COMfort Eye Trial (COMET) results - a non-inferiority, randomized, investigator-masked, two-parallel group, phase III clinical trial, to evaluate the efficacy and safety of a preservative free formulation of latanoprost versus a reference drug (Xalatan®) in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT).

AIM: To prove non-inferiority of preservative-free (PF) latanoprost versus benzalkonium chloride (BAK) containing latanoprost in lowering intraocular pressure (IOP) in primary open-angle glaucoma (POAG) or ocular hypertension (OHT) patients. DESIGN AND METHODS: This phase III, randomized, investigator-masked trial primarily aimed to demonstrate non-inferiority of YSLT PF latanoprost 50 µg/ml (Yonsung GmbH) to latanoprost (Xalatan®) 50 µg/ml (Pfizer) in reducing IOP from Baseline to Week 12. Secondary aims included conjunctival hyperemia evaluation and difference in ocular comfort levels. Total 130 patients with POAG or OHT were enrolled and randomized (1:1 ratio) to receive YSLT or latanoprost, instilling eye drops daily for 12 weeks. RESULTS: At Week 12, mean diurnal IOP reduction was -7.67 ± 2.104 mmHg for YSLT PF latanoprost and -7.77 ± 2.500 for latanoprost. The 97.5% confidence interval of between-treatment group difference in IOP reduction from Baseline to Week 12 was [-0.846, +∞), not crossing the non-inferiority margin of -1.5 mmHg. A low incidence of mild topical treatment emergent adverse events (TEAEs) was observed in both groups, while no serious TEAEs were reported. CONCLUSIONS: YSLT eye drops demonstrated non-inferiority to latanoprost in reducing IOP. Both products were well tolerated without serious TEAEs reported.

Copper-promoted dehydrosulfurative carbon-nitrogen cross-coupling with concomitant aromatization for synthesis of 2-aminopyrimidines.

Copper-promoted dehydrosulfurative C-N cross-coupling of 3,4-dihydropyrimidin-1H-2-thione with amine accompanied by concomitant aromatization to generate 2-aryl(alkyl)aminopyrimidine derivatives is described. The reaction proceeded well with a wide range of thiono substrates and aryl/aliphatic amines as the coupling partners, offering efficient access to biologically and pharmacologically valuable 2-aryl(alkyl)aminopyrimidines with rapid diversification.

Oxidative Dehydrosulfurative Carbon-Oxygen Cross-Coupling of 3,4-Dihydropyrimidine-2-thiones with Aryl Alcohols.

A Pd-catalyzed/Cu-mediated oxidative dehydrosulfurative carbon-oxygen cross-coupling reaction of 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) with aryl alcohols is described. Due to the ready availability of diverse DHPMs and aryl alcohols, the reaction method offers facile access to biologically and pharmacologically valuable 2-aryloxypyrimidine derivatives with rapid diversification.

Oxidative Dehydrosulfurative Cross-Coupling of 3,4-Dihydropyrimidine-2-thiones with Alkynes for Access to 2-Alkynylpyrimidines.

A reaction method is described for the one-step synthesis of 2-alkynylpyrimidines from 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) via dehydrosulfurative Sonogashira cross-coupling with concomitant oxidative dehydrogenation using a Pd/Cu catalytic system. Together with the ready availability of DHPMs possessing various substituents at the C4-C6 positions, this transformation offers rapid and general access to diverse 2-alkynylpyrimidine derivatives.

Boric Ester and Thiourea as Coupling Partners in a Copper-Mediated Oxidative Dehydrosulfurative Carbon-Oxygen Cross-Coupling Reaction.

A copper-mediated oxidative dehydrosulfurative carbon-oxygen cross-coupling reaction with boric ester and six-membered cyclic thiourea for single-step production of densely substituted 2-alkoxypyrimidines incorporated in a privileged scaffold is described. This is the first demonstration of boric ester acting as an alkoxy donor in a metal-catalyzed coupling reaction to produce ether. The reaction method offers a shortcut for producing 2-alkoxypyrimidine derivatives with rapid diversification and expands the utility of boric ester and the scope of Liebeskind-Srogl-type reactions.

Dehydrosulfurative C-N Cross-Coupling and Concomitant Oxidative Dehydrogenation for One-Step Synthesis of 2-Aryl(alkyl)aminopyrimidines from 3,4-Dihydropyrimidin-1H-2-thiones.

A method for the synthesis of 2-aryl(alkyl)aminopyrimidines from readily available 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) via dehydrosulfurative C-N cross-coupling and concomitant oxidative dehydrogenation under a Pd/Cu catalytic system is described. This reaction protocol provides unprecedented diversity of fully substituted 2-aryl(alkyl)aminopyrimidines in a single step from a wide range of DHPMs and amine coupling partners.

