Some Closely Related Compounds

The reversibility of lactone hydrolysis in HMG-CoA reductase inhibitors has been demonstrated at gastric pH and temperature (pH 2.0, 37°) [186], For the prodrug lovastatin (8.148), reversible lactone hydrolysis to its active hydroxy acid (8.149) occurred with a f1/2 value of ca. 1 h and an equilibrium constant close to one. Similar results were obtained for some closely related compounds. In contrast, this reversible hydrolysis was much slower under the nearly neutral pH conditions of the intestine. 

The present review is to be regarded as a continuation of Fletcher s article1 the facts described therein will not be repeated here unless required for the understanding of recent developments. Because of the considerable expansion of cyclitol chemistry, it is not practicable to cover, as Fletcher did, all compounds of the cyclitol group. Only the inositols, the quercitols, and the inosamines, their derivatives, and some closely related compounds will be discussed the tetrahydroxycyclo-hexanes and -hexenes, and quinic and shikimic acids—on which subjects many important papers have appeared—are not reviewed here.3... 

Figures for K, the dissociation constant of the enzyme-inhibitor complex, obtained under strictly comparable conditions with mouse-liver preparations, are shown in Table VIII for D-glucaro-1,4-lactone and some closely-related compounds, all of which act competitively. Table IX gives figures obtained with the enzyme from female-rat preputial gland and various substrates within the limits of these experiments, Kt for boiled D-glucarate or boiled galactarate solutions was little affected by changes in the purity of the enzyme or the pH of test. In accordance with theory, similar values of Ki for any one inhibitor were obtained with different substrates, with the notable exception of o-nitrophenyl /8-galacturonide.

The mass spectra of columbin (97) and some closely related compounds have been published and discussed.22b The most prominent cleavage reaction possibly involves a cyclic mechanism in which one molecule of C02 is eliminated and a stable vinylfuran ion is produced, (97)—>[98] ... 

Crystalline penicillin prepared synthetically was obtained for the first time by Professor du Vigneaud and collaborators (6). One of the major problems in their work was that of isolating crystalline active material from a reaction mixture originally containing approximately 0.1% of active material. Previous to, their work, extensive attempts by several laboratories to isolate or even to increase the activity had been so discouraging that many workers considered the activity to be due to some closely related compound. However,... 

The NMR spectra of the parent compounds of the pyrido-[2,3-d]- and -[3,4- f]-pyridazine systems have been studied, together with those of some closely related derivatives parent compound, 282). In the pyrido[4,3-c]pyridazine series, only the spectrum of the dihydro compound (302) has been recorded <79X2027). 

In the [3,2-c ] series the spectra of the parent compound and some closely related analogues have been compared with those predicted from MO calculations of electron densities. The results confirm the predicted occiurence of a considerable degree of bond localization in these compounds <80KGS54l), as was previously found in their deaza (cinnoline) analogues <67JCS(B)1243). Other comparisons of NMR values with those expected from MO calculations for a series of azanaphthalenes have included some results with pyridopyridazines <75MI21500). 

A potential problem encountered in these determinations is the ion suppression encountered in the presence of polar/ionic interfering materials which compete with the analyte(s) for ionization (see Section 4.7.2 earlier). Many of these analyses therefore involve some degree of off-line purification and/or an appropriate form of chromatography. Since it is not unusual to encounter closely related compounds that are not easily separated, it is also not unusual to employ both of these approaches, as in the following example. This illustrates the use of HPLC as a method of purification and demonstrates that highly efficient separations are not always required for valuable analytical information to be obtained. 

No product has as yet been isolated that is believed to have the bromonium ion ring intact, but some closely related ionic compounds are known. The latter compounds could have the bromonium and iodonium structure but their colors and the probable stability of the alternative carbonium, ion make it unlikely.282... 

Methods can be based on some preconceived concept of bonding, with ionic and covalent extremes, or on pattern recognition based on the periodic table. Miscellaneous methods of limited applicability link bond strength with other physical properties. The a priori calculation of heats of formation by wave mechanics is possible in theory. In practice, the most widely applied method incorporates experimental data to derive atom or bond parameters which can then be used for calculations on closely related compounds. 

A mass transfer coefficient determined from some subsurface soil column elution studies was inverse log-linearly related to the octanol-water partition coefficient (i.e., K0Vf) for closely related compounds, and polarity in the molecule caused an additional decline in the mass transfer coefficient. 

Recently, CE has been developed for the analysis of drug substances. It is not employed with great frequency for quality control (owing to inherent sensitivity issues), but on occasion, CE procedures can be employed when HPLC procedures have failed to adequately measure the impurities. CE is particularly useful for the separation of closely related compounds such as the diastereomers and enantiomers of compounds with more than one chiral center. Figure 1.8 illustrates the separation of the diastereomers quinine (QN) and quinidine (QD) and some impurities using CE [17]. 

Comparison of carbon-13 shifts of some phosphorus compounds and some closely related ethers, sulphides and amines... 

Although this was not appreciated at the time, these compounds were first handled by Busch and Becker in 1896. Their study continued until a more extensive report by Busch and Schmidt was published in 1929,195 However, Busch and his co-workers were apparently unaware of some closely related work reported by von Pechmann in 1896. These earlier studies have been interpreted by Farrar, extended by Christopherson and Treppendahl, and brought to a definitive conclusion by the Sheffield group. This history is an interesting facet of the development of the chemistry of meso-ionic heterocycles. 

No examples of true leuco derivatives of the most common aminochromes with a 3-hydroxyl group (i.e. 3,5,6-trihydroxyindolines) have been isolated. However, such derivatives have been obtained from some aminochromes (or closely related compounds) without a 3-hydroxyl group, and these leuco compounds can be very easily reoxidized to the corresponding aminochromes. One of the best known examples of a reaction of this type is the very facile oxidation of leuco-rubreserine (20) to rubreserine (21).101,102... 

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