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A small set of acyclic analogs 5 were prepared to explore their structure-activity relationships (SARs) relative to heterocyclic core, opioid receptor (OR) agonists 4. Compound 5l was found to have very favorable OR binding affinities at the δ and μ ORs (r K(i) δ=1.3 nM; r K(i) μ=0.9 nM; h K(i) μ=1.7 nM), with less affinity for the κ OR (gp K(i) κ=55 nM). The OR functional profile for 5l varied from the previously described dual δ/μ OR agonists 4, with 5l being a potent, mixed dual δ OR antagonist/μ OR agonist [δ IC(50)=89 nM (HVD); μ EC(50)=1 nM (GPI); κ EC(50)=1.6 μM (GPC)]. Compound 5l has progressed through a clinical Phase II Proof of Concept study on 800 patients suffering from diarrhea-predominant Irritable Bowel Syndrome (IBS-d). This Phase II study was recently completed successfully, with 5l demonstrating statistically significant efficacy over placebo.

We present a pair of 15 cm × 15 cm all-phosphorescent OLED light panels with high efficacy and extended operational lifetime. Panel 1 operates at 1,000 cd/m2 with power efficacy = 62 lm/W. At a higher luminance of 3,000 cd/m2, power efficacy = 49 lm/W, CRI = 82, CCT = 2,950 K and CIE 1931 (x, y) = (0.446, 0.417). Similar high efficacy performance is recorded for Panel 2, which has lifetime to LT70 ∼ 4,000 hrs at 3,000 cd/m2. Excellent lifetime is enabled by a new light blue phosphorescent materials system and by the use of efficient phosphorescent emitters that ensure very low panel temperature without any additional thermal management.

The synthesis, spectral characteristics, and X-ray structures for dirhodium(II) tetrakis[methyl 2-oxooxazolidin-4(S)-carboxylate], Rh2(4S-MEOX)4, and the related dirhodium(II) tetrakis[methyl 5(R)-methyl-2-oxooxazolidin-4(S)-carboxylate], Rh2(4S-THREOX)4, are reported. Comparison is made between these 2-oxooxazolidin-ligated dirhodium(II) catalysts for metal carbene transformations and those with comparable 2-oxopyrrolidine ligands, especially dirhodium(II) tetrakis[methyl 2-oxopyrrolidine-5(S)-carboxylate], Rh2(5S-MEPY)4. Structure-selectivity comparisons reveal that Rh2(4S-MEOX)4 provides higher enantiocontrol and, in some cases, higher diastereocontrol than Rh2(5S-MEPY)4 in intramolecular carbon-hydrogen insertion reactions of sterically demanding diazoacetates and diazoacetamides and is the catalyst of choice for highly enantioselective diazodecomposition of adamantyl diazoacetates and N-(tert)butyldiazoacetamides. The structurally analogous Rh2(4S-THREOX)4 is nearly identical with Rh2(4S- MEOX)4 in its overall effect on selectivity. The net advantage of Rh2(4S-MEOX)4 lies in its wider openness for metal carbene transformations.

A series of N-carboxy, N-alkyl, and N-carboxamido azabicyclo[2.2.2]octane carboxamides were prepared and assayed for inhibition of α4β1-VCAM-1 and α4β7-MAdCAM-1 interactions. Potency and α4β1/α4β7 selectivity were sensitive to the substituent R1–R3 in the structures 6, 7, and 8. Several compounds demonstrated low nanomolar balanced α4β1/α4β7 in vitro activity. Two compounds were selected for in vivo leukocytosis studies and demonstrated increases in circulating lymphocytes up to 250% over control.

Vasopressin receptor antagonists can elicit ion-sparing diuretic effects (i.e., aquaresis) in vivo by blunting the action of the circulating hypophyseal hormone arginine vasopressin. We have identified two new series of basic tricyclic benzodiazepines, represented by general structure 1, which contain compounds that bind with high affinity to human V2 receptors. For example, (S)-(+)-8 and 5 are potent and selective V2 receptor antagonists with pronounced aquaretic activity in rats on oral administration.

The synthesis, resolution, and stereochemical characterization of novel piperazino-, thiazino-, and oxazinobenzodiazepines are described. The absolute stereochemistry of the heterotricycles was determined by using X-ray crystallography and the enantiomeric purity was determined by using Pirkle-solvent NMR techniques and chiral HPLC.

