Method of producing derivatives of thiozolidinedione or their sodium salts

专利摘要:
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.
公开号:SU1496634A3
申请号:SU853966456
申请日:1985-10-02
公开日:1989-07-23
发明作者:Мегуро Канадзи；Фудзита Такеси
申请人:Такеда Кемикал Индастриз, Лтд (Фирма)；
IPC主号:

专利说明:

31496634
phenyl i R - C; | -C5-alkyl, or when X denotes a sulfur atom, m O, n 2, then R is cyclohexyl, C-C alkyl, phenyl; RQ is hydrogen, or their sodium salts, which have the properties of lowering blood glucose and lipids and can be used as therapeutic agents for diabetes, tO
The aim of the invention is to develop a method for obtaining new biologically active thiazolidinedione derivatives of general formula (I).
Example 1. A mixture of 2-imino-15 -5-G4- 2- (5-methyl-2-phenyl-4-oxazolyl) ethoxyI benzyl-4-thiazolidinone (18.8 g), 2 n, HC1 (200 ml) and ethanol (200 ml) are boiled for 12 hours, after which the solvent is distilled off under reduced pressure. The residue was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The chloroform layer wasCalcined,%: C 63.95, H 4.6; N 7.1.
C2, H,
Found,%: C 63.84j H 4.63; N 6.9.
Example 23. A mixture of 2-imino-5 - (4 2- 5-methyl-2- (1-methylcyclohexyl) -4-oxazole 1 ethoxy-benzyl) -4- -thiazolidinone (9.5 g), 2 N.H.N. 100 ml) and ethanol (100 ml) are boiled for 1-5 hours. The reaction mixture is poured into water and the aqueous mixture is extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried with magnesium sulfate and concentrated. The oily residue was dissolved in methanol (10 ml) and 10 g of 28% sodium methoxide in methanol was added to the resulting solution. Ether (100 ml) is then added, the separated crystals are collected by filtration, and after recrystallization from ethanol, 5- (4-G2-5-methyl-2- (1-methylcyclohexane) is obtained with water and dried with magnesium sulfate. 25 hexyl) -4-oxazolyl ethoxy benzyl) -, the solvent is distilled off, and the -2,4-thiazolidinedione is obtained as the sodium (5-methyl-2-fennl-4-0 x Zolyl) salt (5.1 g, 51.5%). Colorless prisms with so-called 250-251 ° C (with decomposition - it).
30 Calculated,%: C, 61.32; H, 6.04; N 6.22.
ethoxy benzylCH-2,4-thiazolidine indione (18 g, 95.7%). By recrystallization from ethanol, colorless needles were obtained with a temperature of 113-114 C.
Calculated,%: C 64.69; H 4.93, N 6.86.
With „NgoN 804
Found,%: C 64.48; H 4.91; N 6,75. Examples 2-21. According to the procedure of Example 1, the compounds listed in Table 1 are prepared.
Example 22. A mixture of 2-amino-5-4- (5-methyl-2-phenyl-4-oxazole 1 - methoxy) benzyl-4-thiazolidinone (11.4 g), 1N. (100 ml) and. dioxane (100 ml) stirred for 5 h
35
C23H27N204SNa
Found,%: C 61.47, - H 6.15; N 6j48.
Examples 24-26. By the method similar to the method of example 23, receive compounds shown in table 2.
40
Examples 27-32. Analogously to Example 1, the compounds listed in Table 3 are prepared.
Example 33 Similarly, at 24, with a yield of 79.2%, obtained by sodium chloride, and then poured into water 45 the salt of the 5- (4- 2-5-methyl-2- (1-) salt and extracted with chloroform. Chloro-methyme layer -3-Sch1-clohexenyl) -4-oxazolyl roform is washed with water, dried with magnesium sulfate and concentrated, the Oily residue is chromatographed on a column filled with silica gel (200 g), and in fractions eluted with a mixture of chloroform-methanol (100: 1),
50
(5-methyl-2-phenyl-4-oxazole-1 methoxy) benzyl-2,4-thiazolidinedione (6.7 g, 58.8%) are obtained. Recrystallization from a mixture of ethyl acetate - hexane was obtained colorless plates with so pl. 162-163 ° C. Elemental analysis for
55
it is xyT benzyl) -2,4-thiazolidinedione. By recrystallization from methanol-ethyl acetate mixture, colorless prisms were obtained with mp. 245-24b with (with decomposition),
Calculated,%: C, 61.59; H 5.62; N 6.25.
Cj, Hj5N204SNa
Found,%: C 61.7; H 5.59-, N.6.01.
Preparation of starting imino-derivatives of general formula (11) and intermediates for them.
Calculated,%: C 63.95, H 4.6; N 7.1.
C2, H,
Found,%: C 63.84j H 4.63; N 6.9.
Example 23. A mixture of 2-imino-5 - (4 2- 5-methyl-2- (1-methylcyclohexyl) -4-oxazole 1 ethoxy-benzyl) -4- -thiazolidinone (9.5 g), 2 N.H.N. 100 ml) and ethanol (100 ml) are boiled for 1-5 hours. The reaction mixture is poured into water and the aqueous mixture is extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried with magnesium sulfate and concentrated. The oily residue was dissolved in methanol (10 ml) and 10 g of 28% sodium methoxide in methanol was added to the resulting solution. Ether (100 ml) is then added, the separated crystals are collected by filtration and, after recrystallization from ethanol, 5- (4-G2-5-methyl-2- (1-methylcyclohexyl) -4-oxazolyl ethoxy benzyl) -2-4,4 is obtained. thiazolidinedione in the form of sodium salt (5.1 g, 51.5%). Colorless prisms with so-called 250-251 ° С (with decomposition).
C23H27N204SNa
Found,%: C 61.47, - H 6.15; N 6j48.
Examples 24-26. By the method similar to the method of example 23, receive compounds shown in table 2.
