Showing papers on "Bicyclic molecule published in 2008"
Patent•
22 May 2008TL;DR: The bicyclic nucleosides comprising a substituted amino group in the bridge are useful for enhancing properties of oligomeric compounds including nuclease resistance, in certain embodiments, the oligomerics hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA as mentioned in this paper.
Abstract: Provided herein are bicyeMc nucleosides comprising a substituted amino group in the bridge, oligomeric compounds having at least one of these bi cyclic nucleosides and methods of using the oligomeric compounds. The bicyclic nucleosides comprising a substituted amino group in the bridge are useful for enhancing properties of oligomeric compounds including nuclease resistance, in certain embodiments, the oligomeric compounds hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.
298 citations
Patent•
06 Jun 2008TL;DR: In this paper, saturated and unsaturated carbocyclic bicyclic nucleosides are used for enhancing properties of oligomeric compounds including nuclease resistance, and methods of using these compounds are described.
Abstract: Provided herein are saturated and unsaturated carbocyclic bicyclic nucleosides, oligomeric compounds prepared therefrom and methods of using these oligomeric compounds. The saturated and unsaturated carbocyclic bicyclic nucleosides are useful for enhancing properties of oligomeric compounds including nuclease resistance.
297 citations
Patent•
01 Jul 2008TL;DR: In this paper, the 6-disubstituted bicyclic nucleosides, oligomeric compounds prepared therefrom and methods of using the oligomerics are described.
Abstract: The present disclosure describes 6-disubstituted bicyclic nucleosides, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, the 6-disubstituted bicyclic nucleosides each comprise a 2'-O-C(Ri)(R2)-4' or 2'-O- C=(R3)(R.4)-4' bridge wherein each R is, independently a substituent group and Ri and R2 include H. The 6-disubstituted bicyclic nucleosides are useful for enhancing properties of oligomeric compounds including nuclease resistance. In certain embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.
234 citations
TL;DR: 2-cyano-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)acetamide was utilized as key intermediate for the synthesis of some new coumarin 2, pyridine 3,pyrrole 4, thiazole 7, and pyrazolo[5,1-c]triazine and aminopyrazole 9.
231 citations
Patent•
21 Nov 2008TL;DR: In this article, the authors presented novel carbocyclic α-L-bicyclic nucleosides and oligomeric compounds comprising at least one of them, which are useful for enhancing one or more properties of the oligomerics they are incorporated into including nuclease resistance.
Abstract: The present invention provides novel carbocyclic α-L-bicyclic nucleosides and oligomeric compounds comprising at least one of these carbocyclic α-L-bicyclic nucleosides. The carbocyclic α-L-bicyclic nucleosides are useful for enhancing one or more properties of the oligomeric compounds they are incorporated into including nuclease resistance.
178 citations
TL;DR: Mechanistic studies show that addition of aniline-d2 occurs in a syn fashion and suggest that the catalytic cycle comprises oxidative addition ofAniline to form a bis-anilide hydride complex, followed by migratory insertion of olefin and reductive elimination of product in a series of steps involving iridium complexes containing ancillary bisphosphine and arylamide ligands.
Abstract: A set of catalytic, intermolecular hydroaminations of strained bicyclic olefins and dienes are reported that occur in both high yield and high enantioselectivity. These reactions occur with a catalyst generated from [Ir(cyclooctene)Cl]2, sterically hindered and electron-rich derivatives of the Segphos and BIPHEP family of ligands, and a soluble base. This system catalyzes the addition of various anilines to norbornene, norbornadiene, and other bicyclic olefins. The products from addition of p-anisidine can be transformed to BOC-protected norbornylamine and to substituted cyclopentanes in nearly enantiopure form. Mechanistic studies show that addition of aniline-d2 occurs in a syn fashion and suggest that the catalytic cycle comprises oxidative addition of aniline to form a bis-anilide hydride complex, followed by migratory insertion of olefin and reductive elimination of product in a series of steps involving iridium complexes containing ancillary bisphosphine and arylamide ligands.
