Method of producing derivatives of thiazolidine-4(s)-carboxylic acid or its salts with alkali or alk

专利摘要:
The invention relates to thiazole derivatives, in particular the preparation of thiazolidin-4 (5) -carboxylic acid (TK) derivatives, or b salts with alkali or alkaline earth metals, or its ester of general formula (I) C () (CH 3) -C () C --- C (0) OK2 -YKz-CH () -, where R is furyl-2, 5-nitrofuryl-2, thienyl-2, 1-methylpyrrolyl-2, benzofuryl-2, pyridyl-3 , pyridyl-4, 2-methyl-3-hydroxy-5-hydroxymethyl-pyridyl-4, indanyl-5, oxymethyl, which can be monosubstituted by halogen, acetoxy group, CHj, N0, OH, COOH, СНзБ, disubstituted phenyl halogen, 2-carboxy-3,4 dimethoxyphenyl or 3,5-dibromo- 4-hydroxyphenyl; K - H, the equivalent of alkali metal alkali-earth metal or C-C-alkyl; K-And, C-C-alkanoyl, which can be replaced by a 4-chlorophenoxy group, provided that R is acetoxyphenyl, when K-3 is acetyl, which have the ability to regenerate liver damage, which can be used in medicine. The goal is to create a method for obtaining new biologically active substances, which are mixtures of a smaller number of diastereomers and include only active forms. Synthesis of TC lead by the reaction of compounds of formulas (II) M (III) HS-C- (4СНз) (- CHj) -C (4H) C (0) OHj-ShKs (II) and R-CHO (III), where R, RI, except R, is acetoxyphenyl, in the case when K. o - H. The process is carried out: a) in water and / or methanol at a temperature from room temperature to the boiling temperature of the reaction mixture, when R is H; b) in a solution of HCl in diethyl ether at room temperature, when Rj is 4-alkanoyl. The target product (CP) is obtained: a) as a free acid; b) converting the acid to the salt with an alkali or alkaline earth metal; c) to the C- | -C-alkyl ester and / or Cp (with R 3) is reacted with ang angride or chloroanhydride of the corresponding carboxylic acid in water, or pyridine, or dichloromethane in the presence of a tertiary amine. In this case, a CP is obtained, where Rj is C-C-alkanoyl, which may be substituted by a 4-chlorophenoxy group. If CP (with RI is oxyphenyl) and acetic anhydride is used with "9 fS,
公开号:SU1443800A3
申请号:SU864027696
申请日:1986-06-18
公开日:1988-12-07
发明作者:Дьердьдеак Золтан；Ковач Иштван；Богнар Реже；Хорват Геза；Миле Терезиа；Крушпер Юдит；Пустаи Ференц；Фекете Марианн；Янчо Шандор；Балинт Янош；Михок Илдико；Якаб Аттила；Йенеи Андраш；Сенде Бела；Лапиш Карой
申请人:Биогал Дьедьсердьяр (Инопредприятие)；
IPC主号:

专利说明:

RID, then get CPU with R, is acetoxyphenyl. Tests show that in case of CCl poisoning, galactosamine and allyl alcohol, CPU have liver protecting activity comparable to that of Catergen with an LD5g toxicity of 550-5000 mg / kg. 2 tab.
one
The invention relates to a method for producing new chemical compounds, namely, derivatives of thiazolidin-4 (5) -carboxylic acid or its salts with alkali or alkaline-earth metals or its esters, which have the property to generate liver damage and can be used in medicine.
The purpose of the invention is to obtain new biologically active derivatives of thiazolidine-4-carboxylic acids, which are mixtures of a smaller number of diastereomers, including only active forms.
In these examples, the NMR spectra are taken with dimethylsulfide.
Example 1. 5,5-Dimethyl-2- (5-nitropyryl-2) -thiazolidin-4 (S) -carboxylic acid,
15 g (0-1 mol) of D-penicillin (D, B5B-dimethylcysteine) (compound of formula (II), where RJ is a hydrogen atom) is dissolved with stirring in 190 ml of ion-free water, after which the resulting solution is mixed dropwise with stirring m for 10-12 minutes with 12.5 g (0.1 mol) of a solution of 5-nitrofurfurol in 60 ml of methyl alcohol. The reaction mixture is further stirred for about 1 hour, and the precipitate is precipitated with oKpameHHbL4 in a sandy color product. The crystalline 5,5-dimethyl-2- (5-nitrofuryl-2) -thiazolidine-4 (8) -carboxylic acid is filtered off, washed with 20 ml of ion-free water, and then dried in air. This gives 23 , 9 g (87.7%) of crude product. This product is dissolved by heating in 26 ml of methyl alcohol, the solution is filtered, the filtrate is mixed dropwise with 8-10 ml of free from the presence of ionic water until crystallization begins. The crystallization mixture is placed in the refrigerator. The crystalline product is filtered off, washed with 15 ml of 50% methyl alcohol and dissolved at a temperature of maximum 55 ° C. The result is 19.7 g (72.3%) of the title compound, mp, 147-148 ° C.
 -159 (from 0.829, dimethyl sulfoxide). M 272.3. fO Calculated,%: N 10.29; S 11.78, C, oH,
Found,%: N 10.14; S 11.78. IR spectrum: 3304 (NH) and 1725 (CO) CM V as well as 2480 cm (indicating the amphoteric ionic structure).
 H-NMR: 1.34 and 1.65 (C-methyl-cis); 1.40 and 1.69 (C-methyl trans); 5.77 (H-2) and 3.6.4 (H-4) cis-isomer and 5.71 (H-2) and 3.70 (H-4) million trans-isomer. 20 Example 2. 5,5-Dimesh-1- 2- (furyl-2) -thiazolidin-4 (3) -carboxylic acid.
A mixture consisting of 4.27 g of D-ne-25 of nicillamine and 2.48 ml of furfural in 90 ml of 30% methyl alcohol is stirred for 8 hours. Immediately after this, the solution is evaporated to dryness. The semi-crystalline product formed. The crystalline product is crystallized by trituration with diethyl ether. M.p. 141-143 ° C.
L1 + 103 ° (c = 0.602, dimethyl sulfoxide). M 227.3. 25 Calculated,%: N 6.16; S 14,10. ,
Found,%: N 5.92; S 13.69. IR center: 1721 cm PsO). H-NMR spectrum: 1.22 and 1.53. (C-methyl, trans); 1.28 and 1.56 (C-methyl-cis); 3.58 (H-4) and 5.70 (H-2) cis-isomer and 3.60 (H-4) and 5.66 (H-2) mpn of the trans-isomer.
Example 3. 5,5-Dimethyl-2- (thi-enyl-2) -thiazolidin-4 (3) -carboxylic acid.
31
1.5 g (10 mmol) of B-penicillamine is dissolved at room temperature and stirred in 150 ml of methyl alcohol, after which 0.92 mp (1.12 g, 10 mmol) of thiophene-2-apydehyde is added to the prepared solution. . Then the mixture is further stirred for 48 hours and immediately thereafter evaporated in vacuo. The residue is dissolved in boiling benzene with stirring, and petroleum ether is added to the solution so that the indicated compound is precipitated. Yield 1.5 g (61.6%), so pl. 129-13GS.
Co (Jii +56 (c 0.549, dimethyl sulfoxide). M 243.3.
Calculated,%: N 5.75; S 26.35.

