UA142117U - 4- [3- (5-Bromo-2-hydroxyphenyl) -5-phenyl-3,4-dihydropyrazol-2-yl] -5H-thiazol-2-one having antitumor activity - Google Patents

Abstract

4- [3- (5-Bromo-2-hydroxyphenyl) -5-phenyl-3,4-dihydropyrazol-2-yl] -5H-thiazol-2-one of General formula: having antitumor activity.

Description

A useful model concerns the synthesis of organic compounds and pharmacy, in particular, the preparation of biologically active 4-I3-(5-Bromo-2-hydroxyphenyl)-5-phenyl-3,4-dihydropyrazol-2-yl|-5H-thiazol-2-one, which shows antitumor activity and can be used in clinical medicine as an antitumor drug.

Among the thiazole/thiazolidone-pyrazoline conjugates developed within the framework of the "tybrid-pharmacophore approach", a derivative of pseudothiohydantoin with a pyrazole fragment in the 5th position, which inhibits necroptosis, was identified. pestoriov ippiriyug, pesgoviaip-7 / Utsap, Spepduye; 2pepdu, UMUeipopo; YuOeadiegem, AiIehei Gei ai. //Vioogdapis apa Meadisipa! Spetivigh and eyege. - 2008. - Mine. 18. Ivv. 18. - R. 4932-4935), pyrazolyl-thiazolidinone-4 derivatives that selectively inhibit certain lines of lung cancer (bZupipeviv, sNagasiegigayop, apiisapseg, apa apiyohidapi asiimyu oi zote pem/ IpPiagoiidip-4-ope5 ip MSE-7 seiYiv5. / Agip M. Ivioog, Opapua 5ipii, Rgakazy! Zpeinu This! a!.) //Me«hisipa! Snetivgu Vezeagsy. - 2013. - Mine. 22. 585. 2. - P. 758-767), a series of (5-aryl-3-phenyl-pyrazolyl)-thiazol-2-ones and (5-aryl-3-phenyl-pyrazolyl)-thiazol-4-ones , which inhibited the growth of lung cancer and leukemia cell lines (NamguiuShk, 0., gtepKom5Ku, V., MazuiepKo, O., 2argshiko, Y, S2eiPMa, A., 5 Gezuk, K. (2009). Zupipevib5 oi pomei

Shiagoope-based sotroipaz sopiaipipa rugagoiipe toiveiiu apa emaiYiyayop oi iNeig apiisapseg asiimiu.

Eshmgoreap |oitai oi tedisipa! Science, 44(4), 1396-1404.

Pyrazole derivatives are studied in the context of the search for new anticancer drugs. One such compound is pyrazoloacridine, which causes cytotoxicity by intercalating into DNA and, accordingly, inhibiting the synthesis of RNA, DNA and the activity of topoisomerase I and I! IAdieyi, A. A., SVpaggop,

M., Kom/pzkKu, E. K., Zmipdep, R. A., MiPSheg, u., Keia, 9. M., zeroy I eoroia, 9., Atez M. M., Kashitapp,

Z.N. (1998). Emesi oi rugagoIoasiiidipe (MS 366140) op OMA Yuyuroizotegazez I apa I. Siipisai sapseg gezeeagsy, 4(3), 6683-6911.

Ruxolitinib, whose molecule contains a pyrazole nucleus, is a drug used to treat primary myelofibrosis:

What's up

The mechanism of its action is related to the inhibition of Janus-kinase 1/2. Although ruxolitinib is currently the only oral drug for the treatment of patients with myelofibrosis characterized by symptomatic splenomegaly and debilitating disease-related symptoms,

Because it is not effective for eliminating the primary causes of hemoblastosis | Mazsagepnav, 9., 5 Neutap,

A. (2012). Vikhoiyipir: She ytvi ESA arrgomei IPpegaru og She igeaitepi oi tuePoibgoviv. Siipisa sapseg gezeeagsi, 18(11), 3008-3014).

A compound of the formula is also known

Zoo min / xx

M (o); which is a derivative of thiazolidine and is used to treat patients with erythremia |Mashkovsky

M.D. Medicines. In two volumes. T. 2. - Izd. 14th, new. - Moscow: Novaya Volna, 2002. - P. 417). The described drug is known under the name imiphos. However, this drug also has a number of disadvantages, in particular, leukopenia and thrombocytopenia may develop when it is used, therefore it is contraindicated for patients with severe exhaustion, anemia, leukopenia and thrombocytopenia.

