SU1436876A3 - Method of producing derivatives of thiazolidindion - Google Patents

Abstract

Thiazolidinedione derivatives represented by general formula (I), (wherein R<1> represents H or an optionally substituted hydrocarbon or heterocyclic residue, R<2> represents H or an alkyl optionally substituted by hydroxy, X represents O or S, Z represents hydroxylated methylene or carbonyl, m represents 0 or 1, n represents an integer of 1 to 3, L and M each represents H or, when taken together, one bond) and salts thereof are novel and are effective in reducing blood sugar level and blood lipid level of mammals, thus being useful as agents for treating diabetes and hyperlipemia.

Description

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The invention relates to a method for producing new biologically active chemical compounds, namely, thiazolidinedione derivatives, which have the ability to lower blood glucose and lipids, which suggests the possibility of using these compounds in medicine as therapeutic agents for the treatment of diabetes, hyperlipemia and their complications.

The purpose of the invention is to obtain new

2

measures. A mixture of ethyl benzamide, α-α-coracetotic acid (49.4 g) is heated

2 hours at 120 ° C. After cooling, an aqueous solution of sodium bicarbonate is added to the mixture and extracted with ethyl acetate. The extract is rinsed with water, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel using a mixture of ethyl ether and hexane (1: 9) for extraction, and the ethyl ether was obtained in the form of an oil.

thiazolidinedione derivatives possessing 2-phenyl-4-oxazole acetic acid with an enhanced ability to reduce co-15 (26.4 g; 28%).

blood glucose and. . NMR spectrum (), o: 1.27 (3N, Example 1. A mixture (5-me triplet, I 7 Hz); 3,68 (3N, singyl-2-phenyl 4-oxazolyl) ethoxybenzo years old); 4.15 (2H, quartet, 1 7 Hz); zaldehyde (5 g), 2,4-thiazolidivdione 7.4 (3N, multiplet); 7.67 (1H, sing- (3.8 g), piperidine (0.32 ml) and eta - 20 years); 8 (2H, multiplet). nola (100 ml) is boiled under interme diation of Example 18. A mixture of cyclohexene for 5 hours. After cooling of centiocarboxamide (5 g), ethyl crystals formed are separated and the ether of 4-chloroacetoacetic acid is filtered off to obtain (5 - -. ( 5.74 g) and ethanol (50 ml) are boiled in methyl 2-phenyl-4-oxazolyl) ethoxy ben 25 1 h. After dilution with water, the mixture is ziliden 1-2), 4-thiazolidinedione (5.1 g; extracted with ethyl acetate Extract

 washed with an aqueous solution of sodium bicarbonate and water, dried (MgSO4) and concentrated. The residue is chromatographed on silica gel using a mixture of ethyl acetate and hexane (1: 4) to sublimate to give 2-cyclohexyl-4-thiazol-cyclic acid ethyl ester as an oil (6.3 g; 70.9%), or IR -spectrum (undiluted), see: 1735; 1255.

NMR spectrum (CDCl1): 1.28 (3N, triplet, I 7 Hz); 1.2-2.3 (UNN, multiplet); 2.97 (1H, multiplet); the procedures described in Examples 16-40 (2H, singlet); 4.17 (2H, quartet, 26. Hz); 7 (1H, singlet).

Example 16. Mixture of butylamide Example 19. To a stirred (19.88 g) and 1,3-dichloroacetone, heated and ice-cooled suspension lithium for 1.5 hours at 130 ° C. After aluminum hydride (8.8 g), the mixture is diluted with water in dry ethylene, the neutral ether is added with an aqueous solution of bicarbonate and the methyl ether solution is added dropwise over 1.5 hours and extracted with ethyl acetate. by ether. 5-methyl-2-phenyl-4-oxazole acetic acid. The extract is washed with water, dried lots (54 g) in dry ethyl ether. K (MgSO4) and concentrated. The residue of the cleaved reaction mixture was cooled on silica gel using

76.8%); Recrystallization from a mixture of chloroform - ethanol gives colorless needles with mp, 213-214 ° C,

Elemental analysis is performed.

Imported,%: C 65.01; H 4.46; N 6.69,

CijHijN.

Found,%: C 64.81; H 4.55; N 6.78.

Examples 2-15. Conducted according to the procedure of Example 1, to obtain the desired compounds listed in Table 1.

