前苏联专利SU1240356A3 Method of producing thiazolidine derivatives

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专利摘要:
New thiazolidine compounds of the formula (I) having anti-ulcer activity are disclosed: <IMAGE> (I) wherein Ar is a 2-furyl or a phenyl, naphthyl or pyridyl group optionally substituted by one or more C1-4-alkyl, C1-4-alkoxy, halo-C1-4-alkoxy, dihalomethyl, trihalomethyl, hydroxyl or nitro groups or by a group of the formula (II), <IMAGE> (II) wherein Y is nitrogen or CH; Z is cyano or carbamoyl if Y is nitrogen, and represents a nitro group if Y is CH. Also disclosed are several processes for preparing the new compounds as well as pharmaceutical compositions and method of treatment employing same.
公开号:SU1240356A3
申请号:SU843799805
申请日:1984-10-17
公开日:1986-06-23
发明作者:Эзер Элемер；Харшаньи Кальман；Домани Дьердь；Спорни Ласло；Матуз Юдит；Хегедюш Бела；Паллаги Каталин；Сабадкаи Иштван；Тетеньи Петер
申请人:Рихтер Гедеон Ведьесети Дьяр Рт (Инопредприятие)；
IPC主号:

专利说明:

one
The invention relates to methods for producing new thiazole derivatives, which have pharmacological activity, and can be used in medicine.
The purpose of the invention is the creation of new thiazolidine derivatives possessing. anti-ulcer activity without adverse effects on the body.
PRI and measures 1. 3-Bensh1-2-cyanimy utiazolidine (compound A).
To a boiling mixture of 1.27 g (10 mmol) of 2-cyanimothiazoline, 2 ml of acetone fi 1.52 g of calcined carbonate. 1.3 ml (11 mmol) of benzyl bromide are added. After boiling (4 hours), the precipitated salt is filtered off and the filtrate is evaporated. The crystalline residue is triturated with ether and filtered. Obtain 2.03 g of 3-benzyl-2-cyanimino-thiazoludine (93.5% of theory), mol.m. 217.29, m.p. 102-104 ° C. After recrystallization, the melting point remains unchanged.
Found,%; C 60.98} H 5.02; N 19.57 j S 14.96.
C 41 (3
Calculated,%: C 60.80; H 5.10i N 19.34J S 14.76.
IR spectrum (KBr), cm1 2190,
1570, - (wide).
NMR (CDClI), MF: 3.38, multipat (2), -S-CHj-: 3.85 multiplet
2), N-CHj - heterocyclic.); 4.65 singlet (2), H-CHg -. (Phenyl) i 7.38
singlet (5), -Ag-N.
Similarly to the method described, the following compounds teach. ; . 3-Benzyl-2- (carbamosh1imino) -thiazolidine, mol.m. 235.31, mp. 143-. after recrystallization from ethanol m.p. rises to 148 ° C.
Found,%: C 56.10 H 5.46, N18.10.
.
Calculated,%: C 56.15 J H 5.97; N 17.86.
IR Spectrum (KBr), 3320, 3260, 1645, 1540; C N-,
NMR (CDClI + DHCO - dg), m G, 05 triplet (2), - S-CHj-; 3.5 triplet (2), N-CHj - (reterocyclic); 4.75 singlet (2), N-CHj - (phenyl); 5.6; 7.32 singlet (5), Ag-H.
3562. :;
3-Benzyl-2-nitromethylenothiazolidine, T.Sh1. 136-138 ° C, after recrystallization from 140 ml of ethanol, 4.08 g of pure product is obtained, mol.m. 236.30, m.p. 139 ° C. Found,%: C 55.81, H, 4.99; N 11.89.
Calculated,%: C 55.91 {H 5.12 N 11.86.
IR spectrum (KBG),, 1633, C-C-, 1535, 1354, L-NOj.
NMR (CDClI), ppm: 3.1-S-CHj triplet; 3.8 ppm triplet;:; N — CHj- (heterocyclic .-) 4.43 singlet, N — CH2- (); 6.97 singlet, 7.0-7.3 mn Tiplet, -Ag-H.
2-Cyan # 1ino-3- (4-methoxybenzyl) - -thiazolidine, mol.m. 247j31, ttpl. 99- 102 ° C.
Found %: C 58.35, - H 5.17.
; s, 2H ,, Nz08. :
Calculated,%: C 58.28, H 5.30. IR spectrum (KVg),: 2840, -O-CHji 2185; . 1570, 1608, 814, -Ar.
NMR (CDClI), ppm; 3.3 multiplet, -S-CHj-; 3.7 multiget, rN-CH -; 3.75 singlet, -O-CH, 4.43 singlet, N-CH2- (CgH, j); 6.9 quadruplet, -Ag-H.
2-Cyanimino-3- (2-furylmethyl) - -thiazolidine, mol.m. 207.25, m.p. 124-125 C.
Found,%: N 20.38, -S 15.44.
Calculated,%: N 20.28; S 15.47. HK-cneKTpjr (KBr),. : 2185j
1750, 1238, - С-О-СГ,
795- -Ar-H. NMR (CDCIj), MD: 3.3 multiplet,
-S-CHj -; .3,7. multiplet, -N-CH (heterocyclic); 4.57 singlet
-N-CH ,, - Arv 6.3 doublet, -Ar- (3.4) H;
7.3 multiplet-Ar- (5) H. 2-Cyanimino-3- (4-methylbenzyl) -thiazolidine, mol.m. 231.31 t.p. 102104 ° C.
Found,%: C 62,16GN 5.52; S 13.96. .
With „.Н ,, Нз8
Calculated,%: C 62.26; H 5.66; S 13.85.
JK-spectrum (KBG), CM S 2190, -CsN; 1590, 1260, -S-CH, -; 792 -Ar.
NMR (CDClI), ppm; 2.31 singlet, -CH3, 3.3 multiplet, -S-CH -; 3.7 multiplet, (heterocyclic) J
3 .. 1