 .
20IK-spectrum: 1714 cm- (CO).
 H-NMR Spectrum: 1.35 (s, C-SPZ); 1.6 (s, C — CH :,); -3.38 (L, W); 3.38 (b, III); 3.64 (S, H4, III); 5.78 (s, 1P,%); 7.42 (t, 7.8 (d); 8.0 (d);
25 8.45 (dd); 8.63 (d); pyrridyl-H.
Example 6. 5,5-Dimethyl-2- (4-pyridyl) -thiazolidin-4 (B) -carboxylic acid 7.5 g (50 mmol) of D-penicillium-amine are dissolved in 45 ml of water, after which the prepared solution mixed dropwise with a solution of 4-, 7 ml (10 mmol) pyridine-4-aldehyde in 21 ml of methyl alcohol. The mixture is stirred for an additional 3 hours, and then the precipitate is filtered off and washed with ethyl alcohol. 6.5 g (54.5%) of the crude product recrystallized from ethyl alcohol. Found,%: N 5.31; S 26.62. H-NMR Spectrum: 1.3 (s, 3N, C-CH1); 1.6 (s, 3p, C-CH); 3.42 (s, W); 3.62 (s, 1H, H); 5.9 (s, 1H, nr; 6.98-7.52 (t, 4H, thiophene-H).
Example 4. 5,5-Dimethyl-2- (M-methylirrolrol-2) -thiazolidin-4 (B) is carboxylic acid.
To a solution of 1.5 g (10 mmol) of D-nenicillamine in 100 ml of methyl alcohol 30 was added at room temperature 1.09 g (1.0 ml, 10 mmol). N-methylpyrrolyl-2-aldehyde. After 48 h, the reaction mixture was evaporated in vacuo, the resulting residue was dissolved in boiling benzene, the solution was decolorized with activated charcoal, and then filtered. Upon cooling of the solution, the said compound precipitates. The result is 1.54 g (67.5%) 40 P temperature 60-80 C. So pl. 149126-128 ° C. + 42.7 ° (c 1.32, dimethyl sulfoxide). M 238.3.
Calculated,%: N, 11.75; S 13.46.
product, so pl.
IZv + 87.5 ° (c 0.471, dimethyl sulfoxide). M 240.3.
Calculated,%: N 11.66; S 13.34.
that adding petroleum ether
about ,
C ,, H ,, N, 0, S. Found,%: N
C, .H ,, N, 0, S
eleven
Found,%: N 11.24; S 13.44. IR spectrum: 1721 cm - (CO). H-NMR Spectrum: 1.25 (s, C-CH 3); 1.65 (s, C-CHj) j 3.38 (b, IN); 3.55
45
C ,, H ,, N, 0, S. Found,%: N
12.07; S 13.63.
IR spectrum: 1722 cm (CQ).
Example 7. 5,5-Dimesh1-2- (2-benzofuryl) -thiazolidin-4 (5) -carbono- (t, 3H + 1H: N-CH3 + H4); 5.77 (s, 1H, H); gp wa acid.
5.90 (t, 1H); 6.13 (t, 1H); 6.68 (t, 1.5 g (10 mmol) D-pepitsillamina
dissolved in 150 ml of methyl alcohol with stirring, after which 1.46 g (1.39 ml, 10 mmol) of a 2-form solution of 1.5 g (10 mmol) of B-penenzofuran was added to the prepared solution. The reaction mixture is heated with acyllamine in 30 ml of water at 0.94 ml (1.07 g, 10 mmol) (pyri-H), pyrrole-H, at room temperature and stirring.
Example 5. 5,5-Dimethyl-2- (3-pyridyl) -thiazolidin-4 (5) -carboxylic acid.
55
It is heated for 48 hours at its boiling point, and then the solution is evaporated in vacuo. Syrupy residue
din-3-aldehyde. After 10 minutes, the crystalline product begins to precipitate. The reaction mixture is further stirred for 1 hour, after which the non-purified product is separated by filtration, washed with water and dried. The crude product is dissolved in boiling water, the solution is filtered, and then cooled, with the result that a crystalline product is precipitated. Yield 1.9 g (79.7%) of the title compound, mp. 164-165 C.
: cfl (s 0.556, dimethyl sulfoxide). M 238.30.
Calculated,%: N, 11.75; S 13.46.
WITH,,
Found,%: N 11,17; S 13.69.
IR spectrum: 1714 cm- (CO).
 H-NMR Spectrum: 1.35 (s, C-SPZ); 1.6 (s, C — CH :,); -3.38 (L, W); 3.38 (b, III); 3.64 (S, H4, III); 5.78 (s, 1P,%); 7.42 (t, 7.8 (d); 8.0 (d);
8.45 (dd); 8.63 (d); pyrridyl-H.
Example 6. 5,5-Dimethyl-2- (4-pyridyl) -thiazolidin-4 (B) -carboxylic acid 7.5 g (50 mmol) of D-penicillium-amine are dissolved in 45 ml of water, after which the prepared solution mixed dropwise with a solution of 4-, 7 ml (10 mmol) pyridine-4-aldehyde in 21 ml of methyl alcohol. The mixture is stirred for an additional 3 hours, and then the precipitate is filtered off and washed with ethyl alcohol. 6.5 g (54.5%) of the crude product is recrystallized from ethyl alcohol P at a temperature of 60-80 C. T. pl. temperature 60-80 ° C. 149ta when adding petroleum ether
about ,
C ,, H ,, N, 0, S. Found,%: N
12.07; S 13.63.
IR spectrum: 1722 cm (CQ).
benzofuran. The reaction mixture is heated
It is heated for 48 hours at its boiling point, and then the solution is evaporated in vacuo. Syrupy residue
dissolved in boiling benzene, and then the solution is filtered. As a result of the addition of petroleum ether to the solution, the compound indicated in the precursor is precipitated in crystalline form. Yield 1.9 g (68.6%), mp 96 ° C.
t + 215 ° (c 0.511, dimethyl sulfoxide). M 277.3.
Calculated,%: N 5.06; S 11.56.
WITH,.
Found,%: N 4.90; S 11.31.
IR spectrum: 1721 cm (CO).
 H-NMR Spectrum: 1.33 (s, C-CH); 1.66 (s, C-CHj); 3.38 (b, III); 3.75 (s, W, H); 5.89 (s, W, H); 6.92 (d); 7.27 (m); 7.59 (m), aromatic hydrogen.
Example 8. 5,5-Dimethyl-2 - (5-indanyl) -thiazolidin-4 (5) -carboxylic acid.
1.5 g of D-penicillamine is dissolved at room temperature in 100 ml of methyl alcohol, after which 1.44 g (10 mmol) of 5-form III Indan is added to the prepared solution.
After 48 h, the reaction mixture was evaporated. The residue obtained is dissolved in diethyl ether, the solution is dried, decolorized with activated charcoal and then filtered. As a result of the addition of petroleum ether to the filtrate, the product is precipitated. The crude product is dissolved in boiling ethyl alcohol, the solution is decolorized with activated charcoal, filtered, and then mixed dropwise with water until cloudy. Upon cooling of the solution, the title compound is precipitated as a crystalline substance. The result is 1.57 g (57.1%) of the product
10 D
sulfoxide). M 275.342,
Calculated 11,65
ScN ,, H, 0.8.
Found,%; S 11.75.
IR spectrum: 1722 cm- (CO). H-NMR spectrum: 1.32 (s, C-CH3); 1.6 (s, C-CH3); 3.88 (b, sh); 3.62 (s, W, LU); 5.76 (s, 1H, Hj).
Example 9. 5,5-Dimethyl-2- (3-nitrophenyl) -thiazolidin-4 (S) -carboxylic acid and its magnesium salt.
4.48 g (3d mmol) of D-penicillamine and 4.53 g (30 mmol) of the 3-nitrobenzalde hydroxide are dissolved in 90 mp of 30%
N1 ° +18
m.p. 140-142 s. ° (with 0.551,
dimethyl
five
0
g
five
Q
five
0
five
0
methyl alcohol. The solution is stirred for 3 hours, then the precipitated product is filtered off and washed with methyl alcohol. The product is recrystallized from methanol by adding water. Yield 7.17 g (84.6%).
0.22 g (5 mmol) of magnesium oxide are suspended in 30 ml of water; 2.82 g (10 mmol) of 5,5-dimethyl-2- (3-nitrophenyl) -thiazolidin-4 (3 ) -carboxylic acid, after which the mixture is kept at 60 ° C until complete dissolution of the solids. The clear solution is evaporated to dryness in vacuo, and the residue obtained is dried in a desiccator over phosphorus pentoxide. As a result, the product is obtained in quantitative yield as a syrupy substance.
The combined acid has a mp, 139-.
 -26.4 ° (c 0.588, dimethyl sulfoxide), M 282.3,
N 9.92; S 11.36.
Calculated,%;