The sodium salt of 5- (4- 2- 5-methyl-2- (1- -metsh1-3-shch1clohexenyl) -4-oxazolyl
it is xyT benzyl) -2,4-thiazolidinedione. By recrystallization from methanol-ethyl acetate mixture, colorless prisms were obtained with mp. 245-24b with (with decomposition),
Calculated,%: C, 61.59; H 5.62; N 6.25.
Cj, Hj5N204SNa
Found,%: C 61.7; H 5.59-, N.6.01.
Preparation of starting imino-derivatives of general formula (11) and intermediates for them.
51496634
Example 34 2- (2,5-Dimethyl-4-oxazolyl) ethanol (17 g) and 4-fluoronitrobenzene (17 g) are dissolved in H, H-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 temperature, the reaction mixture was transferred to water (1 l). The precipitated crystals are collected by filtration and recrystallized from a mixture of ethyl acetate-hexane to obtain (undiluted), 1735.
NMR (CDClp, ppm: 2.33 (EF, singlet); (2H triplet, I 7 Hz); 3-3.5 (2H, multiplet), 3.65 (ZN, singlet) {4-4.4 (3N, multiplet); 6, 6-7, 2 (4H, multiplet); 7, (3N, multiplet); 7.9 (2H, multiplet)
To a solution of the resulting oily product (12.4 g) in ethanol (100 ml) was added thiourea (2.1 g) and sodium acetate (2.3 g), and the mixture was boiled for 3 hours. Then the reaction mixture is concentrated (2,5-dimethyl-4-oxazolyl) ethoxy-nitrate and the residue is neutralized with saturatedbenzene (27.5 g, 87%) as colorless columns with mp. 97-98 S.
Calculated,%: C 59.94; H 5.58; N 10.68.
S, ZN14 “04
Found,%: C 59.72, H 5.44, N 10.63.
In a similar way, compounds shown in Table 4 are prepared.
Sodium bicarbonate was then added with ether (50 ml) and hexane (50 ml). After stirring for 10 and the separated 20 crystals, the crystals were separated by filtration and the result was 2-imino-5- {4- 2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy benzyl-4-thiazolidinone (6 , 1 g, 53.5%). Recrystallization from ethanol to semi
Example 35. A solution (5-. 25 of colorless prisms with so-called pieces of 212-methyl-2-phenyl-4-oxazolyl) ethoxy nitrobenzene (10.5 g) in methanol (100 ml) is subjected to catalytic hydrogenation with 10% Pd -C (50 wt.%, 3 g). After filtration, the catalyst is. The filtrate is concentrated to give the amino derivative as an oily substance, which is dissolved in a mixture of acetone (100 ml) and methanol (100 ml), after which a 47% aqueous solution of hydrogen bromide (22 g) is added. A solution of sodium nitrite (2.4 g) in water (8 ml) is added dropwise to the resulting solution at a temperature not higher than 3 ° C. After stirring the solution for 15 minutes at 5 ° C, methyl acrylate (16.3 g) was added and the reaction mixture was heated to 38 ° C. To the mixture obtained in small
213 ° C.
Calculated N 10.31.
s, n „. N30,5
%: C, 64.85; H, 5.19;
thirty
35
22 ai Found: C 64.85; H 5.0;
N 10.25.
The compounds presented in Table 5 were obtained in a similar way (the given yields are presented as common fluxes in terms of the initial nitro compounds). .about .
Example 36. To a stirred solution of 4-acetyl-5-methyl-2-phenyl oxazole (12 g) in chloroform, a solution of bromine (10.5 g) in chloroform (10 ml) is added at 50 ° C. The mixture is continued to be heated for 30 minutes at 55 s, after which it is poured into a saturated aqueous solution of sodium bicarbonate.
in portions with vigorous stirring - DZ (500 ml). The chloroform layer is separated,
The scientific research institutes add cuprous oxide (1 g), continue stirring until the gaseous nitrogen is stopped, after which the reaction mixture is concentrated. The residue is alkalinized by adding aqueous ammonia and the aqueous mixture is extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried with magnesium sulfate, and concentrated to give 2-bromo-3-G4- (5-methyl- | 2-phenyl-4-oxazolyl) ethoxyPhenylZiropionic acid methyl ester as a crude oily product (12.6 g , 88.7%).
the aqueous layer is extracted with chloroform. The combined chloroform layers are washed with water and dried over magnesium sulfate. After evaporation of the solvent
50 is obtained in the form of crystals of 4-bromo-acetyl-5-metsh1-2-phenyloxazole (14.5 g, 86.3%). Recrystallization from a mixture of ethyl ether - hexane to obtain colorless rods with so pl.
55 88-89 ° C.
Example 37. A mixture of 4-bromo-acetyl-5-methyl-2-phenyloxazole (33.8 g), p-hydroxy-detanilide, potassium carbonate (27.6 g), and methyl IR (undiluted), 1735.
NMR (CDClp, ppm: 2.33 (EF, singlet); (2H triplet, I 7 Hz); 3-3.5 (2H, multiplet), 3.65 (ZN, singlet) {4-4.4 (3N, multiplet); 6, 6-7, 2 (4H, multiplet); 7.4 (3N, multiplet); 7.9 (2H, multiplet).
To a solution of the resulting oily product (12.4 g) in ethanol (100 ml) was added thiourea (2.1 g) and sodium acetate (2.3 g), and the mixture was boiled for 3 hours. The reaction mixture was then concentrated and the residue was neutralized with a saturated aqueous solution of sodium bicarbonate, after which ether (50 ml) and hexane (50 ml) were added. After stirring for 10 and the separated 20 crystals, the crystals were separated by filtration and the result was 2-imino-5- {4- 2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy benzyl-4-thiazolidinone (6 , 1 g, 53.5%). Recrystallization from ethanol yields .25 colorless prisms with m. Pcs. 212213 ° C.