The design, synthesis, and biological activity of novel α 4 β 1 and α 4 β 7 integrin antagonists, containing a bridged azabicyclic nucleus, are reported. Conformational analysis of targets containing an azabicyclo[2.2.2]octane carboxylic acid and known integrin antagonists indicated that this azabicycle would be a suitable molecular scaffold. Variation of substituents on the pendant arylsulfonamide and phenylalanine groups resulted in potent α 4 β 1 -selective and dual α 4 β 1 /α 4 β 7 antagonists. Potent compounds 11i , 11h , and 14 were effective in the antigen-sensitized sheep model of asthma. ©2003 Elsevier Science Ltd. All rights reserved.

We present the results of a study using vibrational circular dichroism (VCD) for (+)-1, which furnished an unambiguous determination of its absolute configuration as S. The most abundant conformation of (+)-1 in CDCl3 solution was also established. Chirality 14:215–219, 2002. © 2002 Wiley-Liss, Inc.

1,3-Dioxan-5-yl diazoacetates are valuable substrates for highly diastereoselective and enantioselective carbon-hydrogen insertion reactions. trans-2-(tert-Butyl)-1,3-dioxan-5-yl diazoacetate is a direct precursor to 2-deoxyribono-1,4-lactone in up to 81% ee, whereas cis-2-(tert-butyl)-1,3-dioxan-5-yl diazoacetate yields only the protected 2-deoxyxylono-1,4-lactone in up to 96% ee. However, trans-2-aryl-1,3-dioxan-5-yl diazoacetate (aryl = phenyl or 2-naphthyl) forms the precursor to 2-deoxyxylono-1,4-lactone in up to 95% ee but with the mirror image configuration of that produced from the trans-2-(tert-butyl) analogue. The catalysts that are most suitable for these carbon-hydrogen insertion reactions are chiral dirhodium(II) carboxamidates. 1,3-Dialkoxy-2-propyl diazoacetates give mainly 2-deoxyxylono-1,4-lactone derivatives (>90:10) with generally high enantiocontrol, but replacement of hydrogen at the 2-position of these 2-propyl diazoacetates led to a mixture of products.

The Sonogashira reaction of a resin-bound iodobenzoic acid with trimethylsilyl acetylene followed by TBAF desilylation provided a polymer-supported aryl acetylene, 3. Treatment of 3 with an aldehyde and a secondary amine in dioxane in the presence of CuCl catalyst results in the generation of resin-bound propargylamines. The final products (4) were cleaved from the resin and obtained in excellent yields and purity.

Summary Dirhodium(II) tetrakis[methyl 1-(3-phenylpropanoyl)imidazolidin-2-one-4(S)-carboxylate], Rh 2 (4S-MPPIM) 4 , provides significant enhancement in enantiocontrol for intramolecular cyclopropanation reactions of allylic diazoacetates and optimal enantiocontrol/diastereocontrol for intramolecular C-H insertion reactions of secondary alkyl diazoacetates.

Diazo decomposition of allylic and homoallylic diazoacetates loa-p and 22a-j catalyzed by chiral dirhodium(I1) tetrakis[methyl 2-pyrrolidone-S(S)-carboxylate], Rhz(SS-MEPY)4 (7), and its enantiomer, Rhz(5RMEPY)4 (S), produces the corresponding intramolecular cyclopropanation products l la-p and 23a-j in good to excellent yields and with exceptional enantioselectivity. Higher enantiocontrol is observed with allylic diazoacetates than with their homoallylic counterparts, but allylic diazoacetates are subject to greater variations in enantioselectivities with changes in substitution patterns on the carbon-carbon double bond. For example, the enantioselectivities in the intramolecular cyclopropanations of 3-allcyl/aryl-2(Z)-alken-l-y1 diazoacetates are generally 194%, whereas the cyclizations of the homologous 4-alkyl/aryl-3(Z)-alken1-yl diazoacetates are typically in the range of 70-90% ee. The corresponding 3-alkyYaryl-2(E)-alken-l-y1 and 4-alkyl/aryl-3(E)-alken-l-yl diazoacetates undergo cyclization with slightly lower ee’s (54-85%). Although the Rh@-MEPY)4-catalyzed cyclization of the 2-methallyl diazoacetate 1Oc proceeds with only 7% ee, alternative chiral dirhodium(I1) catalysts, including those with methyl N-acylimidazolidin-2-one-4(S)-carboxylate ligands such as Rh2(4S-MACIM)4 (14) and Rhz(4S-MPAIM)d (E) , may be employed to increase the level of enantiocontrol to 78 and 65%, respectively. Some allylic diazoacetamides also undergo highly enantioselective cyclization to form cyclopropyl lactams as illustrated by the diazo decomposition of N-allyl diazoacetamide (19) in the presence of dirhodium(II) tetrakis[methyl 2-oxazolidinone-4(S)-carboxylate], Rhz(4SMEOXk, to give the 3-azabicyclo[3.1.0]hexan-2-one 20 in 98% ee. The absolute configuration and the level of enantiocontrol in these intramolecular cyclopropanations have been interpreted by a transition state model in which the important determinants are (i) the preferred conformation about the rhodium-carbon bond; (ii) the trajectory of approach of the double bond to the metallocarbene center; and (iii) the orientation of the double bond with respect to the chiral face of the catalyst.

