch, and between groups C and D in the total area. The average thickening of the intima and the aorta was measured and the results are shown in table 6.

TABLE 6 Intimation of the intima (mu) in the aorta The values actually measured are represented as the average value plus or minus a standard error (μm). The numbers in parentheses represent the percentage of thickening of the intima against the control group. A significant difference was observed between groups D and F in the aortic arch, between groups C and E and between groups D and F in the total aorta (p <0.05), according to the Mann U test. Whitney. The intimal thickening of the intima was calculated by the cross-sectional area of the intima of the aortic tunic, a section of the arch and two sections of the thoracic and abdominal portions, divided by the length of the measurement of the tunic. A slight suppression of thickening of the intima was observed in group B, while suppression of hypertropia was not observed in groups C and D. The suppression of intimal thickening in groups E and F was observed against that of the groups C and D. The content of aortic cholesterol was measured. The tunica media and the intima of the tunic in the aortic arch and in the thoracic and abdominal aorta were detached with forceps and cut into small parts. The portions were treated with a mixture of 2: 1 by volume of chloroform and methanol. The chloroform phase was separated and evaporated to dryness and the residue was dissolved in isopropanol. Total cholesterol and free cholesterol were measured by a conventional enzymatic method. The results are shown in tables 7a and 7b.

TABLE 7a Content of aortic arch cholesterol TABLE 7b Level of thoracic and abdominal aortic cholesterol The data are represented by the average plus or minus standard error (mg / g of tissue). The values in parentheses indicate the percentage against the control. A significant difference against the control group was observed by the unpaired Student's test: * p <; 0.05; ** p < 0.02. As clearly seen in table 7, total cholesterol levels of the thoracic and abdominal aorta are lower in groups E and F than in groups B, C and D. There has been no clear trend between levels of free cholesterol and esterified. The results are similar to those of the injury area regimen. The incidence and degree of? Antama of the four legs was measured. The results are shown in table 6.

TABLE A The data in parentheses express the number of damaged legs / number of legs examined. The severity of xanthoma was evaluated according to the following criteria: (-) without lesions (+> light injury (++) moderate injury (+++) severe injury * p <0.05, ** p <0.01 significantly in control group * 1) p 0.01 significantly different between groups B and F * 2) p < 0.05 significantly different between groups D and F * 3) p < 0.05 significantly different between groups B and E * 4) p < 0.01 significantly different between groups B and F * 5) p 0.01 significantly different between groups C and E * 6) p < 0.01 significantly different between groups D and F * 7) p 0.05 significantly different between groups B and E * 6) p 0.01 significantly different between groups B and F * 9) p < 0.01 significantly different between groups D and F * 10) p < 0.01 significantly different between groups D and F * 11) p < 0.01 significantly different between groups B and F * 12 > p < 0.01 significantly different between groups C and E * 13) p < 0.01 significantly different between groups D and F As clearly seen in table 6, the control group showed a 100% incidence of xanthoma in all the anterior legs and hind legs. Groups B, C and D showed a slightly less frequent incidence of? Antoma. Groups E and F, the combination groups, showed a significantly lower frequency of incidence of? A. The trend is similar in the frequency of massive xanthoma, where groups E and F showed a very low frequency of xanthoma, or no occurrence of it, unlike groups A to D. The total results are those of the two combinations of pravastatin, an inhibitor of HMG-CoA reductase and one of the sensitizers of thiazolidinedioneinsulin exhibit synergistic effects on the treatment of atherosclerosis and on the occurrence of xanthoma.

EXAMPLE 3 The synergism of the HMG CoA reductase inhibitors and the tinzslidino-dionoinsulin sensitizers on the regression of atherosclerotic lesions established in the rabbit model fed with cholesterol were examined. White male New Zealand rabbits (5 months old) were fed for 2 months with a diet of 2% cholesterol, at the end of which time, rabbit serum cholesterol increased from 1,100-4,100 mg / dl . The rabbits were randomly grouped (3-9 animals per group) and the test samples were administered orally for two months, while they were fed a normolipidemic diet. The dose of the test samples was: in the case of pravastatin alone, 3 mg / kg or 5 mg / kg; in the case of fluvastatin only 0.6 mg / kg or 1.5 mg / kg in the case of troglitazone alone 10 mg / kg; in the case of Compound A "olo, 2.5 mg / kg In the case of combination groups, the dose was: pravastatin 3 mg / kg + troglitazone 10 mg / kg pravastatin 5 mg / kg + Compound A 2.5 mg / kg fluvastatin 0.6 mg / kg + troglitazone 10 mg / kg and fluvastatin 1.5 mg / kg + Compound A 2.5 mg The results are shown in terms of the percentage of the area of lesion in the thoracic aorta.