Calculated N 10.31.
s, n „. N30,5
%: C, 64.85; H, 5.19;
0
five
22 ai Found: C 64.85; H 5.0;
N 10.25.
The compounds presented in Table 5 were obtained in a similar way (the given yields are presented as common fluxes in terms of the initial nitro compounds). .about .
Example 36. To a stirred solution of 4-acetyl-5-methyl-2-phenyloxazole (12 g) in chloroform, a solution of bromine (10.5 g) in chloroform (10 ml) is added at 50 ° C. The mixture is continued to be heated for 30 minutes at 55 s, after which it is poured into a saturated aqueous solution of sodium bicarbonate.
the aqueous layer is extracted with chloroform. The combined chloroform layers are washed with water and dried over magnesium sulfate. After evaporation of the solvent
50 is obtained in the form of crystals of 4-bromo-acetyl-5-metsh1-2-phenyloxazole (14.5 g, 86.3%). Recrystallization from a mixture of ethyl ether - hexane to obtain colorless rods with so pl.
55 88-89 ° C.
Example 37. A mixture of 4-bromo-acetyl-5-methyl-2-phenyloxazole (33.8 g), p-hydroxy-detanilide, potassium carbonate (27.6 g) and methyl ethyl ketone (400 ml) is boiled under stirring for 3 hours. The solvent was then distilled off and 300 ml of water, 300 ml of ether and an AO TOO of hexane were added to the residue. The resulting mixture was stirred for 10 minutes at room temperature, after which the crystals (23.5 g, 58.3%) of 4- (4-acetamidophenoxyacetyl) -5-methyl-2-phenyloxazole were isolated by filtration. By recrystallization from ethanol, colorless prisms are obtained with m.p.
Calculated,%: C 68.56; H 5.18; N 8.
CaoHi8Ni04
Found,%: C 68.53; H 5.15; N 8.05.
The resulting 4- (4-acetamidophenoxy-acetyl) -5-methyl-2-phenyloxazole (7.5 g) is suspended in methanol (80 ml), after which sodium borohydride (810 mg) is added to the suspension during ice cooling. The mixture was stirred for 30 minutes. After adding acetic acid (2 ml), the solution was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried with magnesium sulfate, and concentrated to give 4- 2-hydroxy-2- - (5-methyl-2-phenyl-4-oxazolyl) ethoxy-acetanilide (6.8 g, 90.7%). Recrystallization from ethyl acetate gives colorless needles with mp. 166-167 C.
Calculated,%: C 68.17, H 5.72; N7.95.
CjoH oNiOv
Found,%; C 68.26J H 5.65 N 8.11.
A mixture of 4- 2-hydroxy-2- (5-methyl--2-phenyl-4-oxazole 1) ethoxy acetanilide (11.5 g), 4 N. COLE (100 ml) and ethanol (100 ml) is boiled for 24 h The reaction mixture is then poured into water, the crystals formed are collected by filtration, and after recrystallization from ethanol, 4-2-hydroxy-2- (5-methyl-2-phenyl-4-oxazolyl) is obtained (9.7 g, 96%) in the form of colorless prisms, so pl. 139-140 0.
Calculated,%: C 69.66i H 5.85, N 9.03.
C, gH, gNj03
Nsh-scheno,%: C 69.43, H 5.76; N 8.95.
4- 2-HYDROXY-2- (5-methyl-2-phenesh1-4-oxazolyl) ethoxy (aniline
(18.5 g) was dissolved in methanol (50 ml) and acetone (150 ml) and 47% was added to the resulting solution.
aqueous hydrobromic acid (41 g). Then, at a temperature not exceeding 5 ° C, a solution of sodium nitrite (4.5 g) in water (10 ml) is added dropwise to the resulting mixture. Mixture
the mixture is stirred for 15 minutes at which time methyl acrylate (30.4 g) is added and heated to. With vigorous stirring, cuprous oxide (2 g) was added to the reaction mixture in small portions and stirring continued until the evolution of nitrogen was stopped. After concentration, the residue is added by addition of aqueous ammonia and extracted with ethyl acetate.
The ethyl acetate layer was washed with water, dried with magnesium sulfate and concentrated to give i 2-bromo-3- (D-2-hydroxy-2- (5-methyl--2-phenyl-4-oxazolyl) ethoxy / phenyl methyl ester).
propionic acid. in the form of a crude oily product (27 g, 98.5%).
NC (undiluted), 3300, 1735.
NMR (CDClI) S, Ppm: 2.4 (EH, singlet), 3 (1H, broad band); 3.1 G (1H, double doublet, J 14 and 7 Hz) J 3.39 (1H, double doublet, J 14 and 7 Hz); 3.68 (ZN, singlet) - 4-4.5 (ZN, multiplet), 5.05 (1H, double
doublet, I 8 and 5 Hz); 6-7.2 (4H, multiplet), 7.4 (3N, multiplet); 7.9 (2H, multiplet).
0
The resulting oil product (27 g) is dissolved in ethanol (270 ml) and thiourea (4.5 g) and sodium acetate (48 g) are added to the solution. The mixture was boiled for 4 hours, then concentrated. The residue was neutralized with a saturated aqueous solution of sodium bicarbonate. Water (300 ml) and ether (200 mp) were added to the mixture, and then stirred for 30 minutes at room temperature. The resulting crystals are collected by filtration to give 2-imino-5- | 4- 2- -hydroxy-2- (5-methyl-2-fench 1-4-oxa-aol yl) ethoxy benz1-4-thiazole. Dinone (13 , 5 g, 54%). By recrystallization from methanol-chloroform, colorless needles with mp. 238-239 ° C.
Calculated,%: C 62.4j H 5J N 9.92.
CI.
Found,%: C, 62.24; H, 4.77; N, 9.79.
