No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Ring Opening of Pyrrolinium Ions Enabled Regioselective Synthesis of 4-Alkyl N -Arylpyrazoles
Abstract
An unprecedented method for the regioselective synthesis of 1,3-diaryl 4-alkyl pyrazoles has been reported. A wide variety of 1,3-diaryl 4-alkyl pyrazoles were synthesized as a single regioisomer via a ring-opening cyclization reaction of unsaturated pyrrolinium ions in the presence of arylhydrazines. This method avoids using additional alkylation steps and hazardous oxidants that generally are essential for the synthesis of 4-alkyl N-arylpyrazoles.
... [5b-f,19] Traditional synthesis methods frequently use transition metal-catalyzed alkylations. [20] In recent developments, pyrrolinium ions have been utilized to form 4-alkylated-1-aryl-pyrazoles. [21] Despite excellent yields, existing methodologies still possess inherent limitations. Hence we have conceived a sustainable approach to the synthesis of alkylated pyrazoles from easily accessible starting precursors. ...
The first chemoselective C4‐benzylation of 5‐aminopyrazoles, utilizing a 3 mol% squaric acid catalyst, is disclosed. In this process, ortho‐quinone methides are efficiently generated from 2‐hydroxybenzyl alcohols in water under mild conditions. This method successfully delivers a wide range of C4‐benzylated 5‐aminopyrazoles, achieving moderate to excellent yields while demonstrating high chemoselectivity, which is further confirmed by mechanistic studies. Notably, the protocol uses water as an eco‐friendly solvent, requires a low organocatalyst loading, and eliminates the need for column chromatography.
Herein, we report a highly regioselective one-pot synthesis of pyrazolo[3,4-b]pyridines via the reaction of 3-arylidene-1-pyrrolines with aminopyrazoles. The reaction proceeds through the sequential nucleophilic addition/electrophilic substitution/C-N bond cleavage and provides easy access to pyrazolo[3,4-b]pyridine derivatives featuring a primary amino group. Moreover, the reaction can be terminated at the electrophilic substitution stage, thus providing convenient entry to the hardly accessible pyrazolopyrrolopyridine scaffold.
Background
The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain.
Methods
Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated.
Results
A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19).
Conclusions
At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216.)
Two efficient highly regioselective routes for the synthesis of unsymmetrically substituted 1-aryl-3,5-bis(het)arylpyrazoles with complementary regioselectivity starting from active methylene ketones have been reported. In the first protocol, the newly synthesized 1,3-bis(het)aryl-monothio-1,3-diketone precursors [prepared by condensation of active methylene ketones with het(aryl) dithioesters in the presence of sodium hydride] were reacted with arylhydrazines in refluxing ethanol under neutral conditions, furnishing 1-aryl-3,5-bis(het)arylpyrazoles 7, in which the het(aryl) moiety attached to the thiocarbonyl group of monothio-1,3-diketones is installed at 3-position. In the second method, the corresponding 3-(methylthio)-1,3-bis(het)aryl-2-propenones (prepared in situ by base induced alkylation of 1,3-monothiodiketones) were condensed with arylhydrazines in the presence of potassium-t-butoxide in refluxing t-butanol yielding 1-aryl-3,5-bis(het)arylpyrazoles 9 with complementary regioselectivity (Method A). The efficiency of this protocol was further improved by developing a one-pot, three-component procedure for the synthesis of pyrazoles 9, directly from active methylene ketones, by reacting in situ generated 3-(methylthio)-1,3-bis(het)aryl-2-propenones with arylhydrazines in the presence of sodium hydride (instead of potassium t-butoxide as base). The structures and regiochemistry of newly synthesized pyrazoles were confirmed from their spectral and analytical data along with X-ray crystallographic data of three pairs of regioisomers.
Pyrazoles are ubiquitous structures in medicinal chemistry. We report the first regioselective route to C3-hydroxyarylated pyrazoles obtained through reaction of pyrazole N-oxides with arynes using mild conditions. Importantly, this method does not require the C4 and C5 positions of the pyrazole to be functionalized to observe regioselectivity. Using this method, we completed the synthesis of a recently reported JAK 1/2 inhibitor. Our synthesis produces the desired product in 4 steps from commercially available starting materials.
The development of ionic liquid crystals (ILCs) using pyrrolidinium cation has received considerable interest due to their higher electrochemical stability. However, high charge density associated with low charge distribution in the fully saturated pyrrolidine ring leads to the high melting temperature of the materials due to strong ionic interactions. Herein, the synthesis and evaluation of the structure-property relationship of a new class of pyrrolinium-based ionic liquid crystals has been reported. The metal-free direct C-H functionalization of pyrrolidine, followed by the N-alkylation of resulting pyrroline produced the pyrolinium moiety that serves as the unprecedented polar head of the mesogens. These ionic mesogens having a partially unsaturated pyrrolidine ring were found to stabilize numerous mesophases over a wide thermal range including room temperature. © 2021 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.