162 citations
161 citations
TL;DR: In this article, the development of a family of chiral bicyclic triazolium salts is described, and treatment of these salts with base provides a nucleophilic carbene which may be used as an organic catalyst for asymmetrization.
Abstract: The development of a family of chiral bicyclic triazolium salts is described. Treatment of these salts with base provides a nucleophilic carbene which may be used as an organic catalyst for asymmet...
155 citations
TL;DR: In biodistribution studies in rats, the distribution of radioactivity of the [ (18)F]PBR compounds paralleled the known localization of PBRs and appeared to be the best candidate for evaluation as an imaging agent for PBR expression in neurodegenerative disorders.
Abstract: The fluoroethoxy and fluoropropoxy substituted 2-(6-chloro-2-phenyl)imidazo[1,2- a]pyridin-3-yl)- N, N-diethylacetamides 8 (PBR102) and 12 (PBR111) and 2-phenyl-5,7-dimethylpyrazolo[1,5- a]pyrimidin-3-yl)- N, N-diethylacetamides 15 (PBR099) and 18 (PBR146) were synthesized and found to have high in vitro affinity and selectivity for the peripheral benzodiazepine receptors (PBRs) when compared with the central benzodiazepine receptors (CBRs). The corresponding radiolabeled compounds [ (18)F] 8 [ (18)F] 12, [ (18)F] 15, and [ (18)F] 18 were prepared from their p-toluenesulfonyl precursors in 50-85% radiochemical yield. In biodistribution studies in rats, the distribution of radioactivity of the [ (18)F]PBR compounds paralleled the known localization of PBRs. In the olfactory bulbs, where the uptake of radioactivity was higher than in the rest of the brain, PK11195 and Ro 5-4864 were able to significantly inhibit [ (18)F] 12, while little or no pharmacological action of these established PBR drugs were observed on the uptake of [ (18)F] 8, [ (18)F] 15, and [ (18)F] 18 compared to control animals. Hence, [ (18)F] 12 appeared to be the best candidate for evaluation as an imaging agent for PBR expression in neurodegenerative disorders.
149 citations
TL;DR: It is worth noting that the replacement of the thiazole nucleus for the benzo[d]thiazole bicyclic system in the parent 2-(benzylidene-2-ylimino)thiazolidin-4-one leads to significant antifungal properties against both yeasts and moulds, properties not shown by the analogous 2-thiazolyl- and 2-benzo[ d]isothiazoly l-imino-5-
142 citations
TL;DR: Some of the synthesized compounds showed potent anti-inflammatory activity along with minimal ulcerogenic effect and lipid peroxidation, compared to those of ibuprofen and flurbiprofen, and moderate antimicrobial activity against tested bacterial and fungal strains.
TL;DR: Palladium catalysed intramolecular guanidine transfer to alkenes can be accomplished with copper chloride as the oxidant to give bicyclic guanidines with complete selectivity and in high yields.
TL;DR: A Rh(I)-catalyzed [3 + 2] reaction of trans-VCP-enes, where VCP acts as a three-carbon synthon to furnish five-membered carbocycles, is demonstrated.
Abstract: Vinylcyclopropane (VCP) has been well applied as a five-carbon component, rather than a three-carbon component, in transition-metal catalyzed cycloadditions. Here we demonstrate a Rh(I)-catalyzed [3 + 2] reaction of trans-VCP-enes, where VCP acts as a three-carbon synthon to furnish five-membered carbocycles. This novel cycloaddition is efficient in generating bicyclic cyclopentanes in good yields from simple and easily prepared substrates. When cis-VCP-ene is used as the substrate, VCP acts as a five-carbon unit to give a [5 + 2] cycloadduct. Rationalization of the [3 + 2] and [5 + 2] cycloadditions of VCP-enes has been proposed.
