HU204820B - Process for producing thiazolidinedione derivatives and pharmaceutical compositions comprising such compounds - Google Patents

Abstract

The present invention relates to the preparation of thiazolidinedione derivatives of formula (I). In the formula (I), the dotted line represents a bond or does not represent a bond, V is -CEUCH-, -N = CH-, or -S-, W is CH2, CHOH, CO, C = NOR or CH = CH-, Seven unsubstituted pyridyl, furyl, 4- or 5-thiazolyl optionally substituted with one or two substituents, or 4-oxazolyl, wherein one substituent is hydrogen or C1-C3 alkyl, and the other 3-7 is hydrogen; C-cycloalkyl, phenyl, C 1 -C 3 alkoxyphenyl, furyl or thienyl, R is hydrogen or methyl, and n is 1,2 or 3. These compounds have hypoglycemic and hypocholesterolemic effects a) HU 204 820 BA description: 17 pages (including 2 tabs)

Description

The present invention relates to a process for the preparation of thiazolidinone derivatives of the formula (I).

The thiazolidinone slides of the present invention are useful as pharmaceuticals with hypoglycaemic and hypocholesterolaemic activity. The invention relates to the preparation of such pharmaceutical compositions.

Despite the early discovery of insulin and its subsequent use in the treatment of diabetes, and the subsequent discovery of sulphonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide) and biguanidines (e.g.

The use of insulin, which is required in approximately 10% of diabetic patients in whom synthetic hypoglycaemic agents are ineffective (type 1 diabetes mellitus, insulin dependent diabetes mellitus), requires multiple daily injections, usually by self-injection. To determine the correct dose of insulin, it is often necessary to measure the amount of sugar in the urine or blood. Insulin overdose causes hypoglycaemia, the effects of which may be due to an abnormal level of sugar in the blood or a coma, which may lead to death. Treatment of non-insulin-dependent diabetes mellitus (Diabetes mellitus type H) usually consists of a combination of diet, exercise, oral agents (such as sulfonylureas and, more seriously, insulin). Unfortunately, the clinically available hypoglycaemic agents have other toxic effects. In any case where one of them does not suit the individual case, the other agent may still be successful, and it is therefore understood that hypoglycemic agents are required which are less toxic or successful where the others are inappropriate.

In addition, atherosclerosis, the atherosclerosis associated with hardening of the artery walls, is today believed to be the leading cause of death in the United States of America and in Western Europe. The pathological consequence leads to atherosclerosis and coronary artery occlusion, which are described in detail by Ross and Glomset in New England Journal of Medicine 295, 369-377 (1976). In the earliest stages of this process, 'fat strips' are formed in the cervical, coronary and cerebral arteries (arteries) and in the aorta. These lesions are yellow due to the presence of fat (lipid) deposits, which are mainly found in the smooth muscle cells and in the large atrial cells of the arteries of the arteries and mediastinum and are traced back to most of these lipids. In addition, it is likely that most of the cholesterol found in these fat strips is derived from the plasma. These fat strips contribute to the formation of a "fibrous platelet" consisting of accumulated endothelial smooth muscle cells, which are filled with lipid and surrounded by extracellular lipid, collagen, elastin, and proteoglucan.

These cells and the intercellular material form a fibrous cap that covers the deeper deposits of cellular tissue and the extracellular lipid. The lipid is primarily free and esterified cholesterol. Fibrous hematopoiesis develops slowly and then over time calcifies and dies, undergoing a "complex lesion" that explains arterial obstruction and predisposition to wall thrombosis and arterial muscle spasms, which are characteristic of advanced atherosclerosis.

It is strongly accepted as an epidemiological evidence that hyperlipidemia (increased fat in the blood) is a primary risk factor (risk factor) that is responsible for cardiovascular disease (CVD) and is a consequence of atherosclerosis. In recent years, leading medical practitioners have re-focused their efforts on lowering plasma cholesterol and especially low-density lipoprotein cholesterol, an important step in preventing CVD. There are now known "normal" ceilings, which are much lower than what was once estimated. As a result, a large portion of the Western population has been shown to be at high risk for developing or progressing to CVD due to the high risk factor. Individuals who have an independent risk factor associated with hyperlipidemia are particularly at risk. These independent risk factors are glucose tolerance and hypertension resulting from left ventricular hypertrophy, particularly in urine. Cardiovascular disease is particularly prevalent among diabetics, at least in part, due to the existence of multiple independent risk factors. The successful treatment of hyperlipidemia in the general population and in particular in diabetics is of special and exceptional medical importance.

The first step in the recommended medical treatment for the prevention of hyperlipidemia is dietary intervention. Since diet alone is not sufficient for many patients, other patients remain at high risk and treatment should be by pharmacological means. New drugs for the treatment of hyperlipidemia therefore have a great potential benefit for a large number of individuals at high risk for the development of CVD. Furthermore, it is particularly important to develop a single therapeutic agent which can successfully treat both hyperlipidemia and hypoglycaemia and additionally have a diabetic property.

In addition to the above-mentioned hypoglycemic agents, many other compounds having this type of activity have been described, as described by Blank in Burger's Medical Chemistry, Fourth Edition, Part I, John Wiley and Sons, N. Y. (1979), pp. 1057-1080.

Schnur, U.S. Pat. No. 4,367,234, describes oxazolidinediones having the hypoglycaemic action of Formula A, wherein the phenyl ring is generally mono- or multisubstituted in ortho / meta situations. It also notes that 4-fluorophenyl ana2

HU 204,820 Β

Except for yoga, para-substituted derivatives are either ineffective or have a minor hypoglycaemic effect.

Schnur, U.S. Pat. No. 4,342,771, discloses hypoglycemic agents of formula (B) wherein Y is hydrogen or alkoxy, Y 'is hydrogen or alkyl, and Y' is hydrogen or halogen. <

Schnur, U.S. Pat. No. 4,617,312, describes hypoglycemic thiazolidinediones of formula C wherein R ^{c is} lower alkyl, X ^a is F, Cl or Br, and Y ^is hydrogen, chloro, lower alkyl, or lower alkoxy. However, it is noted that the compounds contain an alkoxy group as an ortho substituent and a hydrogen or halogen atom as a para substituent.

U.S. Patent No. 4,340,605 to Kawamatsu et al. Discloses compounds of formula D wherein R ^{e is a} bond or a lower alkylene group, and when R ^d is an optionally substituted five- or a six-membered heterocyclic group containing one or two heteroatoms N, O and S, then L ¹ and L ² are each hydrogen. Due to the lack of hypoglycaemic and platelet triglyceride-lowering effects of certain non-ether analogs, the dashed portion of the structural formula, including ether oxygen, is an important factor in the useful activity of this series of compounds. [Sohda et al., Chem. Pharm. Bull. Japan, Vol. 30, pp. 3580-3600 (1982)].

Eggler et al. U.S. Pat. No. 4,703,052 discloses thiazolidinedione compounds of the general formula (E) in which the dotted line represents an optional bond, RJ is H, methyl or ethyl, X ^b is O, S , SO, SO ₂ , CH ₂ , CO, CHOH or NR ^k , where R ^{k is} hydrogen or acyl, while R ^g , R ^b , R 'and R 1 are R ^g , R ^h and R' are hydrogen or methyl and R 1 optionally substituted phenyl, benzyl, phenethyl or styryl.

The present invention provides a process for the preparation of thiazolidinedione derivatives of formula (I) and their pharmaceutically acceptable salts and their pharmaceutically acceptable acid addition salts when the compounds contain basic nitrogen. In this formula, the dashed line represents a bond or no bond,

V is -CH = CH-, -N = CH- or -S-,

W is> CH ₂ ,>CHOH,> CCVC = NOR or CH «= CH-,

Seven unsubstituted pyridyl, furyl, optionally one or two substituents, 4- or 5-thiazolyl, or 4-oxazolyl, one of which is hydrogen or C 1-3 alkyl and the other is C 3-7 cycloalkyl, phenyl, C 1-3 alkoxyphenyl, furyl or thienyl,

R is hydrogen or methyl, and n is 1, 2 or 3.

Preference is given to compounds in which the dotted line does not represent a bond, and in particular compounds in which W is CO or CHOH. Particularly preferred compounds are those wherein V is -CH = CH-, -CH = N- or -S- and n is 2, in particular those wherein Sev is oxazolyl, pyridyl or thiazolyl.

Most preferred are compounds having seven oxazol-4-yl, thiazol-4-yl or thiazol-5-yl groups, especially those having a 2 - [(2-thienyl) -, (2-furyl) , phenyl or substituted phenyl] -5-methyl-4-oxazolyl.