Example 38. In a manner similar to that described in Example 37, p the following compounds are obtained: 4- (4-α-acetamidophenoxyacetyl) -2,5-dimethyloxazole, m.p. 223-224 0, yield 55.9%, (2,5-dimethyl-4-oxazolyl) -2-hydroxyethoxyacetanilide, m.p. 157-158 ° C, yield 93.3%} 4- 2- (2,5-dimethyl-4-oxazole1) -2- -sidroxyethoxy aniline, oily product, IR (undiluted), 3300 (broad band), yield 99.1%; 2-amino-5-G4-2-hydroxy-2- (2,5-dimethyl-4-oxazole 1) ethoxy | benzyl-4-thiazolidinone, t.s. 238-239 C, yield 54%.
Example 39. A mixture of 4-chlorme-: Thyl-5-methy-1-2-phenyloxazole (12 g), p-hydroxyacetanilide (13.1 g), potassium carbonate (16.6 g) and DKP (150 ml is stirred for 3 hours at 110 ° C., after which they drink in hydrogen.The aqueous mixture is extracted with ethyl acetate, the ethyl acetate layer is washed with water, dried with magnesium sulfate, and concentrated to give 4- (5-methyl-2-phenyl-4-oxazolyl) acetanilide (18 g , 95.7%). Colorless plates with mp 154-155 ° C. are obtained by recrystallization from ethanol.
Calculated,%: C, 70.79; - H, 5.63; N 8.69. - C, H, eNiO,
Found,%: C, 70.67, H, 5.57; N 8.58.
A mixture of 4- (5-methyl-2-phenyl-4-oxazole 1 xmethoxy) acetanilide (17.5 g), 4 N, potassium hydroxide (150 ml) and ethanol (150 ml) is boiled for 20 h, and then concentrated to about half the original volume. The precipitated crystals were filtered off to afford 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) aniline (14.7 g, 96.7%). By recrystallization from ethanol, colorless prisms are obtained with a mp. 129-130 C.
Calculated,%: C, 72.84; H 5.75; N 9.99.
C h giOz
Found,%: C 72.79} H, 5.7; N, 9.87.
The resulting 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) aniline (14.5 g) is converted similarly
9663410
Example 37 and receive 2-imino-5- 4- - (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl-4-thiazolidinone (11.8 g, 57.3%). Recrystallization of the mixture of chloroform - methanol gives colorless plates with so pl. 257-258 C.
Calculated,%: C 64.11; H 4.87; N 10.68.
10 С, Н,
Found,%: C 64,16; H 4.8; N 10.8.
Example 40. To a mixture of - (2-chlorophenyl) -5-methyl-4-oxazolyl
15 ethoxy nitrobenzene (22.9 g), acetic acid (150 ml) and water (50 ml) are added in portions of reduced iron at 70 ° C. After stirring for 2 hours with an insoluble material
20 is filtered, the filtrate is concentrated under reduced pressure. Water was added to the filtrate and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried.
25 with magnesium sulfate and concentrated to give 4-H2-2- (2-chlorophenyl) -5-methyl-4-oxazolyl ethoxy-aniline (20.5 g, 97.6%) as a crude oily substance.
30 NMR (CDCl,), ppm: 2.35 (N,
singlet), 2.93 (2H, triplet, Hz); 3.77 (2H, singlet) 4.15 (2H, triplet, J 7 Hz); 6.56 (2H, doublet, J 9 Hz); 6.75 (2H, doublet, J
22 9 Hz); 7.2-7.5 (3N, multiplet), 7.9 (1H, multiplet).
The resulting oily product (20.5 g) is dissolved in acetone (100 ml) and methanol (100 ml) and
A solution of 47% hydrobromic acid aqueous solution (45 g) is added to the 40 solution. Then, a solution of sodium nitrite (4.8 g) in water (10 ml) is added dropwise to the resulting mixture at a temperature not higher than 5 ° C. After stirring for 15 minutes at 5 ° C, methyl acrylate (33 g) is added to the si, and all is heated at. With vigorous stirring, the mixture was added to the mixture by adding cuprous oxide (2 g) in small portions and stirring was continued until the gaseous nitrogen was stopped. The reaction mixture is concentrated under reduced pressure, and the hydroxide is alkalinized by the addition of aqueous ammonia and extracted with ethyl acetate. tatom. The ethyl acetate extract is washed with water, dried with magnesium sulfate, and concentrated to obtain in the form
oily product of methyl ester of 2-bromo-3- (2- (2-chlorophenyl) -5-methyl-4-oxazolylSethoxy-jenyl) propionic acid (24.5 g).
NMR (CDCl 2), ppm: 2.37 (E3, singlet); 2.97 (2H, triplet, J 1 Hz) 3.12 (1H, double doublet, J 14 and 7 Hz) J 3.38 (1H, double doublet, J 14 and 7 Hz); 4.1-4.4 (3N, multiplet); 6.7-7.5 (7H, cartoon); 7.9 (1H, multiplet).
The resulting oily product (24.5 g) is dissolved in ethanol (250 ml) and thiourea (4.9 g) and sodium acetate (5.2 g) are added to the solution. The mixture was boiled for 10 hours, then concentrated. Water was added to the resulting residue, and the crystals formed were separated by filtration. By recrystallization from ethanol-dichloromethane mixture, 5- (4-G7-H2- (2-chlorophenyl) -5-methyl 1 L -1
-4-oxazolyl ethoxyJbenzyl -2-amino-4-thiazolidione (9.6 g, 34.1%), so pl. 174-176 ° C.
 Calculated,%: C 59.79, H 4.56; N 9.51.
Cj H oNjOjSCl
Found,%: C 59.69 H 4.6; N 9.34.
Example 41. In a manner analogous to example 40, crystals are obtained (yield 53.1% in terms of the corresponding nitro derivative) by 2-but-5- (4-2-5 methyl-2- (2-thienyl) -4- -oxazole-1-ethoxy benzyl) -4-thiazolidinone. By recrystallization from methanol-dichloromethane mixture, colorless prisms are obtained with mp. 171-172 ° C.
Calculated,%: C 58.09; H 4.63; N 10.16.
CjjjH N O Si
Found,%: C 57.86, H 4.59; N 10.04.
. Example 42. A solution of - (4-benzyl-oxyphenyl) -5-methyl-4-oxa-zolyl ethoxyrstrobenzene (10.65 g) in methanol (200 ml) is subjected to catalytic hydrogenation over 10% Pd / C (50% by weight, 4 g) . After the catalyst is filtered off, the filtrate is concentrated to give 4-G2-G2- (4-hydroxyphenyl) -1
