Syntheses of Aryl Thioethers via Aromatic Substitution of Aryl Halides at 0 to 25 °C.

In this study, we developed mild conditions for the synthesis of an aryl thioether via aromatic substitution using aryl halides, which is a process that has rarely been studied. Aromatic substrates such as aryl fluorides activated with a halogen substituent are difficult to use for substitution reactions, but by using 18-crown-6-ether as an additive, these were successfully converted to their corresponding thioether products. Under the conditions we established, in addition to a wide variety of thiols, less-toxic and odorless disulfides could be used directly as nucleophiles at 0 to 25 °C.

Etherification via Aromatic Substitution on 1,3-Disubstituted Benzene Derivatives.

In this study, we developed a method for etherification via aromatic substitution at the ipso-position of an electron-withdrawing group (EWG) that exists at the meta-position of another EWG. To heighten the reactivity of the substitution reaction, we added a t-BuOK solution in tetrahydrofuran (THF) to a mixture of an aromatic substrate, an alcoholic nucleophile, and 18-crown-6-ether in dimethylformamide (DMF), which proved to be a particularly effective sequence. Under the conditions we established, aromatic substrates that are difficult to use for substitution reactions such as aryl fluorides activated with either a bromide or a chloride substituent were aptly converted to corresponding ether products at 25 °C. This reaction would potentially be useful to link an alcohol to an additional functional group through further chemical transformations via the use of a residual bromide or chloride substituent.

Aryl Ether Syntheses via Aromatic Substitution Proceeding under Mild Conditions.

In this study, mild conditions for aromatic substitutions during the syntheses of aryl ethers were developed. In the reaction conditions, the choices of solvent, base, and the sequence for the addition of the reagents proved important. A wide variety of alcohols were used directly as nucleophiles and smoothly reacted with aryl chlorides that possessed either a nitro or a cyano group at either the ortho- or para-position. Controlled experiments we performed suggested that the reaction underwent a charge-transfer process mediated by a combination of DMF and tert-BuOK.

Influences of Phenyl Rings on NHC Ligands with Bicyclic Architectures.

In addition to phosphanes, olefins, amines, and amides, over the past two decades N-heterocyclic carbene (NHC) has emerged as a useful alternative ligand. Based on a number of derivatization studies on NHC ligands, imidazol-2-ylidene and imidazolin-2-ylidene became the standard heterocyclic form, and bulky substituents have commonly been introduced on the nitrogen(s) adjacent to carbenic carbons. Our group previously developed NHCs equipped with noncarbenic carbons with a bicyclic architecture that gives them unique steric properties that make them bulky but accessible. In this study, we synthesized a novel type of NHC ligand that possesses a bicyclo[2.2.1]heptane architecture, and we compared five derivatives using copper-catalyzed allylic arylations with aryl Grignard reagents. The regioselectivity of the substitution obviously indicates that a phenyl ring over an active site has a characteristic effect on the resultant copper catalysts when γ-substitution is the major pathway.

An N-Heterocyclic Carbene-Nickel Half-Sandwich Complex as a Precatalyst for Suzuki-Miyaura Coupling of Aryl/Heteroaryl Halides with Aryl/Heteroarylboronic Acids.

A nickel half-sandwich complex supported by our original NHC ligand was developed as a robust precatalyst for Suzuki-Miyaura cross-coupling. The addition of PPh3 was a crucial element in the suppression of side reactions and in accelerating the cross-coupling reaction. By employing the optimal conditions, aryl-aryl, heteroaryl-aryl, and heteroaryl-heteroaryl couplings were achieved.

A dramatic synergistic effect of a flexible achiral linker on a rigid chiral cis-1,2-diamine bifunctional organocatalyst.

The combination of a "rigid" chiral bicyclic cis-1,2-diamine skeleton with steric bulkiness and a "flexible" achiral linker was newly designed as a bifunctional organocatalyst framework and it showed excellent catalytic activity of up to 0.05 mol%, accompanied by the reversal of enantioselection depending on the position of the linker, in an amine-thiourea organocatalyzed asymmetric Michael reaction.

A Study of the Strength of a Template Molecule-A Functional Monomer Interaction That Affects the Performance of Molecularly Imprinted Polymers and Its Application to Chiral Amplification.

A novel type of molecularly imprinted polymer (MIP), N-benzoyl-(S)-valine anilide-imprinted polymer (IP-2), was prepared using hydrogen-bonding interactions as a main force in the pre-polymerization step. The performance of the IP-2 was evaluated via batch procedure and compared with a (S)-valine anilide-imprinted polymer (IP-1) that was prepared using an ionic interaction that is stronger than hydrogen bonding. Although both polymers showed a preferential adsorbability for (S)-amino acid derivatives, different performances were observed in terms of adsorbability and enantioselectivity. In addition, the IP-2 was able to recognize the enantiomer of a valine-derived chiral catalyst. This phenomenon was applied to a chiral amplification reaction, and a highly selective asymmetric Mannich-type amination was achieved using the combination of a racemic catalyst and a MIP.

