The Top Ten Drugs

Levothyroxine is used to treat hypothyroidism (an underactive thyroid gland). Thyroid hormone can be made from beef and pork thyroid, but this lacks standardization and it is difficult to control dosage. The synthetic drug is more desirable. Levothyroxine is one of two important thyroid hormones. It is converted into the second important hormone, liothyronine, in the body. The key step in the synthesis of structures such as levothyroxine is the substitution of an iodonium salt by an iodinated phenol. Siql-like reactions on an aromatic ring are not common, but an iodonium salt provides a good leaving group. 

Hydrocodone is an opium analgesic (pain reliever) and antitussive (cough suppressant). It is related in structure to other alkaloids used as drugs, such as morphine and codeine (see Section 8). It increased 20% in number of prescriptions for one year. Its synthesis from codeine is by simple reactions. 

Catalytic reduction of codeine gives dihydrocodeine and Oppenauer oxidation (a ketone such as acetone and an aluminum alkoxide, the ketone being reduced to an alcohol) gives hydrocodone. Hydrocodone can also be prepared directly from codeine with a metal catalyst, which isomerizes the allylic alcohol to a ketone. Codeine is prepared by methylation of morphine, which is isolated from the opium poppy. Hydrocodone is more potent than codeine. Acetaminophen is a mild analgesic and is discussed in Section 8. 

Omeprazole is an antiulcer drug. It is a proton pump inhibitor. This substituted benzimidazole inhibits gastric acid secretion to help acid/peptic disorders and duodenal ulcers. It interferes with the proton pump in the mucous lining of the stomach, the last stage of acid production. It can turn off stomach acid in as little as one hour. Lansoprazole (no. 12) has a similar structure. 

Amlodipine is a calcium channel blocker used to treat hypertension and angina pectoris. Calcium channel blockers block the passage of calcium, an essential factor in muscle contraction, into the heart and smooth muscles. Such blockage interferes with the contraction of these muscles, which in turn dilates the veins that supply blood to them. This reduces blood pressure. 

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Figurel.1 Chemical structures of the best-selling drugs of 2001 [4], Nine of the top ten drugs are low-molecular-weight compounds.

Another fast-growing worldwide drug was Zyprexa with sales of US 4.0 billion in 2002. Pharmacia and Pfizer s competing COX-2 inhibitor, Celebrex, generated US 3.1 billion in sales with a 32 percent increase compared to the previous year. Zoloft replaced Vioxx, which dropped out completely in the top ten drugs [2]. Vioxx was withdrawn from the market in 2004 because of severe side effects. 

Finally, a chemoenzymatic enantioconvergent procedure led to (S)-ibuprofen in four steps and 47% overall yield (Fig. 11.2-20). The latter compound is a widely used antiinflammatory drug and pain remedy and is one of the top ten drugs sold worldwide l,HH. In the key step, the conditions for the enantioconvergent hydrolysis of para-iso-butyl-a-methylstyrene oxide was optimized (elevated substrate concentration at +4 °C) to afford the non-reacted epoxide in >95 % ee[136l After separation from the epoxide, the formed diol (70% ee) was recycled via a two-step sequence via the corresponding bromohydrin, which was cyclized back to give ( )-epoxide. The latter material was subjected to repeated biocatalytic resolution in order to improve the economy of the process. 

The Pediatric Use Working Group, chaired by Miriam Pina (1995) (FDA Division of Pulmonary Drugs), examined data that the FDA had acquired on 1994 pediatric prescriptions from IMS. From these they identified the top ten drugs used off label in children Albuterol, Phenergan, Ampicillin... 

Input SMILES of the top ten drugs in the field of medicine and generate 3D structures using Corina and ChemAxon tools also perform similarity searching in PubChem and Scifinder. 

Predict NMR, IR, UV, and mass spectra of the top ten drug compormds using any of the available spectra prediction programs and online tools... 

