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At least 91 records · Page 5Linked to original sources
PubMed1989

Anti-asthmatic activity of newly synthesized calcium antagonists: 2-n-butyl-1 (N-methyl-n-[2-(N',N'-dimethylamino)ethyl]amino) -5,6-methylenedioxy-indene and -indane.

The anti-asthmatic activity of the newly synthesized methylenedioxyindene (MDI) derivatives, 2-n-butyl-1 (N-methyl-N-[2-(N', N' -dimethylamino)ethyl]amino)-5, 6-methylenedioxy-indene (MDI-C) and -indane (MDI-D), were investigated in vitro and in vivo in guinea pigs. The in vitro pharmacological activity of both derivatives was compared to that of 8-(diethylamino)octyl-3,4, 5-trimethyoxybezoate hydrochloride. All three agents caused a concentration-dependent inhibition of the antigen-induced contraction of sensitized guinea pig tracheal smooth muscle. In histamine and leukotriene D4-induced contractions of guinea pig tracheal smooth muscle, each agent showed clear antagonistic actions. Additionally, all three agents demonstrated potent calcium antagonistic actions via inhibition of guinea pig tracheal smooth muscle contractions caused by CaCl2 in a high potassium and Ca-free medium and by compound 48/80 in a solution of ethylene glycol bis(beta-aminoethylether)-N,N,N',N'-tetraacetic acid in a contained Ca-free medium. MDI-C and MDI-D inhibited the antigen-induced release of histamine and slow reacting substance of anaphylaxis from sensitized guinea pig lung tissue. Lastly, both MDI is clearly inhibited asthmatic respiratory disorders without affecting blood pressure in guinea pigs.

Animals↗
PubMed1999

Cannabimimetic indoles, pyrroles and indenes.

In the course of efforts to develop new nonsteroidal antiinflammatory agents, it was discovered that 1-aminoalkyl-3-aroylindoles have affinity for the cannabinoid brain (CB1) receptor. This led to the synthesis of well over 100 cannabimimetic aminoalkylindoles by the group at Sterling Winthrop, and to the development of structure-activity relationships (SAR) for these compounds. These SAR require a heterocyclic aminoethyl group attached to the indole nitrogen, and a 1-naphthoyl group at C-3 for significant receptor affinity. Other workers subsequently demonstrated that an aminoalkyl group was not necessary for cannabinoid activity, but that an N-alkyl group of four to six carbons was sufficient. This led to the discovery that 1-propyl-3-(1-naphthoyl)indole is a selective ligand for the peripheral cannabinoid (CB2) receptor, and to the development of a series of cannabimimetic pyrroles. Comprehensive SAR for this group of cannabinoids have been developed. Two groups have described cannabimimetic indenes, which have been employed as rigid models for the receptor interactions of cannabimimetic indoles with the CB1 receptor. There is some evidence that the indoles interact at a somewhat different site on the receptor than traditional cannabinoids.

Animals↗
PubMed1992

Effects of a benz[e]indene on gamma-aminobutyric acid-gated chloride currents in cultured postnatal rat hippocampal neurons.

Benz[e]indenes (BIs) are tricyclic molecules that can be envisioned as steroids without an A-ring. Because certain steroids are known to alter gamma-aminobutyric acid (GABA) responses in central neurons, we examined the effects of a substituted BI resembling 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-OH-DHP) on GABA-gated chloride currents in cultured postnatal rat hippocampal neurons. The compound, BI-1, reversibly potentiated GABA currents at concentrations of > 10 nM, with an EC50 value of 0.2 microM. BI-1 increased the apparent affinity of GABA for its receptor, decreasing the GABA EC50 from 9 microM to 3 microM. BI-1 had no effect on the shape of the GABA current-voltage relationship and did not alter the GABA reversal potential. The effects of BI-1 were not altered by benzodiazepine or picrotoxin site antagonists. At concentrations up to 10 microM, where maximal effects on GABA currents were seen, BI-1 did not directly activate a membrane current. This contrasts with the effects of 3 alpha-OH-DHP, which activated chloride currents at concentrations that were subsaturating for GABA potentiation. These results suggest that the BIs may be useful for determining the mechanisms by which steroids potentiate GABA responses and directly gate chloride channels.