Safety analysis of zolpidem in elderly subjects 80 years of age or older: adverse event monitoring in Japanese subjects.

OBJECTIVES: Prescriptions of non-benzodiazepine sedative hypnotics, e.g. zolpidem, for insomnia in elderly subjects 80 years of age or older have markedly increased in the USA. However, a meta-analysis of the risks and benefits of hypnotics in older people reported the benefits associated with hypnotics use are outweighed by the risks. This study aimed to investigate the safety of zolpidem administration in extremely old elderly. METHODS: The prevalence of adverse reactions to zolpidem was investigated in a subpopulation of participants in the Drug Event Monitoring project of the Japan Pharmaceutical Association. A total of 1011 (316 males and 695 females) zolpidem users, including 261 (25.8%) subjects 80 years of age or older without cognitive or mental complications, were eligible for the analysis. RESULTS: The elderly and female patients were prescribed significantly lower doses of zolpidem than their counterparts. Adverse symptoms after the last prescription were reported by 60 (5.9%) subjects. The most common symptoms were impaired balance and/or falls (1.8%) and morning drowsiness (1.3%). The multiple logistic regression analyses showed that subjects 80 years of age or older were at lower risk of adverse symptoms (odds ratio 0.39, 95% confidence intervals: 0.17-0.88). CONCLUSION: Our findings in a real-world clinical setting suggest that low-dose zolpidem can be safely prescribed to subjects 80 years of age or older without cognitive or mental complications.

A Bicyclic N-Heterocyclic Carbene as a Bulky but Accessible Ligand: Application to the Copper-Catalyzed Borylations of Aryl Halides.

Imidazol-2-ylidene and imidazolin-2-ylidene are frequently employed as the core structures of N-heterocyclic carbene (NHC) ligands, because these have two nitrogen sites adjacent to carbenic carbons. The electronic and steric effects of N-substituents to a bound metal have been aptly studied, and bulky substituents have commonly been introduced on nitrogen(s). However, too much bulkiness can sometimes result in an ineffectiveness of the hindered substrates. In this study, we thoroughly compared our original bicyclic NHC, which has bulky substituents on its noncarbenic carbons, with ubiquitous NHC ligands to probe its steric properties. A well-defined bicyclic NHC-CuCl complex was successfully synthesized and applied to the copper-catalyzed borylations of aryl halides at ambient temperature. A bicyclic NHC-CuCl proved to be a better catalyst than commonly used NHC ligand-Cu complexes, particularly for sterically hindered substrates, which suggested that the bicyclic NHC ligand offered a bulky but accessible environment to the bound copper.

Absence of gargling affects topical adverse symptoms caused by inhaled corticosteroids in females.

OBJECTIVE: Topical adverse events caused by inhaled corticosteroids (ICS) are suspected to be more common in females. Although gargling or mouth washing after inhalation is recommended as the gold standard for preventing adverse events due to ICS, the preventive effects of this method have not been confirmed in real-world studies. This study aimed to examine the association between gargling or mouth washing and the incidence of topical adverse symptoms in males and females in daily practice. METHODS: We analyzed a subpopulation of participants in the Drug Event Monitoring (DEM) project of the Japan Pharmaceutical Association. An anonymous survey was performed in February 2010, to assess the self-perception of topical adverse symptoms during ICS use by conducting interviews of pharmacists using structured questionnaires. RESULTS: A total of 412 males and 480 females were included. The patients used a dry-powder inhaler (DPI) (71.2%), pressurized meter-dose inhaler (pMDI) with (7.5%) or without (16.6%) a spacer or inhalation solution (4.7%) as the delivery device. Topical adverse symptoms occurring after previous prescriptions were reported by 41 (4.6%) subjects. The common symptoms were hoarseness, stomatitis and dry mouth (1.3%, 1.1% and 1.1%, respectively). In the multiple regression model, the presence of symptoms was found to be significantly associated with the absence of gargling or mouth washing after inhalation [adjusted odds ratio (OR): 3.75, 95% confidence interval (95%CI): 1.33-10.59, p = 0.012]. When stratified by gender, the absence of gargling or mouth washing was identified to be a risk factor in females only (OR: 4.32, 95%CI: 1.11-16.87, p = 0.035) and not in males (OR: 3.26, 95%CI: 0.65-16.33, p = 0.151). Furthermore, the association between the absence of gargling or mouth washing and the incidence of topical adverse symptoms was significant in the patients using DPI (OR: 4.85, 95%CI: 1.66-14.14, p = 0.004), but not in those using the other devices. CONCLUSIONS: In this study, the absence of gargling or mouth washing after ICS use was associated with topical adverse symptoms, especially in females. To achieve good adherence to treatment and improve the quality of life, female patients with asthma should strictly practice the gargling or mouth washing method.