TABLE 9 The measured values are actually expressed by the mean value ± the normal error. The amounts in parentheses represent the reduction in percentage of injuries against the control group. As is clear from Table 9, each of the HMG CoA reductase inhibitors or the thiazolidinodionoinsulin sensitizers alone showed little or no reduction of the lesions while all the combination groups of the two components showed a synergistic reduction of the injuries EXAMPLE 4 The synergism of the HMG CoA reductase inhibitors and the tinzolidin-dionoinsulin sensitizers was examined by another regression model, ie the regression of preformed atherosclerosis in haters. Hamsters Fib males (approximate weight 130g) received a diet containing 0.05% cholesterol for 13 weeks. They were randomly pooled (2-7 animals per group), and then test samples were administered for 4 weeks while the hamsters received a normolipidemic diet. Pravastatin and fluvastatin were mixed with drinking water at a dose of 3 mg / kg and 1.5 mg / kg respectively, while troglitazone was mixed with the diet at a dose of 30 mg / kg or 100 mg / kg. In the case of the combination groups, the dose was 3 mg / kg + 30 mg / kg or 3 mg / kg + 100 mg / kg for pravastatin + the troglitazin group, and 1.5 mg / kg + 3 mg / kg for fluvastatin + the troglitazone group. Arterial lesions were evaluated by the extension of the area stained with red oil 0 (0R0), as described in Atherosclerosis, 114, 19-26 (1995). Specifically, the aortic arch was stained with ORO to prepare face specimens. The percentage area that was positive to the GOLD stain over the entire area was measured to represent the degree of aortic injury. After treatment, total serum cholesterol and triglyceride level does not differ signi fi cantly between the groups. The results are shown in table 10. PICTURE IO p < 05 There was a significant difference (p <0 05) between the control and the group receiving pravastatin + troglitazapa 3 mg / kg + 100 mg / kg and between the group receiving pravastatin alone and the group receiving pravastatin + troglitazana 3 mg / kg + 100 mg / kg. As is clear from Table 10, regression of aortic lesions was not observed in the groups administered pravastatin, fluvastatin or troglitazone (30 mg / kg), alone, although regression was observed with troglitazone alone at a dose of 100. mg / kg. In the case of the combination of pravastatin and troglitazone, renoresio was observed, with a dose-dependent tendency based on troglitazone. In the case of the combination of fluvastatin and troglitazana, a similar synergistic regression of aortic lesions was observed. In summary, it can be concluded that the combination of the HMG CoA reductase inhibitor and the thiazolidinedioneinsulin sensitizer exhibit, as a class, both preventive and curative effects on atherosclerosis and on xanthoma.

PREPARATION 1 -C4- (1-Methylbenzimidazol-2-ylmethoxy) benzl-iazolidin-2,4-dione Ka) Methyl 4-nitro ene-iacetate A mixture of 56g of 4-nitrophenol, 90g of methyl broacetate, 100g of potassium carbonate and 500 ml of dimethyl ormamide was stirred at room temperature for 2 days. At the end of that time, the solvent was removed by distillation under reduced pressure. The resulting residue was mixed with water and the aqueous mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was triturated with hexane to give 63.3g of the title compound, melting at 96-99 ° C.

Kb) Methyl 4-aminoenoxyacet A solution of 30. g of methyl 4-nitrophenacetacetate [prepared as described in step a) above! 500 ml of ethanal was stirred in a nitrogen atmosphere and in the presence of 5.0 g of palladium on carbon at 10% w / w for 6 hours. At the end of that time, the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure, to give 25.6 g of the title compound having a value Rf = 0.79 (in thin layer chromatography on silica gel; of development: ethyl acetate). l (c) Methyl 4- (2-bromo-2-butoxycarbonylethyl-3-1-yl) -phenoxyacetate) 96 g of aqueous hydrobromic acid at 47% w / w, followed by 33 ml of an aqueous solution containing J2.6 g of sodium nitrite was added to a solution of 25.6 g of methyl 4-a-doxyl noxenacetate [prepared as described in step (b) above! in 263ml of a mixture of 2: 5 by volume of methanol? acetone, while cooling with ice, and the resulting mixture was stirred, while cooling with ice for 30 minutes. 16. g of butyl acrylate were then added and the reaction mixture was stirred for an additional 30 minutes, while cooling with ice. Then 3.2g of copper (I) bromide was added to the mixture, and it was stirred overnight at room temperature. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was mixed with an aqueous solution of sodium chloride. It was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Upon distilling off the solvent, 51.7 g of the title compound having an Rf = 0.46 value was obtained (on silica gel thin layer chromatography); development solvent: a 5: 1 by volume mixture of hexane and ethyl acetate) as a crème product.

Kd) 5-C4-) Ethoxycarb or lmetoxy) benzylthiazolidin-2,4-dione A mixture of lOOg of methyl 4- (2-bromo-2-butoxycarbonyl-1-1-yl) phenoxyacetate ["prepared as described in step (c) above3, 22p of thiourea and 200 ml of ethanol were heated under reflux for 2.5 hours, after which 2N aqueous hydrochloric acid was added to the reaction mixture.The mixture was then heated under reflux for 5 hours At the end of that time, the reaction mixture was freed from the solvent by distillation under reduced pressure.The resulting residue was diluted with water and the aqueous mixture was extracted with ethyl acetate.The extract was dried over anhydrous magnesium sulfate, then from which the solvent was removed by distillation under reduced pressure.The resulting residue was purified by chromatography through silica gel using a volume of 2: 5 by volume of ethyl acetate and hexane as eluent, to give 19.4g of the composed of the title, melting at 105-106 ° C. 1 (e) b-C4- (l-methyl-taenimidazol-2-ylmethoxy) -benzyl-3-thiazolidin-2,4-dione A mixture of one l.Og of N-methyl-1,2-phenylenediane, 3.6g of 5 - [4- (ethoxycarbonylmethoxy) benzyl 3-tiazolidin-2,4-dion [prepared as described in step (d) above 3, 20 ml of concentrated aqueous hydrochloric acid, 10 ml of 1,4-dioxane and 10 ml) of water were heated under reflux for 5 hours. At the end of that time, the insoluble materials that had precipitated from the reaction mixture were collected by filtration and the precipitate thus obtained was dissolved in tetrahydrofuran. The water was then added to the solution. The resulting aqueous mixture was neutralized by adding sodium bicarbonate and then extracting with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using ethyl acetate and mixing the ethanol as the eluent. The product was then recrystallized twice from a mixture of tetrahydrofuran and ethyl acetate, to give i.3g of the title compound, melting at 230 ~ 23lßC.

