Thalidomide Barbiturates

Bromocresol green (3.8...5.4) aliphatic carboxylic acids[103,187 — 204] triiodobenzoic acid [205], derivatives of barbituric acid [206] amphetamine derivatives [207, 208] phenazones, morazone [209] alkaloids [91, 209] nephopam [210] phenyramidol metabolites [211] diethylalkylacetamide derivatives [212] zipeprol (Mirsol) [213] thalidomide and hydrolysis products [214] cyclohexylamine derivatives [215] herbicide residues [216]... 

The glutarimide best known to the lay public, thalidomide (40), owes its reputation not to efficacy, but to the wholly unanticipated and tragic teratogenic effects elicited by this compound. It might be noted that the very efficacy and lack of the usual barbiturate side effects shown by this drug led to its prescription as a hypnotic for expectant mothers. Condensation of the phthalimide of glutamic acid (39) with ammonia at elevated... 

The importance of producing pharmaceuticals in enantiomerically pure forms was brought to the public s attention with the thalidomide (Formula 4.2) tragedy in the early 1960s. Thalidomide, as a racemic mixture, was originally produced in 1953 as a sedative and a non-addictive alternative to barbiturates. It was later found that it alleviated many of the unpleasant symptoms of early pregnancy but by 1961 its use had been linked with an increase in the number of severe birth deformities and it was withdrawn. It... 

Thalidomide, a prescription drng nsed as a tranqniUzer and flu medicine for pregnant women in Enrope to replace dangerous barbiturates that cause 2000 to 3000 deaths per year by overdoses, was found to cause birth defects. Thalidomide had been kept off the market in the United States because of the insistence that more safety data be produced for the drug. 

Several other cyclic imidic compounds containing a piperidine-2,6-dione skeleton (glutethimide, pyrido- and amino-glutethimide, thalidomide) and having similar hypnotic-sedative activity as barbiturates were resolved on a vancomycin CSP [7,157],... 

Thalidomide was a sedative and a h)rpnotic that first went on sale in 1956 in West Germany. Between 1958 and 1960, it was introduced in 46 countries under 51 different trade names. It was first introduced in the UK market in April 1958 under the name Distaval. It enjoyed good sales because of its prompt action, lack of hangover and addiction observed with barbiturates, and apparent safety. 

Thalidomide was initially selected as Candidate K17. It was discovered from peptide research but promoted as being structurally related to barbiturate with hypnotic properties, beyond those of the classic barbiturate Luminal, but without toxicity. 

Thalidomide enhances the sedative actions of alcohol, barbiturates, chlorpromazine, and reserpine (118), perhaps by additive effects on their several pharmaco-djmamic actions (196), although other mechanisms have been described (197). 

Fig. 3.1 Thalidomide was developed as a non-addictive sedative as an alternative to barbiturates. Following its administration to pregnant women, it was found that the babies were bom with truncated limbs (phocomeUa). At the time this was perceived as a classic case of the pharmacological activity residing in one enantiomer (R-) and the undesirable toxicological effect residing in the other enantiomer. The simation is now known to be much more complex than this (see text and reference cited therein).

Animal studies have shown an increase in CNS depressant activity when thalidomide was given with alcohol, barbiturates, chlorpromazine and reserpine. ... 

There was no elear relationship between thalidomide eleatanee and the eoneunent use of enzyme inducers such as rifampicin (rifampin), or phenobarbitai in a study in patients with glioma. For the possible additive CNS depressant effect with barbiturates, see CNS depressants, above. 

Examples of complete resolutions on a preparative as well on an analytical scale are thalidomide (2), ifosfamide (3), praziquantel (4) mianserin (5) and barbiturates like (6) and (7). 

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