Animals↗
PubMed2002

Lewis Acid mediated reactions of zirconacyclopentadienes with aldehydes: one-pot synthetic route to indene and cyclopentadiene derivatives from aldehydes and benzyne or alkynes.

One-pot procedures for the preparation of highly substituted indenes, tetrahydroindenes, and cyclopentadienes have been developed by using a combination of zirconocene-mediated Cbond;C-bond-forming reactions with Lewis acid mediated activation of carbonyl groups. The carbonyl groups of aldehydes were deoxygenated in the reaction and behaved formally as a one-carbon unit. A variety of Lewis acids were checked and showed different reactivities in this reaction.

Journal Article↗
PubMed2005

Indene and pseudoazulene discotic liquid crystals: a synthetic and structural study.

Several new liquid-crystalline indene and pseudoazulene systems are reported. These molecules give rise to either columnar hexagonal mesophases and/or columnar plastic phases. The unique nature of these compounds stems from their non-classical discotic structure. Although the molecules have rigid aromatic cores, they lack terminal tails and instead the polarizable atoms (S, halogens) or polar groups (CN, CO) act as unusual soft parts. On the basis of many structurally related materials, we conclude that for this type of compound molecular stacking in the solid state is a prerequisite for the appearance of a columnar mesophase, although other intermolecular interactions within the layers are also important in establishing liquid-crystalline order. The behavior reported for these mesomorphic molecules opens up new possibilities in the search for related molecular interactions that might be useful for the construction of supramolecular architectures with particular properties.

Journal Article↗
PubMed2005

Synthesis of the indene, THF, and pyrrolidine skeletons by Lewis acid mediated cycloaddition of methylenecyclopropanes with aldehydes, N-tosyl aldimines, and acetals.

Methylenecyclopropanes (MCPs 1) react with aldehydes, N-tosyl aldimines, and acetals to give the corresponding indene, THF, and pyrrolidine cycloaddition products in the presence of BF3 x OEt2 under mild reaction conditions. Some special transformations of MCPs 1 with aldehydes have been reported in this paper. A plausible reaction mechanism has been discussed, which is based on a deuterium-labeling experiment and the Prins-type reaction mechanism.

Journal Article↗
PubMed2005

Rhenium-catalyzed formation of indene frameworks via C-H bond activation: [3+2] annulation of aromatic aldimines and acetylenes.

A rhenium complex, [ReBr(CO)3(thf)]2, catalyzes the reaction of an aromatic aldimine with an acetylene to give an indene derivative in a quantitative yield. The reaction proceeds via C-H bond activation, insertion of the acetylene, intramolecular nucleophilic cyclization, and reductive elimination. In contrast to ruthenium and rhodium catalysts, which are usually employed in this type of reaction, the rhenium catalyst promotes the intramolecular nucleophilic cyclization of the alkenylmetal species generated by insertion of the acetylene.

Journal Article↗
PubMed2006

Insertion of polar and nonpolar unsaturated molecules into carbon-rhenium bonds generated by C-H bond activation: synthesis of phthalimidine and indene derivatives.

A rhenium complex, [ReBr(CO)(3)(thf)](2), catalyzes the reaction of an aromatic aldimine with an isocyanate and an acetylene to give a phthalimidine and an indene derivative in a quantitative yield, respectively. The reactions proceed via C-H bond activation, insertion of the isocyanate or the acetylene, intramolecular nucleophilic cyclization to the aldimine of the generated amido- or alkenyl-rhenium species, and reductive elimination. In contrast to ruthenium and rhodium catalysts, which are usually employed in this type of reaction, the rhenium catalyst promotes the insertion of a polar unsaturated molecule. This occurs more easily than the insertion of a nonpolar unsaturated molecule.