Due to the ease of preparation and the level of activity, the following compounds are most preferred:

5- {4- [3- (2-phenyl-5-methyl-4-oxazolyl) -propionxl] benzyl} thiazolidine-2,4-dione;

5 - {[5- (l-hydroxy-3- (2-phenyl-5-methyl-4-oxazolyl) propyl) -2-pyridyl] methyl} -thiazolidin-2,4-dione;

5 - {[5- (3- (2-phenyl-5-methyl-4-oxazolyl) propionyl) -2-thienyl] methyl} thiazolidine-2,4-dione; and that

5 - {[5- (l-hydroxy-3- (2-phenyl-5-methyl-4-oxazolyl) propyl) -2-thienyl] methyl} thiazolidine-2,4-dione.

The term "pharmaceutically acceptable cationic salts" includes, without limitation, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts), aluminum salts, ammonium salts and organic amines. salts such as benzathine (N, N'-dibenzylethylenediamine), choline, diethanolamine, acetylene diamine, nolumin (N-methylglucamine), benetamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol) and procaine are mentioned as salt-forming agents. A particularly preferred salt is the sodium salt.

The term "pharmaceutically acceptable acid addition salts" includes, without limitation, hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, extract, methanesulfonate (mesylate), and p-toluenesulfonate.

The invention also relates to the preparation of pharmaceutical compositions containing the compounds of the formula I or their pharmaceutically acceptable salts as active ingredients. These formulations contain the active ingredient together with a pharmaceutically acceptable carrier. The drug can be used to reduce blood glucose (glucose) and blood cholesterol in patients with hyperglycaemia or hypercholesterolaemia. The present invention encompasses lowering blood glucose in hyperglycemic patients, comprising administering an effective amount of a compound of Formula (j) to a patient, and lowering blood cholesterol in hypercholesterolaemic patients receiving an amount of a compound of Formula (I). drugs that lower blood cholesterol. Administration of the active ingredients in general

EN 204820 Β in the form of pharmaceutical preparations. We invent the same way that

a) For the preparation of compounds of formula φ wherein the dashed line represents a bond, the thiazolidine-2,4-dione is reacted with an aldehyde of formula n, optionally protected as the silyl ether of the CHOH group in W; and then removing any protecting group present, or

b) reducing a compound of formula φ wherein the dashed line does not represent a bond, reducing a compound of formula φ wherein the dashed line represents a bond; obsession

c) reducing a compound of formula (ΠΙ) wherein W is CO and Sev and V are as defined above; obsession

d) reducing a compound of formula φ in which W is; CHOH or yCH ₂ ; reducing a compound of formula W in which W is CO or CHOH); obsession

e) oxidizing a compound of formula φ in which W is a COO group to produce a compound of formula φ in which W is a dCO group; or 25

f) for the preparation of a compound of formula φ in which W is -CH = CH- and n is 1 or 2, or a compound of formula φ in which W is XCHOH and n is 2 or 3, dehydrated or

g) for the preparation of a compound of the formula amely in which W is> C »NOR, a compound of the formula W in which W is) CO is reacted with a compound of the general formula H ₂ NORA, generally R, and optionally a free φ and converting the compound of formula I into a pharmaceutically acceptable salt thereof.

The thiazolidinedione derivatives of formula φ are readily prepared. Most commonly, compounds of formula 40 φ in which the dashed line represents a bond are prepared by reacting a thiazolidine-2,4-dione (φ with an aldehyde of formula V in which V, W, X, Y, Z, Z ¹ and n is as defined above In this step, the reagents 45 are heated in the presence of a weak base to form olefins of formula φ in which the dashed line represents a bond. Usually 10 to 50% molar excess of one of the two reagents is used to In a preferred embodiment, the aldehyde of formula (Π) and the thiazolidinedione are catalytically added to a secondary amount of the reaction medium. in the presence of an amine, preferably pyrrolidine or piperidine Typically, the secondary amine used as the catalyst is used in an amount of 0.05-0.20 molar equivalents and is reacted in a solvent inert to the reaction, such as lower alkanol (e.g., methanol, ethanol, n-propanol, isopropanol). Temperature does not play a decisive role, but is usually carried out above room temperature to complete the reaction at a reasonable rate but works below 100 ° C to minimize side reactions. The reflux temperature of a lower alkanol solvent is particularly suitable. In this method, if desired, if W is CHOH, in this case the protected form of the alcohol (e.g., dimethyl tert-butylsilyloxy ether derivatives) and when W is > CO, the protected form of the ketone (e.g. cyclic ketals with glycol) can be used for condensation. The protecting group may then be removed in a conventional manner, for example by acid catalyzed hydrolysis. Such protecting groups are generally used only when they are already present as part of the synthesis of the aldehyde of formula (Π).

The term "reaction inert solvent" as used herein and throughout this specification refers to a solvent that does not interfere with the reaction and does not react with the starting materials, reagents, intermediates, or end products to adversely affect the desired product yield.

Alternatively, the aldehyde (Π) and the thiazolidine-2,4-dione are thoroughly mixed in a molar excess, preferably 2 to 4 times molar excess, with anhydrous sodium acetate, and the mixture is heated to a temperature sufficient to melt , so generally at about 140170 ° C. At this temperature, the reaction is substantially complete in 5 to 60 minutes. The desired olefin of formula φ, where the dashed line represents a bond, is then isolated, for example, by stirring and filtration. This gives a crude product which is purified, if desired, for example by crystallization or by conventional chromatography. In this method, when W is an XCO group, it is preferable to reduce the excess thiazolidine and / or protect the ketone group in the form of a ketal as described above.

The resulting olefinic products are potent hypoglycemic agents, but also serve as intermediates for the preparation of the corresponding reduced compounds of formula φ in which the dotted line does not represent a bond. The reduction of olefins above can be accomplished using a variety of reducing agents known to reduce the carbon-carbon double bond, but preferred methods include hydrogen in the presence of a noble metal catalyst or sodium amalgam in methanol.

In the case where the reduction step is carried out using hydrogen in the presence of a noble metal catalyst, a convenient method for carrying out the conversion is to obtain a solution of an olefinic compound of formula φ in which the

The dotted line represents a bond, stirred or shaken in a solvent inert to the reaction, in an atmosphere of hydrogen gas, or in an atmosphere of hydrogen mixed with an inert diluent, preferably with nitrogen gas, in the presence of a noble metal hydrogenation catalyst. Suitable solvents for this reaction are those which essentially dissolve the starting compound, but which do not themselves hydrogenate or are not hydrogenated. Examples of such solvents include ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane; low molecular weight amides such as Ν, Ν-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; and lower alkyl carboxylic acids such as formic acid, acetic acid, propionic acid and isobutyric acid. A particularly preferred solvent is tetrahydrofuran, particularly when W is CO).

The introduction of hydrogen gas into the reaction medium is accomplished in a conventional manner by feeding the olefinic compound, solvent, catalyst and hydrogen into a reaction vessel and sealing the vessel. The pressure inside the reaction vessel may vary from about 1100 kg / cm ² . The preferred pressure range when the atmosphere inside the reaction vessel is substantially pure hydrogen is from about 2 kg / cm ² to about 5 kg / cm ² . The hydrogenation is generally carried out at a temperature in the range of about 0 ° C to about 60 ° C, preferably in the range of 25 to 50 ° C. When the preferred temperatures and pressures are employed, hydrogenation generally takes place within a few hours, for example between about 2 hours and about 20 hours. The noble metal catalysts used in this hydrogenation reaction may be of the type used in the conversion, such as alladium, platinum and rhodium. Palladium catalysts are advantageous because such catalysts are not easily poisonous with sulfur. The catalyst is usually present in an amount of from about 0.01% to about 25% by weight, preferably from about 0.1% to about 10% by weight, based on the weight of the olefinic compound. It is often convenient to suspend the catalyst on an inert carrier, and particularly preferred is a palladium catalyst suspended in an inert carrier such as carbon.

In the case where the olefinic compound W is a carbonyl group (or a protected ketal form thereof) or a carbinol group (CHOH), the more advanced hydrogenation conditions generally do not allow only the preparation of compounds of formula I in which the dashed line no longer represents a bond. , but it is also possible to prepare compounds having a Wmethylene group, which can be prepared from the carbonyl group via the carbinol group.

In the case where the hydrogenation of the methylene double bond (and optionally other groups) is substantially complete, the desired compounds of formula (I) wherein the dashed line does not represent a bond are then isolated by conventional means such as removal of the catalyst by filtration. , the solvent is evaporated and the product is purified, if desired, by well-known techniques such as crystallization or chromatography.

