Process Development of a CRF₁ Receptor Antagonist Based on the Selective Chlorination of a Benzimidazolone via Chlorine Migration

A practical synthesis of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1<i>H</i>-benzo­[<i>d</i>]­imidazole <b>1</b>, a novel corticotropin-releasing factor 1 (CRF₁) receptor antagonist, has been developed. The key chemical transformations were (1) a novel regioselective chlorination at the 4-position of a benzimidazolone intermediate with 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione in the presence of sodium tertiary butoxide via a chlorine migration mechanism (<i>N</i>-3 to <i>C</i>-4) and (2) a one-pot, three-step dehydroxylation sequence (dehydration, isomerization, and hydrogenation) of a benzylic tertiary alcohol in the presence of <i>p</i>-toluenesulfonic acid and a Pd catalyst. The endgame was also optimized for quality and yield improvement. The chromatography-free six-step process starting from a commercially available material afforded <b>1</b> in 35% overall yield and greater than 99% purity

Development of a Practical Synthesis of a Peripherally Selective Noradrenaline Reuptake Inhibitor Possessing a Chiral 6,7-<i>trans</i>-Disubstituted-1,4-oxazepane as a Scaffold

A practical synthesis of a peripherally selective noradrenaline reuptake inhibitor that has a chiral 6,7-<i>trans</i>-disubstituted-1,4-oxazepane as a new class of scaffold is described. The amino alcohol possessing the desired stereochemistry was obtained with excellent dr and ee, starting from a commercially available aldehyde via a Morita–Baylis–Hillman reaction, Michael addition, isolation as maleic acid salt, reduction, and diastereomeric salt formation with (+)-10-camphorsulfonic acid. The desired single stereoisomer obtained at an early stage of the synthesis was used for seven-membered ring formation in fully telescoped processes, providing the chiral 6,7-<i>trans</i>-disubstituted-1,4-oxazepane efficiently. In addition to controls of dr and ee of the chiral 1,4-oxazepane, and control of <i>N</i>,<i>O</i>-selectivity in S_N2 reaction of the intermediate mesylate with a pyridone derivative, finding appropriate intermediates that were amenable to isolation and upgrade of purity enabled a practical chiral HPLC separation-free, column chromatograph-free synthesis of the drug candidate with excellent chemical and optical purities in a higher overall yield

Chronic Pain in the Japanese Community--Prevalence, Characteristics and Impact on Quality of Life.

Chronic pain is recognized as a public health problem that affects the general population physically, psychologically, and socially. However, there is little knowledge about the associated factors of chronic pain, such as the influence of weather, family structure, daily exercise, and work status.This survey had three aims: 1) to estimate the prevalence of chronic pain in Japan, 2) to analyze these associated factors, and 3) to evaluate the social burden due to chronic pain.We conducted a cross-sectional postal survey in a sample of 6000 adults aged ≥20 years. The response rate was 43.8%.The mean age of the respondents was 57.7 years (range 20-99 years); 39.3% met the criteria for chronic pain (lasting ≥3 months). Approximately a quarter of the respondents reported that their chronic pain was adversely influenced by bad weather and also oncoming bad weather. Risk factors for chronic pain, as determined by a logistic regression model, included being an older female, being unemployed, living alone, and no daily exercise. Individuals with chronic pain showed significantly lower quality of life and significantly higher psychological distress scores than those without chronic pain. The mean annual duration of absence from work of working-age respondents was 9.6 days (range 1-365 days).Our findings revealed that high prevalence and severity of chronic pain, associated factors, and significant impact on quality of life in the adult Japanese population. A detailed understanding of factors associated with chronic pain is essential for establishing a management strategy for primary care

EQ-5D value sets reported by clinical studies in Japan.

<p>EQ-5D value sets reported by clinical studies in Japan.</p

Influence of chronic pain on health-related quality of life and psychological distress.

<p>Statistical analysis undertaken with independent <i>t</i> test; mean values are shown within the columns, error bars represent standard deviation.</p

Social and demographic characteristics of all respondents, and those with or without chronic pain.

<p>^a Full-time workers were categorized as: primary (agriculture, forestry and fishery); secondary (mining, manufacturing and construction); or tertiary (service industries).</p><p>Social and demographic characteristics of all respondents, and those with or without chronic pain.</p