Quinine analogs

In 1997 scientists from SmithKIine Beecham published a series of quinine analogs as CGRP antagonists (Daines et al.1997, W09709046). These compounds displayed only weak affinities for the human CGRP receptor in the micromolar range and were therefore not of great importance (Daines et al., 1997). 

Daines, R.A., Sham, K.K.C., Tagged, J.J., Kingsbury, W.D., Chan, J., Breen, A., Disa, J., Aiyar, N. Quinine analogs as non-peptide calcitonin gene-related peptide (CGRP) receptor antagonists, Bioorg. Med. Chem. Lett. 1997, 7, 2673-2676. 

Rabe69,70 and others,71-75 carrying out syntheses of quinine analogs and isomers, used this method for building up the quinuclidine ring. In these cases the starting compounds were haloketone deriva-... 

These methods were used for the preparation of quinuclidine,301114 117 2-,23,24 g 24 ancj 4-alkylquinuclidines,25 and quinuclidine-2-carboxylic acid.118 Prelog s attempts to prepare quinine analogs by quinuclidine ring closure starting from the tribromoalkyl derivative (57) failed.119... 

Use of 2-formylquinuclidine (75) in reactions with organomagnesium compounds led to a new method for the synthesis of quinuclid-2-ylcarbinols (94), which are quinine analogs.145... 

Fig. 14.1 A CYP2D6 inhibitor HypoGen pharmacophore model derived from quinidine and quinine analogs (Hutzler et a I., 2003) showing (a) the mapping of a training set compound, (b) the substrate debrisoquine...

Hutzler JM, Walker GS, Wienkers LC (2003) Inhibition of cytochrome P450 2D6 structure-activity studies using a series of qui-nidine and quinine analogs. Chem Res Toxicol 16, 450-459. 

The stereochemistry of the product is determined by step a, in which the proton is transferred from the quinine to the coordinated carbonyl, and the quinine is considered associated with the substrate making it more susceptible to nucleophilic attack by the cobalt(I) (Fig. 3). The mechanism is analogous to some biological oxidoreductase systems, where the site that determines the stereochemistry is remote from the active cata-... 

The analogous reagent prepared from (-)-quinine and LiAlD4 reduced arenecarbaldehydes to the corresponding (S)-( + )-l-deuterio alcohols in 16 to 35% e.e. (86). 

C9-epi-122 98% conv. (99% ee) after 30h, respectively (Figure 6.40). This structure-efficiency relationship supported the results already published by the Soos group for quinine- and quinidine-derived thioureas (Figure 6.39) [278]. C9-epimeric catalysts were found to be remarkably more efficient in terms of rate acceleration and stereoinduction than the analogs of natural cinchona alkaloid stereochemistry. This trend was also observed for the corresponding (thio)ureas derived from DHQD as shown by the experimental results in Figure 6.40 [279]. 

Many 1-azaquinolizinium compounds have been reported to be fluorescent and 2-(p-tolyl)-l -azaquinolizinium ion (240) and some analogs, when excited by irradiation at 340 nm, show a luminescent intensity comparable with that of quinine sulfate (74JPR875). 

In view of the high chemotherapeutic activity of Cinchona alkaloids, of which quinine is the most important as an antimalarial medicine, scientists of many countries have spent much time investigating syntheses of quinine and its analogs. 

The suppression of malarial fever by quinine is etiological. However, quinine also reduces other febrile temperatures to normal, analogous to the other antipyretic drugs, i.e., by adjustment of the temperature-regulating centers, primarily through increased heat loss, assisted somewhat by diminished heat production. 

Under similar oxidative conditions, with activation of the aromatic C-H bond, some arenes could be used directly as aryl sources [41]. Unfortunately, by analogy with the Friedel-Crafts acylation, this reaction is regioselective for very few substrates only. High regioselectivity was, however, obtained if coordinating substituents on the arenes facilitate an orthopalladation reaction by a Pd(II) species [42]. After carbometallation and reductive elimination, Pd(0) is released, which has to be converted into the initial Pd(II) species in an extra oxidation step. Usually, quinines are used for this purpose, but in combination with certain heteropolyacids as cocatalysts even molecular oxygen can be employed as the oxidant. 

Exploiting the structure-based strategy, the quinuclidinyl and the piperidinyl side chains of quinine (QN) and mefloquine (MF) were, respectively, substituted with a ferrocene moiety while maintaining a basic amino group (Fig. 16). In vitro, lower activities than the parent compounds were reported [106], In acidic aqueous solution, these ferrocenyl analogs seemed to be unstable, leading to the formation of the presumably inactive carbeniums. 

The description above bears some resemblance to the reversible folding/unfolding of proteins. A speculative conclusion from this analogy would be that an increase in temperature should be followed by an increased exposure of hydrophobic side-chains. Hypothetically, an increase in bitter taste, relative to a standard quinine solution, should be observed at elevated temperatures whether this is found in practice or not remains to be investigated. 

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