Treatment of atherosclerosis and xanthoma

 

(57) Abstract:

The invention relates to medicine. The combination of one or more inhibitors of HMG-COA reductase (e.g., pravastatin, lovastatin, simvastatin, fluvastatin, mevastatin or atorvastatin) and one or more to insulin sensitizing agents (e.g., troglitazone, pioglitazone, englitazone, BRZ-49653, 5-(4-{ 2-[4,2'-pyridylethyl)ethylidenemalonate] ethoxy} benzyl)-thiazolidin-2,4-dione, 5-{4-(5-methoxy-3-methylimidazo[5,4-b]pyridine-2-yl-methoxy)benzyl} thiazolidin-2,4-dione or its hydrochloride, 5-[4-(6-methoxy-1-methylbenzimidazole-2-yl-methoxy)benzyl]thiazolidin-2,4-dione, 5-[4-(1-methylbenzimidazole-2-yl-methoxy)benzyl] thiazolidin-2,4-dione and 5-[4-(5-hydroxy-1,4,6,7-tetramethylbenzidine-2-yl-methoxy)benzyl] thiazolidin-2,4-dione) is administered for the treatment of arteriosclerosis and/or xanthomas. A packaged pharmaceutical preparation containing this combination. The method of treatment more effective. 3 C. and 75 C.p. f-crystals, 10 PL.

The present invention relates to methods and compositions for the treatment and prevention of arteriosclerosis and/or xanthomas.

Recently, worldwide there is a trend towards higher incidence of coronary arter is listed. Among the factors responsible for this increase, it is possible to note the change in lifestyle, including "Western" diet that contains a lot of meat, and the adoption of this diet, even in those countries where it is not traditional, as well as an overall increase in the average age of the population. As a result, these diseases, particularly arteriosclerosis, widely spread, and atherosclerosis is well known as a possible cause of sudden death, for example, as a result of such consequences of atherosclerosis such as myocardial infarction.

One of the main risk factors are important in the development of these diseases is the high level of lipids in blood plasma, in particular high cholesterol. There have been many attempts to use an agent that lowers cholesterol to prevent and treat these diseases, and found a lot of connections, to a greater or lesser extent, with this effect. For example, one such compound that is well known and successfully applied, is pravastatin, which is an agent of regulating lipids, and inhibitor of 3-hydroxy-3-methyl-glutaryl-carrement And reductase (herein referred to as "inhibitor of HMG-COA, REDWO, what do rabbits receiving pravastatin, can prevent coronary arteriosclerosis and xanthoma, but its efficiency is still insufficient (Biochimica et Biophysica Acta, 960, 294-302 (1988)). Experiments on the control of coronary atherosclerosis and xanthomas was performed using a combination of the two agents, regulatory lipids, pravastatin and cholestyramine, which is well known as an agent to reduce the levels of lipoproteins, but the efficacy of this combination remains insufficient (Atherosclerosis, 83, 69-80, 1 (1990)).

In the patent application of Japan Coca N Hei 7-41423 it is assumed that a specific class of agents that improve insulin resistance, such as troglitazone, can be effective in the treatment and prevention of arteriosclerosis, including atherosclerosis, but in this case, the effectiveness of such compounds is not entirely satisfactory.

Currently, it has been unexpectedly discovered that the use of a combination of one or more inhibitors of HMG-COA reductase inhibitor and one or more to insulin sensitizing agents demonstrates a synergistic effect and better prevents and/or treats arteriosclerosis and/or xanthoma than each of the components of this combination on OTDEL securely to heal.

Thus, the aim of the present invention is to provide a combination of one or more inhibitors of HMG-COA reductase inhibitor and one or more to insulin sensitizing agents or agents that improve insulin resistance.

Another and more specific objective of the present invention is to provide such a combination, demonstrating a synergistic effect.

Another objective of the present invention is to provide methods and compositions using such a combination, for the prevention and/or treatment of arteriosclerosis and/or xanthomas.

Other objectives and advantages of the present invention will become apparent from the subsequent description.

Thus, in the first aspect of the present invention is a method of prevention or treatment of arteriosclerosis or xanthoma, which includes the introduction of a patient suffering from or Prednisolonum to arteriosclerosis or xanthoma, the first agent selected from the group consisting of inhibitors of HMG-COA reductase inhibitor and the second agent selected from the group consisting of to insulin sensitizing agents; these first and second agents are administered together or within such a period th of pharmaceutical compositions for the treatment or prevention of arteriosclerosis or xanthoma, which contains a first agent selected from the group consisting of inhibitors of HMG-COA reductase inhibitor and a second agent selected from the group consisting of to insulin sensitizing agents; these first and second agents are in a mixture or in separate packages.

In another aspect the present invention relates to pharmaceutical compositions for the treatment or prevention of arteriosclerosis or xanthoma, which contains a first agent selected from the group consisting of inhibitors of HMG-COA reductase inhibitor and a second agent selected from the group consisting of to insulin sensitizing agents.

Currently, experimental data suggest that the synergistic effect is caused by the interaction between the mechanisms of action of two classes of compounds, inhibitors of HMG-COA reductase and to insulin sensitizing agents, and, thus, it is assumed that the chemical structure of these compounds is less important than their activity. Accordingly, as the first agent you can use any compounds having inhibitory activity against HMG-COA reductase, while the second agent can use any connected is changing for the treatment or prevention of hyperlipemia and may include naturally occurring substances, formed during the metabolism of microorganisms, synthetic substances extracted from them, and fully synthetic substances. Among these compounds, preferred examples include pravastatin, lovastatin, simvastatin, fluvastatin, mevastatin and atorvastatin. Pravastatin is described in Japanese patent publication N Sho 61-13699 and in U.S. patent N 4346227 and 4448979; its formula is (as sodium salt) 1,2,6,7,8,8 and hexahydro-6,8-tetrahydroxy - 2-methyl-1-naphthalenemethanol sodium. Lovastatin is described in Japanese patent application Koca N Sho 58-16875 and European patent N 22478; its formula 6-{2-[1,2,6,7,8,8 and hexahydro-8-(2-methylbutyrate)- 2,6-dimethyl-1-naphthyl] ethyl} tetrahydro-4-hydroxy-2H-Piran-2-it. Simvastatin is described in Japanese patent application KoKai N Hei 1-1476 and in the European patent N 33538; its formula 6-{2-[1,2,6,7,8,8 and hexahydro-8-(2,2-dimethylbutylamino)-2,6-dimethyl-1-naphthyl] ethyl}-tetrahydro-4-hydroxy-2H-Piran-2-it. Fluvastatin described in Japanese patent publication N Hei 2-46031 and in U.S. patent N 4739073; its formula is (as sodium salt) 7-[3-(4 - forfinal)-1-methylethyl)-1H-indol-2-yl)] -3,5-dihydroxy-6-heptanoate sodium. Mevastatin described in Japanese patent application KoKai N Hei 1-216974 and in U.S. patent N 5006530, 5169857 and 5401746; its formula is (as sodium salt) 7-(4-forfinal)patent application Koca N Hei 3-58967 and in U.S. patent N 5273995; its formula is 2-(4-forfinal)-5- (1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-(2,4 - dihydroxycinnamate) acid.

