CS241096B2 - Method of thiazolidine derivatives preparation - Google Patents

Description

The invention relates to a process for the preparation of novel thiazolidine derivatives which are suitable for the preparation of pharmaceutical compositions. In particular, the invention relates to a process for the preparation of novel thiazolidine derivatives of the general formula I

CHjArZ <-

(I) where is

Ar is 2-furyl or phenyl, naphthyl or pyridyl, optionally substituted with at least one halogen atom, at least one C 1 -C 4 alkyl, C 1 -C 6 alkoxy, C 1 -C 4 haloalkoxy or dihalomethyl group; or trihalomethyl, hydroxyl and / or nitro or II

(II)

Y is N or —CH,

Z is cyano or carbamoyl when Y is nitrogen or nitro when Y is —CH.

The novel thiazolidine derivatives of the formula I are valuable anti-ulcer agents, i.e. they are highly effective for the treatment of gastrointestinal ulcers.

The novel thiazolidine derivatives of formula (I) are of great therapeutic significance since the number of people suffering from gastric or duodenal ulcers continues to increase in both absolute and relative amounts. Although numerous known pharmaceutical compositions for the treatment of ulcers ranging from 4,5-dihydrothiazoles to relatively novel 4-aryl-4-hydroxy-4,5-dihydrothiazoles (U.S. Pat. No. 4143148), these compounds are substantially structurally different from the compounds of the present invention. invention.

With respect to the mechanism of action, known anti-ulcer agents have a very varied action. Newly discovered histamine-H2 antagonists such as cimetidine (N-cyano-N'-methyl-N '- [(5-methylimidazol-4-yl) methylthiojethylguanidine) form a balanced group and are characterized by inhibiting selectively histamine-induced gastric acid secretion . From ^{tricyiklických!} 6H-pyrido [2,3-h] - [l, 4] benzodiazepines, pirenzepine is known, which is (5,11-dihydro-l [(4-methyl-piperazinyl) acetyl] - However, 6H-pyrido- [2,3-b] - [1,4] benzodiazepin-B-one, as a substance that inhibits ulcer formation as much as atropine, is free from other antichoenergic effects (eg inhibition of peristalsis, impaired eye accommodation, salivation inhibition) Various autacids that do not inhibit gastric acid overproduction bind excess acid are also commonly used.

The novel thiazolidine derivatives of the general formula (I) prepared according to the invention have a broad spectrum of activity and are therefore suitable for the treatment of gastrointestinal ulcers which arise as a result of various pathological mechanisms and can be used successfully for treating ulcers caused by non-steroidal anti-inflammatory agents. Certain preferred compounds of these anti-ulcer agents, such as 3-benzyl-2-cyanoiminothiazolidine, have another important advantage since, unlike known histamine H2 receptor antagonists, they do not have functional groups from which undesired carcinogenic N-nitro compounds can be formed in the body.

There are several possibilities for the chemical classification of the novel compounds of formula (I) prepared by the process of the invention. According to the nomenclature used in Chemical Abstracts, these compounds may be considered as substituted carboxylic acid derivatives, for example cyanomide, urea and the like, having a heterocyclic residue as a substituent. On the other hand, they are compounds, for example compounds containing a substituent of the formula -NO2 at the 2-position, whose heterocyclic moiety can be considered as the main structural element to which, for example, the aforementioned side chain is attached as a substituent. For the sake of uniformity, all of the compounds of formula (I) are referred to herein as thiazolidine derivatives, which clearly indicates the unsaturated nature of the side chain at position 2 (e.g., the cyanoimine and nitromethylene chains).

The compounds of formula (I) wherein each symbol is as defined above are prepared according to the invention by a process characterized in that the 2-substituted thiazolidine derivative of formula (V) is alkylated.

AND

Y (γ) wherein Y and Z are as defined above, on a nitrogen atom with a compound of formula VI

Ar - CH 2 - X (VI) wherein Ar is as defined above and wherein X is a halogen atom or a reactive ester group, and optionally in a compound of formula I wherein Ar, Y and Z are as defined above, one substituent is converted to another a substituent within the meaning of the individual symbols in a manner known per se.

The reaction of the compound of formula (V) with the compound of formula (IV) is generally carried out in an organic solvent, preferably methanol, ethanol, acetone or ether, for example dioxane or acetomitrile, and alkali metal hydroxides, carbonates can be used as acid binders. or alcoholates or organic bases, for example quaternary ammonium compounds. The reaction is generally carried out at the boiling point of the solvent used. After filtering off the precipitated salt, the product is isolated by crystallization or evaporation of the reaction mixture and, if appropriate, subjected to further purification by methods known per se.

