Medicinal chemist acids

A chance observation made some time prior to the full structural elucidation of cocaine in fact led to one of the more important lasses of local anesthetics. It was found that the simple ethyl e. ter of p-aminobenzoic acid, benzocaine (25), showed activity. 1-. a local anesthetic. It is of interest to note that this drug, I 1rst introduced in 1903, is still in use today. Once the struc-iiire of cocaine was established, the presence of an alkanolamine iiiniety in cocaine prompted medicinal chemists to prepare esters "I aminobenzoic acids with acyclic alkanolamines. Formula 26 11 presents the putative relationship of the target substances with cocaine. 

The medicinal chemists subsequently discovered an improved route to racemic acid 9 that started with 2-bromo-2-cyclopente-l-one 11 (Scheme 7.2) [5]. Suzuki-Miyaura cross-coupling of 11 with 4-fluorophenyl boronic acid 12 provided 13 in 67% yield. Conjugate addition of cyanide furnished ketone 14 in 71% yield. Reduction of 14 with NaB H4 gave a 2.8 1 mixture of desired 15 and undesired 16 which were separated by silica gel chromatography. The observed diastereoselec-tivity with the cyano group was similar to ester 6. Hydrolysis of 15 with 5 M NaOH in MeOH gave racemic acid 9 in 91% yield, which was resolved as outlined in Scheme 7.1. 

As one would anticipate, the time honored Schotten-Baumann reaction and its variants are the key steps in putting this group of substances together. Their intrinsic interest to the medicinal chemist depends upon their pharmacological properties and, in some cases, preparation of some of the less common benzoic acid analogues. 

For insufficiently understood reasons, there exist relatively few reports on the use of phenols and hydroxylamines as pro-moieties of active carboxylic acids. Medicinal chemists perhaps perceive these pro-moieties as potential sources of toxicity problems (see below). Furthermore, an aryl pro-moiety may unfavorably influence on solubility. 

In conclusion, we note the paucity of metabolic data on sulfuric acid esters, compared to the wealth of information on esters of N- and P-containing acids. One of the reasons for this state of affairs is presumably a lack of interest of medicinal chemists in preparing esters of S-containing acids. But because of the numerous applications of such compounds, is it hoped that more metabolic data will become available in a near future. 

One of the most important phase II conjugation reactions is that catalyzed by the glucuronyl transferases. A number of functional groups have the potential to be glu-curonidated as shown in Table 7.3, but phenol and carboxylic acid functions are of prime importance to the medicinal chemist. 

Selection of the reagents was based on the Pfizer internal compound collection which allowed speedy acquisition of any selected compound. A set of primary amines, secondary amines, and carboxylic acids which were not commercially available were chosen for consideration. These acids and amines were designed by medicinal chemists via a Pfizer internal screening file enrichment effort to be novel and diverse, and more importantly, were not part of any existing Pfizer fragment collection. The MW... 

Medicinal chemists have used isosterism for the design of safe, effective drug substances for many years. During the development of anti-ulcer medications, for example, it was found that metiamide (38) greatly reduced acid secretion in the gastrointestinal tract by antagonizing H2-receptor sites. Its potential as auseful anti-ulcer medication was lessened by adverse effects caused by the thiourea moiety, a toxicophore (Table 4.1). This moiety is essential for H2-receptor blockade, but bestows toxicity. 

Oxadiazoles have often attracted the attention of medicinal chemists as stable bioiso-steres of metabolically labile esters. 1,3,4-Oxadiazoles are generally prepared by cyclodehydration of 1,2-diacylhydrazines or their equivalents. Symmetrical 2,5-disubstituted examples were able to be rapidly prepared in a one-pot condensation-cyclodehydration of benzoic acids (2 equiv) with hydrazine dihydrochloride, in the presence of... 

In conclusion, the CAI activity of spiro-(3-lactams, their antiviral and antibacterial properties, their potential as efficient (3-tum nucleators and (3-tum mimetics, and their application as synthons for a,a-disubstituted (3-amino acids motivated synthetic and medicinal chemists to design novel spirocyclic (3-lactams. Several approaches to the stereoselective synthesis of spiro-(3-lactams have been described in this review. However, ketene-imine cycloaddition (Staudinger Reaction) shows much versatility for the access to diversely functionalized spiro-(3-lactams. In addition, we have developed a facile route to novel spiro-(3-lactams by using... 

It has been found that viruses (Appendix 10) utilize a number of virus specific enzymes during replication. These enzymes and the processes they control are significantly different from those of the host cell to make a useful target for medicinal chemists. Consequently, antiviral drugs usually act by either inhibiting viral nucleic acid synthesis, inhibit attachment to and penetration of the host cell or inhibit viral protein synthesis. 

The successive discoveries of cephalosporin C (1945), cephamycin (1971), thienamycin (1976), clavulanic acid (1975), nocardicin (1976), sulfazecin (1981), etc. The structural diversity found in the natural compounds inspired the medicinal chemists for side-chain modifications of the penam and penem cores (see Section 2.03.11). 

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