Journal Article↗
PubMed2003

Discovery and preclinical characterization of (+)-3-[4-(1- piperidinoethoxy)phenyl]spiro[indene- 1,1'-indane]-5,5'-diol hydrochloride: a promising nonsteroidal estrogen receptor agonist for hot flush.

In our studies of the development of a novel class of selective estrogen receptor modulators, (+)-3-[4-(1-piperidinoethoxy)phenyl]spiro[indene-1,1'-indane]-5,5'-diol hydrochloride (1) was found to be an estrogen receptor ligand with beneficial effects in rat models for human hot flush. Moreover, 1 was found to have beneficial effects on lipid and bone metabolism while maintaining marginal effects on the uterus and breasts. These findings suggest that 1 would provide a new treatment for hot flush.

Animals↗
PubMed1996

The simulated binding of (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]meth yl] -1H-inden-1-one hydrochloride (E2020) and related inhibitors to free and acylated acetylcholinesterases and corresponding structure-activity analyses.

The simulated binding profiles of acetylcholine, ACh, and the inhibitor (+/-)-2,3-dihydro-5,6- dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-on e hydrochloride (E2020), 1, and some of its analogs to acetylcholinesterase, AChE, were determined using full force field energetics and allowing complete conformational flexibility in both the ligand and receptor. A new mode of binding of ACh to AChE was found which involves the carboxyl oxygen of ACh interacting with Gly 118 and 119. Multiple modes of binding of 1 and some of its analogs were found which include alignment models observed in previous more restricted modeling studies. The key ligand-receptor interactions identified, and the corresponding energetics, are consistent on a relative basis, with observed binding constants for both the individual isomers of each of the inhibitors, as well as among the inhibitors themselves. The multiple modes of binding of 1 to AChE arises from small changes in binding at a single subsite and also from multiple subsite changes. Thus, an independent subsite model for ligand-receptor binding holds for some modes of binding, but not for others. A comparison of the simulated AChE-1 (and analog inhibitors) binding models to the receptor-independent 3D-QSARs previously developed for this class of inhibitors reveals extensive mutual consistency. The findings from these two modeling studies provides greater guidelines for inhibitor design than can be realized from either one. The combined docking and 3D-QSAR studies permit a detailed understanding of the SAR of more than 100 compound 1 analog inhibitors. A simple molecular recognition model can also be gleaned from the docking studies. A cylindrical "plug" (the inhibitor) having a large dipole moment must sterically fit into a cylindrical hole (the active site gorge of AChE), the lining of which also has a large dipole moment. Our simulations suggest that the dynamic "back door" to the active site of AChE does not form a large enough opening for sufficiently long time periods so as to be an effective entrance/exit pathway.

Acetylcholine↗
PubMed2001

Molecular basis for enantioselectivity of lipase from Chromobacterium viscosum toward the diesters of 2,3-dihydro-3-(4'-hydroxyphenyl)-1,1,3-trimethyl-1H-inden-5-ol.