Sensitizing insulin agent, the other active ingredient according to the present invention, may be referred to also as an agent for improving insulin resistance, and is commonly used for the prevention and/or treatment of diabetes. This term includes a wide variety of compounds, usually thiazolidinedione connection oxazolidinedione connection and oxadiazole connection.

These compounds are described, for example, in Japanese patent applications KoKai N Ne 4-69383 and Hei 7-330728, WO 89/08651, WO 91/07107, WO 92/02520, WO 94/01433 and U.S. patent N 4287200, 4340605, 4438141, 4444779, 4461902, 4572912, 4687777, 4703052, 4725610, 4873255, 4897393, 4897405, 4918091, 4948900, 5002953, 5061717, 5120754, 5132317, 5194443, 5223522, 5232925, 5260445; in the European patent N 676398, etc. Among these compounds, preferred examples include troglitazone, pioglitazone, englitazone, RZ-49653, 5-(4-{ 2-[l-(4,2'-pyridylethyl)ethylidenemalonate] ethoxy} benzyl)-thiazolidin-2,4-dione (herein "the Connection And"), 5-{-4-(5-methoxy-3-methylimidazo [5,4-b] pyridine-2-yl-methoxy)benzyl} thiazolidine-2,4-dione (preferably in the form of its hydrochloride), 5-[4-(6-methoxy-1-methylbenzimidazole-2-yl-methoxy)benzyl-benzimidazol-2-yl-methoxy)benzyl] thiazolidin-2,4-dione. Troglitazone described in Japanese patent publication N Ne 2-31079 and in U.S. patent N 4572912; its formula is 5-{4-[(6-hydroxy-2,5,7,8 - tetramethylchroman-2-yl)-methoxy] benzyl} -2,4-thiazolidinedione. Pioglitazone is described in Japanese patent publication N Sho 62-42903 and N Hei 5-66956 and in U.S. patent N 4287200, 4340605, 4438141, 4444779 and 4725610; its formula is 5-{4-[2-(5-ethylpyridine-2-yl)ethoxy} benzyl} -2,4-thiazolidinedione. Englitazone described in Japanese patent publication N Hei 5-86953 and in U.S. patent N 4703052; its formula is 5-[3,4-dihydro-2-(phenylmethyl)-2H-benzopyran-6-yl-methyl] -2,4-thiazolidinedione. BRZ-49653 described in Japanese patent application KoKai N Ne 1-131169 and in U.S. patent N 5002953, 5194443, 5232925 and 5260445; its formula is 5-{4-[2-methyl-2-(pyridin-2-yl-amino)ethoxy] benzyl} 2,4-thiazolidinedione. Connection As described in the European patent N 708098. 5-{4-(5-metaco-3-methylimidazo[5,4-b]pyridine-2-yl - methoxy)benzyl}-thiazolidine-2,4-dione and its hydrochloride) described in Japanese patent application KoKai N Hei 7-330728 and in the European patent N 676398. The above compounds can be obtained according to the known methods mentioned above. 5-[4-(6-methoxy-1 - methylbenzimidazole-2-yl-methoxy)benzyl] thiazolidin-2,4-dione, 5-[4-(1-methylbenzimidazole-2-yl-methoxy)benzyl] thiazolidin-2,4-dione and 5-[4-(5-hydroxy-1,4,6,7-tetramethylbenzidine-2-yl-methoxy) benzyl] thiazole.

The active ingredients that are used in the present invention include, first, one or more inhibitors of HMG-COA reductase, and, secondly, one or more to insulin sensitizing agents or agents that improve insulin resistance. According to the present invention, the combination of an inhibitor of HMG-COA reductase and to insulin sensitizing agent demonstrates a synergistic effect compared to the use of each of the ingredients separately, as shown below. Interestingly, this synergism is evident even in the case where the connection of these two classes are not always present in the body at the same time. In other words, a synergistic effect is observed even when the concentration of one of the compounds of these two classes in the blood is less than that required myself to this connection to show any significant effect. I suppose, though it's just an assumption that when the connection of one of the two classes is injected into the body and transported to the receptor, it activates the selector in vivo. After some time the level of this compound in the blood can drop to values at which the effect was no longer to be observed, however, the "switch" is of arteriosclerosis and/or xanthomas, inherent in the compounds of this class. When the patient is in this state, enter the connection of another class, the effect for the prevention and/or treatment of arteriosclerosis and/or xanthomas can be combined with the effect of the previous introduction of another connection, and the effects of the two compounds favorably act synergistically. Of course, it is obvious that in clinical practice it may be convenient also the introduction of two connections at the same time. Thus, an inhibitor of HMG-COA reductase and to insulin sensitizing agent can be administered simultaneously in the form of a combined preparation. Alternatively, if you mix these two agents is difficult due to incompatibility or for other reasons, for example because of the difficulty of mixing technology, these two active agents can be entered separately in the form of single doses. As described above, since the connection of these two classes show a combined synergistic effect, you can enter them almost simultaneously or with a convenient intervals. The maximum interval that is acceptable to the introduction of the connections of these two classes to achieve the synergistic effect of the present invention, can be installed clinical practice or experiments on iotimeout be entered in mostly orally. Accordingly, the connection of the two classes can be made separately, in the form of two standard dosage forms, or can be physically mixed with obtaining pay the standard dosage forms. Examples of such compositions include, for example, powders, granules, tablets or capsules. These pharmaceutical preparations can be produced by conventional means, well known in the pharmacy.

In the present invention the individual doses of inhibitors of HMG-COA reductase and to insulin sensitizing agents, and the ratio of inhibitors of HMG-COA reductase and to insulin sensitizing agents can widely vary depending on the activity of each connection, and other factors such as condition, age and body weight of the patient. For example, in the case to insulin sensitizing agent, power BRZ-49653 almost 100 times more than troglitazone in vivo in animals with simulated diabetes, resulting in a dose of these two compounds can theoretically differ by almost two orders of magnitude and, in practice, differ by almost an order of magnitude.

The dose of each of the inhibitors of HMG-COA reductase and to insulin sensitizing agents, if they are applied on delinom the use of these two compounds for ordinary purposes, i.e. as antihyperlipidemic and antidiabetic agents. Their doses are further reduced to some extent due to the synergic effect of the combination of compounds of these two classes. For example, if pravastatin and troglitazone used in accordance with the present invention, their doses are preferably in the range from 1 to 40 mg, from 1 to 500 mg, respectively, compared to the range of 5 to 80 mg, and from 10 to 1000 mg, respectively, if these compounds are used for ordinary purposes as antihyperlipidemic and antidiabetic agents.

In most cases, although, as noted above, doses of inhibitors of HMG-COA reductase and to insulin sensitizing agents of the present invention can be widely varied, the daily dose is normally in the range from 0.01 to 40 mg, preferably from 1 to 40 mg, and from 0.05 to 500 mg, preferably from 1 to 500 mg, respectively.

The ratio between the compounds of these two classes may also vary widely, however, it is preferable that the ratio of inhibitor of HMG-COA reductase and to insulin sensitizing agent was in the range of from 1:200 to 200:1 by weight, preferably from 1:100 to 10:1 and Bo is the agent in accordance with the present invention is preferably introduced simultaneously or almost simultaneously in daily doses, described above, and can be single or divided doses.