Tylo-4-oxazolyl I ethoxyDaniline (6.21 g, 78.2%). Recrystallization from methanol gives brownish prisms from mp, 184-185 C.
Calculated,%: C 69.66; H 5.85, N 9.03. - Happy birthday,
Found,%: C 69.69; H 5.87;
N 9.01.
The resulting crystals (6.11 g) were dissolved in acetone (40 ml) and methanol (20 Mji), after which a 47% aqueous solution of hydrobromic acid (7.7 ml) was added to the solution. Then, at a temperature not higher than 5 ° C, a solution of sodium nitrite (1.44 g) is added dropwise to the mixture obtained.
in water (3 mp). After stirring for 15 minutes at 5 ° C, methyl acrylate (12 ml) is added to the mixture and the whole is heated to 38 ° C. Then, with vigorous stirring, cuprous oxide was added to the resulting mixture in small portions. (1 g) and stirring was continued until the release of gaseous nitrogen was stopped. The reaction mixture is concentrated, the residue is alkalinized.
by adding aqueous ammonia and extracting with ethyl acetate. The ethyl acetate extract is washed with water, dried over magnesium sulfate, and concentrated to obtain cf methyl crystals.
2-bromo-3- (4- | 2- 2- (4-hydroxy-phenyl) -5-methyl-4-oxazolyl ethoxy-phenyl) -propionic acid ester.
The whole amount of the crystals obtained was dissolved in ethanol (100 ml) and thiourea (2.28 g) and sodium acetate (2.46 g) were added to the solution, the resulting mixture was boiled for 2 hours. The reaction mixture was poured into water, the resulting crystals are separated
filtration and successively washed with water and &amp; By recrystallization from methanol and dichloromethane, 2-imino-5- ((2- (4-hydroxyphenyl) -5-methyl-4-oxase olyl ethoxy-benzyl) -4-thiazol dinonone (5.35 g, 66.5%) is obtained as colorless prisms, mp 175-177 ° C.
. Calculated,%: C 61.1, H 5.13J N 9.72.
, N, 04S 0.5H20
Found,%: C 61.02, - H 4.92; N 9.56. .
Example 43. In a manner analogous to example 34, the compounds shown in Table 6 are obtained.
Example 44 In a manner analogous to example 35, the compounds shown in Table 7 are obtained (the given yields are given as general
outputs in terms of the original nitro-derivative).
Example 45. In a manner analogous to example 37, the following compounds are prepared: 4- (4-acetamidophenoxy-siacetyl) -2-cyclohexyl-5-methyloxa-aol, m.p. , yield 48.1%, (2-cyclohexyl-5-methyl-4-oxa-) -2-hydroxyethoxy acetanilide Q so pl. 125-126 ° C, yield 98.4%, - (2-cyclohexyl-5-methyl-4-oxazolyl) - -2-hydroxyethoxy | aniline, but the lower the product, IR (undiluted), see: 3350 (wide strip), output f5
98.1%, 2-C2-cyclohexyl-5-methyl-4-oxazolyl) -2-hydroxy-ethoxy benz-jJ-2-imino-4-thiazolidinone, m.p. 167-168 ° C, yield 34.4%.
Example 46. In a manner analogous to Example 40, the following compounds were prepared: 4-f2-2- (4-chlorophenyl) -5-methyl-4-oxazolyl ethoxy aniline, m.p. 245-246 ° C, yield 59.9%, 2-bromo-3- (4- (4-: sulphenyl) -5-methyl-4-oxazazyl 1 ethoxy Phenyl) propionic acid methyl ester, oily product, IR (undiluted), 1740, youCn ioN OS
Found,%: C 67.2; H 5.94 N 8.12.
The resulting crystalline substance is subjected to the reaction of an analogue of example 42 to obtain 2-imino-5- - (5-methyl-2- (3-methylthiophenyl-4-oxazolyl ethoxy gbenzsh1) -4-thiazo-lidinone. By recrystallization from cm Si ethyl acetate - methanol, the resulting colorless prisms with a melting point of 182-183 s
Calculated,%: C 60.91; H 5.11; N 9.26.
.
Found,%: C 60.42; H 4.76; N 9.06.
Example 48. In a manner similar to Example 47, the following compounds are prepared: 4- | 2- 5-methyl-2- (3- -trifluoromethylphenyl) -4-oxazolyl 1 is
lj
SI-aniline, so pl. 121-122 ° C, yield 97.5%; 2-imino-5- (4- 2- 5-methyl-2- - (3-trifluoromethylfesch) -4-oxazolyl 25 ethoxy) benzyl) -4-thiazolidinone, mp 212-213 ° C, yield 42.2 %
Example 49. The effect of reducing blood glucose and plasma lipids was studied in mice.
35
course 92.7%, 5 - ((4-chlorophenyl) -5-30 KKAU mice (male, age –methyl-4-oxazole1 ztoxy1benzyl) –2-imino-4-thiazolidinone, mp. 238-239 C, yield 49.5%.
Example 47. A solution of - 5-methyl-2- (3-methylthiophenyl) -4-oxazolyl ethoxy nitrobenzene (8.8 g) in methanol (100 ml) is subjected to catalytic hydrogenation with 10% Pd / C (50 wt.% , 10 g), then the catalyst is filtered off to obtain 4- 2-5-methyl-2- (3-methylthiophenyl) -4-oxazolyl | ethoxyDaniline (5.9 g, 72.8%). Recrystallization from mixture
8-10 weeks, in each group of 5 mice, test compounds were given in an amount of 0.001% or 0.005% in B1, a mixture with a CE-2 powdered diet produced by CEEL -Japan Jnc., Tokyo, for 4 days. The animals had free access to diet and water. Blood samples were collected from the orbital venous plexuses of the mice. Blood glucose was determined by the method of glucose oxidase, plasma triglycerides (TG) were determined enzymatically using the Cleantech test kit. TG-S Kit (Jatron). Relevant measurements were used to calculate in accordance with the equation:
hexane get bes - X g, h o,