In the compound of formula (I) obtained, a substituent may be converted to another substituent within the meaning of the individual substituents of the compound of formula (I). For example, a cyano group Z may be hydrolyzed to a carbamoyl group in an aqueous acidic medium. If a compound of formula (I) wherein Z is cyano is reacted with an acid such as hydrochloric acid in a non-aqueous medium, an immediately separable iminochloride is formed from which the desired compound of formula (I) wherein Z is carbamoyl can be prepared. alkali in an aqueous medium.

Another example of converting a substituent of a compound of formula I to another substituent is the conversion of optional substituents on the Ar group by methods known per se. Thus, a methoxy group in a compound of Formula I wherein Ar is a methoxy group substituted with a phenyl group can be converted to a hydroxyl group by reacting the compound with boron bromide in an organic solvent and basifying the reaction mixture. Similarly, the hydroxyl group in the compound of formula (I) may be converted to other substituents within the meaning of the above-mentioned meanings of the individual symbols by known methods.

A preferred representative compound of formula (I) is 3-benzyl-2-cyanoiminothiazolidine (compound A). The results of the pharmacological tests carried out with this compound are described below, but it is noted that the other compounds of formula I also have significant activity.

The pharmacological activity of the novel compounds of the formula I prepared by the process according to the invention is examined by these methods.

Exam by Shay

This assay was first described by Shay et al. in 1945 (Gastroenterology 56, pp. 5-13, 1945). Female H-Wistar rats (120-150 g) were fasted for 24 hours. Water is available at will. Pylorus is ligated to the animals under mild ether anesthesia. The test substance is administered during the operation. Four hours after treatment, animals are sacrificed with a large portion of ether. The stomach is excised and incised at the point of great curvature. The volume and pH of the contents are determined, and in certain cases the production of hydrochloric acid is titrated.

Aspirin-induced gastric ulcer test

Non-steroidal anti-inflammatory agents are known to induce gastrointestinal ulcers to some extent (Drugs and Peptic Ulcer, Ed. Pfeiffer. CRC Press, New York, 1982). The anti-ulcer compounds are extensively tested by the so-called aspirin-induced ulcer assay. For this test, female rats weighing 120 to 150 grams were fasted for 24 hours. They can consume water at will. Gastric ulcer is induced by oral administration of 100 mg / kg aspirin (as a suspension in Tween 80). The test compound is administered concomitantly with aspirin and also orally. Rats are sacrificed by a large dose of ether 4 hours after treatment. The stomach is excised and dissected at the point of great curvature. The contents are washed out slightly and the haemorrhagic disturbances of the glandular surface are calculated. The results of the test are evaluated and the number of gastric ulcers or rats that do not have ulcers is determined. '

Intestinal ulcers induced by indomethacin

Among non-steroidal anti-inflammatory agents, indomethacin not only induces gastric ulcers as a side effect, but can also largely cause intestinal ulceration. Depending on the. the dose size can be intestinal ulceration deadly, periitonitis kills the animal due to intestinal perforation.

(a) Indomethacin-induced lethal intestinal ulceration

Non-starved female H-Wistar Fr.

241098 weighing 120 to 160 g are each treated orally with 15 mg / kg indomethacin (as a suspension in Tween 80). The test substance is administered orally following administration of indomethacin. Under these conditions, intestinal ulceration (ulceration) occurs after approximately 48 to 72 hours.

After assessing the development of intestinal ulcers, the so-called inflatable technique described by Ezer and Szporny (J. Pharm. Pharmacol. 27, 866, 1975) is used. In this way, the progress of ulceration can be quantitatively recorded. Intestinal wall strength, expressed in Pa, decreases gradually in parallel with the ulceration process.

(b) Indomethacin-induced ulceration not leading to death i. Unsuppressed female H-Wistar rats weighing 120 to 150 g are each treated with an oral administration of 7.5 mg / kg indomethacin to induce intestinal, non-lethal ulceration. At 4 hours, 24 hours, and 48 hours after indomethacin treatment, rats were orally administered test compound. Rats are sacrificed 24 hours after the last treatment and 72 hours after indomethacin ulcer induction. Ulceration is assessed by an inflatable test.

Gastric necrosis induced by absolute alcohol

This method was introduced by A. Robert (Gastroenterology 77, 433 (1979)) together with the term cyitoprotection. Female H-Wistar rats weighing 120-150 g were fasted for 24 hours. They can consume water at will.

The test compound is administered orally 30 minutes prior to administration of 0.5 ml / 100 g of body weight by gavage. Two hours later, rats are sacrificed with a large portion of ether. The stomach is excised and dissected at the point of greatest curvature.

The etching induced by the administered ethanol is located on the stomach corpus as numerous linear hemorrhagic bands of inecrotized tissue. The etch length is measured in millimeters (Derlenko and Long, Proc. Exp. Biol.

and Med. 166, p. 394 (1981)) and the length of the median etching on the stomach is determined. The degree of protection is expressed as a percentage with respect to the control test.