Another variant of reducing the olefinic compounds of formula (ff), wherein the dotted line represents a bond, is that the reduction is carried out with conventional sodium amalgam or metal magnesium, usually at ambient or above ambient temperatures, as described below. In the case where W is a CO group in the olefin, this method can generally also produce a compound of formula ff wherein the dashed line does not represent a bond and W is CHOH.

Compounds of formula (ff) wherein W is CHOH can be readily prepared by reduction of the corresponding compounds with conventional sodium borohydride wherein W is xCO; and compounds of formula (ff) wherein W is CO can be readily obtained by conventional chromium oxidation, such as chromic acid or pyridinium dichromate, by oxidation of the corresponding compounds wherein W is CHOH. In the case where W is > C = NOR, the compounds of formula (I) may conveniently be prepared by conventional reaction of the corresponding carbonyl compound (W = CO) with an H ₂ OR compound. In the case where W is -CH = CH-, the compounds of formula (ff) can be readily prepared by conventional dehydration of the corresponding alcohol compounds wherein W is dCHOH.

Pharmaceutically acceptable cationic salts of the compounds of the present invention can be readily prepared by reacting the acid form with a suitable base, usually in an equivalent amount in an auxiliary solvent. Typical bases for this purpose include sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, piperazine and tromethamine.

The salts may be isolated by evaporation of the solution to dryness or addition of a non-solvent. In many cases, salts are preferably prepared by mixing a solution of the acid with a solution of various salts of the cation (sodium or potassium ethyl hexanoate, magnesium oleate) using a solvent (e.g. ethyl acetate) from which the desired cationic salt precipitates, however, the salt may be isolated by other means such as concentration of the solution and / or addition of a non-solvent.

The acid addition salts of the compounds of the present invention can be readily prepared by reacting the base form with the appropriate acid. In case the salt is a monobasic salt

EN 204820 Β (e.g., hydride, hydrobromide, p-toluenesulfonate, acetate), a salt of a hydroformate of a dibasic acid (e.g., hydrogen sulfate, succinate) or a dihydroformate of a tribasic acid (e.g., dihydrogen phosphate, acitrate); with a single molar excess of 5 and the usual molar excess. However, in the case that salts such as sulfate, hemisuccinate, hydrogen phosphate or phosphate are to be prepared, the acid must be used in the appropriate and exact chemical equivalents. The free base 10 and the acid are usually combined in a co-solvent from which the desired salt precipitates or otherwise isolated, such as by concentration and / or by the addition of a non-solvent.

Thiazolidine-2,4-dione is commercially available. The aldehydes of general formula (Π) may be prepared by various conventional methods, for example by weak oxidation of amprimeric alcohol reagents such as manganese dioxide under conditions known for the preparation of aldehydes from primary alcohols and ketones from secondary alcohols; reacting the corresponding aralkyl bromides with n-butyllithium followed by NN-dimethylformamide at a temperature from -80 ° C to -70 ° C; by reaction with a suitable 4-substituted benzaldehyde (or corresponding thiophene or pyridine analog) substituted heterocyclic derivative such that

- (CH 2 -WG) is a bridge-forming group.

For example, in the form normally protected by an aldehyde group or in the form of an aldehyde precursor:

-CH ₂ X '+ EtOCOCH ₂ CO-> (I) base / (2) acidCH ₂ CH ₂ Co-C ^ X ¹ + CH ₃ CO - ► Base -CH ₂ CH ₂ CO-CH ₂ CH ₂ MgBr + HCO-> - CH ₂ CH ₂ CH ₂ H-CHO + CH ₃ CO -> - CH = CH-CO-ch ₂ ch ₂ co-ch ₂ ch ₂ cooh- * -ch ₂ ch ₂ co-CH ₂ CH ₂ CH ₂ Br -> -CH ₂ GH ₂ CH ₂ -CH ₂ CH ₂ CO- * -CH ₂ CH ₂ C-NOH-ch ₂ ch ₂ choh—> -ch ₂ ch ₂ co-ch ₂ ch ₂ choh -> - ch ₂ ch = ch-CH ₂ CH ₂ CHOH -> - CH ₂ CH ₂ CH ₂ - 45

-ch ₂ ch = ch -> -ch ₂ ch ₂ ch ₂ One skilled in the art will appreciate that the synthesis of compounds of formula I may be varied by coupling a precursor aldehyde (or mesylate / halide) with a thiazolidine-2,4-dione. , completing the side chain as a final step in one of the synthetic methods for the number of aldehydes of formula (Π) as described above.

The compounds of formula (I) obtainable by the process of the present invention are readily adapted for clinical use as active ingredients in hypoglycaemic or hypocholesteremic pharmaceutical compositions.

The activity required for this prior clinical application is determinant in the hypoglycaemic activity assay in ob / ob mice as follows:

Five to eight weeks old BI / 6J-oh / ob mice (s

Five from JacksonLaboratory, Bar Harbor, Maine) were housed in standard cages under standard animal care conditions. A week's practice! over time, the animals were weighed and 25 microliters of blood was collected by ocular route before any treatment. Blood samples were then diluted 1: 5 with saline which was

It contained 2.5 mg / ml sodium fluoride and 2% sodium heparin and was kept on ice for metabolic analysis. The animals were then dosed with 5 to 50 mg / kg of drug, 50 mg / kg of ciglitazone positive control daily for 5 days (U.S. Patent 4,467,902 to Sohda et al., Chem. Pharm. Bull., Vol. pp.4460-4465.1984) or a carrier. Each drug was administered in a vehicle containing 0.25% (w / v) methylfluorose. On day 5, the animals were again weighed and blood was collected (ocularly) for measurement of blood metabolite levels. The newly collected samples were centrifuged for two minutes at 10,000 x g at room temperature. The supernatant was analyzed for glucose with the ABA 200 Bichromatic Analyzer using the Agent Glucose UV reagent system (hexokinase method) using standards of 20, 60 and 100 mg / dL. Modified version of the reagent system by Richterich and Dauwalder, described in Schweizersche Wochenschrift 101, 860 (1971). Platelet glucose was then calculated by the following equation:

Platelet glucose (mg / dl) = sample value x 5 x 1.67 x 8.35 x sample value with 5 dilution factors and 1.67 platelet hematocrit adjustment (accepted hematocrit 40%).

The vehicle-treated animals maintain substantially unchanged hyperglycemic glucose levels (e.g., 250 mg / dL), whereas positive control animals have reduced glucose levels (e.g., 130 mg / dL). Glucose levels normalized by test compounds are expressed as% glucose, for example, glucose levels equal to 100% of the positive control.

Assays described below demonstrate that the compounds of formula I are effective in lowering serum cholesterol levels in mammals.

Female mice (C67Br) cd strain J from Jackson Laboratory, Bar Harbor, Maine, were used at 8-12 weeks of age. The animals were habituated for 2 to 4 weeks, during which time the animals had free access to water and standard laboratory food. The animals were then randomized into three groups of 6-7 animals per group. All three groups received food containing 0.75% cholesterol, 31% sucrose, 15.5% starch, 20% casein, 17% cellulose, 4.5% corn germ oil, 5% coconut oil, 0.25% colic acid, It contained% salt and 2% vitamin. Animals consumed as desired for 18 days; and administered between 9 and 11 am for the last 5 days by oral gavage

With the aid of 204,820 Β, the control group received 5 ml / kg vehicle (0.1% aqueous methylcellulose) and the test compounds were administered the test compounds in doses of 0.1-10 mg / kg / day. After the fourth dosing day, the animals were fasted overnight from 5 pm. The following morning, the fifth and final dose of the drug was administered to the animals in the test group and, three hours later, the animals were sacrificed by cutting off their heads. Blood was taken from the body part, which was allowed to coagulate, and the serum was analyzed enzymatically with an Abbot VP automated analyzer for HDL cholesterol, LDL and VLDL cholesterol, and total cholesterol. Whether LDL + VLDL cholesterol levels, total cholesterol levels, or LDL + VLDI7HDL ratios were evaluated, it was found that the compounds of the present invention generally had a beneficial effect on lowering cholesterol levels.

