Medicines Sildenafil

Even on a relatively small subset of reused data, it is possible to license old medicines for new therapeutic applications and greatly reduce the costs of clinical development—many of these reused medicines have already passed muster for pharmacokinetic safety, so smaller-scale clinical trials are possible, saving considerable money (e.g., Arakis—soon to become Sosei). Even Sildenafil may have new indications [39]. There are huge potential reserves of information to mine in each and every large pharmaceutical company ... 

Adulteration, which can be accidental or deliberate, is another problem. Many herbal products have been found to contain prescription or OTC drugs and dangerous heavy metals. In 1998, for example, the California Department of Health reported that 32% of Asian herbal medicines sold in that state contained undeclared pharmaceuticals or heavy metals. A subsequent study of more than 500 Chinese herbal medicines found that about 10% of them contained undeclared drugs or toxic levels of metals. The FDA and other investigators have also detected sildenafil, colchicine, adrenal steroids, alprazolam, and other prescription drug ingredients in products claimed to contain only natural ingredients. 

Scheme 1. Pfizer medicinal chemistry synthesis of sildenafil (1).

The initial medicinal chemistry route for the early syntheses of sildenafil required -1540 kg solvent/kg API. After four years of development, a modified chemical route and process led to a 93.9% reduction in the total amount of solvent used. The continued optimization of the sildenafil process as it went into commercial production further reduced the amount of solvent used from 94 to 19 kg solvent/kg API. Several highly hazardous solvents were also eliminated from the production scheme including DCM, methanol, and diethyl ether. Upon implementation of solvent recovery, the total amount of solvent required was only 5 kg solvent/kg API produced [17, 20]. The final commercial route used only 0.32% of the total solvent used for the initial synthesis. 

The synthesis of sildenafil serves as an excellent example of the demands of commercial chemistry. The route described contains all of the desired attributes required in chemical development, namely a safe, robust route, a convergent synthesis and a high yielding process. The authors managed to improve the yield from 7.5 % in the medicinal chemistry to 75.8 % overall from pyrazole 3. The synthesis also has an exceptionally low environmental impact. Only toluene and ethyl acetate are organic waste while the other solvents (ethanol and tert-butanol) can be treated in the water plants. The synthesis has been... 

The pharmaceutical businesses produce drugs and medicinal products of many kinds. One of the great revolutions of modern life has been the expectation that humans will survive diseases because of a treatment designed to deal specifically with that disease. The most successful drug ever is ranitidine (Zantac), the Glaxo-Wellcome ulcer treatment, and one of the fastest-growing is Pfizer s sildenafil (Viagra). Success refers both to human health and to profit ... 

I. Goldstein, T. F. Lue, H. Padma-Nathan, et al. Oral sildenafil in the treatment of erectile dysfunction. The New England Journal of Medicine 338, 1397 (1998). 

Although not strictly alternative medicine, the incubation of a West Indian centipede in alcohol for several weeks is alleged to result in the formation of a compound that has effectiveness in erectile dysfunction. If this compound is similar to sildenafil and inhibits phosphodiesterases, it would be contraindicated in a patient who is being treated with... 

The medicinal chemistry route was completely linear and produced sildenafil citrate in 3.8% overall yield from 2-pentanone. Although these facts made it suboptimal for commercialization, the route was fully suitable for early project supply. Of course all steps were modified to make them suitable for scale-up. Some of the most important modifications were the following ... 

SCHEME 16.1 The medicinal chemistry route to sildenafil citrate. 

Sildenafil citrate originally entered development as a candidate for the treatment of angina, but the early clinical results were disappointing. In 1994 Pfizer ran a small phase Ila trial with 12 patients suffering from male erectile dysfunction. Ten of those patients showed major improvements in their erections. Suddenly the project changed overnight. Sildenafil citrate had been the lowest-priority project in the Pfizer development portfolio, and now it became one of the highest. The medicinal... 

As previously mentioned, nitropyrazole 5 is one of the regulatory starting materials for sildenafil citrate, so not surprisingly the compound has attracted the attention of fine chemical companies and within Pfizer. The optimization of the condensation reaction to make intermediate 1 has been previously reported. In the medicinal chemistry synthesis, conversion of 1 to compound 3 was accomplished via reaction with hydrazine followed by a methylation reaction. Clearly a more efficient way of making this transformation is to use a regioselective condensation reaction with methylbydrazine. " " ... 

Figure 19.4 Examples of drugs that were derived from translational chemistry, translational research and translational medicine, respectively (1) d-tubocurarine (2) propranolol and (3) esmolol. Also shown is sildenafil, (4), which is probably best considered to have been derived from a composite of all three of these drug discovery starting points. See text for details.

Isosteres (i.e. molecules of the same shape but with different atom combinations) of purines are also important as medicines allopurinol is used to treat gout and Sildenafil achieved international fame, under the trade name Viagra, for the treatment of impotence. Some natural products can be viewed as purine isosteres oxanosine and tubercidin, both obtained from Streptomyces, have anti-microbial and anti-cancer activity. 

Baxendale, I.R. and Ley, S.V. (2000) Polymer-supported reagents for multi-step organic synthesis apphcation to the s3mthesis of sildenafil. Bioorganic Medicinal Chemistry Letters, 10, 1983-1986. 

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