Investigation of the above-described tests has shown that 3-benzyl-2-cyaniminothiazoline (compound A), which is a preferred representative compound of formula (I) prepared by the process of the invention, appears to be a very potent anti-ulcer compound in these pharmacological trials.

This compound inhibits gastric acid secretion in the Shay rat at a low dose (ED 50 = 5.3 mg / kg i.p.). Aspirin-induced gastric ulceration by concomitant administration of Compound A orally (ED50 = 2.1 mg / kg p.o.) is also inhibited.

Compound A is also effective in the absolute alcohol necrosis assay recently introduced by Robert et al. (Gasroenterology 77: 433-443, 1979). In particular, it is noted that the concomitant administration of Compound A inhibits indomethacin-induced intestinal ulceration. This result is important because cimetidine, one of the most potent anti-ulcer agents, cannot inhibit indomethacin-induced intestinal ulceration (Ezer and Szporny, J. Pharm. Pharmacol., 33, 250-251, 1981; Der Soldato et al. Brit. J. Pharmacol., 67, 33-37 (1979); GL Kaufman et al., Proc. Soc. Exp. Biol. 181: 512-514 (1970).

This is supported by the clinical results obtained by Mitchell and Sturrcck (Brit. Med. J. 284, 731 (1982)), which show that co-administration of cimetidine and indomethacin results in perforations in rheumatic patients who simultaneously suffer from gastric ulcers. Anticholinergic compounds (for example Propantheline, Gastrixon) cannot prevent indomethacin-induced intestinal ulceration.

The results of the above tests are summarized in Tables 1 to 6 below; the abbreviations used have the following meaning:

n = number of animals tested b. w = body weight t. s = strength

Table 1

Inhibitory action of Compound A on gastric acid secretion in Shay rats (ligation of pylorus: 4 hours)

Treatment n Dose mg / kg i.p. Acid secretion μπιοί HCl / 100 g b. W. Inhibition θ / ο Note control 20 May - 429 _, Compound A 5 1,25 436 0 Compound A 10 2.5 358 17 Compound A 10 5.0 301 30 ED50 - 5.3 Compound A 20 May 10.0 0 100 ALIGN! Compound A 5 25.0 0 100 ALIGN!

T a b at 1 k and 2

Effect of Compound A, administered by various routes, on inhibition of gastric acid secretion (Shay rats, 4 hours)

Method of administration n Dose Gastric acid secretion mg / kg ml / 100 g b. W. volume inhibition min min

operations i. p. 5 10 2.5 42% 3.7 15 min ago c. 5 10 2.8 35% 1.5 15 min ago operations p. c. 5 10 2.3 47% 4.1 control 5 - 4.3 - 1.0

Table 3

Inhibition of aspirin-induced gastric ulcers by concomitant treatment with Compound A

Treatment n Dose pg mg / kg Number of ulcers Inhibition ulcers % Ulcerated animals «/ o Aspirin 20 May 100 ALIGN! 15.7 + 3.0 - 0 Aspirin * Compound A 10 100 + 1.5 9.5 ** 40 0 Aspirin * Compound A 17 100 + 3.0 6,8+ 57 23 Aspirin * Compound A 17 100 + 6.0 4,7+ 71 29 Aspirin * Compound A 14 100 + 12.0 2,2+ 86 66 Aspirin * Compound A 17 100 + 25.0 2,3+ 85 41 * * p less than 0.05, * p less than 0.1 ED 50 = 2.1

T a b at 1 k and 4

Dose-dependent inhibition of indomethacin-induced intestinal ulceration with concomitant administration of compound A

(indomethacin = AND; Compound A = A) Treatment n Batch o. Intestinal strength Resistance Note mg / kg wall 72 hours intestinal after treatment walls kPa ° / o nor- almost

control AND 30 16 15 Dec 31.2 4- 0.7 100 ALIGN! 20 May x / p <0.0: 1 with respect to the group indomethacin 6.2 ± 1,6 I + A 10 15 + 15 16.2 4- 2,7 52 And I 10 16 + 25 25.9 4- 2,5 8'3 ^X I + A 20 May 15 + 50 30.4 + 7.1 97 ^x ED10 = 50 I-cimetidine 10 15 4- 150 6.3 4- 3,4 21 I-Na-salicylate 10 15 4- 25 17.8 + 2,3 57 ^x ED10 = 50 14 ~ Na-salicylate 10 15 4- 50 31.2 ± OJ 100 ^x

