Two Routes to 4‑Fluorobenzisoxazol-3-one in the Synthesis of a 5‑HT₄ Partial Agonist

A potent 5-HT₄ partial agonist, <b>1</b> (PF-04995274), targeted for the treatment of Alzheimer’s disease and cognitive impairment, has been prepared on a multi-kilogram scale. The initial synthetic route, that proceeded through a 4-substituted 3-hydroxybenzisoxazole core, gave an undesired benzoxazolinone through a Lossen-type rearrangement. Route scouting led to two new robust routes to the desired 4-substituted core. Process development led to the efficient assembly of the API on a pilot plant scale under process-friendly conditions with enhanced throughput. In addition, crystallization of a hemicitrate salt of the API with pharmaceutically beneficial properties was developed to enable progression of clinical studies

Long Directional Interactions (LDIs) in Oligomeric Cofacial Silicon Phthalocyanines and Other Oligomeric and Polymeric Cofacial Phthalocyanines

Crystal structures have been determined for the three-member set of cofacial silicon phthalocyanines, ((<i>n</i>-C₆H₁₃)₃SiO)­[SiPcO]_1–3(Si­(<i>n</i>-C₆H₁₃)₃). The staggering angles between adjacent rings in the dimer and trimer of this set are ∼16°. The interactions leading to these angles have been investigated by the atoms-in-molecules (AIM) and reduced-density-gradient (RDG) methods. The results show that long directional interactions (LDIs) are responsible for these angles. A survey of the staggering angles in various cofacial phthalocyanines described in the literature has revealed the existence of significant LDIs in a number of them. It is apparent that in many cases the ability of LDIs to dominate the forces giving rise to the staggering angles observed in cofacial phthalocyanines depends on their inter-ring separations

Long Directional Interactions (LDIs) in Oligomeric Cofacial Silicon Phthalocyanines and Other Oligomeric and Polymeric Cofacial Phthalocyanines

Crystal structures have been determined for the three-member set of cofacial silicon phthalocyanines, ((<i>n</i>-C₆H₁₃)₃SiO)­[SiPcO]_1–3(Si­(<i>n</i>-C₆H₁₃)₃). The staggering angles between adjacent rings in the dimer and trimer of this set are ∼16°. The interactions leading to these angles have been investigated by the atoms-in-molecules (AIM) and reduced-density-gradient (RDG) methods. The results show that long directional interactions (LDIs) are responsible for these angles. A survey of the staggering angles in various cofacial phthalocyanines described in the literature has revealed the existence of significant LDIs in a number of them. It is apparent that in many cases the ability of LDIs to dominate the forces giving rise to the staggering angles observed in cofacial phthalocyanines depends on their inter-ring separations

Long, Directional Interactions in Cofacial Silicon Phthalocyanine Oligomers

Single crystal structures have been determined for the three cofacial, oxygen-bridged, silicon phthalocyanine oligomers, [((CH₃)₃SiO)₂(CH₃)SiO](SiPcO)_2–4[Si(CH₃)(OSi(CH₃)₃)₂], and for the corresponding monomer. The data for the oligomers give structural parameters for a matching set of three cofacial, oxygen-bridged silicon phthalocyanine oligomers for the first time. The staggering angles between the six adjacent cofacial ring pairs in the three oligomers are not in a random distribution nor in a cluster at the intuitively expected angle of 45° but rather are in two clusters, one at an angle of 15° and the other at an angle of 41°. These two clusters lead to the conclusion that long, directional interactions (LDI) exist between the adjacent ring pairs. An understanding of these interactions is provided by atoms-in-molecules (AIM) and reduced-density-gradient (RDG) studies. A survey of the staggering angles in other single-atom-bridged, cofacial phthalocyanine oligomers provides further evidence for the existence of LDI between cofacial phthalocyanine ring pairs in single-atom-bridged phthalocyanine oligomers

