Structure-activity relationships among analogues of pemedolac, cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]indole-1-acetic acid, a potent analgesic agent

Abstract

The syntheses of analogues of pemedolac (cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]indol e-1-acetic acid), a potent analgesic, are described. They were tested for analgesic and antiinflammatory effects in vivo and for inhibition of prostaglandin production in vitro. Analysis of structure-activity relationships shows that analgesic activity in this series is associated with 1S-cis stereochemistry, the presence of a pi-system (allyl or benzyl) at position 4, and a log P value greater than 4.0.

Novel Greener Microwave-Assisted Deprotection Methodology for the 1,3-Dioxolane Ketal of Isatin Using Calix[n]arenes

“…22 Many analogues of isatin have been prepared to find new bioactive compounds, particularly those with antiviral, anti-inflammatory, anticonvulsant, antichagasic, and antitumor activity. 21,[23][24][25][26] This is the case for the antitumor compound sunitinib (2), 27 the analgesic pemedolac (3), 28 isatins bearing halogens and nitro groups in the aromatic ring (4, 5, and 6), 29,30 and isatin-type 5'-(4-alkyl/aryl-1H-1,2,3-triazoles) (7 and 8). 31,32 In nature, isatin derivatives can be found in the parotid gland of Bufo, bacteria (Streptomyces albus), fungi (Chaetomium globosum), and other organisms such as mammals and plants.…”

Enantioselective Organocatalytic Intramolecular Ring-Closing Friedel−Crafts-Type Alkylation of Indoles

“…As part of our ongoing project on the enantioselective organocatalysis, we demonstrate that this elegant methodology is amenable to organocatalytic intramolecular ring-closing Friedel−Crafts alkylation of indolyl α,β-unsaturated aldehydes in this communication. Importantly, this strategically new approach allows the construction of THPIs and tetrahydro-β-carbolines (THBCs) from simple substrates.…”

A Direct Access to 3-(2-Oxoalkyl)indoles via Aluminum Chloride Induced C−C Bond Formation

“…Among the classical methods for the synthesis of indole ring, the Fischer indole synthesis, the Batcho−Limgruber synthesis (from o -nitrotoluenes and dimethylformamide acetals), the Gassman synthesis (from N -haloanilines), the reductive cyclization of o -nitrobenzyl ketones, and the Madelung cyclization of N -acyl- o -toluidines are used very often. While a number of methods are available for the synthesis of 3-alkyl-substituted indoles, , only a few are known for the synthesis of 3-(2-oxoalkyl)indoles. These includes (a) the alkylation of indole with α-diazocarbonyl compounds 8a,b or nitroethane (followed by the treatment with either NaOMe/TiCl 3 or Fe/HOAc), 4c,8c (b) the ring opening of epoxides by indole in the presence of lanthanide cations 6d or organometallic reagents [followed by oxidation in the presence of Al(OPr- i ) 3 or Swern's reagent], ,8d,e (c) the Lewis acid mediated reaction of 3-(trimethylsilyl)indoles with Michael acceptors,8f (d) a two-step method involving the reaction of 3-indolylacetic acid with acetic anhydride in the presence of AcONa followed by the subsequent hydrolysis of the resulting 1-acetyl-3-indolylacetone,8g and (e) other methods. 8h,i However, many of these methods suffer from several drawbacks (e.g., the use of either unstable diazo compounds or moisture-sensitive organometallic reagents or expensive catalysts) and are only useful for the synthesis of specific indole derivatives.…”