Table 5

Indomethacin-induced procedure (7.5 mg / kg p / o non-lethal intestinal ulceration in case of cimetidine and additionally treated with Compound A (indomethacin = I, Compound A = A 1) Treatment 4, 24, 48 hours after indomethacin treatment n Dose pg mg / kg Intestinal wall strength 72 h after indomethacin treatment kPa Group untreated individuals 30 - 31.2 + 0.7 AND AND 32 7.5 25.0 + 1.5 (B) 1- | cimetidine 12 7.5 + 3 X 50 24.8 + 1.0 C I + cimetidine 12 7.5 + 3 X 100 26.6 + 1.4 D I + A 10 7.5 + 3 X 25 23.8 + 2.7 F I + A 10 7.5 + 3 X 50 33.6 + 5.3 G Notes to Table 5: A - Β p less than 0.05, B, C, D, F. N. S., B to G p less than 0.01. T a b at 1 k and 6 Cytoprotective effect hem compounds A against gastric necrosis induced by absolute aifcoho- Treatment n Batch of o. mg / kg Medium Cyto Length etching of protection mm / stomach Note control 112 82.4 + 5 _ Compound A '6 1.5 52.5 + 19 37 ^x Compound A 12 3.0 34.8 + 10 58 ^x ED 6 = 2.8 Compound A 12 6.0 29.9 + 9 64 ^x Compound A 13 12.0 32.9 + 5 60 ^x Compound A 6 25.0 18.0 + 8 78 ^x cimetidine 5 6.0 46.0 + 10 44 ^x cimetidine 5 12.0 63.0 + 18 24 cimetidine 10 25.0 55.0 + 12 33 EDso unpredictable cimetidine 15 Dec 50.0 34,0 4- 10 59 ^x cimetidine 12 100.0 ^x p less than 0.01 relative to control 47.0 + 16 43 ^x

The values in Table 1 demonstrate that Compound A acts to reduce gastric acid secretion in a dose-dependent manner. It is very important that Compound A effectively inhibits gastric juice secretion even when administered orally, as evidenced by the rat-Shay values reported in Table 2.

Compound A inhibits the formation of aspirin-induced gastric ulcers when co-administered with aspirin in a dose-dependent manner. Induction of gastric ulcers of 20 mg / kg oral dose of indomethacin is also effectively inhibited.

The results are shown in Table 3. Table 4 illustrates the inhibition of lethal intestinal ulceration induced by indomethacin administered at a dose of 15 mg / kg by the oral route.

Compound A exhibits dose-dependent action on indomethacin-induced intestinal ulceration (15mg / kg bp) The results obtained with so-called non-lethal intestinal ulceration appear to be particularly important. In these tests, treatment was started 4 hours after indomethacin-induced ulceration (7.5mg / kg). kg poj

Thus, post-treatment was performed 4 hours, 24 hours and 48 hours after indomethacin treatment. The values in Table 5 show that cimetidine and ranitidine are ineffective in this assay, while compound A can normalize intestinal wall strength in a dose-dependent manner.

Compound A is effective against gastric necrosis induced by absolute alcohol. According to the results shown in Table 6, cytoprotection is dose-dependent.

On the basis of pharmacological tests can be said. that Compound A has a broad scope, broader than, for example, cimetidine. It shows a combined action, as evidenced by the fact that this compound is effective in three different ulcers, characterized by three completely different pathogenic mechanisms:

1. gastric ulcer induced by aspirin,

2. intesfinal ulcer induced by indomrethacin,

3. Absolute alcohol induced gastric necrosis.

Compound A has good oral absorption, as evidenced by comparison of i.p., s.c. and p.o.

In accordance with toxicological assays, compound A has a high therapeutic index.

For toxicological assays, water-insoluble compound A is used for i.p. and oral administration as a suspension of compound A in Tween 80. For intravenous administration, the compound of formula I is administered dissolved in dimethylformamide.

1. A dose of 200 mg / kg will cause nausea in the test animals, but not death (within three days).

2. After 250 mg / kg, no death is detected within two weeks, but after a dose of 1,500 mg / kg i., P. the animals die within 30 minutes.

3. Oral administration of a dose of 1,500 mg / kg results in three out of 10 deaths within 24 hours, no deaths are observed next week, animal behavior and food consumption are normal.

The invention is illustrated by the following non-limiting examples.

Example 1

3-Ben'zyl-2-cyanomethylmolidine

Into the boiling mixture. 1.27 g (10 mil moles) of 2-cyanoiminothiazoline (2-thiazolidinylidene dicyanamide), 25 ml of acetone and 1.52 g of anhydrous potassium carbonate are added dropwise with 1.3 ml (11 millimoles) of benzyl bromide.

The mixture is maintained at reflux for 4 hours, the salt is filtered off and the acetone solution. The residue is triturated with ether and filtered to give 2.03 g (93.5% of theory) of 3-benzyl-2-cyaniminothiazolidine, m.p. 102-104 ° C. Recrystallization does not change the melting point.