Compounds and compositions of the present invention can be administered in various forms depending on the disease or disorders, being treated and the age, condition and body weight of the patient, which is well known to specialists. For example, if the compound or composition must be administered orally, they must be made in the form of tablets, capsules, granules, powders or syrups; or for parenteral administration, they should be made in the form of solutions for injection (intravenous, intramuscular or subcutaneous), drugs for drip infusion or in the form of suppositories. For application to the mucous membrane of the eyes, they should be made in the form of eye drops or eye ointments. These preparations can be manufactured by conventional means and, if desired, the active ingredient can be mixed with any conventional auxiliary substance, such as a filler, binding agent, disintegrity agent, lubricant, corrigent, solubilizers agent, suspendisse agent, emulsifier or covering agent.

Examples of fillers that can be used are organically the starch, such as corn starch, potato starch, a-starch, dextrin and carboximetilkrahmal, cellulose derivatives such as crystalline cellulose; maltamedia hydroxypropylcellulose, hypromellose, carboxymethylcellulose, carboxymethylcellulose calcium and carboxymethylcellulose-sodium with internal bridges; Arabian gum; dextran; Pulluane and inorganic fillers, including derivatives of silicon, such as light silicic acid anhydride, synthetic aluminum silicate and aluminate of metasilicate magnesium; phosphates such as calcium phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate.

Lubricating agents which can be used include stearic acid, metallic stearates such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as beeswax and spermaceti waxes; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DZ-leucine; sodium salts of fatty acids; laurilsulfate, such as sodium lauryl sulfate and lauryl sulfate, magnesium; silicates such as silicic acid anhydride and silicic acid hydrate polyvinylpyrrolidone; macrogol; and the same compounds as those mentioned above as fillers.

Dezintegriruetsja agents that can be used include the same compounds as those mentioned above as fillers; and chemically modified starches and cellulose, such as croscarmellose sodium, carboxymethyl-starch-sodium and polyvinylpyrrolidone with internal bridges.

Stabilizers that can be used include peroxybenzoate, such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; along with dehydroacetic acid and sorbic acid.

The corrigentov that can be applied include sweeteners, podnikatel and spices.

The present invention is further illustrated by the following examples, which show increased activity that is achieved by the synergistic combination of the present invention. In addition, subsequent songs illustrous pharmaceutical compositions which can be prepared, and preparation that illustrous the preparation of some to insulin sensitizing agents used in the present who hyperlipidemia Watanabe, described in Biochimica et Biophysica Acta, 960, 294-302 (1988)) blind were collected in the control group (7 animals, group A), the group receiving only pravastatin (5 animals, group B), the group receiving only troglitazone (7 animals, group C), and the group receiving the combination of both active substances (6 animals, group D). Pravastatin is administered orally using a stomach probe at a dose of 50 mg/kg/day once a day, and troglitazone given with food containing 100 mg/kg of substance, for 32 weeks. The amount consumed was limited to 120 g per rabbit per day. The animals took the blood directly before the experiment and after 4, 8, 12, 16, 24, 28 and 32 weeks after the start of the experiment, and in each sample was determined by total cholesterol (mg/DL). These levels are expressed in percentage (%) of the levels defined immediately before the beginning of the experiment. The results are presented in table. 1. Animals were killed and dissected through 32 weeks to determine (a) the percentage of the affected area (%) in General, in the thoracic or abdominal aorta; (C) stenosis (%) coronary artery, and (C) frequency (%) xanthomas in the interphalangeal joints.

The results are presented in table. 2, 3 and 4. Measured values are presented as mean value+standard is cholesterol in plasma after 32 weeks of the experiment between group D (which received the combination of both agents) and group B (which received only pravastatin). On the contrary, in the ratio of the percentage area of the lesion (area of lesions/total area of the artery in %) there was a clear synergism when compared to group D (combined treatment) and groups b and C (one treatment agent), as shown above. Observed synergism in the prevention of stenosis of the coronary arteries in the left anterior descending artery, left circumflex artery and right coronary artery. The development of xanthomas in the interphalangeal joints was completely prevented in group D, which demonstrated, thus, a clear synergism.

Thus, although we detected no significant difference in the levels of plasma cholesterol between groups treated with a combination of an inhibitor of HMG-COA reductase and to insulin sensitizing agent, and a group who received only a single active agent, a combination of both active agents synergistically prevented the progression of atherosclerosis, particularly in the thoracic aorta. These results could not be present based on previously known data in this field.

Example 2.

Male rabbits NPV (with hereditary hyperlipidemia Watanabe), virtually nonexistent arterial lesions, were selected blind in KANUPP) the group treated only pioglitazone oral (7 animals, 20 mg/kg group), the group treated with oral 5-(4-{ 2-[1-(4-2'-pyridylethyl) ethylidenemalonate]ethoxy}benzyl)thiazolidine-2,4-dione (herein connection And, as described in EP 708098, 7 animals, 10 mg/kg, group D), the group treated with oral combination of pravastatin and pioglitazone (6 animals, 50 + 20 mg/kg, group E), and the group treated with oral combination of pravastatin and connections And (7 animals, 50 + 10 mg/kg, group F).

Each test compound was administered within eight months the rabbits in the form of a water suspension (0,5% added carboxymethylcellulose). In the control group was injected only 0.5% solution of carboxymethylcellulose. After one month after the beginning of the introduction and further it was found that the level of serum cholesterol in groups B, E and F are maintained at a lower level than in the control group, and these groups showed lower levels of serum cholesterol on 22-34%. However, in groups C and D were observed decrease in the levels of serum cholesterol.

The percentage area of lesions in the aortic arch and in the entire aorta is presented in table. 5. Actually measured values presented here control group;*p less than 0.05,**p less than 0.01; significant difference compared with control U-test Mann-Whitney.

Significant difference (p less than 0.05) was observed between groups b and F, and between groups C and E and between groups D and F in the aortic arch, and between groups C and E in the entire aorta.

Measured average thickening of the intima of the aorta; the results are presented in table. 6. Actually measured values are presented here as mean plus or minus standard error (μm). Numbers in parentheses represent the percentage of intimal thickening from the control group. Significant difference was observed between groups D and F in the aortic arch and between groups C and E and between groups D and F in the entire aorta (p less than 0.05) U-test Mann-Whitney. The average intimal thickening was calculated by the cross-sectional intima of the aorta at the aortic arch and two lateral sections in the thoracic and abdominal parts, divided by the average length of the shell.

A slight suppression of intimal thickening was observed in group b, while in groups C and D were not observed suppression of hypertrophy. In contrast, groups C and D groups E and F were observed suppression of intimal thickening.

We determined the content of cholesterol in the aorta. The middle and inner shell d is sue 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 determined by conventional enzymatic method. The results are presented in table. 7a and 7b.

Data are presented as mean plus or minus standard error (mg/g tissue). Values in parentheses represent the percentage of control. Significant difference compared to control group was observed by unpaired t-criterion of student:*p less than 0.05; **p less than 0.02.