, 54 singlet, N-CH ,,. (fenien); 7.10 singlet, -Ag-H.
3- (2-Furylmethyl) -2-nitromethylene-azolidine, mp. 190-192 ° C. After recrystallization from nitromethane, the melting point remains unchanged. IR spectrum (KBG), cm: 1543, 1340, -NOj; 1640, 3130, 757 furan, 5C-HJ 1243,: C-0-C.
NMR (trifluoroacetic acid), MD: 3.7 triplet, -S-CH -; 6 triplet, li N-CH -; 5.07 singlet, 5N-CH2 - (C Hz 0), 6.3 doublet, -CH-NO; 6.5 multiplet, furan (3.4) H; 7.5 multiplet, furan 5H. .2-Cyanimino-3- (4-hydroxybenzyl) - -thiazolidine, m.p. 175-177 C.
IR spectrum (KVg),: 2190, -CrN, 1570, 3210 ,. -HE; 1610, 840, -Ar. . . NMR (CDClg), ppm, 3.4 multiplet, -S-CHj; 3.7 multiplet, N-CH2-; 4.5 singlet, -Ag-CH ,, -; 6.9 quad- plet -Ag-N; 9.47 singlet, - OH.
Example 2. 2-Cyanimino-W-. - (4-chlorobenzsh1) -thiazolidine.
3.82 g (30 mmol) of 2-cyanimino-thiazolidine, 4.9 g (30 mmol) of 4-shchor besyl chloride and 4.3 g of calcined potassium carbonate are boiled in 100 ml. acetone for 5 hours. At the end of the reaction, the inorganic salt is separated by filtration and the acetone solution is evaporated. Crystalline residue comfort from 40 ml of isopropanol. 6,26 g of 2-cyanimino-3- (4- -chlorobenzyl) -tyaz olydine (83% of theory) are obtained, mol. M. 251.74 mp. 131 - 133 ° С
Found,%: C 52.72; H4.18, N 16.49.
С „Н, ОСШзЗ
Calculated,%: C, 52.48; H 4.00, N 16.69.
IR spectrum (KBG), cm: 2185, -CrN; 1560, 1092, -Ar-Cl.
NMR (COCl3 + DMCO - dg), ppm: 3.3 multiplet (2), -S-CH -; 3.8 multiplet (2), -Nj-CH - (heterocyclic) {4.50 singlet (2), :: N-CH2 (); 7.12 singlet (4), -Ag-H.
PRI me R 3. 2-Cyanimno-Z- - (3,4-dichlorobenzyl) -thiazolidine.
Analogously to Example 2 3.82, g (30 mmol) of 2-cyaniminothiazoline and 6 g (31 mmol) of 3,4-dichlorobenzene;
15
20
five
0
40356-4.
After the reaction is complete, the residue after evaporation is recrystallized from 50 ml of ethanol. 6.8 g of 2-cyanimino-3- (3,4-di-5-chlorobenzyl) -thiazolidine are obtained, mol. M. 286.18, mp. 130-1.32 ° C.
Found,%: C, 46.12; H 3.18i S 11.22.
WITH"
10 Calculated,%: C 46.16i H 3.17 {S 11.21;
IR spectrum (KBG), cm: 2190, 1570, 1060, -Ar-Cl.
-. . ,,
NMR (CBC1), ppm, 4 multiplet (2), -S-CHj-; 3.7 multiplet (2). L-CH3- (heterocyclic). {4.56 singlet (2), N-CH2- (3,4-dichlorophenyl) 6.9-7.5 multiplet (3) -Ag-H.
Example 4. 2-Sch1-animino-3- - - (4-nitrobenzyl) -thiazolidine.
2.54 g (20 mmol) of 2-cyanimino-thiazolidine, 3.43 g of 4-nitrobenzyl chloride and 2.85 g of anhydrous potassium carbonate are boiled for 6 hours in 80 ml of acetone. The precipitated salt is filtered off, the solution is evaporated and the residue is crystallized from 30 ml of acetonitrile. Get 3,66 g (70% according to theory) 2-cyanimino-3- (4-. -Nitrobenzyl) -thiazolidine, mol.m. 262.29, m.p. 171 ° C. . . Found:%: 50.36; H 3.94; : N 21.46. ..
C,; H, oN 0.3.
5 Calculated,%: C 50.37 | H 3.84; N 21.36. .
IR Spectrum (KBG), 2190}, 1575, 1505, 1343, -NQj.
NMR (C1) Cl3 + DMSO-dg), M.D.: 3.4 0 multiplet (2), -S-CH -; 3.8 multiplet (2), ;;; N-CHj-; 4.65 singlet (2), ::: N-CHj - (-irrNOj) f 7.35 doublet (9 H) (2) -Ag-H (2.6), 8, U5 doublet (9 N., ) (2), -Ag-H (3.5). 5 Example 5. 2-Cyanimino-3- - (2-oxCi-5-nitrobenzyl) -thiazotdine.
3.82 g (30 mmol) of 2-cyanimine, o- - thiazolidine, 5.63 g (30 mmol) of 2-ox-5-nitrobenzyl chloride, and 4, 3; g 0 of anhydrous potassium carbonate in 100 ml of acetone is boiled t for 6h. After cooling the reaction mixture, the precipitates are separated by filtration (9.85 g) and dissolved in 600 ml of 5 hot water. The solution is filtered, the clear filtrate is acidified to pH 3 and cooled, the precipitate is separated by filtration and dried. Obtain 5.1 g of 2-cyanimino-3- (2-hydroxy-5-nitrbenznl) -thiazolidine, the product recrystallized from pyridine melts at 253-255 ° C, mol.m. 278.29.
Found,%: C 47.78, H 3.71, N 20.01.
С „Н, рЫ40,8, Calculated,%: С 47.47; H 3.62; N20.13. . J.
IR spectrum (KBG),: 31.00, (wide) -OH} 2190, 1575,, l522, 1338, VNOj. ,
NMR (CBC1 + DMCO - dg), ppm: j 3.4 multiplet (2), -S-CHj-; 3.8 multiplet (2), (heterocyclic), 4.54 singlet (2), -CHj- (2-OH, S-Oj-CjHj); 6.88 - triplet (I), -Ar-H (3); 8.00 multiplet (2), -Ar-H (4.6), 3.9 doublet (1), -OH.
