4.5- Diarylpyrazoles

Diarylpyrazole compound docking into the active site of cyciooxygenase-2 (COX-2) as an inhibitor. Different orientations are tested to optimize the steric, eiectrostatic and hydrogen boding interactions. 

Figure 3.6 Docking simulations. (Source Liu H, Huang X, Shen J, et al. Inhibitory mode of 1,5-diarylpyrazole derivatives against cyclooxygenase-2 and cyclooxygenase-1 molecular docking and 3D QSAR analyses, Journal of Medicinal Chemistry 45 4816-4827 (2002). Used with permission.)...

Menozzi G, Fossa P et al (2008) Rational design, synthesis and biological evaluation of new 1, 5-diarylpyrazole derivatives as CBj receptor antagonists strucmrally related to rimonabant. Eur J Med Chem 48 2627-2638... 

Humphries PS, Finefield JM (2006) Microwave-assisted synthesis utilizing supported reagents a rapid and versatile synthesis of 1, 5-diarylpyrazoles. Tetrahedron Lett 47 2443-2446... 

Tsuji, K., Nakamura, K., Konishi, N., Tojo, T., Ochi. T.. Senoh, H.. and Matsuo, M., Studies on antiinflammatory agents. Part 4. Synthesis and pharmacological properties of 1,5-diarylpyrazoles and related derivatives, Chem. Pharm. Bull., 45. 987, 1997. 

Desiraju, G.R., Gopalakrishnan, B., Jetti, R.K.R., Raveendra, D., Sarma, J.A.R.P. and Subramanya, H.S. (2000) Three-dimensional quantitative structural activity relationship (3D-QSAR) studies of some 1,5-diarylpyrazoles analogue based design of selective cyclooxygenase-2 inhibitors. Molecules, 5, 945-955. 

Penning TD, Taiiey JJ, Bertenshaw SR, et ai. Synthesis and bioiogicai evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide (SC-58635, celecoxib). J Med Chem 1997 40 1347-1365. 

This happened, for example, with some COX-2 inhibitors. See Penning, T.D., et al. Synthesis and biological evaluation of the 1,5-Diarylpyrazole class of cyclooxygenase-2 inhibitors Identification of the... 

In addition to 1,3-dicarbonyl as a reactant for the Knorr pyrazole synthesis, several variants exist as the 1,3-dicarbonyl group surrogate. Enaminone is one example. Reaction between ethyl-4-iodobenzylacetate and I. N-dimethylformamide dimethylacetal (DMFDMA) provided the enaminone. Subsequent condensation between the enaminone and 2,4-dichlorophenyl-hydrazine afforded the pyrazole as an advanced intermediate for 1,5-diarylpyrazole derivatives as CBi receptor antagonists. 

Finally, a facile and regioselective synthesis of rimonabant was accomplished through an enamine-directed 1,3-dipolar cycloaddition." In the presence of triethylamine, hydrazonoyl iodide was converted into the nitrile imine in situ. The subsequent 1,3-dipolar cycloaddition with the morpholine enamine provided the 1,5-diarylpyrazole, which was transformed into rimonabant. 

Mamaghani and Dastmard (2009) reported an efficient and practical method for the regioselective synthesis of 1,5-diarylpyrazoles (21) in excellent yields (80%-90%) by the reaction between Baylis-Hillman adducts (19) and phenylhydrazine hydrochloride (20) in 1,2-dichloroethane (DCE) under ultrasonic irradiation with reaction times of 60-180 min at 60°C (Scheme 8.7). 

Chromones behave similarly toward both hydroxylamine and hydrazines interestingly, ring opening O/C-2 is frequently followed by re-cychzation to azoles. This is illustrated by the reaction of chromone with phenylhydrazine, which can be conducted either to chromone phenylhydrazone (5) or (via the enehydrazine 4) to the 1,5-diarylpyrazole 6 ... 

SCHEME 20 Synthesis of 1,5-diarylpyrazoles 29 over HY zeolite catalyst. 

M. Nikpassand, M. Mamaghani, M.A. Zarq anchi, N.O. Mahmoodi, M. Mirzaeinejad, A convenient synthesis of 1,5-diarylpyrazoles from Baylis-FliUman adducts using HY-zeolite, Chin. Chem. Lett. 21 (2010) 5-8. 

By definition, cannabinoids comprise a variety of distinct chemical classes which bind to the cannabinoid receptor. These include the classical cannabinoids structurally related to tetrahydrocannabinol, the non-classical cannabinoids, the aminoalkylindoles, the eicosanoids related to the endocannabinoids, 1,5-diarylpyrazoles, quinolines and atylsulphonamides and additional compounds that do not fall into these standard classes. According to their production and origin, there are three types of cannabinoids phytocannabinoids, endogenous cannabinoids, and synthetic cannabinoids. 

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