A method for synthesis of N-arylpyrazoles by palladium-catalyzed coupling of aryl triflates with pyrazole derivatives is described. Using tBuBrettPhos as a ligand, the palladium-catalyzed C–N coupling of a variety of aryl triflates including ortho-substituted ones with pyrazole derivatives proceeded efficiently to give N-arylpyrazole products in high yields. 3-Trimethylsilylpyrazole was found as an excellent pyrazole substrate for the coupling, and the corresponding product, 1-aryl-3-trimethylsilylpyrazole, also served as a great template for syntheses of N-arylpyrazole derivatives, as demonstrated by regioselective halogenation at 3-, 4- and 5-positions of the pyrazole ring.
A facile and efficient synthetic strategy for chemoselective synthesis of monocyclic/tricyclic-fused pyrazoles was developed and it was oriented by different 3-position substituents (H or Cl) on the chromones. The reaction proceeded in a one-pot sequential way with a broad substrate scope and moderate to excellent yields.
An efficient, one-pot and metal-free process for the preparation of 3,5-disubstituted and 3,4,5-trisubstituted pyrazoles on multi-gram scale was developed. One-pot condensation of ketones, aldehydes and hydrazine monohydrochloride readily formed pyrazoline intermediates under mild conditions. Oxidation of pyrazolines, in situ, employing bromine afforded a wide variety of pyrazoles. The methodology offers a fast, and often chromatography-free protocol for the synthesis of 3,4,5-substituted pyrazoles in good to excellent yields. Alternatively, a more benign oxidation protocol affords 3,5-disubstituted or 3,4,5-trisubstituted pyrazoles by simply heating pyrazolines in DMSO under oxygen.
An alternative highly regioselective synthetic method for the preparation of 3,5-disubstituted 4-formyl-N-arylpyrazoles in a one-pot procedure is reported. The methodology developed was based on the regiochemical control of the cyclocondensation reaction of β-enamino diketones with arylhydrazines. Structural modifications in the β-enamino diketone system allied to the Lewis acid carbonyl activator BF3 were strategically employed for this control. Also a one-pot method for the preparation of 3,5-disubstituted 4-hydroxymethyl-N-arylpyrazole derivatives from the β-enamino diketone and arylhydrazine substrates is described.
Consecutive four-component coupling-coupling-cyclocondensation syntheses of pyrazoles and pyrimidines were developed by taking advantage of the provisional, sequentially Pd-catalyzed one-pot generation of alkynones from aryl iodides, ethynyl magnesium bromide, and acid chlorides. This one-pot methodology allows the concise, diversity-oriented generation of a set of donor, acceptor, and donor-acceptor substituted pyrazoles, which are interesting fluorophores. Most distinctly, donor-acceptor pyrazoles display remarkably red-shifted emission maxima and pronounced positive solvochromicity, spanning an overall range from 363 nm (cyclohexane) to 595 nm (acetonitrile). DFT and TD-DFT calculations elucidate the electronic structure and the photophysical behavior. Upon photonic excitation, a considerable charge-transfer character becomes apparent, which rationalizes the origin of huge Stokes shifts and solvochromic behavior.
We have developed inter- and intramolecular C-H alkenylation reactions of pyrazoles. The catalyst, derived from Pd(OAc)2 and pyridine, enabled the oxidative alkenylation of pyrazoles containing a variety of functional groups at the C4 position. Activated alkenes, including acrylate, acrylamide, and styrene derivatives, and enamides could be installed in this process. The sequential C-H alkenylation and cyclization reactions gave rise to fused bicyclic pyrazoles, providing a new strategy to annulate readily available pyrazole compounds.
A metal-free method for direct β-C(sp(3))-H functionalization of aliphatic amine was developed. The method is based on a reaction that yields enamine directly from the corresponding aliphatic amine, which otherwise requires the aid of metallic reagent and/or external oxidant. The reaction is operationally simple, general, and highly efficient in functionalizing both cyclic and acyclic amines. Structurally diverse unsaturated imines were obtained from N-heterocycles, while acyclic amines provided 2-alkyl cinnamaldehyde and benzopyran derivatives with excellent E/Z-selectivity.
An operationally simple and high yielding protocol for the synthesis of polyfunctional pyrazoles has been developed through one-pot, three-component coupling of aldehydes, 1,3-dicarbonyls, and diazo-compounds as well as tosyl hydrazones. The reaction proceeds through a tandem Knoevenagel condensation, 1,3-dipolar cycloaddition, and transition metal-free oxidative aromatization reaction sequence utilizing molecular oxygen as a green oxidant. The scope of the reaction was studied by varying the aldehyde, 1,3-dicarbonyl and diazo-component individually.