EXAMPLE 6. 2-Cyanimino-3- - (3-hydroxybenzyl) -thiazolidine.
A mixture of 3.82 g (30) of 2-cyano-: iminothiazolidine, 6.10 g (30 mmol) of cresylboric acid acetate and 4 of 30 g of anhydrous potassium carbonate in 100 ml of tone is heated under reflux for 6 hours. filtering off the precipitate, the filtrate is evaporated to dryness, the oily residue (8.75 g) is cleaved with 50 ml of 2 N for removal of the ester phenyl group. sodium hydroxide solution at room temperature. The reaction mixture is acidified, the separated oil is separated, the AC crystallized from acetonitrile, and recrystallized from 50% acetone. 1.98 g of 2-cyanimino-3- (3-hydroxybenzyl) -thiazolidine-, mol.m. 233.29, m.p. 126-128 C.
Found,%: C 56.70 i H 5.07; S 13.75 | N 17.83. С „Н ,, NjOS
Calculated,%: C 56.63 / H 4.75, S 13.75i N 18.02.
Zh-spectrum (KVg),: 3260,. 1230, -OH; 2190, -SgN; 1570, - NMR CBCI3 + DMSO-dg), ppm {3.3 multiplet (2), -S-CHj-; 3.7 multiplet (2), N-CH - (heterocyclic); 4.48 singlet (2), rN-CH - (oxyphenyl), 6.5-7.4 multiplet (A) Ar-H; 8.6 doublet (1), - OH. - And p im 7. 7. 2-Cyanimino Z- - (1-naphthylmethyl) thiazolidine.
Sulfur 3.82 g (30 mmol) 2-cyaniminothiazolidine, 5.56 g (30 mmol)
1-chloromethylnaphthalene and 4.3 g of potassium carbonate in 100 ml of acetone are refluxed for 56 hours. The precipitate is removed from the still hot reaction mixture by filtration, and the product begins to precipitate during filtration. After concentration and retention in a refrigerator, a total of 6.5 g of 2-cyanimino-3- (1-naphthylmethyl) -thiazolidine (81.15% of theory) are obtained, the product recrystallized from acetonitrile melts at 167 ° C, mol. 267.34. 15% found: C, 67.32; H 4.80 N, 15.78; S, 11.06. CjjH NjS Calculated,%: C 67.39; H 4.90 N, 15.72; S 12.00.
20 IR spectrum (KBG),: 2190,, 1580,.
NMR (CDClj + DMSO-dg), MD: multiplet (2), -S-CHj-; 3.6 multiplet (2), -N-CH, j- (heterocyclic. Of 25 4.92 singlet (2), -N-CH - (naphthyl), 7.0-7.9 multiplet (7), - Ar-H.
Example 8. 3.3- (1,4-Kcilylene) -5ttC - (2-cyaniminothiazolidine). , Q A mixture of 4.5 g (26 mmol) of 1,4-xylylene dichloride, 6.36 g (50 mmol) of 2-cyanimothiazolidine, and 7.17 g of anhydrous potassium carbonate in 150 ml of acetone are refluxed for 7h, cooled in the refrigerator, the reaction mixture is filtered. Of. a separate precipitate (15.48 g) is extracted with an inorganic part with cold water, c. 8.1 g 3, s - - (1,4-xylyl en) - 5t / c- (2-cIminimothiazolidine) (91.0% of theory), recrystallized from. 70 ml of dimethylformamide product melts at 275-278 ° C, mol.m. 356.47. Found: C 53.70 / H 4.78 S 17.85J N 23.37.-
Calculated,%: C 53.91; N. 4.52; S 17.99; N 23.58. IR spectrum (KVg): 2180;
1570, ::; c-N- ..
NMR (DMSO-dg), ppm i3.4 multiplet (4),.-S-CHj-i 3.7 multiplet (4), -N-CHj- (heterocyclic), 4.50 syn- 5 glut (4), -N-CHj- (phenylene), 7.18 singlet (4), -Ag-H.
Example 9. 2-Cyanimino-3- (6- -methyl-2-pyridylmethyl) -thiazolidine.
five
five
/
A mixture of 3.3 g (26 mmol) of 2-cyaniminothiazolidine, 4.03 g (28.5 mmol) of 2-chloromethyl-6-methylpyridine and 3.9 g of anhydrous potassium carbonate in 60 ml of acetone is boiled in reverse refrigerator until the starting thiazoline compound was completely consumed (approximately 6 hours). After filtering off the separated salt, the solvent was distilled off and the residue was crystallized by addition of 40 mL of diethyl ether
5.43 g of 2-cyanimino-3 - (6-methyl-2-pyridsh1methyl) -thiazolidine (89.9% of theory) are obtained, the product recrystallized from ethyl acetate melts at 114 ° C, mol.m. 232.30.
Found,%: C 56.77, H 5.12, N 24.18.
C ,, H,
Calculated,%: C 56.67; H 5.20, N 24.12.
IR spectrum (KBG), cm: 2190,, -teN; 1570,.
NMR (CDClI), ppm: 2.48 singlet (3), -pyridyl-CH, i 3.3 multiplet (2), -S-CHg-, 3.9 multiplet (2), N-CHj- ; 4.60 singlet (2)::; N-CH2-Pyj 6.9 doublet (2), —Ru — 2.5 N; 7.4 (1), —Ru 4-H.
