HU194199B - Process for producing new thiazolidinedione derivatives and pharmaceutical compositions containing them as active agents - Google Patents

Abstract

Thiazolidinedione derivatives represented by general formula (I), (wherein R<1> represents hydrogen or an optionally substituted hydrocarbon or heterocyclic residue, R<2> represents hydrogen or an alkyl group optionally substituted by hydroxy, X represents oxygen or sulfur, m represents 0 or 1, and n represents an integer of 1 to 3) and salts thereof are new compounds effective in reducing the blood sugar and blood lipid levels, thus being useful for treating diabetes and hyperlipemia.

Description

The present invention relates to novel thiazolidinedione derivatives and their salts and to pharmaceutical compositions containing them. The compounds of the invention reduce blood sugar and fat levels.

Various biguanidine and sulfonylurea derivatives have been used to heal sugar. However, biuganidine derivatives are hardly used because they cause lactic acidosis, while sulfonylureas are potent hypoglycemic agents, but often reduce blood sugar levels excessively, and therefore require great care. Thus, there was a need for an anti-diabetes drug that was free of the listed disadvantages. A 22636/1980. and 64586/1980. Japanese Patent Laid-Open Publication No. 2,800,198 and Chemical and Pharmaceutical Bulletin, 30, 3563 (1982), 30, 3580 (1982) and 32, 2267 (1984), reported that various thiazolidinedione derivatives had a remarkable effect on reducing blood fat and sugar levels, Diabetes, 32, 804 (1983), describes the antidiabetic effect of ciglitazone. However, none of the compounds have become commercially available pharmaceuticals.

It has been found that the compounds of the present invention are particularly potent in lowering blood fat and sugar levels and are expected to be much more potent than previously known compounds.

The compounds of the invention are represented by formula (I)

R ¹ is hydrogen, thienyl, furyl, pyridyl, C 1 -C 5 alkyl, C 4 -C 7 cycloalkyl optionally substituted with C 1 -C 4 alkyl, or C 4 -C 7 cycloalkenyl, (C 4 -C 7 cycloalkyl) - ( C 1-4 -alkyl, phenyl-C 1-4 -alkyl, or optionally mono-, halo, C 1-4 -alkyl, trifluoromethyl, hydroxy, C 1-4 -alkylthio or phenyl, mono- or di-substituted with (1-4C) alkoxy,

R ² is hydrogen or C 1-5 alkyl optionally substituted at the α-position by a hydroxy group,

X is oxygen or sulfur,

Z is hydroxylated methylene or carbonyl, m is 0 or 1, n is 1 to 3,

L and M are each independently hydrogen or L and M together form a bond.

The compounds of the invention are prepared as follows:

a) a compound of the general formula (I-1), wherein R ¹ , R ² , X, Z, m, L and M are as defined, or a salt thereof having the general formula (I); reacting a compound of formula wherein R ² , R ² , X and m are as defined and Y is halogen, with a compound of formula (I): wherein L and M are as defined, or a salt thereof, and optionally a compound of formula (13), wherein R ¹ , R ² , X, η, L and M are as defined, or a resulting compound of formula (1-2), wherein R ¹ , R, X, n, L and M are as defined - or a salt thereof is reduced with a complex metal hydride, or

b) A compound of the formula (IV) wherein Z is a hydroxymethylene group and R ² is a hydrogen atom, or a salt thereof, for the preparation of a compound of formula (I) or a salt thereof which is a narrower rock. C 1 -C 5 alkyl, R ¹ , X, m and n are as defined - hydrolyze and, if desired, form a compound of formula C-4 wherein Z is a carbonyl group or a salt thereof, wherein Z is a hydroxymethylene group. -4) a compound or a salt thereof is oxidized to an optionally substituted, R ² is hydroxy is appropriate to prepare the compounds or salt thereof having 1-5 carbon atoms alkylating a compound of R ² containing 1 to 5 carbon atoms (1 and / or dimethyl sulfoxide and acetic anhydride —Brominating the compound of formula (4) or a salt thereof with N-bromosuccinimide and then hydrolyzing it in the presence of a mineral acid, or

c) a compound of formula (I) as defined in the introduction, or a salt thereof, which is a narrow group of compounds of formula (I), wherein R, R, X, Z, m and n are as defined above; wherein R ¹ , R ² , X, Z, m and n are as defined above, with a compound of formula (VI) or a salt thereof, and, if desired, reacting a compound of formula (I-4) wherein R, R, X, Z, m and n are catalytically reduced with hydrogen in the presence of Pd / C to give a compound of formula (I-5), wherein R, R ² , X, Z, m and n are as defined above. converting any of the products obtained above into a salt.

The above general terms (I), (I-1), (1-2), C-3), (1-4), (1-5), (II), CTII), CV), and (V) In the formulas R *, alkyl may be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl. Cycloalkyl may be, for example, cyclobutyl, dclopentyl, cyclohexyl or dcloheptyl. The dkloalkenyl group is 1-cyclopentenyl, 2-cyclopentenyl,

3-diclopentenyl, Ι-cyclohexenyl, 2-dclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3cycloheptenyl. Examples of cycloalkylalkyl include dclobutylmethyl, cyclopentylmethyl, cilohexylethyl, cyclohexylpropyl, cycloheptylmethyl and cycloheptylethyl. Examples of phenylalkyl include benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl or 1-phenylpropyl. When R ^l is phenyl which may be mono- or disubstituted in the ring selected from halogen (e.g. fluorine, chlorine or iodine), hydroxyl, trifluoromethyl, lower alkoxy (1-4 carbon atoms, eg. Methoxy, ethoxy , propoxy, isopropoxy or butoxy), lower alkyl (C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl or butyl), and lower alkylthio (e.g. 1-3). alkylthio such as methylthio, ethylthio, propylthio or isopropylthio).

In the context of R ^2, lower alkyl is a C 1 -C 5 atom such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or penile. C 1-4 alkyl groups are preferred and C 1-3 alkyl groups are particularly preferred. Alkyl groups may contain a hydroxyl group at the α-position.

When L and M form a bond in the formulas (I), 0-1), 0-2), 0-3) and (ΠΙ), the carbon at each end of the bond is double bonded. In the case where L and M form a bond, the compound of formula (1) may be represented by the formula (I-5). When L and M are each independently hydrogen, the compound of formula (I) is represented by the formula (0-4).

In formula (II), the halogen atom in Y is preferably chlorine, bromine or iodine.

Compounds of formula 0 having an acidic nitrogen atom in the thiazolidine ring may form salts with bases. Such bases are salts of pharmaceutically acceptable salts such as sodium, potassium, aluminum, magnesium or calcium.

The compounds of formula (I) or salts thereof may be prepared by the following processes:

Compounds of formula (I) wherein n is 1 or salts thereof, i.e. compounds of formula (0-1) or salts thereof (hereinafter together referred to as compounds of formula (0-1)) are compounds of formula (II): by reacting a compound of formula (III) or a salt thereof (hereinafter referred to collectively as a compound of formula (III)) and then reducing the resulting product, if desired.

The reaction of the compounds of formula (I) and (III) is generally carried out in the presence of a suitable solvent and base to give compounds of the formula (I) in which n is 1.

Examples of the solvent include dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dimethoxyethane. The base may be, for example, sodium hydride, potassium anhydride, sodium amide, sodium alkoxide (e.g., sodium methoxide, sodium ethoxide), potassium alkoxide (e.g., potassium butoxide). The reaction is preferably carried out by reacting 1 mole of the compound of the formula II with 2 moles of the base to form the dianon, followed by the addition of 1 mole of the compound of the formula 011 to carry out the reaction. The condensation reaction is usually carried out at a temperature of 0 to 120 ° C, preferably 20 to 100 ° C, and the reaction time is usually 3 to 5 hours.

When the starting compound used in said reaction is a compound of formula 01) wherein m is 1, a compound of formula 0-1 is obtained wherein m is 1 and Z is carbonyl. If this compound is reduced, if desired, a compound of formula 0-1) wherein m is 1 and Z is -CH (OH) - can be prepared.

The compounds of formula (0-2) or their salts (hereinafter referred to as compounds (0-2)) can be converted into compounds of formula (0-3) or their salts (hereinafter compounds of formula (0-3)) by reduction. The reduction is readily carried out with sodium borohydride in a solvent such as alkanol (e.g. methanol, ethanol, 2-propanol, 2-methoxyethanol), optionally mixed with Ν, Ν-dimethylformamide. 0.3 to 2 moles of sodium borohydride are used per mole of the compound (0-2). The reaction temperature is -10 ° C to 100 ° C and the reaction time is 3 to 5 hours.

The compounds of formula 1-3 can be converted to the compounds of formula 0-2 by oxidation. The oxidation reaction can be readily carried out with activated DMSO oxidase using dimethylsulfoxide (DMSO) and an electrophilic reagent (e.g. acetic anhydride, dicyclohexylcarbodiimide (DCC), phosphorus pentoxide) or chromic acid oxidation.

Activated DMSO oxidation is accomplished by adding an electrophilic reagent such as acetic anhydride, DCC or phosphorus pentoxide (optionally mixed with benzene, pyridine, ether) in DMSO. Generally, a large excess of dimethyl sulfoxide is used, the reaction temperature depending on the electrophilic reagent used, is -10 ° C to 60 ^U C, and the reaction time is 1 to 30 hours. The oxidation of chromic acid can be carried out with Jones reagent (chromium-1-oxide / sulfuric acid / acetone), chromium trioxide in acetic acid, chromium trioxide in pyridine or in a pre-prepared chromium trioxide / pyridine complex in dichloromethane. Calculated for the compound of formula 0-3). 3 to 2 equivalents of chromium (VI) ions are used. The reaction temperature is -10 ° C to 60 ° C, preferably 0-30 ° C, and the reaction time is 3 to 5 hours.

Compounds of formula (I) or salts thereof, wherein L and M are hydrogen, that is, compounds of formula (0-4) (hereinafter referred to collectively as compounds of formula (0) to (4)) may be prepared by the process of step (b). hydrolysis of its salt (hereinafter referred to collectively as "0V"). H-drolysis is generally carried out in a suitable solvent in the presence of water and mineral acid. The solvents generally used are alcohols (e.g. methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, 2-methoxyethanol), dimethylsulfoxide, sulfolane, dioxane, dimethoxyethane. The mineral acid is, for example, hydrochloric acid, hydrobromic acid, sulfuric acid in an amount of 0 to 10 mol, preferably 0.2 to 3 mol, per mole of compound (IV). Usually large amounts of water are used. The reaction is usually carried out under heating, the reaction temperature usually being 60-150 ° C. Reaction times generally range from a few hours to tens of hours.

