UA4773U - A compound 5-[(4-chlorophenyl)methylidene]-2-(4-oxyanilino)-4,5-dihydrothiazole-4-on which reveals an antitumor activity - Google Patents

Abstract

A utility model concerns the synthesis of the compound 5-[(4-chlorophenyl)methylidne]-2-(4-oxyanilino)-4,5-dihydrothiazole-4-on of the formula: , which reveals an antitumor activity.

Description

A useful model relates to the synthesis of organic compounds and pharmacy, in particular to the production of biologically active compounds, namely 5-((4-chlorophenyl)methylidene|-2-(4-oxyanilino)-4,5-dihydrothiazol-4-one, which exhibits antitumor activity and can be used in clinical medicine as an oncological medicine.

Well-known medicinal products with antitumor activity, for example, flutorafur /Mashkovsky M.D.

Medicines. In two volumes. T. 2. - Izd. 13th, new. - Kharkiv: Torsing. - 1998. - P. 457/. Fluorafur is a prodrug of fluorouracil. Antitumor activity is due to the formation of fluorouracil in the body, which suppresses the development of some neoplasms. This medicine has the necessary therapeutic properties, but with long-term use it is characterized by significant side effects: leukopenia, thrombocytopenia, diarrhea, vomiting, etc. Ftorafur is contraindicated for leukocyte levels below 37109/l and platelets below 1007109/l, in the terminal stages of the disease, with acute profuse bleeding and severe anemia.

A compound of the formula mm is also known

Rom ocho, which is a derivative of thiazolidine and is used for the treatment of patients with erythremia in the advanced stage of the disease / Mashkovsky, M.D. Medicines. In two volumes. T.2. - Ed. 13th, new. - Kharkiv:

Torsing, 1998. - P. 448 /. The described compound is a medicine - imiphos.

However, the named drug has a number of disadvantages, in particular, leukopenia and thrombocytopenia may develop when it is used. Imiphos is contraindicated, in particular, for patients with severe exhaustion, anemia, leukopenia, and thrombocytopenia.

The basis of the proposed useful model is the task of creating such antitumor substances that would be more effective, in particular, when used therapeutically against the background of reducing side effects (leukopenia, thrombocytopenia, vomiting) due to the creation and use of less toxic thiazolidine derivatives.

The given task is solved by using the proposed substance synthesized /- 5-((4-chlorophenyl)methylidene|-2-(4-oxyanilino)-4,5-dihydrohiazol-4-one of the formula

IF) (Fi that exhibits antitumor activity.

The mentioned compound can be obtained using the first variant of the proposed method, which includes operations of interaction of 2-(4-oxyanilino)-4,5-dihydrothiazol-4-one with p-chlorobenzaldehyde under the conditions of the Knievenagel reaction in the medium of acetic acid and the catalyst of anhydrous sodium acetate, and 2-(4-oxyanilino)-4,5-dihydrothiazol-4-one is synthesized by aminolysis of ethyl 2-(4-oxo-4,5-dihydrothiazol-2h-ylsulfanyl)acetate with p-aminophenol in an alcoholic medium, and ethyl 2- (4-oxo-4,5-dihydrothiazol-2-ylsulfanyl)acetate is obtained by alkylating the triethylammonium salt of 2-thioxothiazolidin-4-one with ethyl chloroacetate in an acetone medium.

The mentioned compound can be obtained using the second variant of the proposed method, which includes the interaction of p-oxyphenylthiourea with monochloroacetic acid and p-chlorobenzaldehyde in the presence of a two-fold excess of anhydrous sodium acetate in acetic acid. The synthesized compound is a yellow crystalline powder, soluble in DMSO and DMF, sparingly soluble in acetic acid, insoluble in alcohol, acetone, water, and ether.

Known physicochemical methods were used to prove the composition and structure of the synthesized compound, in particular

PMR - spectroscopy and elemental analysis. The obtained results indicate the conformity of the synthesized compound with the claimed one.

Determination of antitumor activity of 5-|(4-chlorophenyl)methylidene|-2-(4-oxyanilio)-4,5-dihydrothiazol-4-one.

For 5-I(4-chlorophenyl)methylidene|-2-(4-oxyanilino)-4,5-dihydrothiazol-4-one, pre-screening of antitumor activity on Z lines of human cancer cells, acting on them with only one dose of the drug and conducting experiment using the method of fluorescent staining / a) A. Mopk5, O. Zscaiego, R. 5Kepap, V.

Zpotakeg, K. Rashcii, Y. Miviisa, S. Noze, 9. Iapdieu, R. Stotve, A. Maiidgo-M/oNi, M. Stau-Sooagisi, N. Satrei, 4.