Considering the above, the search for new synthetic anticancer agents combining pyrazole and thiazolidone cycles in the molecule is relevant for modern medicinal chemistry.

The basis of a useful model is the task of creating an effective antitumor agent with fewer side effects and an acceptable toxicological profile.

The problem is solved by the fact that the synthesized 4-(3-(5-Bromo-2-hydroxyphenyl)-5-phenyl-3,4-dihydropyrazol-2-yl|-5H-thiazol-2-one of the general formula: and: M /

M M p

Hg that has an antitumor effect.

The synthesized compound is a light yellow crystalline powder, soluble in DMF, sparingly soluble in acetic acid, alcohols, and insoluble in ether and water.

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

The declared 4-I3-(5-Bromo-2-hydroxyphenyl)-5-phenyl-3,4-dihydropyrazol-2-yl|-5H-thiazol-2-one is obtained in two stages:

I) synthesis of 4-bromo-2-(3-phenyl-4,5-dihydro-1H-pyrazol-5-ylphenol in the reaction of 3-(5-Bromo-2-hydroxyphenyl)-1-phenyl-prop-2-ene -1-one with hydrazine hydrate;

II) interaction of the obtained 3,5-diaryl-4,5-dihydro-1H-pyrazole with 4-thioxo-2-thiazolidinone, which leads to the formation of the target product: (о, Й, Фи в) -k id

INN, Kh ra

ХО --- Мн 5779 С (в) о ж /

EUN M

M -o a, S A

Vg about Z

Hg

Determination of antitumor activity was carried out by ip mio on 55 cancer cell lines under the action of substances in concentrations of 107-108 M in accordance with the standard procedure for evaluating the antitumor activity of compounds at the US National Cancer Institute (Mayiopa! Sapseg Ipziyshe oi Maiiopai

Ipziyshe oi Neakp, O5A), within the framework of UOemeIortepi Tpegareshis Rgodgat (according to the contract between the specified institution and Danylo Lviv National Medical University

Halytskyi). As a result of the conducted experimental studies, dose-dependent C was obtained

Z parameters: IdSivo - the logarithm of the concentration of the tested substance, which inhibits the growth of 50 Fo cells, IDTOII - the logarithm of the concentration of the tested substance, which completely inhibits the growth of cells, DI Svo - the logarithm of the concentration of the tested substance, which causes the death of 50 95 cells IVouy, M.K. , 5 Rashii, K. 0. (1995). oh rgasiisa! sopzidegaynop5 apa arriisayop5 oi te

Mayiope! Sapseg Ipviyshie ip mygo apiisapseg disgusted divsomegu zsteep. Opa Yuemeiortepi Vezveagsi,

Z4A(2), 91-1091.

In the conditions of the experiment, the results of which are shown in the Table, the claimed 4-I3-(5-Bromo-2-hydroxyphenyl)-5-phenyl-3,4-dihydropyrazol-2-yl|-5H-thiazol-2-one showed high antitumor activity action

The claimed compound showed marked inhibition of the growth of almost all cancer cell lines. The lowest effective inhibitory concentration values for 4-I3-(5-Bromo-2-hydroxyphenyl)-5-phenyl-3,4-dihydropyrazol-2-yl|-5H-thiazol-2-one were observed for the leukemia panel. The most sensitive leukemic cell line to the action of the claimed substance was line 5A (yield--7.45), also 4-I3-(5-Bromo-2-hydroxyphenyl)-5-phenyl-3,4-dihydropyrazol-2-yl|- 5H-thiazol-2-one completely inhibited the growth of leukemia lines at submicromolar concentration values (9). The declared 4-I(3-(5-Bromo-2-hydroxyphenyl)-5-phenyl-3,4-dihydropyrazol-2-yl|-5H-thiazol-2-one was characterized by high antitumor activity against the non-small cell lung cancer line MCI- NZ22M (IdaiIvo--6.51), as well as in relation to colon cancer lines NST-116 (Davo--6.52), ovarian cancer OMSAV-3 (IdSiIvo--6.61), breast cancer MSE? (Idsivo --6.52).