The compounds of formula 0-5 or their salts (hereinafter compounds of formula 0-5) can be prepared by the method of ac) from the compounds of formula V with the compounds of formula VI or their salts (hereinafter collectively ). The reaction is usually carried out in a solvent in the presence of a suitable base. Solvent / base system solvents employ suitable systems in which the solvent is, for example, an alkanol (e.g. methanol, ethanol, propanol, 2-propanol, butanol, isobutanol,

2-netoxylethanol), dimethylformamide, dimethylsulfide, sulfolane, acetonitrile, dioxane, dimethoxyethane or acetic acid, and the base is, for example, an amine (e.g. pyrrolidine, piperidine, morpholine, piperazine, diethylamine, diisopropyl). amine, triethylamine), sodium alkoxide (e.g., sodium methoxide, sodium ethoxide), potassium carbonate, sodium carbonate, sodium hydride,

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-acetate. Generally, from 0.01 to 3 moles, preferably 0.1 to 1 moles, of base are used per mole of compound (V), generally from 1 to 5 moles, preferably from 13 to 3 moles, of the compound (VI). The condensation reaction is generally carried out at a temperature of from 0 to 150 ° C, preferably from 20 to 100 ° C, for a period of from 0.5 to 50 hours.

The compounds of formula (I-4) may also be prepared by reduction of compounds of formula (I-5) obtained by process (c). The reaction is generally carried out by catalytic reduction in a suitable solvent for the catalyst. Suitable solvents are generally alcohols (e.g. methanol, ethanol, propanes), ethers (e.g. dioxane, dimethoxyethane, tetrahydrofuran), ethyl acetate, acetic acid, dimethylformamide. The catalyst may be, for example, palladium carbon black, palladium carbon, platinum oxide. The reaction may be carried out at normal temperature and pressure, or may be carried out at elevated temperature (about 40-100 ° C) and pressure to accelerate the reaction.

R ² is, following the procedure compound of formula or a salt thereof (I) an alkyl hydroxy groups b to the α-position), prepared as described in Scheme I) [wherein R ³ is hydrogen or lower alkyl (e.g. methyl, ethyl , propyl, isopropyl, butyl, isobutyl), the other substituents are as defined above].

When compounds or salts containing the Compounds (1-6) of the formula, i.e., a lower alkyl group, R ² is -CH ₂ -R ³ corresponding formula [hereinafter referred to collectively as (1-6) a compound of formula] is halogenated, (VII ) or a salt thereof (hereinafter referred to as a compound of formula VII).

The compound of formula (VII) can then be hydrolyzed to form the compounds of formula (I-7) or salts thereof (hereinafter compounds of formula (I-7)). Preferably, the compound (I-6) may be halogenated in the presence of a radical initiator, such as benzoyl peroxide or α, α'-azobisisobutyronitrile, with N-bromo or N-chlorosuccinimide. The reaction may conveniently be carried out under reflux in a solvent such as carbon tetrachloride or chloroform. Generally 0.01 to -0.2 moles of the radical initiator are used per mole of the compound (1-6). The resulting halogenated derivative (VII) may, if desired, be directly hydrolyzed without isolation of the α-hydroxy derivative (compound (I-7)) after isolation and purification. The hydrolysis is preferably carried out with a mineral acid in a suitable solvent. Suitable solvents are, for example, dioxane, tetrahydrofuran or dimethoxyethane, and the mineral acids are, for example, hydrochloric acid or sulfuric acid. The reaction temperature is 20-100 ° C and the reaction time is 03-10 hours.

The thiazolidinediones of formula (I) according to the invention may be isolated and purified by conventional means, for example by evaporation, evaporation under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer or chromatography.

The compounds of formula I according to the invention and their salts have excellent blood glucose and blood fractions inhibitory activity in mammals (e.g. mice, rats, cats, dogs, monkeys, horses and humans) and all have acute and subacute toxicity. Thus, the thiazole derivatives of formula I are useful in the treatment of hyperlipaemia and diabetes. The compounds are generally administered orally, such as in the form of tablets, capsules, powders or granules, but may also be administered in the form of powders for injection, solutions, suppositories, and pellets. For the treatment of diabetes mellitus and hyperlipaemia in adults, the daily dose is Opi-10 mg / kg orally, 0005-10 mg / kg orally, and these doses are preferably administered once or twice daily 4 times per week.

The compound of formula (V) used as starting material for process c) of the present invention is prepared, for example, as follows:

In) Preparation of compounds of formula V-1, i.e. compounds of formula V wherein m is 0:

the reaction is illustrated in Scheme a) (wherein the substituents have the meanings given above).

Conversion of compounds of formula VIII to compounds of formula X is accomplished by condensation of compounds of formula VIII with the general formula IX in the presence of sodium hydride. The reaction is carried out in a solvent such as dimethylformamide, dimethyl szulfcxidban, tetrahydrofuran price room dimethoxy -ethyl or - at a temperature between 30 and 10 ° C ^U C. Conversion of compound (X) to compound (V-1) is accomplished by heating the compound in aqueous solution of formic acid in the presence of Raney nickel alloy.

(b) Preparation of compounds of formula (V-2), ie clyan of formula (V) wherein m is 0 and n is 1 or both m and n are 1 and Z is carbonyl:

The reaction is illustrated in Scheme b (wherein the substituents have the meanings given above).

The condensation reaction of the compounds of formula (II) with the compound of formula (XI) results in the preparation of compounds of formula (V-2), usually in a solvent such as dimethylformamide, tetrahydrofuran, acetone or methyl ethyl ketone. (e.g., sodium carbonate or potassium carbonate) at 0-150 ° C.

l.c) Preparation of Compounds of Formula V-3, i.e. Compounds of Formula V wherein m and n are 1 and Z is hydroxymethylene:

The reaction is illustrated in Scheme c (wherein the substituents have the meanings given above). The reaction of the compounds of formula (H-1) with the compound of formula (XII) is carried out in a similar manner to the reaction of the compounds of formula (II) with the compound of formula (XI) above. The resulting compound of formula (ΧΙΠ) is then prepared in a manner known per se, for example with sodium borohydride in a solvent such as methanol; in ethanol or Ν, Ν-dimethylformamide or a mixture thereof to form compounds of formula (XIV) which are subsequently converted to compounds of formula (V-1) as described for the conversion of compounds of formula (X) into compounds of formula (V-1) 3).

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2a) Preparation of compounds of formula IV-1, i.e. compounds of formula TV, wherein m is 0:

The reaction is illustrated in Scheme d) (wherein R ⁴ is hydrogen or lower alkyl, the other substituents are as defined above):

In the formulas (XVJH) and (XIX), the lower alkyl group in the formula R ⁴ is 1-4 carbon atoms, such as methyl, ethyl, propyl or butyl.

In converting the compound of formula VIII to the compound of formula XVI, the compound of formula VIII is condensed with the compound of formula XV, for example in the presence of sodium hydride. The reaction may be carried out in a solvent such as dimethylformamide or tetrahydrofuran at a temperature of -10 ° C to 30 ° C. The subsequent reaction for converting a compound of formula (XVI) into a compound of formula (XVII) can be easily carried out, for example, by employing a compound of formula (XVI) in a known manner, using a palladium-carbon catalyst, or zinc or iron and acetic acid. The compounds of formula (XVII) may be isolated as a pure product or further reacted without isolation or purification. The conversion of the compound of formula XVII to the compound of formula XIX is accomplished by the so-called Meerwein arylation reaction wherein the compound of formula XVII is diazotized in the presence of hydrogen halide (HY) followed by acrylic acid or its formula XVIII. ester in the presence of a copper catalyst (e.g., copper (I) oxide, copper (II) oxide, copper (I) chloride, copper (II) chloride, copper (I) bromide or copper (II) bromide). The compound of formula (XIX) may be purified by chromatography or may be used in the next step without isolation or purification.

Compounds of formula (IV-1) may be prepared by reaction of compounds of formula (XIX) with thiourea.

The reaction is usually carried out in a solvent such as alcohol (e.g. methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, 2-methoxyethanol), dimethylsulfoxide or sulfolane. The reaction temperature is 20-180 ° C, preferably 60-150 ° C. 1-2 mol of thiourea are used per mole of compound (XIX). Hydrogen halide is formed as a by-product in the reaction and is carried out in the presence of, for example, sodium acetate or potassium acetate. Generally, 1 to 15 scribes are used per mole of the compound of formula (XIX) from sodium or potassium acetate. The reaction gives compounds of formula IV-1 which may be isolated if desired, but may be directly hydrolysed without isolation.

Compounds of formula (XVII) wherein R ¹ is hydroxylated phenyl can be synthesized by condensation of compound (VIII) wherein R ¹ is substituted by benzyloxy with compound (XV) and the resulting compound (XVI). The compound of formula (II) is catalytically reduced to simultaneously reduce the nitro group and debenzylate.

Compounds of formula (XVII) may also be synthesized according to Scheme (e) (wherein the substituents have the meanings given above):

The compound of formula (XXI) is prepared by condensing the compound of formula (II-2) with the compound of formula (XX). This reaction is usually carried out in a solvent such as dimethylformamide, tetrahydrofuran, acetone or methyl ethyl ketone in the presence of a base such as sodium carbonate or potassium carbonate. The resulting compound of formula XXI is hydrolyzed to give compound of formula XVII. The hydrolysis reaction is carried out with a mineral acid (e.g. hydrochloric acid, hydrobromic acid or sulfuric acid) or more preferably an alkali metal hydroxide (e.g. sodium hydroxide or potassium hydroxide) in a solvent such as methanol, ethanol, propanol or 2-propane. in propanol under reflux.

2b) Preparation of compounds of formula IV-2, i.e. compounds of formula IV wherein m is 1:

The reaction is illustrated in Scheme (f) (where the substituents have the meanings given above),

The condensation reaction of the compounds of formula (Π-3) with the compound of formula (XX) is carried out in a similar manner to the condensation reaction of the compounds of formula (II-2) and the formula (XX). The compound of formula (XXII) thus obtained is reduced in known manner with sodium borohydride in methanol or ethanol, and the compound of formula (XXIII) thus obtained is hydrolyzed as described in the conversion of compound of formula (XXI) to give compound of formula (XXIV). we get a compound. Similarly to the preparation of compounds of formula (IV-1) from compounds of formula (XVII), compounds of formula (IV-2) are prepared from compounds of formula (XXIV) via compounds of formula (XIX-1).

Starting compounds of formula II wherein m is 0 are, for example, J. Am. Chem. Soc., 56, 470 (1934) or 219.169. Japanese Patent Application Laid-open No. 6,198,198, according to the invention, or analogous thereto.

Compounds of formula (H-4), i.e. compounds of formula (II) wherein m is 1, may be prepared as follows:

3. The reaction is illustrated in Scheme g) (wherein the substituents have the meanings given above):

The reaction is carried out by halogenating the compounds of formula (XXV). Preparation of these compounds ^1, for example in Chem. Bér.84,96 (1951), Nihon Kapaku Zasshi, 86, 942 (1965), Bull. Soc. Chim. Fraice, 9, 3962 (1968), J. Chem. Soc., C. 1397 (1968), or in German Patent Publication No. 2.152557, or analogous thereto. The halogenation is carried out, for example, with halogen, preferably bromine, in a suitable solvent (e.g. chloroform or carbon tetrachloride) at a temperature of 30-60 ° C.

The starting compound (VIII) used in the preparation of compounds of formula (IV-1) may be prepared by the following processes:

a) compounds of the formula VIII-1, ie

194.199 for the preparation of compounds of formula VIII wherein n is 2:

The reaction is illustrated in Scheme (h) (wherein R ^s is lower alkyl).

The reaction of the compounds of formula (XXVI) and (XXVII) is carried out in a solvent such as an alkanol (e.g. methanol, ethanol or propanol) or without a solvent by heating at 40-150 ° C.