from m.p. 110-11GS. C 67.03-H 5.92
Q 5
Found,%: C 67.2; H 5.94 N 8.12.
The resulting crystalline substance is reacted as in Example 42 to give 2-imino-5- - (5-methyl-2- (3-methylthiophenyl) -4-oxazolyl ethoxy gbenzsh1) -4-thiazolidinone. By recrystallization from ethyl acetate-methanol, colorless prisms are obtained. 182-183 p.
Calculated,%: C 60.91; H 5.11; N 9.26.
.
Found,%: C 60.42; H 4.76; N 9.06.
Example 48. In a manner analogous to example 47, the following compounds are obtained: 4- | 2- 5-methyl-2- (3- -trifluoromethylphenyl) -4-oxazolyl-1-cyclJ
SI-aniline, so pl. 121-122 ° C, yield 97.5%; 2-imino-5- (4- 2- 5-methyl-2- - (3-trifluoromethyl) = 4-oxazolyl; 5 ethoxy) benzyl) -4-thiazolidinone, m.p. 212-213 ° C, yield 42.2%.
Example 49. The action of reducing the content of glucose in the blood and plasma lipids was studied in mice.
KKAU mice (male, age
8–10 weeks, in a Kachda group of 5 mice), the tested compounds were given in an amount of 0.001% or 0.005% in B1, a mixture with CE-2 powdered diet, produced by CEEL -Japan Jnc., Tokyo, for 4 days. The animals had free access to diet and water. Blood samples were collected from the orbital venous plexuses of mice. Blood glucose was determined by the method of glucose oxidase, plasma triglycerides (TG) were determined enzymatically using the Cleantech test kit. TG-S Kit (Jatron). Relevant measurements were used to calculate in accordance with the equation:;
(Measurements for the control group) Measurements Д22 2ЁЁЁЁ215Й222 РУпп)
(Measurements for control group) x
The results are shown in Table 8 (for comparison, data are given for a known compound of similar chemical structure, a dash means a test).
As can be seen from table 8, the compounds obtained by the proposed method showed a statistically significant
100.
blood glucose lowering activity and TG reduction, while the control compound in the dosage used in this test did not show significant activity.
Toxicity tests were carried out according to the following procedure.
15
Male mice belonging to the ICR strain at the age of 6 weeks. deprived of food for 6 hours. Each test group consisted of 6 mice. Then, each of the tested compounds in the form of an aqueous suspension containing 10% gum arabic was orally administered at a rate of 1000 mg / kg. After applying the substances, the mice were observed for 7 days. and during this period, food and water were given to animals without restriction.
The test results are presented in Table 9.
As can be seen from the above data, the compounds obtained can be classified as low toxic.
Thus, the thiazolidinedione derivative of general formula (I) and its salts can be used to treat hyperlipemia, diabetes and their complications in humans. They can be administered orally in such dosage-Hbfe forms as tablets, capsules, powders, granules, etc., and they can also be administered parenterally in such dosage forms as injectable solutions, suppositories and lozenges, depending on the specific case. When used as a therapeutic agent for diabetes or hyperlipemia, the compound can be administered to an adult patient for its oral administration at a dosage of 0.01-10 mg / kg per day or parenteral administration at a dosage of 0.005-10 mg / kg per day, and the dosages indicated It is advisable to take once a day or two to four times a day, with interruptions.
rmula
sixteen.
the invention
The method of producing thiazolidinedione derivatives of the general formula
K-jteVtCH VO-O-CHrCH-Cj-O
AI .- -
I} X 1
 / 7
about ii)
in which, when X denotes an oxygen atom, m O and n 1-3, then R ;, is C-C-alkyl, cyclohexyl, 1-methyl-cyclohexyl, 1-methyl-3-cycrhex-salen, furt, thienesh, phenyl, 4-methoxyphenyl, 4-hydroxyphene1, 2- or 4-chlorophene, 3,4-dimethoxyfekyl, 3-methylphenyl, 3-methylthiophenyl-3-trifluoromethylphenyl, cyclohexylmethyl; Rj is hydrogen, C -Cj-alkyl, or when X means an oxygen atom tn 1, n 1, Z is hydroxymethylene, then R C -Cz-alkyl, cyclohexyl, phenyl, RC-Cj-alkyl or when X means an atom sulfur, m O, p 2, then R, is cyclohexyl, alkyl, phenyl, R is hydrogen, or their sodium salts, characterized in that the compound of the general formula
N-j- (ZV (CH ,,
R, VB,
i
 k
where, Rj, Z, m, X and n have the indicated values, are subjected to hydrolysis in the medium of ethanol or dmixane in the presence of water and salts or sulfuric acid when heated, followed by conversion of the target product in the free form III in the form of sodium salt

