3.5- Diaryl-1,2,4-pyrazoles

The most important class of CBi receptor antagonists identified to date are the 1,5-diaryl-pyrazoles. This class includes rimonabant (382), first described in patent applications from Sanofi just over a decade ago [263, 264]. Rimonabant has proved invaluable in the elucidation of carmabinoid receptor pharmacology, as described in the section on therapeutic applications below. 

Several studies have been reported on the application of conformational restraint to the 1,5-diaryl-pyrazole series in an attempt to provide compounds with modified properties. In one approach, a Sanofi-Synthelabo patent application claimed a series of conformationally restrained compounds, exemplified by compound (391). Compounds of the invention were stated to be CBi receptor antagonists with K[ values below 5 x 10 M and selectivity over CB2 receptors of at least 10-fold [274]. 

Patent applications from Pfizer disclosed 1,5-diaryl-pyrazoles bearing bioisosteric replacements for the 3-carboxamide moiety. One application showed that the amide could be replaced by a-aminoketones as exemplified by compound (416) [284]. The corresponding alcohols and their ethers were also described, including compounds that allowed the amine substituent and ether to form a ring system, such as a morpholine unit. This application also allowed for the replacement of the 1,5-diaryl-pyrazole by a 1,2-diaryl-imidazole bearing a 3-carbonyl substituent, as exemplified by compound (417). A further patent application from Pfizer claims compounds in which imidazoles replace the 3-carboxamide moiety in the 1,5-diaryl-pyrazole... 

The diaryl pyrazole derivative celecoxib (Celebrex /Pharmacia, Pfizer), the fiiranone derivative rofecoxib (Vioxx /Merck), and the isoxazole derivative valdecoxib (Bextra /... 

Chimenti F, Fioravanti R, Bolasco A et al (2007) Monoamine oxidase isoform-dependent tautomeric influence in the recognition of 3,5-diaryl pyrazole inhibitors. J Med Chem 50 425 28... 

A small set of 1,4-diaryl pyrazoles was prepared using this approach. The low reactivity toward different dipoles of unconjugated enamines represents the main drawback. As expected, attempts by the same authors in preparing 4-alkylpyrazoles to use enamines derived from hexanal and (R)-(-i-)-citronellal gave rise to extremely pure compounds but in poor yields. 

Xu LL, Zheng CJ, Sun LP, Miao J, Piao HR. S5rnthesis of novel 1,3-diaryl pyrazole derivatives bearing rhodanine-3-fatty acid moieties as potential antibacterial. Eur. J. Med. Chem. 2012, 48,174-178. 

Organ et al. from York University demonstrated that a diarylated IH-pyrazole-based library, based on the structure of the potent COX II inhibitor Celecoxib [4-(3-trifluoromethyl-5-(4-methylphenyl)-lH-pyrazol-l-yl)benzenesulfonamide], could be rapidly prepared using MAOS [59]. Microwave-accelerated Suzuki reaction on 4-(5-iodo-3-methyl-lH-pyrazol-l-yl)-benzenesulfonamide using heterogeneous Pd/C was the principal diversification step investigated (Scheme 41). The interest of the team in microwave... 

It is a NSAID which has COX-2 selectivity. It is a diaryl substituted pyrazole. 

Anodic oxidation of l,3-diaryl-5-methyl-A2-pyrazoline-5-carboxylic acids in CH3CN-Et4NBF4 proceeded with decarboxylation to the aromatized pyrazoles in high yield.414 Similarly, electrochemical oxidation of N-acetyl-2,3-substituted A4-pyrroline-2-carboxylic acids in water-tetrahydrofuran (3 1) containing KOH forms the corresponding pyrroles (80-98%).415... 

While examples of intermolecular electrophilic additions to 7t-deficient heterocycles are reported less frequently than with -excessive heterocycles, intramolecular electrophilic cyclization strategies can be used to access some heterocycles of interest. In some cases, different reaction conditions can afford isomeric heterocycles as exemplified in the cyclization of 1,2-diaryl ketols with 2-amino-pyrazoles. With hydrogen chloride in the reaction media, pyrrolo[2,3-c]pyrazoles (170) are obtained, whereas imidazo[l,2-6]pyrazoles (171) were obtained in the absence of hydrogen chloride (Scheme 29) <84JHC945>. Cycloacylation of the a-(thiazolylthio)acetic acid (172) was accomplished with phosphorus oxychloride to give thiazole (173) (Equation (50)) <56AC(R)275>. 

Quinolyl)pyrazoIo[3,4-i7]pyridazincs were prepared by cyclocondensation reactions of an anilino-pyrazole acid with acetaldehyde <02JHC869>. Cyclopentadienyl-derived y-diketones and arylhydrazines condensed to 4-(l,4-diaryl-2//-cyclopent[d]pyridazin-2-yl)-benzenesulfonamides <02H(57)2383>. Sulfonated polyfphthalazinone ether sulfone)s 37 were prepared by polycondensation of 4-(4-hydroxyphenyl)phthalazinone 36 with various ratios of disodium 5,5 -sulfonylbis(2-fluorobenzenesulfonate) and bis(4-fluorophenyl)sulfone <02P5335>. 

Arylcyclopropanes can also be obtained in reasonable yields by heating mixtures of aryl triphenylphosphoranylidenehydrazones 9 and chalcones 10 in a solvent (usually dibutyl ether).Presumably, the reaction does not involve a free carbene instead dipolar addition of the in situ generated diazo compound to the C-C double bond of the enone takes place. The resulting 4,5-dihydro-3/f-pyrazole is thermally unstable and extrudes nitrogen, thus affording 2,3-diaryl-l-benzoylcyclopropanes 11. °... 

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