The resulting compound of formula (XXVIII) is reduced to compound of formula (VIII-1) by known methods, such as lithium aluminum hydride. Compounds of formula (XXVHI) wherein X is O are described in U.S. Patent No. 201,771. and Japanese Patent Laid-open Publication Nos. 219,169 and 219,199, or analogous methods thereof.

4.b) Compounds of formula VIII wherein n is 1 can be prepared, for example, by the method described in 219.169. Japanese Patent Application Laid-Open No. 6,198,198 or an analogous procedure.

The following Examples, Reference Examples and Experimental Examples illustrate the invention but do not limit it.

Example 1

To a solution of 5- (4-Hydroxy-xyl-benzyl) -2,44-azo-azide indione (9.4 g) in Ν, Νg-dimethylformamide (80 mL) was added 60% sodium hydride (3.4 g) and the reaction mixture. Stir for 30 minutes. To the reaction mixture was added a solution of 4- (chloromethyl) -2-phenyloxazole (9.6 g) in N, N-dimethylformamide (20 mL) at room temperature. The resulting reaction mixture was stirred at 70 ° C for 1 hour, then poured into taste and the aqueous reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (magnesium sulfate) and evaporated to give 5- [4- (2-phenyl-4-olazolylmethoxy) benzyl] -2,4-thiazolidinedione (9.1 g, 47.4%). The product was recrystallized from ethanol to give colorless needles, m.p. 188-189 ° C.

Analysis for C ₂ Ohi ₆ N ₂ 0 ₄ S: Calcd: C 63.15%, H 4.24%, N 7.36%, found C% 63.19, H% 4.16, N% 7.23.

2-9. example

Similarly to Example 1, the compounds listed in Table I were prepared.

The number of the example R ¹ R ² X OpfC) Recrystallization Yield solvent (%) Second phenyl H S 164-164 acetone-hexane 403 Third C ₃ H ₇ - H 0 114-115 ethanol 353 4th ch ₃ H s 181-182 methanol-dichloromethane 39.7 5th ch ₃ H 0 192-193 methanol-dichloromethane 283 6th phenyl ch ₃ 0 162-163 ethyl acetate-hexane 79.0 7th 3-pyridyl H s 205-206 methanol 12.6 8th 4-pyridyl H s 209-211 methanol 393 9th benzyl ch ₃ 0 258-260 methanol 289

Example 10

Add 60% oily sodium hydride (1.32 g) to a solution of 5- (4-hydroxybenzyl) -2,4-thiazolidinedione (3.35 g) in Ν, Ν-dimethylformamide (30 mL), then the reaction mixture was stirred for 30 turns. A solution of 4- (chloromethyl) -2- (1-methyldichlohexyl) oxazole (331 g) in Ν, Ν-dimethylformamide (5 mL) was added dropwise to the resulting reaction mixture at room temperature. The resulting reaction mixture was stirred at 60 ° C for 1 hour, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (magnesium sulfate) and evaporated. The oily residue was chromatographed on a silica gel column (70 g). Elution with hexane / ethyl acetate (2: 1, v / v) gave 5- 4- {2- (1-methyldichlohexyl) -4-oxazolylmethoxy] benzyl-2,4-thiazolidinedione. oil. To the resulting oil was added a solution of sodium 2-ethylhexanoate in isopropanol (2N, 3 mL) and the resulting reaction mixture was treated with ether. The precipitated crystals were collected by filtration to give 5-4- (2- (1-methylcylohexyl) -4-oxazolylmethoxy-1-benzylthiazolidine. Recrystallization from 45 _n k of methanol gave colorless plates, m.p. 285-287 ° C (dec).

Elemental analysis based on the formula C _{2 2} Η _{2 3} N ₂ O ₄ SNa:

H, 5.49; N, 6.63. Found: C, 59.76; H, 5.56; N, 632.

Example 11

Similarly as in Example 10, the sodium salt of 5- (4- (2-dichlohexyl-4-thiazolylmethoxy) benzyl) -2,4-thia55 zolidinedione was obtained in a yield of 20.4%. recrystallization gave colorless prisms, mp .: 298-300 ° C (decomposition) Elemental analysis for C 2 ₀ lI ₂₄ N ₂ O ₃ S5Na Calcd.:

Found: C, 56.42; H, 5.02; N, 6.72. Found: C, 56.59; H, 4-9; N, 6.60.

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Example 12

2-Imino-5- 4- {2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyl -4-thiazolidinone (183 g), 2N hydrochloric acid (200 mL) and ethanol ( 200 ml) was refluxed for 12 hours. The solvent was evaporated under reduced pressure. The residue was neutralized with saturated aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform layer was washed with water and dried (magnesium sulfate). The solvent was distilled off to give 5- {4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyl-2,4-thiazolidinedione (180 g, 95.7%). Recrystallization from ethanol gave birth plot needles, m.p .: 113R Analysis for CjiHíoN ₂ 0 ₄ S: Calcd: C% 64.69, H% 4.93, N% 636,% Found: C 64.48, H % 4.91, N% 6.75.

13-32. Example ¹⁰ Similarly to Example 12, Example II was prepared. Compounds listed in Table II.

Table H. Compounds of Formula I-4 ²

The example m n R ¹ R ² X Mp. (° C) Recrystallization Evade- number solvent pro- duction (%) 13 0 1 phenyl Η O 188-189 ethanol 55.6 14 0 2 ch ₃ H S 142-143 methanol 75> 15 0 2 ch ₃ Η O 184-185 methanol-dichloromethane 46.2 16 0 2 whetting H S 113-114 methanol 90.8 17 0 2 phenyl Η O 109-110 ethyl acetate-hexane 679 18 0 2 ch ₃ CH ₃ O 200-201 me tan ol-chloroform 91 ^ 19 0 2 C ₃ H ₇ Η O 8-88 ether-hexane 279 20 0 2 c ₂ h ₅ H S 148-149 ethanol-dichloromethane 84.3 21 0 2 -C ₃ H ₇ H S 107-108 ethyl acetate-hexane 72.6 22 1 2 phenyl CH ₃ O 165-166 acetonTiexán 513 23 0 2 phenyl C.H.O. 105-111 ethyl acetate-hexane 88.7 24 0 2 4-methoxy- phenyl CH ₃ O 167-168 ethanol 933 25 0 2 ch ₃ CJH _and O 185-190 ethanol-chloroform 90.1 26 0 2 2-furyl CH ₃ O 114-115 methanol 52.1 27 0 2 2-thienyl CH ₃ O 144-145 methanol-dichloromethane 60.0 28 1 1 ch ₃ CH ₃ O 214-215 ethanol-chloroform 33.6 29 0 2 3-methyl phenyl CH ₃ O 90-100 etilacetátdiexán 83.1 30 0 2 3,4-dimethoxyphenyl oxyphenyl CH 3 O 167-168 ethanol-dichloromethane 89.1 31 0 2 2-chloro-thenyl CH ₃ O 93-94 ether-hexane 67.6 32 0 2 4-hydroxy- phenyl CH ₃ O 213-214 methanol-chloroform 67.3

Example 33

2-Imino-5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) g] -benzyl] -4-thiazolidinone (11.4 g), 1 N sulfuric acid solution (100 mL) and dioxane (100 mL) were stirred at 80 ° C for 5 hours and then poured into water. The aqueous reaction mixture was extracted with chloroform. The chloroform layer was washed with water, dried (magnesium sulfate) and evaporated. The oily residue was chromatographed on silica gel 55 columns (200 g) and the fractions eluted with chloroform / methanol (100: 1, v / v) to give 5- [4- (5-methyl-2-phenyl-4-oxazole-1-ol). ylmethoxy) benzyl] -2,4-thiazolidinedione (6.7 g, 583% ethyl acetate T / / after recrystallization from hexane gave colorless plates, mp .: 162-163 ° C. tlemanalízis the CjiHi 60 N ₂ O ₈ S ₄ ratings: calcd: C% 6395, H% 4.60, N% 7.10% found: C 63 34% H 4.63% N 69O.

The IR and NMR spectra of the thermoflc were identical to those of the compound of Example 6.

Example 34

2-Imino-5- <4- (2- [5-methyl-2- (1-methylcyclohexyl) 4-oxazolyl] ethoxyl] benzyl} -4-thiazolidinone (93 g), 2N hydrochloric acid ( 100 ml) and ethanol (100 ml) are refluxed for 15 hours, the reaction mixture is poured into water and the aqueous mixture is extracted with ethyl acetate, the ethyl acetate phase is washed with water, dried (magnesium sulfate) and evaporated.

The oil was dissolved in methanol (10 mL) and 10 g of 28% sodium methoxide solution in methanol was added. To the resulting solution was added ether (100 mL) and the resulting crystals were collected by filtration and recrystallized from ethanol to give 5- (4- {2- [5-methyl-2- (1-methylethylcyclohexyl) -4-oxazoyl]]. -ethoxy-benzenesulfo-2,4-thiazolidinedione sodium salt (5.1 g, 515%) was obtained. The colorless prisms have a melting point of 250-251 ° C (dec.).

Elemental analysis based on the formula C ₂₃ H _{2 7} N ' ₂ O ₄ SNa:

calculated: C% 61.32, H% 6j04, N 6.22%, _5% Found: C 61.47, H 6.14%, N 6.48%.

35-37. example

Similar to Example 34, the compound of Example III was prepared. Compounds listed in Table II.

III. ' See Table II for compounds of Formula I-4 ³

The number of the example R ¹ R ² X Mp. (° C) (Dec) Recrystallization solvent Evade- pro- duction (%) 35 cyclohexyl H S 289-291 methanol 81.0 36 cyclohexyl H SHE 269-271 (1/2 Hydrate) ethanol 33.6 37 cyclohexyl ch ₃ 0 273-275 methanol 71/2

Example 38

1) 4-4- [2- (5-Methyl-2-phenyl-4-oxazolyl) -ethoxy] -benzyl-2,4-thiazolidinedione (6) is added in portions under reflux and reflux. , 0 g) and α, α'-azobisisobutyronitrile (05 g) in carbon tetrachloride (150 ml). The resulting reaction mixture was refluxed for 10 minutes, washed with water and dried (magnesium sulfate). The solvent was distilled off to give 5- 4- [2- (5-bromo-methyl-2-phenyl-4-oxazolyl) -ethoxy] -benzyl-2,4-thiazolidinedione as a crude oil (about 8 g).

IR (net) cm- ¹ : 1750.1690.

NMR δ (ppm) in _CDCl3: 3.03 (2HT J = 7Hz), 2.9-3.2 (IH, m), 3:48 (1H, dd, J = 14 and 5 Hz), 4.24 ( 2H, t,

J = 7Hz), 4.45 (1H, dd, J = 9 and 5Hz), 4.61 (2H, s), 681 (2H, d, J = 9Hz), 7.10 (2H, d, J2). 9Hz), 7.4 (3H, m), 45

8.0 (2H, m), 8.70 (1H, broad s).