The compounds of Formula © may be administered clinically to mammals, including man, either orally or via the parenteral route. Oral administration is advantageous as it is more convenient and avoids the possible pain and discomfort of injection. However, in cases where the patient is unable to swallow the drug, or in the case of absorption following oral administration, such as disease or other abnormal conditions, it is essential that the drug be administered parenterally. For both modes of administration, the daily dose will range from about 0.10 mg / kg to about 50 mg / kg of patient body weight, with the preferred daily dose being about 0.10 to 10 mg / kg of body weight. Administration can be in single or divided doses. Of course, the best dose for each patient should be determined and the patient's response to the administered dose should be established. Usually, treatment should start with smaller doses and then gradually increase to determine the most appropriate dose. This amount will vary with the compound employed and the condition of the patient being treated.

The compounds of Formula © or their pharmaceutically acceptable salts are generally used in the form of pharmaceutical compositions. The pharmaceutical compositions contain, in addition to the active ingredient, pharmaceutically acceptable carriers or diluents. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The active ingredient must be present in the pharmaceutical composition in an amount sufficient to provide the desired dosage amount as stated above. Thus, for oral administration, the active compounds of formula © are combined with suitable solid or liquid carriers or diluents to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions may, if desired, contain further ingredients such as sweeteners, fillers, and the like. For parenteral administration, the compounds may be combined with sterile aqueous or organic solvent media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, water, propylene glycol, and the like may be employed, but aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts of compounds of Formula I may also be employed. The injectable solutions prepared in this manner may be administered intravenously, intraperitoneally, subcutaneously or intramuscularly, with intramuscular administration being preferred.

The invention is further illustrated by the following examples, but the scope of the invention is not limited to the detailed description. The names are those of Rigaudy and Klesney, IUPAC Nomenclature of Organic Chemistry, 1979 Ed., Pergammon Press, New York, 1979. The abbreviations IHF, DMF and DMSO are the names of tetrahydrofuran, dimethylformamide and dimethylsulfoxide. Percentages are by weight unless otherwise indicated.

Example 1

5- [4- [3- (5-Methyl-2-phenyl-4-oxazolyl) -propionyl] -phenylmethylene] -thiazolidine-2,4-dione g (0.05 mol) 4- [3 - (5-methyl-2-phenyl-4-oxazolyl / propionyl) -benzaldehyde, the title product of Preparation 4, 11.7 g (0.10 mol) of thiazolidine-2,4-dione and 0.85 g (0 (01 moles) of piperidine were mixed with each other in 300 ml of ethanol and refluxed for 24 hours, cooled to 0 ° C, diluted slowly with 600 ml of ether and stirred for 1 hour at 0 ° C, followed by precipitation of the crude product. by filtration. The crude product was then triturated with 150 mL of warm acetic acid (40-50 ° C). The resulting slurry was cooled to room temperature, diluted with 300 mL of ether and the purified title product (14.2 g) was isolated by filtration.

Mp 224-225 ° C.

Yield 71%.

2-8. examples

5- [4- (3- (Substituted) Proponyl] -phenylmethylene] -thiazolidine-2,4-dione

In the event that the procedure described in FIGS. by the molar equivalent of the appropriately substituted benzaldehydes prepared according to the methods of preparation, the following products are obtained:

Ηϋ 204820 Β

Song substitute Yield: (%) Op. (° C) 2 2-phenyl-4-oxadiazolyl 55 228-230 3 2- (4-methoxy-phenyl) -5-methyloxazoline 76 221-222 4 2- (2-thienyl) -5-methyl-4-oxazolyl 62 237-238 5 2- (2-furyl) -5-methyl-4-oxazolyl 75 236-237 6 2-cyclohexyl-5-methyl-4-oxazolyl 46 gumi® 7 2-phenyl-4-thiazolyl 55 205-207 8 2-phenyl-4-methyl-5-thiazolyl 35 208-210

1 H-NMR (DMSO-d 6) delta (ppm) 1.2-2.0 (m, 10H), 2.2 (s, 3H), 2.7 (m, 3H), 3.3 (t 2H), 7.7 (d, 2H), 7.8 (s, 1H), 8.1 (d, 2H).

Example 9

5- [4- / 3- (5-methyl-2-phenyl-4-oxazolyl) propionyl / benzyl] -tíazoIídm-2,4-dione

Title product of Example 1 14,2g hydrogenated in 800 ml of THF for 10 g of Pd / C catalyst in a Paar shaker at 3,43.10 ⁵ Pa at room temperature for 24 hours. The catalyst is then removed by filtration and washed with THF over diatomaceous earth. The combined filtrate and washings were stripped to give a gum which was crystallized by trituration with hexane / ethyl acetate (250 mL, 1: 1). 11.4 g of the title compound are recrystallized.

M.p .: 145-146'C.

Analysis for C2 ₃ H ₁₈ N ₂ O ₄ S: Calcd: C, 65.70; H, 4.79; N, 6.66% Found: C: 65.67, H: 4.76, N: 6 59%.

'10 -16. examples

5- [4- / 3- (Substituted) propionyl / benzyl] thiazolidine-2,4-dione

The procedure described in the previous example is followed and steps 2-8. The following compounds are converted to the following compounds:

Song substitute Yield: (%) Op. (° C) 10 2-phenyl-4 ~ oxazoIfl 80 151-155 11 2- (4-methoxy-phenyl) -5-methyl-4-oxazolyl 63 173-174 12 2- (2-thienyl) -5-methyl-4-oxazolyl 82 157-158 13 2- (2-furyl) -5-methyl-4-oxazoline 88 155-156 14 2 cxUdohexiI-5-methyl-4-oxazolyl 50 190-195® 15 2-phenyl-4-benzothiazolyl 60 139-142 16 2-phenyl-4-methyl-5-thiazolyl 82 118-120

The sodium salt was prepared as described in Example 23.

Example 17

5- [4- [3- (2-Phenyl-5-methyl-4-oxazolyl) -1-hydroxypropyl] benzyl] thiazolidine-2,4-dione

0.70 g of the title compound prepared in Example 9 is suspended in 50 ml of isopropanol at room temperature. NaBH ₄ (0.15 g) was then added to the suspension and stirred for 2 hours and concentrated in vacuo to a small volume. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 200 mL). The organic layers were combined, washed with brine, dried over MgSO ₄ , and stripped in vacuo. The residue was chromatographed and eluted with 1: 1 ethyl acetate / hexane to 1% acetic acid. 0.32 g of the expected product are obtained.

Mp: 50-55 ”C.

tlc (TLC): R f = 0.40 (1: 1 hexane) ethyl acetate - 2.5% acetic acid) 0.28 (2: 1 CH 2 Cl 2).

Example 18

5 - {[5 / 3- (2-phenyl-5-methyl-4-oxazolyl) propionyl / -2

pyridyl] methylene} thiazolidine-2,4-dione

The title product of Preparation 17 (0.42 g, 1.35 mmol) in ethanol (2 mL) was treated with thiazolide-2,4-dione (0.315 g, 2.7 mmol) and piperidine (0.030 mL). The mixture was heated at reflux for 18 hours, then cooled and the precipitated solid was collected by filtration. This gives 0.14 g of the title compound. Mp 228-230 ° C.

Yield: 25%.

Example 19

5 - {[5 / 3- (2-phenyl-5-methyl-4-oxazolyl) -l-hydroxypropyl) -2-pyridyl] methyl} thiazolidine-2,4-dione

To the title product prepared in the previous example (0.14 g) in methanol (20 ml) was added 10% 1% Na / Hg amalgam and the mixture was stirred for 3 hours. The organic phase is decanted and the solvent is evaporated off under vacuum. The residue is taken up in 10 ml of water and the pH is adjusted to 4.5 with 1 N Ηθ and extracted with 3 x 10 ml of CH ₂ Cl ₂ . The organic layers were combined, dried over MgSO ₄ , stripped in vacuo

HU 204820 Β afraid. This gave 130 mg of a residue which was taken up in CH ₃ OH: CHCl ₃ 3:17, filtered through silica gel and eluted with the same solvent system. 92 mg of the title compound are obtained in the form of a foam.

1 H-NMR (CDCl ₃ ) delta (ppm): 8.53 (d, J = 1.8 Hz, 1H), 7.95 (m, 2H), 7.74 (dd, J = 2.2.8, 1Hz, 1H), 7.42 (m, 3H), 7.18 (d, J = 8.0Hz, 1H), 4.91 (dd, J = 3.9, 8.3Hz, 1H), 4, 83 (ddd, J = 1.4, 3.8, 10.2Hz, 1H), 3.77 (ddd, J = 3.5,3,5,16Hz, 1H), 3.34 (ddd, J = 1. 6.9,8.16Hz, 1H), 2.69 (m, 2H), 2.33 (s, 3H), 2.08 (m, 2H).