Baseline contents are obtained by

ethyl acetate (20 ml) was added dropwise with ice and then water (50 ml) was carefully added. The white precipitated precipitate was filtered off and the filtrate was concentrated to give 2- (5-methyl-2-phenyl-4-oxazolyl) ethanol in

triplet, I 7.5 Hz); 1.79 (2H, sex-like crystals (45.8 g; 96.2%). Pett, I 7.5 (Hz) I 2.72 (2H, triplet, recrylated by fatigue from ethyl acetate I 7.5 Hz) ; 4.47 (2H, singlet); 7.53

(1H, singlet).

to extrude a mixture of ethyl ether and hexane (1: 9) to obtain 4-chloromethyl-2-propyloxazohg (10.7 g; 35.3%) as an oil.

NMR spectrum (CDC1,),: 0.97 (3N,

tata and hexane get colorless rods with so pl. 73-74 S.

tata and hexane get colorless rods with so pl. 73-74 S.

Example 20. 2- (2,5-dimethyl-4-oxazolyl) ethanol (17 g) and 4-fluoronitrobenzene (7 g) are dissolved in N, N-dimethylformamide (150 ml) and to the resulting solution is added 60% sodium hydride in oil (6 g) dropwise with vigorous stirring. After stirring for 1 hour at room. Water is added to the residue, the mixture is extracted with ethyl acetate, the extract is washed with water, dried (MgSO4) and concentrated. The oily substance obtained is chromatographed on a column filled with silica gel, and from the fractions washed with a chloroform-hexane mixture (1: 1 v / v), the reaction mixture is obtained in 4 IQQ 2- (5-methyl-2-feshyl). -4-oxazolyl) is transferred into water (1 l), the benzadide dehyde crystals precipitated — in the form of a crystal, they are peeled off by filtration and transferred to a substance (5.2 g; 78.5%). from a mixture of ethyl acetate and crystallization from a mixture of ether and hexane, - th hexane to give 4 -2- (2,5-dysane; get colorless needles with so pl.

methyl 4-oxazolyl) ethoxy nitrobenzene 15 82-84 C

(27.5 g; 87%) as colorless columns with mp. 87-98 S.

Calculated,%: C 59.94; H 5.58; N 10.68.

C, 74.25; H 5.57;

Calculated N 4.56.

 C ,, HnN03. Found,%: C 74.47; H 5.53; N 4.34.

C, H, N, 0,

H 5.44;

N

 Found,%: C 59.72; 10.63.

In the same manner as above, the starting compounds obtained in Table 2 were obtained. ,

Example 21. Analogously to Example 20, the starting compounds shown in Table 3 are obtained.

Example 22. 2- (5-methyl-2-fe

nyl-4-oxazolyl) ethanol (6 g) and 4-; Fluorobenzonitrile (5.4 g) was dissolved in tetrahydrofuran (70 ml) and 60% sodium hydride in oil (1.4 g) was added to the resulting solution with vigorous stirring and ice-cooling. The reaction mixture is stirred for 18 hours at room temperature, then poured into ice-cold water (0.5 l). The aqueous mixture is neutralized with acetic acid, the resulting crystals are separated by filtration and 4- (5-methyl-2-phenyl-4-oxazolyl) ethoxy benznitrile (7 g; 77.5%) is obtained. Recrystall

In a manner similar to that, the initial contents are obtained.

Colorless prisms with a mp. 119-45 presented in table.6. 120 ° C.

Calculated,%: C, 74.98; H 5.3; N 9.2

Example 25. A mixture of ts1-5-metip-2-phenyloxase of cyanophenol (3 g), carbo (6.9 g) and methyl ethyl ketone is boiled for 2 hours. The reaction is then concentrated under reduced pressure to a residue (g) (100 ml) and ether (100 m is sewed and the samples are separated by filtration. The mixture from chloroform is obtained .- (5-methyl-2сazolyl) -2-oxoethoxy benzo

Noo

Found,%: C 74.9; H 5.01; N 9.28 In the same manner as above, the starting compounds obtained in Table 4 were obtained.