PREPARATION 2 -C4- (6-metho-l-me i-benzimidazole-2-i-1-methoxy) -benz-13-iazolidin-2-4.-dione 2 (a) 5-Methoxy-2-nitroaniline 70 ml of a 26% ethanolic solution of sodium methoxide at room temperature was added to a solution of 25 g of 5-chloro-2-pitroaniline in 500 ml of 1 , 4-dioxane, and the resulting mixture was heated under reflux for 4 hours, after which the solvent was removed by distillation under reduced pressure. The resulting residue was diluted with water, and the resulting aqueous mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel using a gradient elution method, with mixtures of ethyl acetate and hexane in ratios ranging from 1: 4 to 1: 2 by volume according to the eluent, give 16.3g of the title compound, melting at J24-J2ß ° C. 2 (b) Nt-Butoxycarbonyl l-5-methoxy-2-nitroaniline 25g of di-t-butyl dicarbonate, 15ml of pyridine and 0.6g of 4-dimethylamino-ir idine were added at room temperature to a solution of of 5-methoxy-2-nitroaniline [prepared as described in step (a) above3 in 500 ml of dehydrated tetrahydrofuran, and the resulting mixture was stirred for two hours. At the end of this time, the reaction mixture was liberated from the solvent by distillation under reduced pressure and the resulting residue was diluted with water. The resulting aqueous mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel using a mixture of 1: 10 by volume of ethyl acetate and hexane as the eluent, to give J2.5g of the title compound, melting at 112-114 °. C. 2 (c) N-t-Butoxycarbon i 1-N-m t i 1-5-meto? i-2-n it oan i 1ina A solution of 49.6 g of N-t-buto-icarbonyl-5-ethoxy-2-nitroaniline [prepared as described in step (b) above was added! in 300 ml of dehydrated dime ilformamide, while cooling with ice, to a suspension of 12.0 g of sodium hydride (as a 55% dispersion w / w in mineral oil) in 300 ml of dehydrated dimethylformamide, and the resulting mixture was stirred at room temperature for 30 min, after which 17.2 ml of methyl iodide was added at room temperature. The reaction mixture was stirred for 1 hour, after which it was allowed to stand overnight at room temperature. It was then concentrated to about one fifth of its original volume by evaporation under reduced pressure. The concentrate was mixed with ice-water and the resulting aqueous mixture was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. Upon distillation of the solvent, 52.lg of the title compound was obtained, melting at J22-124 ° C. 2 < d) N-Me il-5-methoxy-2-ni roaniline 750 ml of a 4 N solution of acid chloride in 1,4-dioxane was added to 52 g of Nt-butoxycarbonyl-N-met i 1-5-methoxy -2-pitroani lina [prepared as or described in step (c) above! at room temperature and the resulting mixture was stirred for 2 hours. At the end of that time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the resulting residue was mixed with water and ethyl acetate. The mixture was then neutralized by the addition of sodium bicarbonate, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. At the distillation of the solvent, 35.3 g of the title compound were obtained, melting at 107 -110 ° C. 2 (e) 5-Meto? IN-me i1-1.2-phenylene ia ina 346 g of tin chloride were added to a mixture of 35 g of N-met il-5-methoxy-2-nitroaniline [prepared as described in step (d) above !, 900 ml of t-butanol and 100 ml of ethyl acetate at room temperature and the resulting mixture was stirred at 60 ° C for 2 hours, after which 11 g of sodium borohydride was added. in portions at 60 ° C for a period of 1 hour. The reaction mixture was then stirred at 60 ° C for 3 hours after which it was allowed to stand at room temperature for 2 days. Subsequently it was poured into ice-water and the aqueous mixture was neutralized by the addition of sodium bicarbonate. The mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the mixture by distillation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 3: 2 by volume mixture of ethyl acetate and acetone as eluent. , to give 21.9 g of the title compound having a value Rf = 0.16 (on thin layer chromatography on silica gel: developing solvent: a 1: 1 by volume mixture of ethyl acetate and hexane). 2 (f) 5- (4-Me oxycarbvonylme oxybenzyl) -3-triphenyl-1-methylthiazolidin-2,4-dione 126 g of cesium carbonate was added at room temperature to a solution of 120 g of 5- (4-hydroxybenzyl) -3 ~ triphenylmethyl iazslidin-2,4-dione in 2.5 liters of acetone, followed by 36 ml of methyl or methyl acetate and the resulting mixture was stirred for 1 hour. At the end of that time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the resulting residue was mixed with water. The aqueous mixture was then extracted with ethyl acetate. The extract was washed with water and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate.