Analysis for CuHnNsS (217.29):

calculated:

% C, 60.80;% H, 5.10;% N, 19.34.

14.76% S;

found:

% C, 60.98;% H, 5.02;% N, 19.57.

14.96% S.

IR spectrum (KBr):

190 cm-1 —C-N,

-1 570-cm “ ¹ = CN— (wide)

NMR Spectrum (CDCl3):

3.38 ppm m (2) —S — CH2—

3.85 ppm ml (-2) = N - CH 2 - (heterocyclic)

4.65 ppm S (2) = N-Cl-12 - (phenyl)

7.38 ppm S (5) - Ar - H

Example 2

2-Cyanoimino-3- (4-chlorobenzyl) thiazolidine

3.82 g (30 millimoles) of 2-cyaniminothiazolidine, 4.9 g (30 millimoles) of 4-chlorobenzyl chloride, and 4.3 g of anhydrous potassium carbonate are boiled in 100 ml of acetone for 5 hours. The inorganic salt was filtered off and the acetone solution was evaporated. The residue was recrystallized from 40 ml of isopropanol to give 6.26 g (83 percent of theory) of 2-cyanimino-3- (4-chlorobenzyl) thiazolidine, m.p. 131 DEG-133 DEG C. The product was isolated by filtration.

Analysis for C 11 H 10 ClN 3 S (251.74): calculated:

% C, 52.48;% H, 4.00;% N, 16.69; found:

52.72% C, 4.18% II, 16.49% N.

IR spectrum (KBr):

185 cm ¹ - CN

H5-6O cm ^-1 = -C = N—

-1-092 cm -1 ¹ —Ar — Cl

NMR Spectrum (CDCl3 + DMSO-d6):

3.3 ppm m (2) - S - ΟΡΚΟ, 8 ppm ml (2) = N - CH 2 - (heterocycle)

4.5 ppm S (2) = N - CH2 - (CsHi - Cl)

7.12 ppm S (4) - Ar - H

Example 3

2-Cyanoimino-3- (3,4-dichlorobenzyl) thiazolidine

3.82 g (30 millimoles) are allowed to react

2-cyanimmothiazolidine and 6 g (31 millimoles) of 3,4-dichlorobenzyl chloride as described in Example 2, and the evaporated residue is recrystallized from 50 ml of ethanol to give 6.8 g of 2-cyanimino-3- (3, 2-cyanimidothiazolidine). 4-dichlorobenzyl) thiazolidine, m.p. 130-132 ^and C,

Analysis for C 11 H 9 Cl 2 N 3 S (286.18): calculated:

C, 46.16; H, 3.17; S, 11.21; found:

H, 3.18; H, 11.22.

IR spectrum (KBr):

190 cm -1 - C = N

1570 cm ¹ = C = N—

060 cnr ¹ —Ar — Cl NMR spectrum (CDCl3):

3.4 ppm m (2) —S — CH2—

3.7 ppm m (2) = N - CH 2 - (heterocyclic)

4.56 ppm si (2) = N - CH 2 - (3,4-dichlorophenyl)

6.9 to 7.5 ppm m (3) - Ar - H

He attaches

2-Cyanimino-3- (4-nitrobenzyl) thiazolidine

It is boiled in 80 ml of acetone for 6 hours

2.54 g (20 millimoles) of 2-cyanoiminothiazolidine,

3.43 g of nitrobenzyl chloride and 2.95 g of anhydrous potassium carbonate. The salt formed is filtered off, the solution is evaporated and the residue is recrystallized from 30 ml of acetonitrile. 3.66 g (70% of theory) of 2-cyanimino-3- (4-nitrophenyl) thiazolidine of melting point 171 DEG C. Analysis for C11 H10 N4 O2S (262.29):

calculated:

% C, 50.37;% H, 3.84;% N, 21.36; found:

% C, 50.318;% H, 3.94;% N, 21.46.

IR spectrum (KBr):

190 cm ^-1 - C = N

575 cm ^-1 = C —N—

505, 1334 cm- ¹ —NO2 NMR Spectrum (CDCl3 DMSO-dB):

3.4 ppm m (2) —S — CH2—

3.8 ppm m (2) = N - CH 2 -

4,65! ppm s (2) = N - CH 2 - C 6 H 4 - p - NO 2 7.35 ppm di (2) - Ar - H (2.6)

8.05 ippm d (2) —Ar — H (3.5)

Example 5 '

2-Cyanimino-3- (2-hydroxy-5-nitrobenzyl) thiazolidine

3.82 g (30 mmol) of 2-cyanimiinothiazolidine, 5.613 g (30 mmol) of 2-hydroxy-5-nitrobenzyl chloride and 4.3 g of anhydrous potassium carbonate are boiled in 100 ml of acetone for 6 hours; the mixture was cooled and the precipitate was filtered off. 9.85 g of crude material are obtained, which is then dissolved in 600 ml of hot water, the impurities are filtered off, the pH is adjusted to 3, the mixture is cooled, filtered and the precipitate is dried. There was thus obtained 2-cyanimino-3- (2-hydroxy-5-nitrobenzyl) thiazolidine (5.1 g), m.p. 253 DEG-255 DEG C. after recrystallization from pyridine.