Example 23. A mixture of 4-p- (5-methyl-2-phenyl-4-oxazolyl) ethoxy benzynitrile (6.5 g), Reney nickel alloy (6.5 g) and 70% formic acid (100 ml) are boiled for 2 hours. The insoluble material is filtered off and the filtrate is concentrated under reduced pressure. Water is added to the residue, the mixture is extracted with ethyl acetate, the extract is washed with water, dried (MgSO4) and concentrated. The oily substance obtained is chromatographed on a column filled with silica gel, and from the fractions washed with a mixture of chloroform-hexane (1: 1 v / v), get (5-methyl-2-pshyl-4-oxazolyl) ethoxy benzadehyde -in the form of a crystalline substance (5.2 g; 78.5%). By recrystallization from a mixture of ether and hex, the colorless needles with m.p.

82-84 С

C, 74.25; H 5.57;

Calculated N 4.56.

 C ,, HnN03. Found,%: C 74.47; H 5.53; N 4.34.

In the same manner as above, the starting compounds shown in Table 5 are obtained.

Example 24. A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (3.12 g), 4-hydroxybenzaldehyde (1.83 g), potassium carbonate (2.28 g) and dimethylformamide (40 ml) is stirred 1 h at 110 C. Then the reaction mixture is poured into ice water, the resulting crystals are collected by filtration and 4- (5-methyl-2-phenyl-4-oxazolyl) methoxybenzaldehyde is obtained (4.4 g; D 99.8%) . By recrystallization from a mixture of ether and hexane, colorless prisms are obtained with a mp of 112-113 ° C.

Calculated,%: C 73.71; H 5.15; N 4.86.

CjgH.NOj.

Found,%: C 73.87; H 5.26; N 4.81.

In a manner similar to the above, the starting compounds were obtained.

presented in table.6.

0

g

Example 25. A mixture of 4-bromoacetate 1-5-metip-2-phenyloxazole (7 g), p-cyanophenol (3 g), potassium carbonate (6.9 g) and methyl ethyl ketone (100 ml) was boiled for 2 h. The reaction mixture was then concentrated under reduced pressure, and water (100 ml) and ether (100 ml) were added to the residue. The formed crystals are stirred and filtered off. Recrystallization from a mixture of chloroform and ethanol gives .- (5-methyl-2-phenyl-4-oxazazolyl) -2-oxoethoxy benzonitrile.

(6.3 rj 78.8%) in the form of brownish prisms with mp 202-203 s.

Example 26. To a suspension of 4-f2- (5-methyl-2-phenyl-4-oxazolyl) -2-oxo-ethoxyZbenzonitrile (5.5 g) in methanol (100 ml) and K, H-dimethylformamide (50, ml ) sodium borgvdrid (0.654 mg) was added, followed by stirring for 1 hour at room temperature. The reaction mixture is poured into water and the crystals formed are separated by filtration to give 4-G2-hydroxy-2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy-benzonitrile (5, g; 92.7%), Cross-5 man’s falsity.

used in this test did not show significant activity.

Thus, the proposed compounds have the effect of reducing blood glucose and lipids in mammals (e.g., dogs, rats, dogs, cats, monkeys, horses, humans) and show a low degree of toxicity from the point of view of acute and subacute toxicity. Thus, the thiazolidinedione derivatives are of interest for the treatment of hyperlipemia, diabetes and their residualization from acetone to obtain toothless needles with a mp of 176-177 C.

The test of derivatives, thiazolidinedione,

The effect of reducing the content of glu-20 to be introduced parenterally into such

and

plasma lipids (TT),

goats blood on mice.

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KICA mice. (males, age 8-10 weeks 3 in each group of 5 mice) give the test compounds in the dietary mixture in an amount of 0.001% or 0.005% in the powdered diet CE-2 (CLEA lapan 1 ° C, Tokyo) for 4 days. The animals have free access to diet and water. Blood samples are taken from the orbital venous plexuses of the young. Blood glucose is determined by the method of oxodases glucose, t plasma triglycerides (TG) are determined fermentatively. using the Cleantech TG-Skit (latron) sales test kit. Relevant measurements are used for the calculation in accordance with the following equation:

dosage forms such as injection solutions, suppositories and pellets, depending on the case. When used as a therapeutic agent for treating diabetes or hyperlipemia, the compound may be prescribed for an adult patient to be taken orally at a dosage of 0.1 - 10 mg / kg per day or parenteral 30 doses administered at 0.005-10 mg / kg day, and these dosages are preferably applied once a day, or two to four times a week.