As follows from the table. 7, the levels of total cholesterol in the thoracic and abdominal aorta were lower in groups E and F than in groups b, C and D. there was Not a clear trend between the levels of free and esterified cholesterol. These results are similar to those for the intensity of the lesions.

Determined the frequency and severity of xanthomas on four legs. The results are presented in table. 8.

As can be seen from the table. 8, in the control group xanthoma met in 100% of cases for all front and rear extremities. In groups B, C and D frequency xanthomas was somewhat less. In groups E and F who received a combination of active agents, the frequency of xanthomas was significantly lower. The same trend in the case of wt is A to D.

The meaning of these results is that two combinations of pravastatin, an inhibitor of HMG-COA reductase, and one of thiazolidindiones to insulin sensitizing agents have demonstrated synergistic effects in the treatment of atherosclerosis and the presence of xanthomas.

Example 3.

Studied the synergistic effect of inhibitors of HMG-COA reductase and thiazolidindiones to insulin sensitizing agents in relation to the regression of existing atherosclerotic lesions in rabbits who were given cholesterol.

Male new Zealand white rabbit (5 months of age) within two months they were fed a diet with 2% cholesterol, and at the end of this period, serum cholesterol in these rabbits was increased to 1,100-4,100 mg/DL.

Rabbits were distributed blind method according to groups (3-9) animals per group and gave them compound orally for two months, while they received normal lipid diet. The dosage of the tested compounds was as follows: in the case of one of pravastatin 3 mg/kg or 5 mg/kg; in the case of one of fluvastatin 0.8 mg/kg or 1.5 mg/kg; in the case of one troglitazone 10 mg/kg; in case only the connection of A 2.5 mg/kg In the case of comb is unity And 2.5 mg/kg; fluvastatin 0.8 mg/kg + troglitazone 10 mg/kg and fluvastatin 1.5 mg/kg + compound And 2.5 mg/kg

The results represent the percentage of the affected area in the thoracic aorta (table. 9).

Actually measured values are presented here as mean standard error. Values in parentheses represent the percentage reduction of lesions compared with the control group.

As can be seen from the table. 9, each of the inhibitors of HMG-COA reductase or thiazolidinediones to insulin sensitizing agents individually did not cause or caused a small decrease in losses, while all combinations of these two components showed a synergistic reduction in lesions.

Example 4.

Synergistic inhibitors of HMG-COA reductase and thiazolidinedione to insulin sensitizing agents studied in different model regression, i.e. regression of previously formed atherosclerosis in hamsters. Male hamsters F1b (weighing about 130 g) were given a diet containing 0.05% cholesterol, for 13 weeks. Of these animals are blind way formed a group (2 to 7 animals per group), and then gave the subjects the drugs within 4 weeks, while the rats received a diet with a normal content of EMA as troglitazone mixed with feed at a dose of 30 or 100 mg/kg

In the case of the combined groups, the dose was 3 mg/kg + 30 mg/kg or 3 mg/kg + 100 mg/kg group pravastatin + troglitazone and 1.5 mg/kg + 30 mg/kg group fluvastatin + troglitazone.

Arterial damage was assessed by the length of the square, okrashivaniya red oil O (ORO) as described in Atherosclerosis, 114, 19-28 (1995). Namely, the arc of aorta were stained with ORO for sample preparation front. Calculate the percentage of area that was stained ORO, from the entire area, and that was the extent of injury of the aorta.

After treatment between groups was not observed significant difference in total cholesterol and triglycerides in the blood serum. The results are presented in table. 10.

As can be seen from the table. 10, was not observed regression of aortic lesions in the groups treated with pravastatin, fluvastatin or troglitazone (30 mg/kg) separately, although there was a regression when using troglitazone separately in the dose of 100 mg/kg

In the case of the combination of pravastatin and troglitazone was observed regression dose-dependent in relation to troglitazone trend. In the case of the combination of fluvastatin and troglitazone observed similar synergistic regression of aortic lesions.

Su is th to insulin agent demonstrates how the class of preventive and therapeutic effects against atherosclerosis and xanthomas.

Preparation 1

5-[4-(1-methylbenzimidazole-2-yl-methoxy)benzyl-thiazolidine-2,4-dione

1(a) methyl-4-nitrophenoxyacetic

A mixture of 56 g of 4-NITROPHENOL, 90 g of methylpropanoate, 100 g of potassium carbonate and 50 ml of dimethylformamide was stirred at room temperature for two days. At the end of this time the solvent was removed by distillation under reduced pressure. The obtained 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, then the solvent was removed by distillation under reduced pressure. The obtained residue was washed with hexane to obtain a 63.3 g specified in the title compound, which melted at 98-99oC.

1(b) methyl-4-aminophenoxyethanol

The solution 30,8 g methyl-4-nitrophenoxyacetic (prepared as described in step (a) above) in 50 ml of methanol was shaken in an atmosphere of hydrogen and in the presence of 5.0 g of 10%/palladium on charcoal for 6 hours At the end of this time the reaction mixture was filtered, and the filtrate was concentrated by evaporation under reduced pressure to get 25,8 g specified in the title compound, having a value of Rf= 0,79 (thin-layer chromatog-1-yl)-phenoxyacetate

98 g of 47% in/in aqueous Hydrobromic acid, and then 33 ml of an aqueous solution containing 12.8 g of sodium nitrite was added to a solution of 25.8 g of methyl-4-amino-phenoxyacetate (prepared as described in step (b) above) in 263 ml of a mixture of 2:5 by volume of methanol and acetone, cooling in ice, and the resulting mixture was stirred while cooling in ice for 30 minutes and Then was added 18.2 g of butyl acrylate, and the reaction mixture was stirred for another 30 min, cooling in ice. Then to the mixture was added 3.2 g of copper bromide (1), and the mixture was stirred over night at room temperature. At the end of this time the reaction mixture was freed from solvent by distillation under reduced pressure, and the residue was mixed with aqueous solution of sodium chloride. Then it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After removal of the solvent by distillation was received of 51.7 g specified in the connection header with a value of Rf= 0,46 (on thin layer chromatography on silica gel; allocating a solvent mixture of 5:1 by volume of hexane and ethyl acetate) in the form of a crude product.

1(d) 5-[4-(ethoxycarbonylmethoxy)benzyl]thiazolidin-2,4 - dione
oC.

1(e) 5-[4-(1-methylbenzimidazole-2-yl-methoxy)benzyl]- thiazolidine-2,4-dione

A mixture of 1.0 g of N-methyl-1,2-phenylenediamine, 3.8 g of 5-[4-(ethoxycarbonylmethoxy)benzyl] thiazolidin-2,4-dione (prepared as described in step (d) above), 20 ml of concentrated aqueous hydrochloric acid, 10 ml of 1,4-dioxane and 10 ml of water was heated under reflux for 5 hours At the end of this time, insoluble materials deposited in the sediment from react the m to the solution was added water. The resulting aqueous mixture was neutralized by adding sodium bicarbonate and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the obtained residue was purified column chromatography on silica gel using ethyl acetate and then ethanol as eluent. This product is then recrystallized twice from a mixture of tetrahydrofuran and ethylacetate obtaining 1.3 g specified in the title compound with so pl. 230-231oC.