Analysis for C11H10N4O3S (278.29):

calculated:

% C, 47.47;% H, 3.62;% N, 20.13; found:

% C, 47.78;% N, 3.71;

IR spectrum (KBr):

100 cm ^-1 (wide) —OH

190 cm. ” ¹ —C = N

575 cm ¹ = C = N—

522, 3138 cm- ^{1 1} -NO2 NMR spectrum (CDCl 3 + DMSO-d 6):

^from 3.4 ppm m (2) —S — CH2 '3.8 ppm m (2) = N — CH2- (heterocyclic)

4.54 ppm s (2) = N-CH 2 - (2-OH, 5-NO 2 -C 6 H 3)

6.88 ppm t (1) —Ar — H (3)

8.00 ppm m (2) -Ar-H (4.6) to 9 ppm b (1) -OH

Example 6

2-Cyanimino-3- (3-hydroxybenzyl) thiazolidine

3.82 g (30 millimoles) of 2-cyanoiminothiazolidine, 7.10 g (30 millimoles) of m-cresol bromide diacetate and 4.30 g of anhydrous potassium carbonate are boiled in 100 ml of acetone for 6 hours. The precipitate was filtered off and the filtrate was evaporated to dryness. There was thus obtained 8.75 g of an oily material which was hydrolyzed with 50 ml of 2 N sodium hydroxide solution to remove the phenyl ester group.

After acidification, an oily product is obtained in the form of a precipitate which is recrystallized from acetonitrile and then from 50% acetone to give 1.98 g of 2-cyanimino-3- (3-hydroxybenzyl) thiazolidine, m.p. 126-128 ° C. .

Analysis for C11H11N3OS (233.29): calculated:

C 56.63, H 4.75, S 13.75,

N, 18.02;

found:

C 56.70, H 5.07, S 13.75,

17.83% N.

IR spectrum (KBr):

260, 1230 cm -1 -OH

190 cm ^-1 - C = N

570 cm ^-1 = C = N—

NMR Spectrum (CDCl3 + DMSO-d6):

3.3 ppm m (2) —S — CH2

3.7 ppm mu (2) = N - CH 2 - (heterocyclic)

4.48 ppm s (2) = N - CH 2 - (hydroxyphenyl)

6.6 to 7.4 ppm m (4) -Ar-H

8.6 b (l) - OH

Example 7

2-Cyaniminc-3- (1-naphthylmethyl) thiazolidine

3.82 g (30 mmol) of 2-cyaniminothiazolidine, 5.56 g (30 mmol) of 1-chloromethylnaphthalene and 4.3 g of potassium carbonate are boiled in 100 ml of acetone for 6 hours. The precipitate is filtered off while still hot; 6 parts of product precipitated already during filtration. After concentration and storage in a refrigerator, 16.5 g (81.15% of theory) of 2-cyano-amino-3- (1-naphthylmethyl) -thiazolidine of melting point 167 DEG C. are obtained after recrystallization from acetonitrile. Analysis for C 18 H 11 N 5 S (267.34): calculated:

% C, 67.39;% H, 4.90;% N, 15.72;

12.00% S;

found:

% C, 67.32;% H, 4.80;% N / 15.78;

11.96% S.

IR spectrum (KBr):

190 cm @ -1 = C = N

580 cm ¹ = C = N—

NMR Spectrum (CDCl3 + DMSO-d6):

3.2 ppm mi (2) - S - CH 2 -

3.6 ppm m (2) —N — CH2— (heterocyclic)

4.92 ppm s (2) = N - CH 2 - (naphthyl)

7.0 to 7.9 ppm m (7) -Ar-H

Example 8

3,3‘- (1,4-xylenilen) -bis- (2-cyaniminothiazolidine)

4.5 g (26 millimoles) of 1,4-xylilenedichloride, 6.36 g (50 mol) of 2-cyaniminothiazolidine and 7.17 g of potassium carbonate are boiled in 150 ml of acetone for 7 hours, the mixture is placed in a refrigerator and filtered. after cooling. Filtration gave 15.48 g of precipitate from which the impurities were dissolved in cold water. Yield: 8.1 g (91% of theory) of 3,3 ‘(1,4-xylilene) -bis- (2-cyaniminothiazolidine), m.p.

Analysis for C 18 H 18 H 6 S (356.47): calculated:

53, 91% C, 4.52% H, 17.99% S,

N, 23.58;

found:

C 53.70, H 4.78, S 17.85,

23.37% N.