С „11,4N-.0,5.
Found,%: N 9,12; S 11.02.
IR spectrum: 1726cm-PSC). H-NMR Spectrum: 1.36 (s 3N, CH 3); 1.69 (s, 3N, SN3); 3.57 (s ,, 1H, H-4);
5.76 (s, 1H, H-2); 7.65 (t, 1H); 7.95 (dd, 1H); 8.21 (dd, W); 8.39 (s, W), (arom, signal).
Magnieva conbil dl- -45 (with 0.63, water). (M 586.8).
Calculated,%: N 9.55; 5.10,93
C-i4Hail4gN, OgSi,
Found,%: N 9.33 | S 10.99,
Example 10, 5,5-Dimetsht-2- (4-fluorophenyl) -thiazolidine-4 (S) -carboxylic acid and its potassium salt.
9.0 g (60 mmol) of B-penicylpamine is dissolved by stirring in 200 ml of water, after which 6.31 ml (60 mmol) of p-fluorobenzaldehyde in 40 ml of methyl alcohol are added to the prepared solution. The mixture was stirred for 3 hours, after which the precipitate formed was separated (13.8 g, 90%). The crude product recrystallizes from methyl alcohol by adding water.
1.0 g of potassium carbonate is dissolved in 10 ml of water, 2j55 g (10 mmol) of 5,5-dimethyl-2- (4-fluorophenyl) -thiazolidin-4 (5) -carboxylic acid are added to the prepared solution. after which the reaction mixture is heated on a steam bath at. When carbon dioxide is removed, the solution goes into solution. The solution is evaporated to a syrupy consistency, and then the residue is dried in a desiccator over phosphorus pentoxide to constant weight. Salt is a hygroscopic powdered} Q substance.
The free acid has a mp of 126-127 ° C.
Co / Ji, + 86.9 ° (c 0.473, dimethyl sulfoxide). M 255.3. With
Calculated,%: N 5.49; S 12,56.
.
Found,%: N 5.56; S 12.47.
Example 11. 5,5-Dimethyl-2- (p-methylmercaptophenyl) -thiazolidine- 20 4 (8) -carboxylic acid,
4.48 g (30 mmol) of D-penicillamine and 3.99 ml (30 mmol) of p-methyl mercapto benzaldehyde are stirred for 6 hours in 90 MP of 30% aqueous methyl alcohol 25%. The resulting white precipitate is filtered off. The yield of 8.26 g (97.1%). The substance crystallizes from methyl alcohol by adding a small amount of water, m.p. 150-152 ° C.
 + 174.4 ° (c 0.516, dimethyl sulfoxide). M 283.4.
Calculated,%: N 4.94; S 22.63.
With nil „NOiSi.
Found,%: N 4.85; S 22.31.
IR spectrum: 2950 and 2914 cm ČSNE); 1720 (CO).
 H-NMR spectrum: 1.30 (s, C-CH,); 1.36 (s, C-CHj); 1.55 (s, C-CHj); 1.65 (s, C-CHj); 2.45 (s, 4-CH 3); 2.48 (s, 4-CH3); 3.56 (s, H-4); 3.69 (s, H-4); 5.60 (s, H-2); 5.82 (s, H-2); 7.17-7.45 (m, arom).
Example 12, 5,5-Dimethyl-2- (2-car-boxyphenyl) -thiazolidin-4 (S) -carboxylic acid.
6 g (30 mmol) of 2-carboxybenzaldehyde and 6 g (30 mmol) of D-penicillamine in 44 MP of water are stirred for 3 hours. The precipitate formed is filtered off and washed with aqueous methyl alcohol. Yield 9.85 g (82.6%), The crude product is recrystallized from aqueous methyl alcohol, mp, 185-186 ° C,
thirty
35
40
45
50
55
Calculated,%: N, 4.98; S 11.40,
C, 3H ,, NO, S
Found%: S 11.39.
IR spectrum: 1763 and 1705 cm- (CO)
 H-NMR Spectrum: 1.50 (s, 3N, CH 3); 1.60 (s, 3N, SN); 3.41 (L, S, 2H, OH); 4.51 (s, W, H- 4); 6.45 (s, 1H, H-2); 7.87 (s, 4H, arom,).
Example 13. 5,5-Dimethyl-2- (3,4-dimethoxy-2-carboxyfenche:) - thiazolidin-4 (S) -carboxylic acid.
2.1 g (10 mmol) of opioic acid are dissolved in 30 ml of boiling water. The solution is cooled to a temperature of approx. 60 ° C, and then the solution is mixed with, 5 g (10 mmol) of D-penicillamine. An oily product is precipitated from the opalescent solution, which crystallizes overnight. The yield is 2.75 g (80.5%). The product is recrystallized from methyl alcohol by adding water. After that, the product has a mp. 90-9GS.
0/7 326 ° (c 0.772, methyl alcohol). M 341.4.
Calculated,%: N 4,10; S 9.39.
With 1uN gNOjS.
Found: N: 4.21, S, 9.21.
IR spectrum: 1721 and 1690 cm- (CO). i-NMR spectrum: 1.50 (s, 3N, .CH3); 1.60 (s, 3N, SN3); 3.50 (LP, OH); 3.79 (s, 3N, SNS); 3.84 (s, 3N, OCH h); 4.43 (s, 1H, H-4); 6.335 (s, 1H, H-2); 7.35 (q, 2H, arom.).
Example 14, 5,5-Dimethyl-2-hydroxymethyl-thiazolidin-4 (3) -carboxylic acid.
3.0 g (50 mmol) of glycolaldehyde and 7.5 g (30 mmol) of D-penicillamine are stirred in 30 ml of 30% methyl alcohol for 6 hours. The resulting precipitate is filtered and recrystallized from 40 ml of boiling water. As a result 2.17 g (22.7%) of the title compound are obtained; mp 179-180 ° C,
Co / 3 +167 (with 0.62, 10% sodium hydrogen carbonate solution). M 191.2,
Calculated,%: N 7.32; S 16.76,
With TN "N03S,
Found,%: N 7.44; S 16.78,
IR spectrum: 1635 cm (CO).
 1 H NMR Spectrum: 1.20 and 1.55 (C-me. +385 (c. 0.51, methyl teat, cis); 3.20 (); 3.41 (CHL-B);
alcohol), M 281.3,
3.44 (H-4) and 4.58 (H-2), both cis.
Q
with
0
five
0
five
0
five
0
five
Calculated,%: N, 4.98; S 11.40,
C, 3H ,, NO, S
Found%: S 11.39.
IR spectrum: 1763 and 1705 cm- (CO)
 H-NMR Spectrum: 1.50 (s, 3N, CH 3); 1.60 (s, 3N, SN); 3.41 (L, S, 2H, OH); 4.51 (s, W, H- 4); 6.45 (s, 1H, H-2); 7.87 (s, 4H, arom,).
Example 13. 5,5-Dimethyl-2- (3,4-dimethoxy-2-carboxyfenche:) - thiazolidin-4 (S) -carboxylic acid.
2.1 g (10 mmol) of opioic acid are dissolved in 30 ml of boiling water. The solution is cooled to a temperature of approx. 60 ° C, and then the solution is mixed with, 5 g (10 mmol) of D-penicillamine. An oily product is precipitated from the opalescent solution, which crystallizes overnight. The yield is 2.75 g (80.5%). The product is recrystallized from methyl alcohol by adding water. After that, the product has a mp. 90-9GS.
0/7 326 ° (c 0.772, methyl alcohol). M 341.4.
Calculated,%: N 4,10; S 9.39.
With 1uN gNOjS.
Found: N: 4.21, S, 9.21.
IR spectrum: 1721 and 1690 cm- (CO). i-NMR spectrum: 1.50 (s, 3N, .CH3); 1.60 (s, 3N, SN3); 3.50 (LP, OH); 3.79 (s, 3N, SNS); 3.84 (s, 3N, OCH h); 4.43 (s, 1H, H-4); 6.335 (s, 1H, H-2); 7.35 (q, 2H, arom.).
Example 14, 5,5-Dimethyl-2-hydroxymethyl-thiazolidin-4 (3) -carboxylic acid.
3.0 g (50 mmol) of glycolaldehyde and 7.5 g (30 mmol) of D-penicillamine are stirred in 30 ml of 30% methyl alcohol for 6 hours. The resulting precipitate is filtered and recrystallized from 40 ml of boiling water. As a result 2.17 g (22.7%) of the title compound are obtained; mp 179-180 ° C,
Co / 3 +167 (with 0.62, 10% sodium hydrogen carbonate solution). M 191.2,
Calculated,%: N 7.32; S 16.76,
With TN "N03S,
Found,%: N 7.44; S 16.78,
IR spectrum: 1635 cm (CO).
 H-NMR Spectrum: 1.20 and 1.55 (C-methyl, cis); 3.20 (); 3.41 (SNL
3.44 (H-4) and 4.58 (H-2), both cis.
Example 15, 5,5-Dimethyl-2- (3,5-dib.rom-4-hydroxyphenyl) -thiazolidine-4 (5) -carboxylic acid.
5.6 g (20 mmol) of 3,5-dibromo-4-oxibenealdehyde and 3 g (20 mmol) of B-penitslamin are stirred in 100 ml of 30% methyl alcohol for 16 hours. The precipitate formed is filtered and washed with water. methyl alcohol. Yield 6.77 g (82.3%). The product is recrystallized from a mixture of ethyl alcohol, dimethylformamide and water, after which it has a mp. 154-155 C.
(+ 87 ° (c. 1.362, dimethyl sulfoxide). M 411.1.
Calculated,%: N 3.41; S 7.80; Br 38.88.

