Barbiturates Coumarins

Reaction of chloroacetic acid with cyanide ion yields cyanoacetic acid [372-09-8] C2H2NO2, (8) which is used in the formation of coumarin, malonic acid and esters, and barbiturates. Reaction of chloroacetic acid with hydroxide results in the formation of glycoUc acid [79-14-1]. 

Maintenance doses widely vary among patients (e.g., from 1 to 20 mg/day for warfarin), and are influenced by diet (variable vitamin K intake) and medications that affect coumarin metabolism (decreased drug clearance e.g., cotrimoxazole, amiodarone, erythromycin increased clearance e.g., barbiturates, carbamaze-pine, rifampin). Thus, regular monitoring is needed... 

In the Diels-Alder reaction with inverse electron demand, the overlap of the LUMO of the 1-oxa-l,3-butadiene with the HOMO of the dienophile is dominant. Since the electron-withdrawing group at the oxabutadiene at the 3-position lowers its LUMO dramatically, the cycloaddition as well as the condensation usually take place at room or slightly elevated temperature. There is actually no restriction for the aldehydes. Thus, aromatic, heteroaromatic, saturated aliphatic and unsaturated aliphatic aldehydes may be used. For example, a-oxocarbocylic esters or 1,2-dike-tones for instance have been employed as ketones. Furthermore, 1,3-dicarbonyl compounds cyclic and acyclic substances such as Meldmm s acid, barbituric acid and derivates, coumarins, any type of cycloalkane-1,3-dione, (1-ketoesters, and 1,3-diones as well as their phosphorus, nitrogen and sulfur analogues, can also be ap-... 

Drugs that may affect repaglinide include CYP 450 inhibitors (eg, clarithromycin, erythromycin, ketoconazole, miconazole), CYP 450 inducers (eg, barbiturates, carbamazepine, rifampin), beta blockers, calcium channel blockers, chloramphenicol, corticosteroids, coumarins, estrogens, gemfibrozil, isoniazid, itraconazole, levonorgestrel and ethinyl estradiol, MAOIs, nicotinic acid, NSAIDs, oral contraceptives, phenothiazines, phenytoin, probenecid, salicylates, simvastatin, sulfonamides, sympathomimetics, thiazides and other diuretics, and thyroid products. 

Phenobarbital and Barbiturates, chloramphenicol, chlorpromazine, cortisol, coumarin anticoagulants,... 

The necessary amino aldehydes are accessible from widely available amino acids and amino alcohols. In addition to N,N-dimethyl barbituric acid shown in Figure 5.3, other 1,3-dicarbonyl compounds can be employed, such as cydohexane-1,3-diones or coumarines (Figure 5.5). 

Phenobarbital and other barbiturates1 Barbiturates, chloramphenicol, chlorpromazine, cortisol, coumarin anticoagulants, desmethylimipramine, digitoxin, doxorubicin, estradiol, phenylbutazone, phenytoin, quinine, testosterone... 

Dicarbonyl compounds, such as malonate derivatives, can also be classified under two categories. As well as reacting simply as a three-atom bis-electrophilic fragment (as in the synthesis of barbiturate 10.25 (page 77), an alternative reactivity is available. Condensation (by nucleophilic attack) of the active methylene carbon and electrophilic reaction at just one of the carbonyl groups is a two-atom nucleophilic/electrophilic profile, as seen in the preparation of coumarin 9.16. 

Tuberculous patients lacking in liver N-acetyl transferase who are treated with isoniazid are likely to develop polyneuritis (39). An enzyme abnormality is also responsible for the precipitation of acute intermittent porphyria by the barbiturate drugs (40). Likewise, the rare hereditary resistance to coumarin anticoagulant drugs is thought to be due to an enzyme deficiency (41). 

Barbituric acid derivatives, history and applications 88PHA827. Benzodiazepine receptor ligands as drugs 89FES345. Coumarine-based antioxidants 88KFZ1438. 

Other adverse effects Barbiturates and carbamates (but not benzodiazepines, buspirone, zolpidem, or zaleplon) induce the formation of the liver microsomal enzymes that metabolize dmgs. This enzyme induction may lead to multiple drug interactions. Barbiturates may also precipitate acute intermittent porphyria in susceptible patients. Chloral hydrate may displace coumarins from plasma protein binding sites and increase anticoagulant effects. 

Since spasms may be the result of disorders of the central nervous system, papaverine is administered frequently in the form of salts of acidic drugs, which, on their own, exert a sedative or analgesic action. Examples of such molecular combinations are papaverine diethyl barbiturate (m.p. 138°), papaverine dipropyl barbiturate, papaverine phenobarbiturate (Pavemal, m.p. 145-146°), and papaverine coumarin-3-carboxylate (m.p. 129°). 

Cases have been described in patients taking ethyl biscoumacetate who were treated with amobarbital, heptabarb, or secobarbital." Cases have also been described of apparent resistance to coumarins in patients taking barbiturates," and of bleeding in patients who were stabilised on a coumarin and a barbiturate when they stopped taking the barbitu-... 

The effects of the coumarins are substantially reduced by the barbiturates. Primidone is metabolised to phenobarbital and is expected to interact similarly. 

DaytonPG, Tarcan Y, Chenkin T, Weiner M The influence of barbiturates on coumarin plasma levels and prothrombin response. J Clin Invest (1961) 40,1797-1802. 

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