Nitration of 2‐Aryl‐1,1‐dihalocyclopropanes Containing Methyl or Phenyl Group

Lin, Lee-Huey; Lin, Shaw‐Tao; Yang, H.

doi:10.1002/jccs.199800032

Cited by 3 publications

(1 citation statement)

References 7 publications

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“…Phenyl(bromodichloromethyl)mercury (PhHgCBrCl 2 ) and phenyl(tribromomethyl)mercury were prepared according to the method of Seyferth and Lambert [1969]. Compounds 10a-c and 11a-b were synthesized using the reported methods as illustrated in Figure 3 [Magarian and Benjamin, 1975;Zimmerman et al, 1978;Lin et al, 1998]. All other reagents were purchased from Aldrich Chemical (Milwaukee, WI).…”

Section: Introductionmentioning

confidence: 99%

Design, syntheses, and evaluation of novel 1,1‐dihalo‐2,3‐diphenylcyclopropanes as potential cyclooxygenase‐2 (COX‐2) inhibitors with analgesic‐antiinflammatory activity

Rao

Habeeb

Knaus

2002

Drug Development Research

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A group of (Z)-and (E)-1,1-dihalo-2-(4-substituted-phenyl)-3-phenylcyclopropane [(Z)-10, (E)-11] stereoisomers having a variety of substituents (H, Br, Cl, F, NO 2 , SO 2 Me) at the para-position of the C-2 phenyl ring in conjunction with either two chloro or bromo substituents at C-1 were synthesized for in vivo evaluation as analgesic and antiinflammatory (AI) agents, and as potential selective cyclooxygenase-2 (COX-2) inhibitors. This group of compounds (10-11) exhibited significant analgesic activity since 4% NaClinduced abdominal constriction was reduced by 44-73% at 30 min, and 48-77% at 60 min, post-drug administration relative to the reference drugs aspirin and celecoxib (58 and 32% inhibition at 30 min postdrug administration) for a 50 mg/kg intraperitoneal dose. In the 1,1-dichloro group of compounds, a Cl or MeSO 2 substituent at the para-position of the C-2 phenyl ring generally provided superior analgesic activity. The most active analgesic compound, (E)-1,1-dichloro-2-(4-methanesufonylphenyl)-3-phenylcyclopropane (11h) inhibited abdominal constriction by 72 and 77% at 30 and 60 min post-drug administration, respectively. AI activities, determined using the carrageenan-induced rat paw edema assay, showed that this class of (Z)-10 and (E)-11 compounds exhibited AI activities in the inactive-to-moderate activity range (1.5-45% inhibition) for a 50 mg/kg oral dose. The AI potency order, with respect to the para-substitutent on the C-2 phenyl ring, for the (Z)-10 compounds was NO 2 > MeSO 2 ≈ H ≥ Cl, and for the (E)-11 compounds was H ≥ MeSO 2 > Cl ≈ Br. (E)-1,1-dibromo-2-(4-methanesufonylphenyl)-3-phenylcyclopropane (11l), which was the most active AI compound, reduced inflammation by 45 and 37% at 3 and 5 h post-drug administration, respectively. The (E)-11 stereoisomer was generally a more potent AI agent than the corresponding (Z)-10 stereoisomer. In vitro COX-1 and COX-2 inhibition studies showed that (E)-1,1-dichloro-2-(4-nitrophenyl)-3-phenylcyclopropane (11c) inhibited COX-1 (IC 50 = 278.8 µM) and COX-2 (IC 50 = 80.5 µM) for a COX-2 selectivity index of 3.5, whereas (E)-1,1-dichloro-2-(4-methanesulfonylphenyl)-3-phenylcyclopropane (11h) was a more potent inhibitor of COX-1 and COX-2, but it was more selective for COX-1 (COX-1 IC 50 = 0.59 µM, COX-2 IC 50 = 3.04 µM). A molecular modeling (docking) study for (E)-1,1-dichloro-2-(4-methanesulfonylphenyl)-3-phenylcyclopropane (11h) on the active site of the human COX-2 isozyme shows it binds in the center of the active site with the 1,1-dichloro substituents oriented in the direction of the mouth of the channel towards Arg 120, and the C-2 MeSO 2 moiety oriented towards the apex of the active site with the S-atom of the MeSO 2 substituent positioned about 6.56 Å inside the entrance to the secondary pocket (Val 523 ) of COX-2. In contrast, the corresponding (Z)-10h stereoisomer assumes a different position

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Section: Introductionmentioning

confidence: 99%

Design, syntheses, and evaluation of novel 1,1‐dihalo‐2,3‐diphenylcyclopropanes as potential cyclooxygenase‐2 (COX‐2) inhibitors with analgesic‐antiinflammatory activity

Rao

Habeeb

Knaus

2002

Drug Development Research

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Synthesis and Reactivity of 3‐Halo‐4,5‐dihydroisoxazoles: An Overview

Zana

Galbiati

2021

ChemistrySelect

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The 3‐halo‐4,5‐dihydroisoxazole moiety is an interesting emerging feature in medicinal and organic chemistry fields. The properties of this nucleus are intimately correlated with the nature of the halogen substituent, ranging from inertness to instability. In between, the 3‐bromo‐Δ2‐isoxazoline scaffold stands out as a handleable and easily affordable electrophilic warhead, able to react with nucleophilic active sites of different enzymes, determining inhibitory effects. However, the importance of 3‐bromo‐Δ2‐isoxazolines does not rely only upon their biological activity. In fact, they are valuable synthetic intermediates, presenting a peculiar reactivity spectrum that allows access to useful chemical functions, ranging from variously decorated dihydroisoxazoles to β‐hydroxynitriles, β‐hydroxyesters, and γ‐hydroxyamines. The synthesis of 3‐bromo‐Δ2‐isoxazolines is predominantly based on the 1,3‐dipolar cycloaddition, a pericyclic reaction accompanied by a remarkable regio‐ and stereo‐selectivity. Thus, this intermediate lends itself especially well to the production of complex molecules with regio‐ and stereo‐chemical requirements.

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