In the following years, the number of new products kept growing exponentially. The pharmaceutical market of recombinant proteins in 2005 comprised 134 approved products, with an approximate sales value of 35 billion dollars. The top ten drugs accounted for 26.2 billion dollars. These included Etanercept... 

Now, for this second edition, an attempt was made to list the top prescription drugs in the U.S. as of 1985-some ten years later than the earlier tabulation. This new listing was done by the author based on his interpretation of the sales list by trade name in the magazine/1/ne/-/car) Druggist for February 1986 it gives approximate rank by generic product as of the date of manuscript preparation in 1986. See Table 2. 

The chemical, biological, and physical characteristics of the drug substance can be manipulated and hence optimized by conversion to a salt form. Every compound that exhibits acid or base characteristics can participate in salt formation. Various salts of the same compound often behave quite differently because of the physical, chemical, and thermodynamic properties they impart to the parent compound. Table 1 lists the top ten FDA approved commercially marketed final drug forms and Table 2... 

There are five basic sources of pharmaceuticals. By dollar value of products, fermentation is probably the most important, whereas by tonnage, chemical synthesis is dominant. Fermentation is used for antibiotics such as penicillins and tetracyclines. Chemical synthesis provides drugs such as the psychotropics and antihistamines. Animal extracts provide hormones. Biological sources lead to vaccines and serums. Vegetable extracts provide steroids and alkaloids. The top ten pharmaceutical companies in order of revenues are the following Merck, Pfizer, Bristol-Myers Squibb, Johnson ... 

The top ten best-selling single enantiomer drugs in 1996 are given in Table 31.1.1 Because we are only concerned with small molecules, peptide products such as insulin and erythropoietin have been ignored because they are outside of the realms of chemical approaches. 

The ultimate goal in most industrial research is to develop economically attractive processes or products. The technology of asymmetric hydrogenation of 2-arylacrylic acids is probably most useful for the production of naproxen and S-ibuprofen. Naproxen is currently one of the top ten prescription drugs in the world S-ibuprofen is the active isomer in the popular anti-inflammatory drug ibuprofen. Figures 5 and 6 summarize two commercially feasible processes for the manufacturing of these products. 

The top ten best-selling drugs worldwide accounted for sales of US 44.7 billion in 2002. Within the total world market, Lipitor was the top-selling drug in 2002, with US 8.6 billion in sales, compared with US 5.4 billion in 2000 (Table 10.3) [2]. 

The chemical structures, names, and therapeutic areas of the top ten best-selling drugs based on the IMS worldwide review 2003 are given hereafter [11],... 

Biologies have taken some time to get off the ground but are making slow and steady progress. Table 45.7 shows the global sales of the top ten. These add up to 33 billion, compared with 60 billion for the top ten conventional drugs. Thus, they are serious players in the pharmaceutical market. 

The pressure on pharmaceutical companies to produce new drugs is intense. It is estimated that, to remain competitive, a top-ten drug company must quadruple the number of new drugs it launches each year [155]. However, the discovery of new lead compounds and the subsequent development process is extremely high risk and expensive. Obvious-... 

The manufacture of fine chemicals, particularly drugs, fragrances, and flavors, is undergoing a major revolution now as a result of the capability of chemists to prepare these chemicals, mainly drugs, in their purest isomeric forms (as stereoisomers). This shift to pure forms has been described by Brown in the following words (1990) (see also Deutsch, 1991) A mixture of stereoisomers in a medicine will (now) need to be justified just the same way as any other mixture of compounds. Indeed, in the United States today (as in many other advanced countries), the use of pure enantiomeric forms is practically a requirement since extensive justification is needed to continue with racemates (FDA, 1992). As a consequence, the combined sales of the chiral top ten drugs (ammoxydllin, enalapril, ampicillin, captopril, pravastatine, diltiazem, ibuprofen, lovastatin, naproxen, and fluoxetine) in 1994 amounted to more than 16 billion dollars (Sheldon, 1996). (Of these, ibuprofen and fluoxetine are still sold as racemates.)... 

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