Solventless condensation of a diketone and a hydrazine in the presence of a catalytic amount of sulfuric acid at room temperature afforded pyrazole derivatives 3a–3i and 4g–4i in high yields. The condensation of 2,4-pentanedione and hydrazides gave similar results, while the reaction between 1-phenylbutane-1,3-dione and hydrazides under the same conditions afforded 4,5-dihydro-5-hydroxypyrazole derivatives 6a and 6b, which can be transformed to 4i
(for 6b) or a mixture of 1-acylpyrazole and 3i
(4i)
(for 6a) by thermolysis in the presence of a catalytic amount of sulfuric acid. Similar reaction of ethyl acetoacetate with phenylhydrazine or hydrazine formed 2-pyrazolin-5-one 8 and 3-pyrazolin-5-one 9, respectively. Reactions of 2,4-dinitrophenylhydrazine with 2,4-pentanedione and ethyl acetoacetate yielded hydrazones 10 and 11, respectively.
We describe a general approach for the synthesis of allylated and benzylated pyrazoles. An electron-withdrawing substituent, such as nitro, chloro, and ester groups, at C4 renders the Lewis basic nitrogen atom to be less basic and the C-H bond more acidic than the ones of the parent ring, enabling Pd-catalyzed C-H allylation and benzylation reactions of pyrazoles. The new method expanding the scope of the C-H functionalization of pyrazoles beyond arylation reactions provides a rapid access to complex pyrazole compounds.
A highly efficient Pt-catalyzed [3,3] sigmatropic rearrangement/cyclization cascade of N-propargylhydrazones is reported. The process provides expedient access to a variety of highly functionalized pyrazoles. The substrate has good substituted group compatibility, and the bioactive 3-CF3 pyrazoles could be synthesized easily with this method.
An iron-catalyzed route for the regioselective synthesis of 1,3- and 1,3,5-substituted pyrazoles from the reaction of diarylhydrazones and vicinal diols has been developed. This method was found to be practical with wide substrate scope.
The factors affecting regioselectivity during the formation of 1,5-diarylpyrazoles from aryl hydrazines and 1,3-diketones are identified and the regioisomers were characterized by 1D NOESY, LC–NMR and X-ray analyses. A simple alteration in the usual reaction conditions is reported, which allows the exclusive formation of 1,5-diarylpyrazoles.
In the presence of activated carbon, Hantzsch 1,4-dihydropyridines and 1.3.5-trisubstituted pyrazolines were aromatized with molecular oxygen to the corresponding pyridines and pyrazoles in excellent yields.
5-(2′-Alkoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-ones, and in particular our preferred compound, sildenafil (VIAGRATM), discovered through a rational drug design programme, are potent and selective inhibitors of the type 5 cGMP phosphodiesterase from both rabbit platelets and human corpus cavernosum. Sildenafil is currently in the clinic for the oral treatment of male erectile dysfunction.
A simple, efficient and eco-friendly procedure has been developed for the aromatisation of various pyrazolines in heterogeneous media using clay-supported copper(II) nitrate (claycop) under ultrasound activation. The reaction rate enhancement and the sonication effect are discussed.
Recently, we developed a novel triaryl-substituted pyrazole ligand system that has high affinity for the estrogen receptor (ER) (Fink, B. E.; Mortenson, D. S.; Stauffer, S. R.; Aron, Z. D.; Katzenellenbogen, J. A. Chem. Biol.1999, 6, 205). Subsequent work has shown that some analogues in this series are very selective for the ERα subtype in terms of binding affinity and agonist potency (Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Sun, J.; Katzenellenbogen, J. A. J. Med. Chem.2000, submitted). We now investigate how this pyrazole ER agonist system might be converted into an antagonist or a selective estrogen receptor modifier (SERM) by incorporating a basic or polar side chain like those typically found in antiestrogens and known to be essential determinants of their mixed agonist/antagonist character. We selected an N-piperidinyl-ethyl chain as a first attempt, and introduced it at the four possible sites of substitution on the pyrazole core structure to determine the orientation that the pyrazole might adopt in the ER ligand binding pocket. Of these four, the C(5) piperidinyl-ethoxy-substituted pyrazole 5 had by far the highest affinity. Also, it bound to the ER subtype alpha (ERα) with 20-fold higher affinity than to ERβ. In cell-based transcription assays, pyrazole 5 was an antagonist on both ERα and ERβ, and it was also more potent on ERα. Based on structure-binding affinity relationships and on molecular modeling studies of these pyrazoles in a crystal structure of the ERα–raloxifene complex, we propose that pyrazoles having a basic substituent on the C(5) phenyl group adopt a binding mode that is different from that of the pyrazole agonists that lack this group. The most favorable orientation appears to be one which places the N(1) phenol in the A-ring binding pocket so that the basic side chain can adopt an orientation similar to that of the basic side chain of raloxifene.
