Alkaloids quinidine

Cinchona alkaloids quinidine gluconate injection quinine sulfate... 

The tetracyclic alkaloid quinine 1 and the diastereomeric alkaloid quinidine 2 share a storied history. Eric Jacobsen of Harvard recently completed (J. Am. Chem. Soc. 2004, 126, 706) syntheses of enantiomerically-pure 1 and of 2. For each synthesis, the key reaction for establishing the asymmetry of the target molecule was the enantioselective conjugate addition developed by the Jacobsen group. 

Following the development of synthetic antimalarial agents, such as chloroquine and mefloquine, the use of Cinchona alkaloid quinine declined. However, with the emergence of chloroquine-resistant and multiple-drug-resistant strains of malarial parasites, its use has become firmly reestablished. Quinine is the drug of choice for severe chloroquine-resistant malaria due to Plasmodium falciparum. In the U.S., the related alkaloid quinidine is recommended because of its wide availability and use as an antiarrhythmic agent. In many clinics in the tropics, quinine is the only effective treatment for severe malaria unfortunately, decreasing sensitivity of P. falciparum to quinine has already been reported from Southeast Asia. 

The mechanochemical technique has also been applied to the asymmetric opening of me o-anhydrides, catalyzed by the cinchona alkaloid quinidine (Scheme 8.4). A simple procedure affords the optically active dicarboxylic acid monoesters in high yields. Even mixtures of purely solid substrates react under these conditions, and no solvent is required, which significantly simplifies the product isolation step. ... 

These nitrogen-containing natural products, often with powerful biological properties, are not usually incorporated into target molecules. However, they are important in asymmetric syntheses as the foundations of many reagents and catalysts. Quinine 119 is familiar as an anti-malarial and an ingredient in tonic water. Quinine and its twin cinchona alkaloid quinidine 118 are referred to as pseudo enantiomers. Each occurs naturally as one enantiomer only but the two structures are nearly enantiomeric only the vinyl side-chains disturb the symmetry and they act as enantiomers. The vinyl side-chains are reduced and two molecules of, say, dihydroquinine (DHQ) are joined... 

From the data presented it is clear that introduction of the antibiotic simultaneously with an aqueous suspension of HDS leads to an increase in the maximum concentration of the preparation in blood from 2 to 21 p,g mL . The sharp increase in the absorption of the curative substance provides an increase in its biologic availability. Analogous effects were observed for substances of other classes, such as alkaloids (quinidine), carbohydrate (xylose), organic substances (voltarene). Thus, the stodies of absorption showed that maximum concentration of quinidine in... 

Use activity In medicine as an antihypertensive, tranquilizer, especially as anti-arrhythmic agent the latter activity corresponds to that of the Cinchona alkaloid quinidine by blockade of sodium channels inhibition of glucose uptake in mitochondria of cardiac muscle tissue. A. is poorly resorbable and has a low bioavailability. 

Keywords Alkaloids quinidine cinchona alkaloids cinchonidine cinchonine quinine... 

Among four major Cinchona alkaloids, quinidine and cinchonine were most active in the malaria therapy followed by quinine and cinchonidine. For example, quinidine is two- to threefold more active than quinine in both chloroquine-sensitive and chloroquine-resistant strains of P. falciparum [224]. Due to its cardiac... 

Today, three Cinchona species are cultivated for the production of quinine. C sticcirubra yields the red bark , C. legderiana the brown bark , and C. calisaya the yellow bark (Dewick, 2002). In addition to quinine, the barks contain significant amounts of three other quinoline alkaloids quinidine, the diastereomer of quinine, which is used as an antiarrhythmic, and 6-demethoxy analogs of the two alkaloids, cinchonine and cinchonidine. 

More recently, another group investigated this reaction with quinidine (10mol%) at 80 °C in 1,2-dichloroethane, and after two days the product was obtained with only 13% yield and 33% ee [12]. Under high-pressure conditions (lOkbar) and with cinchona alkaloids Matsumoto obtained the product with very high yields (87-100%) and low or moderate enantioselectivity. The best results in terms of enan-tioselectivity (51% ee) were observed in toluene with the alkaloid quinidine (Scheme 21.1 and Table 21.1). 