2) The oily substance obtained in 1) (about 8 g) is dissolved in dioxane (100 ml) and 2N hydrochloric acid solution (100 g) is added. The reaction mixture was refluxed for 7 hours and then poured into water. The aqueous reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (magnesium sulfate) and evaporated, and the residue was chromatographed on a silica gel column (200 g). From the fractions eluted with ether / hexane (1: 1 v / v), 5- 4- [2- (5-hydroxymethyl-2-phenyl-oxazolyl) -ethoxy] -benzyl-2,4-thiazolidinedione (1.31 g) was obtained. , 21.0%). The product was recrystallized from acetone / hexane to give colorless plates, m.p. 98-99 ° C.

H, 4.75; N, 6.60. Found: C, 62.08; 11%, 456; N, 6.49 Found: C, 62.25; H, 4.75;

Example 39

5- [4- (4-Thiazolylmethoxy) benzyl] -2,4-thiazolidine dione was prepared as in Example 1. Yield 18.1%. Recrystallization from acetone / hexane gave colorless needles, m.p. 151-153 ° C.

Elemental Analysis for C 14 H 12 N ₂ O ₃ S ₂ Calculated: C 52.42, H 3.78, N 8.74, Found C 52.75, H 3.78, N 8.74.

40-45. example

Similar to Example 12, the compound of Example IV was prepared. Compounds listed in Table II.

194.199 'IV. Compounds of formula (I-4 *)

The number of the example m n R * ' R * Mp. (° c) Recrystallization solvent Evade- pro- duction (%) 40 0 2 dlohexil- metu ch ₃ 135-136 acetone 4 hexane 89.4 41 0 2 4-chlorophenyl ch ₃ 173-174 ethanol 92.1 42 0 2 3- (methyl-thio) - phenyl ch ₃ 161-162 ethanol 95/0 43 0 2 2 <trifluoro- methyl) phenyl ch ₃ 163-164 ethanol 88.0 44 1 1 cyclohexyl ch ₃ oily substance - 55.0 45 0 3 phenyl ch ₃ 130-131 ethylacetate -hexane 94 JO

Example 46

Similarly as in Example 34, 5- [4- [2- (5-methyl-2-methyl-3-dichlohexenyl) -4-oxazolyl] ethoxybenzyl] -2,4-thiazolidinedione was prepared. sodium. Yield 79.2%. The product was recrystallized from methanol / ethyl acetate to give colorless prisms, m.p. 245-246 ° C (dec).

Elemental analysis based on the formula C ₂₃ H ₂₅ N ₂ O ₄ SNa:

H, 5.62; N, 6.25. Found: C, 61.70; H, 539; N, 6/01.

Example 47

Acetic anhydride (1.0 mL) was added to 5- 4- (2- (2,5-dimethyl-4-oxazolyl) -2-hydroxyethoxylbenzyl-2,4-thiazolidinedione (03 g) in dimethylsulfoxia (10 mL) The reaction mixture was poured into water, extracted with ethyl acetate, the ethyl acetate layer was washed with water, dried (magnesium sulfate) and evaporated to give an oily residue. g) Chromatograph and recover the fractions eluted with benzene / acetone (9: 1, v / v) to give 5- 4- [2- (23-dimethyl-4-oxazolyl) -2-oxoethoxy] benzyl-2,4- recrystallization from ethyl acetate / hexane gave off-colorless plates, m.p. 161-162 ° C.

Analysis calculated for C ₇ LLI OIS _e N _2: Calcd: C 56.66%, H 4.47%, N 7.77%, found C% 56.62, H% 4.38, N% 7, 60th

Example 48

Similarly to Example 47, 5- 4- [2- (5-methyl-2-phenyl-4-oxazolyl) -2-oxoethoxy] benzyl was prepared.

-2,4-thiazolidinedione. Yield 81.3%. Recrystallization from ethyl acetate / hexane gave prismatic stele, m.p. 168-169 ° C.

Example 49

4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] benzaldehyde (5.0 g), 2,4-Thiazolidinedione (3.8 g), Piperidine (O, 32 ml) and ethanol (100 ml) was stirred for 5 hours under reflux. After cooling, the precipitated crystals are separated by filtration to give 5-4- (2- (5-methyl-2-phenyl-4-xazolyl) -ethoxy) -benzene-diene-2,4-thiazolidinedione (5, Recrystallization from chloroform / ethanol gave colorless needles, m.p. 213-214 ° C.

Analysis calculated for C ₂₂ H ₁₈ N ₂ O ₄ S: C, 65.01; H, 4.46; N, 639. Found: C, 6431; H, 435; N, 6.78.

50-63. example

The compounds listed in Table V were prepared as described in Example 49.

194 199

5 Compounds of formula ( ¹ )

Table V

The number of the example R * R ² X m Y ' n Op.fC) Recrystallization Solvent 1 pro- duction (%) 50 CH? H S 0 2 215-216 ethanol-chloroform 81.6 51 phenyl H S 0 - 1 235-237 methanol-chloroform 899 52 phenyl H S 0 - 1 210-211 methanol-chloroform 90.6 53 phenyl H 0 0 - 1 244-246 DMF-water 80 3 54 phenyl C ₂ H _S. 0 0 2 175-176 ethanol-chloroform 719 55 2-chlorophenyl CH? 0 0 - 2 217-218 ethanol chloroform 82.7 56 4-chlorophenyl CH? 0 0 __ 2 2.14-215 ethanol-dichloromethane 913 57 3- (methylthio phenyl CH? 0 0 - 2 85-187 ethanol chloroform 67.0 58 3,4-dimethoxyphenyl CH? 0 0 - 2 243-244 DMF-water 83.1 59 2-thienyl CH? 0 0 - 2 221-222 ethanol-chloroform 483 60 CH? CH? 0 1 CO- 1 234-235 ethanol-chloroform 62.7 61 phenyl CH? 0 1 OH -CH- 1 252-2533 methanol-chloroform 58.6 62 1-methylcyclohexyl CH? 0 0 - 2 172-175 ethanol-chloroform 53.1 63 4-methylcyclohexyl CH? 0 0 2 158-159 ethanol-chloroform 56.0

Example 64

60% Oily Sodium Hydride (0.24 g) was added to a solution of 4- (4-hydroxybenzylidene) -2,4-thiazolidinedione (0.664 g) in Ν, Ν-dimethylformamide (20 mL) and the reaction mixture was stirred for 30 minutes. A solution of 4- (chloromethyl) -5-methyl-2-phenyloxazole (0.623 g) in Ν, Ν-dimethylformamide (10 mL) was added dropwise to the resulting reaction mixture under ice-cooling.

The resulting reaction mixture was stirred at room temperature for 5 hours and then poured into water. The aqueous reaction mixture was acidified with acetic acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (magnesium sulfate) and evaporated. The residue was chromatographed on a silica gel column (50 g). Fractions eluted with ethyl acetate / hexane (13, v / v) afforded 5- [4- (5-methyl-2-phenyl-4-

-oxazolylmethoxy-benzylidene] -2,4-thiazolidinedione (0.49 g, 4/8%) · The product was recrystallized from chloroform / methanol to give colorless prisms, mp 225-226 ° C.

Analysis for C ₂ N ₂ O4S phi _BC Calc'd: en Calculated: C% 64.27, H% 4.11, N% 7.14, found C% 64.49, H% 3.96, N% 636th

Example 65

60% Oily sodium hydride (0.24 g) was added to 5- (4-hydroxybenzylidene) -2,4-thiazolidinedione (0.663 g) in Ν, Ν-dimethylformamide (20 mL). and the reaction mixture was stirred for 30 minutes. A solution of 4- (bromoacetyl) -5-methyl-2-phenyloxazole (0341 g) in Ν, Ν-dimethylformamide (10 mL) was added dropwise to the resulting reaction mixture under ice-cooling. 60

The reaction mixture was stirred for 30 minutes under ice-cooling and then poured into ice water. The aqueous phase is acidified with acetic acid. The precipitated solid was collected by filtration, washed with water and crystallized from acetone to give 5-4- [2- (5-methyl-2-phenyl-4-oxazolyl) -2-oxoethoxy] -benzylidene-2,4-thiazoldinedione (0.42). g, 32.3%). The product was recrystallized from chloroform / methanol to give colorless needles, m.p. 244-245 ° C.

Analysis calculated for C ₂₂ H ₆ N ₂ O ₅ S: C, 62.85; H, 334; N, 6.66; found: C, 6230; H, 3.69; N, 6 $ 3. .

Example 66

Sodium borohydride (0.16 g) was added under ice-cooling to 5- 4- [2- (2,5-dimethyl-4-oxazolyl) -2-oxoethoxy] benzylidene-2,4-thiazolidinedione (1.5 g). methanol in a 1: 1, v / v, 40 v / v mixture of methanol / N, N-dimethylformamide. After stirring for 20 minutes under ice-cooling, the reaction mixture was poured into ice-water and the aqueous phase was acidified with acetic acid. The precipitated crystals were collected by filtration to give 5- 4- (2- (2,3-dimethyl-4-oxazolyl) -2-hydroxy-ethoxy) -benzylidene-2,4-thiazole-dione (1.47 g, 97.5%). / after recrystallization from methanol gave colorless prisms, mp .: 223-224 ° C. calculated for C ₇ Hi Elernanalízis ₆ N ₂ amount 0jS salt. Found: C 56.66%, H 4.47%, N 7.77% Found: C, 5636; H, 4.55; N, 7.56.

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Example 67

Similarly to Example 66, 5- 4- {24-hydroxy-2- (5-methyl-2-phenyl-4-oxazolyl) -ethoxyl-benzylidene-2,4-thiazolidinedione (the same as in Example 61) was prepared. 4- [2- (5-diethyl-2-phenyl-4-oxazolyl) -2-oxoethoxy] benzylidene-2,4-thiazolidinedine tin, m.p. 252-253 ° C.

Example 68

032 mL of 28% sodium methoxide in methanol was added dropwise to 5- 4- (2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzylidene-2,4-thiazolidinedione (0.50 g). The crystals were collected by filtration to give 5- 4- (2- (5-methyl-2-phenyl-4-oxazolyl-ethoxy) -benzylidene-2

The sodium salt of 4-thiazolidinedione (0.43 g, 81.6%) was obtained. The product was recrystallized from methanol to give colorless prisms, m.p. 286-288 ° C.

Elemental analysis based on C ^ HnNj-CLSNa:

H, 4.00; N, 6.54. Found: C, 61.44; H, 3.82; N, 6.85.

Example 69

5- 4- [2- (5-Methyl-2-phenyl-4-oxazolyl) -ethoxy] -benzylidene-2,4-thiazolidinedione (500 mg), 10% Pd / C (50% Moisture, 1f) g) and acetic acid (50 mL) were hydrogenated at 70 ^V under atmospheric pressure for 3 hours. To the reaction mixture was added methanol (20 mL) and chloroform (20 mL) and heated at 60 ° C for 5 min. The resulting reaction mixture was filtered hot and the filtrate was concentrated in vacuo. The residual solution in ethyl acetate was washed with saturated aqueous sodium bicarbonate solution and water and dried over magnesium sulfate. The solvent was removed and the residue was recrystallized from ethanol to give 5- 4- {2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyl-2,4-thiazolidinedione (a).

The title compound was obtained as crystalline material (415 mg, 82.7%), m.p. 113-114.