2,3-Dihydro-3-(4'-hydroxyphenyl)-1,1,3-trimethyl-1H-inden-5-ol, 1, is a chiral bisphenol useful for preparation of polymers. Previous screening of commercial hydrolases identified lipase from Chromobacterium viscosum (CVL) as a highly regio- and enantioselective catalyst for hydrolysis of diesters of 1. The regioselectivity was > or =30:1 favoring the ester at the 5-position, while the enantioselectivity varied with acyl chain length, showing the highest enantioselectivity (E = 48 +/- 20 S) for the dibutanoate ester. In this paper, we use a combination of nonsymmetrical diesters and computer modeling to identify that the remote ester group controls the enantioselectivity. First, we prepared nonsymmetrical diesters of (+/-)-1 using another regioselective, but nonenantioselective, reaction. Lipase from Candida rugosa (CRL) showed the opposite regioselectivity (>30:1), allowing removal of the ester at the 4'-position (the remote ester in the CVL-catalyzed reaction). Regioselective hydrolysis of (+/-)-1-dibutanoate (150 g) gave (+/-)-1-5-dibutanoate (89 g, 71% yield). Acylation gave nonsymmetrical diesters that varied at the 4'-position. With no ester at the 4'-position, CVL showed no enantioselectivity, while hindered esters (3,3-dimethylbutanoate) reacted 20 times more slowly, but retained enantioselectivity (E = 22). These results indicate that the remote ester group can control the enantioselectivity. Computer modeling confirmed these results and provided molecular details. A model of a phosphonate transition state analogue fit easily in the active site of the open conformation of CVL. A large hydrophobic pocket tilts to one side above the catalytic machinery. The tilt permits the remote ester at the 4'-position of only the (S)-enantiomer to bind in this pocket. The butanoate ester fits and fills this pocket and shows high enantioselectivity. Both smaller and larger ester groups show low enantioselectivity because small ester groups cannot fill this pocket, while longer ester groups extend beyond the pocket. An improved large-scale resolution of 1-dibutanoate with CVL gave (R)-(+)-1-dibutanoate (269 g, 47% yield, 92% ee) and (S)-(-)-1-4'-monobutanoate (245 g, 52% yield, 89% ee). Methanolysis yielded (R)-(+)-1 (169 g, 40% overall yield, >97% ee) and (S)-(-)-1 (122 g, 36% overall yield, >96% ee).

Chromobacterium↗
PubMed2003

Generation and reactivity toward oxygen of carbon-centered radicals containing indane, indene, and fluorenyl moieties.

Resonance-stabilized radicals containing indane, indene, and fluorenyl moieties exhibit attenuated reactivity toward oxygen. Rate constants of approximately 10(5) M(-1) s(-1) were observed for the most stabilized radicals. The dependence of k(OX) (rate constant for radical trapping by oxygen) on the corresponding bond dissociation energies revealed that stereoelectronic effects are more important than steric effects in determining the low radical reactivity with oxygen. Scavenging by the nitroxide TEMPO was also examined, and revealed that in this case steric effects are more important than in the case of oxygen. The rate constants for the hydrogen abstraction by cumyloxyl and tert-butoxyl radicals generated thermally and photochemically have been determined in benzene, and were in the range of ca. (1-13) x 10(6) M(-1) s(-1), showing that benzylic stabilization has a modest effect on substrate reactivity as a hydrogen donor toward alkoxyl radicals.

Journal Article↗
PubMed2006

PtBr2-catalyzed transformation of allyl(o-ethynylaryl)carbinol derivatives into functionalized indenes. Formal sp3 C-H bond activation.

The PtBr2-catalyzed reaction of 1-ethynyl-2-(1-alkoxybut-3-enyl)benzenes at 120 degrees C in CH3CN gave functionalized indenes in good to allowable yields. Most probably, the hydrogen at the terminal alkyne is transferred to the adjacent internal beta-carbon to form an (eta2-vinylidene)platinum carbene intermediate, which activates the sp3 C-H bond at the benzylic carbon. This reaction pathway is supported by DFT calculations which suggest that the formation of the Pt-vinylidene complex is the rate-limiting stage for the whole transformation.

Journal Article↗
PubMed2006

Sequential ruthenium-catalyzed hydroamination and rhenium-catalyzed C-H bond activation leading to indene derivatives.

[reaction: see text] Formal [3 + 2] annulation of arylacetylenes and alpha,beta-unsaturated carbonyl compounds is achieved in a one-pot reaction by successive treatment of the acetylenes with aniline and a catalytic amount of Ru(3)(CO)(12) and NH(4)PF(6) and C-H bond activation catalyzed by [ReBr(CO)(3)(thf)](2). The result suggests that the second rhenium-catalyzed indene formation is not disturbed by the first catalyst system.

Journal Article↗