The foie solvent was removed by distillation under reduced pressure, after which 1 liter of diethyl ether was added to the oily residue. The mixture was then agitated ultrasonically for 10 minutes. The precipitated solid was collected by filtration, to give 126.3 g of the title compound, melting at 156-162 ° C. 2 (a) 5- (-methoxycarbonylmethoxybenzyl) riazolidin-2,4-dione 1700 ml of acetic acid and then 400 ml of water at room temperature were added to a suspension of 344 g of 5 (4-me oxycarbonoi Ime oxybenz 1) -3 -tr ifenilmet ilt iazolidin-2,4-dione [prepared as described in step (f) above! 400 ml of 1,4-dioxans and the resulting mixture was stirred for 5 hours at 60 ° C. At the end of this time, the reaction mixture was liberated from the solvent by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a mixture of 1: 2 by volume. ethyl acetate and hexane, a 2: 1 by volume mixture of ethyl acetate and hexane and then ethyl acetate as eluants, to give 161.7 g of the title compound, melting at 100-106 ° C. 2 (h) 5-C4- < 6-Methoxy-1-methyl-benzedazol-2-ylmethoxy) -benzylthiazolidin-2,4-dione A mixture of 21.6 g of 5-methoxy-N-meth i 1-1, 2-fn lenedi ina [prepared] was heated under reflux for 60 hours. as described in step (c) above !, 63.4 g of 5- (4-methoxycarbonylmethoxybenzyl) -thiazolidin-2,4-dione [prepared as described in step (g) above!, 250 ml of 1, 4-dioxane and 750 ml of concentrated aqueous hydrochloric acid. At the end of that period, the reaction mixture was cooled with ice, after which the solid matter was collected by filtration. 600 ml of a 5% w / v aqueous solution of sodium bicarbonate was added to that solid, and the resulting mixture was stirred at room temperature for 2 hours. The insoluble materials were collected by filtration and dissolved in a mixture of 1000 ml of dimethylformamide and 200 liters of methanol. The resulting solution was decolorized by treatment with activated carbon, which was removed by filtration. The filtrate was then concentrated by evaporation under reduced pressure to a volume of about 50 ml. The resulting concentrate was added to 750 ml of diethyl ether and the solution thus obtained was allowed to stand for 2 days. At the end of that period, the resulting precipitate was collected by filtration, to give 20.1 g of the title compound, melting at 267-271 ° C and having a value Rf = 0.66 (on thin layer chromatography on silica gel; using a methylene chloride development solvent containing 5% v / v ethanol).

