Über die Autorin bzw. den Autor

Daniel Lednicer, PhD, is the acclaimed author of several books on drug synthesis and discovery. His career has been devoted to the search for new therapeutic agents. Dr. Lednicer spent two decades at the bench as a chemist at the Upjohn Company. He has also served as director of chemical research at Mead Johnson, director of pharmaceutical sciences at Adria Laboratories, and pharmaceutical manager at Analytical Biochemistry Laboratories. Most recently, he was a project officer at the National Cancer Institute.

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Your Blueprint for Successful Drug Synthesis and Design

Guiding readers through tested-and-proven strategies for designing and conducting drug synthesis, this Second Edition features the latest developments in the field, including new examples of drug synthesis from major pharmaceutical companies. Examples are selected from the multivolume work, titled The Organic Chemistry of Drug Synthesis. This new, expanded edition focuses on the organic chemistry used for drug preparation. Drugs have been selected based on the illustrative value of the chemistry used for their synthesis. Structures in chemical schemes have been carefully drawn to clarify individual reactions.

Brief discussions of medicinal chemistry provide readers with a snapshot of the activity and the mechanism of action of various drugs. Salient principles of drug action are presented in capsule form at appropriate points. In addition, the claimed therapeutic effects of each pharmaceutical agent are noted along with the discussion of its preparation.

Strategies for Organic Drug Synthesis and Design has been updated with a host of new drugs, including drugs that address new therapeutic areas and drugs developed with the use of novel chemistry. These include:

• Tubulin Inhibitors (Taltobulin)

• Antimalarial arteflene

• Neuraminidase Antivirals (Zanamavir, Oseltamavir, and Peramavir)

• COX-2 Inhibitor NSAIDs (Celecoxib, Cimicoxib, and Valdecoxib)

Written by an experienced and successful author and pharmaceutical scientist, this book meets the needs of the growing community of researchers in pharmaceutical R&D as well as medical professionals who need to understand the design and synthesis of pharmaceutical agents. It is also recommended as a graduate-level medicinal chemistry textbook.

Aus dem Klappentext

Your Blueprint for Successful Drug Synthesis and Design
 
Guiding readers through tested-and-proven strategies for designing and conducting drug synthesis, this Second Edition features the latest developments in the field, including new examples of drug synthesis from major pharmaceutical companies. Examples are selected from the multivolume work, titled The Organic Chemistry of Drug Synthesis. This new, expanded edition focuses on the organic chemistry used for drug preparation. Drugs have been selected based on the illustrative value of the chemistry used for their synthesis. Structures in chemical schemes have been carefully drawn to clarify individual reactions.
 
Brief discussions of medicinal chemistry provide readers with a snapshot of the activity and the mechanism of action of various drugs. Salient principles of drug action are presented in capsule form at appropriate points. In addition, the claimed therapeutic effects of each pharmaceutical agent are noted along with the discussion of its preparation.
 
Strategies for Organic Drug Synthesis and Design has been updated with a host of new drugs, including drugs that address new therapeutic areas and drugs developed with the use of novel chemistry. These include:
* Tubulin Inhibitors (Taltobulin)
* Antimalarial arteflene
* Neuraminidase Antivirals (Zanamavir, Oseltamavir, and Peramavir)
* COX-2 Inhibitor NSAIDs (Celecoxib, Cimicoxib, and Valdecoxib)
 
Written by an experienced and successful author and pharmaceutical scientist, this book meets the needs of the growing community of researchers in pharmaceutical R&D as well as medical professionals who need to understand the design and synthesis of pharmaceutical agents. It is also recommended as a graduate-level medicinal chemistry textbook.

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Strategies for Organic Drug Synthesis and Design

John Wiley & Sons

Chapter One

1.1. PROSTAGLANDINS

It is highly likely that those not themselves involved in scientific research perceive the development of new knowledge within a given area of science as a linear process. The popular view is that the understanding of the specific details of any complex system depends on prior knowledge of the system as a whole. This knowledge is in turn believed to derive from the systematic stepwise study of the particular system in question. The piecemeal, almost haphazard, way in which the details of the existence and later the detailed exposition of the arachidonic acid cascade were put together is much more akin to the assembly of a very complex jigsaw puzzle. This particular puzzle includes the added complication of incorporating many pieces that did not in fact fit the picture that was finally revealed; the pieces that would in the end fit were also found at very different times.