Found %: N, 3.56; S 7.77; Br 38.22.
IR: 1708 (CO).
 H-NMR Spectrum: 1.27 (s, CH3); Bw (s, syz); 1.52 (s, CH3); 1.61 (s, CH3); 3.50 (s, H-4); 3.57 (s, H-4); 5.50 (s, H-2); 5.74 (s, H-2); ЗЗ45 (Ьг, ОН); 7.46, 7.70 (arom.); 9.98 (bh, he).
Example 16 5,5-Dimethyl-2- (2 methyl-5-hydroxymethyl-3-hydroxypyridyl-4) -thiazoidin-4 (8) -carboxylic acid.
1.5 g of C10 mmol) D-penicillamine and O., 56 g of potassium hydroxide are dissolved in 1 O ml of water. The prepared solution is removed from 2.03 g (10 mmol pyridoxal hydrochloride, after which the mixture is mixed for 16 hours. The precipitate is then filtered. Yield 2.26 g (75., 7%). The product is purified by heating it in ethyl alcohol at boiling point of the mixture. mp. 201-202 C. +68.1 M 298.3.
Calculated,%: N 9.39; S 10.74.
C ,,, 0, S.
Found,%: N 9.30; S 10,54.
IR spectrum: 3340 and 3292 cm (OH); 1725 cm- (CO).
 n-NMR spectrum: 1.66 and 1.83. (C-methyl, trans); 1.71 and 1.91 (C-methyl
cis); 2.83 (arom, methyl); about 5 (CH 6.56 (H-2) cis; 6.68 (H-4 trans).
Example 17. 5,5-Dimesh1-2- (2,4-dichlorophenyl) -thiazolidin-4 (S) -
carboxylic acid.
3.0 g (20 mmol) of D-penicillamine is dissolved in 65 MP of water. To cook
0
0
five
five
0

