Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas Yu Zhou,† Jiang Wang,† Zhanni Gu,† Shuni Wang,† Wei Zhu,† Jose ́ Luis Aceña,*,‡,§ Vadim A. Soloshonok,*,‡,∥ Kunisuke Izawa,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastiań, Spain Department of Organic Chemistry, Autońoma University of Madrid, Cantoblanco, 28049 Madrid, Spain IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, 48013 Bilbao, Spain Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, Japan 533-0024

Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II–III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas

The Golden Age of Transfer Hydrogenation

The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.

Palladium-catalyzed carbonylation reactions of aromatic halides in the presence of various nucleophiles have undergone rapid development since the pioneering work of Heck and co-workers in 1974, such that nowadays a plethora of palladium catalysts are available for different carbonylative transformations. The carboxylic acid derivatives, aldehydes, and ketones prepared in this way are important intermediates in the manufacture of dyes, pharmaceuticals, agrochemicals, and other industrial products. In this Review, the recent academic developments in this area and the first industrial processes are summarized.

Palladium-catalyzed carbonylation reactions of aryl halides and related compounds.

The last 15 years of hydroformylation and carbonylation chemistry are reviewed, including technical and commercial aspects.

Progress in hydroformylation and carbonylation

Transmission of substituent effects through oxygen and sulfur atoms part 1 and 2, (1)h and (13)c chemical shifts of ring-substituted phenyl vinyl ethers and sulfides

Practical Synthesis of α-Aminoalkyl-α′-chloromethylketone Derivatives. Part 1. Choromethylation of N-Protected 3-Oxazolidin-5-ones.

PCT No. PCT/JP91/01619 Sec. 371 Date Sep. 15, 1992 Sec. 102(e) Date Sep. 15, 1992 PCT Filed Nov. 26, 1991 PCT Pub. No. WO92/09605 PCT Pub. Date Jun. 11, 1992.Optically active pyrrolidine derivative represented by the following formula (XI): (XI) wherein R1 represents a benzyl group R2 represents an alkyl group having 1 to 6 carbon atoms, R3 represents an alkyl group having 1 to 6 carbon atoms, a benzyl group or an allyl group, R4 is selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may be substituted with a protected hydroxyl group, a vinyl group, a phenyl group which may be substituted, a benzyl group which may be substituted, and a heterocyclic ring having 1 to 4 nitrogen or/and oxygen atoms, and R5 represents a hydrogen atom or a methyl group. This compound can be an intermediate for synthesis of carbapenem antibiotic compounds.

Kunisuke Izawa

Papers

Transmission of substituent effects through oxygen and sulfur atoms part 1 and 2, (1)h and (13)c chemical shifts of ring-substituted phenyl vinyl ethers and sulfides

Practical Synthesis of α-Aminoalkyl-α′-chloromethylketone Derivatives. Part 1. Choromethylation of N-Protected 3-Oxazolidin-5-ones.

Optically active pyrrolidine derivative

Synthesis and Resolution of 2,3-Diamino-1-cyclohexanols.