Mauo, M. Voua // 9). May Sapseg, Ppivi. - 1991. - 83. - R. 757-766; B) R. I egeshpge, p. Kopipadep, K.O. Russia, U. Rottieeg //

U. Mai. Sapseg Ipwee - 1994. - 86. - R. 1239-1244; c) 5.-S. Kio, N.-27. And hey, 9U.-R. Utsapd. M.-T. Pp, T.-b. UMy, 9.-U. snap,

O. And edpiseg. K.O. Russia, S.M. Pp, E. Natei, K.-N. And yes // 9. Mod, Spet. - 1993. - 36. - R. 1146-1156/. According to the results of anticancer prescreening of 5-|((4-chlorophenyl)methylidene|-2-(4-oxyanilino)-4,5-dihydrothiazol-4-one on Z cancer cell lines, it was established that the percentage of cell growth relative to the control (10095) on MSE7 line (breast cancer) is 5095, on MCI-NAbO (lung cancer) - 2595, and on 5E-268 (CNS cancer) - 669".

On the basis of prescreening, thorough antitumor IP myo screening was carried out / a) A. Mopkz5, 0. Zscaiego, R.

ZKepap, A. 5potakeg, K. Rush, YuO. Miviisa, S. Nove, 9. I apdieu, R. Stopize, A. Maiidgo-Mo!y, M. Stau-Sooagisy, N.

Satrei, u. Mauos, M. Voua // 9. Mai. Sapseg Ipwee - 1991. - 83. - R. 757-766; B) RE. I eteshpge, S. Kopipadep, K.O. Russia,

U. Rottieeg // U. Mai. Sapseg Ipwee - 1994. - 86. - R. 1239-1244; c) 5.-S. Kyo, N.-7. And ee, 9U.-R. Utsapo, M.-T. Sp, T.-6. UMy, 4.-). Spapo, 0. And Edpiseg, K.O. Russia, S.M. "p, E. Natei, K.-N. Geye // U. Med, Snet. - 1993. - 36. - R. 1146-1156/, which consisted in testing the claimed compound in at least 5 concentrations at 10 -fold dilution on 60 human cancer cell lines. The anticancer activity of 5-(4-chlorophenyl)methylidene-2-(4-oxyanilino)-4,5-dihydrothiazol-4-one was studied on leukemia cell lines (IeKketia) (SCAE-SEM , NI-60(TV), K-562, MOI T-4, ARMI-8226, 58), non-small cell lung cancer (Mop-Zptai! Seyi Hypd Sapseg) (AB5B49/ATOSS, EKUH, NOR-62, NOR-92 , MSI-H2g26, MSI-

Nag3, MCI-NZ22M, MCI-H4i60, MOSI-H522), epithelial cancer (Soyop Sapseg) (SOHO 205, NSS-2998, NST-116, NST-15, HT2g9, KM12, 5MU-620), CNS cancer (CM5 Sapseg) (5E-268, 5E-295, 5E-539, 5MV-19, 5MV-75, 0251), melanomas (Meiapota) (OH IMMI, MAGME-ZM, 5K-MEII-2, 5K-MEII-28, 5K-MEI-5, OASOS-257, OASO-62), ovarian cancer (Omapap Sapseg) 2A!OM1, OMSAV-3, OMSAV-4, OMSAV-5, OMSAV-8, 5K-OM-3), kidney cancer (Vepay! Sapseg) (786-0,

А498, ASNM, SAKI-1, АХЕ 393, ТК-10, 00-31, 5М12С), prostate cancer (Rgoviaie Sapseg) (ROS-3, 0О-145), breast cancer (Vgeazi Sapseg) (МСЕ7, MSIAOV- VE5, H5 578T, MOA-MV-435, VT-549, T-470, MOA-MV-231/АТСО).

Under the conditions of the experiment, 5-|(4-chlorophenyl)methylidene|-2-(4-oxyanilino)-4,5-dihydrothiazol-4-one showed high anticancer activity (to Co and IudioTaI « -4) on most of the studied cell lines ( table 1).