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Claims (1)

Invention Formula The method of obtaining derivatives of thi ldindione of the general formula 51G (% (“2) p-o-Okzn t - y measurements for control groups measurements for processed groups - - - - - - - - - - - - --.-. -; j (measurements for control group) The obtained test results of the thiazolidshire derivatives for glucose withdrawal are shown in Table 7, where for comparison data are given for a known compound of a similar chemical structure. As can be seen from Table 7, the proposed compounds showed a statically significant activity in reducing blood glucose and / or reducing TT content, while the control compound in the dosage. falsifications in humans. What concerns the way used in this test did not show significant activity. Thus, the proposed compounds have the effect of reducing blood glucose and lipids in mammals (e.g., dogs, rats, dogs, cats, monkeys, horses, humans) and show a low degree of toxicity from the point of view of acute and subacute toxicity. Thus, thiazolidinedione derivatives are of interest for the treatment of hyperlipemia, diabetes and their consumption, they are usually administered orally in dosage forms such as tablets, capsules, powders, granules, etc., as well as they can dosage forms such as solutions for injection, suppositories and pellets, depending on the particular case. If used as a therapeutic agent for treating diabetes or hyperlipemia, the compound may be administered to an adult patient for oral administration in a dosage of 0.1 - 10 mg / kg per day or parenteral 30 administration in a dosage of 0.005-10 mg / kg per day, and it is desirable to apply these dosages once a day or two to four times a week. breaks. 35 0 Invention Formula The method of obtaining the thiazo ldindione derivatives of the general formula 51G (% (“2) p-o-Okzn t - schO  X × iT R about five 0 five where R, is lower alkyl, cyclohexyl, substituted lower alkyl, cyclohexenyl, substituted lower alkyl, phenyl or phenyl, substituted by a chlorine atom, methylthio or methoxy group, or thienyl; hydrogen or lower alkyl; oxygen or sulfur; hydroxymethylene or carbonyl; . m O or I; n, 1 or 2, characterized by the fact that the compound of the general formula R, X Z N-gt- (Z) - (CH,) - podjergayut interaction with the compound - II II "1 L / niem formula ". K2 ABOUT " four. where r, |, r, x, z, m and n have the indicated values. , -t (% (sn4-o-Os. OCH5 sn, o OOCN, o oh oh 12 CH, CH, oh 13 CH, oh. odey ABOUT " four. about f Table 1 Ethanol - 81.6 chloroform Methanol - 89.9 chloroform The same 90.6 DMF-80.5 water Ethanol - 71.9 chloroform 217-218 The Same 82.7 215 Ethanol - 91.2 dichloromethane 187 Ethanol - 67.0 chloroform 2 2 CO-1 OH I CH1 243-244 daFA-water "83.1 221-222 Ethanol - 48.2 chloroform 234-235 The Same 62.7 252-253.5 Methanol- 58.6 chloroform B1- | t-CH2CH20-4-b2 nl%. Shut off CH, table 2 113 - 114 Ethyl acetate- 82.1 hexane 89 - 90 Ether-hexane 77,6 eleven СНзО- Cl sn ; 4v / j CHjS sn. // iCFj sn. J / ABOUT, sn. 1436876 12 Continuation of table 2 forms 89 - 90 Ether-hexane 58,0 104 - 105 Methanol 87.5 112- 113 Ethyl acetate 92.4 111 - 112, 0 , 1436876 TableA Y, -J-CH2CH20- Q-CN 2 t (, : n n c, n ,. sn, sn. S oh oh SNr SN about sn, - about CH, O HE m (CH) - (GH2)) - CHO 75.5-76.5 Ether-hexane 90-91- - 128.5-130 Ether-hexane 105-106 Ether 134-135 ether-hexane 110-111, 128-129 Acetone-90.3 Hexane 89-91 Ether-hexane 74,8 Oil .39,7 4.6 Table 5 60-61 71.4 15 S.Nu Cl jrn, ci-4j 3 CHjS Q- CH, CHjO, 150 - (- CHj Oh oh ABOUT Oh oh U sn, SN, SN 1436876 sixteen Continuation of table.5 Butter Ether-gek- 85.2 San 74-75 - 113-114, 0 59.5 81-82 n 54.5 85-89 Ether . 70.3 Butter 95.5 130.5-132 Ethanol 94.3 17 143687618 Table 7 . " Test P 0.05; p p p 0.01; P 0,001 , "