Example 20

5 - {[5 / (Dimethyl-t-butylsilyloxy) -3- (2-phenyl-5

methyl-4-oxazolyl) propyl / -2-thienyl] methylene} thiazolidine-2,4-dione

1.81 g (4.1 mmol) of the title product of Preparation 23, 0.96 g (8.2 mmol) of thiazolidine-2,4-dione and 0.1 mL (0.82 mmol) of piperidine are combined in 40 mL of ethanol and refluxed for 4 hours. The solvent was evaporated in vacuo and the residue was taken up in 40 mL of ethyl acetate, washed with 2 x 25 mL of 0.5 N HCl and 3 x 25 mL of water, dried over MgSO ₄ , and stripped. This gives 2.17 g of the title compound as an oil.

TLC: Rf = 0.35 (CHC1 _3).

In a similar manner, another product of Preparation 23 is converted to 5 - {[5- (1-dimethyl-tert-butylsilyloxy) -3- (2-phenyl-5-methyl-4-oxazolyl) propyl] -1- methyl-vagybenziI /] - methylene} -tiadiazolidin-2,4-dione.

Example 21

5- {5- [1- (Dimethyl-tert-butylsilyloxy) -3- (2-phenyl-5-methyl-4-oxazolyl) -propyl] -2-thienylmethyl} -thiazolidine-2,4-dione

The title compound (2.17 g, 4.0 mmol) from the previous example and 40 g of 1.2% Na / Hg amalgam in 100 ml of methanol were combined and stirred for 3.5 hours at room temperature. The organic phase is decanted and stripped to an oil in vacuo. The oil was suspended in water (50 mL), acidified to pH 2 with 6N HCl and extracted with CH ₂ Cl ₂ (3 x 50 mL). The organic layers were combined, dried over MgSO ₄ , and stripped. 1.56 g of the expected product are thus obtained in the form of an oil.

tlc: Sf = 0.60 (1:19 CH ₃ OH / CHCl ₃ mixture) is.

Example 22

5 - {[5- / 1-Hydroxy-3- (2-phenyl-5-methyl-4-thiazolyl) propyl] -2-phenyl] methyl} -thiazolidine-2,4-dione

1.28 g of the title product of the previous example, 50 ml of 6N HCl and 50 ml of THF are combined and the mixture is stirred for 1 hour at room temperature. The pH of the mixture was then adjusted to 3 with saturated NaHCO ₃ solution and the mixture was extracted with ethyl acetate (3 x 75 mL). The combined organic extracts were washed with 1x75 ml of water, dried over _MgSO4 and concentrated in vacuo. The residue was chromatographed on a 4 mm silica gel plate eluting with ethyl acetate / hexane (1: 9). Yield: 0.51 g of the title compound having an Rf of 0.1. The product is an oil.

tlc: Rf = 0.2 (1:19 _CH3 OH7CHC1 ₃ mixture) is.

In a similar manner, 5 - {[5- (1-hydroxy-3-phenyl-5-methyl-4-oxazolyl) propyl] -2-thienyl] methylene} thiazolidine-2 is obtained after conversion from the product of Example 20. 4-dione.

Example 23

5 - {[5- / 1-Hydroxy-3- (2-phenyl-5-methyl-4-thiazolyl) propyl] -2-thienyl] methyl} thiazolidine-2,4-dione sodium salt

The title product (169 mg, 0.40 mmol) obtained in the previous example was dissolved in ether (5 mL). Sodium 2-hexanoate (69 mg, 0.41 mmol) was added to the solution. The resulting suspension was stirred and enough ethyl acetate (5 mL) was added until it became a solution. The solution was then stirred overnight at room temperature and the precipitated solid was collected by filtration. 65 mg of the title compound are obtained.

Mp 206-210 ° C.

Example 24

5 - {[5- [3- (2-Phenyl-5-methyl-4-thiazolyl) -propionyl] -ethyl] -methyl} -thiazolidine-2,4-dione

The title product of Example 22 (0.16 g, 0.37 mmol) was dissolved in CH ₂ Cl ₂ (10 mL) and pyridinium dichromate (281 mg, 0.75 mmol) was added. After stirring overnight, 3 g of diatomaceous earth and 40 ml of ether are added, the whole is then filtered through diatomaceous earth and washed with ether. The filtrate and washings were evaporated in vacuo and the residue was chromatographed on a 2 mm silica gel plate eluting with ethyl acetate / hexane (1: 19 to 1: 1) to afford the desired product. . This gave 110 mg of the title compound, which was isolated as a white solid and recrystallized from ethyl acetate / hexane to give 88 mg of the purified product.

Mp 164-166 ° C.

Analysis: Calculated for C ₂₁ H ₁₈ N ₂ O ₄ S ₂ : C, 59.14; H, 4.25; N, 6.57. Found: C, 58.89; H, 4.23; 6.30%.

Example 25

5- [4- / 3- (2-furyl) -2-propenoyl / benzoyl] thiazolidine-2,4-dione, potassium salt

Potassium tert-butoxide (123 mg, 1.1 mmol) was dissolved in ethanol (10 mL) with stirring. 5- (4-Acetylbenzyl) -thiazolidine-2,4-dione (249 mg, 1.0 mmol) was added and the mixture was stirred vigorously for 15 minutes. Then 2-furfural (106 mg, 1.1 mmol) was added. After 10 minutes the product begins to precipitate, and after 20 minutes the product begins to precipitate. filtered and washed with ether to give 182 mg of the title compound, m.p. 270-275 ° C (dec.). * tlc: Rf = 0.5 (1: 1 ethyl acetate / hexane / 5% acetic acid). mixture).

Example 26

5- [4- / 3- (2-furyl) propionyl / benzyl] -thiazolidin-2,4

-dione

420 mg of the title product prepared in the previous example and 420 mg of 10% Pd / C catalyst in 40 ml of methanol are hydrogenated on a Parr shaker at 3.5 atmospheres for 4 hours. The tlc assay then shows that the starting compound is converted to the desired product (Rf = 0.8 in the tlc system of the previous example). The catalyst was filtered off and washed with methylene chloride. The filtrate and washings were combined and the solvent was evaporated, and the residue was chromatographed on silica gel (30 g) with ethyl acetate: hexane / 2.5% acetic acid (1: 1) to give the title compound as a gum (127 mg). has the same properties as above.

Example 27

5- [4- / 3- (2-furyl) propionyl / benzyl] thiazolidine-2,4

-dione sodium salt

The title product (127 mg, 0.47 mmol) obtained in the preceding example was dissolved in ethyl acetate (2 mL) with heating. Sodium 2-ethylhexanoate (79 mg, 0.47 mmol) was dissolved in ethyl acetate (2 mL). The title compound is obtained as a white solid which is isolated by filtration and washed with ether. Thus 90 mg of the desired compound are obtained.

Mp: 265-270'C (dec.).

Example 28.

5- [4- / 3- (l-hydroxyethyl) -3- (2-pyridyl) propyl / Price & l] thiazolidine-2,4-dione

A mixture of 345 mg (1.44 mmol) of 4- [5- (2-pyridyl) -propionyl] benzaldehyde, 210 mg (1.8 mmol) of thiazolidine-2,4-dione and 300 mg (3.6 mmol) of sodium acetate was added. Heat at 40 ° C for 30 minutes. The resulting mass was cooled, broken and triturated with water to give 5- [4- [3- (2-pyridyl) propionyl] benzyl] thiazolidine-2,4-dione intermediate, which was isolated by filtration. This intermediate was dissolved in 15 mL of methanol and treated with 3 g of 3% sodium amalgam and then stirred overnight. The solution was decanted, diluted with water (20 mL), neutralized with 1 N HCl and then extracted with ethyl acetate (3 x 15 mL). The combined extracts were washed with 15 mL of brine, dried over magnesium sulfate and concentrated in vacuo. The product was purified by flash chromatography eluting with dichloromethane / methanol (15: 1). 60 mg of a yellow solid are obtained.

Yield 12%.

HRMS: (High resolution mass spectrum calculated for ³⁹ C 23 H 11 N 4 O 3 S): 343.1166 Found: 343.1055 δ Example 29

5- {4- [3- (5-methyl-2-phenyl-4-oxazolyl) -l-propenyl] Methoxybenzyl-2,4-dione

A solution of the title product of Example 17 (0.25 g) in F ₃ CCOOH (3 mL) was heated at reflux for 5 hours, then cooled, stripped, and purified by flash chromatography on silica gel. Elution was carried out with 30: 1 CH ₂ Cl ₂ / CH ₃ OH. This gives 225 mg of the title product.