Example 70

4- [2- (5-methyl-2-phenyl-4-oxazolyl) -2-oxoethoxy] benzylidene-2,4-thiazolidinedione (1.0 g), Pd-carbon black (3 g) and dioxane (100 mL) ) was hydrogenated at 40 C ^b and atmospheric pressure. After 4 hours, additional Pd carbon black (3 g) was added and hydrogenation continued for 4 hours. The catalyst was filtered off and the filtrate was evaporated to give 5-4- (2- (5-methyl-2-phenyl-4-oxazolyl) -2-oxoethoxy] benzyl-2,4-thiazolidinedione (identical to Example 48). compound) as a crystalline solid (0.95 g, 94.1%). ethyl acetate / hexane, after recrystallization from a mixture of szfritelen needles, m.p. 168-169 ^U C .;

Reference Example 1

A mixture of butyramide (19/88 g) and 13-dichloroacetone (24.14 g) was heated at 130 ^U for 15 hours. After cooling, the reaction mixture was diluted with water, neutralized with aqueous sodium bicarbonate solution and extracted with ethyl ether. The extract was washed with water, dried (magnesium sulfate) and evaporated. The residue was chromatographed on a silica gel column with acetone / hexane (13) to give 4- (chloromethyl) -2-propyloxazole as an oil (10.70 g, 35.3%). NMR (CDCl ₃ ) δ: 097 (3H, t, J = 75 Hz), 1.79 (2H, sext, J = 75 Hz), 2.72 (2H, t, J = 7, S Hz), 4 , 47 (2H, s), 753 (1H, s).

Reference Example 2

A mixture of benzamide (60.0 g) and ethyl 4-chloroacetoacetate (493 g) was heated at 120 ° C for 2 hours. After cooling, aqueous sodium bicarbonate solution was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with water, dried (magnesium sulfate) and evaporated. The residue was purified by silica gel column chromatography with ethyl ether / hexane (19) to give ethyl 2-phenyl-4-oxazole acetate as an oil (26.4 g, 28.0%). NMR (CDCl 3) δ: 137 (3H, t, J = 7Hz), 3.68 (3H, s),

4.15 (2H, q J = 7Hz), 7.4 (3H, m), 7.67 (1H, s), 8.0 (2H, m).

Reference Example 3

A mixture of cyclohexane thiocarboxamide (5.0 g), ethyl 4-chloroacetoacetate (5.74 g) and ethanol (50 mL) was heated under reflux for 1 hour. After dilution with water, the reaction mixture was extracted with ethyl acetate. The extract was washed with water, dried (magnesium sulfate) and evaporated. The residue was purified by silica gel column chromatography with ethyl acetate / hexane (14) to give ethyl 2-cyclohexyl-4-thiazole acetate as an oil (63 g, 709%).

IR (net): 1735, 125 cm -1.

NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7Hz), 1 3-23 (10H, m), 297 (1H, m), 377 (2H, s), 4.17 (2H) , q, J = 7Hz), 7.C (1H, s).

Reference Example 4

A solution of methyl 2-phenyl-4-oxazole acetate (54 g) in dry ethyl ether (150 mL) was added dropwise with lithium aluminum hydride (83 g) in dry ethyl ether (700 mL) with stirring and ice-cooling for 15 hours. prepared suspension. To the resulting reaction mixture was added dropwise ethyl acetate (20 mL) under ice-cooling, and water (50 mL) was added continuously. The resulting white precipitate was filtered off and the filtrate was evaporated to give 6- (5-methyl-2-phenyl-4-oxazolyl) ethanol as a crystalline material (453 g, 963%). Recrystallization from ethyl acetate / hexane gave colorless bars, m.p. 73-74 ° C.

Reference Example 5

2- (25-Dimethyl-4-oxazolyl) ethanol (17.0 g) and 4-fluoronitrobenzene (17.0 g) were dissolved in N, N -dimethylformamide (150 mL) and the resulting solution was added dropwise with vigorous stirring. % sodium hydride in oil (6.0 g). The reaction mixture was stirred for 1 hour at room temperature, poured into water (1 liter) and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate / hexane to give 4- (2- (2,5-dimethyl-4-oxazolyl) ethoxy] nitrobenzene (275 g, 87.0%)

-111

194.199. Colorless columnar crystals, m.p. 97-98 “C.

Analysis for C _t3 H ₁₄ N ₂ O _4: Calcd: C% 5994, H, 538%, 10.68% N, Found g; C, 59.72; H, 5.44; N, 10.63.

In a similar manner to that described in Example VI. Compounds listed in Table II.

VI. spreadsheet

Compounds of formula XVI ¹ R * R ^J X Op. <° c) Recrystallization solvent Evade- pro- duction (%) CH ₃ H S 101-102 methanol-ether 70.0 ch ₃ H SHE 101-102 methanol 71.3 Fenfen H s 102-103 methanol 503 phenyl H 0 112-113 methanol 923 1-methyl-dclohexyl ch ₃ 0 oily material - 92.0 phenyl ch ₃ 0 94-95 methanol 80.1 C ₃ H ₇ Η 0 70-71 ether-hexane 47.6 cyclohexyl . H s 62-63 methanol 73.2 dklohexfl H 0 61-62 methanol 70.6 c ₂ h ₅ H s 63-64 ethyl acetate-hexane 67.8 Iso-C3H7 c ₂ h ₅ 0 71-72 ethanol 91.6 4-methoxyphenyl ch ₃ SHE ' 113-114 ethyl acetate-hexane 82.1 ch ₃ c ₂ h ₅ 0 89-90 ether-hexane 77.6 cyclohexyl ch ₃ 0 oily material - 703 2-furyl _x ch ₃ 0 121-122 methanol-dichloro- methane 69.1 2-thienyl ch ₃ 0 107-108 methanol-water 74.7 3-methylphenyl ch ₃ 0 79-80 ethanol 85.4 3,4-dimethoxyphenyl ch ₃ 0 124-125 etanol4doroform 913 2-chlorophenyl ch ₃ 0 89-90 ether-hexane 58.0 4- (phenyl-methoxy phenyl ch ₃ 0 137-138 methanol-dichloro- -methane 743

Example 6 reTerenda

1) A solution of 4- (2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] n-trobenzene (105 g) in methanol (100 mL) was 10% Pd / C (5% moisture, 3.0). g) is catalytically hydrogenated over the catalyst, and after filtration of the catalyst, the filtrate is evaporated to give the amino compound as an oily substance, dissolved in a mixture of acetone (100 mL) and methanol (100 mL) and Hydrogen bromide solution (22 g) A solution of sodium nitrite (2.4 g) in water (8 ml) was added dropwise at a temperature of up to 5 ° C. The solution was stirred for 15 minutes at 5 ° C and methyl acrylate (5 g) was added. 163 g) and the reaction mixture is heated to 38 [deg.] C. Powdered copper (I) oxide is added in small portions with vigorous stirring and stirring is continued until the evolution of nitrogen gas is complete and the reaction mixture is evaporated. ammonium hydroxide solution and the aqueous reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (magnesium sulfate) and evaporated to give methyl 2-bromo-3- 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl. Propionate was obtained as a crude oil (12.6 g, 88.7%).

IR (nett) cm-1: 1735.

¹ NMR δ (ppm) in CDCl 3: 233 (3H, s), 293 (2H, t, (net) cm ^-1 : 1735).

J = 7Hz), 3.0-33 (2H, m), 3.65 (3H, s), 4O-4.4 (3H, ₅₅ m), 6.6-7 3 (4H, m), 7.4 (3H, m), 79 (2H, m).

2) Thiourea (2.1 g) and sodium acetate (23 g) are added to a solution of the oil obtained in Step 1 (12.4 g) in ethanol (100 ml) and the reaction mixture is stirred at reflux for 3 hours. . The reaction mixture thus obtained is neutralized with a saturated aqueous solution of sodium bicarbonate,

-121

A mixture of ether (50 mL) and hexane (50 mL) was added 194.199. The reaction mixture was stirred for 10 minutes and the precipitated crystals were collected by filtration to give 2imino-5- 4- [2- (S-methyl-2-phenyl4.oxazolyl) ethoxy] benzyl-κ 44 -azolidinone (6.1 g, 53 g). , 5%). Recrystallization from ethanol gave colorless prisms, m.p. 212-213 ° C.

Elemental analysis based on CjjHj iN ₃ O ₃ S:

H, 5.19; N, 10.31. Found: C, 64.85; H, 5.00; N, 10.25. 10

In a similar manner to that described in Preparation VII. The compounds listed in Table III. Yield is the total yield calculated for the starting nitro compound.

VII. Compounds of formula (VI ¹⁾ of the formula

R ¹ R ² X op- ec) Recrystallization solvent Evade- pro- duction (%) CH? Η S 185-136 methanol 28.4 CH? Η SHE 202-204 methanol-dichloro- 46.6 phenyl Η S 182-133 methane methanol 44.9 phenyl Η 0 211-213 methanol-dichloro- 42.3 ch ₃ ch ₃ 9 239-240 methane methanol-dichloro- 56.0 1-methyl-cyclo- ch ₃ SHE 180-131 methane ethanol 51.6 Hexyl C ₃ H ₇ Η SHE 175-176 methanol 38.3 cyclohexyl Η s 182-134 methanol 32.1 cyclohexyl Η 0 203-205 methanol-dichloro- 38.4 c ₂ h _s Η s 168-169 methane methanol 46.9 -C ₃ H ₇ Η s 172-173 methanol-dichloro- 42.5  phenyl c ₂ h _s 0 190-191 methane ethanol 23.7 4-methoxyphenyl ch ₃ 0 213-214 ethanol 53.5 ch ₃ c ₂ h ₅ 0 208-209 ethanol-chloroform 33.8 cyclohexyl ch ₃ 0 171-172 ethanol-water 38.8 2-furyl ch ₃ 0 222-224 methanol-dichloro- 41.0 3-methylphenyl ch ₃ 0 194-195 methane ethanol 45.0 3,4-dimethoxyphenyl ch ₃ 0 197-198 ethanol-chloroform 32.6

Reference Example 7

To a solution of 4-Acetyl-5-methyl-2-phenylxazole (12.0 g) in chloroform (100 ml) was added a solution of bromine (105 g) in chloroform (10 ml) at 50 ° C with stirring. The reaction mixture was heated at 55 ° C for 30 min and poured into saturated aqueous sodium bicarbonate (500 mL). The chloroform phase is separated and the aqueous phase is extracted with chloroform. The combined chloroform layers were washed with water and dried (magnesium sulfate). Evaporation of the solvent gave 4- (bromoacetyl) -54-methyl-2-phenyloxazole as a crystalline solid (14.5 g, 86.3%). Recrystallization from ethyl ether / hexane gave colorless bars, m.p. 88-89 ° C.

Referendum Example 8

1) 4- (Bromoacetyl) -5-methyl-2-phenyloxazole (33.8 g), p-hydroxyacetanilide, potassium carbonate (27.6 g) and methyl ethyl ketone (400 mL). ml) for 3 hours with stirring and

-131

194.199 Reflux. The solvent was distilled off and 300 ml of water and ether (300 ml) / hexane (100 ml) were added to the residue. The resulting reaction mixture is stirred for 10 minutes at room temperature and the crystals of 4- (4-acetamido-phenoxy-aoethyl) -5-methyl-2-phenyloxazole are recovered by filtration. Recrystallization from ethanol gave colorless prisms, m.p. 175-176 ° C.