The regioselectivity of the condensation of electronically unsymmetrical 1,3-diaryl-1,3-diketones with 2-hydrazinopyridine and 2,6-bis-hydrazinopyridine to form N-(2-pyridyl)-3,5-diarylpyrazoles was studied. Significant electronic effects on regioselectivities were observed, and regioselectivities were opposite to those exhibited by perfluoroalkyl/alkyl 1,3-diketones. The electronic effects correlate well to the difference between the Hammett σ+ coefficients of the para substituents on the aryl rings.
2‐Arylbenzoxazoles and 2‐arylbenzimidazoles were synthesized by the reaction of aldehydes with 2‐aminophenol and O‐phenylenediamines in the presence of iodine. 1,3,5‐Trisubstituted pyrazoles were synthesized from chalcones and hydrazines in the presence of iodine. CDRI Communication No. 6509.
We have found that certain tetrasubstituted pyrazoles are high-affinity ligands for the estrogen receptor (ER) (Fink et al. Chem. Biol. 1999, 6, 205−219) and that one pyrazole is considerably more potent as an agonist on the ERα than on the ERβ subtype (Sun et al. Endocrinology 1999, 140, 800−804). To investigate what substituent pattern provides optimal ER binding affinity and the greatest enhancement of potency as an ERα-selective agonist, we prepared a number of tetrasubstituted pyrazole analogues with defined variations at certain substituent positions. Analysis of their binding affinity pattern shows that a C(4)-propyl substituent is optimal and that a p-hydroxyl group on the N(1)-phenyl group also enhances affinity and selectivity for ERα. The best compound in this series, a propylpyrazole triol (PPT, compound 4g), binds to ERα with high affinity (ca. 50% that of estradiol), and it has a 410-fold binding affinity preference for ERα. It also activates gene transcription only through ERα. Thus, this compound represents the first ERα-specific agonist. We investigated the molecular basis for the exceptional ERα binding affinity and potency selectivity of pyrazole 4g by a further study of structure−affinity relationships in this series and by molecular modeling. These investigations suggest that the pyrazole triols prefer to bind to ERα with their C(3)-phenol in the estradiol A-ring binding pocket and that binding selectivity results from differences in the interaction of the pyrazole core and C(4)-propyl group with portions of the receptor where ERα has a smaller residue than ERβ. These ER subtype-specific interactions and the ER subtype-selective ligands that can be derived from them should prove useful in defining those biological activities in estrogen target cells that can be selectively activated through ERα.
mPGES-1 is a promising target for development of new anti-inflammatory drugs. We aimed to create mPGES-1 inhibitors by modifying the structure of NSAIDs by replacing the carboxylic acid functionality by sulfonamide moieties. Compounds were also tested for 5-LOX inhibition. The most potent mPGES-1 inhibitor was lonazolac derivative 22 (IC(50) = 0.16 μM), while the best 5-LOX inhibition was attained by indomethacin derivative 17 (IC(50) = 0.9 μM). Inhibition of COX-1 activity was completely removed.
Recently reported syntheses of 3(5)-aminopyrazoles, 4-aminopyrazoles, and 1-aminopyrazoles as well as of diaminopyrazoles and their general pattern of reactivity towards mono-and bidentate electrophiles have been surveyed. Emphasis has also been laid on techniques for ascertaining the site selectivity in reactions with electrophiles, including single crystal X-ray structure analysis, 1 H-15 N HMBC, and NOE intensity difference experiments as well as other modern 2D NMR techniques. Some thermally induced cycloadditions have also been treated.
Synthesis of pyrazoles via electrophilic cyclization of α,β-alkynic hydrazones by copper(I) iodide is described. When treated with copper(I) iodide in the presence of triethylamine in refluxing acetonitrile, α,β-alkynic hydrazones, prepared readily from hydrazines and propargyl aldehydes and ketones, undergo electrophilic cyclization to afford pyrazole derivatives in good to excellent yields. The reaction appears to be general for a variety of α,β-alkynic hydrazones and tolerates the presence of aliphatic, aromatic, and ferrocenyl moieties with electron-withdrawing and electron-donating substituents.
Progress made in the preparation of substituted pyrazoles from 2000 to mid-2010 both in solution and on solid phase is presented. The search for new and efficient procedures for the synthesis of pyrazole derivatives has experienced an unprecedented growth during this period. One-pot procedures and the use of new reaction conditions have made it possible to overcome limitations such as the preparation of the starting materials or the lack of regioselectivity in the synthesis of substituted pyrazoles. The Michael-type addition of N-monosubstituted hydrazones to nitroolefins, reported for the first time in 2006, has emerged as a versatile method for the regioselective synthesis of a plethora of alkyl-, aryl-, and heteroaryl-substituted pyrazoles. Stille, Sonogashira, Negishi, and Heck C-C cross-coupling reactions have been applied to the regioselective introduction of alkenyl, alkynyl, acyl, and (het)aryl substituents at the C-3, C-4, and C-5 positions of prepared pyrazoles bearing adequate heteroatoms containing functionalities.