PREPARATION 3 -C4- (5-hIDR0XI-1.4.6.7-TETRAMETILBENCIMIDAZ0L-2-IL-METOXY) BENCIL3TRIAZ0LIDIN-2.4-DI0NA 3 (a) Trimethylbenzoquinone A suspension of 25.6 g of ferric chloride in 50 ml of water was added at room temperature in a solution of 20 g triflethylhydroquinone in 150 ml of acetone, and the resulting mixture was stirred for 1 hour, then of which it was left to rest for two days. At the end of that period, it was concentrated to approximately half its original volume, and the concentrate mixed with water. The resulting aqueous mixture was extracted with ethyl acetate, and the extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the resulting residue was purified by column chromatography through silica gel, using a mixture of 1: 6 by volume of ethyl acetate and hexane as the eluent, to give 16.9 g of the title compound having a value Rf = 0.46 (on silica gel thin layer chromatography: developing solvent: a 1: 6 by volume mixture of ethyl acetate and hexane). 3 (b) 2.3.6-Trimethylbenzoauinone-4-imane A solution of 7.04 g of hydroxylamine hydrochloride in 30 ml of water was added at room temperature to a solution of 16.9 g of trie-benzoquin a [prepared as described in step (a) above! in 150 ml of methanol, and the resulting mixture was stirred for 2 hours, after which it was allowed to stand for 2 days. At the end of this period, the reaction mixture was diluted with 1000 ml of water. The precipitate that separated was collected by filtration and recrystallized from a mixture of ethyl acetate and hexane to give 11.2 g of the title compound melting at 166-190 ° C. 3 (c) 4-Hydroxy-2.3.5-tri * ethylaniline 152 g of sodium hydroxysulfite were added, while cooling with ice, to a mixture of 36.15 g of 2,3,6-trimethylbenzaquinone-4-o? ima [prepared as described in step (b) above! and 660 ml of an aqueous IN solution of sodium hydroxide and the resulting mixture was stirred at room temperature for 1 hour after which it was allowed to stand overnight. The reaction mixture was poured into ice-water and the pH of the aqueous mixture was adjusted to a value of 4 to 5 by the addition of 5 N aqueous hydrochloric acid, after which it was neutralized with sodium bicarbonate. The mixture thus obtained was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, after which the crystalline residue was triturized with diisopropyl ether and collected by filtration. After washing with diisopropyl ether, 30.1 g of the title compound were obtained, melting at 131-134 ° C. 3 (d) Nt-btoxycarbonyl-H-hydroxy-2,3,5-trimethylaniline 22.0 ml of triethylamine were added at room temperature to a solution of 20 g of 4-hydroxy-2,3,5-tri-ylaniline [prepared as described in step (c) above! in 500 ml of tetrahydrofuran, followed by 34.6 g of di-t-butyl dicarbonate, and the resulting mixture was stirred for 6 hours, after which it was allowed to stand overnight. At the end of this period, the reaction mixture was liberated from the solvent by distillation under reduced pressure, and the resulting residue was washed with water. The resulting aqueous mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, after which the crystalline residue was triturated with hexane, to give 31.9 g of the title compound, melting at 156-161 ° C. 2 < e) N-methy1-4-hydro i-2.3. S-trimethylamino A solution of 15 g of N-t-butaxycarbopi 1-4-hydroxy-2,3,5-trimethylaniline [prepared as in step (d) above! in 200 ml of dehydrated tetrahydrofuran were added to a suspension of 6.6 g of lithium-aluminum hydride, 300 ml of dehydrated tetrahydrofuran, while cooling with ice, and the resulting mixture was stirred at room temperature for 3 hours, after which it was heated under reflux for 2 hours. At the end of this period, a mixture of 10 ml of water and 30 ml of tetrahydrofuran was added to the reaction mixture in order to destroy any excess lithium-aluminum hydride. The reaction mixture was then stirred at room temperature for 1.5 hours, from which the insoluble materials were filtered with the aid of a Ceiite auxiliary (trademark). Those materials were washed with ethyl acetate, and the ethyl acetate washes were combined and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a mixture of 1: 3 by volume of ethyl acetate and hexane co or eluent to give 5.1 g of the compound of title, melting at 120 - 122 ° C. 3 < f > Nt-butoxycarboni-1-N-methy1-4-hydroxy-2.3.5-trimethylaniline 5.0 ml of triet and a solution of 7.92 g of di-t-butyl dicarbonate in 30 ml of tetrahydrofuran were added at room temperature to a 5.0 g solution of N-met il-3-hiriro? i-2,3,5 ~ trimethylane 1 ina [prepared as described in step (e) above! in 70 ml of tetrahydrofuran, and the resulting mixture was stirred for 1 hour, after J or which was allowed to stand overnight. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the resulting residue was mixed with water. The aqueous mixture was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. After distillation of the solvent, the residual crystals were triturated with hexane and collected by filtration. 7.35 g of the title compound were obtained, melting at 163-166 ° C. 3 (q) Nt-butoxycarbonyl-1-N-methyl-4-acetoxy-2,3,5-trimethylaniline 5.64 ml of dehydrated triethylamine and 2.9 ml of acetyl chloride were added at room temperature a solution of 7.2 g of N-butoxycarbonyl-N- methyl-4-hydroxy-2,3,5-t.ri-ethylaniline [prepared as described in step (f) above 3 in 100 ml of tetrahydrofuran dehydrate, and the resulting mixture was stirred for 1 hour, after which which was left to rest during the night. The reaction mixture was then diluted with water and the aqueous mixture was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, after which the residue was triturated by ice-cold ice to cause crystallization. The crystals were collected by filtration and washed with yarn cooled chill to give 6.25 g of the title compound, melting at 103-104 ° C. 3 < h) N-methy1-4-acetoxy-2.3.5-tri-ethylaniline hydrochloride A mixture was prepared by adding 100 ml of a solution of 4 N acid chloride in 1,4-dioxane to 5.45 g of Nt-butoxycarboni 1-N -met i 1-4-acetox i-2,3, 5-tr ime i lapi 1 ina [prepared as described in step (g) above! at room temperature and stirred for 3 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure and the resulting residue was triturated with diisopropyl ether. The crystals thus obtained were collected by filtration, after which they were washed with diisopropyl ether to give 4.36 g of the title compound, melting at 172-176 ° C. 3 (i) N-Methyl-4-acetoxy-2,3,5-trimethyl-6-notroaniline 4.3 g of N-me i-l-4-acetoxy-2,3,5-trilylamine hydrochloride [prepared as described in step (h) above! they were added to the ice-cold concentrated aqueous nitric acid, and the resulting mixture was stirred, while cooling with ice, for 10 minutes and then at room temperature for 10 minutes. At the end of this time, the reaction mixture was poured on ice and the aqueous mixture was neutralized by the addition of sodium bicarbonate after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, after which 50 ml of diisopropyl ether and 50 ml of hexane were added to the residue. The mixture was subsequently stirred ultrasonically for 5 minutes. The insalubrious precipitates were triturated with a mixture of 1: 1 by volume diisoprotic ether and blood. The resulting crystals were collected by filtration, after which they were washed with a mixture of 1: 1 by volume diisopropanol ether and hexane to give 2.76 g of the title compound, melting at 143-146 ° C. 3 (j) 4-Acetoxy-N-methyl-3,5,6-trimethyl-1,2-phenylenediamine A solution of 1.65 g of N-methyl-4-acetoxy-2,3-5-t.ri and il-6-nit .roani 1 ina fpreparada as described in step (f) above! in a mixture of 20 ml of ethanol and 20 ml of ethyl acetate was stirred at room temperature for 3.5 hours and then at 40 ° C for 3 hours in a hydrogen atmosphere and in the presence of 0.2 g of platinum oxide. At the end of that time, the reaction mixture was filtered to remove the platinum oxide and the filtrate was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a mixture of 1: 1 by volume of ethyl acetate and hexane co or the eluent to give 1.3 g of the title compound, melting at 113-116 °. C. 3 (k) 5-C4- (5-Hydroxy-1,4-6,7-tetramethylbenzimidazole- 2. ylmethoxy) benzyl! thiazolidin-2,4-dione A mixture of 1.0 g of 4-acetaxy-N-methyl-3,5,6-tri et yl-1,2-phenylenediamine [prepared as described in step (j) above ! 2.7 g of 5- (4-methoxy arb nor lmethoxybenz i 1) thiazole idin-2,4-di na [prepared as described in step 2 (g) above of preparation 2! 5 ml of 1.4 dioxane and 25 ml of concentrated aqueous hydrochloric acid was heated under reflux for days. At the end of this time, the reaction mixture was added to ice-water and the resulting mixture was neutralized by the addition of sodium bicarbonate. It was then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, after which the residue was purified by chromatography through silica gel, using ethyl acetate as the eluent. The fractions containing the title compound were collected and the solvent was removed by distillation under reduced pressure, to give a red residual oil. 150 ml of diethyl ether was added to the oil, and the mixture was stirred ultrasonically for 5 minutes. The precipitate that separated was collected by filtration and dissolved in 300 ml of tetrahydrofuran. The resulting solution was concentrated to a volume of between about 10 ml and 20 ml by reduced evaporation. 200 ml of ethyl acetate was added to the concentrate and the mixture was stirred ultrasonically for 20 minutes. The precipitate that separated was collected by filtration to give 0.52 g of the title compound, melting at 240-244 ° C and having a value Rf = 0.44 (on silica gel thin layer chromatography; ethyl).

FORMULATION 1 CAPSULES 0.5 g of pravastat in-sodium, 20 g of troglitazone, 1.5 g of crospavidana (disintegrator of pol ivinilpirrol ina) and 0.2 g of sodium lauryl sulfate were mixed. The mixture was divided among 100 empty capsules (number 1) to give 100 capsules, each containing 5 mg of pravastat in-sodium and 200 mg of troglitazana.