A solution of 3.5 g (20 mmol) of 2,4-dichlorobenzaldehyde in 17 ml of methyl alcohol is added. The mixture is stirred for 16 h, after which the precipitate is filtered and washed with 50% methyl alcohol. The output of 5.82 g (95%), so pl. 150-151 C.
L3 353 (with 0.45, dimethyl sulfoxide). M 306.2;
Calculated,%: C1 23.16; S 10.47.
C H jCljNO jS.
Found,%: C1 23.79; S 10.60.
IR spectrum: 1700 cm PSS).
 n-NMR spectrum: 1.30 and 1.50 (C-methyl, cis); 3.35 (W); 3.71 (H-4, cis); 5.88 (H-2, cis).
 Example 18, 5,5-Dimethyl-2- (p-tolyl) -thiazolidin-4 (5) -carboxylic acid.
1.50-g (10 mmol) of D-penicillamine and 1.18 ml (10 mmol) of p-toluol aldehyde are stirred in 30 ml of 30% methyl alcohol for 1 hour. The crystalline precipitated out is filtered and washed with 30% - Nm methyl alcohol. Yield 2.25 g (89.5%). The product can be recrystallized from methyl alcohol by adding water. M.p. 89-90 ° C.
, 53.5 ° (c 0.784, dimethyl sulfoxide), M 251.3.
Calculated,%: N 5.57; S 12.76.
, -,,
Found,%: N 5.51; S 12.1 K
IR spectrum: 1740 cm- (CO). n-NMR spectrum: 1.26 and 1.54 (C-me-, thyl, cis); 1.36 and 1.69 (C-methyl, trans); 2, -28 (arom., CH3); 3.58 (H-4, cis); 5.81 (cis); 3.64 (H-4, trans); 5.58 (H-2, trans).
Example 19, 5,5-Dimethyl-2- (4-hydroxyphenyl) -thiazolidin-4 (S) -carboxylic acid.
1.49 g (10 mmol) of D-penicillamine is added to 30 ml of 30% methyl alcohol, and then 1.26 g (10 mmol) of paraoxybenzaldehyde in 20 MP of 30% methyl alcohol is added to the prepared solution. The mixture is stirred for 20 hours, then the precipitate is filtered and recrystallized from aqueous ethyl alcohol. Yield 2.3 g (94.8%) of the title compound, mp. which is 207-209 C,
WJD + 91.3 ° (c 0.2, dimethylformamide). M 253.2,
n
Calculated,%: N 5.53; S 12.64.
 , HUz5.
Found,%: N 5.43; S 12.60.
IR spectrum: 1630, 1608, 1589 cm- (CO).
 n-NMR spectrum: 1.32 and 1.57 (C-methyl, cis); 1.34 and 1.66 (C-methyl, trans); 2.71 (OH, cis); 2.88 (OH, trans); 3.56 (H-4) and 5.76 (H-2), both cis; 3.62 (H-4) and 5.55 (H-2), both trans.
Example 20. 5,5-Dimesh1-2- (2-hydroxyphenyl) -thiazolidin-4 (8) -carboxylic acid.
4.5 g (30 mmol) of D-penicillamine and 3.16 ml (30 mmol) of salicylic aldehyde are stirred for 3 hours in 90 ml of 30% methyl alcohol. The precipitate is filtered off, washed with 50% methyl alcohol, and then dried. The result is 7.05 g (92.7%) of the title compound. The compound obtained is recrystallized from methyl alcohol, after which it has a melting point of 203 ° C. 179-181 ° C.
 129.8 ° (c 0.48, dimethylformamide). M 253.2,
Calculated,%: N 5.53; S 12.64.
C.H jNOjS.
Found,%: N 5.36; S 12.25.
IR spectrum: 1638 cm.
 H-NMR spectrum: 1.30 and 1.48 (C-methyl, cis); 1.35 and 1.69 (C-methyl, .trans); 3.16 (OH); 3.64 (H-4) and 5.76 (H-2) -, both trans, and 3.67 (H-4), as well as 5.90 (H-2), both cis.
Example 21. 3-Acetyl-5,5-dimethyl-2 (K) - (p-fluorophenyl) -thiazolidine-4 (8) -carboxylic acid.
5.74 g (30 mmol) of N-acetyl-D-nenicilylamine and 3.2 ml of p-fluorobenzaldehyde are stirred in 20 ml of diethyl ether saturated with gaseous hydrogen chloride. After 5-6 minutes, an oily substance is formed, which crystallizes after 30 minutes during grinding. The precipitate is filtered off and washed with diethyl ether.
1443800
12
ten
15
20
25
thirty
40
45
H-NMR Spectrum: 1.60 (s, 3N, CH); 1.45 (8, 3N, CH); 1.83 (s, 3H, NCOCHj); 4.71 (s, W, H-4); 6.32 (s, 1H, H-2); 7.05-7.35 (multiplet, 4H, arom.).
Example 22. 3-Acetyl-5,5-dimethyl-2 (R) - (p-chlorophenyl) -thiazolidine-4 (8) -carboxylic acid.
3.73 g (30 mmol) of N-acetyl-B-penicillamine are suspended in 18 ml of ethereal hydrogen chloride solution, after which 4.2 g (30 mmol) of parachlorobenzaldehyde are added to the suspension with stirring. After complete dissolution (after about 12 minutes), the product begins to precipitate. The filtered product is washed with diethyl ether. Yield 8.32 g (88.4%). After recrystallization from ethyl acetate, the product has so pl. 197-198 S.
 230.5 (with 0.59, methyl alcohol). M 313.8.
Calculated,%: N, 4.46; S 10.22; Cl 11.30.
Cl
, Found
N 4.41; S 10.18;
11.11.
IR spectrum: 1742 cm PSS).
 H-NMR Spectrum: 1.45 (s, 3N, CHj); 1.59 (s, 3N, CHj); 1.85 (s, .3N, NCOCHj); 4.71 (s, 1H, 4-H); 6.32 (s, W, 2H); 7.33 (multiplet, 4H, arom.)
Example 23. 3-Acetyl-5,5-dimethyl-2 (5) - (p-chlorophenyl) -thiazolidine-4 (5) -carboxylic acid.
2.71 g (10 mmol) of 5,5-dimethyl-2- (p-chlorophenyl) -thiazolidine-4 (S) -carboxylic acid are suspended in 5.6 ml of boiling water, after which the prepared suspension is added 5.6 ml of acetic anhydride. The mixture is heated at its boiling point for 8 minutes, and all the solid goes into solution. When the mixture is cooled, the product begins to precipitate. Yield: 2.39 g (76.1%). The product is recrystallized from water by adding these
Yield: 7.81 (87.5%). The product of alcohol, after which so pl. product is 203-205 C.
° (with 1.44, dimethyl- 319.8.
crystallized from ethyl acetate.
after which its so-called is 144-145 C.
 111.5
CO (; D +206.9. M 297.3.
Calculated,%: N 4.71; S 10.78,
, FNOjS.
Found,%: N 4.80; S 11.12.
sulfoxide). M
Calculated,%: 01 11.30; S 10.22. 55C ijClNOaS.
Found,%: Cl 11.94; S 9.97.
IR spectrum: 1742 cm (CO).
IR spectrum: (amide.).
1730 cm (CO) and 1626 cm
1443800
12
0
five
0
five
H-NMR Spectrum: 1.60 (s, 3N, CH); 1.45 (8, 3N, CH); 1.83 (s, 3H, NCOCHj); 4.71 (s, W, H-4); 6.32 (s, 1H, H-2); 7.05-7.35 (multiplet, 4H, arom.).
Example 22. 3-Acetyl-5,5-dimethyl-2 (R) - (p-chlorophenyl) -thiazolidine-4 (8) -carboxylic acid.
3.73 g (30 mmol) of N-acetyl-B-penicillamine are suspended in 18 ml of ethereal hydrogen chloride solution, after which 4.2 g (30 mmol) of parachlorobenzaldehyde are added to the suspension with stirring. After complete dissolution (after about 12 minutes), the product begins to precipitate. The filtered product is washed with diethyl ether. Yield 8.32 g (88.4%). After recrystallization from ethyl acetate, the product has so pl. 197-198 S.
 230.5 (with 0.59, methyl alcohol). M 313.8.
Calculated,%: N, 4.46; S 10.22; Cl 11.30.
0
0
five
Cl
, Found
N 4.41; S 10.18;
11.11.
IR spectrum: 1742 cm PSS).
 H-NMR Spectrum: 1.45 (s, 3N, CHj); 1.59 (s, 3N, CHj); 1.85 (s, .3N, NCOCHj); 4.71 (s, 1H, 4-H); 6.32 (s, W, 2H); 7.33 (multiplet, 4H, arom.).
Example 23. 3-Acetyl-5,5-dimethyl-2 (5) - (p-chlorophenyl) -thiazolidine-4 (5) -carboxylic acid.
2.71 g (10 mmol) of 5,5-dimethyl-2- (p-chlorophenyl) -thiazolidine-4 (S) -carboxylic acid are suspended in 5.6 ml of boiling water, after which the prepared suspension is added 5.6 ml of acetic anhydride. The mixture is heated at its boiling point for 8 minutes, and all the solid goes into solution. When the mixture is cooled, the product begins to precipitate. Yield: 2.39 g (76.1%). The product is recrystallized from water by the addition of this ethanol, followed by so pl. product is 203-205 C.
lovogo alcohol, then so pl. product is 203-205 C.
° (with 1.44, dimethyl- 319.8.
 111.5
sulfoxide). M
Calculated,%: 01 11.30; S 10.22. With ijClNOaS.
Found,%: Cl 11.94; S 9.97.
IR spectrum: (amide.).
1730 cm (CO) and 1626 cm
13144380014
 H-hNMR spectrum: 1.36 (s, 3N, CH3);
1.61 (in, 3N, snd); 1.86 (N-constant);
4.60 (s, 1H, H-4); 6.27 (s, W, H-2); 7.33 (s, 2H, H-3, 5); 7.76 (s, 2H, H-2, 6),
Example 24. 3-Acetyl-5,5-dimethyl-2 (8) - (2-acetoxyphenyl) -thiazolidine-4 (8) -carboxylic acid.
A mixture consisting of 1.0 g 5,5-di for 5 min at 100 ° C. After oh-methyl-2- (2-hydroxyphenyl) -thiazolidin-4 (3) -lap from the reaction mixture as a carboxylic acid, 7 ml of pyridine and 3 ml of acetic anhydride, incubated for 20 hours. Then the reaction mixture is evaporated, then 15 (73.3%), so pl. 214-218 ° C. Toluene is distilled off three times from the residue, -101 (from 0.71, methyl, and 20 ml of the latter are used each time. The crystalline product is recrystallized from a mixture of acetone and petroleum ether. As a result, 20 get 0.9 g (67.5%) specified