Example 10. 2-Cyanimino-3- - (6-dichloromethyl-2-pyridam1methyl) - -thiazolidine. 6, 6 g (52 mmol) of 2-cyanimine-thiazo-lidine, 12 g (57 mmol) of 2-dichloromethyl-6-chloromethylpyridine and 7.9 g of anhydrous potassium carbonate in 240 ml of acetone are reacted in the same way as the examples given. After filtering off the resulting salt and distilling off the solvent, the residue is triturated with ether and crystallized from acetonitrile. 5.2 g of 2-cyanimino-3- (6-dichloromethyl-2-pyridylmethylU-thiazolidine) are obtained (33% of theory), mol. M 301.19, mp. 122 ° C.
Found,%: C 43.91 H 3.46, S 10.80.
, oCl2N S
Calculated,%: C 43.86 ,, H 3.34 S 10.64.
ShS-spectrum (KBV),: 2180, 1560, (wide) 718 -CH-CJ.
NMR (CDCl 3), ppm, 3.34 triplet (2), -S-CHj-; 3.97 triplet. (2), N-CHj-; 4.62 singlet (2), :: N-CH.j (phenyl); 6.50 singlet (1), -Py-CHj-J 7.0-7.8 multiplet (3) ,, -Ru-H.
According to the proposed invention, among the compounds of general formula (I) obtained, especially 3-benzyl-. -2-cyanimothiazolidine (compound A) has a preferred singularity. properties. The rest of the compounds obtained by the general formula (I) were also, to a more or less low degree, significantly active.
For the pharmacological study of the proposed compounds, the methods described are used.
Shay's ulcer.
Female H-Wistar rats weighing 120-15Qg each hold no food for 24 hours in trellis cages and supply them only with drinking water. The pylorus of the animals is then subjected to a soft etheric drug and is simultaneously treated with trap-inhibitory sound, which is investigated by the substance, which is studied by the inhibitor. After 4 hours, the animals are killed by ether narcosis. The animals' stomachs are taken out, the volume and pH are measured - the value of the stomach contents, in some cases the formation of hydrochloric acid is determined by titration.
35
Ulcer due to aspirin. It is known that nonsteroidal anti-inflammatory drugs in various
NOY can cause the formation of gastric and intestinal ulcers. Based on this action, the aspirin model has been successfully used for the test of suppressing ulcers. Female H-Wistar rats weighing 12–150 g for 24 hours without food are supplied only with water, then by oral administration using a suspension prepared with Tween IN with 100 mg / kg acetylsalicylic acid cause the formation of irritant in the glandular part of the stomach of animals. Simultaneously with acetylsalicylic acid, the test compound was also administered orally to the animals. After 4 hours, the animals are sacrificed and brown-red erosions on the glandular part of the stomach are counted. When evaluating the results, the average number of finding shchs in the stomach of ulcers, or the number of animals without ulcers, is indicated.
.Ball by indomethacin ..
Indomethacin (1 - (- Chlorobenzene) -5-methoxy-2-methylindol-3-acetic acid), a nonsteroidal anti-inflammatory agent, has not only gastric ulcer causing side effects, but also leads to an extremely strong formation of ulcers in thin intestine. This formation in the small intestine, depending on the dose, can also be fatal, since the inflammation of the peritoneum due to intestinal perforation is fatal.
dhi Indomethacin is a fatal model of intestinal ulcers.
For these experiments, female H-Wistar rats weighing 120-150 g each were fed, which are fed normally. By oral doses of 15 mg / kg indomethacin (in the suspension prepared with tween 80, they cause fatal intestinal ulcer formation. The test compounds are also administered orally to animals after indomethacin treatment. In order to develop intestinal ulcers, as opposed to gastric ulcers, a longer time is required (approximately 48 72 hours).
For the evaluation of the formation of stars, the so-called method of inflation is used, due to this method it is possible to quantitatively follow the process of formation of sounds. The strength at the time of rupture of the walls of the chi1Ts (, the cistern, which is indicated in mm Hg, gradually decreases with the increase in the intensity of the zoomed shape.
:. ff- Indomethacin-induced non-fatal intestinal ulcer model.
Normally fed H-Wista rats weighing 120-150 g each are treated orally with 7.5 mg / kg indomethacin to induce non-fatal intestinal ulcers. After 4 hours, the desired doses of the test compound were also orally administered to the animals, and this treatment was repeated after 24 and 48 hours. 24 hours after the last treatment, i.e. 72 hours after induction of induction from induction with the help of indomethacin, the animals are sacrificed, and the so-called puff method is also used to assess the formation of sounds.