Analysis for C ₂₀ H ₁₈ N ₂ O _4: Calcd: C% 6856, H% 5.18, N% 8.00; found: C% 6853, H% 5.15, N% 805th

2) 4- (4-Acetamido-phenoxyl-acetyl) -5-methyl-2-phenyloxazole (75 g) obtained in Step 1) is suspended in methanol (80 ml) and the suspension is cooled in portions with sodium borohydride. (810 mg) was added. The reaction mixture was stirred for 30 minutes. To the reaction mixture was added acetic acid (2 mL) and the solution was poured into water and the aqueous phase was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (magnesium sulfate) and evaporated to give 4- [2-hydroxy-2- (5-methyl-2-phenyl-4-oxazolyl) -ethoxy] -acetanilide (60 g). , 90.7%). Recrystallization from ethyl acetate gave colorless needles, m.p. 166-167 ° C.

Analysis calculated for C ₂ oH ₂ oN ₂ 0 ₄ S: Calcd: C% 68.17, H% 5.72, N% 705, found: C% 6806, H% 5.65, N% 8.11.

3) 4- [2-Hydroxy-2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -aoethanilide (115 g), 4N potassium hydroxide (100 mL) and ethanol (100 mL) the mixture is refluxed for 24 hours. The reaction mixture was poured into water and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 4- {2- (hydroxy-2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy) aniline (9.7 g, 96%). , 0%) as colorless prisms, m.p. 139-140 C.

Analysis calculated for C ₈ H ₁₈ N ₂ O _3: Calcd: C, 69.66%; H, 505%, N 9.03%, found C% 69.43, H% 5.76, N% 805th

4) 4- [2-Hydroxy-2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] aniline (185 g) was dissolved in a mixture of methanol (50 mL) and acetone (150 mL). To the solution was added 47% aqueous hydrobromic acid. A solution of sodium nitrite (45 g) in water (10 ml) was added dropwise at a temperature of up to 5 ° C. The mixture was stirred at 5 ° C for 15 min then was added methyl acrylate (30.4 g) and heated to 38 ° C _Z. Copper (I) oxide (2.0 g) was added to the reaction mixture in small portions with vigorous stirring and the reaction mixture was stirred until the evolution of nitrogen gas was complete. The reaction mixture was evaporated, the residue was made basic with ammonium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (magnesium sulfate), and evaporated to give methyl 2,4-rom-3-4- [2-hydroxy-2- (5-methyl-2-phenyl-4-oxazolyl). ) ethoxy] phenylpropionate as a crude oil (27.0 g, 985%) ·

IR (net) cm ^-1 : 3300.1735.

NMR δ (ppm) in CDCl3: 2.40 (3Hs), 30 (1H, broad), 3.11 (1H, djd, J = 14 and 7Hz), 3.39 (1H, d4, j = 14 and 7Hz), 3.68 (3H, s), 40-4-5 (3Hjn), 055 (1Hjd jd, J = 8 and 5Hz), 60-70 (4H jn), 7.4 ( 3H, m), 70 (2H, m).

5) The oil (27.0 g) obtained in (4) is dissolved in ethanol (270 ml) and thiourea (45 g) and sodium acetate (48 g) are added. The reaction mixture was refluxed for 4 hours and concentrated. The residue was neutralized with saturated aqueous sodium bicarbonate solution. To the reaction mixture was added water (300 mL) and stirred for 30 minutes at room temperature. Precipitated crystals were collected by filtration to give 24mino-5- 4- [2-hydroxy-2/5-methyl-2-phenyl-4-oxazolyl) -ethoxy] -benzyl] -4-thiazolidinone (135 g, 54.0%). The product was recrystallized from methanol / chloroform to give colorless crystals, m.p. 238-239 ° C. Analysis for C ₂ H _{2 2} j N ₃ O ₄ S: Calcd: C, 62.40%; H, 500%, N 9.92%, found: C% 6204, H% 4.77, N% 9, 79th

Reference Example 9

In the same manner as in Reference Example 8, the following compounds were prepared:

1) 4- (4-Acetamidoenenoxyacetyl) -2,5-dimethyloxazole 223-224 ° C, 550% yield.

2) 4- (2- (2 -dimetil4 5-oxazolyl) -2-hydroxy-ethoxy] -aretanilid.op ^U .: 157-158 C. Yield 930%.

3) 4- (2- (2,5-Dimethyl-4-oxazolyl) -24hydroxyethoxy-artilin, oily substance, IR (net) cm- ¹ : 3300 (broad), 99.1% yield).

4) 2-imino-5- 4- [2-hydroxy-25-dimethyl] 4-oxazolyl) -oxybenzyl 4-thiazolidinone, m.p. 238-239 ° C, 54.0% yield.

Reference Example 10

1) 4- (Chloroethyl) -5-methyl-2-phenyl] oxazole (120 g), p-hydroxyacetanilide (13.1 g), potassium carbonate (16.6 g) and dimethylformamide (150 ml) was stirred at 110 ° C for 3 hours and poured into water. The aqueous reaction mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with water, dried (magnesium sulfate) and evaporated to give 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) acetanilide (18%). , 0 g, 95.7%). Recrystallization from ethanol gives plates in winter color, m.p. 154-155 ° C.

Analysis calculated for C ₉ Hi ₈ N ₂ O _3: Calcd: C 70.79%, H 5.63%, N 8.69% Found: 70.67% C,% H 557, N 8582%) of A mixture of 4- (5-methyl-2-phenyl-4-oxazolylmethoxyacetanilide (175 g) in 4N potassium hydroxide solution (150 mL) and ethanol (150 mL) obtained in Step 1) was refluxed for 20 hours. The crystals were collected by filtration to give 4- (o-methyl-2-phenyl-4-oxazolylmethoxy) aniline (14.7 g, 96.7%). recrystallization gave colorless prisms, m.p. 129-130 ° C.

Analysis for C 7H1 ₈ N ₂ O _2: Calcd: C% 72.84, H% 5.75, N% 909, found: C% 72.79, H% 5.70, N% 907th

3) The 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) aniline obtained in Step 2) is reacted as described in Reference Example 8, Steps 4 and 5, to give 2-yno-5 [4- ( 5-Methyl-2-phenyl-4-oxazol-1-methoxy) -benzyl] -4-thiazolidinone (110 g, 570%) is obtained. Recrystallization from chloroform / methanes gave colorless plates, m.p. 257-258 ° C.

Analysis for C 1 ₃ KG ₉ N ₃ O ₃ S: Calcd: C% 64.11, H% 407% N 10.68, found C% 64.16, H% 400% N 1000th

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Reference Example 11

1) To a mixture of 4- 2- {2- (2-Chlorophenyl) -5-methyl-4-oxazolyl] ethoxyl-nitrobenzene (22 g), acetic acid (150 mL) and water (50 mL) At reduced temperature C (iron, 6 g) was added. The reaction mixture was stirred for 2 hours at 80 ° C, the insoluble material was filtered off and the filtrate was concentrated under reduced pressure. Water was added to the filtrate and the aqueous reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (magnesium sulfate) and evaporated to give 4- [2- (2- (2-chlorophenyl) -5-methyl-4-oxazolyl) ethoxyaniline as a crude oil (203 g). , 97.6%). NMR δ (ppm) in CDCl3: 2.35 (2H3), 293 (2H, t, J = 7Hz), 3.77 (2H3), 4.15 (2H, t, J = 7Hz), 636 (2H, d, J = 9Hz), 6.75 (2H, d, J = 9Hz), 72-73 (3H, m), 79H2).

2) The oily substance (203 g) obtained in step 1) was dissolved in a mixture of acetone (100 ml) and methanol (100 ml) and 47% aqueous hydrobromic acid (45 g) was added. A solution of sodium nitrite (43 g) in water (10 ml) was added dropwise to the resulting reaction mixture at a temperature of up to 5 ° C. The reaction mixture was stirred at 5 ° C for 15 minutes, methyl acrylate (33 g) was added and the mixture was heated to 38 ° C. The reaction mixture thus obtained is stirred with vigorous stirring, and copper (I) oxide (2 g) is added and stirring is continued until the evolution of nitrogen gas is complete. The reaction mixture was concentrated under reduced pressure and the residue was made basic with ammonium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (magnesium sulfate) and evaporated to give methyl 2-bromo-3- <4- 2- (2- (2-chlorophenyl) -5-methyl-4- oxazolyl] -ethoxy-phenyl> -propionate as a crude milky mother (243 g).

NMR δ (ppm) in CDCl3: 237 (3H, s), 2.97 (2H, t, J = 7Hz), 3.12 (1H44, J = 14 and 7Hz), 3β8 (1H, djd, J-14 and 7Hz), 4.1-4.4 (3H, m), 6.7-73 (7Hm), 79 (1H, m).

3) The oily material from step 2 (243 g) was dissolved in ethanol (250 mL) and thiourea (49 g) and sodium acetate (52 g) were added. The resulting reaction mixture was refluxed for 10 hours and then concentrated. Water was poured onto the residue and the precipitated crystals were collected by filtration. Recrystallization from ethanol / dichloromethane gave 5 <4- [2- (2- (2-chlorophenyl) -5-methyl-4-oxazoyl) -ethoxybenzyl] -2-imino-4-thiazolidinone (9.6 g). , 34, l%), m.p. 174-176 ^D C.

Analysis calculated for C ₂₂ H ₂₀ N ₃ O ₃ SCl: C, 59.79; H, 436; N, 931. Found: C, 59.69; H, 4.60; N, 934.

Referendum Example 12

All. Crystals of 24mino-5- <4- {2- [5-methyl-2- (thienyl) 4-oxazolyl] -ethoxy} -benzyl} -4-thi (zolidinone) were prepared in a similar manner to that described in Reference Example 1. Prepared from methanol / dichloromethane recrystallization gave colorless prisms, mp .: 171-172 ° C Elemental analysis CjoH ₁₉ N ₃ 0 ₃ S ₂ Calcd.:

H, 4.63; N, 10.16. Found: C, 5736; H, 439; N, 10/04.

Reference Example 13

1) A solution of 4- ^ 2- [2- (4-Benaloxyphenyl) -5-methyl 4-oxazolyl 1-ethoxy} nitrobenzene (10.65 g) in methanol (200 mL) Pd / C (50% moisture, 4.0 g) was catalytically hydrogenated. The catalyst was filtered off and the filtrate evaporated to give 4- 2- [2- (4-hydroxyphenyl) -5-methyl-4-oxazolyl] ethoxyaniline (621 g, 782%). Recrystallization from methanol gave brownish prisms, m.p. 184-185 ° C.

I Ilemanalízis C _g H _2, «N ₂ 0 ₃ basis: Calcd: C, 69.66%; H, 535; N, 9.03. Found:% 69.69; H, 537; N, 9.01.