The Rh¹¹‐catalyzed carbenoid addition of diazoacetates to olefins was investigated with [Rh₂{(4S)‐phox}₄] (1;phox = tetrakis[(4S)‐tetrahydro‐4‐phenyloxazol‐2‐one]), [Rh₂{(2S)‐mepy}₄] (2; mepy = tetrakis[methyl (2S)‐tetrahydro‐5‐oxopyrrole‐2‐carboxylate]), and [Rh₂(OAc)₄] (3). While catalysis with 2 and 3 afford preferentially trans‐cyclopropanecarboxylates, the cis‐isomers are the major products with 1. In general, the enantioselectivities achieved with 1 and 2 are comparable. Additions catalyzed by 1 are strongly sensitive to steric effects. Highly substituted olefins afford cyclopropanes in only poor yield. The preferential cis‐selectivity observed in reactions catalyzed by 1 is attributed to dominant interactions between the ligand of the catalyst and the substituents of both olefin and diazoacetate, which overrule the steric interactions between olefin and diazoacetate in the transition state for carbene transfer.

Diazodecomposition of 1,3-dialkoxy-2-propyl diazoacetates catalyzed by chiral dirhodium(II) carboxamides results in highly enantioselective and diastereoselective carbon-hydrogen insertion which forms 3,5-dialkyl 2-deoxyxylolactones in up to 98% enantiomeric excess.

Diazodecomposition of 1,3-dialkoxy-2-propyl diazoacetates catalyzed by chiral dirhodium(II) carboxamides results in highly enantioselective and diastereoselective carbon-hydrogen insertion which forms 3,5-dialkyl 2-deoxyxylolactones in up to 98% enantiomeric excess.

The synthesis, spectral characteristics, and X-ray structures for dirhodium(II) tetrakis[methyl 2-oxooxazolidin-4(S)-carboxylate], Rh2(4S-MEOX)4, and the related dirhodium(II) tetrakis[methyl 5(R)-methyl-2-oxooxazolidin-4(S)-carboxylate], Rh2(4S-THREOX)4, are reported. Comparison is made between these 2-oxooxazolidin-ligated dirhodium(II) catalysts for metal carbene transformations and those with comparable 2-oxopyrrolidine ligands, especially dirhodium(II) tetrakis[methyl 2-oxopyrrolidine-5(S)-carboxylate], Rh2(5S-MEPY)4. Structure-selectivity comparisons reveal that Rh2(4S-MEOX)4 provides higher enantiocontrol and, in some cases, higher diastereocontrol than Rh2(5S-MEPY)4 in intramolecular carbon-hydrogen insertion reactions of sterically demanding diazoacetates and diazoacetamides and is the catalyst of choice for highly enantioselective diazodecomposition of adamantyl diazoacetates and N-(tert)butyldiazoacetamides. The structurally analogous Rh2(4S-THREOX)4 is nearly identical with Rh2(4S- MEOX)4 in its overall effect on selectivity. The net advantage of Rh2(4S-MEOX)4 lies in its wider openness for metal carbene transformations.

Summary Dirhodium(II) tetrakis[methyl 1-(3-phenylpropanoyl)imidazolidin-2-one-4(S)-carboxylate], Rh 2 (4S-MPPIM) 4 , provides significant enhancement in enantiocontrol for intramolecular cyclopropanation reactions of allylic diazoacetates and optimal enantiocontrol/diastereocontrol for intramolecular C-H insertion reactions of secondary alkyl diazoacetates.

A novel method for the efficient synthesis of 1,8-diazabicyclo[4.3.0]non-3-ene-7,9-diones 5 (bicyclic hydantoins) starting from ureas or Z-protected aminoacids has been developed. The key step is a ring-closing metathesis (RCM) reaction of diallyl substituted hydantoins 3 catalyzed by the ruthenium-carbene complex bis(tricyclohexylphosphine)benzilidine ruthenium dichloride ( 4 ).