Induced with absolute alcohol model of gastric necrosis.
Female H-Wistar rats weighing 120-150 g each are kept 24 hours without food and
supply only drinking water. Then the animals are orally treated with the test compound. And after 30 minutes, they are given 0.5 ml per 100 g of body weight — absolute alcohol through a probe. 2 hours after giving alcohol, the animals are killed, the stomach is removed, cut along a large bulge, washed slightly and stretched. The longitudinal neurotic bands visible on the glandular part are measured in millimeters and are evaluated according to Derelanko and Long. Indicate
5 the average length of lesions on the stomach, a measure of gastric cytoprotection is expressed as a percentage of fi calculated on control animals.
0 Pharmacological studies carried out in the course of the methods described have shown that they are considered as a particularly preferred representative of compounds of the general formula
5 (I) 3-benzyl-2-cyanimothiazoline
(Compound A) in all tests proved to be a very active inhibitory agent. This compound inhibits the secretion of gastric acid.
0 Shay-rats already in low doses (ED 5.3 mg / kg intraperitoneally). Aspirin (acetylsalicylic acid) -induced gastric ulcers, with simultaneous oral administration, are pressurized - ((Eodud 2.1 mg / kg orally). In the recently introduced Robert test with necrosis due to absolute alcohol, this compound is also active. Compound A of the simultaneous administration suppresses indometadine-induced intestinal sound formation, since the known agent dimetidin-N-cyano 5 -N-methyl-n- (2-) (5-methyl-1H-imidazole) is considered to be the best inhibitor. -4-yl) methyl (-thio) -ethylamine-yanidine cannot suppress indomethacin-induced intestinal ringing. This observation was confirmed by clinical trials: in patients suffering from laryngitis and rheumatism, with simultaneous treatment with cimetidine and indomethacin, perforations appear. Indomethin-induced intestinal ringing also cannot be inhibited by the anticholinergic agents used in human therapy.
In tab. 1-6 use the abbreviations: n is the number of animals, v. - body weight.
Table 1 shows the inhibitory acid-inhibiting acid of the gastric juice, the effect of compound A in the case. Shay rats (binding the pylorus of the stomach for 4 hours) in Table 2 - suppressive excretion of gastric acid, effect of Compound A on various treatments of the Shay rat after 4 hours in Table 3 - suppression of gastric / acetylsalicylic acid gastric ulcers concurrent treatment with compound. And in table 4 — dose-dependent inhibitory effect of compound A against indomethacin-induced intestinal formation with simultaneous treatment | f in table 5 — effect on 7.5 mg / kg induced oral doses of indomethacin, n fatal intestinal zvoobrazova- .nie due to additional processing and cimetidine sootvetstvenyo soe- union of Af in Table 6 - cytoprotective effect of compound A against absolute alcohol-induced gastric necrosis.
From the presentation in the table.1 data it can be seen that the compound reduces the excretion of gastric acid, depending on the dose. Compound A actively suppresses in Shay rats, also by oral administration, the allocation of gastric acid acid, as follows from the data in Table 2.
Acetylsalicylic acid-induced stomach formation in the stomach is suppressed, depending on the dose, by simultaneous treatment with Compound A, as well as induced by 20 mg / kg oral indomethacin gastric ulcers. The inhibitory effect of compound A on acetylsalicylic acid-induced ring formation is presented in Table 3.
The data in Table 4 show an inhibitory effect against oral doses of indomethacin on the small intestine induced by 15 mg / kg. Here the suppressive effect depends on the dose of compound A.
Important are the results obtained in experiments with the non-fatal model of intestinal ulcers. Treatment with compound A begins
.-
t
5 S 15 20 25