2) The crystals obtained in step 1 (6.11 g) were dissolved in a mixture of acetone (40 ml) and methanol (20 ml) and 47% aqueous hydrobromic acid (7.7 ml) was added. The resulting reaction mixture was added dropwise to a solution of sodium nitrite (1.44 g) in water (3 mL) at a temperature of up to 5 ° C. The reaction mixture was stirred for 15 minutes at 5 ° C, methyl acrylate (12 mL) was added and the mixture was heated to 38 ° C. The resultant reaction mixture is mixed with vigorous stirring of powdered copper (I) oxide in small portions. Stirring was continued until nitrogen evolution had ceased and the reaction mixture was evaporated. The residue was made basic with ammonium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (magnesium sulfate) and evaporated to give methyl 4,4-rom-3- <4- 2- [2- (4-hydroxyphenyl) -5-methyl-4-oxazole]. -ethoxyl-phenyl> -propionate is obtained.

3) All crystals obtained in step 2) are dissolved in ethanol (100 mL) and thiourea (228 g) and sodium acetate (2.46 g) are added to the solution. The reaction mixture was heated to reflux for 2 hours with stirring. The reaction mixture was poured into water, the precipitated crystals were collected by filtration and washed with water, ether. After recrystallization from methanol / chloromethane, 2min o -5- [4- (2- (4-hydroxyphenyl) -5-methyl-4-oxazolyl] ethoxybenzyl) -4-thiazzoBdinone was obtained as colorless prisms. 35 g, 663%), m.p. 175-177 ° C.

Body analysis based on C ₂₂ H ₂ iN ₃ O ₄ S'1 / 2 H ₂ 0:

H, 5.13; N, 9.72. Found: C, 6192; H, 492; N, 936.

-151

Similarly as described in Reference Example 5, Vili is prepared. Compounds listed in Table II.

• Vni. Compounds of formula XVI ³ (x = O)

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Reference Example 14

n R ¹ R ³ Qp- CC) Recrystallization solvent pro- duction (%) 2 dclohe xylmethyl ch ₃ oily material - - 803 2 4-methylcyclohexyl ch ₃ oily - 803 2 4-chlorophenyl ch ₃ material 153-154 ethyl acetate 94.7 2 3- (methylthio) phenyl ch ₃ 104-105 methanol 873 2 3- (trifluoromethyl) phenyl ch ₃ 112-113 ethyl acetate-hexane 92.4 3 phenyl ch ₃ 111-112 ethyl acetate-hexane 90 JO

Reference Example 15

In a similar manner to that described in Reference Example 6, the compound of Example IX was prepared. Compounds listed in Table II.

IX. Table IV (IV ³ )

n R ¹ R ³ Op. (° C) Recrystallization solvent pro- duction (%) 2 dclohe xylmethyl ch ₃ 180-182 methanol 41.7 2 4-me til-dklohe xil ch ₃ 136-138 ethyl acetate 37.3 3 phenyl ch ₃ 179-180 ethanol 36.1

Example lő.referencia

In a similar manner to that described in Reference Example 8, the following compounds were prepared:

1) 4- (4-Acetamido-phenoxyacetyl) -2-dichlohexyl-5-methyl-oxazole m.p. 158-159 ° C, yield 48.1%, m.p.

2) 4- |? (2-dichlohexyl-5-methyl-4-oxazolyl) -2-hydroxyethoxy] -acetanilide, m.p. 125-126 ° C, yield 98.4%;

3) 4- (2- (2-Dichlohexyl-5-methyl-4-oxazolyl) -2-hydroxy-ethoxyleniline, oily substance, IR (net) cm * ¹ : 3350 (yield), 98.1% yield. .

4) 5- 4- {2- (2-Cyclohexyl-5-methyl-4-oxafolyl) -2H-hydroxy-ethoxy] -benzyl -2-imino-44-azolidinone, m.p. 167-168 ° C, 34.4%.

^ou Reference example 17

All. The following compounds were prepared analogously to Reference Example 1.1) 4- (2- [2- (4-Chlorophenyl-5-methyl-4-oxazolyl) -ethoxy] -c-aniline, m.p. 145-146 ° C. 59.9%

2) Methyl 2-bromo-3- [4- [2- (4-chlorophenyl) -5-methyl-4-oxazolyl] ethoxy] phenylpropylate, oily substance, IR (net) cm- ¹ : 1740, yield 92.7%,

3) 5 <4- (2- [2- (4-Chloro-phenyl) -5-methyl-4-oxazolyl] -ethoxy-benzenyl) -24mlno-4-thiazole-dione, m.p.

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Reference Example 18

1) A solution of 4- (2- (5-Methyl-2 <3-methylthiophenyl) 4-oxazolyl] -ethoxy-nitrobenzene (83 g) in methanol (100 mL) at 10% Pd / C (50% moisture) The catalyst was filtered off to give 4- 2- (5-methyl-2- (3-methylthiophenyl) 4-oxazolyl) ethoxyaniline (5.9 g, 723%). . Ethyl acetate / hexane after recrystallization from a mixture of colorless prisms, mp .: 110-111 ° C Elemental analysis for C ₉ H ₂ oN ₂ 0 ₂ S amount based salt. Found: C% 67.03, H% 5 p2, N, 8.23. Found: C, 67.20; H, 5.94; N, 8.12.

2) The crystals obtained in Step 1) are reacted according to Steps 1 and 3 of Reference Example 13 to give 2-imino-5- <4-2- [5-methyl-2- (3-methylthio) phenyl) 4-oxazolyl-ethoxy-benzyl <4-thiazolidinone. Recrystallization from ethyl acetate / methanol gave colorless prisms, m.p. 182-183 ^U C.

Calcd for C ₃ H ₃ N _{3 3 3 3} 0 ₃ S: Calcd: C 60pl%, H 5.11%, N 9.26% Found: C 60.42%, H 4.76%, N % 9.06.

Reference Example 19

In a similar manner to that described in Reference Example 18, the following compounds were prepared:

1) 4- (2- (5-methyl-2- (3-trifluoroethylphenyl) 4-oxazolyl) -ethoxy] aniline m.p. 121-122 ° C, 97.5% yield;

2) 2-min 4- (4- {2- [5-methyl-2-trifluoromethylphenyl) -4-oxazolyl] ethoxy} -4-thiazolidinedione, m.p. ·%

REFERENCE EXAMPLE 20 (Z) -5- (4- (2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] benzylidene) -2,4-thiazolidinone (200 mg) in acetonitrile (750 mL) of the solution was quenched in a quartz tube under nitrogen with a high pressure mercury lamp (300 W) for 3 hours. recrystallization from dichloromethane / ethanol afforded (E) 5- 4- [2- (5-Methyl-2-phenyl-4-oxazolyl) -ethoxy] -benzylidene-2,4-thiazoloddione (40 mg, 20P%). needle crystals are obtained, m.p. 216-217 ^U C.

Analysis for C _2J Hi _S N ₂ O4S: Calcd: C% 65.01, H% 4.46, N% 639, Found: C 64.69%, H 4.26%, N 7.11%.

Subsequent elution with hexane / ethyl acetate (1: 1, v / v) gave (Z) -5- 4- [2- (5-n'-ethyl-2-phenyl-415-oxazolyl) -ethoxy] -benzylidene. -2,4-thiazolidinedione (138 rag, -69.0%) is obtained.

Referendum Example 21

2- (5-Methyl-2-phenyl-4-oxalolyl) ethanol (6.0 g) and 4-fluorobenzonitrile (5.4 g) were dissolved in tetrahydrofuran (70 mL) and added to the solution with ice-cooling and vigorous stirring. % sodium hydride in oil (1.4 g). The reaction mixture was stirred for 18 hours at room temperature and then poured into ice water (03 L). The aqueous phase is neutralized with acetic acid and the precipitated crystals are collected by filtration. This gives 4- (2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -benzonitrile (7.0 g, 773%). Recrystallization from ether / hexane gives colorless prisms, m.p. -120 ° C Elemental analysis calculated for C ₉ H ₆ N ₃ Oi: C, 74.98; H, 5.30; N, 9.20. Found: C, 74.90; H, 5.01. N, 9.28.

Similarly to the procedure described, the compounds listed in Table X are prepared.

Table X (X ¹⁾ a compound of formula

R ¹ R ² X Mp. (° C) Recrystallization solvent Yield: (%) ch ₃ H S 753-763 éteriexán 57.7 phenyl H S 90-91 ether-hexane 673 phenyl] C ₂ H _s SHE 1283-130 ether-hexane 65 3 2-chlorophenyl ch ₃ SHE 105-106 ether 59.6 4-chlorophenyl ch ₃ 0 134-135 ether-hexane 749 3 <methylthio) phenyl CH? SHE 110-1113 ether-hexane 83.1 3,4-dimethoxyphenyl CH? SHE 128-129 acetone-hexane 903 2-thienyl CH? SHE 89-91 ether-hexane 743 1-methylcyclohexyl CH ₃ SHE oily material - 59.7 l-methyl--cyclohexylbenzo CH? SHE oily material 42.6

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Referendum Example 22

4- (2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] benzonitrile (63 g). Raney nickel alloy (63 g) in 70% formic acid solution (100 mL) for 2 hours. The insoluble material is filtered off and the filtrate is evaporated under reduced pressure, water is added to the residue and the mixture is extracted with ethyl acetate, the ethyl acetate phase is washed with water, dried (magnesium sulfate) and evaporated. column chromatography eluting with chloroform / hexane (1: 1, v / v) afforded 4- [2- (5-methyl-2-phenyl-4-oxazolyl) -ethoxy] -benzaldehyde from ether / hexane. After recrystallization, needle crystals of sphenolite are obtained, m.p. 82-84 ° C.

Analysis calculated for C ₁₉ H ₁₇ NO ₃ : C, 74.25; H, 537; N, 436. Found: C, 74.47; H, 533; N, 434.

Similarly to the procedure described in Example XI. compounds shown in Table II.

XI, compounds of formula feed (V ¹⁾

R ¹ R X m n Mp. (° C) ......... _Ί Recrystallization Yield solvent (%) ch ₃ H s 0 2 69-70 ether-hexane 75.7 phenyl Η s 0 2 60-61 ether-hexane 71.4 phenyl C ₂ Hj 0 0 2 oily material - 85.2 2-chlorophenyl ch ₃ 0 0 2 74-75 ether-hexane 81.0 4-chlorophenyl ch ₃ 0 0th 2 113-114 ether-hexane 593 3 (methylthio) phenyl ch ₃ 0 0 2 81-82 ether-hexane 543 3,4 _n -diethoxyphenyl. ch ₃ 0 0 2 85-89 ether 703 2-thienyl CH? 0 0 2 oily material - 953 1-methyl--cyclohexylbenzo ch ₃ 0 0 2 75-76 ether-hexane 80.6 4-methyl-dclohexenyl ch ₃ 0 0 2 oily material - 683 phenyl ch ₃ 0 0 2 136-137 acetone 71.1

Referendum Example 23

4- (Chloromethyl) -5-methyl-2-phenyloxazole (3.12 g), 4-hydroxybenzaldehyde (1.83 g), potassium carbonate (2.28 g) and dimethylformamide (40 g). ml) was stirred at 110 ° C for 1 hour. The reaction mixture is poured into ice-cold water and the precipitated crystals are collected by filtration. There was thus obtained 4 - [(5-methyl-2-phenyl-4-oxazole) 41-methoxy] -benzaldehyde (4.40 g, 99.8%). Ether / hexane recrystallization from a mixture of _u perhaps colorless prisms, mp .: 112-113 ° C. Elemental Analysis: Calculated for C _{18 H 12} NO ₃ : C, 73.71; H, 5.15; N, 4J87. Found: C, 73.87; H, 5.26; N, 4.81.

