Medicinal chemistry thiophenes

Thiophene is a usefiil template for four-carbon homologation via reduction [9], as well as a bioisostere of the benzene ring and other heterocydes in medicinal chemistry. Thiophene is a n-electron-excessive heterocycle. It favors electrophilic substitution, which, similar to metalation, takes place preferably at the a-positions due to the electronegativity of the sulfiir atom [10]. In comparison to the oxygen atom in fiiran, the sulfiir atom in thiophene has lower electronegativity, so its lone pair electtons are more effectively incorporated into the aromatic system. The aromaticity of thiophene is in between that of benzene and fiiran. As a consequence, the difference in reactivity of a-halothiophenes and 3-halothiophenes is not as pronounced as that of the corresponding halofiirans. 

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity, nie synthesis of this compound starts by a multi-step conversion of hydroxy thiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycinc ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 (shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22]. 

Benzothiophenes have always been of interest for medicinal chemistry and can be found in a number of marketed drugs such as Sertaconazole (Gineder-mofix), Zileuton (Leutrol) and Raloxifene (Evista). The classical synthesis of benzo thiophenes starts from thiophenols, reacting with bromoacetaldehyde dimethyl acetal, followed by cycUzation using strong acid. An alternative and more convenient route was also described starting from benzaldehydes which... 

Ferreira, I.C.F.R. Calhelha, R.C. Estevinho, L.M.. Queiroz, M.J.R.P. (2004). Screening of antimicrobial activity of diarylamines in the 2,3,5-trimethylbenzo[b]thiophene series a structure-activity evaluation study. Bioorganic Medicinal Chemistry Letters, Vol.l4, No.23, (December 2004), pp. 5831-5833, ISSN 0960-894X... 

The coupling of thiophene derivatives, particularly thiopheneboronic acids, is frequently employed in medicinal chemistry and also in materials science. In a recent example 2-thiopheneboronic acid was coupled with a triazolopyridine derivative (6.4.) in the presence of [1,1-bis(diphenylphosphino)ferrocenyl]palladium dichloride in 83% yield6... 

Much of the current interest in benzo[ ]thiophene chemistry owes its origins to the wide range of biological and other activities shown by many of its derivatives. In medicine, benzo[ ]thiophene derivatives have been patented as laxatives,7 contraceptives,8 and antiinfluenza agents.9 In... 

The electron-rich thiophene and benzothiophenes are widely used as isosteres of their phenyl cousins in medicinal chemistry. These ring systems can be found in many pharmaceuticals with varied therapeutic applications such as the inhibition of platelet aggregation, treatment of asthma, chronic obstructive pulmonary disorder (COPD), bipolar disorder, psychosis, and prevention of osteoporosis, among many others. ... 

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. 

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