55
35
"
only when the formation of animals in animals has already been induced 4 hours earlier due to 7.5 mg / kg of pe1p6 indomethacin. In this case, we are talking about additional processing, namely, after 4.24 and 48 hours after the introduction of indrmetacinde. From the data of Table 5 it can be seen that under these conditions cimetidine is inactive, while compound A can normalize, depending on the dose, the strength at the moment of rupture of the intestine (intestine).
. Compound A is active against absolute alcohol-induced gastric necrosis. As shown by the data of table 6, this cytoprotection depends on the dose. .
Based on the results, compound A can be considered as an active inhibitory agent, whose spectrum of action exceeds by width the best products obtained in this area. The complex mechanism of action of compound A indicates that this compound is active in three models of ulcers with different mechanisms: in the model with induced acetylsalicylic acid - gastric ulcers, in the model with inddamethacin of small intestinal ulcers, in the model with induced absolute alcohol necrosis of the stomach.
A comparison of the results obtained with oral, intraperitoneal and subcutaneous administration shows that compound A is well absorbed when administered orally,
Based on the results of toxicological observations, compound A has a high therapeutic index.
Since compound A is insoluble. in water, toxicological studies used a suspension prepared with tween 80 for oral and, respectively, intraperitic. No use of biologically active substances. For intravenous administration, the biologically active substance was dissolved in dimethylformamide. The following observations have been made; 100 mg / kg intravenously: animals feel bad, no animal dies within 3 days, 250 mg / kg intraperitoneapuncture: within 2 weeks none at all, 1500 mg / kg intraperitoneally: animals die within 30 min , 1500 mg / kg orally: out of ten animals, three die within 24 hours, the rest remain alive even after a week, their behavior and food intake are normal. Example 11. Drug. .
To prepare a tablet drug (1000 tablets), use the following substances containing g: 3-Benzyl-2-cyanimino-thiazolidine (biologically active substance) 50 Starch75
Note ckie. 3
Milk-sugar 55 Talk10
Polyvinylpyrrolidone 6
Ammonium stearate 3 Colloidal silicic acid1 Finely ground biologically active substance is mixed with milk sugar and talc, the powder mixture is mixed with a solution of polyvinylpyrrolidone to form a paste
and granular through a sieve. The dried grains are mixed with magnesium stearate and colloidal silicic acid and the 3fTy mixture is pressed into -1000 tablets weighing 0.2 g each.
Table 1
Table 2
p 4: 0.01, compared with the indometacin group
ED
100
50
T a b l and c a 3
Control
Compound A
- -
-, .., II
Cimetidine I.