1,3-Dioxan-5-yl diazoacetates are valuable substrates for highly diastereoselective and enantioselective carbon-hydrogen insertion reactions. trans-2-(tert-Butyl)-1,3-dioxan-5-yl diazoacetate is a direct precursor to 2-deoxyribono-1,4-lactone in up to 81% ee, whereas cis-2-(tert-butyl)-1,3-dioxan-5-yl diazoacetate yields only the protected 2-deoxyxylono-1,4-lactone in up to 96% ee. However, trans-2-aryl-1,3-dioxan-5-yl diazoacetate (aryl = phenyl or 2-naphthyl) forms the precursor to 2-deoxyxylono-1,4-lactone in up to 95% ee but with the mirror image configuration of that produced from the trans-2-(tert-butyl) analogue. The catalysts that are most suitable for these carbon-hydrogen insertion reactions are chiral dirhodium(II) carboxamidates. 1,3-Dialkoxy-2-propyl diazoacetates give mainly 2-deoxyxylono-1,4-lactone derivatives (>90:10) with generally high enantiocontrol, but replacement of hydrogen at the 2-position of these 2-propyl diazoacetates led to a mixture of products.

A series of guanidine triazinediones were identified as potent PK1 receptor antagonists. A compound in this series inhibited the PK1 invoked prosecretory response in rat ileum tissue.

A novel series of pyridazinone-functionalized phenylalanine analogues was prepared and evaluated for inhibition of cellular adhesion mediated by alpha4beta1/VCAM-1 and alpha4beta7/MAdCAM-1 interactions. Concise syntheses were developed and applied for exploration of structure-activity relationships pertaining to the pyridazinone ring as well as the N-acyl phenylalanine scaffold. Potent dual antagonists of alpha4beta1 and alpha4beta7 were generated from an amide subseries; antagonists selective for alpha4beta7 were identified from urea and carbamate-based subseries. The pharmacokinetic properties of selected members of the series have been determined in rats and demonstrate that the use of ester prodrugs and alterations to the amide linkage can lead to improved oral bioavailability in this series. An alpha4beta7-selective member of the carbamate subseries (36c), upon oral administration, demonstrated in vivo efficacy in the mouse DSS colitis model.

The alpha4beta1 integrin, expressed on eosinophils and neutrophils, induces inflammation in the lung by facilitating cellular infiltration and activation. From a number of potent alpha4beta1 antagonists that we evaluated for safety and efficacy, 1 was selected as a lead candidate for anti-asthma therapy by the inhalation route. We devised an optimized stereoselective synthesis to facilitate the preparation of a sufficiently large quantity of 1 for assessment in vivo. Administration of 1 to allergen-sensitive sheep by inhalation blocked the late-phase response of asthma and abolished airway hyper-responsiveness at 24h following the antigen challenge. Additionally, the recruitment of inflammatory cells into the lungs was inhibited. Administration of 1 to ovalbumin-sensitized guinea pigs intraperitoneally blocked airway resistance and inhibited the recruitment of inflammatory cells.

The design, synthesis, and biological activity of novel alpha(4)beta(1) and alpha(4)beta(7) integrin antagonists, containing a bridged azabicyclic nucleus, are reported. Conformational analysis of targets containing an azabicyclo[2.2.2]octane carboxylic acid and known integrin antagonists indicated that this azabicycle would be a suitable molecular scaffold. Variation of substituents on the pendant arylsulfonamide and phenylalanine groups resulted in potent alpha(4)beta(1)-selective and dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. Potent compounds 11i, 11h, and 14 were effective in the antigen-sensitized sheep model of asthma.

The synthesis and biological testing of a novel series of nonpeptide vasopressin receptor antagonists, containing a bridged bicyclic nucleus, are reported. Variation of substituents (R(1)-R(3)) in general formula 3, and the configuration of the stereocenter, resulted in potent V(2)-selective (e.g., 5) and balanced dual V(1a)/V(2) (e.g., 10) compounds. Data from receptor binding, cell-based functional, and in vivo assays are presented [corrected]

The syntheses of 11-ethyl and 11-cyclopropyldipyrido[2,3- b :3′,2′- f ]azepines, analogs of the HIV-1 reverse transcriptase inhibitor nevirapine 1 , are described. These compounds exhibit potency equivalent to nevirapine in the inhibition of wild-type and some mutant RT enzymes.

