Piperidine-Based Drug Discovery

Ruben Vardanyan

• Publisher: Elsevier
• Year: 2017
• Print ISBN: 9780128051573
• eBook ISBN: 9780128134283
• Topic: Physical Sciences
• Subtopic: Organic Chemistry

Piperidine-Based Drug Discovery outlines the complexities of Piperidine scaffold use in drug discovery, including derivative chemistry, structural properties, methods of synthesis and practical implementations. Piperidine scaffolds are the cornerstones of over 70 commercialized drugs (including multiple blockbusters). Designed as a guide for both experts and students working in this and related areas, it is hoped that this volume will encourage and inspire the continued design and development of novel pharmaceuticals based on Piperidine and its derivatives.Heterocyclic compounds are of central importance to medicinal chemistry, as demonstrated by the high percentage of marketable drugs that feature heterocyclic fragments in their structures. As starting points for drug discovery they offer a broad range of attractive properties, and a detailed understanding of the particular characteristics of each is of great benefit to researchers.The most commonly used heterocycle among US FDA approved pharmaceuticals, Piperidine is an extremely important building block in the synthesis of medicinal agents. This heterocycle and its derivatives exhibit a number of important functionalities and have been employed variously as CNS modulators, antiaggregants, anticoagulants, antihistamines, anti-cancer drugs and analgesics.- Explores this extremely important heterocycle to a high level of detail- Describes synthesis methods for 70 current drugs based on Piperidine scaffolds- Gives drug designers all the key knowledge required to develop new drugs utilizing Piperidine- Provides pharmacologists a solid overview of the chemical background of existing Piperidine-based drugs

Chapter 1

Introduction

Abstract

This chapter provides one of the possible classifications of the types of piperidine derivatives, which have become drugs on pharmaceutical market and a brief overview of reactions used for the synthesis of functional piperidine derivatives, which served as starting material for the synthesis of described drugs. Review involves methods of piperidine ring creation based on the nucleophilic substitution of two leaving groups in a linear chain, intermolecular Michael reactions, hydroamination reactions used for intramolecular cyclization of amino olefins to piperidine derivatives, aza-Diels–Alder reactions, intramolecular ene reactions, ring-closing metathesis reactions. The review also considered different approaches for the synthesis of piperidin-2-, 3- and 4-ones, which are probably the most versatile starting materials for the synthesis of piperidine-based drugs and which include Petrenko-Kritschenko reaction, Dieckmann condensation, and a number of other miscellaneous methods. Review includes also nucleophilic addition reactions to the carbonyl group of piperidin-4-ones, nucleophilic substitution reactions involving α-carbon of piperidin-4-ones and synthesis and transformations of 4-cyano-4-phenylpiperidines.

Keywords

Piperidine drug classification; synthesis of functional piperidine derivatives

1.1 The Scope of the Material Under Consideration

Heterocyclic compounds constitute the largest and most varied family of organic chemistry that is gaining enormous importance in chemical and pharmaceutical industry. Numerous agrochemicals, information storages, electronics, plastics and optics modifiers and stabilizers, cosmetics additives, etc., are heterocyclic in nature.

Piperidine and its functionalized derivatives are increasingly popular building blocks in a vast array of synthetic protocols. The piperidine ring can be recognized in the structure of many synthetic compounds of practical interest and in the structure of many alkaloids and other natural or synthetic compounds with various biological activities known today. Piperidine is the compound which gives black pepper its spicy taste and gave the name of the compound in question.

Today it is possible to assert unequivocally that the mainstream of pharmaceuticals is heterocyclic and the leading heterocycle in the structure of pharmaceuticals is piperidine, which is the most encountered heterocycle found in pharmaceutical agents [1].

A search of the chemical and patent literature reveals thousands of references to this simple ring system, which is present in the structures of potential drugs in clinical and preclinical research.

As of October 8, 2015, the day of beginning the work on this monograph, 93,984 references containing the concept “piperidine” were found in SciFinder–the world’s largest and most reliable collection of chemistry and related science, which, of course, is not an exhaustive number of publications on the subject under consideration. By January 10, 2017, the date on which work on this monograph was completed, that number grew to 97,972, which constitutes the appearance of roughly 4000 additional publications within a year and a half. Information about piperidine-containing compounds exists in publications and patents that do not contain the word piperidine as well as in other sources of scientific information, which we did not use. For example, by analyzing the scaffold content of the CAS Registry from more than 24 million organic compounds it has been found that the most frequently occurring references on heterocycles concern piperidine (191.803) [2].

