Richard Friary

ENANTIOMERIZATION OF AN ATROPISOMERIC DRUG

The antipsoriatic 10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzo[b][1,8] naphthyridin-5(7H)-one, Sch 40120, is chiral only because it lacks planarity and possesses a stereogenic axis. It comprises short-lived, interconverting atropisomeric enantiomers distinguished by the chlorine substitutent. The atropisomers form diastereomeric complexes with the shift reagent (R)-(−)-2,2,2-trifluoro-1-(9-anthryl)ethanol, which were detected by 1H NMR spectroscopy. Liquid chromatography on an ovomucoid chiral column isolated each enantiomer from the racemic mixture. Re-injections of the separated enantiomers onto the same column held constant at 10°C established that each enantiomer formed the other. Under identical chromatographic conditions, both stereoisomers independently recreated the racemic mixture. The calculated enantiomer half-life lasted 1.6 min at the physiological temperature of 37°C. Simulations of dynamic liquid chromatograms acquired with a chiral stationary phase indirectly yielded values of the half-lives. The chromatograms were modeled with the computer program SIMUL. Also determined were the rate constants for enantiomerization and the corresponding Gibbs free energies of activation, all at varying temperatures. At 37°C, the rate constant and activation energy respectively equaled 0.213 min−1 and 21.6 kcal mole−1. An Arrhenius plot was linear. The intractably brief life spans necessitated development of the racemic drug, rather than advancement of one enantiomer only. The pharmacological, biological, and chemical consequences of molecular asymmetry inherent to the drug were therefore nil.

Intramolecular transaminations of enaminones: a synthesis of fused, polycyclic, N-aryl pyridones

Abstract 2-Arylamino-3-pyridinecarbonyl chlorides acylated the β-carbon atoms of enamines, and the resulting enaminones cyclized to give a series of fused polycyclic N-aryl pyridones. The series included 10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzo[b][1,8]naphthyridin-5(7H)-one (Sch 40120 ), an antipsoriatic agent.

Intramolecular cycloadditions of nitrones joined by amides to olefins

Abstract Six nitrones joined by amides to olefins were prepared in situ from the related ketones 1–3 with N-methy]- and benzylhydroxylamines. The nitrones added intramolecularly to the olefins, and the cycloadditions gave the 6-lactams 4–9 stereoselectively and regiospecifically. Chemical correlations, CMR spectroscopy and two X-ray crystallographic analyses established that the relative stereochemistries of the six cycloadducts 4–9 were identical.

Synthesis, structure, and reductive rearrangement of a novel tricyclic isoxazolidine

Abstract N-Oxidation of 2-methyl-3β-phenyl-2,3α,3aβ,6aβ-tetrahydrothieno [2,3-d] isoxazole-4,4-dioxide (1) gave a nitrone (2) which underwent an intramolecular 1,3-dipolar cycloaddition yielding a tricyclic isoxazolidine (4). A single-crystal X-ray analysis unequivocally established the structure of 4 as 9β-phenyl-2-oxa-6-thia-1-azatricyclo[3.3.1.03,7]nonan-4α-o1-6,6-dioxide. LiA1H4 and LiA1D4, reduced 4 exhaustively and rearranged it profoundly to isotopomers 5 and 6, respectively ; a novel Grob fragmentation may have mediated the rearrangement. Inter alia, measurements of 13C-13C coupling constants and of m z ratios of fragment ions yielded the complete structures of 5 and 6. They are 5β-phenyl-8-thia-6-azabicyclo[3. 3. 1]octan-2α-o1 and its 3α-deuterio analog, respectively.

Oxidative cleavage of a tricyclic pyridone to a bicyclic lactam-dione

Abstract Two equivalents cf anhydrous m-chloroperbenzoic acid (m-CPBA) cleaved the pyridone ring of 10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzo[b][1,8]naph forming; the ten-membered lactam α-diketone 12-(3-chlorophenyl)-7,8,9,10-tetrahydropyrido[2,3-b]azecine-5,6,11(12H)-trione. Under aqueous conditions, one equivalent of m-CPBA and the same pyridone formed the lactam α-ketol 12-(3-chlorophenyl)-7,8,9,10-tetrahydro-6-hydroxypyrido[2,3-b]azecine-5,11(6H, 12H)-dio

Transfer hydrogenolysis: an improved synthesis of (R)-(-)-α-Methyl Histamine

Abstract Ammonium formate in the presence of palladium on carbon in methanol reacted with (S)-(+)4-(2-Amino-3-chloropropyl)-imidazole to give optically pure (R)-(−)-α-methyl histamine at atmospheric pressure.

