UA123803U - 5- (4-CARBOXYMETHYLBENZILIDEN) -3- {2- [2- (2,6-DICHLOROPHENYLAMIN) PHENYL] ACETYLAMINO} -2-THOXOTHIAZOLIDIN-4-ON ANTI-ANTIQUE DETERMINATION - Google Patents

Abstract

5- (4-Carboxymethylbenzylidene) -3- {2- [2- (2,6-dichlorophenylamino) phenyl] acetylamino} -2-thioxothiazolidin-4-one of formula: exhibiting antiexudative activity.

Description

A useful model belongs to the field of organic chemistry, namely, the synthesis of new heterocyclic compounds and pharmacy, in particular, the preparation of biologically active compounds that exhibit anti-exudative effects, and can be used in clinical medicine as an anti-inflammatory drug.

Nonsteroidal anti-inflammatory drugs (NSAID33) include a group of drugs with different chemical structures that have anti-inflammatory, analgesic, antipyretic, and antiplatelet effects. Among the specified medicines are derivatives of salicylic acid, or salicylates (acetylsalicylic acid, diflunisal), anthranilic acid, or fenamates (mefenamic acid, niflumic acid), phenylacetic acid (diclofenac sodium), indolylacetic acid (indomethacin, etodolac), arylpropionic acid (ibuprofen , naproxen, ketoprofen), para-aminophenol (paracetamol, phenacetin), pyrazolone-5 (antipyrin, analgin, butadione), coxib (celecoxib, rofecoxib, parecoxib), etc.

The majority of NSAIDs are organic acids, which determines certain features of their separate pharmacokinetic parameters, including distribution in the body (E.M. Yueap. PR, She sotropepi oi 09 R sopigoiipu 5igisiige-asiimiu heiaiopepir atopadvi pop-5iegoidai! apii-ipPattaiyogu agidv, Choshigpai oi RIPaptasu apa Ryaptasoiodu, 1996, 48, 233-239), as well as an ulcerogenic effect and an undifferentiated effect on the biosynthesis of inflammatory prostaglandins by inhibiting

COX-2, as well as physiologically important (inhibition of COX-1) (K.O. Raipetoga. Rgoiye apa tesNapiztvo oi davigoipieviip! apa oiyeg zide eMesiv oi popviegoida! apii-ipiyattaiyugu apd5 (M5ZAIIIYUOv5), TNe

Ategisap dTsoshtsgtpa! of Meadisipe, 1999, 107 (6), 27-35). In particular, when using sodium diclofenac (Voltaren), pain in the epigastric area, nausea, vomiting, diarrhea, abdominal cramps, flatulence, anorexia, and an increase in the level of aminotransferases in blood serum may be observed. Gastrointestinal bleeding, ulcers of the stomach and small intestine, which may be accompanied by bleeding or perforation, are less common. The drug cannot be prescribed for peptic ulcer disease of the stomach and duodenum, in the first trimester of pregnancy. With long-term use, it is necessary to monitor the blood picture.

One of the priority areas of biological research for 4-thiazolidinone derivatives is the study of anti-inflammatory activity. A fundamental study of a group of heteryl-substituted di-tert-butylphenols made it possible to identify new double COX-2/5-I OX inhibitors, among which

It turned out to be a representative of the group of 4-thiazolidones - bagiteiope (S. Spapieg, S. Miznaih. Yuptsai ippibyiope oi susiohudepase-2 (SOH-2) apa 5-Irokhudepase (5-GOH) ab a pem/ zigaiedu yuyu rgomide zaieeg pop- vivgoida! apii-ipPataiyugu adgpob5, Etoreap Washigpa!oi Meadisipai Spetivigu, 2003, 38, 645-659).

The therapeutic index characterizes the significant advantage of the indicated compound over non-steroidal anti-inflammatory drugs, which confirms the perspective of the synthesis of new compounds with anti-inflammatory action based on the 4-thiazolidinone "matrix".

Therefore, the search for synthetic anti-inflammatory agents from the group of 2-thioxothiazolidin-4-one (rhodanine) derivatives with a fragment of the well-known non-steroidal anti-inflammatory agent "Voltaren" is relevant for modern pharmaceutical and medical chemistry.

The basis of a useful model is the task of creating an effective remedy with an anti-exudative effect and minor side effects.

The problem is solved by the fact that the synthesized 5-(4-carboxymethylbenzylidene)-3-(2-(2-(2,6-dichlorophenylamino)phenyl|acetylamino)-2-thioxothiazolidin-4-one of the formula:

SI

(in)

M Nm 5 Mt niv 5th 9th schi o 5 (c) which shows antiexudative activity.

The synthesized compound is a light yellow crystalline powder, soluble in DMF and DMSO when heated, insoluble in acetic acid, acetonitrile, alcohols, acetone, benzene, water and ether.

To prove the composition and structure of the synthesized compound, well-known physicochemical methods were used, in particular PMR spectroscopy and elemental analysis. The obtained results indicate the conformity of the synthesized compound with the claimed one.