Example 26. C-Acetyl-5,5-dimethyl-2 (3) - (p-tolyl) -thiazolidin-4 (5) - carboxylic acid.
To a suspension of 2.51 g (10 mmol) of 5,5-dimethyl-2- (p tolyl) -thiazolidine-4 (S) -carboxylic acid in 5.6 ml of boiling water, 5.6 ml of acetic anhydride was added. The mixture is kept in
A crystalline substance is precipitated, which is recrystallized from isopropyl alcohol. Yield 2.15 g
alcohol). M 293.3.
Calculated,%: N 4.77; S 10.93.
S jH ,, 1 GOZ S
Found,%: N 4.66; S 10.91.
IR spectrum: 1732 cm (CO).
compounds, m.p. 214-216 S.
c / + 34 ° (c 0.47, chloroform) M 337.18.
Calculated,%: N 4.13; S 9.40.
C ,, H,
Found,%: N 4,00; S 9.33.
IR spectrum: 1778 and 1760 (CO) and 1614 cm (amide.).
 1 H-NMR Spectrum: 1.28 and 1.58 (C-mesonic acid, tyl); 1.73 (N-COCH3); 2.29 (0-COCH3); 0.47 g (2 mmol) of 5,5-dimethyl-2 (3) H-NMR spectrum: 1.35 (s, .ЗН, СН,); 1.59 (s, 3N,); 1.81 (s, 3N, NCOCHj); 2.30 (s, 3N, arom. -SI); 4.58 (s, 1H, H-4); 6.23 (s, W, H-2); 7.14-7.63 (multiunchet, 4H, arom.).
Example 27. 3-Acetyl-5,5-dimethyl-2 (3) -phenylthiaz-olidin-4 (3) -car3, 36 (III); 4.47 (H-4), 6.34 (H-2).
Example .25. 3-Acetyl-5,5-dimethyl-3 (B) - (2,4-chlorophenyl) -thiazolidin-4 (3) -carboxylic acid.
5,5-Dimethyl-2- (2,4-dichlorophenyl) -thiazolidin-4 (8) -carboxylic acid is suspended in 5.56 ml of boiling water.
35
phenylazolidin-4 (3) -carboxylic acid is suspended in 5 ml of pyridine, after which the suspension is cooled to 5 ° C with ice water. Then
The prepared suspension shift
0.17 g of acetyl chloride is added dropwise to the suspension. The mixture is additionally stirred for 1 h, and then drunk in 60 ml of 2 n. a solution with 5.56 MP of acetic anhydride, d of sulfuric acid, cooled with water, the mixture is cooled approximately with ice. After 1 h, the precipitate is filtered for 6 minutes at 100 ° C, then cooled, washed with water and then dried, after which the mixture is diluted with a shat. The product is recrystallized by adding approximately 10 ml of ethyl alcohol through drives. The crystalline substance is filtered from the solution to the water solution. As a result. Yield: 2.57 g (73.8%). A yield of 0.38 g (70.3%) of the title compound is obtained, m.p. 216-217 C,
0 (7 - 109 (with 0.686, methyl alcohol). M 270.3.
Calculated,%: N 5.18; 3 11.43. C nN nNOjS
Found,%: N 5.30; S 11.27. IR spectrum: 1732 cm- (CO); 1621 cm (amide.).
The product is recrystallized from aqueous methyl alcohol. M.p. 233-235 C.
Cc / 7 -142 °. M 350.08. Calculated,%: S 9.20.
50
Found,%: S 9.08.
IR spectrum: 1738 (CO).
 H-NMR Spectrum: 1.27 (s, CHj); 1.37 (s, CHP; 1.56 (s, CHj); 1.60 (s,
CHij); 2.02 (N-COCH3); 4.49 (s, H-4), 55 i ,, 62 (s, 3H, CH 3); 1.85 (s, 3H, 4.78 (s, H-4); 6.27 (s, H-2); 6-44 NCOCH3); 4.60 (s, 1H, H-4); 6.24 (s,
(s, H-2), 7.60-8.00 (multiplet, 3N, arom.).
H-NMR Spectrum: 1.37 (s, 3N, CBj);
1H, H-2); 7.30-7.75 (multiplet, 5P, arom.).
Example 26. C-Acetyl-5,5-dimethyl-2 (3) - (p-tolyl) -thiazolidin-4 (5) - carboxylic acid.
To a suspension of 2.51 g (10 mmol) of 5,5-dimethyl-2- (p tolyl) -thiazolidine-4 (S) -carboxylic acid in 5.6 ml of boiling water, 5.6 ml of acetic anhydride was added. The mixture is kept in
for 5 min at 100 ° C. After cooling from the reaction mixture, there was a gap (73.3%), so pl. 214-218 pp. -101 (c 0.71, methyl
A crystalline substance is precipitated, which is recrystallized from isopropyl alcohol. Yield 2.15 g
for 5 min at 100 ° C. After cooling from the reaction mixture, there was a gap (73.3%), so pl. 214-218 pp. -101 (c 0.71, methyl
alcohol). M 293.3.
Calculated,%: N 4.77; S 10.93.
S jH ,, 1 GOZ S
Found,%: N 4.66; S 10.91.
IR spectrum: 1732 cm (CO).
 H-NMR spectrum: 1.35 (s, .ЗН, СН,); 1.59 (s, 3N,); 1.81 (s, 3N, NCOCHj); 2.30 (s, 3N, arom. -SI); 4.58 (s, 1H, H-4); 6.23 (s, W, H-2); 7.14-7.63 (multiunchet, 4H, arom.).
Example 27. 3-Acetyl-5,5-dimethyl-2 (3) -phenylthiaz-olidin-4 (3) -car
phenylazolidin-4 (3) -carboxylic acid is suspended in 5 ml of pyridine, after which the suspension is cooled to 5 ° C with ice water. Then
0.17 g of acetyl chloride is added dropwise to the suspension. The mixture is additionally stirred for 1 h, and then drunk in 60 ml of 2 n. sulfuric acid solution cooled with ice water. After 1 h, the precipitate is filtered, washed with water and then dried. The product is recrystallized from ethyl alcohol by adding water to the solution. As a result, 0.38 g (70.3%) of the title compound is obtained, m.p. 216-217 C,
 (s, 3H, CH 3); 1.85 (s, 3H, H3); 4.60 (s, 1H, H-4); 6.24 (s,
H-NMR Spectrum: 1.37 (s, 3N, CBj);
 i ,, 62 (s, 3H, CH 3); 1.85 (s, 3H, NCOCH3); 4.60 (s, 1H, H-4); 6.24 (s,
1H, H-2); 7.30-7.75 (multiplet, 5P, arom.).
Example 28. 3-Acetyl-5,5-dimethyl-2 (3) - (4-acetoxyphenyl) -thiazolidine-4 (8) -carboxylic acid.
1.5 g of 5,5-dimethyl-2- (p-hydroxyphenyl) -thiazolidin-4 (8) -carboxylic acid is held for 20 min in a mixture of 15 ml of pyridine and 3 ml of acetic anhydride. Then the mixture is evaporated. Toluene is distilled off from the residue twice, each time taking in an amount of 30 mp. The residue is recrystallized from a mixture of acetone and petroleum ether. The result is 1.5 g (75%) of the compound
specified so pl. 199-201 s. -61.7 ° (with 0.52, chloro
forms). M 337.18.
Calculated%: N 4.12; S 9.43.
With f Il NOi-S.
Found,%: N 4.15; S 9.42.
IR spectrum: 1734-1770 cm- (CO).
 1 H-NMR spectrum: 1.30 and 1.51 (C-methyl); 2.27 (HCOCH3); 3.36 (OH); 4.55 (H-5); 6.45 (H-2).
Example 29. 3-Acetyl-5,5-dimethyl-2 (3) - (p-fluorophenyl) -thiazolidin-4 (8) -carboxylic acid.
5.1 g (20 mmol) of 5,5-dimethyl-2- (p-fluorophenyl) -thiazolidine-4 (S) -carboxylic acid are suspended in 11.2 ml of boiling water, after which the prepared suspension is added dropwise to the prepared suspension. m 11.2 m of acetic anhydride. The reaction mixture was incubated for -5 at. After cooling, a crystalline substance is precipitated from the reaction mixture. The result is 5.83 g (98%) of the product.
T
A solution of 1.17 g (5 mmol) of 5,5-dimethyl-2- |) enylthiazolidin-4 (8) -carboxylic acid and 0.7 ml of triethylamine in 20 ml of dichloromethane is cooled until the cooled solution is mixed with stirring with a solution of 2- (p-chlorophenoxy) -isobutyric acid chloride in 4 ml of dichloromethane. The mixture is stirred for 3 hours and then extracted with water. The organic is recrystallized from sulfur dioxide.
C ethyl alcohol and diethyl ether. M.p. 193.5 ° C.
S -95.8 ° (with 0.62, methyl alcohol). M 297.3.
Calculated,%: N 4.71; S 10.78.
C AN FNOJS.
Found,%: N 4.63; S 10.85.
IR spectrum: 1735 cm- (CO); 1626 cm (amide.).
 n-NMR spectrum: 1.37 (C-CH ,, s, 3N); 1.62 (C-CH3, S, 3N); 1.85 (N-SaNe); ° 4.60 (H-4, S, III); 6.24 (H-2, d, .Ш); 7.05 (H-3, H 5, S, 2H); 7.80 (H -2, n-b, S, 2H) ..
Example 30. 3-Acetyl-5,5-dimethyl-2 (5) - (5-nitrofuryl-2) -thiazol-55 dyn-4 (5) -carboxylic acid.
2.72 g (10 mmol) of 5,5-dimethyl-2- (5-nitrofuryl-2) -thiazolidin-4 (S) with dye, and then evaporated. The syrupy product is crystallized from methyl alcohol with the addition of water. This gives 1.39 g (64%) of the indicated compound, m.p. 177-178 C.
12 O (with 0.9A, dimethyl sulfone seed). M 433.9.
Calculated,%: N 3.23; S 7.39; C1 8.17
C, tH 9ClNO S
Found,%: N 3.11; S 7.68; C1 8.14.
. IR: 3017 and 2975 (CH3); 1740 (CO); 1609 (amide II).
 n-NMR spectrum: 1.32; 1.39; 1.44 and 1.55 (4 X 3s, CH3); 5.04 (s, 1H,, H-4); 6.25 (s, W, H-2); 6.75-7.35 (multiplet, 9 N, arom.).