In vitro metabolism of 10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzo[b][1,8]naphthyridin-5(7H)-one, a topical antipsoriatic agent. Use of precision-cut rat, dog, monkey and human liver slices, and chemical synthesis of metabolites

The metabolism of SCH 40120, which is the clinically effective antipsoriatic drug 10‐(3‐chlorophenyl)‐6,8,9,10‐tetrahydrobenzol[b][1,8]naphthyridin‐5(7H)‐one, was determined in vitro. Rat, dog, cynomolgus monkey, and human liver slices hydroxylated the aliphatic, cyclohexenyl ring of the drug and conjugated the resulting carbinol. The identified metabolites comprised the corresponding 6‐, 7‐, and 9‐carbinols, the glucuronide of the 6‐carbinol, and the 6‐ketone derived from the parent drug.

Evaluating Companies and Job Offers

To assist in evaluating companies, the chapter presents criteria falling into several categories. It covers corporate status and future, living costs, home prices, forms of compensation other than salary, career prospects, bosses, patenting and publishing, and retirements. Appreciating the importance of these topics empowers job seekers to investigate openings, ask pertinent interview questions, and elicit answers that are helpful in evaluating companies. The chapter provides means to obtain information about companies. Seeking or taking employment in a given company calls for critical judgment in making a series of choices. In looking for a job, one crucial choice lies in deciding whether the job seeker wants to work for a large company or a small one. Small firms, especially start-ups, offer an innovative, entrepreneurial, and exciting climate well-suited to some temperaments. Growing in many directions, they provide radiating opportunities for advancement. For larger companies, it is difficult to sustain the exhilaration that research often bring. In addition, the chapter also describes the various fields in which one can find his/her job.

Elements of Drug Discovery and Development

This chapter summarizes the strategy and tactics of drug discovery and development and describes an organizational structure in which pharmaceutical industry chemists work. Efforts to create drugs originate a variety of jobs for organic chemists, many of whom work in fully integrated pharmaceutical companies. The employers engage them in six basic operations: discovering, developing, registering, manufacturing, marketing, and monitoring drugs. Medicines fall into three broad functional categories—diagnostic, prophylactic, and therapeutic. Diagnostic products detect or probe diseases, while prophylactic agents prevent them. Many prophylactic agents are biological products, such as vaccines, although some are small molecules, such as ascorbic acid (vitamin C). Therapeutic agents treat diseases and are usually small molecules. To manufacture drugs in these three classes, special companies exist throughout the international pharmaceutical industry. Some drug companies carry out no preclinical chemical or biological research at all and nor any process chemistry or production. These companies are clinical research organizations (CROS), which contract to take experimental drugs through phases I–III of human studies. Moreover, other pharmaceutical companies exist not to market drugs without discovering lead compounds but to find lead compounds without selling finished drugs. Drug discovery firms—an outcome technological innovations—are newcomers in the industry.

Chemical Development: Challenge in Organic Synthesis

This chapter provides an overview of chemical development. Chemical developments, of especially process chemistry, form a subdiscipline of organic chemistry. A compound worthy of chemical development offers commercial value as a medicine. Developmental work, therefore, involves only a drug candidate with desirable and selective pharmacological activities, which are specified as early as possible in the corresponding discovery effort. The chosen compound optimizes potency and selectivity in one or more animal models of a human disease. It shows high activity in a mechanism-based assay for antagonism, agonism, or enzyme inhibition and displays suitable pharmacokinetics. Chemical developers advance the chosen compound without seeking a pharmacologically superior substance deliberately or finding one serendipitously. Clinical physicians or discovery pharmacologists are more likely to make such a commercially valuable and serendipitous discovery than developmental chemists. Driven by sales potential, each development campaign, therefore, concentrates on a single outstanding compound. In addition, the chapter also discusses the purpose of chemical development.