The claimed compound is obtained as a result of the Kniovenagel reaction of /3-(2-(2-(2,6-dichlorophenylamino)phenyl|acetylamino)-2-thioxothiazolidin-4-one with methyl (4-formyl)benzoate (4-carboxymethylbenzaldehyde) in a medium acetic acid and the presence of an equimolar amount of anhydrous sodium acetate.

The antiexudative activity of 5-(4-carboxymethylbenzylidene)-3-12-(2-(2,6-dichlorophenylamino)phenyl|acetylamino)-2-thioxothiazolidin-4-one was studied according to the well-known method of IStefanov O.V. Preclinical studies of medicines. Guidelines /

O.V. Stefanov. - Kyiv, 2001. - 527 si on the carrageenan model of inflammatory swelling of the paw of non-linear white rats of both sexes weighing 180-220 g. Inflammatory swelling was caused by injections under aseptic conditions of 0.1 ml of 2,906 carrageenan solution under the aponeurosis of the sole of the rear limb of the rat . The presence of an inflammatory reaction was determined by the change in the volume of the limb by the oncometric method at the beginning of the experiment and after 4 hours. after the introduction of a phlogogenic agent.

In 40 min. before the introduction of the carrageenan solution, the animals were injected intraperitoneally with the substance under investigation at a dose of 50 mg/kg of body weight. For comparison, under similar conditions, the antiexudative effect of known non-steroidal anti-inflammatory drugs was studied: diclofenac sodium - 8 mg/kg and ketanovac - 10 mg/kg.

The study of the toxicometric parameters of the claimed compound was studied according to the well-known method of O. V. IStefanov. Preclinical studies of medicines. Guidelines /

O.V. Stefanov. - Kyiv, 2001. - 527 p... The substance was administered in doses of 500, 800, 1000 and 1500 mg/kg body weight during a single parenteral administration of a suspension of the substance to white mice of both sexes weighing 18-22 g. As a control, a group of animals that were administered purified water. The animals were observed for 14 days.

As a result of the study of the toxicity parameters, it was established that the value of IUbo allows to assign the studied compound to the IM safety class, that is, according to the degree of toxicity and danger, it meets the requirements for medicinal products.

The obtained data of experimental studies are given in the Table.

Table

Results of the study of antiexudative activity and acute toxicity of 5-(4-carboxymethylbenzylidene)-3-(2-(2-(2,6-dichlorophenylamino)phenyl|acetylamino)-2-thioxothiazolidin-4-one drug mg/kg per hour. , Uo inflammatory reaction, 90 mg/kg

Control -Y11111111012665 11111111 Her

Natriduclofenac.//// 8 | .7717171717117721111111111111111430 | -

Ketanov/////////777777171110Ї777777111779М11111111111111111975 declares

As can be seen from the data given in the Table, the claimed compound is stable

It has anti-exudative activity, which is not inferior in the experiment to known non-steroidal anti-inflammatory drugs with a low toxicometric profile.

To understand the proposed useful model, below is an example of the preparation of 5-(4-carboxymethylbenzylidene)-3-(2-(2-(2,6-dichlorophenylamino)phenyl|acetylamino)-2-thioxothiazolidin-4-one.

The compound is synthesized as follows.

Synthesis of 5-(4-carboxymethylbenzylidene)-3-(2-(2-(2,6-dichlorophenylamino)phenyl|acetylamino)-2-thioxothiazolidin-4-one. 0.005 mol of 3-( 2-(2-(2,6-dichlorophenylamino)phenyl|acetylamino)-2-thioxothiazolidin-4-one and anhydrous sodium acetate, add 0.0055 mol of methyl (4-formyl)benzoate and 10 ml of acetic acid and heat with reflux in a refrigerator for 5 hours. The reaction mixture is cooled, the reaction product is filtered, washed successively with acetic acid, water, ethanol, and diethyl ether, dried and recrystallized from a mixture of DMF-acetic acid (1:2).

A light yellow crystalline powder is obtained. Output - 78 Fo. T. pl. - 270-271 76.

Gross formula SgvNizSi2MzO45".

Found, 9o: M 7.62; 510.97.

Calculated, 905: M 7.34; 5 11.20.

NMR "H (0M50O-yv, 400 MHz), b, m.p.: 3.84-3.92m (5Н, СНСО, СООСН»); 6.ЗО0d (1Н, arom., 9-7.68 Hz ); 6.92t (1H, arom., 9U-7.3 Hz); 7.09t (IN, arom., 9U-7.7 Hz); 7.19t (1H, arom., 9-81 Gu) ; 7.52-7.36m (2H, arom., Ag-MN-Ak); 7.52d (2H, arom., U-8.0 Hu); 7.82d (2H, arom., U-8, 3 Hz); 7.99s (IN, -CH:); 8.10d (2H, arom., U-8.2 Hz); 11.74s (IN, SOMN).

Claims (1)

USEFUL MODEL FORMULA 5-(4-Carboxymethylbenzylidene)-3-12-(2-(2,6-dichlorophenylamino)phenyl|iacetylamino)-2-thioxothiazolidin-4-one of the formula: SI (c) H NM -zhfFS mA on 5-X and s o Z (c), which shows antiexudative activity.