Table 1

Anticancer activity of 5-|(4-chlorophenyl)methylidene|-2-(4-oxyanilino)-4,5-dihydrothiazol-4-one Peikemia (Penseti) (mop-Vtai Sei cipo Sapoeo)

Epithelial cancer (sp sapoeia) bak dno (SMB Sapsei

Melanoma (Meiapota) ovarian cancer (Omatap Sapoei)

Breast cancer (Vgeavi

Sapseg) " - the results of a repeated study

Study of the cytotoxicity of 5-(4-chlorophenyl)methylidene|-2-(4-oxyanilino)-4,5-dihydrothiazol-4-one

The cytotoxicity of 5-K(4-chlorophenyl)methylidene|-2-(4-oxyachlino)-4,5-dihydrothiazol-4-one was determined using the immunological method of "spontaneous rosettes", which is based on the formation of spontaneous rosettes by human T-lymphocytes with with ram erythrocytes, which indicates the number of lymphocytes and their functional state in response to the action of chemical substances or physical influences / a) Golovistikov M.N., Rahmattulin I.M., Fassakhov R.S.

Effect of histamine on the ability of guinea pig T-lymphocytes to spontaneous rosette formation //

Immunology - 1981. - Me3. - P.22-24; B) Lymphocyte! / edited by J. Claus. - M.: "Mir", 1990. - 393 p.; with)

Chernushenko E.F., Kogosova L.S. Immunological studies in the clinic. - Kyiv: "Health", 1978. - 160 bs/.

At the same time, a cell is considered rosette-forming if at least five foreign erythrocytes (ram erythrocytes) are fixed on its surface.

With an average value of the number of rosette-forming cells in the control sample of 60,020.5, the 956Е-РОК value of 57,541.5 and cytotoxicity, respectively, 4.295, was established for the tested compound at a concentration of 5.8102M, at a concentration of 9.697109М - the value of 95Е-РОК - 34.0:х2, 0 and cytotoxicity - 43.895, at a concentration of 36.07109M -

UoE-ROC - 38.5:1.5 and cytotoxicity, respectively - 36.495. The obtained results indicate a low level of cytotoxicity of the investigated substance, which meets the requirements for a potential anticancer drug.

Study of the acute toxicity of 5-|(4-chlorophenyl)methylidene|-2-(4-oxyanilino)-4,5-dihydrothiazol-4-one

The toxicity of the claimed compound was studied by the express method / a) Prozorovsky V.B., Prozorovskaya M.P.,

V.M. Demchenko Express-method for determining the average dose efficiency and its error // Pharmacology and toxicology - 1978. - Me4. - pp. 497-502;

Preclinical studies of medicinal products (methodological recommendations) / sub. ed. A.V.

Stefanova. - K.: "Avicenna", 2002. - 568 s/.

The acute toxicity of 5-|(4-chlorophenyl)methylidene|-2-(4-oxyanilino)-4,5-dihydrothiazol-4-one was studied by intraperitoneal administration of different doses of the claimed compound. At the same time, the value of IO5o was evaluated by survival in 4 groups of rats. The results of the research are shown in Table 2.

Table 2

Experimental results of studying the acute toxicity of 5-|(4-chlorophenyl)methylidene|-2-(4-oxyanilino)-4,5-dihydrothiazol-4-one

The number of animals that died 0 | 0 | 0 | 0 | 0 | 0 | 1 | 71 | 2 (Terminizagibelii/-:/ / | - | - | - | - | - | - | 28 | 27 | 2428

According to the obtained results, the death of experimental animals with intraperitoneal administration of 5-|(4-chlorophenyl)methylidene|-2-(4-oxyanilino)-4,5-dihydrothiazol-4-one in concentrations of 1260-2000 mg/kg occurs within 24- 28 hours from the moment of injection. It was established that the average lethal dose of the claimed compound is 1410 (1100-1700). This makes it possible to assign 5-|(4-chlorophenyl)methylidene-2-(4-oxyanilino)-4,5-dihydrothiazol-4-one to the M safety class, i.e., in terms of toxicity and danger, the claimed compound meets the requirements for medicinal means

Thus, the claimed compound exhibits high antitumor activity against the background of sufficiently low toxicity and is a promising anticancer agent.

To understand this useful model, below is an example of stepwise preparation of 5-((4-chlorophenyl)methylidene-2-(4-oxyanilino)-4,5-dihydrothiazol-4-one from 2-thioxothiazolidin-4-one.

Synthesis of the triethylammonium salt of 2-thioxothiazolidin-4-one. 10.1 g (0.1 mol) of triethylamine is added to a suspension of 13.3 g (0.1 mol) of 2-thioxothiazolidin-4-one in 50 ml of isopropanol. Heat in a water bath until a solution is formed.

After cooling, the precipitate is filtered, washed with isopropanol and ether, and dried.

Recrystallized from benzene. Exit 8395. Ttopl. 80-8170.

Found, 90: M 11.95; 5 27.36. SeNivM2gO5".