TL;DR: A new methodology for the synthesis of bicyclic peptides by using a reconstituted cell-free translation system under the reprogrammed genetic code offers a powerful means of mRNA-programmed synthesis of various peptides with uniform bicyclic scaffolds.
Abstract: Here we report a new methodology for the synthesis of bicyclic peptides by using a reconstituted cell-free translation system under the reprogrammed genetic code. Cysteine (Cys) and three different nonproteinogenic amino acids, Cab, Aha, and Pgl, were simultaneously incorporated into a peptide chain. The first cyclization occurred between the chloroacetyl group of Cab and the sulfhydryl group in Cys in situ of translation, and the second cyclization on the side chains of Aha−Pgl via Cu(I)-catalyzed azide−alkyne cycloaddition was performed. This offers us a powerful means of mRNA-programmed synthesis of various peptides with uniform bicyclic scaffolds.
TL;DR: The synthesis and spectroscopic properties of a series of boron-free meso-aryl-substituted [14]triphyrin(2.2.1.1) compounds represent the first examples of free-base contracted porphyrinoids with 14 π-electron aromatic systems containing only the standard pyrrole and isoindoline moieties of the p Morphyrins and tetrabenzoporphyrins.
Abstract: The synthesis and spectroscopic properties of a series of boron-free meso-aryl-substituted [14]triphyrin(2.1.1) compounds containing either peripheral bicyclo[2.2.2]octadiene (BCOD) (2a−c) or benzene rings (3a−c) (aryl = phenyl a, 4-fluorophenyl b, and 4-methylbenzoatephenyl c) are reported. These compounds represent the first examples of free-base contracted porphyrinoids with 14 π-electron aromatic systems containing only the standard pyrrole and isoindoline moieties of the porphyrins and tetrabenzoporphyrins.
TL;DR: An asymmetric total synthesis of (-)-incarvillateine, a natural product having potent analgesic properties, has been achieved in 11 steps and 15.4% overall yield.
Abstract: An asymmetric total synthesis of (-)-incarvillateine, a natural product having potent analgesic properties, has been achieved in 11 steps and 15.4% overall yield. The key step is a rhodium-catalyzed intramolecular alkylation of an olefinic C-H bond to set two stereocenters. Additionally, this transformation produces an exocyclic, tetrasubstituted alkene through which the bicyclic piperidine moiety can readily be accessed.
TL;DR: In this article, DPA-714 and its tosyloxy derivative (N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide) were synthesized using a simple one-step process, which has been fully automated on Zymate-XP robotic system.
Abstract: Recently, a novel series of 2-phenylpyrazolo[1,5-a]pyrimidineacetamides has been reported as selective ligands of the translocator protein (18 kDa). Within this series, DPA-714 (N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide, Ki=7.0 nM) is a compound, which had been designed with a fluorine atom in its structure, allowing labelling with fluorine-18 (half-life: 109.8 min) and in vivo imaging using positron emission tomography. DPA-714 and its tosyloxy derivative (N,N-diethyl-2-(2-(4-(2-toluenesulfonyloxyethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide) as precursor for the labelling with fluorine-18 were synthesized in two steps from DPA-713 (N,N-diethyl-2-(2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide) and obtained in 32 and 42% yields, respectively. [18F]DPA-714 was synthesized using a simple one-step process (a tosyloxy-for-fluorine nucleophilic aliphatic substitution), which has been fully automated on our Zymate-XP robotic system. It involves: (A) reaction of K[18F]F-Kryptofix®222 with the tosyloxy precursor (4.5–5.0 mg, 8.2–9.1 µmol) at 165°C for 5 min in dimethyl sufloxide (0.6 mL) followed by (B) C18 PrepSep cartridge pre-purification and finally (C) semi-preparative high-performance liquid chromatography (HPLC) purification on a Waters X-Terra™ RP18. Typically, 5.6–7.4 GBq of [18F]DPA-714 (>95% chemically and radiochemically pure) could be obtained with specific radioactivities ranging from 37 to 111 GBq/µmol within 85–90 min (HPLC purification and SepPak®-based formulation included), starting from a 37 GBq [18F]fluoride batch (overall non-decay-corrected and isolated radiochemical yield: 15–20%). Copyright © 2008 John Wiley & Sons, Ltd.