FORMULATION 2 TABLETS 40 g of a 5% w / v aqueous solution of hydroxypropylcellulose was added to a mixture of 5 g of pravastat in-sodium, 2. g of compound A, 24 g of hydroxypropylcellulose (lower degree of substitution) and 66.9 g of lactose, and the resulting mixture was kneaded to give a composition. This composition was passed through a 10 mesh sieve (normal Tyler sieve) and dried, after which it was passed through a 15 mesh sieve (normal Tyler sieve) to give equal grains. 11.9 g of the grains and 0.1 g of magnesium stearate were mixed and the mixture was tableted with a tabletting machine, giving tablets of 6.5 ml in diameter and 120 g of dough, each containing 5 mg of pravastat in -sodium and 2 mg of compound A.

Claims (6)

1. NOVELTY OF THE INVENTION CLAIMS 1. - The use for the manufacture of a medicament for the prevention or treatment of arteriosclerosis or xanthoma, of a first agent selected from the group consisting of HMG-CcA reductase inhibitors and a second agent selected from the group consisting of insulin sensitizers, said first and second agents being provided in a form in which they can be administered together or within a period in such a way that they act together in synergistic fashion.
2. 2. Use according to claim 1, further characterized in that said inhibitor of HMG-COA reductase is pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin or atorvastat in.
3. 3. A use according to claim 1, further characterized in that said inhibitor of HMG-COA reductase is pravastatin.
4. 4. A use according to claim 1, further characterized in that said inhibitor of HMG-COA reductase is lovastatin.
5. 5. A use of conmunity with claim 1, further characterized in that said inhibitor of HMG-COA reductase is simvastatin. 6. - A use according to claim 1, further characterized in that said inhibitor of HMG-COA reductase is fluvastatin. 7. A use according to claim 1, characterized in that said inhibitor of HMG-COA reductase is rivastatin.
6. 6. A use according to claim 1, further characterized in that said inhibitor of HMG-COA reductase is atorvastat in. 9. A use according to claim 1, further characterized in that said insulin sensitizer is a thiazole idone compound, a compound of oxazolidinedione or an oxathiadiazole compound. 10. The use according to claim 9, further characterized in that said insulin sensitizer is trogl itasone, dioglitazone, englitazone, BRL-49653, 5- (4-C2- [l- < 4-2 '- p id ilphenyl id) and ilidenoa inoxi-letoxy benzyl-iazolidine-2,4-dione, 5-C4- (5-methoxy-3-metlimidazol-S, 4-b3p-id id-2-yl-ethoxy) -benzyl > thiazolidine-2,4-dione, 5- [4- (6-methoxy-l-methylbenzyl-idazol-2-ylme-oxy) benzyl-iazolidine-2,4-dione, 5- [4- (1-meth i Jbenc midazole- 2-ylmethoxy) benz 11-thiolidine-2,4-dione and 5- [4- (5-hydryl-l, 4,, 6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl-azol idine 2,4- Mrs. 11. A use according to claim 1, further characterized in that said insulin sensitizer is troglitazone. 12. - A use according to claim 1, further characterized in that said insulin sensitizer is pioglitazone. 13. A use according to claim 1, further characterized in that said insulin sensitizer is englitazone. 14. Use according to claim 1, further characterized in that said insulin sensitizer is BRL-49653. 15. A use according to claim 1, further characterized in that said insulin initiator is 5- (4-C2- [1- (4-2'-pyridylphen i 1) -ethylidepeoaminoxy-letoxy> benzyl) -t iazol idine-2,4-ione. 16. A use according to claim 1, further characterized in that said insulin initiator is 5-C4- (5-meto? I -3-metlimidazol [5,4-bl-pyridin-2-ylmethoxy) benzyl. > -t-iazolidine-2,4-dione or its hydrochloride. 17. A use according to claim 1, further characterized in that said insulin initiator is 5- [4- (6-methoxy-l-methylbenzimidazol-2-yl-methoxy) benzylthiazolidin-2,4-dione. . 16. A use according to claim 1, further characterized in that said insulin initiator is 5- [4- (1-methyl-1-methylbenzimidazol-2-ylmethoxy) -benzyl-thiazolid-2,4-dione. 19. A use according to claim 1, further characterized in that said insulin initiator is 5- [4- (5-hydroxy-l, 4,6,7-tetramethylbenz imidazol-2-yl ethoxy) -benzyl iazolidine-2,4-dione. 20. A use according to claim 1, further characterized in that said inhibitor of HMG CaA reductase is pravastatin and said insulin sensitizer is troglitazone. 21. A use according to claim 1, further characterized in that said HMG CoA reductase inhibitor is pravastatin and said insulin sennabilizer is pioglitazone. 22. A use according to claim 1, further characterized in that said inhibitor of HMG CoA reductase is pravastatin and said insulin sensitizer is englitazone. 23. Use according to claim 1, further characterized in that said inhibitor of HMG CoA reductase is pravastatin and said insulin sensitizer is BRL-49653. 24. A use according to claim 1, characterized in that said inhibitor of HMG CoA reductase is pravastatin and said insulin sensitizer is 5 (4 2 [1 (4,2'-pyridylf nyl) and ilityleneaminoxytoxy> benzyl) -thiazolidine-2,4-dione. 25. A use according to claim 1, further characterized in that said inhibitor of HMG CoA reductase is pravastatin and said insulin sensitizer is 5-C4- (5-methoxy-3-met ili idazal [5,4-bl -pyridin-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione or its hydrochloride. 