Pfizer 480 Subject

After clavulanic acid, the penicillanic acid derivatives (particularly the corresponding sulfone analogs) have been the subject of intense research in the -lactamase inhibitor area. From this extensive investigation, two compounds (sulbactam and tazobactam) from this class have been successfully introduced into clinical use. The penicillanic acid sulfones are /3-laclamasc inhibitors that are quite homologous to clavulanate in both their mechanism of action and in the spectrum of -lactamases susceptible to their action. The first notable success in this field was the discovery of sulbactam 7 (Fig. 7), which was reported by Pfizer chemists in 1978 and shown to possess potent inhibitory activity, principally for class A //-lactamases. It had greater affinity for class C types than clavulanate. From careful comparison of its structure to clavulanate, a rational basis for the similarities between the two is apparent. Both lack a C-6 substituent. Since the absence (or presence) of this substituent is an important, but not exclusive, factor in //-lactamase recogni-... 

Kissel, Ramsden, and other researchers at Pfizer and Chirotech jointly published a novel chiral synthesis of pregabalin (2) in 2003 based on asymmetric hydrogenation (Burk et al., 2001, 2003). Their synthesis started with the condensation of isobutyralde-hyde with acrylonitrile under Baylis-Hillman conditions to give allylic alcohol 65. This alcohol was activated as the carbonate 66 and subjected to palladium-catalyzed car-bonylation conditions to give cyanoester 67. The ester 67 was hydrolyzed and converted to... 

We are grateful to Susan Hagen and Derek Pflum at Pfizer, and Professor John Montgomery of the University of Michigan and his students Ryan Baxter, Christa Chrovian, and Hasnain A. Malik for proofreading portions of the manuscript. Jared Milbank helped in collating the subject index. 

To measure the scalability of a process it is necessary to understand the chemistry and reaction kinetics involved and then to determine their impact on well-defined critical quality attributes desired of the product in order to find the optimum processing window within which there is certainty that the product will be of acceptable quality. However, these data are not readily available for many pharmaceutical chemistry reactions, so a subjective measure of a the scalability, robustness, and greenness of many processes has been developed by Pfizer based on operator knowledge and experience to assist development teams both in the laboratory and in pilot plants to develop greener processes [28]. 

Nine deaths have been reported in children with Prader-Willi syndrome receiving growth hormone. Pfizer issued a safety warning for growth hormone and Prader-Willi syndrome after reviewing seven deaths in male subjects (89). There was an association with severe obesity and severe respiratory impairment. 

The subject of biotechnology first appeared in an earlier edition of this Handbook as a chapter titled industrial Fermentation Principles, Processes and Product, written by Dr. Arthur E. Humphrey of Lehigh University. In later editions he was joined first by Dr. S. Edward Lee and then by Dr. Lewis Ho, both of Pfizer. Chapters 30 and 31 in this edition are an outgrowth of that earlier work, some of which is used in the new chapters. Grateful acknowledgment of this use is made to the authors of that work. 

Replacement of the diethylamino group by other secondary amines with an open chain or cyclic structures resulted in decrease in activity. However, introduction of secondary amino functions enhanced the activity the optimal activity was found in 2-[(isopropyl)aminomethyl]-6-methy -7-nitro-l,2,3,4-tetrahydroquinoline, called U.K, 3883 (13) [12,16], Exploiting the knowledge that hycanthone is the active metabolite of lucanthone, which may be prepared by microbial oxidation, the Pfizer scientists subjected 13 to microbiological oxidation in the presence of Aspergillus sderoticrutn and obtained the hydroxymethyl derivative of UK-3883, which was later known as UK-4271 or oxamniquine (14) [22,23], Oxamniquine proved to be a better... 

Workers at the India Orchid company have shown that the condensation of 2-pentanone with diethyl oxalate may be catalyzed by sodium methoxide which is cheaper than sodium ethoxide. After further condensation with hydrazine hydrate, the pyrazole 18 was obtained as a mixture of methyl and ethyl esters. Methylation with dimethyl sulfate was performed neat, as in the Pfizer medicinal chemistry synthesis. The mixture of the methylated pyrazoles 19 was then nitrated and subjected to ammonolysis to give the desired pyrazole intermediate 5 (Scheme 16.8). 

Liver In an analysis of all Pfizer-sponsored clinical trials of maraviroc, in 2350 subjects, sporadic hepatic enzyme abnormalities were reported in 34 phase I/IIa studies of up to 28 days duration, but there was no apparent dose relationship or association with hyperbilirubinemia [144 ]. In four phase Ilb/III studies there was no significant effect on hepatic enzyme abnormalities or hepatobiliary adverse events up to week 96. The findings were similar in patients co-infected with hepatitis B an or C,... 

Many other industrial applications at large scale are known. This subject has been comprehensively reviewed by Busacca et al. [37], and we will highlight one example here, the case of torcertrapib - which is a powerful cholesteryl ester transfer protein (CETP) inhibitor invented by Pfizer [38]. The key step in this synthesis - which can be scaled-up to multi-kilograms - is a Buchwald-Hartwig reaction involving very cheap l-chloro-4-trifluoromethylbenzene and a chiral amine in the presence of PdfOAcj and DavePhos (Scheme 2.8). Interestingly, PhB(OH)2 was added in order to activate the catalyst. 

Viagra is a trade name marketed by Pfizer Pharmaceutical Company and is chemically sidenafil citrate. Researchers did not start CTeating a drug for impotence. The chemical compound was developed originally for angina (severe but tanporary attack of cardiac pain) and is chemically an inhibitor for an enzyme phosphodiesterase (see the previous section, for example, for the idea of enzyme inhibitor). The drug was not successful in treating heart problems, but many of the test subjects reported their successes in bedroom activity. It turned out that the compound inhibits... 

Issued patents are available on the USPTO website (http //www.uspto.gov) and patents issued after 1976 can be easily searched by inventor, assignee, or subject. Once on the website, cUck on search for patents and then quick search. For example, a quick search of patents issued since 1976 reveals more than 40 issued patents with the inventor name, Einstein (not the Nobel Prize winning physicist), more than 3,800 patents with Pfizer as an assignee, and more than 500 with the concept, chiral alcohol. Searching the patent literature is a valuable tool. It provides the reader with a synopsis of the art, with references, and best methods. Patents typically give experimental results. They are also a good way to understand the research direction and focus of a company because most companies patent their important results. 

These findings suggest that polymyxin formation and sporulation are subject to joint control and that there may be a functional relationship between these processes. However, even though polymyxin is undoubtedly an important metabolite, as the amount produced may exceed 10% of the bacterial dry weight, very few clues exist as to its possible function. It had been suggested that peptide antibiotics are structural components of the spore coat (Bernlohr and Novelli, 1962), and Jann and Eichhorn (1964) have reported the presence of DBA in spores of B. circulans. However, careful analysis of spores and sporecoats of B. polymyxa strain Pfizer 2459 failed to reveal the presence of significant amounts... 

---