ten
15
20
25


Jq 35
carboxylic acid is dissolved in 5.6 MP of water. The solution is heated on a steam bath to a temperature, then the heated solution is mixed with 5.6 MP of acetic anhydride, after which the mixture is additionally heated for 3 minutes. After adding water from the reaction mixture, the product is precipitated (2.6 g, 84.3%). The original compound is prepared as described in Example 1. mp. the final product 191-194 C.
 -315.8 ° (c 0.938, dimethyl sulfoxide). M 308.3.
Calculated,%: N 9.08; S 10.40.
C “H ,, N., 0, S
Found,%: N 8.72; S 10.13.
IR spectrum: 1740 cm- (CO). n-NMR spectrum: 1.30 and 1.41 (CHR; 1.57 and 1.61 (CHj); 2.03 (NCOCH); 3.45 (OH); 4.50 and 4.79 (H -4); 6.37 and 6.71 (H-2); 6.95; 7.16; 7.71 and 7.76 (arom.).
Example 31. 3- (2-p-Chlorophenoxyisobutyryl) -5,5-dimethyl-2 (5) -phenylthiazolidin-4 (5) -carboxylic acid.
A solution of 1.17 g (5 mmol) of 5,5-dimethyl-2- |) enylthiazolidin-4 (8) -carboxylic acid and 0.7 ml of triethylamine in 20 ml of dichloromethane is cooled until the cooled solution is mixed with stirring with a solution of 2- (p-chlorophenoxy) -isobutyric acid chloride in 4 ml of dichloromethane. The mixture is stirred for 3 hours and then extracted with water. Organic Sulfuric Magician

and then evaporated. The syrupy product is crystallized from methyl alcohol with the addition of water. This gives 1.39 g (64%) of the indicated compound, m.p. 177-178 C.
12 O (with 0.9 A, dimethyl sulfoxide). M 433.9.
Calculated,%: N 3.23; S 7.39; C1 8.17
C, tH 9ClNO S
Found,%: N 3.11; S 7.68; C1 8.14.
. IR: 3017 and 2975 (CH3); 1740 (CO); 1609 (amide II).
 n-NMR spectrum: 1.32; 1.39; 1.44 and 1.55 (4 X 3s, CH3); 5.04 (s, 1H,, H-4); 6.25 (s, W, H-2); 6.75-7.35 (multiplet, 9 N, arom.).
 one
Example 32. Methyl 5,5-dimethyl 2 (8) - (5-nitrofuryl) -thiazolidine-4 (3) -carboxylic acid ester.
2.72 g (10 mmol) of 5., 5-dimethyl-2- (5-nitrofuryl) -thiazolidin-4 (S) -carboxylic acid is dissolved at room temperature in 50 ml of methyl alcohol, and then to the resulting solution while cooling, an ethereal solution of diazomethane, prepared from 4.45 g (43.2 mol) of nitroso methylcarbamide, is added. The reagent is added in small portions until a yellow color remains. After about 1 h, an excess of diazomethane is destroyed by adding a couple drops of lenticular acetic acid. As a result of the distillation of the solvent from the reaction mixture, the product is obtained in the form of a syrup-porous substance colored in pale yellow color.
Mass spectrum: 286 (M). M 285, 304
IR spectrum: 1743 cm (CO) (in kWh). Go (7,194 (c 0.670, chloroform).
 n-NMR spectrum: 1.3 (ZN, C-CHj) 1.68 (ZN, C-CHj) 3.8 (4H, 0-CH 5.7 (1H, Hj); 6.63 (1H, 7.26 (1H).
Example 33. Getting pills with the corresponding proposed biologically active substance, mg:
Biologically active
substance too ..
Potato starch 30
Milk sugar50
Bela gelatin 10
Sodium salt of carboxymethylcellulose 1
Polyvdo 2
Talc36
Magnesium stearate, 4
Colloidal dioxide
flint 3
Titanium dioxide1
Iron Oxide 2
Sucrose106
Uklekislm calcium 55