QuinidJne. Quinidine, an alkaloid obtained from cinchona bark (Sinchona sp.), is the dextrorotatory stereoisomer of quinine [130-95-0] (see Alkaloids). The first use of quinidine for the treatment of atrial fibrillation was reported in 1918 (12). The sulfate, gluconate, and polygalacturonate salts are used in clinical practice. The dmg is given mainly by the oral (po) route, rarely by the intravenous (iv) route of adniinistration. It is the most frequentiy prescribed po antiarrhythmic agent in the United States. The clinical uses of quinidine include suppression of atrial and ventricular extrasystoles and serious ventricular arrhythmias (1 3). 

The cinchona alkaloids of practical importance are quinine, quinidine, cinchonine and cinchonidine, but, in addition, over twenty others have been isolated from cinchona and cuprea species. Their names and formulae are as follows ... 

For the separate determination of the four principal components in the total alkaloids, the method in general use is based on the isolation of quinine and cinchonidine as d-tartrates, of cinchonine as the base in virtue of its sparing solubility in ether, and of quinidine as the hydriodide. Types of this method have been described by Chick, and special modifications designed for use in the analysis of totaquina are given in the British Pharmacopoeia 1932 and in a special report by the Malaria Commission of the League of Nations. Goodson and Henry have critically examined this process and shown that, with care, it gives satisfactory... 

Cmchonine, C19H22ON2. This alkaloid is usually present in cinchona and cuprea barks. One of the best sources is Cinchona micrantha bark. It occurs in the crude quinine sulphate mother liquors. The mixed alkaloids recovered from these may be extracted with ether to remove quinidine and cinchonidine and the insoluble residue boiled with successive small quantities of alcohol, from which cinchonine crystallises on cooling. The crude alkaloid is neutralised with dilute sulphuric acid and the sulphate recrystallised from boiling water. Cinchonine so prepared contains quinidine, from which it may be freed by crystallisation from boiling alcohol until it ceases to exhibit fluorescence in dilute sulphuric acid. It will then still contain 10 to 15 per cent, of dihydrocinchonine, which may be removed by reprecipitation as the cuprichloride, B. 2HC1. CuClj, or by the simpler mercuric acetate process of Thron and Dirscherl. ... 

The ethereal solution of crude quinidine and cinchonidine, obtained as described under cinchonine, is shaken with dilute hydrochloric acid, the excess acid neutralised with ammonia and sodium potassium tartrate added. The base is recovered from the precipitated tartrate by dissolving the latter in dilute acid and pouring the filtered solution in a thin stream, slowly and with constant stirring, into excess of ammonia solution. The crude alkaloid is converted into the neutral sulphate, and this recrystallised... 

Cinchotine (Hydrocinohonine, more correctly dihydrocinchonine, Cinchonifine, >fs-Cinchonine), C19H24ON2. This alkaloid occurs in commercial cinchonine to the extent of about 14 per cent. and may be prepared from this source by the mercuric acetate process, or more conveniently by the hydrogenation of commercial cinchonine previously freed from quinidine. ... 

These results indicate that quinine and quinidine differ in structure from cinchonine and cinehonidine in containing a methoxyl group in position 6 in a quinoline nucleus. The identity of the other oxidation products, meroquinenine, cincboloiponic and loiponic acids, in all foiu" cases indicates that the second half of the molecule has the same structure in all four alkaloids. Further, this second half must be joined to the quinoline nucleus at position 4 by a group capable of conversion into carboxyl. 

These changes have been experimentally demonstrated only for quinine and quinidine, but in view of the optical identity of the quinuclidine degradation products from the principal cinchona alkaloids, it may be assumed that in all of them the total dextrorotatory effect at C and C is made up of a dextrorotatory effect at C exceeding a laevorotatory effect at C. ... 

In the ease of the dextrorotatory pair, einchonine and quinidine, these hydroxydihydro-bases may lose a molecule of water between the two. CHOH. groups at positions 9 and 10 with the formation of ether oxides, represented by formula (C) of which there should be a pair of stereoiso-merides for eaeh alkaloid. This type of compound has not been obtained from the laevorotatory bases, einchonidine and quinine. 

As found in commerce, the cinchona alkaloids are not necessarily pure quinidine, for example, may contain up to 30 per cent, of dihydroquinidine. Working with carefully pmdfied specimens of the four chief cinchona alkaloids and their dihydro-derivatives, Buttle, Henry and Trevan found the results recorded in the table (p. 471) in tests with malaria in canaries. The figures in brackets represent the dose of quinine necessary to produce the same degree of protection as unit dose of the alkaloid named. To the results are also added the data found later by the same authors, with Solomon and Gibbs, for some of the transformation products (p. 449) of quinine and quinidine. The Roman numeral at the head of each column refers to the type formula on p. 470. 

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