We report data for a pair of singlestack all-phosphorescent 15 × 15 cm 2 organic light emitting-diode (OLED) light panels with high efficacy, long lifetime, and very low operating temperature: Panel 1 has 62 lm∕W efficacy, CRI ¼ 81 and lifetime to LT70 ¼ 18;000 h at 1000 cd∕m 2 , while Panel 2 has 58 lm∕W efficacy, CRI ¼ 82 and lifetime to LT70 ¼ 30;000 h at 1000 cd∕m 2 . Operating at a higher luminance of 3000 cd∕m 2 , Panel 2 has 49 lm∕W efficacy with lifetime to LT70 ¼ 4000 h. Excellent panel lifetime is enabled by a stable light blue phosphorescent materials system. Panel temperatures are within 10°C of ambient temperature at 3000 cd∕m 2 . Panel 2 was further used as a building block to demonstrate an all-phosphorescent OLED luminaire for under-cabinet lighting applications. Operating at approximately 3000 cd∕m 2 , theluminairedelivers570lmwith52 lm∕Wtotalsystemefficacy,CRI ¼ 86andCCT ¼ 2940 K.© 2012 Society of Photo-Optical Instrumentation Engineers (SPIE). (DOI: 10.1117/1.JPE.2.021205)

In this work we report exceptional efficacy, lifetime and color stability for all-phosphorescent white stacked organic light-emitting devices (SOLED®s). We report data for all-phosphorescent white SOLED pixels with two emissive units connected in series by a charge generation layer (CGL). At 3,000 cd/m 2 , efficacy = 54 to 56 lm/W and lifetime to 70% of initial luminance LT70 ≈ 20,000 h, with color rendering index (CRI) = 82 to 83 and chromaticity meeting Energy Star criteria. We further report data for a 15 cm×15 cm white SOLED panel that operates at 3,000 cd/m 2 with 48 lm/W efficacy, CRI = 86 and chromaticity meeting Energy Star criteria. The panel has extremely low operating temperature that is only 6.4°C above ambient, and exceptional lifetime of LT70 ≈ 13,000 h when operated at 3,000 cd/m 2 .

— In this paper, the design criteria for scaling up from small-area organic light-emitting-diode (OLED) pixels to large-area OLED light panels is described. Particular focus is placed on using phosphorescent OLEDs (PHOLEDs) to maximize panel efficacy and uniformity and minimize operating temperature. Data for a pair of all-phosphorescent 15 × 15 cm OLED light panels are also presented: Panel 1 has 62-lm/W efficacy, CRI = 81, CCT = 3180K, and lifetime to LT70 = 18,000 hours at 1000 cd/m2 and Panel 2 has 58-lm/W efficacy, CRI = 82, CCT = 2640K, and lifetime to LT70 = 30,000 hours at 1000 cd/m2. Operating at a 3000 cd/m2 (7740 lm/m2), Panel 2 has 49-lm/W efficacy with lifetime to LT70 = 4000 hours. Excellent panel lifetime is enabled by a stable light-blue phosphorescent materials system and by the use of efficient phosphorescent emitters that ensure very low panel temperature without any additional thermal management.

A novel method for the efficient synthesis of 1,8-diazabicyclo[4.3.0]non-3-ene-7,9-diones 5 (bicyclic hydantoins) starting from ureas or Z-protected aminoacids has been developed. The key step is a ring-closing metathesis (RCM) reaction of diallyl substituted hydantoins 3 catalyzed by the ruthenium-carbene complex bis(tricyclohexylphosphine)benzilidine ruthenium dichloride ( 4 ).

Intramolecular carbon-hydrogen insertion of metal carbenes generated by catalytic diazo decomposition of diazocarbonyl compounds is a facile methodology for carbon-carbon bond formation.1-3 Although there are notable exceptions,& five- membered-ring formation is preferred,7J and regioselectivity is generally subject to defined electronic effects.9JO Enantiocontrol has recently been achieved with selected substrates through the use of chiral or homochiral dirhodium(I1) carboxamides,11J2 or carbo~ylates,~~J~ but even with dirhodium(I1) tetrakis[methyl

Secondary benzylic and allylic diazoacetates undergo dirhodium(II)-catalysed diazo decomposition to form, competitively or exclusively, ketone and vinylidene products from intramolecular hydride abstraction in catalyst ligand-dependent molar ratios.