Preparation of 2

5- [4-(6-methoxy-1-methylbenzimidazole-2-yl - methoxy)-benzyl]thiazolidin-2,4-dione

2(a) 5-methoxy-2-nitroaniline

70 ml of 28% V/o solution of sodium methoxide in methanol was added at room temperature to a solution of 25 g of 5-chloro-2 - nitroaniline in 500 ml of 1,4-dioxane, and the resulting mixture was heated under reflux for 4 h, after which the solvent was removed by distillation under reduced pressure. The obtained 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 RAS is she on silica gel, using the method of gradient elution with mixtures of ethyl acetate and hexane ranging from 1:4 to 1:2 by volume as the eluent to obtain 16.3 g specified in the title compound with so pl. 124 to 128oC.

2(b) N-t-butoxycarbonyl-5-methoxy-2-nitroaniline

25 g of di-t-butylboronic, 15 ml of pyridine and 0.6 g of 4-dimethylaminopyridine was added at room temperature to a solution of 16 g of 5-methoxy-2-nitroaniline (prepared as described in step (a) above) in 500 ml digidratirovannogo of tetrahydrofuran, and the resulting mixture was stirred for 2 hours At the end of this time the reaction mixture was freed from solvent by distillation under reduced pressure, and the obtained 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, then the solvent was removed by distillation under reduced pressure. The obtained residue was purified column chromatography on silica gel using a mixture of 1:10 by volume of ethyl acetate and hexane as eluent, to obtain 12.5 g specified in the title compound with so pl. 112-114oC.

2(C) N-t-butoxycarbonyl-N-methyl-5-methoxy-2-nitroaniline

R is datirovannaja of dimethylformamide was added, cooling in ice, to a suspension of 12.0 g of sodium hydride (55% in/in dispersion in mineral oil) in 300 ml digidratirovannogo of dimethylformamide, and the resulting mixture was stirred at room temperature for 30 min, then was added to 17.2 ml under the conditions at room temperature. The reaction mixture was stirred for 1 h, after which it was left to stand overnight at room temperature. It was then concentrated to approximately one-fifth of its original volume by evaporation under reduced pressure. This concentrate was mixed with ice-water and the resulting aqueous mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride in that order, after which it was dried over anhydrous sodium sulfate. After removal of the solvent by distillation got to 52.1 g specified in the title compound with so pl. 122-124oC.

2(d) N-methyl-5-methoxy-2-nitroaniline

750 ml of a 4N solution of hydrogen chloride in 1,4-dioxane was added to 52 g of N-t-butoxycarbonyl-N-methyl-5-methoxy-2-nitroaniline (prepared as described in step (C) above) at room temperature, and the resulting mixture was stirred for 2 hours At the end of this time reacciona the ode and ethyl acetate. This mixture is then neutralized by adding 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. After removal of the solvent by distillation received 35,3 g specified in the title compound with so pl. 107-110oC.

2(e) 5-methoxy-N-methyl-1,2-phenylenediamine

346 g of tin chloride (2) was added to a mixture of 35 g of N-methyl-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 60oC for 2 h, after which was added by portions 11 g of sodium borohydride at 60oC for approximately 1 h, the Reaction mixture was then stirred at 60oC for 3 h, after which it was left to stand at room temperature for two days. Then it was poured into ice-water, and the aqueous mixture was neutralized by adding 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 obtained residue ve eluent, with the receipt of 21.9 g specified in the title compound, having a value of Rf= 0,18 (on thin layer chromatography on silica gel; allocating a solvent mixture of 1:1 by volume of ethyl acetate and hexane).

2(f) 5-(4-methoxycarbonylbenzyl)-3-triphenylmethyl - thiazolidin-2,4-dione

126 g of cesium carbonate were added at room temperature to a solution of 120 g of 5-(4-hydroxybenzyl)-3 - triphenyltetrazolium-2,4-dione in 2.5 l of acetone, and then added 36 ml of methylpropanoate, and the resulting mixture was stirred for 1 h At the end of this time the reaction mixture was freed from solvent by distillation under reduced pressure, and the obtained residue was mixed with water. This aqueous mixture was then extracted with ethyl acetate. The extract was washed with water and then saturated aqueous sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, after which the oily residue was added 1 l of diethyl ether. The mixture then was stirred by ultrasonic waves for 10 minutes Precipitated precipitated solid substance was collected by filtration to obtain 126,3 g specified in the title compound with so pl. 158-162oC.

Yali at room temperature to a suspension of 344 g of 5-(4 - methoxycarbonylbenzyl)-3-triphenyltetrazolium-2,4-dione (prepared as described in step (f) above) in 400 ml of 1,4 - dioxane, and the resulting mixture was stirred for 5 h at 80oC. after this time the reaction mixture was freed from solvent by evaporation under reduced pressure, and the obtained residue was purified column chromatography on silica gel using a mixture of 1:2 by volume of ethyl acetate and hexane, a mixture of 2:1 by volume of ethyl acetate and hexane and then ethyl acetate as eluents to obtain of 161.7 g specified in the title compound with so pl. 100-106oC.

2(h) 5-[4-(6-methoxy-1-methylbenzimidazole-2-yl-methoxy)- benzyl] thiazolidin-2,4-dione

A mixture of 21.8 g of 5-methoxy-]-N-methyl-1,2-phenylenediamine (prepared as described in step (e) above), and 63.4 g of 5-(4-methoxycarbonylbenzyl)-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 was heated under reflux for 60 hours At the end of this time the reaction mixture was cooled with ice, after which the solid was collected by filtration. This substance was added 800 ml of 5% V/o aqueous solution of sodium bicarbonate, and the resulting mixture was stirred at room temperature for 2 hours and Then insoluble materials were collected by filtration and dissolved in revenage coal, which was then removed by filtration. The filtrate is then concentrated by evaporation under reduced pressure to a volume of approximately 50 ml of the Obtained concentrate was added to 750 ml of diethyl ether, and the thus obtained solution was left to stand for two days. After this time the precipitate was collected by filtration receipt of 20.1 g specified in the title compound with so pl. 267-271oC and a value of Rf= 0,68 (on thin layer chromatography on silica gel; allocating the solvent is methylene chloride with 5% o/o ethanol).

Preparation of 3

5-[4-(5-hydroxy-1,4,6,7-tetramethylbenzidine-2-yl-methoxy) benzyl]-thiazolidine-2,4-dione.

3(a) trimethylxanthine

A suspension of 25.6 g of ferric chloride (3) in 50 ml of water was added at room temperature to a solution of 20 g of trimethylhydroquinone in 150 ml of acetone, and the resulting mixture was stirred for 1 h, after which it was left to stand for two days. At the end of this time it was concentrated to approximately half the original volume and the concentrate was mixed with water. The resulting aqueous mixture was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride in the specified order is the first pressure, and the obtained residue was purified column chromatography on silica gel using a mixture of 1:6 by volume of ethyl acetate and hexane as eluent to obtain 16,9 g specified in the title compound with a value of Rf= 0,48 (on thin layer chromatography on silica gel; allocating a solvent mixture of 1:6 by volume of ethyl acetate and hexane).