Electrophilic cyclizations of α,β-alkynic hydrazones by molecular iodine were investigated for the synthesis of 4-iodopyrazoles. α,β-Alkynic hydrazones were readily prepared by the reactions of hydrazines with propargyl aldehydes and ketones. When treated with molecular iodine in the presence of sodium bicarbonate, α,β-alkynic hydrazones underwent electrophilic cyclization to afford 4-iodopyrazoles in good to high yields. Iodocyclization was general for a wide range of α,β-alkynic hydrazones and tolerated the presence of aliphatic, aromatic, heteroaromatic, and ferrocenyl moieties with electron-withdrawing and electron-donating substituents.
The synthesis of 3,4,5-trisubstituted pyrazoles via a tandem catalytic cross-coupling/electrocyclization of enol triflates and diazoacetates is presented. The initial scope of this methodology is demonstrated on a range of differentially substituted acyclic and cyclic enol triflates as well as an elaborated set of diazoacetates to provide the corresponding pyrazoles with a high degree of structural complexity.
We prepared three discreet cohorts of potent non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) based on the recently reported 3-cyanophenoxypyrazole lead 3. Several of these compounds displayed very promising anti-HIV activity in vitro, safety, pharmacokinetic and pharmaceutical profiles. We describe our analysis and conclusions leading to the selection of alcohol 5 (UK-453,061, lersivirine) for clinical development.
The development of estrogen pharmaceutical agents with appropriate tissue-selectivity profiles has not yet benefited substantially from the application of combinatorial synthetic approaches to the preparation of structural classes that are known to be ligands for the estrogen receptor (ER). We have developed an estrogen pharmacophore that consists of a simple heterocyclic core scaffold, amenable to construction by combinatorial methods, onto which are appended 3-4 peripheral substituents that embody substructural motifs commonly found in nonsteroidal estrogens. The issue addressed here is whether these heterocyclic core structures can be used to prepare ligands with good affinity for the ER.
We prepared representative members of various azole core structures. Although members of the imidazole, thiazole or isoxazole classes generally have weak binding for the ER, several members of the pyrazole class show good binding affinity. The high-affinity pyrazoles bear close conformational relationship to the nonsteroidal ligand raloxifene, and they can be fitted into the ligand-binding pocket of the ER-raloxifene X-ray structure.
Compounds such as these pyrazoles, which are novel ER ligands, are well suited for combinatorial synthesis using solid-phase methods.
Most ligands for the estrogen receptor (ER) are not well suited for synthesis by combinatorial means, because their construction involves a series of carbon-carbon bond forming reactions that are not uniformly high yielding. In previous work directed to overcoming this limitation, we surveyed various phenol-substituted five-membered heterocycles, hoping to find a system that would afford both high ER binding affinity and whose synthesis could be adapted to solid-phase methods (Fink et al. Chem. Biol. 1999, 6, 206-219.) In this report, we have developed a reliable and efficient solid-phase method to prepare the best of these heterocycles, the tetrasubstituted pyrazoles, and we have used this methodology to produce small, discrete libraries of these novel ER ligands. We used a combination of FT-IR and nanoprobe (1)H NMR-MAS to characterize intermediates leading up to the final pyrazole products directly on the bead. We also developed a scavenging resin, which enabled us to obtain products free from inorganic contaminants. We prepared a 12-member test library, and then a 96-member library, and in both cases we determined product purity and ER binding affinity of all of the library members. Several interesting binding affinity patterns have emerged from these studies, and they have provided us with new directions for further exploration, which has led to pyrazoles having high affinity and potency as agonists and antagonists toward the ER alpha subtype.
A regioselective synthesis has been developed for the preparation of unsymmetrical 1,3,5-triaryl-4-alkylpyrazolines and -pyrazoles by treatment of alpha-benzotriazolyl-alpha,beta-unsaturated ketones with monosubstituted hydrazines followed by alkylation at the 4-position of the pyrazoline ring. Reaction of alpha-benzotriazolyl-alpha,beta-unsaturated ketones with hydroxylamine gives 3,5-disubstituted isoxazoles regioselectively.