IR spectrum (KBr):

180 cm @ -1 = c

570 cm -1 = C '= iN -.

NMR Spectrum (DMSO-d 6):

3.4 ppm m (4) —S — CH2—

3.7 ppm m (4) = N - CH 2 - (heterocyclic)

4.50 ppm S (4) = N - CH 2 - (phenylene)

7.18 ppm S (4) - Ar - H

Example 9

2-Cyano-3 ^and NO - '(6-methyl-2-pyridylmethyl) thiazolidine or 2- [(2-ikyanimino-3-thiazolidinyl) methyl) -6-methylpyridine

3.3 g (26 millimoles) of 2-cyaniminothiazolidine, 3.9 g of anhydrous potassium carbonate and 4.03 g (28.5 millimoles) of 2-chloromethyl-6-methylpyridine are boiled in 60 ml of acetone until all starting thiazolidine compounds consumed (6 hours). The precipitated salt is filtered off, the solvent is distilled off and the residue is recrystallized from 40 ml of diethyl ether. 5.43 g (89.9 percent of theory) of the title compound of melting point 114 DEG C. are obtained after recrystallization from ethyl acetate.

Analysis for C11H12N1S (232.30):

calculated:

% H, 5.20;% N, 24.12; found:

% H, 5.12;% N, 24.18.

IR spectrum (KBr):

190 cm ^{-1 -} C = N

1570 cm ¹ = C = N—

NMR Spectrum (CDCl3):

2.48 ppm s (3) - -Py — CHs 3.3 PPm m (2) —S — CH2— 3,9 ppm mf 2) = N — CH2— 4.6 PPm with (2) = = N — CH2— (Py) 6.9 ppm d (2) - -Py 2,5-H 7.4 ppm & (1) - -Py — H

Example 10

2-Cyanimino-3- (6-dichloromethyl-2-pyridylmethyl) thiazolidine or 2 - [(2-cyanimino-3-thiazolidinyl) methyl] -6-dichloromethylpyridine

6.6 g (52 ml) of 2-cyaniminothiazolidine, 7.9 g of anhydrous potassium carbonate and 12 g (57 mmoles) of 2-diichloromethyl-6-chloromethylpyridine in 240 ml of acetone are reacted as described in the preceding examples. The precipitated salt was filtered off, the solvent was evaporated and the residue was triturated with ether, filtered and recrystallized from acetonitrile to give 5.2 g (33%) of the title compound, m.p. 122 ° C.

Analysis for C 11 H 10 Cl 2 N 4 S (301.19): calculated ·:

G, 43.86; H, 3.34; S, 10.64; found:

% C, 43.91;% H, 3.46;

IR spectrum (KBr):

180 ^cm-1 C = N

560 cm @ ¹ = CH - Cl NMR spectrum (CDCl3):

3.34 ppm t (2) —S — CH2—

3.97 ppm t (2) = N - CH 2 -

4.62 ppm 9 (2) = N - CH 2 - (phenyl)

6.50 ppm s' (1) -Py-CH =

7.0 to 7.8 ppm m, (3) -Py-H

The following compounds were also obtained from the corresponding starting materials by the method described in Example 1:

3-Benzyl-2- (carbamoylamino) thiazolidine (m.p. 148 ° C)

Analysis for C17H18NOSOS (235.31): calculated:

% C, 56.15;% H, 5.57;% N, 17.86; found:

. % H, 5.46;% N, 18.10.

IR spectrum (KBr):

3320, 3.260 cm @ ^{-1 -} NH2

1645 cm -1 = C = O

540 cm -1 = C = N—

NMR Spectrum (CDCl 3 + DMSO-d 6):

3.05 pipm t (2) —S — CH2—

3.50 ppm t (2) = N - CH 2 - (heterocyclic)

4.75 ppm s (2) = N - CH 2 - (phenyl)

5.60 ppm b (2) - NH 3 7.32 ppm s (5) - Ar - H

S-benzyl-4-nitromethylenthiazolidine (m.p. 139 ° C)

Analysis for C11H12N2O2S (236.30):

calculated:

% C, 55.91;% H, 5.12;% N, 11.86; found:

H, 4.99; N, 11.89.

IR spectrum (KBr):

633 cm -1 = C = C =

535, 1354 cm ^-1 - NO 2

NMR Spectrum (CDCl3):

3.10 ppm t - S - CH 2 -

3,80 ppm t = N — CH2— (heterocyclic)

4.43 ppm s = N — CH2- (C & H5)

6.97 ppm s-CH =

7.0 to 7.3 ppm m-Ar-H

2-cyanimino-3- (4-methoxybenzyl) thiazolidine (m.p. 99-102 ° C)

Analysis for C12H13N3OS (247.31):

calculated:

58.28 O / o C, 5.30% H; found:

58.35% c, 5.17% H.

