Tetrazolic acid

Acid-like includes carboxylic acid, tetrazole, sulphonamide (ionizable NH) etc. Amide like includes (substituted) amide. Tetrazole, sulfonamide, etc. Ester-like includes tertiary amide (substituted, no NH) ureas, urethane, sulfonamide, etc. 

Cyclic versus non-cyclic replacements a. Cyclic replacements of non-cycllc functional groups e.g. phenol/Indole substitutions e.g.carboxylic acid/tetrazole substitutions ... 

Yoo et al.97 used the solid support not only as a tether for the synthesis of biphenyltetrazole derivatives, but also as a protecting group for the acidic tetrazole moiety. The latter functionality was prevented from interfering with subsequent chemistry. Specifically, a support-bound dihydropyran was... 

CA 16,3399(1922) (Cryst compds of mixed crysts double salts contg the K salt of Dinitro-dinitrosobenzene and difficultly sol salts of hydrazoic acid, Tetrazole derivs, etc are suitable for use in initiators) 57)H.Rathsburg,BritP 185,55 5... 

The fatty acid tetrazole, 5-(ll-methoxyundecyl)-l-(phenylmethyl)-lH-tetrazole, (II), and derivatives have has been prepared and is discussed (3). 

The prototypical representatives of the group are the carboxylic acids. However, a huge number of bioisosteres such as sulfonic or phosphonic acids, tetrazoles or 3-hydrox-yisoxazoles are available (see Chapter 15). In addition functions like esters, amides, peptides, aldehydes, primary alcohols and related functions can work as prodrugs or bioprecursors (see Chapter 36). 

Compound 19 is a potent benzazepinone growth hormone secretagogue that suffers from poor bioavailability in dog (F = 2%) The molecule exists in a zwitterionic form that is presumably the cause for the poor bioavailability. Two key structural modifications were required to improve the PK profile. The acidic tetrazole was replaced with a number of amide and urea substituents before identifying the key methyl urea moiety, which resulted in an 8-fold increase in activity over 19. Further, shortening the amino acid side chain decreased the pK of the amine from 9.2 to 7.5. The combination of changes provided compound 20, which resulted in a 60-fold increase in activity over parent compound 19 and increased oral bioavailability in dogs to 24%. 

Noting the similarity of (NH) tetrazole pKs to those of carboxylic acids, tetrazoles have often been used as bioequivalent replacements for CO2H, and as general variants, in pharmacologically active compounds (Chapter 33). The acid replacement extends to the tetrazole analogue of proline (p. 567), which is more solnble than proline itself, but retains its catalytic properties for condensation reactions. 

Pemirolast, with an acidic tetrazole isosteric replacement for a carboxylic acid functionality, is used topically in the eye to prevent itching associated with allergic conjunctivitis. It is an inhibitor of the release of histamine and other inflammatory mediators, including leukotrienes. Significant use as a systemic agent has been reported, and it has been shown to be of value in preventing restenosis after percutaneous coronary angiopathy. 

In the Pfizer in-house IC50 data set, there are 1059 pairs of compounds consisting of a carboxylic add and the equivalent tetrazole that have been tested in the same assay. In order to define a binding environment for the acid/tetrazole, an attempt was made to map each pair to its most relevant pocket in the PDB ligand database by identifying the most similar cocrystallized ligand in a protein from the same family. 

Each compound pair was classified as the acid, tetrazole, or neither being better using a threefold potency window as a cutoff. The effects of burial on the relative successof tetrazole and acid are shown in Figure 10.10. As can be seen, in the general case, tetrazoles appear to be more potent than the equivalent acids, possibly because of their increased size (though the dogP values are systematically around 0.3 lower). 

Benzyl-protected amidites generally give better results than f-butyl amidites in the presence of the weakly acidic tetrazole, di-t-butyl phosphite esters have a tendency to lose a t-butyl group, leading to formation of the corresponding iZ-phosphonate 5 (12, 37) (Figure 4). Fortunately, this byproduct can be converted to the desired phosphate by treatment with iodine in pyridine (38). 

As in the case of compound XIII in the nicotinic acid series, the acidic tetrazole moiety has also been incorporated into a hexestrol analog to afford the hypocholesterolemic agent LII [163]. 

Selective Phosphitylation of the Primary Hydroxyl Group of Nucleosides. 5-Ethylthlo l//-tetrazole has been used for the selective S -phosphitylation of nucleosides. The commonly accepted mechanism involves protonation of a phosphoramidite by the weakly acidic tetrazole, followed by nucleophilic attack by tetrazollde ion giving a tetrazoyl phosphoramidite (2) (eq 2). The nucleophilic attack of the 5 -hydroxyl group then produces the phosphite triester, which is then carried through further transformations (eq 3). ... 

A dual-activation way is invoked based on the similar widely accepted catalytic mode of activation for L-proline catalyst. In this context, the acidic tetrazole moiety activates the electrophilic imine by a hydrogen-bonding interaction, and the pyrrolidine moiety would activate the nucleophilic P-ketoester via formation of an enamine intermediate. The stereochemistry of the acidic tetrazole moiety seems to be crucial for the stereoselectivity in the final products. This... 

Retinoid structures have been synthesized in which the terminal functional group is formally incorporated in a heterocyclic ring system. (all- )-Retinonitrile (156) reacted with aluminum azide to give the acidic tetrazole (635) (Dawson et aL, 1980). 

Free 5-ATZ contains the acidic tetrazole ring and the basic amino group. Its chemical behavior is similar to that of amino acids. Free 5-ATZ forms a monohydrate that loses water of crystallization above 100 C. The melting temperatore of 5-ATZ is 203 °C [2]. This compound is very hygroscopic, soluble in hot water, acetone, and ethanol [1,2]. 

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