3(b) 2,3,6-trimethylbenzoquinone-4-oxime

Solution? 7.04 baby mortality g of hydroxylamine hydrochloride in 30 ml of water was added at room temperature to a solution of 16.9 g of trimethylbenzoquinone (prepared as described in step (a) above) in 150 ml of methanol, and the resulting mixture was stirred for 2 h, after which it was left to stand for two days. At the end of this time the reaction mixture was diluted with 1000 ml of water. The separated precipitate was collected by filtration and recrystallized from a mixture of ethyl acetate and hexane to obtain 11.2 g specified in the title compound with so pl. 188-190oC.

3(C) 4-hydroxy-2,3,5-trimethylaniline

152 g of hydrosulfite sodium was added under ice cooling to a mixture 36,15 g of 2,3,6 - trimethylbenzoquinone-4-oxime (prepared as described in step (b) above) and 880 ml of 1N aqueous sodium hydroxide solution, and the resulting mixture was stirred at on the ice-water and the pH of the aqueous mixture is brought up to 4-5 by adding 5H aqueous hydrochloric acid, after which it was neutralized with sodium bicarbonate. Thus obtained 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 then removed by distillation under reduced pressure, after which the crystalline residue was washed with diisopropyl ether and collected by filtration. After washing diisopropyl

ether was given to 30.1 g specified in the title compound with so pl. 131-134oC.

3(d) N-t-butoxycarbonyl-4-hydroxy-2,3,5-trimethylaniline

22,0 ml of triethylamine was added at room temperature to a solution of 20 g of 4-hydroxy-2,3,5-trimethylaniline (prepared as described in step (C) above) in 500 ml of tetrahydrofuran, and then added 34,6 g of di-t-butylboronic, and the resulting mixture was stirred for 6 h, after which it was left to stand over night. At the end of this time the reaction mixture was freed from solvent by distillation under reduced pressure, and the obtained residue was mixed with water. The resulting aqueous mixture was extracted with ethyl acetate. The extract was washed with nesisaraly under reduced pressure, after that, the crystalline residue was washed with hexane to obtain 31,9 g specified in the title compound with so pl. 158-161oC.

3(e) N-methyl-t-hydroxy-2,3,5-trimethylaniline

A solution of 15 g of N-t-butoxycarbonyl-4-hydroxy-2,3,5-trimethylaniline (prepared as described in step (d) above) in 200 ml digidratirovannogo of tetrahydrofuran was added to a suspension of 6.8 g of hydride lithium aluminium 300 ml digidratirovannogo of tetrahydrofuran while cooling with ice, and the resulting mixture was stirred at room temperature for 3 h, after which it was heated under reflux for 2 hours after which time the mixture of 10 ml of water and 30 ml of tetrahydrofuran was added to the reaction mixture to destroy the excess hydride lithium aluminium. The reaction mixture was then stirred at room temperature for 1.5 h, after which the insoluble materials were filtered through Celite filter (trade name). These materials were washed with ethyl acetate, and these washings were combined and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified column chromatography on silica gel using a mixture of 1: 3 by volume ethyl acetate and hex-butoxycarbonyl-N-methyl-4-hydroxy-2,3,5 - trimethylaniline

5.0 ml of triethylamine and a solution of a 7.92 g of di-t-butylbenzoate in 30 ml of tetrahydrofuran was added at room temperature to a solution of 5.0 g of N-methyl-4-hydroxy-2,3,5-trimethylaniline (prepared as described in step (e) above) in 70 ml of tetrahydrofuran, and the resulting mixture was stirred for 1 h, after which it was left to stand over night. At the end of this time the reaction mixture was freed from solvent by distillation under reduced pressure, and the obtained residue was mixed with water. The aqueous mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride in that order, after which it was dried over anhydrous magnesium sulfate. After removal of the solvent by distillation crystalline residue was washed with hexane and collected by filtration. Received 7,35 g specified in the title compound with so pl. 163-166oC.

3(g) N-t-butoxycarbonyl-N-methyl-4-acetoxy-2,3,5 - trimethylaniline

5,64 ml digidratirovannogo of triethylamine and 2.9 ml of acetylchloride was added at room temperature to a solution of 7.2 g of N-t-butoxycarbonyl-N-methyl-4-hydroxy-2,3,5-trimethylaniline (prepared as described in step (f) above) in 100 ml digidratirovannogo tetrahydrofurane then diluted with water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, then the residue was washed with cooled in ice hexane to induce crystallization. The crystals were collected by filtration and washed with cooled in ice hexane to obtain 6.25 g specified in the title compound with so pl. 103-104oC.

3(h) N-methyl-4-acetoxy-2,3,5-trimethylaniline hydrochloride

A mixture prepared by adding 100 ml 4H solution of hydrogen chloride in 1,4-dioxane to the 5.45 g of N-t-butoxycarbonyl-N-methyl-4 - acetoxy-2,3,5-trimethylaniline (prepared as described in step (g) above) at room temperature was stirred for 3 hours At the end of this time the reaction mixture was freed from solvent by distillation under reduced pressure, and the obtained residue was washed with diisopropyl ether. Thus obtained crystals were collected by filtration, then washed with diisopropyl ether to obtain 4,36 g specified in the title compound with so pl. 172-176oC.

3(i) N-methyl-4-acetoxy-isano in step (h) above) was added to ice concentrated aqueous nitric acid, and the resulting mixture was stirred while cooling with ice for 10 min and then at room temperature for 10 minutes At the end of this time the reaction mixture was poured into ice-water, and the aqueous mixture was neutralized by adding 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, and then to the residue was added 50 ml of diisopropyl ether and 50 ml of hexane. The mixture was then stirred by ultrasound for 5 minutes Insoluble precipitate was washed with a mixture of 1:1 by volume of diisopropyl ether and hexane. The obtained crystals were collected by filtration, then washed with a mixture of 1:1 by volume of diisopropyl ether and hexane to obtain 2.76 g specified in the title connection so pl. 143-146oC.

3(j) 4-acetoxy-N-methyl-3,5,6-trimethyl-1,2-phenylenediamine

A solution of 2.65 g of N-methyl-4-acetoxy-2,3,5-trimethyl-6-nitroaniline (prepared as described in step (i) above) in a mixture of 20 ml ethanol and 20 ml of ethyl acetate was shaken at room temperature for 3.5 h and then at 40oC for 3 h in an atmosphere of hydrogen and in the and platinum, and the filtrate is freed from solvent by distillation under reduced pressure. The obtained residue was purified column chromatography on silica gel using a mixture of 1:1 by volume of ethyl acetate and hexane as eluent to obtain 1.3 g specified in the title compound including square 113-116oC.

