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Synthesis of Pyrazoles Containing Benzofuran and Trifluoromethyl Moieties As Possible Anti-Inflammatory and Analgesic Agents

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Synthesis of Pyrazoles Containing Benzofuran and Trifluoromethyl Moieties As Possible Anti-Inflammatory and Analgesic Agents Z. Naturforsch. 2015; 70(7)b: 519–526 Awatef A. Farag, Mohamed F. El Shehry, Samir Y. Abbas*, Safaa N. Abd-Alrahman, Abeer A. Atrees, Hiaat Z. Al-basheer and Yousry A. Ammar Synthesis of pyrazoles containing benzofuran and trifluoromethyl moieties as possible anti-inflammatory and analgesic agents DOI 10.1515/znb-2015-0009 and anti-inflammatory drugs present a wide range of prob- Received January 9, 2015; accepted February 4, 2015 lems such as efficacy and undesired effects including gas- trointestinal tract (GIT) disorders and other unwanted effects. This situation highlights the need for novel, safe and Abstract: Searching for new anti-inflammatory and anal- effective analgesic and anti-inflammatory compounds [1–3]. gesic agents, we have prepared a series of novel pyrazoles Since the first pyrazolin-5-one was prepared by Knorr containing benzofuran and trifluoromethyl moieties. The [4] in 1883, many papers have reported on the anti-inflam- pyrazole derivatives have been synthesized via two routes matory, analgesic and antipyretic evaluation of several starting from 5-(3-(trifluoromethyl)phenyl azo) salicylal- pyrazoles, pyrazolin-3-ones and pyrazolidine-3,5-diones dehyde. The first route involved the synthesis of 2-acetylb- [5–9]. Many of these derivatives such as phenylbutazone, enzofuran and then treatment with aldehydes to afford febrazone, feclobuzone, mefobutazone, suxibuzone and the corresponding chalcones. The cyclization of the latter ramifenazone have found their clinical application as chalcones with hydrazine hydrate led to the formation of nonsteroidal anti-inflammatory drugs (NSAIDs) [10]. new pyrazoline derivatives. The second route involved the The benzofuran derivatives have attracted due to their synthesis of benzofuran-2-carbohydrazide and then treat- biological activities and potential application as pharma- ment with formylpyrazoles, chalcones and ketene dith- cological agents [11]. Additionally, various benzofuran ioacetal derivatives to afford the corresponding pyrazole derivatives possess anti-inflammatory [12], antidepres- derivatives. Some of the synthesized compounds exhib- sant [13], anti-oxidant [14], anticonvulsant [15] and anal- ited anti-inflammatory and analgesic activities. gesic activity [16]. In addition, many investigations have indicated that Keywords: analgesic agents; anti-inflammatory; benzo- the introduction of a trifluoromethyl group in bioactive furan; pyrazoles; trifluoromethyl. compounds often improves their pharmacodynamic and pharmacokinetic properties. The CF3 group has significant effects on the binding affinity in drug–receptor complexes and it can increase membrane permeability and stability 1 Introduction against metabolic oxidation [17]. Encouraged by the above facts and in continuation Analgesic and anti-inflammatory drugs are used in many of our interest in the synthesis of bioactive heterocyclic diseases for relief of pain and inflammation. Most analgesic compounds [18–22], we anticipated that the introduction of the important benzofuran moiety and the CF3 group to *Corresponding author: Samir Y. Abbas, Organometallic and a pyrazole nucleus might generate a new group of biologi- Organometalloid Chemistry Department, National Research Centre, cally active compounds that may be potent, selective and Cairo 12622, Egypt, Tel.: +‏20-233335929, Fax: +20-233370931, less toxic analgesic and anti-inflammatory agents. E-mail: [email protected] Awatef A. Farag: Faculty of Science, Chemistry Department, Al-Azhar University (Girls), Cairo, Egypt Mohamed F. El Shehry: Pesticide Chemistry Department, National 2 Results and discussion Research Centre, Cairo 12622, Egypt Safaa N. Abd-Alrahman, Abeer A. Atrees and Hiaat Z. Al-basheer: 2.1 Chemistry Faculty of Education, Chemistry Department, Taif University, Taif, Saudi Arabia Yousry A. Ammar: Faculty of Science, Department of Chemistry, Initially, the core compound 2-acetylbenzofuran deriva- Al-Azhar University, Cairo, Egypt tive 2 was obtained by coupling 3-(trifluoromethyl) 520 A.A. Farag et al.: Synthesis of pyrazoles containing benzofuran and trifluoromethyl moieties OH NH2 a b F C N F C N CH 3 N CHO 3 N O 3 O CF3 1 2 Scheme 1: Synthetic route for acetylbenzofuran 2: (a) i. HCl, ii. NaNO2, iii. salicylaldehyde, NaOH, stirring, 0 °C; (b) chloroacetone, acetone, K2CO3, reflux, 2 h. benzenediazonium chloride with salicyaldehyde to afford elemental analyses. IR spectra showed the disappearance 5-((3-(trifluoromethyl)phenyl)diazenyl)salicylaldehyde (1) of the C=O band of chalcones. A strong band appeared at which was subsequently used for cyclocondensation with 1590–1602 cm−1 and was assigned to C=N of the pyrazo- chloroacetone in acetone and in the presence of anhy- line ring. Pyrazolines 5 and 6a, b showed an additional drous potassium carbonate (Scheme 1). sharp band in the region 3300–3353 cm−1 due to their NH The presence of the acetyl group in compound 2 stretching vibration. In