Thiophene-containing drugs

The most important clinically useful class of thiophene-containing drugs are the antihis-taminics. Of those in clinical use, compounds based on the tripelennamine structure (361 Ar1 = 2-pyridyl, Ar2 = Ph) have been most widely used. These include methapyrilene (361 Ar1 = 2-pyridyl, Ar2 = 2-thienyl), thenylpyramine (361 Ar1 = 2-pyridyl, Ar2 = 3-thienyl), chloropyrilene (361 Ar1 = 2-pyridyl, Ar2= 2-(5-chlorothienyl)) and methaphenilene (361 Ar1 = Ph, Ar2 = 2-thienyl). It was the success in this field, immediately following World War II, coupled with the new availability of thiophene and homologs by the Socony-Vaccuum Process (Section 3.15.3.1) which led to the explosion in research on biologically active thiophenes. The thiophene antihistaminics are useful drugs, still used in clinical practice. 

Figure 7.3. The mechanism proposed for P450 bioactivation of the thiophene in tienilic acid to a reactive species that binds covalently to the protein (the protein nucleophile is denoted by Protein-XH). The structures of two other thiophene-containing drugs, ticlopidine and clopidogrel, that might be similarly activated are also shown.

The importance of thiophenes in medicinal chemistry can be highlighted by the enormous economic success of thiophene-containing drugs. Pharmaceuticals containing thiophenes such as duloxetine (Cymbalta), olanzapine (Zyprexa), tiotropium (Spiriva), raloxifene (Evista), and zileuton (Zyflo) had combined sales of more than 6 billion in the U.S. in 2010, while the blockbuster drug clopidogrel (Plavix) alone obtained sales in excess of 6 billion in the same year. 

Possible Liabilities of Furan- and Thiophene-Containing Drugs... 

Fig. 5.11 The stractures of three other thiophene-containing drugs. Ticlopidine, clopidogrcl, and OSI-930 may be activated by epoxide formation on the thiophene ring...

In contrast to the pyrrole and thiophene series, the furan nucleus occurs in many plant-derived terpenes such as 2.11. The most important furan-containing drug is 2.12, which reduces gastric acid secretion and is important in the treatment of ulcers. 

The blockbuster drug, clopidogrel (Plavix), is a thiophene-containing inhibitor of platelet aggregation and is used to treat a variety of conditions caused or aggravated by blood clotting. 

Potential toxicity arising from the furan and thiophene ring structures is a concern in designing potential drug leads, but potential leads should not be eliminated on those grounds alone. The success of current pharmaceuticals that contain furan and thiophene moieties is a clear indication that ftiran- and thiophene-containing therapies can be made safe, and even exploited as in the case of clopidogrel. 

The isosteric relationship of benzene and thiophene has often led medicinal chemists to substitute the sulfur containing heterocycle for benzene drugs in biologically active molecules. That this relationship has some foundation in fact is attested by the observation that the resulting analogs often possess full biologic activity. Alkylation of the diamine, 71 (obtained from aniline and the chloroethylamine), with 2-chloromethylthiophene affords the antihistamine methaphenylene (72) The correspond-... 

Recently, several drugs that contain the thiophene moiety have been removed... 

Thiophene seems to be very popular in Li Lilly drugs. Its dual selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for depression, duloxetine (Cymbalta), contains a thiophene. And its atypical antipsychotic drug olanzapine (Zyprexa) has a fused thiophene as its core structure. 

As biosteres of benzene, thiophene and benzothiophene have enjoyed much success in drug discovery. In fact, pharmaceuticals containing thiophene or benzothiophene moieties accounted for several billion dollars a year in sales through much of the 2000 s. Syntheses of many of these therapeutics are well known and provide excellent case studies in the chemistry of thiophenes and benzothiophenes and their utility. 

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