TL;DR: Qualitative SAR studies indicate that the chloro substitution in the imidazole ring and introduction of formyl group at C-5 position of the imiadiazole ring increased the anti-inflammatory and analgesic activity.
TL;DR: Cr(III) complexes with [NON] and [NSN] heteroscorpionate ligands derived from bis(pyrazol-1-yl)methane have been prepared, which are active for ethylene trimerization to 1-hexene with high selectivity as discussed by the authors.
TL;DR: The synthesis of cyclic, branched, and bicyclic oligonucleotides was performed by copper-catalyzed azide-alkyne cycloaddition assisted by microwaves in solution and on solid support to introduce alkyne and bromo functions into the same oligon nucleotide by solid-phase synthesis on a DNA synthesizer.
Abstract: The synthesis of cyclic, branched, and bicyclic oligonucleotides was performed by copper-catalyzed azide−alkyne cycloaddition assisted by microwaves in solution and on solid support. For that purpose, new phosphoramidite building blocks and new solid supports were designed to introduce alkyne and bromo functions into the same oligonucleotide by solid-phase synthesis on a DNA synthesizer. The bromine atom was then substituted by sodium azide to yield azide oligonucleotides. Cyclizations were found to be more efficient in solution than on solid support. This method allowed the efficient preparation of cyclic (6- to 20-mers), branched (with one or two dangling sequences), and bicyclic (2 × 10-mers) oligonucleotides.
TL;DR: The key dinitrile intermediates 4a-d were synthesized by reaction of phenacyl bromide 1 and the appropriate 2-amino-5-bromopyridines to yield 3a-D, and two of the diamidines 7c and 7d were slightly more active than furamidine but less active than azafuramidine in the T. r.
TL;DR: A series of potent 5-hydroxytryptamine 7 (5-HT 7) ligands has been synthesized that contain a 1,3-dihydro-2 H-indol-2-one (oxindole) skeleton and according to the structure-activity relationship observations, compounds unsubstituted at the oxindole nitrogen atom and containing a tetramethylene spacer between the oxindle skeleton and the basic nitrogen atom are the most potent ligands.
Abstract: A series of potent 5-hydroxytryptamine7 (5-HT7) ligands has been synthesized that contain a 1,3-dihydro-2H-indol-2-one (oxindole) skeleton. The binding of these compounds to the 5-HT7 and 5-HT1A receptors was measured. Despite the structural similarity of these two serotonin receptor subtypes, several derivatives exhibited a high selectivity to the 5-HT7 receptor. According to the structure–activity relationship observations, compounds unsubstituted at the oxindole nitrogen atom and containing a tetramethylene spacer between the oxindole skeleton and the basic nitrogen atom are the most potent ligands. Concerning the basic group, besides the moieties of the 4-phenylpiperazine type, halophenyl-1,2,3,6-tetrahydropyridines also proved to be 5-HT7 receptor–ligands. Because of halogen substitution on the aromatic rings, good metabolic stability could be achieved. A representative of the family, 3-{4-[4-(4-chlorophenyl)-piperazin-1-yl]-butyl}-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one (9e′) exhibited selective...
TL;DR: Methyl (4E,7R)-7-hydroxyoctanoate was prepared in 71% yield from ethyl (R)-3-Hydroxybutanoate and on reaction with a series of aldehydes in the presence of TMSOTf gave bicyclic oxygen heterocycles in good yields and with the creation of three new stereogenic centres in a single pot.
TL;DR: This reaction demonstrates the feasibility of olefin insertion into carbodiimide-derived metalacycles and provides a new class of chiral bicyclic amidines as the major products.