Op.:55-57'C.

Yield 94%.

Example 30

5- {4- [3- (5-Methyl-2-phenyl-4-oxazolyl) -propyl] -benzyl} -thiazole-2,4-dione

225 mg of the title product prepared in the previous example are hydrogenated in 25 ml of ethyl acetate over 225 mg of Pd / C for 18 hours. The catalyst is then filtered off over diatomaceous earth, the filtrate is stripped and the residue is purified by column chromatography. He was eluted with hexane / ethyl acetate (3: 2). 130 mg of the title compound are obtained in the form of an oil.

1 H-NMR (300 MHz, CDCl ₃ ) delta (ppm): 1.96 δ (quint, J = 7.5 Hz, 2H), 2.26 (s, 3H), 2.49 (t, J = 7 , 6Hz, 2H), 2.63 (t, J = 7.7Hz, 2H), 3.07 (dd, J = 14, 1.1, 9.7Hz, 1H), 3.47 (dd, J = 14, 1.0 4.0Hz, 1H), 4.47 (dd, J-9.9, 4.0Hz, 1H), 7.11 (AB, 1-8.5¾ 2H), 7.15 (AB, J = 8.6Hz, 2H), 7.37-7.42 (m, 3H), 7.94-7.97 (m, 2H), δ 8.64 (broad, 1H).

Example 31

5- [4- [3- (5-Methyl-2-phenyl-4-oxazolyl) -1-oximinopropyl] benzyl-thiazolidine-2,4-dione 40 0.10 g (0.238 mmol) prepared in Example 9. The title product, 0.041 g (0.595 mmol) of hydroxylamine hydrochloride and 2 ml of pyridine were combined in 3 ml of ethanol and stirred for 18 hours at room temperature. The solvent was removed by stripping and the residue was taken up in 7.5 ml of ethyl acetate. The solution was washed with 5 mL of 18% cold HQ and then with 5 mL of saturated brine, dried over MgSO ₄ and stripped to give 0.086 g of the title compound as a white solid.

Op.:202-205'C.

tlc: Rf = 0.53 (1: 1 hexane: ethyl acetate).

Example 32

5- [4- [3- (5-Methyl-2-phenyl-4-oxazolyl) -1-methoxyimino] -propylbenzyl] -thiazolidine-2,4-dione. deahldroxylamine hydrochloride is replaced with 0.05 g of roethoxylamine hydrochloride, 0.100 g (0.238 rum) of the title product of Example 9 is converted.

HU 204,820 B

0.090 g of the title compound which is further purified by recrystallization from ethyl acetate and hexane.

138-140'C.

Production Method 1

- / 4- (diethoxymethyl) phenyl / ethanol A mixture of

4-Diethoxymethylbenzaldehyde (104 g, 0.5 mol) was dissolved in ether (300 ml) and the resulting solution was cooled to -75 ° C in an acetone-dry ice bath. 390 mL of 1.4 M ethereal lithium (0.55 mol) was added with vigorous stirring at a rate such that the temperature was maintained below -60 ° C. The reaction mixture was allowed to warm to room temperature, stirred at this temperature for 2 hours, then poured into 500 ml of ice water, stirred for 10 minutes and the layers separated. The organic layers were combined, washed with water (500 mL) and brine (500 mL), dried over MgSO ₄ and stripped in vacuo. 110-11.5 g of the expected product are obtained in the form of a light yellow oil.

Yield 98-100%.

Production Method 2

4- (diethoxy-methyl) acetophenone

223 g (1.0 mole) of the title compound prepared in the previous example and 480 g (5.5 mole) of MnO ₂ in 2.5 L of toluene are combined and the mixture is vigorously stirred and the resulting dark suspension is refluxed for 18 hours. . The mixture was then cooled to room temperature, purified by filtration over diatomaceous earth and washed with ethyl acetate. The combined filtrate and washings were evaporated in vacuo to give the crude title compound (196 g) as a light yellow syrup. The product was distilled to give 135 g of the title compound as a purified title product.

Yield 60%.

Fp. 113-115'C (266.6-933.1 Pa / vessel temperature 155-157'C).

Production Method 5

Ethyl 2- / 4- (diethoxymethyl) benzoyl / acetate

The ether (400 ml) was cooled to 0-5 ° C and 32.4 g (1.35 mol, 97% NaH) was added with vigorous stirring followed by 95.6 g (0.81 mol) of diethyl ether directly. After stirring for 25 minutes at room temperature, 120 g (0.54 mol) of the product obtained in the previous preparation and 1 ml of absolute ethanol in 300 ml of ether are added over 25 minutes, while vigorous stirring is continued at room temperature. After heating at this temperature for 6 hours, the reaction mixture was cooled to room temperature and slowly poured into a mixture of 500 mL of 10% HCl and 500 mL of ether, previously cooled to 0 ° C. The aqueous layer was separated and treated with 500 mL of fresh ether. extracted. The organic layers were combined, washed with 500 ml of water and then 500 mL of saturated brine, dried over MgSO ₄ and stripped in vacuo. ly from acetonitrile gave 158 mg of the title product was obtained as a viscous oil.

Yield 99%.

Production Method 4

4- [3- (5-Methyl-2-phenyl-4-oxazolyl) -propionyl] -benzaldehyde

Sodium hydride (3.4 g, 0.14 mol) was combined with THF (250 mL) and cooled to 0 ° C. Subsequently, 41.5 g (0.14 mol) of the title product prepared in the preceding example, dissolved in 250 ml of THF, are added portionwise over 0.5 hour while maintaining the temperature below 25 ° C. After stirring for an additional 0.5 h at room temperature, (5-methyl-2-phenyl-4-oxazolyl) methyl chloride (25.8 g, 0.125 mol) was added and the mixture heated at reflux for 48 h and then cooled. and stripping in vacuo. In this way, the desired intermediate is obtained. The intermediate is taken up in a mixture of 360 ml of acetic acid and 90 ml of concentrated HCl, refluxed for 5 hours, then cooled to room temperature, diluted with 600 ml of water and extracted with 2 x 1 L of ethyl acetate / ether. The organic layers were combined, washed with water (1 L) and brine, dried over MgSO ₄ and the solvent removed in vacuo. The residue was subjected to flash chromatography on silica gel eluting with 1:19 ether / HCl ₃ . This gave 34 g of the title compound as an oil which solidified on standing.

Mp 76-80'C.

Yield 85%.

5- 11. Production Methods. ;

4- / 3- (substituted) -propionyl / benzaldehyde

The same procedure as in the previous example is used, but instead of (5-methyl-2-phenyl-4-oxazolyl) methyl chloride, a molar equivalent of appropriately substituted (oxazolyl) methyl or (thiazolyl) methyl chloride is used. The title product obtained according to the method of Preparation 1 is converted to the following products

HU 204,820 B

Song substitute Yield: (%) op .: CQ 5 2-phenyl-4-oxazolyl 65 oil 6 2- (4-methoxy-phenyl) -5-methyl-4-oxazolyl 38 78-80 7 2- (2-thienyl) -5-methyl-4-oxazolyl 70 tire 8 2- (2-furyl) -5-methyl-4-oxazoline 35 98-100 9 2 cfldohexil-5-methyl-4-oxazolyl 29 tire 10 2-phenyl-4-thiazolyl 41 101-104 11 2-phenyl-4-methyl-5-thiazolyl 29 Ginni

Preparation 12

To 0.77 g (4.61 mmol) of 2- (hydroxymethyl) pyridine-5-carboxylate in 10 ml of DMF was added 0.77 g (1.1 equivalents) of dimethyl tert-butylsilyl chloride and , 47 g (1.5 equivalents) of imidazole. After 1 hour, the reaction mixture was poured into water (30 mL) and extracted with ether (3 x 20 mL). The organic layers were combined, washed with 2 x 20 mL skeleton, dried over MgSO ₄ and stripped in vacuo to give 1.32 g of the title product.

Yield 100%.

PREPARATION 13 tert-Butyl-3- / 3- (dimethyl-tert-butylsilyloxymethyl)

-5-pyridyl / -3-oxopropionate

4.75 mL (9.5 mmol) of 2.0M n-butyllithium in hexane and 1.36 mL (9.7 mmol) of dnisopropylamine in 10 mL of THF were combined at -78 ° C, then warm to room temperature and cool again to -78 ° C. At this temperature, tert-butyl acetate (1.28 mL, 9.5 mmol) was added and the whole stirred for 15 minutes to give the lithium salt of tert-butyl acetate (5.61 mmol), followed by 5 mL of the product of the previous preparation. It is added in THF to a cooled solution of the enol salt. The mixture was heated and stirred at room temperature for 2 hours, then water (50 mL) was added to the reaction mixture and extracted with ether (4 x 20 mL). The organic layers were combined, dried over MgSO ₄ and evaporated in vacuo, and the residue was chromatographed on a 4 mm silica gel plate. Elution with 3: 7 ether / hexane gave 0.94 g of the title compound on the fly.