The puzzle had its inception with the independent observation in the early 1930s by Kurzok and Lieb and later von Euler that seminal fluid contained a substance that caused the contraction of isolated guinea pig muscle strips. The latter named this putative compound prostaglandin in the belief that it originated in the prostate gland; the ubiquity of those substances was only uncovered several decades later. The discovery remained an isolated oddity until the mid-1960s, by which time methods for chromatographic separation of complex mixtures of polar compounds and spectroscopic methods for structure determination were sufficiently advanced for the characterization of humoral substances that occur at very low levels. The isolation and structural assignment of the first two natural prostaglandins, [PGE.sub.1] and [PGF.sub.2], were accomplished by Bergstrom and his colleagues at the Karolinska Institute. (The letter that follows PG probably initially referred to the order in which the compounds were isolated: E refers to 9-keto-11-hydroxy compounds and F refers to 9,11-diols; the subscripts refer to the number of double bonds.) The carbon atoms of the hypothetical, fully saturated, but otherwise unsubstituted carbon skeleton, prostanoic acid, are numbered sequentially starting with the carboxylic acid as 1, and then running around the ring and resuming along the other side chain.

The identification of these two prostaglandins in combination with their very high potency in isolated muscle preparations suggested that they might be the first of a large class of new hormonal agents. Extensive research in the laboratories of the pharmaceutical industry had successfully developed a large group of new steroid-based drugs from earlier similar leads in that class of hormones; this encouraged the belief that the prostaglandins provided an avenue that would lead to a broad new class of drugs. As in the case of the steroids, exploration of the pharmacology of the prostaglandins was initially constrained by the scarcity of supplies. The low levels at which the compounds were present, as well as their limited stability, forced the pace toward developing synthetic methods for those compounds. The anticipated need for analogues served as an additional incentive for elaborating routes for their synthesis.

Further work on the isolation of related compounds from mammalian sources, which spanned several decades, led to the identification of a large group of structurally related substances. Investigations on their biosynthesis made it evident that all eventually arise from the oxidation of the endogenous substance, arachidonic acid. The individual products induce a variety of very potent biological responses, with inflammation predominating. Arachidonic acid, once freed from lipids by the enzyme phospholipase [A.sub.2], can enter one of two branches of the arachidonic acid cascade (Scheme 1.1). The first pathway to be identified starts with the addition of two molecules of oxygen by a reaction catalyzed by the enzyme cyclooxygenase to give [PGG.sub.2]. That enzyme, now known to occur in two and possibly three forms, is currently identified by the acronym COX; it is sometimes called prostaglandin synthetase. The reaction comprises the addition of one oxygen across the 9,11 positions to give a cyclic peroxide while the other adds to the 14 position in a reaction reminiscent of that of singlet oxygen to give a hydroperoxide at 14, with the resulting shift of the olefin to the 12 position and with concomitant isomerization to the trans configuration. The initial hydroperoxide is readily reduced to an alcohol to give the key intermediate [PGH.sub.2]. The reductive ring opening of the bridging oxide leads to the PGF series while an internal rearrangement leads to the very potent inflammatory thromboxanes. It was found later that aspirin and indeed virtually all nonsteroid anti-inflammatory drugs (NSAIDs) owe their efficacy to the inhibition of the cylcooxygenase enzymes.

The reaction of arachidonic acid with the enzyme lypoxygenase (LOX), on the other hand, leads to an attack at the 5 position and rearrangement of the double bonds to the 7,9-trans-11-cis array typical of leukotrienes; the initial product closes to an epoxide, thus yielding leukotriene [A.sub.4]. The reactive oxirane in that compound in turn reacts with endogenous glutathione to give leukotriene [C.sub.4]. This compound and some of its metabolites, it turned out, constitute the previously well-known "slow reacting substance of anaphylaxis" (srs-A), involved in allergic reactions and asthma.

Much of the early work on this class of compounds focused on developing routes for producing the agents in quantities sufficient for biological investigations. There was some attention paid to elaborating flexible routes as it was expected that there might be some demand for analogues not found in nature. This work was hindered by the relative dearth of methods for elaborating highly substituted five-membered rings that also allowed control of stereochemistry. The unexpected finding of a compound with the prostanoic acid skeleton in a soft coral, the sea whip plexura homomalla, offered an interim source of product. The group at Upjohn, in fact, developed a scheme for converting that compound to the prostagland, which they were investigating in detail. The subsequent development of practical total syntheses in combination with ecological considerations led to the eventual replacement of that marine starting material.

The methodology developed by E. J. Corey and his associates at Harvard provides the most widely used starting material for prostaglandin syntheses. This key intermediate, dubbed the "Corey lactone," depends on rigid bicyclic precursors for controlling stereochemistry at each of the four functionalized positions of the cyclopentane ring. Alkylation of the anion from cyclopentadiene with chloromethylmethyl ether under conditions designed to avoid isomerization to the thermodynamically more stable isomer gives the diene (3-1). In one approach, this is then allowed to react with a-chloroacrylonitrile to give the Diels-Alder adduct (3-2) as a mixture of isomers. Treatment with an aqueous base affords the bicyclic ketone (3-3), possibly by way of the cyanohydrin derived from the displacement of halogen by hydroxide. Bayer-Villiger oxidation of the carbonyl group with peracid gives the lactone (3-4); the net outcome of this...