A study of the various factors that affect the properties of molecularly imprinted polymers.

We evaluated the adsorbability and selectivity of (S)-valine anilide imprinted molecularly imprinted polymer (MIP) using a batch procedure that is both independent and precise. This study revealed important information about the relationship between the performance of MIPs and experimental factors such as the components of MIP synthesis and a reaction solvent. Herein, we also describe the problems associated with the preparation of a "non-imprinted polymer," which is often used to evaluate the effect of a template molecule, and we propose a new type of reference polymer, "blank polymer."

A simple, iron-catalyzed, pyridine-assisted hydrogen peroxide epoxidation system.

A simple and inexpensive system comprised of H(2)O(2)-pyridine-FeCl(3)·6H(2)O for the catalysis of olefin epoxidation was established. Intriguingly, the reactivity of this system greatly depends on the amounts of pyridine. Various substrates, including aromatic and aliphatic olefins, were epoxidized by this simple system in moderate to excellent yields.

Sterically congested, "roofed" ß-iminodisulfides as new chiral ligands for palladium-catalyzed, asymmetric allylic alkylation.

The preparation of a new class of "roofed" ß-iminodisulfides from sterically congested, conformationally rigid chiral 2-thiazolidinones is described. A functional survey of palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate proved that symmetrical "roofed" ß-iminodisulfides are efficient chiral ligands, showing enantioselectivity opposite that associated with chiral "roofed" ß-iminothioether ligands.

Higher risk of sulfonylurea-associated hypoglycemic symptoms in women with type 2 diabetes mellitus.

BACKGROUND: Although some evidence suggests that women may be at greater risk for hypoglycemia, no conclusion has been reached, and female sex has not been taken into account in antidiabetic drug-induced hypoglycemia. This study aimed to determine whether females are at a higher risk of sulfonylurea (SU)-associated hypoglycemia in daily clinical practice. METHODS: The incidence of adverse reactions of SU was investigated in 2119 Japanese patients who participated in the Drug Event Monitoring project of the Japan Pharmaceutical Association, which was conducted in Kumamoto prefecture. A multiple logistic regression analysis was used to determine the association between the incidence of hypoglycemic symptoms and female sex, with adjusted odds ratios (ORs) and 95 % confidence intervals (95 % CIs). RESULTS: Female sex was found to be significantly associated with hypoglycemic symptoms (female vs. male; OR 2.04; 95 % CI 1.22-3.41; p = 0.007). The concomitant use of other antihyperglycemic agents (≥2 vs. 0 concomitant drug; OR 2.80; 95 % CI 1.17-6.67; p = 0.021), a shorter duration of diabetes medication (<3 vs. ≥24 months; OR 4.14; 95 % CI 1.06-16.14; p = 0.041) and a longer follow-up period (OR 1.02; 95 % CI 1.00-1.04; p = 0.041) were identified as risk factors for hypoglycemia that were specific to females. CONCLUSION: To the best of our knowledge, this is the first report to focus on female sex as a potential risk factor for SU-associated hypoglycemia. Our results support the importance of individualized therapy, which may be effective not only for reducing the risk of hypoglycemia in females but also the risk of its consequences, such as cardiovascular disease, dementia and increased mortality.

Enantioselective aldol reaction of trimethoxysilyl enol ether catalyzed by lithium binaphtholate.

[reaction: see text] An aldol reaction of trimethoxysilyl enol ether catalyzed by lithium binaphtholate, in which water serves as an additive and plays a pivotal role in stereoselectivities, was developed. This is the first example of an aldol reaction of trimethoxysilyl enol ether catalyzed by a chiral base.

Younger females are at greater risk of vasodilation-related adverse symptoms caused by dihydropyridine calcium channel blockers: results of a study of 11,918 Japanese patients.