Long, Directional Interactions in Cofacial Silicon Phthalocyanine Oligomers

Single crystal structures have been determined for the three cofacial, oxygen-bridged, silicon phthalocyanine oligomers, [((CH₃)₃SiO)₂(CH₃)SiO](SiPcO)_2–4[Si(CH₃)(OSi(CH₃)₃)₂], and for the corresponding monomer. The data for the oligomers give structural parameters for a matching set of three cofacial, oxygen-bridged silicon phthalocyanine oligomers for the first time. The staggering angles between the six adjacent cofacial ring pairs in the three oligomers are not in a random distribution nor in a cluster at the intuitively expected angle of 45° but rather are in two clusters, one at an angle of 15° and the other at an angle of 41°. These two clusters lead to the conclusion that long, directional interactions (LDI) exist between the adjacent ring pairs. An understanding of these interactions is provided by atoms-in-molecules (AIM) and reduced-density-gradient (RDG) studies. A survey of the staggering angles in other single-atom-bridged, cofacial phthalocyanine oligomers provides further evidence for the existence of LDI between cofacial phthalocyanine ring pairs in single-atom-bridged phthalocyanine oligomers

Алгоритм расчета необходимого продовольственного потенциала региона и его реализация

У роботі викладено необхідність розробки стратегії забезпечення населення продовольством на основі аналізу сучасного економічного стану сільськогосподарського виробництва та випуску продукції в регіоні.The need for the strategy of the population provision with food considering modern economic situation with agricultural production is shown. Analysis of food production in the region is conducted

Stereoselective Synthesis of (<i>S</i>)-3-(Methylamino)-3-((<i>R</i>)-pyrrolidin-3-yl)propanenitrile

(<i>S</i>)-3-(Methylamino)-3-((<i>R</i>)-pyrrolidin-3-yl)­propanenitrile (<b>1</b>) is a key intermediate in the preparation of PF-00951966, a fluoroquinolone antibiotic for use against key pathogens causing community-acquired respiratory tract infections including multidrug resistant (MDR) organisms. The current work describes the development of a highly efficient and stereoselective synthesis of <b>1</b> in 10 steps with an overall yield of 24% from readily available benzyloxyacetyl chloride. Two key transformations in the synthetic sequence involve (a) catalytic asymmetric hydrogenation with chiral DM-SEGPHOS-Ru­(II) complex to afford β-hydroxy amide <b>11b</b> in good yield (73%) and high stereoselectivity (de 98%, ee >99%) after recrystallization and (b) S_N2 substitution reaction with methylamine to provide diamine <b>14</b> with inversion of configuration at the 1′-position in high yield (80%), after efficient purification using a simple acid/base extraction protocol

Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects

Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor (D3R) antagonist scaffold, <b>1</b>. Through a hybrid approach, we merged key pharmacophore elements from <b>1</b> and D3 agonist <b>2</b> to yield the novel D3R/D2R antagonist PF-4363467 (<b>3</b>). Compound <b>3</b> was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (≥4/6). In addition to good physicochemical properties, <b>3</b> exhibited low nanomolar affinity for the D3R (D3 <i>K</i>_i = 3.1 nM), good subtype selectivity over D2R (D2 <i>K</i>_i = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, <b>3</b> dose-dependently attenuated opioid self-administration and opioid drug-seeking behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further, traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not observed despite high D2 receptor occupancy (RO) in rodents, suggesting that compound <b>3</b> has a unique in vivo profile. Collectively, our data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction

Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit

The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine-competitive, and cell active inhibitor PFI-3 that binds to certain family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for family VIII was achieved through a novel bromodomain binding mode of a phenolic headgroup that led to the unusual displacement of water molecules that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chemistry program that led to PFI-3 from an initial fragment screening hit is described in detail, and additional analogues with differing family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacological characterization of PFI-3 as a chemical probe, along with phenotypic data on adipocyte and myoblast cell differentiation assays