Calculated, up to: M 11.85; 5 27.08.

Synthesis of ethyl 2-(4-oxo-4,5-dihydrothiazol-2-ylsulfanyl)acetate. A mixture of 23.4 g (0.1 mol) of the triethylammonium salt of 2-thioxothiazolidin-4-one and 12.3 g (0.1 mol) of ethyl chloroacetate in 50 ml of acetone is heated in a round-bottomed flask under reflux for 2 hours. The formed triethylammonium hydrochloride is filtered off, and the filtrate is evaporated in a vacuum. The resulting residue is recrystallized alternately from isopropanol and HCl. Exit 95905.

Thotpl. 78-7976.

Found because: M 6.39; 5 29.24. С7НеМОз5".

Calculated, 95: M 6.45; 5 29.30.

YMRN, 5, m.ch.: 1.27 (t, ZN, SN"); 4.14 (q, 2H, OSNeCH); 4.25 (c, 2H, CH); 4.27 (c, 2H, SNae).

Synthesis of 2-(4-oxyanilino)-4,5-dihydrothiazol-4-one. A mixture of 0.035 mol of ethyl 2-(4-oxo-4,5-dihydrothiazol-2-ylsulfanyl)acetate, 0.035 mol of p-aminophenol in 50 ml of isopropanol is boiled in a reflux flask for 3 hours. The precipitate formed after complete cooling of the reaction mixture is filtered, washed with isopropanol and ether. Recrystallized from acetic acid or butanol.

Exit 9595. Ttopl. 274-27670.

Found because: M 13.45; 5 15.40. SeNeM2O"25.

Calculated, 95: M 13.30; 5 15.20.

TLC, NN: (solvent system): 0.64:20.03 (acetone-hexane 1:1), 0.7920.02 (isopropanol-toluene 1:1), 0.85:50.03 (benzene-methanol 7:3), 0.56:2-0.04 (acetone-chloroform 1:4), UVF spectrum, 5. (Ide): 239 (4.01), 255 (4.23), 281 (4 ,27), 375 (2.60), NMR "H, 5, m, h,: 3.79, 3.88 (27s, 2H, CH"); 6.79, 6.90, 7.46 ( Z"d, AN, aroma, 9-8.4 Hu); 9.20, 9.24 (27s, 1H, OH); 10.78, 11.33 (27s, 1Н, МН).

Synthesis of 5-((4-chlorophenyl)methylschen-2-(4-oxyanilino)-4,5-dihydrothiazol-4-one. A mixture of 0.0048 mol of 2-(4-oxyanilino)-4,5-dihydrothiazol-4- onu, 0.0072 mol of p-chlorobenzaldehyde, 0.0048 mol of anhydrous sodium acetate in 10 ml of acetic acid are heated for 2 hours in a reflux flask. The precipitate formed after complete cooling of the reaction mixture is filtered off, washed with acetic acid, water, ethanol and ether, dried and recrystallized from a mixture of DMF-ethanol (2:1). Yield 8390. T.p. » 32070.

Found, 95: M 8.47; 5 9.69. SivH1SIM2O»5.

Calculated, Fo: M 8.60; 5 9.80.

TLC, NN: (solvent system): 0.69:20.02 (acetone-hexane 1:1), 0.8920.02 (isopropanol-toluene 1:1), 0.76:50.03 (benzene-methanol 7:3), 0.71:30.03 (acetone-chloroform 1:4), UVF spectrum, 5. (Ide): 241 (3.82), 248 (3.58), 272 (3.58 ), 346 (4.40), NMR "H, 5, mp: 6.77, 6.91, 7.49 (Z"d, 4H, 4-OH-SeNae, 9-82 Hz); 7.45-7.64 (m, 5H, 4-C1-SeNa, CH); 9.36, 9.40 (2"s, 1H, OH); 11.30, 12.09 (27s, 1H, MH).

Claims (2)

1. The compound 5-((4-chlorophenyl)methylidene|-2-(4-oxyanilino)-4,5-dihydrothiazol-4-one of the formula: IF) M (which exhibits antitumor activity. 2. The compound according to claim 1, which differs in that it is obtained by the reaction of 2-(4-oxyanilino)-4,5-dihydrothiazol-4-one with p-chlorobenzaldehyde under the conditions of the Knievenagel reaction in the medium of acetic acid and the catalyst of anhydrous sodium acetate. C. The compound according to claim 71, which differs in that it is obtained by reacting p-oxyphenylthiourea with monochloroacetic acid and p-chlorobenzaldehyde in the presence of a two-fold excess of anhydrous sodium acetate in acetic acid.