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

An amino group of an α-amino acid ester is protected as an imine, and it is then reacted with a halomethyllithium to obtain an N-protected-α-aminohalomethylketone. Further, this N-protected-α-aminohalomethylketone is treated with an acid to obtain an α-aminohalomethylketone. This process is suited for industrial production, and can produce an α-aminohalomethylketone and its related compounds economically and efficiently.

Process for producing alpha-aminoketones

A synthetic method was established for 3′-α-fluoro-2′,3′-dideoxyguanosine 1 from guanosine 2 in 27% overall yield and 6 steps. A byproduct 6a of fluorination was identified by NMR studies, its presence strongly supporting our supposition that the fluorination itself proceeded via a bromonium cation.

Synthetic study of 3'-α-fluoro-2',3'-dideoxyguanosine

PURPOSE: To readily and efficiently obtain a compound useful as a synthetic intermediate for various physiologically active substances from an inexpensive raw material by reacting a cyclic acetal or enol ether with carbon monoxide and an acid amide in the presence of a cobalt catalyst. CONSTITUTION: A cyclic acetal expressed by formula I (R 1 is H or 1-10C alkyl; n is 0 or 1) is reacted with carbon monoxide and an acid amide in the presence of a cobalt catalyst in a solvent, such as THF, at 50-200°C to provide the objective substance expressed by formula II or III (R 2 is H or protecting group; R 3 is 1-20C alkyl, substituted phenyl, substituted naphthyl or 1-20C alkenyl; m is an integer of ≥1; n is 0 or 1). The cyclic acetal and acid amide are used at 1:1 molar ratio and the catalyst is used at (1/10)-(1/10000) molar ratio based on the raw material. A cyclic enol ether expressed by formula IV (R 4 is H or carboxy) is used as a starting material to carry out reaction similar to that described above to afford a compound expressed by formula V or VI. COPYRIGHT: (C)1990,JPO&Japio

Production of hydroxy-n-acyl-alpha-amino acid derivative, oligomer and lactone thereof

Novel intermediates of nucleoside derivatives, of which the 6-position of the nucleic acid base moiety is substituted with a halogen atom, are produced. Using those novel intermediates, even substrates, of which the 3′-position of the saccharide moiety is deoxylated, can be substituted at the 2′-position at an extremely high yield. Specifically, by subjecting a 3′-deoxy derivative of inosine to 6-halogenation to give a 6-halide of the derivative, and then subjecting it to 2′-deoxylation/substitution with a fluorine atom or the like, followed by further subjecting it to substitution with an amino group, a hydroxyl group or any other intended substituent at the 6-positioned halogen atom, nucleoside derivatives are produced at a high yield. Methods for producing nucleoside derivatives including 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (FddA) and their related compounds, in a simplified manner, at a high yield and at low costs, and especially Economical methods for substituting substrates, of which the 3′-position of the saccharide moiety is deoxylated, at the 2′-position to produce those nucleoside derivatives on an industrial scale are also provided.

Methods for producing nucleoside derivatives and intermediates therefor

A process for the production of nucleosides represented by the general formula [II], characterized by subjecting a 2’, 3’, 5’-triacyloxynucleoside represented by the general formula [I] to deacylation with 0.01 to 0.5 time by mole as much alkali metal hydroxide as the 2’, 3’, 5’-triacyloxynucleoside. The invention provides a process for the production of nucleosides [II] which little suffers from the formation of by-products and a process for the production of nucleoside derivatives according to the process. Further, the invention also relates to a process of oxidizing a nucleoside represented by the general formula (1) in the presence of a 2,2,6,6-tetramethylpyridine-1-oxyl catalyst and a hypochlorite or hypobromite while controlling the pH within the range of 5 to 9, and a process which comprises extracting a carboxylic acid nucleoside represented by the general formula (2) with an organic solvent under acidic conditions, subjecting the obtained organic solution to back extraction with an aqueous alkaline solution, and neutralizing the obtained aqueous solution by the addition of an acid to crystallize the carboxylic acid nucleoside. According to these processes, specific carboxylic acid nucleosides or salts thereof can be produced at high purity by processes suitable for industrial production. [I] [II] (1) (2) (In the formulae, each symbol is as defined in the description.)

Kunisuke Izawa

Papers

Process for producing alpha-aminoketones

Synthetic study of 3'-α-fluoro-2',3'-dideoxyguanosine

Production of hydroxy-n-acyl-alpha-amino acid derivative, oligomer and lactone thereof

Methods for producing nucleoside derivatives and intermediates therefor

Processes for production of nucleosides