Chemoselective intramolecular alkylation of the Blaise reaction intermediates: tandem one-pot synthesis of exo-cyclic enaminoesters and their applications toward the synthesis of N-heterocyclic compounds.

The intramolecular alkylative reactivity and N/C selectivity of the various Blaise reaction intermediates, which are formed from the reaction of the Reformatsky reagents with ω-chloroalkyl nitriles, did not reach the synthetic potential as an entry to exo-cyclic enaminoesters. To circumvent this issue, various additives were investigated, among which the addition of NaHMDS dramatically enhanced the reactivity and N/C selectivity. This modification provided a highly efficient route for the synthesis of various N-fused heterocyclic compounds, as it requires only two steps from nitriles.

Tandem Blaise-Nenitzescu reaction: one-pot synthesis of 5-hydroxy-α-(aminomethylene)benzofuran-2(3H)-ones from nitriles.

In contrast to the reaction of benzoquinones with ß-enaminoesters providing indoles (Nenitzescu reaction), the tandem one-pot reaction of the Blaise reaction intermediate, zinc bromide complex of ß-enaminoesters, with benzoquinone affords 5-hydroxy-α-(aminomethylene)benzofuran-2(3H)-ones in good to excellent yields (tandem Blaise-Nenitzescu reaction).

One-pot synthesis of 2-pyridones via chemo- and regioselective tandem Blaise reaction of nitriles with propiolates.

The Blaise reaction intermediate, generated in situ from Reformatsky reagent and nitrile, reacted with propiolates in a chemo- and regioselective manner to afford 2-pyridone derivatives in good to excellent yields.

Tandem Blaise-alkenylation with unactivated alkynes: one-pot synthesis of alpha-vinylated beta-enaminoesters from nitriles.

The in situ generated Blaise reaction intermediate, a zinc bromide complex of beta-enaminoester, reacts with various unactivated terminal alkynes and an internal alkyne under mild conditions to afford alpha-vinylated beta-enaminoesters in good to excellent yields.

An effective and general method for the highly regioselective synthesis of 1-phenylpyrazoles from beta-enaminoketoesters, tandem Blaise-acylation adducts.

An effective and general route for the regioselective synthesis of 1-phenylpyrazoles has been developed from beta-enaminoketoesters prepared by tandem Blaise-acylation. This method is applicable to a very broad range of substrates, generating a diverse set of 3-aryl-5-alkyl, 3-alkyl-5-aryl, 3,5-diaryl, and 3,5-dialkyl substituted pyrazoles regioselectively. The dichotomous regioselective synthesis of isotopically discriminated 3-CD(3)-5-CH(3) and 3-CH(3)-5-CD(3) substituted pyrazoles showcases the power of this protocol.

The first chemoselective tandem acylation of the Blaise reaction intermediate: a novel method for the synthesis of alpha-acyl-beta-enamino esters, key intermediate for pyrazoles.

The Blaise reaction intermediate, a zinc bromide complex of beta-enamino ester, could be activated in situ by addition of a stoichiometric or catalytic amount of n-BuLi to allow chemoselective tandem C2-acylation providing alpha-acyl-beta-enamino esters, which are valuable intermediates for the syntheses of tri- and tetrasubstituted pyrazoles.

Nucleophilic fluorination of triflates by tetrabutylammonium bifluoride.

Careful examination of nucleophilicity, basicity, and leaving group ability led us to discover the nucleophilic fluorination of triflates by weakly basic tetrabutylammonium bifluoride, which provides excellent yields with minimal formation of elimination-derived side products. Primary hydroxyl groups as well as secondary hydroxyl groups in acyclic chains or in five-membered rings are excellent substrates, whereas benzylic and aldol-type secondary hydroxyl groups give poor yields as a result of the instability of their triflates.

A new type of self-supported, polymeric Ru-carbene complex for homogeneous catalysis and heterogeneous recovery: synthesis and catalytic activities for ring-closing metathesis.

A novel 2nd generation Grubbs-type catalyst tethering an isopropoxystyrene has been synthesized and automatically polymerized in solution to form a self-supported polymeric Ru-carbene complex, which catalyzed ring-closing metathesis homogeneously, but was recovered heterogeneously.

The decarboxylative Blaise reaction.

Reaction of aryl nitriles with potassium ethyl malonate in the presence of zinc chloride and a catalytic amount of Hünig's base provided beta-amino acrylates in moderate to good yield. Compared to the classical Blaise reaction, this reaction is safer (endothermic), devoid of lacrimatory reagent, and is possible with 0.5-1.0 equiv of zinc chloride.