Table 5
B and Blitz 6
banged
|
II
: i5
12
50.0 100.0
p 0.01 compared with the control.
Continued tab.
34,0t10 47,0116
59 43

权利要求:
Claims (2)
[1]
1. METHOD FOR PRODUCING THIAZOLIDINE DERIVATIVES OF THE GENERAL FORMULA
N-CH ₂ -Ar> _S ^ YZ Ci) where Y is an amino group;
Ζ is a cyano- or carbamoyl group or a radical Υ-Ζ is a group = CH-NO ₂ ;
Ag is phenyl, free, or monosubstituted with hydroxy, methoxy, methyl or nitro, or mono or di-substituted with a halogen atom, or di-substituted with oxy and nitro, pyridyl-2, monosubstituted with methyl or, dichloromethyl, furyl 2- or naphthyl-1, or if Y is an imino group and Z is a cyano group, Ar is a radical of the formula by the reaction of a compound of the general formula
YH.-Z (s) where Y and Z have the indicated ения values, with a compound of the formula
Ag-CH ₂ -X _l where Ag has the indicated meanings,
X is a halogen atom,. · In an organic solvent in the presence of an acid binder, at the boiling point of the reaction mixture.
[2]
2. The method according to claim 1, with the fact that lower alcohol or acetone is used as an organic solvent and potassium carbonate is used as an acid binder.
¹ 1240356