3(k) 5-[4-(5-hydroxy-1,4,6,7-tetramethylbenzidine-2-yl - methoxy)benzyl]thiazolidin-2,4-dione

A mixture of 1.0 g of 4-acetoxy-N-methyl-3,5,6-trimethyl-1,2-phenylenediamine (prepared as described in step (j) above), 2.7 g of 5-(4-methoxy - carbonylmethyl)thiazolidin-2,4-dione (prepared as described in step 2 (g) preparation of 2), 5 ml of 1,4-dioxane and 25 ml of concentrated aqueous hydrochloric acid was heated under reflux for two days. At the end of this time the reaction mixture was added to ice-water, and the resulting mixture was neutralized by adding sodium bicarbonate. Then it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Then the solvent was removed by distillation under reduced pressure, then the residue was purified column chromatography on silica gel using atually by distillation under reduced pressure to obtain a residue in the form of a red oil. To this oil was added 150 ml of diethyl ether, and the mixture was stirred by ultrasonic waves for 5 minutes the precipitation was collected by filtration and was dissolved in 300 ml of tetrahydrofuran. The resulting solution was concentrated to a volume of approximately 10-20 ml by evaporation under reduced pressure. To the concentrate was added 200 ml of ethyl acetate, and the mixture was stirred by ultrasonic waves for 20 minutes the precipitation was collected by filtration to obtain 0.52 g specified in the title compound with so pl. 240-244oC and a value of Rf= 0,44 (on thin layer chromatography on silica gel; emit solvent ethyl acetate).

Example 5.

Preparative form 1

Capsules

Mixed 0.5 g of pravastatin sodium, 20 g troglitazone, 1.5 g of crosspovidone mechanical polyvinylpyrrolidone) and 0.2 g of lauryl sodium. The mixture was divided between 100 empty capsules (n 1) to obtain 100 capsules, each of which contained 5 mg of pravastatin-sodium and 200 mg troglitazone.

Example 6

Preparative form 2

Tablets

40 g of 5% V/o aqueous solution of hydroxypropylcellulose was added to a mixture of 5 g of pravastatin sodium, 2 g of compound A, 24 g hydroxypropylcellulose low-degree of substitution) and 10 mesh (standard mesh Tyler) and dried, then it was passed through a sieve of mesh 15 (standard mesh yler) to obtain pellets of the same size. Mixed 11.9 g of granules and 0.1 g of magnesium stearate, and the mixture was made into tablets using a machine for tabletting, resulting received the tablets with a diameter of 6.5 mm and a weight of 120 mg, each of which contained 5 mg of pravastatin-sodium and 2 mg of compound A.

1. The method of prevention or treatment of arteriosclerosis or xanthoma, including the introduction of a patient suffering from or susceptible to arteriosclerosis or xanthoma, the first agent selected from the group consisting of inhibitors of HMG-COA reductase inhibitor and the second agent selected from the group consisting of to insulin sensitizing agents, these first and second agents are administered together or within a period of time when they can act synergistically.

2. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is pravastatin, lovastatin, simvastatin, fluvastatin, mevastatin or atorvastatin.

3. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is pravastatin.

4. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase s is simvastatin.

6. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is fluvastatin.

7. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase is levastatin.

8. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is atorvastatin.

9. The method according to p. 1, characterized in that said to insulin sensitizing agent is thiazolidindiones connection or oxadiazole connection.

10. The method according to p. 9, characterized in that said to insulin sensitizing agent is troglitazone, pioglitazone, englitazone, BRZ-49653, 5-(4-{ 2-[1-(4-2'-pyridylethyl)ethylidenemalonate] ethoxy}benzyl-thiazolidine-2,4-dione, 5-{4-(5-methoxy-3-methylimidazo-[5,4-b]pyridine-2-yl-methoxy)benzyl} thiazolidine-2,4-dione, 5-[4-(6-methoxy-1 - methylbenzimidazole-2-yl-methoxy)benzyl] thiazolidin-2,4-dione, 5-[4-(1-methylbenzimidazole-2-yl-methoxy)benzyl] thiazolidin-2,4-dione and 5-[4-(5-hydroxy-1, 4, 6, 7-tetramethylbenzidine-2-yl-methoxy)benzyl]thiazolidin-2,4-dione.

11. The method according to p. 1, characterized in that said to insulin sensitizing agent is troglitazone.

12. The method according to p. 1, characterized in that pointed to by then specified to insulin sensitizing agent is englitazone.

14. The method according to p. 1, characterized in that said to insulin sensitizing agent is BRL-49653.

15. The method according to p. 1, characterized in that said to insulin sensitizing agent is 5-(4-{2-[1-(4-2'-pyridylethyl)ethylidenemalonate] ethoxy}benzyl)thiazolidine-2,4-dione.

16. The method according to p. 1, characterized in that said to insulin sensitizing agent is 5-{4-(5-methoxy-3-methylimidazo[5,4-b]-pyridine-2-yl-methoxy)benzyl}thiazolidine-2,4-dione or its hydrochloride.

17. The method according to p. 1, characterized in that said to insulin sensitizing agent is 5-[4-(6-methoxy-1-methylbenzimidazole-2-yl-methoxy) benzyl]thiazolidin-2,4-dione.

18. The method according to p. 1, characterized in that said to insulin sensitizing agent is 5-[4-(1-methylbenzimidazole-2-yl-methoxy)benzyl]thiazolidin-2,4-dione.

19. The method according to p. 1, characterized in that said to insulin sensitizing agent is 5-[4-(5-hydroxy-1,4,6,7-tetramethylbenzidine-2-yl-methoxy)benzyl]thiazolidin-2,4-dione.

20. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is pravastatin, and specified to insulin sensitizing agent is a t the I pravastatin, and specified to insulin sensitizing agent is pioglitazone.

22. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is pravastatin, and specified to insulin sensitizing agent is englitazone.

23. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is pravastatin, and specified to insulin sensitizing agent is BRL-49653.

24. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is pravastatin, and specified to insulin sensitizing agent is 5-(4-{ 2-[1-(4-2'-pyridylethyl)ethylidenemalonate] ethoxy} benzyl)thiazolidine-2,4-dione.

25. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is pravastatin, and specified to insulin sensitizing agent is 5-{4-(5-methoxy-3-methylimidazo[5,4-b]-pyridine-2-yl-methoxy)benzyl}thiazolidine-2,4-dione or its hydrochloride.

26. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is pravastatin, and specified to insulin sensitizing agent is 5-[4-(6-methoxy-1-methylbenzimidazole-2-yl-methoxy)benzyl] thiazolidin-2,4-dione.

28. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is pravastatin, and specified to insulin sensitizing agent is 5-[4-(5-hydroxy-1,4,6,7-tetramethylbenzidine-2-yl-methoxy)benzyl]thiazolidin-2,4-dione.

29. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is lovastatin and specified to insulin sensitizing agent is troglitazone.

30. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is lovastatin and specified to insulin sensitizing agent is pioglitazone.

31. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is lovastatin and specified to insulin sensitizing agent is englitazone.

32. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is lovastatin and specified to insulin sensitizing agent is BRL-49653.

33. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is lovastatin and specified to insulin sensitizing agent is 5-(4-{ 2-[1-(4-2'-pyridylethyl)ethylidenemalonate] ethoxy} benzyl)is lovastatin, and specified to insulin sensitizing agent is 5-{4-(5-methoxy-3-methylimidazo[5,4-b]-pyridine-2-yl-methoxy)benzyl}thiazolidine-2,4-dione or its hydrochloride.

35. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is lovastatin and specified to insulin sensitizing agent is 5-[4-(6-methoxy-1-methylbenzimidazole-2-yl-methoxy)benzyl]thiazolidin-2,4-dione.

36. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is lovastatin and specified to insulin sensitizing agent is 5-[4-(1-methylbenzimidazole-2-yl-methoxy)benzyl] thiazolidin-2,4-dione.

37. The method according to p. 1, characterized in that the inhibitor of HMG-COA reductase inhibitor is lovastatin and specified to insulin sensitizing agent is 5-[4-(5-hydroxy-1,4,6,7-tetramethylbenzidine-2-yl-methoxy)benzyl]thiazolidin-2,4-dione.

38. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is simvastatin and specified to insulin sensitizing agent is troglitazone.

39. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is simvastatin and specified sensib the major inhibitor of HMG-COA reductase inhibitor is simvastatin, and specified to insulin sensitizing agent is englitazone.

41. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is simvastatin and specified to insulin sensitizing agent is BRL-49653.

42. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is simvastatin and specified to insulin sensitizing agent is 5-(4-{ 2-[1-(4-2'-pyridylethyl)ethylidenemalonate] ethoxy} benzyl)thiazolidine-2,4-dione.

43. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is simvastatin and specified to insulin sensitizing agent is 5-{4-(5-methoxy-3-methylimidazo[5,4-b]-pyridine-2-yl-methoxy)benzyl}thiazolidine-2,4-dione or its hydrochloride.

44. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is simvastatin and specified to insulin sensitizing agent is 5-[4-(6-methoxy-1-methylbenzimidazole-2-yl-methoxy)benzyl] thiazolidin-2,4-dione.

45. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is simvastatin and specified to insulin sensitizing agent is 5-[4-(1-methylbenzimidazole HMG-COA reductase inhibitor is simvastatin, and specified to insulin sensitizing agent is 5-[4-(5-hydroxy-1,4,6,7-tetramethylbenzidine-2-yl-methoxy)benzyl]thiazolidin-2,4-dione.

47. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is fluvastatin and specified to insulin sensitizing agent is troglitazone.

48. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is fluvastatin and specified to insulin sensitizing agent is pioglitazone.

49. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is fluvastatin and specified to insulin sensitizing agent is englitazone.

50. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is fluvastatin and specified to insulin sensitizing agent is BRL-49653.

51. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is fluvastatin and specified to insulin sensitizing agent is 5-(4-{ 2-[1-(4-2'-pyridylethyl)ethylidenemalonate] ethoxy} benzyl)thiazolidine-2,4-dione.

52. The method according to p. 1, characterized in that said inhibitor of HMG-COA, elimidate[5,4-b]-pyridine-2-yl-methoxy)benzyl}thiazolidine-2,4-dione or its hydrochloride.

53. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is fluvastatin and specified to insulin sensitizing agent is 5-[4-(6-methoxy-1-methylbenzimidazole-2-yl-methoxy)benzyl] thiazolidin-2,4-dione.

54. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is fluvastatin and specified to insulin sensitizing agent is 5-[4-(1-methylbenzimidazole-2-yl-methoxy)benzyl]thiazolidin-2,4-dione.

55. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is fluvastatin and specified to insulin sensitizing agent is 5-[4-(5-hydroxy-1,4,6,7-tetramethylbenzidine-2-yl-methoxy)benzyl]thiazolidin-2,4-dione.

56. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase is levastatin and specified to insulin sensitizing agent is troglitazone.

57. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase is levastatin and specified to insulin sensitizing agent is pioglitazone.

58. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase is mevastatin, is the, that the specified inhibitor of HMG-COA reductase is levastatin and specified to insulin sensitizing agent is BRL-49653.

60. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase is levastatin and specified to insulin sensitizing agent is 5-(4-{ 2-[1-(4-2'-pyridylethyl)ethylidenemalonate] ethoxy} benzyl)thiazolidine-2,4-dione.

61. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase is levastatin and specified to insulin sensitizing agent is 5-{4-(5-methoxy-3-methylimidazo[5,4-b]-pyridine-2-yl-methoxy)benzyl}thiazolidine-2,4-dione or its hydrochloride.

62. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase is levastatin and specified to insulin sensitizing agent is 5-[4-(6-methoxy-1-methylbenzimidazole-2-yl-methoxy)benzyl]thiazolidin-2,4-dione.

63. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase is levastatin and specified to insulin sensitizing agent is 5-[4-(1-methylbenzimidazole-2-yl-methoxy)benzyl] thiazolidin-2,4-dione.

64. The method according to p. 1, characterized in that said inhibitor of HMG-To the 6,7-tetramethylbenzidine-2-yl-methoxy)benzyl]thiazolidin-2,4-dione.

65. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is atorvastatin and specified to insulin sensitizing agent is troglitazone.

66. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is atorvastatin and specified to insulin sensitizing agent is pioglitazone.

67. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is atorvastatin and specified to insulin sensitizing agent is englitazone.

68. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is atorvastatin and specified to insulin sensitizing agent is BRL-49653.

69. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is atorvastatin and specified to insulin sensitizing agent is 5-(4-{ 2-[1-(4-2'-pyridylethyl)ethylidenemalonate] ethoxy} benzyl)thiazolidine-2,4-dione.

70. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is atorvastatin and specified to insulin sensitizing agent is 5-{4-(5-methoxy-3-methylimidazo[5,4-b]-pyridine-2-yl-methox what hibition HMG-COA reductase inhibitor is atorvastatin, and specified to insulin sensitizing agent is 5-[4-(6-methoxy-1-methylbenzimidazole-2-yl-methoxy)benzyl] thiazolidin-2,4-dione.

72. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is atorvastatin and specified to insulin sensitizing agent is 5-[4-(1-methylbenzimidazole-2-yl-methoxy)benzyl]thiazolidin-2,4-dione.

73. The method according to p. 1, characterized in that said inhibitor of HMG-COA reductase inhibitor is atorvastatin and specified to insulin sensitizing agent is 5-[4-(5-hydroxy-1,4,6,7-tetramethylbenzidine-2-yl-methoxy)benzyl]thiazolidin-2,4-dione.

74. The method according to p. 1, characterized in that the inhibitor of HMG-COA reductase and specified to insulin sensitizing agent are administered together and they act synergistically.

75. The method according to p. 1, characterized in that the inhibitor of HMG-COA reductase and specified to insulin sensitizing agent is administered for a period of time during which they together act synergistically.

76. Packaged pharmaceutical preparation for the treatment or prevention of arteriosclerosis or xanthoma, which contains a first agent selected from the group, with the insulin agents, in which the mentioned first and second agents are in a mixture or Packed separately, and in which the mentioned first and second agents defined in any of paragraphs.1-75.

77. Packaged pharmaceutical preparation according to p. 76, characterized in that the agents are placed in separate parts of the specified package.

78. Pharmaceutical composition for treatment or prevention of arteriosclerosis or xanthoma, characterized in that it contains a mixture of the first agent selected from the group consisting of inhibitors of HMG-COA reductase inhibitor and the second agent selected from the group consisting of to insulin sensitizing agents, in which the mentioned first and second agents defined in any of paragraphs.1-75.

 

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