The synthesis of novel series of structurally related 1H-pyrazolyl derivatives is described. All the newly synthesized compounds were tested for their in vivo anti-inflammatory activity by two different bioassays namely; cotton pellet-induced granuloma and sponge implantation model of inflammation in rats. In addition, COX-1 and COX-2 inhibitory activities, ulcerogenic effects and acute toxicity were determined. The same compounds were evaluated for their in vitro antimicrobial activity against Escherichia coli, as an example of Gram negative bacteria, Staphylococcus aureus as an example of Gram positive bacteria, and Candida albicans as a representative of fungi. The combined anti-inflammatory data from local and systemic in vivo animal models showed that compounds 4, 5, 8, 9, 11 and 12a exhibited anti-inflammatory activity comparable to that of indomethacin with no or minimal ulcerogenic effects and high safety margin (LD(50)>500 mg/Kg). In addition, compounds 4, 7, 10, 12a and 12b displayed appreciable antibacterial activities when compared with ampicillin, especially against S. aureus. Compounds 4 and 12a are the most distinctive derivatives identified in the present study because of their remarkable in vivo and in vitro anti-inflammatory potency and their pronounced antibacterial activities comparable to ampicillin against Gram positive. On the other hand, compound 12a exhibited good selective inhibitory activity against COX-2 enzyme. Therefore, such compound would represent a fruitful matrix for the development of anti-inflammatory-antimicrobial candidates.
The 4-piperidyl moiety and the pyrazole ring in 1-(3-chlorophenyl)-5-(4-phenoxyphenyl)-3-(4-piperidyl)pyrazole 2, which has previously shown improved DNA gyrase inhibition and target-related antibacterial activity, were transformed to other groups and the in vitro antibacterial activity of the synthesized compounds was evaluated. The selected pyrazole, oxazole and imidazole derivatives showed moderate inhibition against DNA gyrase and topoisomerase IV with similar IC(50) values (IC(50)=9.4-25 microg/mL). In addition, many of the pyrazole, oxazole and imidazole derivatives synthesized in this study exhibited potent antibacterial activity against quinolone-resistant clinical isolates and coumarin-resistant laboratory isolates of Gram-positive bacteria with minimal inhibitory concentration values equivalent to those against susceptible strains.
Rimonabant, a selective cannabinoid-1 receptor (CB1) blocker, has been shown to reduce body weight and improve cardiovascular risk factors in obese patients. The Rimonabant in Obesity-Lipids (RIO-Lipids) study examined the effects of rimonabant on metabolic risk factors, including adiponectin levels, in high-risk patients who are overweight or obese and have dyslipidemia.
We randomly assigned 1036 overweight or obese patients (body-mass index [the weight in kilograms divided by the square of the height in meters], 27 to 40) with untreated dyslipidemia (triglyceride levels >1.69 to 7.90 mmol per liter, or a ratio of cholesterol to high-density lipoprotein [HDL] cholesterol of >4.5 among women and >5 among men) to double-blinded therapy with either placebo or rimonabant at a dose of 5 mg or 20 mg daily for 12 months in addition to a hypocaloric diet.
The rates of completion of the study were 62.6 percent, 60.3 percent, and 63.9 percent in the placebo group, the group receiving 5 mg of rimonabant, and the group receiving 20 mg of rimonabant, respectively. The most frequent adverse events resulting in discontinuation of the drug were depression, anxiety, and nausea. As compared with placebo, rimonabant at a dose of 20 mg was associated with a significant (P<0.001) mean weight loss (repeated-measures method, -6.7+/-0.5 kg, and last-observation-carried-forward analyses, -5.4+/-0.4 kg), reduction in waist circumference (repeated-measures method, -5.8+/-0.5 cm, and last-observation-carried-forward analyses, -4.7+/-0.5 cm), increase in HDL cholesterol (repeated-measures method, +10.0+/-1.6 percent, and last-observation-carried-forward analyses, +8.1+/-1.5 percent), and reduction in triglycerides (repeated-measures method, -13.0+/-3.5 percent, and last-observation-carried-forward analyses, -12.4+/-3.2 percent). Rimonabant at a dose of 20 mg also resulted in an increase in plasma adiponectin levels (repeated-measures method, 57.7 percent, and last-observation-carried-forward analyses, 46.2 percent; P<0.001), for a change that was partly independent of weight loss alone.
Selective CB1-receptor blockade with rimonabant significantly reduces body weight and waist circumference and improves the profile of several metabolic risk factors in high-risk patients who are overweight or obese and have an atherogenic dyslipidemia.
[reaction: see text] Highly efficient and regioselective synthesis of 1-aryl-3,4-substituted/annulated-5-(methylthio)pyrazoles and 1-aryl-3-(methylthio)-4,5-substituted/annulated pyrazoles has been reported via cyclocondensation of arylhydrazines with either alpha-oxoketene dithioacetals or beta-oxodithioesters.