In a similar manner to the procedure described, ΧΠ. Compounds listed in Table II.

XII. spreadsheet

R * R ' X m Op. CC) Solvent for recrystallization of gas Yield: (%) phenyl H S 0 88-89 ether-hexane 94.7 phenyl Η , 0 0 993-1003 acetone-hexane 88.7 phenyl ch ₃ 0 1 175-177 chloroform-ethanol 80.4 CH? CH 0 1 1303-132 * ethanol 94.3

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Referendum Example 24

4- (Bromoacetyl) -5-methyl-2-phenyloxazole (7.0 g), p-danophenol (3.0 g), potassium carbonate (69 g), and methyl ethyl ketone ( 100 ml) was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and a mixture of water (100 mL) and ether (100 mL) was added to the residue. The resulting reaction mixture was stirred and the precipitated crystals were collected by filtration. Recrystallization from chloroform / ethanol gave 4- [2- (5-methyl-2-phenyl-4-oxazolyl) -2-oxoethoxy] -benzonitrile (6.3 g, 78.8%) as brownish prisms, m.p. Mp 202-203 ° C.

Referendum Example 25

Sodium borohydride (0.654 g) was added to 4- [2- (5-methyl-2-phenyl-4-oxazolyl) -2-oxoethoxy] benzonitrile (53 g) in methanol (100 mL) and Ν, The reaction mixture was poured into water and the precipitated crystals were collected by filtration to give 4- [2-hydroxy-2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] ] benzonitrile (5.1 g, 92.7%). Recrystallization from acetone gave colorless needles, m.p. 176-177 ° C.

Experimental example

Determination of blood glucose and plasma lipid lowering effect in mice

Test compounds were administered in 0.001% and 0.005% CE-2 powdered food (CLEA, Japan Inc., Tokyo) for four days as a nutrient mixture to KKA ^Y mice (8-10 day old male mice, groups of 5 mice). The animals are given free access to food and water. Blood samples are taken from the nerve vein of the mice. Blood glucose is determined enzymatically by the glucose oxidase method, plasma triglyceride levels (TG) in a commercially available experimental device, the Geantech TG (latron). Measurement data are used in the equation below. The results are shown in ΧΠΙ. The table also shows a comparative result with a known compound of similar chemical structure.

(result for the control group (result for the treated group))

--- x 100 (control group result)

ΧΠΙ. spreadsheet

The number of the example Blood glucose lowering effect (%) TG-lowering effect (%) οροί 0,005 opioid 0P05 1 **** 48 **** 51 2 28 *** - * 31 6 23 *** **** 41 17 ** **** 44 7 - 25 ** - 30 ** 8 21 ** * 35 11 **** 55 **** 59 **** 67 66 **** 13 **** 42 - 52 *** 14 **** 37 - 42 *** 15 **** 39 **** 52 54 *** 63 *** 16 **** 41 **** 58 51 ** 68 *** 17 - **** 55 **** 56 18 **** 52 - **** 65 19 **** 55 - 37 *** 20 **** 56 45 21 **** 54 **** 58 **** 62 **** 81 22 **** 49 **** 55 **** 55 **** 79 23 **** 53 **** 55 **** 63 **** 72 24 **** 46 - 45 *** 25 **** 50 **** 50 **** 41 **** 69 26 **** 50 **** 51 **** 41 **** 72 27 **** 55 **** 51 **** 52 **** 62 33 21 *** **** 53 23 **** 54 36 **** 51 **** 52 **** 58 71 *** t 46 **** 50 **** 55 **** 65 **** 67 49 **** 41 **** 57 41 *** **** 57 51 - **** 54 **** 59 52 **** 31 - 30 ** 54 **** 52 - **** 58 56 - **** 55 - **** 57 59 * 33 - 29 58 <- 36 **** **** 56 54 *** **** 60 62 - 66 **** - **** 51 63 **** 26 **** 59 * 37 **** 61 Control Compound: 1) Ciglitazone 10 - -13

t test: * p0 "05, ** P0.02, *** PQ, 01, **** P 0.001

1) 5- {4 - [(Methyl-cyclohexyl) -methoxy] -benzyl] -2,4-thiatolidinedione

Like the XIII. As shown in Table II, the compounds of the invention have statistically excellent blood glucose and / or TG lowering activity, while the control compound does not show a significant effect at the amount used.

Tablet Preparation Example a) (1) 5- (1- (2 <5-methyl-2-phenyl)

4-oxazolyl) -Exoxy] zyl-2,4-thiazolidinedione 10g (2) lactose 50g (3) wheat starch 15g (4) carboxymethylcellulose calcium 44g (5) magnesium stearate 1 fi 1000 tablets 120g 19

-191

194 199

The total amount of components (1), (2) and (3) and 30 g of component (4) are kneaded with water and the mixture is dried in vacuo and granulated. The resulting granules are mixed with 14 g of component (4) and 1 g of component (5) and the resulting mixture is tabletted on a tabletting machine. 1000 tablets are thus obtained, each containing about 10 mg of active ingredient (1).

(b) (1) 5-4- (2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzylidene-2,4-thiazolidinedione 30 g (2) lactose 50 g (3) wheat starch 15 g (4) carboxymethylcellulose calcium 44 g (5) magnesium stearate 1 g

140 g for 1000 tablets

The total amount of components (1), (2) and (3) and component (4) (30 g) are kneaded with water and the mixture is dried in vacuo and granulated. The resulting granules are mixed with 14 g of component (4) and 1 g of component (5) and the mixture is compressed into tablets to form a tablet. This gives 1000 tablets, each containing 30 mg of the active ingredient (1).

Claims (5)

PATENT CLAIMS A process for the preparation of a compound of formula (I): wherein R * is hydrogen, thienyl, furyl, pyridyl, C 1 -C 5 alkyl, C 4 -C 7 cycloalkyl optionally substituted with C 1 -C 4 alkyl, or C 4 -C 7 cycloalkenyl, C 4 -C 7 cycloalkyl-C 1 -C 4 alkyl, phenyl- C 4 -C 4 alkyl or optionally mono-, C 1 -C 4 -alkyl, trifluoromethyl, hydroxy, C 1 -C 4 -alkylthio, or Phenyl, mono- or di-substituted with (1-4C) alkoxy, R ² is hydrogen or (C 1 -C 5) alkyl optionally substituted at the α-position by a hydroxy group, X is oxygen or sulfur, Z is a hydroxylated methylene or carbonyl group, m is 0 or 1, n is a number between 1 and 3, L and M are independently hydrogen or L and M are bonded together - and pharmaceutically acceptable salts thereof, characterized in that: (a) Compounds of formula (I-1), wherein R *, R ² , X, Z, m, L and M are as defined above, or a salt thereof, which is a narrow group of compounds of formula (I); reacting a compound of formula (III) wherein R ¹ , R ³ , X and m are as defined above, and Y represents a halogen atom, with a compound of formula (III) wherein L and M are as defined, or a salt thereof; Compounds of general formula (I), wherein R *, R ² , X, L and M are as defined, and n is 1, or a salt thereof according to general formula (I-2). compound of the formula: - wherein ^{R1, R2,} X, n, L and M have the abovementioned meaning - or a salt thereof is reduced with a complex metal hydride, or b) for the preparation of a narrower rock of the compounds of the formula I or of the salts thereof, a compound of the formula IV wherein Z is hydroxymethylene and R * is hydrogen having 1 to 5 carbon atoms. alkyl, R ¹ , X, m and n are as defined herein, and optionally form a compound of formula (I-4) wherein Z is a carbonyl group or a salt thereof, wherein Z is a hydroxymethylene group. 4) a compound or a salt thereof is oxidized to dimethyl sulfoxide and acetic anhydride / or desired site for producing compounds or salts thereof containing 1 to 5 carbon atoms in a given R ² with is substituted by hydroxy, R ² is C 1-5 alkyl and (1- 4) a compound of the general formula or a salt thereof with N-bromosuccinic acid br Mozzo and hdrolizáliuk mineral acid, or c) for the preparation of compounds of general formula I-1-5, wherein R ² , R ² , X, Z, m and n are as defined in the foregoing, or salts thereof, a compound of general formula V reacting a compound of formula (I) wherein R *, R ² , X, Z, m and N are as defined above with a compound of formula (VI) or a salt thereof, and optionally reacting a compound of formula (I-4) wherein R ¹ , R ² , X, Z, m and n are as defined above, to give a compound of formula (I-5) wherein R *, R ² , X, Z, m and n are as defined above with hydrogen Pd / C. in the presence of a catalyst, and if desired, form a salt of the product obtained by any of the processes. (Priority: 09.04.1985) 2. A process for the preparation of a compound of formula (I): wherein: R ¹ is hydrogen, thienyl, furyl, pyridyl, C 1-5 -alkyl, optionally substituted with 1-4 carbon atoms (C 4 -C 7) cycloalkyl or C 4-7 -cycloalkenyl, (C 4-7 -cycloalkyl) - (C 1-4 -alkyl), phenyl- C 1 -C 4 alkyl or phenyl optionally or monosubstituted with halogen, C 1 -C 4 alkyl, trifluoromethyl, hydroxy, C 1 -C 4 alkylthio or C 1 -C 4 alkoxy, R ² is hydrogen or (C 1 -C 5) alkyl optionally substituted at the α-position by a hydroxy group, X is oxygen or sulfur, Z is a hydroxylated methylene group, m is 0 or 1, n is a number between 1 and 3, L and M are hydrogen and pharmaceutically acceptable salts thereof i) Compounds of formula (I) which form a narrower rock of formula (I-1) wherein R ¹ , R ² , X, Z, L and M are as defined, m is 0, or a salt thereof (II). ) generally20 -201 194.199 nos, wherein R *, R ² and X are as defined and m is 0, Y is halogen, is reacted with a compound of formula (III) wherein L and M are as defined, or b) for the preparation of a compound of formula (I) or a salt thereof which is a narrower compound of formula (I), a compound of formula (IV) wherein Z is hydroxymethylene, R ² is hydrogen or C 1 -C 5 alkyl pipe port, ^R1, X, m and n are as defined above - is hydrolyzed and optionally substituted by hydroxy, R ² is the preparation of compounds or salts containing 1-5 carbon atoms to a resultant containing 1-5 carbon atoms R ² is The compound of formula (I-4) or a salt thereof is brominated with N-bromosuccanimide and then hydrolyzed in the presence of a mineral acid. (Priority: 3/10/1984) 3. A process for the preparation of a medicament for lowering blood sugar and fat levels, comprising the steps of: The compound of formula (I) according to claim 5, wherein R ¹ , R ² , X, Z, m, n, L, M are as defined in claim 1, is formulated with a pharmaceutical excipient. (Priority: 04/09/1985) 10 4. A process for producing a composition for lowering blood sugar and lipid levels of pharmaceutical compositions, characterized in that a, O obtained according to claim 2) a compound of the formula: - wherein R ^1, R ^2, X, Z, m, η, L, M as defined in Claim 2 - Converted into a pharmaceutical composition using auxiliaries customary in the manufacture of a medicament. (Priority: 3/10/1984)