the 1H NMR spectra of pyrazolines makes it versatile precursor for the synthesis of chalcones 5 and 6a, b, the protons attached to the C-4 and C-5 carbon and pyrazoline derivatives. Thus, the Claisen–Schmidt atoms of the five-membered ring gave an ABX spin system. condensation of 2-acetylbenzofuran (2) with p-nitroben- Chemical shifts and the coupling constant values (cf. zaldehyde in ethanolic sodium hydroxide furnished the Experimental section) unequivocally prove the pyrazoline chalcone derivative 3. Similarly, condensation of com- structures. Their 1H NMR spectra revealed the signals of pound 2 with formylpyrazoles afforded the correspond- CH2 protons of the pyrazoline ring in the region 2.39–3.13 ing chalcone derivatives 4a, b. The structures of the latter and 4.02–4.14 ppm as a pair of doublets. The CH proton products were derived from their spectroscopic as well as appeared as doublet of doublets at δ = 5.09–5.51 ppm. elemental analytical data. For example, the IR spectrum The hydrazide and hydrazones derivatives have proved of compound 3 showed the characteristic band for conju- to be good building blocks for the construction of many gated C=O at 1664 cm−1 and its 1H NMR spectrum displayed biological active heterocyclic compounds. When salicyla- a pair of doublets at δ = 8.36 and 8.49 ppm, with a cou- ldehyde derivative 1 was reacted with ethyl bromoacetate pling constant indicating trans-olefinic protons. The mass in acetone and in the presence of anhydrous potassium spectrum revealed a molecular ion peak at m/z = 465 carbonate at room temperature, the formyl derivative 7 (21 %) corresponding to a molecular formula C24H14F3N3O4. was obtained rather than the expected ethyl 5-(2-(3-(trif- Cyclocondensation of chalcones 3 and 4a, b with hydra- luoromethyl)phenyl)diazenyl)benzofuran-2-carboxylate zine hydrate in boiling ethanol furnished the respec- (8) which was obtained in good yield upon heating of 1 tive pyrazolines 5 and 6a, b (Scheme 2). The structures with ethyl bromoacetate in acetone under a reflux condi- of the pyrazolines were derived from spectral data and tion. Benzofuran-2-carbohydrazide 9 was prepared by the F C N CH 3 N O 3 2 O NO2 NO2 H H c F3C N a F C N N O H 3 N O 5 N NH 3 O Ar H HH Ar F3C N N b F3C N c N O N O N O N N NH Ph N 6a, Ar = C6H5 4a, Ar = C6H5 b, Ar = C6H4-CH3-4 b, Ar = C6H4-CH3-4 Ph Scheme 2: Synthesis of the chalcone and pyrazole derivatives: (a) 4-nitrobenzaldehyde, EtOH, NaOH aq. r. t., 2 h; (b) formylpyrazoles, EtOH, NaOH aq. r. t., 2 h; (c) hydrazine hydrate, EtOH, reflux, 4 h. A.A. Farag et al.: Synthesis of pyrazoles containing benzofuran and trifluoromethyl moieties 521 reaction of the ester derivative 8 with hydrazine hydrate in products were deduced from elemental analysis and spec- boiling ethanol (Scheme 3). Elemental analyses and spec- troscopic data. tral data supported the proposed structures. Condensation of the hydrazide 9 with formylpyrazoles in ethanol under reflux afforded the respective hydrazone derivatives 10a–c. Also pyrazoline derivatives 11a–c were 3 Biological activities prepared through the reaction of hydrazide derivative 9 with some chalcone derivatives. According to previous 3.1 Anti-inflammatory activity work [23–27], which was supported by X-ray structure determinations, the suggested reaction mechanism of the The paw edema test has been widely employed to assay cyclization of chalcones with hydrazides or substituted anti-inflammatory agents. It works by measuring the hydrazines to form pyrazolines involves first the conden- ability of the tested samples in reducing edema induced sation of the free amino group of hydrazide with the car- upon irritant carrageenan. In order to determine the bonyl group of the chalcone and then the attachment of anti-inflammatory activity in acute-phase inflammation the NH group of the hydrazide to the olefinic bond of the in vivo, 11 newly synthesized compounds 4a, 4b, 5, 6a, chalcone. In our case, this would lead to the Ar group to 10a, 10c, 11a–c and 12a, b were selected and evaluated be attached to C-3 of pyrazoline and the Ar′ group to C-5 with a carrageenan-induced mouse paw edema bioassay of pyrazoline. Finally, the reaction of hydrazide 9 with in rats [28] using indomethacin as a reference standard. ketene dithioacetal derivatives in acetic acid under reflux Results were expressed as mean ± SE. The difference gave only a sole product, which was identified as the between vehicle control and treatment groups was tested pyrazole derivatives 12a, b (Scheme 4). The structures of using one-way ANOVA followed by the least significant CHO F C N OC H 3 N O 2 5 O CHO 7 BrCH2COOEt r.t. F C N 3 N OH 1 F C N R 3 N O BrCH2COOEt reflux O 8: R = OC2H5 N2H4 aq, EtOH, reflux 9: R = NHNH2 Scheme 3: Synthetic route for the benzofuran-2-carbohydrazide 9. F3C N a N O CONHN Ar F3C N N O CONHNH2 10a Ar = Ph N 9 O b Ar = C6H4(CH3)-4 N c Ar = C6H4Cl-4 Ph NC SCH3 Ar c Ar′ ,b R SCH3 Ar′ H2N R F3C N N F3C N N N O N Ar N O N SCH3 O 12a R = CN O 12b R = COOEt 11a Ar = C6H5 Ar′ = C6H4Cl-4 11b Ar = C6H5 Ar′ = C6H4Br-4 11c Ar = C6H4CH3-4 Ar′ = C6H4OCH3-4 Scheme 4: Synthesis of the different pyrazole derivatives: (a) pyrazole carbaldehyde, EtOH, reflux, 3 h; (b) AcOH, reflux, 3 h; (c) AcOH, reflux, 4 h.
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