Biologically active thiophenes

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. 

Nucleophilic aromatic substitution reactions of nitro-substituted thiophenes have been utilized to prepare biologically active thiophenes including reverse transcriptase <02H(57)97> and nitric oxide synthase <02JHC857> inhibitors. The addition-elimination reaction of 2-chloro-3-nitrothiophene (56) with metallated indole 57 afforded 58 which was transformed into the corresponding thiophene-fused azepino[5,4,3-cd]indoles 59 <02H(57)1831>. 

Press, J. B. Biologically Active Thiophene Derivatives Revisited 1983-1988. In The Chemistry of Heterocyclic Compounds, Gronowitz, S., Ed. Wiley-Interscience New York, NY, 1991 Vol. 44, pp 397-502. 

Fig. 3 Potentially biologically active thiophene-2-sulfonamides and thiophene-3-sulfonamides [150, 151]...

Pharmaceuticals and Agrochemicals. Thioglycohc acid and its esters are useful as a raw material to obtain biologically active molecules. In cephalosporine syntheses, (4-pyridyl)thioacetic acid [10351 -19-8] (65) and trifluoromethane (ethyl) thioglycolate [75-92-9] (66) are used as intermediates. Methyl-3-ainino-2-thiophene carboxylate can be used as intermediate for herbicidal sulfonylureas (67) and various thiophenic stmctures (68). 

Benzo[6]thiophene, 4-N-methylcarbamoyl-biological activity, 4, 913 Benzo[6]thiophene, 2-methyl-3-vinyl-cycloaddition reactions, 4, 795 Benzo[fc]thiophene, 2-( 1 -naphthyl)-synthesis, 4, 915 Benzo[6]thiophene, 2-nitro-reduction, 4, 815 synthesis, 4, 923 Benzo[6]thiophene, 3-nitro-cycloaddition reactions, 4, 789 Benzo[6]thiophene, 4-nitro-synthesis, 4, 923 Benzo[6]thiophene, 5-nitro-synthesis, 4, 923... 

Benzo[b]thiophene-2,3-quinone, 5-chloro-oxidation, 4, 824 Benzothiophenes, 4, 863-934 biological activity, 4, 911-913 intramolecular acylation, 4, 761 mass spectrometry, 4, 739 metabolism, 1, 242 phosphorescence, 4, 16 reactivity, 4, 741-861 spectroscopy, 4, 713-740 structure, 4, 713-740 substituents reactivity, 4, 796-839... 

B. Compounds of Pharmacological Interest During recent years a certain slackening in interest in the preparation of thiophenes for pharmacological studies can be noticed. As an excellent review on the biological activity of thiophenes has recently been published, the latest developments in this field will only briefly be sketched. 

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-... 

The synthesis of methylimidazole-thiophene compounds was reported by Santos et al. [46] and has been included for completeness, although no biological activity has been reported for these heterocycles. The formation of these imidizole-thiophenes (24a-d), occurs via the condensation of 2-formylthiophene (25) with benzil derivatives (26a-d) in the presence of ammonium acetate to yield the imidazole-thiophene compounds (27a-d). These compounds can then be N-methylated by treatment with iodomethane in... 

Despite the fact that earlier studies indicated little promise, the search for superior biologically and pharmacologically active thiophene compounds continued. 

Benzoheteropines with fused pyrrole, furan, and thiophene rings, of great interest because of their biological activity, are surveyed by Dr. D.O. Tymoshenko of the Albany Molecular Research Institute, New York. These compound classes were considered in both the first and second editions of Comprehensive Heterocyclic Chemistry as part of a host of related multi-atom heterocyclic systems. Other specialized reviews have appeared. However, the present survey is the first comprehensive treatment. 

Oximes and their derivatives are widely used in organic synthesis. A number of reviews are devoted to the chemistry and biological activity of oximes and their derivatives The synthesis, reactions and biological activity of oximes containing a heterocyclic substituent, e.g. furan and thiophene", indole and isatin, pyridine, pyrrole, quinoline and five-membered heterocycles with two heteroatoms have been reviewed. 

A recent extension of this methodology includes condensation of 44 with a variety of substituted benzaldehydes, furfurals, and thiophene carboxaldehydes afforded analogues of 48 in good to excellent yield as shown in Table 6.2 (Fig. 6.6). These products were completely characterized spectroscopically with an excellent discussion of the effects of substituents on the corresponding UV, IR, MS, and NMR spectra. Neutralization of 48 with sodium bicarbonate in aqueous ethanol produced the corresponding free bases uneventfully. These compounds were evaluated both as cyanine dyes and for biological activity. Condensation of 44 with ( )-3-(5-methylfuran-2-yl)-2-propenal affords the expected E, )-dienes 49a and 49b in 50 and 90% yield, respectively (Fig. 6.7). 

A number of non-fused thiophene derivatives also show biological activity including thiophenes which are HTV-l strain MDR inhibitors (e.g., 129) <99BMCL3411>, protein kinase C inhibitors (e.g., 130) <99BMCL2279>, antidepressants (e.g., 131) <99BMC1349>, and a GAB A-AT inactivator (4-amino-4,5-dihydrothiophene-2-carboxylic acid) <99JA7751>. 

Benzene and thiophene rings can of course often be interchanged in biologically active agents. The very broad structural latitude consistent with NSAID activity is by now a familiar theme as well. Preparation of the fused thiophene counterpart of the NSAID piroxicam (Chapter 11) starts with the reaction of thiophene (25-1), itself the product of a multistep sequence, with ethyl A-methylglycinate to give the sulfonamide (25-2). Treatment of that intermediate with a base leads to intramolecular Claisen condensation and thus the formation of the 3-ketoester (25-3). An amide-ester interchange with 2-aminopyridme (25-4) completes the synthesis of tenoxicam (25-5) [25]. 

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