CDPPB [3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide] was recently described as the first centrally active, positive allosteric modulator of rat and human metabotropic glutamate receptor (mGluR) mGluR5 subtype. We explored the structural requirements for potentiation of glutamate-induced calcium release in naturally expressed mGluR5 in cultured rat astrocytes and increasing affinity for the allosteric antagonist binding site by evaluating 50 analogues of CDPPB. In the fluorometric calcium assay, CDPPB exhibited an EC50 value of 77 +/- 15 nM in potentiating mGluR5-mediated responses in cortical astrocytes and a Ki value of 3760 +/- 430 nM in displacing [3H]methoxyPEPy binding in membranes of cultured HEK-293 cells expressing rat mGluR5. The structure-activity relationships showed that electronegative aromatic substituents in the para-position of the benzamide moiety of CDPPB increase potency. Both binding and functional activities were further increased with a halogen atom in the ortho-position of the 1-phenyl ring. These effects of substitution do not match those of either aromatic ring of MPEP [2-methyl-6-(phenylethynyl)pyridine] for the antagonist allosteric binding site. Combination of the optimal substituents and aromatic positions resulted in 4-nitro-N-(1-(2-fluorophenyl)-3-phenyl-1H-pyrazol-5-yl)benzamide (VU-1545) showing Ki = 156 +/- 29 nM and EC50 = 9.6 +/- 1.9 nM in the binding and functional assays, respectively.
[reaction: see text] 1,3-Diketones were synthesized directly from ketones and acid chlorides and were then converted in situ into pyrazoles by the addition of hydrazine. This method is extremely fast, general, and chemoselective, allowing for the synthesis of previously inaccessible pyrazoles and synthetically demanding pyrazole-containing fused rings.
A novel regioselective synthesis of aryl-substituted pyrazolines and pyrazoles has been developed. Substituted phenylhydrazines react with 3-butynol in the presence of a catalytic amount of zinc triflate to give pyrazoline derivatives. The resulting products are easily oxidized in a one-pot procedure to the corresponding pyrazoles.
40 (s, 1H), 8.30− 8.28 (m, 1H), 8.14 (d
- H Nmr
H NMR (600 MHz, CD 3 OD) δ = 8.57 (s, 1H), 8.40 (s, 1H), 8.30−
8.28 (m, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.78−7.75 (m, 1H), 7.70 (s,
1H), 7.63 (d, J = 8.4 Hz, 1H), 7.40−7.38 (m, 1H), 7.18 (d, J = 7.2
m, 2H), 3.20−3.17 (m, 2H), 3.14−3.10 (m, 2H), 2.45 (s, 3H), 1.34−1.30 (m, 3H
- Hz
Hz, 1H), 3.34−3.33 (m, 2H), 3.20−3.17 (m, 2H), 3.14−3.10 (m,
2H), 2.45 (s, 3H), 1.34−1.30 (m, 3H) ppm. 13 C{ 1 H} NMR (151
HRMS (ESI) m/z [M] + Calcd for C 20 H 23 N 4 O 2 + : 351.1816; found: 351.1824. 2-(1-(3,4-Dimethylphenyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl)-Nethylethan-1-aminium Iodide (3t)
- Mhz
MHz, CD 3 OD) δ = 150.4, 150.2, 141.2, 141.1, 136.3, 135.0, 131.4,
130.6, 129.9, 128.9, 123.9, 123.5, 120.8, 117.4, 117.2, 48.4, 44.4, 22.8,
21.6, 11.7 ppm. HRMS (ESI) m/z [M] + Calcd for C 20 H 23 N 4 O 2
+
:
351.1816; found: 351.1824.
2-(1-(3,4-Dimethylphenyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl)-Nethylethan-1-aminium Iodide (3t). According to GP II, 3,4-dimethylphenylhydrazine (0.12 g, 0.84 mmol) and cyclic iminium
ion 1k (50 mg, 0.14 mmol) in 2 mL of CH 3 CN were reacted for 48 h,
and column chromatography (SiO 2, MeOH/DCM, 1:10) of the crude
product gave 3t as a white solid (40 mg, 58%). Mp 218−223°C.
According to GP II, 4-chlorophenylhydrazine (0.12 g, 0.84 mmol) and cyclic iminium ion 1k (50 mg, 0.14 mmol) in 2 mL of CH 3 CN were reacted for 48 h, and column chromatography
- Dmso Mhz
MHz, DMSO-d 6 ) δ = 157.9, 148.1, 147.6, 134.6, 133.6, 132.8,
130.4, 128.5, 122.4, 121.5, 119.9, 116.0, 114.6, 55.5, 46.0, 42.1, 21.2,
11.0 ppm. HRMS (ESI) m/z [M] + Calcd for C 20 H 23 N 4 O 3
+ : 367.1765;
found: 367.1774.