Abstract: A highly enantioselective rhodium-catalyzed [2+2+2] cycloaddition of terminal alkynes and alkenyl carbodiimides has been developed. This reaction demonstrates the feasibility of olefin insertion into carbodiimide-derived metalacycles and provides a new class of chiral bicyclic amidines as the major products. An isonitrile migration process responsible for the formation of the minor cycloadduct can be observed and is highly sensitive to the electronics of alkynyl substrates.
TL;DR: The preliminary pharmacological characterization revealed nanomolar AT 1 receptors affinity for several compounds of the series and a potent antagonistic activity in isolated rabbit aortic strip functional assay for 7c and 8a, suggesting that the permeability is not a limiting factor in the pharmacokinetics of these AT 1 receptor antagonists.
Abstract: Novel AT1 receptor antagonists bearing the pyrazolo[3,4-b]pyridine bicyclic heteroaromatic system (or structurally related moieties) were designed and synthesized as the final step of a large program devoted to the development of new antihypertensive agents and to the understanding of the molecular basis of their pharmacodynamic and pharmacokinetic properties The preliminary pharmacological characterization revealed nanomolar AT1 receptor affinity for several compounds of the series and a potent antagonistic activity in isolated rabbit aortic strip functional assay for 7c and 8a These results stimulated the study of the biopharmaceutical properties of some selected compounds, which were found to be characterized by a permeability from medium to high Remarkably, the least permeable 7c showed both permeability and oral bioavailability (80%) higher than losartan, but its terminal half-life was shorter These results suggest that the permeability is not a limiting factor in the pharmacokinetics of these AT
TL;DR: A series of thiazolo[4,5-d]pyrimidine-2(3H)-one antagonists with markedly improved biological and pharmacokinetic properties are found to be suitable pharmacological tools to probe the in vivo effects of CXCR2 antagonism combined with the associated CCR2 activity.
TL;DR: A one-pot synthesis of benzopyrones and tricyclic spiroketones from hydrative carbocyclization of oxodiyne substrates catalyzed by PtCl2 and PPh3AuCl/AgOTf catalysts is reported.
TL;DR: The synthesis of a new type of C(2)-symmetric chiral diene ligands with a nonbridged bicyclic [3.3.0] backbone was successfully introduced and excellent enantioselectivities as well as good yields are achieved under very mild reaction conditions at room temperature.
Abstract: The synthesis of a new type of C(2)-symmetric chiral diene ligands with a nonbridged bicyclic [3.3.0] backbone was successfully introduced. Using highly efficient lipase-catalyzed transesterification and Suzuki-coupling strategies, a broad family of enantiopure 3,6-disubstituted bicyclo[3.3.0] dienes with different electronic and steric properties could be easily prepared. The application of these new diene ligands in the Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to alpha,beta-unsaturated carbonyl compounds have been examined, and excellent enantioselectivities (up to 98 % ee) as well as good yields are achieved under very mild reaction conditions at room temperature.
TL;DR: A new C3-symmetric drum-shaped homoditopic haxaamino bicyclic cyclophane and its hexachloride and hexaiodide complexes have been synthesized and characterized and dual recognition of guests has been demonstrated.
Abstract: A new C3-symmetric drum-shaped homoditopic haxaamino bicyclic cyclophane and its hexachloride and hexaiodide complexes have been synthesized and characterized and dual recognition of guests has been demonstrated. Single-crystal X-ray analysis illustrates that bicyclic cyclophane has a cavity and side pockets for acetone molecules. The hexaprotonated state of this bicycle shows encapsulation of an iodide inside its cavity, and in hexachloride complex, chloride is recognized as Cl(-)...H2O in each of the three side pockets which are in extensive hydrogen bonding interactions with the water and chlorides. (1)H NMR experiments have also been carried out on hexatosylated cyclophane with the halides to study solution state binding.