The huge contribution in the development of piperidine-derived series of drugs belongs to Otto Eisleb, Anton Ebnother, Solomon Snyder, Samuel McElvain, Ivan Nazarov, Miroslav Protiva, and, of course, the great Dr. Paul Janssen, the most prolific drug inventor of all time: his team has produced more than 60 new therapeutics, most of which belong to the piperidine series [3–5].

This book was conceived as an attempt to show the panorama of drugs, the structure of which contains a piperidine ring, and to show methods for their synthesis. It is necessary to emphasize here the word “drugs.”

Any attempt to create a more or less complete picture of a biologically active compound containing a piperidine ring in its structure was doomed to fail due to the inability to “grasp the immensity” and to show the entire existing material in reasonable frames.

But even the relatively limited list of piperidine drugs also creates a number of problems, the first of which is the mode of their classification and, consequently, the presentation.

One alternative classification is the attempt to build material based on their pharmacological properties thereby putting them into a traditional order according to, e.g., a generally accepted narration in pharmacology textbooks, just as we did in our two previous books [6,7].

However, to put the emphasis on the structure and methods of the synthesis of drugs requires another way of presentation that is more acceptable from the standpoint of an organic chemist. It was decided that the order and degree of substitution of the piperidine ring would be the best way to sort existing piperidine drugs.

So, the collected factual material in general was divided and distributed into chapters and subchapters according to the following generalization: derivatives of 1-substituted piperidines (such as trihexyphenidyl (Artane) (1.1.1)); derivatives of 2-substituted piperidines or 1,2-disubstituted piperidines (such as bupivacaine (Marcaine)) (1.1.2)); derivatives of 3-substituted piperidines and 1,3-substituted piperidines (such as troxipide (Aplace)) (1.1.3)); and tofacitinib (Xeljanz) (1.1.4) (Fig. 1.1).

Figure 1.1 Construction of subchapters in the book.

More diverse groups are represented by derivatives of 4-substituted and 1,4-disubstituted piperidines – fexofenadine (Allegra) (1.1.4), ebastine (Evastin) (1.1.5), astemizole (Hismanal) (1.1.6), indoramin (Baratol) (1.1.7), fentanyl (Sublimaze) (1.1.8), metopimazine (Vogalene) (1.1.9), ketanserin (Sufrexal) (1.1.10) (Fig. 1.2).

Figure 1.2 Structures of some of 1,4-disubstituted piperidine-based drugs.

No less common in the market are 1,4,4-trisubstituted piperidines exemplified by haloperidol (Haldol) (1.1.11), loperamide (Imodium) (1.1.12), trimeperidine (Promedol) (1.1.13), pethidine (Meperidine) (1.1.14), ketobemidon (Cliradon) (1.1.15), pipamperone (Dipiperon) (1.1.16), piritramide (Dipidolor) (1.1.17), alfentanil (Alfenta) (1.1.18), and remifentanil (Ultiva) (1.1.19), which in turn can be subdivided to alcohols, amines, ketones, amides, etc. Examples of these compounds are presented on the (Fig. 1.3).

Figure 1.3 Structures of some of 1,4,4-trisubstituted piperidine-based drugs.

Another group of piperidine drugs could be represented as a combination ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Chapter 1. Introduction
• Chapter 2. 1-Substituted Piperidines
• Chapter 3. 2-Substituted and 1,2-Disubstituted Piperidines
• Chapter 4. 3-Substituted and 1,3-Disubstituted Piperidines
• Chapter 5. 4-Substituted and 1,4-Disubstituted Piperidines
• Chapter 6. Piperidin-4-Ylidene Substituted Tricyclic Compounds
• Chapter 7. Piperidine-Based Nonfused Biheterocycles With C–N and C–C Coupling
• Chapter 8. Piperidine-Based Fused Biheterocycles
• Chapter 9. Piperidine-Based Spiro-Fused Biheterocycles
• Chapter 10. Classes of Piperidine-Based Drugs
• Index–Trade Names
• Index–Substance Classes