26. A use according to claim 1, further characterized in that said inhibitor of HMG CoA reductase is pravastatin and said insulin sensitizer is 5- [4- (6-methoxy-l-methylbenzimidazol-2-yl-methaxy) benzill iazali-dina-2,4-dione. 27. A use according to claim 1, further characterized in that said inhibitor of HMG CoA reductase is pravastatin and said insulin sensitizer is troglitazone. 5- [4- (1-methybenzimidazl-2-yl-methoxy-benzyl-l-yl-idine-2,4-d-ion.) A use according to claim 1, further characterized in that said HMG-CoA inhibitor. reductase is pravastatin and said insulin sensitizer is 5- [4- (5-hyd oxy-l, 4,6, 7-tetramethylbenzimidazol-2-yl-ethoxy) -benzyl-iazol idine-2,4-dione. 29. A use according to claim 1, further characterized in that said inhibitor of HMG-CoA reductase is lovastatin and said insulin sensitizer is troglitazone 30. A use according to claim 1, further characterized in that said inhibitor of HMG-CoA reductase is lavastatin and said insulin sensitizer is pioglitazone 31. - A use according to claim 1, further characterized in that said inhibitor of HMG-CaA reductase is lovastatin and said insulin sensitizer is englitazon. 32. A use according to claim 1, further characterized in that said inhibitor of HMG-CoA reductase is lovastatin and said insulin sensitizer is BRL-49653. 33. A use according to claim 1, further characterized in that said inhibitor of HMG-CoA reductase is lovastatin and said insulin sensitizer is 5- (4-C2- [1- (4-2'-pyridylphenyl) - ethylideneaminoxy! ethoxy benzyl) -thiazole idine-2,4-dione. 34. A use according to claim 1, further characterized in that said inhibitor of HMG-CaA reductase is lovastatin and said insulin sensitizer is 5-. { 4- (5-methoxy-3-methylimidazoC5,4-blpyridin-2-ylmethoxy) benzyl) -thiazolidine-2,4-dione or its hydrochloride. 35. A use according to claim 1, characterized in that said inhibitor of HMG-CoA red? Ctasa is lovastatin and said insulin sensitizer is 5- [4- (6-methoxy-l-me-ilbenzimidazole-2- il-methoxy) benzyl iazsli-di a-2,4-dione. 36. A use according to claim 1, further characterized in that said inhibitor of HMG-CoA reductase is lovastatin and said insulin sensitizer is 5- [4- (1-meth i Jben midazol-2-yl ethoxy) - benzyl-thiazole idine-2,4-dione. 37. A use according to claim 1, characterized in that said inhibitor of HMG-CoA reductase is lovastatin and said insulin sensitizer is 5- [4- (5-hi-roxy-l, 4,6, 7- tetramethi3 im imidazol-2-yl ethoxy) -benzylthiazolidine-2,4-dione. 36. A use according to claim 1, further characterized in that said inhibitor of HMG-CoA reductase is simvastatin and said insulin sensitizer is troglit.zone. 39. A use according to claim 1, further characterized in that said inhibitor of HMG-CoA reductase is simvastatin and said insulin sensitizer is pioglitazone. 40. A use according to claim 1, further characterized in that said inhibitor of HMG-CoA reductase is simvastatin and said insulin sensitizer is englitazone. 41. A use according to claim 1 r further characterized in that said inhibitor of HMG-CoA reductase is if vaßtatin and said insulin sensitizer is BRL-49653. 42.- A use according to claim 1, further characterized in that said inhibitor of HMG-CoA red? ctase is simvastatin and said insulin sensitizer is 5- (4-f2- [l- (4-2 y-pyridylphenyl) -et-ilidenea inooxy 3 to? i benzyl- thiazslidin-2,4-diopa 43. A concomitant use of claim 1, further characterized in that said HMG-CoA reductase inhibitor is simvastatin and said insulin sensitizer is 5-C4- (5-methoxy). 3-methylimidazo [5,4-b3-pyridin-2-ylmetoxy) benzyl >thiazolidin-2,4-dione or its hydrochloride. 44. A use according to claim 1, further characterized in that said inhibitor of HMG-Co reductase is simvastatin and said insulin sensitizer is 5- [4- (6-ethoxy-1-meth i 3 benz imidazole-2) -i lmetoxy) be il3t iazol idin- 2,4-dion. 45. A use according to claim 1, further characterized in that said inhibitor of HMG-CoA reductase is simvastatin and said insulin sensitizer is 5- [4- (1-methyl-3-benzimidazol-2-ylmet-xi) -benzyl-3-azathidin -2,4-diona. 46. A use according to claim 1, further characterized in that said inhibitor of HMG-CoA reductase is simvastatin and said insulin sensitizer is 5- [4- (5-hi-roxy-i, 4,6, 7-tetramet il-benzimidazol-2-ylmethoxy > benzyl-thiazalidin-2,4-diopa 47. A use according to claim 1, further characterized in that the HMG-CoA reductase inhibitor is fluvastatin and the insulin sensitizer is troglitazone. 46. A use according to claim 1, further characterized in that the inhibitor of HMG-CoA reductase is fluvastatin and the insulin sensitizer is pioglitazana 49. A use according to claim 1, characterized in addition to park the inhibitor. of HMG-CoA reductase is fluvastatin and the insulin sensitizer is englitazone 50. A use according to claim 1, further characterized in that the HMG-CoA reductase inhibitor is fluvastatin and the insulin sensitizer is BRL-49653. .- A Use according to claim 1, further characterized in that the HMG-CoA reductase inhibitor is fluvastatin and the insulin sensitizer is 5- (4-C2- [1- (4-2'-pyridylphenyl) -et i lideneaminooxi 3etoxi > benzyl iazolidin-2,4-dione. 52. A use according to claim 1, further characterized in that the HMG-CoA reductase inhibitor is fluvastatin and the insulin sensitizer is 5-C4- (5-methoxy-3-menelimidazo [5,4-b3] -pyridin-2-ylmethoxy) benzyl > thiazolidin-2,4-dione or its hydrochloride. 