The biologically active substance is homogenized together with the excipients that form the core of the tablet, the mixture is granulated and dried, after which tablets are pressed from the mixture. The tablets obtained using the suspension method is covered with a layer of sugar.
Example 34. Getting pills with sootvetsvktsim proposed biologically active substance, mg;
0
five
0
3800
five
five
0
18
Biologically, active substance 100
Milk sugar 21.5 Sodium salt of carboxymethylcellulose 15 Microcrystalline cellulose100
Talc11
Magnesium stearate 4
Colloidal silica 2
Polymer based on acrylic ester of methacrylic acid0.3
Titanium dioxide. 3 Iron oxide pigment O, 1 The biologically active substance is homogenized with excipients. Tablets of 200 mg are obtained from the mixture. The resulting tablets provide a film coating.
To determine the acute toxicity of the compound, it is dissolved in an aqueous solution of sodium carbonate, after which the prepared solutions are administered in experimental animals (CFPL mice, females 40 days old) intraperitoneally (i, p.) Or intravenously (ijv).
In tab. 1 shows some characteristics of the LD u-value.
Table 1
The acute toxicity values are high enough to make possible the therapeutic use of the compounds.
For the study of the protective effect of the fungus, the compounds were introduced into male CFY rats weighing 200-240 g, which were not fed for 18 hours. Liver damage is caused experimentally by carbon tetrachloride, allyl alcohol or galactosacin. The activity of glutamate oxalacetate transaminase (GOT) in serum, the content of triglycerides is determined
1 14438
as well as liver histology,
chesku picture of the liver
In non-fed animals, a liver-damaging substance (1.5 g / kg of carbon tetrachloride, po, 0.75 g / kg of galactosamine ip; 20 mg / kg of allyl alcohol ip) is administered, and 6 hours later, animals are administered inside - peritoneally investigated compound in 100 mg / kg.


In tab. Figure 2 shows the data for determining the activity of glutamate oxalacetate transaminase in serum and triglycerides in the liver.
one
table 2
Control animals
Carbon tetrachloride CC14 carbon tetrachloride + compound in example 1 carbon tetrachloride + compound in example 2 carbon tetrachloride + compound in example 5 carbon tetrachloride + compound in example 7 carbon tetrachloride + compound in example 8 carbon tetrachloride + compound in example 10
Carbon tetrachloride + compound according to example 6 carbon tetrachloride + compound
according to example 11 carbon tetrachloride + compound according to example 9 carbon tetrachloride + compound according to example 4
25
81.7 + 16
269.0 + 14
40t3 86 + 17
thirty
244.0 + 14 51 + 15
229.0t14 84t6
243.0 ± 21 61 ± 14
224.0 + 14 61 + 13
234.0 + 23 76 + 10
227.0 + 40 8Т ± 11
250.0 + 13 88 + 10
235.0 + 19 70 + 14
35
40
45
50
323, Qt34 83t19 55
241.0 + 21,114 + 24
0
20 Continued
l ::::::::
Carbon tetrachloride + Catergen (substance for comparison)
tab. 2
::::: :: s:
241.0 ± 23 77i7
Q
five
five
0
five
0
five
0
five
Catergen: (+) - 2- (3,4-dioxyphenyl-3,5,7-chromantirol (known liver protecting compound).
In the group treated with only tetrachlorinated carbon, the concentration of GO-transaminase in serum increases by a factor of 3.3 as a result of liver tissue damage, which can be explained by the fact that intracellular GOT appears in serum. The triglycerides compound in the liver increased 2.14 times in this group. These changes correspond to the degree of necrotic changes that can be detected in a histological section. With the introduction of the proposed compounds, the activity of CO-transaminase falls indicated in table. 2 way.
The effect of the compounds used in the test for poisoning caused by allyl alcohol.
After 24 hours, the animals are sacrificed, after which the activity of glutamate-pyruvate transaminase (GBS) in serum is determined. After the addition of allyl o alcohol, the level of serum GPT increases from 1.81 + 0.43 µmol / ml-h to 4.16 + 1.63 µmol / cp-h. This level is reduced by administering 100 mg / kg of the compound corresponding to Example 1 to 2.84 + 0.97 µmol / ml ml.
The effect of the compounds used in the test for poisoning caused by galactosamine.
Galactosamine in the liver can be caused by necrosis accompanied by inflammatory symptoms and symptoms of fatty tissue degeneration. The compounds to be tested are administered intraperitoneally to animals 6 hours after galactosamine poisoning. Due to the compounds corresponding to examples 1 and 2, the number of parenchymal necrosis and the severity of changes characteristic of galactosamine hepatitis are reduced.

权利要求:
Claims (1)
[1]
Invention Formula
The method of producing thiazolidin-4 (8) -carboxylic acid derivatives or
2114A3800
salts with alkali or alkali-green metals or its complex s of the general formula
.sn
one
R A
3 SNS
COORr
(I)
ten
gd to
gd
de furyl-2, 5-nitrofuryl-2,
thienyl-2, 1-methylpyrrolyl-2, benzofur-1-2, pyridyl-3, pyridyl-4, 2-methyl-3-hydroxy-5-hydroxymethylpyridyl-4, indanyl-5 hydroxymethyl, free or monosubstituted by methyl, halogen, nitro, oxy-, carboxy-acetoxy or methylthio, or disubstituted by phenyl, 2-carboxy-3,4-dimethoxyphenyl or 3,5-dibromo-4-hydroxyphenyl;
Rj is hydrogen, the equivalent of an alkali or alkaline-earth metal or C -C-alkyl; R 3 is hydrogen or free or substituted by the 4-chlorophenoxy C-C4-alkanoyl group, provided that R. can mean
acetoxyphenyl, only when R 3 means acetyl,
differing in that
compound of general formula
SNS
Hsx he
 (Ii)
K HN - -COOH
 one
0
22
where Cs has the indicated meanings, is reacted with an aldehyde of the general formula
R, CHO,
(Iii)
0
five
20
five
thirty
five
R
so R has the indicated lengths.
none other than acetoxyphenyl5 in the case when Rg is hydrogen,
B water or methyl alcohol or their mixture at a temperature from room temperature to the boiling point of the reaction mixture, or in the case when R is 4 alkanoyl, in a solution of hydrogen chloride in diethyl ether at room temperature, and the desired product is isolated as free acid or its converted to salt with an alkaline or alkaline-earth metal, or to a C -C-alkyl ester, and / or the target product, where Rsr is hydrogen, is reacted with the anhydride or acid chloride of the corresponding carboxylic acid in water or pyridine or in d chloromethane in the presence of a tertiary amine to obtain the desired product where R3 is C-C4 alkanoyl, is free or substituted by 4-chlorophenoxy, and in the case of using the desired product, where R 1 is hydroxyphenyl, and acetic anhydride while simultaneously obtaining the desired product, where acetoxyphenyl .
one

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同族专利:

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公开号 | 公开日

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PL148541B1|1989-10-31|

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IN165646B|1989-12-02|

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GB2177089A|1987-01-14|

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US4775675A|1988-10-04|

---

IL78942D0|1986-09-30|

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FI862608A0|1986-06-18|

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DK259386D0|1986-06-02|

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PL149453B1|1990-02-28|

---

DK259386A|1986-12-19|

---

PT82769A|1986-07-01|

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GB8614616D0|1986-07-23|

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HUT41774A|1987-05-28|

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SU1475905A1|1989-04-30|

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PH22790A|1988-12-12|

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AR241532A1|1992-08-31|

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ES556135A0|1987-12-01|

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PT82769B|1988-04-21|

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GR861517B|1986-10-10|

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JPS6248672A|1987-03-03|

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HU200177B|1990-04-28|

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NO862408L|1986-12-19|

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KR870000312A|1987-02-17|

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GB2177089B|1989-07-19|

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BG46457A3|1989-12-15|

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EP0206197A1|1986-12-30|

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NO862408D0|1986-06-17|

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CN86104085A|1987-04-22|

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ES8800919A1|1987-12-01|

---

DD259866A5|1988-09-07|

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FI862608A|1986-12-19|

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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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HU852388A|HU200177B|1985-06-18|1985-06-18|Process for producing thiazolidinecarboxylic acids and pharmaceutical compositions comprising such compounds|

---