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同族专利:

公开号 | 公开日

FR2542740A1|1984-09-21|

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FI79843C|1990-03-12|

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PL142909B1|1987-12-31|

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SE8401463D0|1984-03-15|

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CS188584A2|1985-06-13|

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NO841002L|1984-09-17|

CH660592A5|1987-05-15|

DD216929A5|1985-01-02|

ES8601170A1|1985-11-01|

NO162858B|1989-11-20|

NL8400817A|1984-10-16|

ATA88284A|1986-12-15|

IT8420057D0|1984-03-15|

IL71249D0|1984-06-29|

SE455945B|1988-08-22|

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PL246683A1|1985-07-16|

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ES8604179A1|1986-01-16|

CA1273933A|1990-09-11|

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SE8401463L|1984-09-17|

YU47384A|1986-10-31|

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PL142749B1|1987-11-30|

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引用文献:

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

EA008865B1|2002-11-22|2007-08-31|Смитклайн Бичам Корпорейшн|2-imino-4-oxothiazoline derivatives|FR3965M|1963-09-18|

DE2205745A1|1972-02-08|1973-08-23|Thomae Gmbh Dr K|N-cyanoimino substd heterocyclic cpds - inters for eg antidiabetics and diuretics|

US4006156A|1975-06-27|1977-02-01|Shell Oil Company|3-Alkyl-2- thiazolidine|

DK173777A|1976-05-03|1977-11-04|Merck & Co Inc|Chain link conveyor and use thereof|

JPH026354B2|1981-04-14|1990-02-08|Taiho Pharmaceutical Co Ltd|

JPH0234949B2|1981-08-03|1990-08-07|Santen Pharma Co Ltd|

DE3133918A1|1981-08-27|1983-03-17|Bayer Ag, 5090 Leverkusen|2-ARYLHYDRAZINO-2-THIAZOLINE, ACYL DERIVATIVES THEREOF, 2-ARYLAZO-2-THIAZOLINE, PRODUCTION METHOD AND THEIR USE FOR CONTROLLING EKTO AND ENDOPARASITES|

JPH0354077B2|1982-06-19|1991-08-19|

JPH033667B2|1982-08-19|1991-01-21|Fujimoto Seiyaku Kk|JPS6051184A|1983-08-30|1985-03-22|Fujimoto Seiyaku Kk|N-cyanoiminothiazolidine derivative and its preparation|

US5204360A|1985-02-04|1993-04-20|Nihon Bayer Agrochem K.K.|Heterocyclic compounds|

US5001138B1|1985-02-04|1998-01-20|Bayer Agrochem Kk|Heterocyclic compounds|

DE3681465D1|1985-02-04|1991-10-24|Nihon Bayer Agrochem K.K., Tokio/Tokyo, Jp|

JP2607369B2|1987-02-20|1997-05-07|興和株式会社|New heterocyclic compounds|

US5122522A|1989-06-21|1992-06-16|The Trustees Of The University Of Pennsylvania|Treatment and control of ocular development|

ES2136686T3|1989-06-21|1999-12-01|Univ Pennsylvania|TREATMENT AND CONTROL OF EYE DEVELOPMENT WITH CHOLINERGIC AGONISTS.|

HU207047B|1989-11-07|1993-03-01|Richter Gedeon Vegyeszet|Process for producing new pyridine derivatives and pharmaceutical copositions comprising same|

US5240918A|1992-03-24|1993-08-31|Egis Gyogyszergyar|2--thiazolidines and process for the preparation thereof|

JP2721805B2|1994-07-22|1998-03-04|日本バイエルアグロケム株式会社|New heterocyclic compounds|

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DE4427539A1|1994-08-04|1996-02-08|Sueddeutsche Kalkstickstoff|2-cyano:imino-thiazolidine prodn. from 2-aminoethane thiol|

DE19904310A1|1999-01-28|2000-08-03|Bayer Ag|Process for the preparation of heterocyclic compounds|

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

HU83888A|HU188852B|1983-03-16|1983-03-16|Process for producing thiazolidine derivatives active against gastric ulcer and intestinal ulcer|

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