2-(1-(4-Chlorophenyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl)-N-ethylethan-1-aminium Iodide (3v). According to GP II, 4-chlorophenylhydrazine (0.12 g, 0.84 mmol) and cyclic iminium ion 1k (50 mg,
0.14 mmol) in 2 mL of CH 3 CN were reacted for 48 h, and column
chromatography (SiO 2, MeOH/DCM, 1:10) of the crude product
gave 3v as a white solid (31 mg, 45%). Mp 242−247°C. FTIR (KBr):
ν̃= 3451, 2958, 2850, 1638, 1535, 1501, 1428, 1397, 1343, 1313,
1273, 1242, 1179, 1077, 1035, 960 cm −1. 1 H NMR (600 MHz,
DMSO-d 6 ) δ = 8.66 (s, 1H), 8.51 (s, 1H), 8.32−8.31 (m, 1H), 8.18
(d, J = 7.8 Hz, 1H), 7.94 (d, J = 9.0 Hz, 2H), 7.85−7.83 (m, 1H),
Substituent effects of N-(1, 3-diphenyl-1 H-pyrazol-5-yl) benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical astrocytes
- C E Mowbray
- C Burt
- R Corbau
- S Gayton
- M Hawes
- M Perros
- I Tran
- D A Price
- F J Quinton
- M D Selby
- P A Stupple
- R Webster
- A Wood
- A Chauhan
- P K Sharma
- N Kaushik
- K Do
- D Wilsker
- J Ji
- J Zlott
- T Freshwater
- R J Kinders
- J Collins
- A P Chen
- J H Doroshow
- S Kummar
- N K Terrett
- A S Bell
- D Brown
- P Ellis
- A Tanitame
- Y Oyamada
- K Ofuji
- M Fujimoto
- K Suzuki
- T Ueda
- H Terauchi
- M Kawasaki
- K Nagai
- M Wachi
- J Yamagishi
- T De Paulis
- K Hemstapat
- Y Chen
- Y Zhan
- S Saleh
- D Alagille
- R M Baldwin
- G D Tamagnan
- P J Conn
−3.21 (m, 2H), 3.10−3.05 (m, 2H), 2.93−2.89 (m, 2H), 1.66−
1.57 (m, 2H), 0.94−0.91 (m, 3H) ppm. 13 C{ 1 H} NMR (101 MHz,
DMSO-d 6 ) δ = 158.0, 148.2, 147.7, 134.7, 133.7, 133.0, 130.5, 128.5,
122.6, 121.6, 120.0, 116.3, 114.8, 55.5, 48.7, 46.6, 21.3, 19.2, 11.0
■ REFERENCES
(1) (a) Mowbray, C. E.; Burt, C.; Corbau, R.; Gayton, S.; Hawes,
M.; Perros, M.; Tran, I.; Price, D. A.; Quinton, F. J.; Selby, M. D.;
Stupple, P. A.; Webster, R.; Wood, A. Pyrazole NNRTIs 4: Selection
of UK-453,061 (lersivirine) as a Development Candidate. Bioorg. Med.
Chem. Lett. 2009, 19, 5857. (b) Chauhan, A.; Sharma, P. K.; Kaushik,
N. Pyrazole: A Versatile Moiety. Int. J. Chem. Technol. Res. 2011, 3, 11.
(c) Do, K.; Wilsker, D.; Ji, J.; Zlott, J.; Freshwater, T.; Kinders, R. J.;
Collins, J.; Chen, A. P.; Doroshow, J. H.; Kummar, S. Phase I Study of
Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in
Patients With Refractory Solid Tumors. J. Clin. Oncol. 2015, 33, 3409.
(2) (a) Terrett, N. K.; Bell, A. S.; Brown, D.; Ellis, P. Sildenafil
(Viagra), a potent and selective inhibitor of type 5 CGMP
phosphodiesterase with utility for the treatment of male erectile
dysfunction. Bioorg. Med. Chem. Lett. 1996, 6, 1819. (b) Tanitame, A.;
Oyamada, Y.; Ofuji, K.; Fujimoto, M.; Suzuki, K.; Ueda, T.; Terauchi,
H.; Kawasaki, M.; Nagai, K.; Wachi, M.; Yamagishi, J. Synthesis and
antibacterial activity of novel and potent DNA gyrase inhibitors with
azole ring. Bioorg. Med. Chem. 2004, 12, 5515. (c) de Paulis, T.;
Hemstapat, K.; Chen, Y.; Zhan, Y.; Saleh, S.; Alagille, D.; Baldwin, R.
M.; Tamagnan, G. D.; Conn, P. J. Substituent effects of N-(1, 3-diphenyl-1 H-pyrazol-5-yl) benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical
astrocytes. J. Med. Chem. 2006, 49, 3332. (d) Bekhit, A. A.; Abdel-Aziem, T. Design, synthesis and biological evaluation of some
pyrazole derivatives as anti-inflammatory-antimicrobial agents. Bioorg.
Tepoxalin". Saunders Handbook of Veterinary Drugs Small and Large Animal
- M Papich
Papich, M. G. "Tepoxalin". Saunders Handbook of Veterinary
Drugs Small and Large Animal, 4th ed.; Elsevier, 2016; p 762.