BACKGROUND AND OBJECTIVE: Adequate control of blood pressure in younger females is of crucial importance, because they are at higher risk of hypertensive target organ damage compared with males of similar age. In addition, female sex is a risk factor for adverse effects of antihypertensive drugs, especially dihydropyridines. This study set out to assess the incidence of adverse reactions during dihydropyridine use in a real-life clinical setting, focusing on the influence of female sex and age. METHODS: The incidence of adverse reactions to dihydropyridine calcium channel blockers were investigated in 11,918 Japanese patients who participated in the Drug Event Monitoring project of the Japan Pharmaceutical Association conducted in Kumamoto prefecture. A multiple logistic regression analysis was used to determine the association between the incidence of adverse symptoms and female sex, with adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Vasodilation-related adverse symptoms occurred significantly more often in females than in males (OR 1.87, 95% CI 1.28-2.71, p=0.001). Furthermore, among females only, the younger age group (<50 years) complained of vasodilation-related symptoms more frequently (OR 2.39, 95% CI 1.02-5.59, p=0.045) and the older age group (≥80 years) complained of vasodilation-related symptoms less frequently (OR 0.56, 95% CI 0.33-0.95, p=0.030) than the middle age group (50-79 years). CONCLUSION: To the best of our knowledge, this is the first report showing that younger females are at high risk for vasodilation-related adverse symptoms during dihydropyridine use in a real-life clinical setting. These results should be verified in clinical studies using larger samples of young patients and more parameters.

Risk factors for adverse symptoms during dipeptidyl peptidase-IV inhibitor therapy: a questionnaire-based study carried out by the Japan Pharmaceutical Association Drug Event Monitoring project in Kumamoto Prefecture.

BACKGROUND: Meta-analyses of randomized clinical trials have reported that dipeptidyl peptidase IV (DPP-4) inhibitors are well tolerated and that the incidence of hypoglycemia with the use of DPP-4 inhibitors is similar to that observed with placebos. However, in general, provider-oriented methods using medical record reviews offer lower rates of non-serious, symptomatic adverse drug reactions (ADRs) than patient-oriented methods. Moreover, severe hypoglycemia occurred in three clinical trials using sitagliptin, but in two of these trials this phenomenon has been previously described only in the drug application data in the US. OBJECTIVE: The aim of this study was to assess the profile of patient-reported symptomatic ADRs under DPP-4 inhibitor therapy and to detect risk factors for hypoglycemic and non-hypoglycemic adverse symptoms in daily clinical practice. METHODS: We analyzed a subpopulation of participants in the Drug Event Monitoring (DEM) project of the Japan Pharmaceutical Association. An anonymous survey was conducted in February 2012 to assess the self-perception of adverse symptoms during a median 28 (4-88) days after the last prescription of DPP-4 inhibitors by means of interviews of pharmacists using structured questionnaires. RESULTS: A total of 864 males and 686 females were included. The prescribed DPP-4 inhibitors included sitagliptin (75.4 %), alogliptin (15.5 %), vildagliptin (8.8 %) and linagliptin (0.3 %). Mild hypoglycemic symptoms were reported by 34 individuals (2.2 %) receiving monotherapy of sitagliptin (10/402) or alogliptin (3/65), or combination therapy of sitagliptin (15/767) or alogliptin (6/176) with other hypoglycemic agents. In the multiple regression model, hypoglycemic symptoms were found to be significantly associated with liver disease, female sex and alcohol consumption more than three times per week. Non-hypoglycemic symptoms were reported by 57 individuals (3.7 %), the most common symptoms of which were gastrointestinal symptoms (2.1 %). Combination therapy was only found to be associated with nonhypoglycemic symptoms. CONCLUSIONS: The present study suggested that hypoglycemic symptoms under therapy with sitagliptin or alogliptin may be associated with liver disease, female sex and alcohol consumption, all of which are potentially capable of leading to poor gluconeogenesis because they decrease the counter-regulatory hormonal responses to hypoglycemia.

Aging enhances maceration-induced ultrastructural alteration of the epidermis and impairment of skin barrier function.

BACKGROUND: Skin maceration is recognized as a risk factor for the development of certain skin lesions. In health care settings, incontinence-associated skin maceration is highly prevalent in the elderly. However, the effect of senescence on maceration has not been fully elucidated. OBJECTIVE: To reveal the enhancement of the maceration-induced ultrastructural alteration and barrier function of the epidermis by aging. METHODS: Skin maceration was reproduced by exposure to agarose gel in human and rat. The ultrastructural alterations in human and rat tissue were observed by transmission electron microscopy. The skin barrier function was evaluated by noninvasive methods in human, and by the transdermal penetration of small- and large-fluorescent molecules in rat. In order to reveal the effect of aging on the skin maceration, we compared these parameters between young and aged rats. RESULTS: In macerated skin, we observed expansion of the interstices of the stratum corneum, spinosum, and basale of the epidermis; disruption of the intercellular lipid structure in the stratum corneum; a decreased number of cell processes in the stratum spinosum and basale. The transdermal penetration test in the rat using two types of fluorescein indicated that maceration disrupted skin barrier function. Furthermore, senescence-enhanced ultrastructural and functional alterations were revealed in the rodent studies. CONCLUSION: This study demonstrates that aging enhances skin maceration. Considering that maceration is a risk factor for the skin damage, the development of technology to promote skin barrier recovery after maceration in the elderly is warranted.