IR spectrum (KBr):

840 cm ^-1 —O — CH3 2185 cm-1 —CsN 1570 cm ^-1 = C —N—

608, 814 cm ^-1 —Ar

NMR Spectrum (CDCl3):

(3.3 ppm m -S-CH 2 -

3.7 ppm m = N - CH 2 -

3.75 ppm with —O — CH3

4.43 ppm s = N — CH2— (C & Hs)

6.90 ppm q —Ar — H

2-cyanimino-3- (2-furylmethyl) thiatzolidine (m.p. 124-125 ° C)

Analysis for C9H9N3OS (207.25):

calculated:

20.28 O / O N, 15.47% S;

found:

20.38% N, 15.44% S.

IR spectrum (KBr):

185 cm ^-1 —C = N

I 570 cm- ¹ = O = N—

II 238 cm ^-1 = C — O — C = 795 cm ^-1 —Ar — H

NMR Spectrum (CDCl3):

3.3 ppm m - S — CH2— 3.7 PPm m = 'N — CH 2 - (heterocyclic) 4.57 ppm s = N - - CH 2 - Ar -6,30 ppm d - Ar - (3,4) H 7.3 ppm m - Ar - (5) H

2-cyanimino-3- (4-methylbenzyl) thiazolidine (m.p. 102-104 ° C)

Analysis for C12H13N3S (231.31):

calculated:

C, 62.2.6; H, 5.66; S, 13.85; found:

% C, 62.10;% H, 5.52;

IR spectrum (KBr):

190 cm ^-1 —C = N

590 cm ¹ = C = W—

260 cm ^-1 - S — CH2—

792 cm- ¹ —Ar

NMR Spectrum (CDCl3):

2.31 ppm with —CH3

3.30 ppm m -S-CH2

3.70 ppm m = H — CH2— (heterocyclic)

4.54 ppm s = -N — CH2— (phenylene)

7.10 ppm β - Ar - H

3- (2-furylmethyl) -2-nitromethylenthiazolidine (m.p. 190-192 ° C)

IR spectrum (KBr):

543, 1340 cm ^"1 -NO 2 from 1 to 6401 ^cm-1 = C = C =

130, 757 ^cm-1 furan == C-H

243 cm ^-1 = C-O-C = furan ring NMR spectrum (CH 3 -COOH):

3.7 ppm t - 3 - CH 2 -

4.6 ppm t - N — CH2— 5.7 ppm with = N-CH 2 - (C 4 H 3 O) 0.3 ppm b = CH-NO 2 6.5 PPm , m furan 3.4 H 7.5 ppm n furan 5 H

2-cyanimino-3- (4-hydroxybenzyl) thiazolidine (m.p. 17-5-177%))

IR spectrum (KBr):

190 cm ^-1 - C = N 1570 cm ^-1 = C-N3 210 cm ^"1 -OH

610, 840 cm ^{-1 -} Ar NMR spectrum (CDCl 3):

3.4 PPm m -WITH- -CH2- 3.7 PPm m = N- -CH2 4,5 PPm with —Ar- -CH2 6.9 ppm q —Ar- -H 9.47 PPm s - —CH

They did

Preparation of a pharmaceutical composition

The pharmaceutical composition in the form of tablets is prepared from the following ingredients (for 10-00 tablets):

g 3-benzyl-2-cyaniminothiazolidine - (active substance) g starch g milk sugar g talc g polyvinylpyrrolidone g magnesium stearate g colloidal silicic acid

200 g

The finely divided active ingredient is mixed with milk sugar and talc, kneaded with the polyivinylpyrrolidone solution and passed through a sieve. The granules are dried, mixed with magnesium stearate and colloidal silicic acid and compressed to 1000 tablets each weighing 0.2 g.

Claims (1)

SUBJECT ILL. A process for the preparation of thiazolidine derivatives of the general formula I INVENTION where it means Y is N or CH, Z is cyano or carbamoyl when Y is N and nitro when Y is CH, characterized in that a substituted thiazolidine derivative of the general formula V is alkylated at the 2-position nitrogen. Ar is 2-furyl or -phenyl, naphthyl or pyridyl, optionally substituted with at least one halogen atom, at least one al, C1 -C4 alkyl, C1 -C6 alkoxy, C1 -C4 haloalkoxy , dihalomethyl or trihalomethyl, hydroxyl and / or nitro or a group of formula II H (y) where Y and Z are as defined above, a compound of formula VI; Ar — CH2 — X (VI) OF N-CN (ti) where z Ar is as defined above and X is a halogen atom or a reactive ester group, and optionally converts a substituent in the obtained compound of formula I wherein Ar, Y and Z are as defined above to another substituent as defined.