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25
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1496634
26
Table 4
V / r-N02
27
1496634
Table 5
-j CH VoRI about R
HhCHo € X
ci-o
CHgS
sgya
ъ
about
3
CHj
CHz CHj CHZ
sn.
sn.
N (cH2Vo-O cHrCH-c o R, VR,
oi
Table 6
-NO nisproduct
e
154
105
113
AND 2
Ethyl acetate
Methanol
80.3
80.8 94.7 87.5
Ethyl acetate - hexane 92.4
Also
90.0
Table 7
Table 8.
33149663434
Table 9
The compound according to I Acute toxicity of the example (LDyo), mg / kg
1000
1000
1000
1000
1000

权利要求:
Claims (1)
[1]
The claims ⁷
- A method of obtaining derivatives of ^z 5 thiazolidinedione of the General formula
N-jrfcVteH ^ -o-O-CHi-CH-c-o
RiXR, s _Y NH '0 в in which, when X is an oxygen atom, w 0 0 and η = 1-3, then R ₄ is C <-C _e -alkyl, cyclohexyl, 1-methylcyclohexyl, 1-methyl-3 -cyclohex15 senyl, furyl, thienyl, phenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 2- or
4-chlorophenyl, 3,4-dimethoxyphenyl, 3-methylphenyl, 3-methylthiophenyl3-trifluoromethylphenyl, cyclohexyl 20 methyl; R ₄ is hydrogen, C ^ -C ^ -alkyl, or when X is an oxygen atom, m = 1, η = 1, Z is hydroxymethylene, then Rj is C4-C3-alkyl, cyclohexyl, phenyl; R ₂ ~ C ^ -Cj-alkyl or 25 when X is a sulfur atom, m = 0, η = 2, then R ₍ is cyclohexyl, alkyl, phenyl, R ₂ ~ hydrogen, or their sodium salts, characterized in that a general formula. '·· "
and NH where Rf ', And _r , Z, W, X and η have the indicated meanings, are hydrolyzed in ethanol or dioxane in the presence of water and hydrochloric or sulfuric acid upon heating, followed by isolation of the target product in free form or in the form sodium salt.
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Table 4
Rt 4 X T.pl., ° C Cross-solvent with allies Exit, % IηIm> IIIIiIIII H s 101-102 Methanol - Ether 70.0 CH ₃H 0 101-102 Methanol 71.3 o- H s . 102-103 __ n_ 50,2 ά H 0 112-113 - 92.2 (η / ™ ³ch ₃0 Oily - 92.0 CH ₃0 duct94-9580, 1 c ₃ H _TH 0 70-71 Ether - Hexane 47.6 <H> H s 62-63 Methanol 73.2 <s> - H 0 61-62 - 70.6 C ₂ H _SH s 63-64 Ethyl Acetate - Hexane 75.7 ic ₃ H ₇H s 62-63 - ”- 67.8 o-^S r ^N 5 0 71-72 Ethanol 91.6 ch ₃ o- £> CH 0 113-114 Ethyl Acetate - Hexane 82.1 ch ₃c ₂ h ₅0 89-90 Ether - Hexane 77.6 <H>^CH h. 0 Oily product70.5 CH 0 121-122 Methanol - Dichloromethane 69.1 V CH 0 107-108 Methanol - Water 74.7 sn _{37 =} v- CH ₃0 79-80 Ethanol 85,4 SI ₃ O ch ₃ oQ- CH 0 124-125 Ethanol - chloroform 91.5 _.ci '& CH ₃0 89-90 Ether - Hexane 58.0
Table
X Mp, ° C. Recrystallization Solvent Exit, CH H s 185-186 Methanol 28,4 CH H 0 202-204 Methanol - Dichloromethane 46.6 Q- H s 182-183 . Methanol 44.9 Cl H 0 211-213 Methanol - Dichloromethane 42.3 CH ₃CH 0 239-240 Also 56.0 <nk ^sngCH 0 180-181 Ethanol 51.6 ϋ, Ηγ H 0 175-176 ’Methanol 38.3 w H s 182-18432.1 Cl H 0 203-205 Methanol - Dichloromethane 38.4 s _r n ₅H s 168-169 Methanol 46.9 iC, H ₇H s 172-173 Methanol - Dichloromethane 42.5 a C _a H ₅0 190-191 Ethanol 23.7 Chjo-o CH 0 213-214 _P_ 53.5 CH^C 2 ^H F 0 208-209 Ethanol - chloroform 33.8 Cl CH ₃0 171-172 Ethanol - Water 38.8 A “b . CH 0 222-224 .Methanol - Dichloromethane .41.0 CH 0 194-195 Ethanol 45.0 CH ₃ O, CH ₃ O <l CH 0 197-198 Ethanol-chloroform 32.6
Table 6
η Rm h Mp, ° C Recrystallization Solvent Exit, % 2 (n> -sn ₂ - sun ₃Oily product - 80.3 2 € X ^SNZsun ₃Also - 80.8 2 C ¹ O CH ₃ S ₄sun ₃153-154 Ethyl acetate 94.7 2sun ₃104-105 Methanol 87.5 2 & sun ₃112-113 Ethyl Acetate - Hexane 92.4 3 ABOUT sn 111-112 Also 90.0
Table 7
η R Rj Mp. ° C Recrystallization Solvent Exit, % 2 (nosn ₂ - sn _e180-182 Methanol 41.7 2 € X ^SNZsun ₃136-138 Ethyl acetate 37.3 3 ABOUT- Chj 179-180. Ethanol 36.1
Table 8
Connection example Blood glucose lowering effect (%) upon administration of the compound,% The action that reduces the content of TG,%, with the introduction of the compound,% 0.001 I 0.005 0.001 | 0.005 1₅₅ ****67 **** 66 **** 2 - • 48 **** - 51 *** 3 - 42 **** - 52 *** 437 **** - 42 *** 5 39 **** 52 *** ’ 54 *** 63 *** 6 41 **** 58 **** 51 * 68 *** 7 - 55 **** - 5θ * "to * 8 - 52 **** - 65 **** 9 - 55 ** - 37 *** 10 - 56 ** ’* - 45 eleven _, ****54 58 ** ’* 62 **** g1 ** "" 12 49 **** 55 **** 55 **** 79M ** thirteen 55 **** 55 "" ** 63 **** 72 * "* ·" 14 - 46 ** ’* - 45 *** fifteen fifty**** fifty**** 41 "*" - * 69 **** 16 fifty***** 51 **** 41 **** 72 **** 17 55 **** 51 ** "* 52 "** x 62 **** 18 49 **** - 61 **** - 19 52 ****5d * "to * - 20 52 **** - 52 **** - ' 21 22 *** - 26 **** - 22 23 *** ' 4!**** 17 ** 44 **** 23 21 *** 53 **** 23 5 ^ "*** 24 - '44 *** " - 33 ** 25 - s1 **** - ' 14 . 26 51 ** "* 52 **** 58 **** 71 **** 27 - 52 **** - 68 **** 28 -. 43 **** - 26 **** 29th - 52 ’***67 **** thirty - 54 **** - 75 **** 31 - 49 **** - 67 3221 **** - 2d ** 33 - 52 **** - 63 ****
Cyclito
zones * (control)10 thirteen
* 5- [4- (1-Methylcyclohexylmethoxy)] benzyl-2,4-thiazolidinedione.
** P 0.02.
“*** P 0.01.
** P 0.001.
Table 9
Connection example Acute toxicity (LD _5o ), mg / kg 1 > 1000 22 > 1000 26 > 1000 27 > 1000 28 > 1000