Yield 56%.

Preparation 14

2 - [(Dimethyl-tert-butylsilyloxy) methyl] -5- [3- (2-phenyl-5-methyl-4-oxazolyl) -2- (tert-butoxycarbonyl) propionyl] pyridine

60% NaOH (107 mg, 2.68 mmol) was washed with hexane (3 x 3 mL) and treated with dry DMF (5 mL). A solution of the title product (0.89 g, 2.44 mmol) in DMF (4 mL) was then added over 2 min and the mixture was stirred at room temperature for 15 min and at 50 ° C for 5 min. ketoester for anion formation. Subsequently, 0.506 g (2.44 mmol) of (2-phenyl-4-methyl-2-oxazolyl) methyl chloride is added at 50 'C and the whole is stirred at 70' C.

After cooling, the mixture was poured into water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, washed with water (2 x 20 mL), dried over MgSO ₄ and evaporated in vacuo.

The residue was chromatographed on a 4 mm silica gel plate eluting with 2: 3 ether / hexane to give 0.71 g of the title compound.

Yield 54%.

This procedure was repeated at 4.76X without chromatography to give 6.43g of the title product.

Yield 100%.

Preparation 15

2 - / (dimethyl-t-butylsilyloxy) methyl / 5- [3- (2-phenyl-5-methyl-4-oxazolyl) propionyl] pyridine

A solution of 6.43 g of the title compound obtained in the preceding Preparation is mixed with 50 ml of CH ₂ Cl ₂ and 50 ml of trifluoroacetic acid and stirred for 2 hours at room temperature. The solvent was removed in vacuo and the residue was taken up in 250 mL of saturated aqueous NaHCO ₃ and extracted with ₃ x 250 mL of ethyl acetate. The organic layers were combined and extracted with ethyl acetate (1 x 250 mL). The combined organic layers were washed with water (1 x 250 mL), dried over MgSO ₄ and evaporated in vacuo. This gave 4.58 g of crude product which was chromatographed on silica gel eluting with 1: 1 hexane / ethyl acetate to give 2.53 g of the purified title compound.

Yield 48%.

Preparation 16

5 - / - (2-phenyl-4-oxazolyl) -propioúil / -pyridin-2

methanol

The title product (2.53 g) obtained in the previous preparation was diluted with THF (50 mL) with 1N HCl (50 mL) and stirred at room temperature for 1 hour, stripped in vacuo and extracted with ethyl acetate (3 x 100 mL). It was washed with water (2 x 50 mL), dried over MgSO ₄ and stripped in vacuo (finally at 50 ° C under high vacuum) to remove the silyl alcohol by-product present, yielding 1.8 g of the title compound as a solid.

M.p. 97-99'C.

Yield 97%.

HU 204,820 B

Production Method 77

-5- / 3- (2-phenyl-5-methyl-4-oxazolyl) propionyl / -pyridine-2-carbaldehyde

2.5 mL of CH ₂ Cl ₂ and 0.075 mL (1.10 mmol) of oxalyl chloride were combined and the mixture was cooled to -60 ° C. DMSO (0.17 mL, 2.40 mmol) was then added dropwise to CH ₂ Cl ₂ (1 mL) over 5 min, and the mixture was stirred while maintaining the temperature at -60 ° C. After one minute, the title compound (0.32 g, 1.00 mmol) obtained in the previous preparation was dissolved in CH 2 Cl 2 (1 mL) over 2 minutes and stirred at -60 ° C for 15 minutes. Triethylamine (70 ml) was added to the solution and the mixture was warmed to room temperature, then poured into water (20 ml) and the aqueous layer was separated and then extracted with CH ₂ Cl _{2 (1} x 20 ml). The organic layers were combined, dried over MgSO ₄ and evaporated to give 0.34 g of crude product as a brown oil. The reaction was repeated to a lesser extent using 0.24 mL of oxalyl chloride in 8 mL of CH ₂ Cl _{2 with} 0.55 mL of DMSO in 3 mL of CH ₂ Cl ₂ and another 1.04 g of the title compound obtained according to the previous procedure. The product was dissolved in CH ₂ Cl ₂ (3 mL) and triethylamine (2.26 mL) was added to give the title compound (1.21 g). The crude product was combined and chromatographed on a 4 mm silica gel plate. 0.44 g of pure title product is obtained in 32% yield. The product is unstable and should be processed immediately.

Production Method 18

Methyl-3- (5-bromo-2-thienyl) -3-oxopropionate

Sodium hydride (1.95 g, 0.045 mol) in a 60% oil dispersion, 50 ml dimethyl carbonate and 40 ml THF was charged into a flask which was flame dried and equipped with stirring and a dropping funnel. 2-Acetyl-5-bromothiophene (5.0 g, 0.024 mol) in THF (20 mL) was added dropwise to the flask. The mixture was then refluxed for 2 hours and then poured into 250 ml of water, acidified to pH 2.0 with 1 N HCl and extracted with 3 x 200 ml ether. The organic layers were combined, dried over MgSO ₄ and evaporated. 6.4 g of the title compound are thus obtained in the form of an oil.

tlc: R f »0.42 (CHCl ₃ )

Yield: 99%.

Production Method 79

Methyl 3- (5-bromo-2-thienyl) -3-oxo-2 - [(2-phenyl-5-methyl-4-oxazolyl) methyl] propionate

The title compound (4.43 g, 0.0168 mole) obtained in the previous preparation, dissolved in DMF (15 mL), was added dropwise to a solution of NaH (0.74 g, 0.0185 mole) in 60% oil, previously washed with hexane and It is stirred in 15 ml of DMF. At this time, we experienced vigorous hydrogen evolution. The mixture was stirred at room temperature for 0.75 hours, at which point hydrogen evolution ceased. Subsequently, 3.5 g (0.0168 mol) of (2-phenyl-4-methyl-4-oxazolyl) methyl chloride were added in one portion and the whole was heated at 70 ° C for 18 hours, then cooled to 60 ml. diluted with water and acidified to pH 3 with 1 N HCl and extracted with 3 x 90 mL of 1: 1 ether / ethyl acetate. The organic layers were combined, dried over MgSO ₄ and evaporated to give 6.89 g of the title product as a dark oil which was pure enough to be used in the next step. If desired, the product may be purified by chromatography on silica gel eluting with 1:19 ethyl acetate / hexane. This gives the title product in the form of a clear oil which is much clearer.

Production Method 20

5-bromo-2- / 3- (2-phenyl-5-methyl-4-oxazolyl) propionyl / -thiophene

To the title product (6.64 g, 0.0153 mole) from the previous preparation in CH 2 OH / THF (1: 1, 250 mL) was added 1N NaOH (125 mL) and the mixture was stirred at room temperature for 4 hours. 3- (5-Bromo-2-thienyl) -3-oxo-2- (2-phenyl-5-methyl-4-oxazolyl) -propionic acid is obtained as an intermediate. The mixture was strongly acidified with 125 mL of 10% HCl. The acidic mixture was stirred for an additional 4 hours then extracted with ethyl acetate (3 x 400 mL). The organic layers were combined, dried over MgSO ₄ and evaporated. 4.7 g of the title compound are obtained in the form of an oil.

TLC: Rf = 0.55 (CHC1 _3).

Yield: 82%.

Production Method 21

5-Bromo-2- (1-hydroxy-3- (2-phenyl-5-methyl-4-oxazolyl) -propyl] -thiophene

0.25 g (0.66 mmol) of the title product obtained in the previous preparation and 9 mg (0.22 mol) of NaBH _{4 are} combined in 5 ml of ethanol and the mixture is stirred at room temperature for 3 hours. The ethanol was cooled in vacuo and the residue dissolved in water (5 mL), adjusted to pH 2 with 1N HCl and extracted with CHCl ₃ ( ₃ x 5 mL). The organic layers were combined, dried over _MgSO4 and evaporated, yielding 0.18 g of the title product as an oil, tlc: Rf = 0.20 (CHC1 _3), 0.40 (1:19 ethyl acetate / hexanes mixture).

In a similar manner, the product obtained according to another previous preparation is converted to 5-bromo-2- [1- (dimethyl-tert-butylsiloxy) -3- (2-phenyl-5-methyl-4-oxazolyl) -propyl] -1- (methyl- or benzyl l-pyrrole.