53. A use according to claim 1, further characterized in that the inhibitor of HMG-CoA reductase is fluvastatin and the insulin sensitizer is 5- [4- (6-metho-methyl-benzimidazol-2-ylmeto-i) -benzyl-3t) iazolidin-2,4-dione. 54. A use according to claim 1 characterized further because the inhibitor of HMG-CaA reductase is fluvastatin and said insulin sensitizer is 5- [4- (l-methyl benzimidazole-2-lmetox i) -benzyl 3t i 2 ? lidin-2,4-dione. 55. A use according to claim 1, further characterized in that the HMG-CoA reductase inhibitor is fluvastatin and the insulin sensitizer is 5- [4- (5-hydro? I-1,4,6,7). -tetrame il-benzyl idazol-2-lmetaxy) benc i 11-t iazol idin-2,4-dione. 56. A use according to claim 1, characterized in that the inhibitor of HMG-CoA red? Ctasa is rivastatin and the insulin sensitizer is troglitazone. 57. A use according to claim 1 characterized in that the inhibitor of HMG-CoA reductase is rivastatin and said insulin sensitizer is pioglitazone. 56. A use according to claim 1, further characterized in that said inhibitor of HMG-CaA reductase is rivastatin and said insulin sensitizer is englitazone. 59. A use according to claim 1, further characterized in that the inhibitor of HMG-CoA reductase is rivastatin and insulin sensitizer is BRL-49653. 60. A use according to claim 1, further characterized in that the inhibitor of HMG-CoA reductase is rivastatin and the insulin sensitizer is 5- (4-f2- [i- (4-2'-pyridyl). -e-ilideneaminooxi-letoxy-benzthiazolidin-2,4-dione 61. A use according to claim 1, further characterized in that the inhibitor of HMG-CoA reductase is rivastatin and the insulin sensitizer is 5-C4. - (5-methaxy-3-methyl-idazo [5,4-bl-pyridin-2-ylme oxy) benzylta zo-lidin-2, 4-dione or its hydrochloride. 62. A use according to claim 1, further characterized in that the inhibitor of HMG-CoA reductase is rivastatin and the insulin sensitizer is 5- [4- (6-methoxy-1-meth i 3 -benz imidazole-2- i lmetoxy) benzyl 3t i zolidin-2,4-dione. 63. A use according to claim 1, further characterized in that the inhibitor of HMG-CoA reductase is rivastatin and the insulin sensitizer is 5- [4- (l-met i3benzimidazol-2-ylmethoxy) -benc i 13t iazol idin-2,4-dione. 64. A use according to claim 1, further characterized in that said inhibitor of HMG-CoA reductase is rivastatin and the insulin sensitizer is 5- [4- (5-hydroxy-l, 4,6, -tetramet 1-bepc imidazo1-2- i lme oxy) -benz i 13t iazole id in-2,4-dione. 65. A use according to claim 1, characterized in that said inhibitor of HMG-CoA reductase is atorvastatin and the insulin sensitizer is troglitazone. 66. A use according to claim 1, further characterized in that the HMG-CoA reductase inhibitor is atarvastatin and the insulin sensitizer is pioglitazone. 67. - A use according to claim 1, further characterized in that said inhibitor of HMG-CoA reductase is atorvastatin and the insulin-releasing sensitivity is epglitazone. 66. A use according to claim 1, further characterized in that the inhibitor of HMG-CoA red? Ctase is atsrvastatin and insulin sensitizer is BRL-49653. 69. Use according to claim 1, further characterized in that the inhibitor of HMG-CaA reductase is atarvastatin and the insulin sensitizer is 5- (4-C2- [l- (4-2'-pyr ilf ni 1) -et-ilidenea inooxy-3-ethoxy benzylthiazolidin-2,4-dione 70.- A use according to claim 1, further characterized in that the inhibitor of HMG-CoA reductase is atarvastatin and the insulin sensitizer is 5- -C4- (5-methoxy-3-methylazide [5,4-b3-pyridin-2-ylmethoxy) benzyl -thiazolidin-2,4-dione or its hydrochloride) 71.- A use in accordance with claim 1, further characterized in that the inhibitor of HMG-CoA reductase is atorvastatin and the insulin sensitizer is 5- [4- (6-methoxy-i-methy3ben i idazol-2-ylmethoxy) benzyl3t i zolidin-2,4 72. A use according to claim 1, further characterized in that the inhibitor of HMG-CoA red? ct sa is atarvastatin and the insulin sensitizer is 5-L4- (l- et i3benzimidazol-2-ylmethoxy). -benc i1 3t iazol id n-2,4-dione. 73. - A use according to claim 1, further characterized in that the inhibitor of HMG-CoA reductase is atorvastatin and the insulin sensitizer is 5- [4- (5-hydroxy-1,4,6,7-tetramethyl-benzimidazole -2-ilmetsx?) Benzyl 13-thiazolidin-2,4-dione. 74.- A packaged pharmaceutical formulation for the treatment or prophylaxis of arteriesclerosis or xanthoma, further characterized in that it comprises a first agent selected from a group consisting of HMG-CoA reductase inhibitors and a second agent selected from the group consisting of of insulin sensitizers, said first and second agents being in mixture or packed separately, wherein the first and second agents are as defined in any of claims 1 to 73. 75.- A pharmaceutical formulation packaged in accordance with claim 74, characterized in that the agents are supplied in separate portions of said package. 76.- A pharmaceutical composition for the treatment or prophylaxis of iesclero is or xanthoma art, characterized in that it comprises a first agent selected from the group consisting of HMG-CoA reductase inhibitors and a second agent selected from the group that consists of insulin sensitizers, wherein said first and second san-bed agents were defined in any of claims 1 to 73.