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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JPS6242903B2|1978-08-04|1987-09-10|Takeda Chemical Industries Ltd|

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JPS6310702B2|1980-01-07|1988-03-08|Takeda Chemical Industries Ltd|

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JPH0257546B2|1982-01-07|1990-12-05|Takeda Chemical Industries Ltd|

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JPS5948471A|1982-09-10|1984-03-19|Takeda Chem Ind Ltd|Thiazolidine derivative|WO1988009661A1|1987-06-10|1988-12-15|Pfizer Inc.|Oxazolidin-2-one derivatives as hypoglycemic agents|

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ES2388555T3|2006-03-16|2012-10-16|Metabolic Solutions Development Company Llc|Thiazolidinedione analogues|

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MX356584B|2006-03-16|2018-06-05|Metabolic Solutions Dev Co|Thiazolidinedione analogues for the treatment of metabolic inflammation mediated disease.|

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US8304441B2|2007-09-14|2012-11-06|Metabolic Solutions Development Company, Llc|Thiazolidinedione analogues for the treatment of metabolic diseases|

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PL2203433T3|2007-09-14|2013-04-30|Metabolic Solutions Dev Co Llc|5--2-oxoethoxy)benzyl)thiazolidine-2,4-dione for use in treating diabetes|

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US8912335B2|2009-12-15|2014-12-16|Metabolic Solutions Development Company, Llc|PPAR-sparing thiazolidinedione salts for the treatment of metabolic diseases|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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PCT/JP1984/000466|WO1986002073A1|1984-10-03|1984-10-03|Thiazolidinedione derivatives, process for their preparation, and pharmaceutical composition containing same|

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