Production Method 22

5-Bromo-2- [1- (dimethyl-tert-butylsilyloxy) -3- (2-phenyl-5-methyl-4-oxazolyl) -propyl] -thiophene

0.47 g (1.24 mmol) of the title product of the previous preparation, 0.21 g (3.12 mmol) of imidazole and 0.24 g (1.56 mmol) of dimethyl tert-butylsilyl chloride are combined. Dry DMF (10 mL) and stir at room temperature for 18 hours. The mixture was then poured into 50 mL of a saturated aqueous solution of Ne.HCO ₃ and extracted with 3 x 60 mL of hexane.

GB 204,820 Β two combined, 2x50 ml of 5% HCl solution and 1x50 ml of water, dried over _MgSO4 and stripped. 0.22 g of the title compound are obtained in the form of an oil, tlc: Rf-0.75 (ethyl acetate / hexane 1:19). 5

Yield: 36%.

23 production method

5- [1- (Dimethyl-tert-butylsilyloxy) -3- (2-phenyl-5-methyl-4-oxazolyl) -propyl] -thiophene-2-carbaldehyde 10

0.22 g (0.45 mmol) of the title product obtained in the previous preparation was dissolved in 10 mITHF and cooled to -78 ° C. To the solution was added 0.25 mL (0.49 mmol) of 2M n-butyllithium in hexane by injection syringe and the resulting mixture was stirred for 20 min at -78 ° C. DMF (0.3 mL) was added and the mixture was warmed to room temperature, stirred for 15 min, then poured into water (25 mL) and extracted with ether (3 x 30 mL). The organic layers were combined, dried over MgSO ₄ and evaporated in vacuo. 0.17 g of the title compound is obtained in the form of an oil. Yield 85%.

In a similar manner, another product obtained according to the preceding preparation is converted to 571- (dimethyl-tert-butylsilyloxy) -3- (2-phenyl-5-methyl-4-oxazolyl) -propyl-251- (methyl or benzyl). -2-carbaldehyde.

Preparation 24

5- (4-Methyl-benzyl) -thiazolidine-2,4-dione g (0.32 mol) 3- (4-acetyl-phenyl) -2-bromopropionic acid, prepared according to the method of Cleland. 51, 1.1971) and thiourea (48.7 g, 0.64 mol) in sulfolane (100 ml) was heated at 105-110 ° C for 5 hours. To the mixture was added 162 ml of 2N HCl and the resulting solution was heated to 105-110 ° C overnight. The solution was cooled, diluted with water and the title product was collected, washed with water and dried to give 75 g. yielding the title compound. 40

Mp: 171-172'C.

Yield 94%.

25th generation

4- [3- (2-Pyridyl) -2-propenyl] -benzaldehyde diethyl 45 cetal (4.5 mmol) 4- (diethoxymethyl) acetophenone and 0.64 mL (6.75 mmol) A solution of 2-pyridinecarbaldehyde in 20 mL of methanol and 13.5 mL of 1 N NaOH was stirred at room temperature for 1 hour. The solution was diluted with water (30 mL) and extracted with ether (2 x 20 mL).

The combined extracts were washed with brine, dried over magnesium sulfate and concentrated. The product was purified by flash chromatography 55 eluting with 2: 1 hexane / ethyl acetate. This gives 0.78 g of oil.

Yield 56%.

26th generation

4- [3- (2-pyridyl) propionyl] benzaldehyde

A solution of the product obtained in the previous preparation (0.78 g, 2.5 mmol) in ethanol (50 mL) containing 10% palladium on carbon (80 mg) was hydrogenated in a Parr apparatus at 3.5 atmospheres for 1 hour. The catalyst was then removed by filtration and the solution concentrated in vacuo.

The resulting oil was dissolved in 10 mL of IHF, 5 mL of 1 N HCl was added and the solution was stirred at room temperature overnight. The solution was then neutralized with 5 mL of 1 N NaOH, diluted with 10 mL of water and extracted with 3 x 15 mL of ethyl acetate. The combined extracts were washed with water (15 mL) and brine (15 mL), dried over magnesium sulfate and concentrated in vacuo. This gave 345 mg of the title compound as an oil.

Yield 58%.

Claims (9)

A process for the preparation of a thiazolidinedione derivative of formula (I) and a pharmaceutically acceptable cationic salt or a pharmaceutically acceptable acid addition salt thereof, wherein the compounds contain basic nitrogen, wherein the dotted line is a bond or a bond; V is -CH = CH-, -N = CH- or -S-, W represents - _CH2} r CHOH,> CO, C ^ NOR or CH = CH, Seven unsubstituted pyridyl, furyl, optionally 4 or 5-thizoyl groups containing one or two substituents, or 4-oxazolyl, one of which is hydrogen or C 1-3 alkyl and the other is C 3-7 cycloalkyl, phenyl, C 1-3 alkoxyphenyl, furyl or thienyl, R is hydrogen or methyl, and n is 1, 2 or 3, characterized in that a) For the preparation of compounds of formula I wherein the dotted line is a bond, the thiazolidine-2,4-dione is reacted with an aldehyde of formula Π, optionally protected as a silyl ether in the CHOH group in W. and then removing any protecting group present; obsession b) reducing a compound of formula (I) wherein the dotted line represents a bond to produce a compound of formula (I) wherein the dashed line does not represent a bond; obsession c) for the preparation of compounds of formula I wherein n is 2, W is -CH ₂ -, -CHOH-> CO, Week and V is a compound of the general formula (ΕΠ) wherein W is CO and H V above, reduced; obsession HU 204,820 B d) reducing a compound of formula 0) wherein W is> CO or> CHOH to produce a compound of formula 0) wherein W is + CHOH or / CH ₂ ; obsession e) oxidizing a compound of formula 0) wherein W is a COO group to produce a compound of formula 0 wherein W is CO; obsession f) dehydrating a compound of formula 0) wherein W is -CH = CH- and n is 1 or 2 or a compound of formula 0) wherein W is CHOH and n is 2 or 3; obsession g) for the preparation of a compound of formula 0 wherein W is ·? C = NOR, a compound of formula 0) wherein W is' CO, is reacted with a compound of formula H ₂ NOR wherein R is as defined herein and optionally a free compound of formula 0 formed to a pharmaceutically acceptable salt thereof. 2. A process according to claim 1 for the preparation of compounds of formula 0 wherein the dotted line is not a bond, W is? CO or CHOH, and V, n and Sev are as defined in claim 1, characterized in that they are derived from appropriately substituted materials. 3. A process according to claim 2 for the preparation of compounds of formula 0) wherein V is -CH = CH-, -CH = N- or -S-, n is 2, W and the dashed line is 2, Week as claimed in claim 1, characterized in that it is based on appropriately substituted materials. The process for the preparation of compounds of formula 0 according to claim 3, wherein Sev is 5-methyloxazol-4-yl which is phenyl, C 1-3 alkoxyphenyl, 2-thienyl or 2-thienyl; substituted with furyl and dashed line and W as defined in claims 2, V and na 3, characterized in that they are based on appropriately substituted materials. A process for the preparation of compounds of formula 0 according to claim 4, wherein V is -CH = N- or -S-, the dashed line and W are as defined in claim 2 of claim 3, and seven are 5-methyl -2-phenyloxazol-4-yl, characterized in that it is based on appropriately substituted materials. A process for the preparation of compounds of formula 0 according to claim 5, wherein V is -CH = CH-, W is CO, Sev is 2- (2-furyl) -oxazol-4-yl or 2 -phenyloxazol-4-yl group, the dashed line is as defined in claims 2 and 3, characterized in that it is based on appropriately substituted materials. The process for the preparation of compounds of formula 0 according to claim 3, wherein Sev is thiazol-4-yl or thiazol-5-yl and the dashed line and W are as defined in claims 2, V and na. , characterized in that it is based on appropriately substituted materials. The process for the preparation of compounds of formula 0 according to claim 3, wherein Sev is pyridyl-2-yl or 2-furyl and the dashed line and W are as defined in claims 2, V and na. , characterized in that it is based on appropriately substituted materials. 9. A process for the preparation of a medicament comprising the preparation of a compound of formula 0) according to claim 1, wherein: R and ---- represent a thiazolidine-2,4-dione derivative according to claim 1, a pharmaceutically acceptable cationic salt or a pharmaceutically acceptable acid addition salt thereof, in admixture with excipients and / or excipients conventionally used in the preparation of a medicament.