Table

Antitumor effect of ip mio 4-3-(5-Bromo-2-hydroxyphenyl)-5-phenyl-3,4-dihydropyrazol-2-yl|-5H-thiazol-2-one

Leukemia

SSVE-SEM -6.47 -5.57 5-4.00

NO-6o0 -6.51 -6.03 5-4.00

Kk-562 -6.02 5-4.00 5-4.00

MY T-4 -6.40 -5.75 5-4.00

FOR -7.45 -6.55 »-4.00

Non-small cell lung cancer

EKUH -6.42 5-4.00 5-4.00

МСИ-Н2З -6.09 5-4.00 5-4.00

MSI-NZ2g2gM -6.51 -4.82 5-4.00

MSI-N4i60 -6.21 »-4.00 »-4.00

Colon cancer

NeST-116 -6.52 5-4.00 5-4.00 net-15 -6.12 5-4.00 5-4.00

ZMU-620 -6.16 »-4.00 »-4.00

CNS cancer

ZE-268 -6.09 5-4.00 5-4.00

ZE-295 -6.20 »-4.00 »-4.00

Melanoma

MY ME-ZM -6.07 -4.65 5-4.00

M14 -6.04 -4.55 5-4.00

ZK-MEG--5 -5.93 -4.68 »-4.00

Ovarian cancer

OMSAV-Z -6.61 -6.17 5-4.00

OMSAV-4 -6.33 5-4.00 5-4.00

МСИ/АОВ-ВЕ5 -6.08 -4.68 »-4.00

Kidney cancer

ASNM -5.84 5-4.00 5-4.00

SAKI-1 -6.14 -5.39 »-4.00

En 000111 5 yuyu ry-145 -5.65 »-4.00 »-4.00

Breast cancer

MSE7 -6.52 5-4.00 5-4.00 t-470 -6.42 5-4.00 5-4.00

MOA-MV-468 -6.20 -4.17 »-4.00

Thus, the claimed compound shows a high antitumor effect and is a promising antitumor agent.

To understand this useful model, below is an example of the preparation of 4-I3-(5-Bromo-2-hydroxyphenyl)-5-phenyl-3,4-dihydropyrazol-2-yl|-5H-thiazol-2-one. The compound is synthesized as follows. 1. Synthesis of 4-bromo-2-(3-phenyl-4,5-dihydro-1H-pyrazol-5-ylphenol. 0.01 mol of 3-(5-Bromo-2-hydroxyphenyl)- 1-phenyl-prop-2-en-1-one and 0.011 mol of hydrazine hydrate solution (50 95), add 20 ml of ethanol and boil for 30 min. After cooling the reaction mixture, the precipitate formed is filtered off and recrystallized from dioxane. 2. Synthesis 4-I3-(-5-Bromo-2-hydroxyphenyl)-5-phenyl-3,4-dihydropyrazol-2-yl|-5H-thiazol-2-one.

A mixture of 4-thioxo-2-thiazolidinone (0.01 mol) and 4-bromo-2-(3-phenyl-4,5-dihydro-1H-pyrazol-5-yl)uphenol (0.01 mol) is boiled in 100 ml of ethanol for 1.5 hours. After cooling the reaction mixture to room temperature, the precipitate formed is filtered off, washed with methanol and recrystallized from a mixture of DMF:ethanol (1:2).

Output 6595. Light yellow crystalline powder. Ttopi-232-234 b. SivNi«ViMz3O25.

Found, 95: M - 10.1; 5 7.7. Calculated, 90: M - 10.3, 5 7.50. NMR "H (300 MHz, OM50O-av), 5, m. h.: 3.25 dd (1H, 1-3.3 Hz, 9da2-20.0 Hz, CH", pyrazol.), 4.0 dd ( 1H, 91-11.1 Hu, da-20.0 Hz, CH», pyrazol.), 4.65 d (1H, 9U-16.8 Hz, CH», thiazol.), 4.87 d (1H , 9U-16.8 Hu, CH», thiazol.), 5.75 dd (1H, u1-3.3 Hz, Ug-20.0 Hu, CH, pyrazol.), 6.83 d (1H, U -8.2 Hz, arom.), 7.1 d (1H, 9U-2.7 Hz, arom.), 7.24 dd (1H, 41-2.7 Hz, 9d2-8.2 Hz, arom. .), 7.47-7.56 m (ZN, arom.), 7.86 d (2H, U-8.2 Hz, arom.).

Claims (1)

FORMULA OF A USEFUL MODEL 4-YZ3-(5-Bromo-2-hydroxyphenyl)-5-phenyl-3,4-dihydropyrazol-2-yl|-5H-thiazol-2-one of the general formula: i: M / M M a ( c) enter in (c) 5 from which exhibits an antitumor effect.