James A. Linn

SOLID-PHASE SYNTHESIS OF TRISUBSTITUTED GUANIDINES

Abstract The solid-phase synthesis of trisubsituted guanidines is reported via aza-Wittig coupling of a solid-supported alkyl iminophosphorane with an aryl or alkyl isothiocyanate to generate the corresponding solid-supported carbodiimide which is then reacted with a primary or secondary amine to afford the desired trisubstituted guanidines.

Discovery of thiophene inhibitors of polo-like kinase.

The discovery and development of a series of thiophenes as potent and selective inhibitors of PLK is described. Identification and characterization of 2, a useful in vitro PLK inhibitor tool compound, is also presented.

New synthetic approaches to estrogen receptor modulators: Imidazo[1,2-a]pyridines

Constrained triarenes have been important templates for selective modulation of the estrogen receptor (ER). For our ER program, we sought an unexplored, synthetically accessible heterocyclic template capable of bearing a broad range of pharmacophores. Traditional approaches to these therapeutics such as raloxifene have relied on an alkoxy moiety to link the arene-based scaffold to the modulating amine group. Alternatively, aryl halide-mediated introduction of alkylene or aryl side chains has not been studied extensively. The synthetic incorporation of pharmacophoric side chains that are carbon-linked to a novel imidazopyridine-based ER recognition motif is disclosed.

Antirhinovirus structure—activity relationships of 6-substituted-9-(4-methylbenzyl)-2-trifluoromethyl-9H-purines

Abstract To evaluate the effect of different 6-substituents on antirhinoviral activity, a series of 6-substituted-9-(4-methylbenzyl)-2-trifluoromethyl-9 H -purines was synthesized and tested. A matrix map of space adjacent to the 6-position was constructed to facilitate structure—activity analysis. This study provided evidence that a lipophilic pocket exists on the virus capsid surface, which accomodates the methyl group of the 6-methylaminopurines.

1,4-Diazabicyclo[2.2.2]octane (DABCO)-catalysed hydrolysis and alcoholysis reactions of 2-amino-9-benzyl-6-chloro-9H-purine

2-Amino-9-benzyl-6-chloro-9H-purine 1 is hydrolysed in refluxing water in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) to give 2-amino-9-benzyl-1,6-dihydro-6-oxo-9H-purine 3; however, 1 reacts with hydroxide ion at ambient temp., or analcohol and potassium carbonate at elevated temperatures, in the presence of DABCO togive 3 or 6-alkoxy-2-amino-9-benzyl-9H-purines 4–8, respectively.

Solid phase synthesis of 1,3,5-trisubstituted pyridin-2-ones

Abstract The solid phase synthesis of 1,3,5-trisubsituted pyridin-2-ones is reported via selective 1 NH- alkylation of 3-amino-5-carbomethoxy-1 H -pyridin-2-one with a solid-supported halo-acid. Coupling of an acid to solid-supported 3-aminopyridinone was followed by saponification of the methyl ester to give the acid. Activation of the acid via the pentafluorophenyl ester allowed reaction with an amine, and cleavage from the solid support with TFA:H 2 O (95:5) provided 1,3,5-trisubstituted pyridin-2-ones.

6-(3-Fluoroanilino)-9-(substituted-benzyl)-2-trifluoromethyl-9H-purines with antirhinovirus activity

Abstract A series of 6-(3-fluoroanilino)-9-(substituted-benzyl)-2-trifluoromethylpurines was synthesized and tested for antirhinovirus activity. Most of the compounds were prepared by alkylation of a 6-anilino-2-trifluoromethylpurine with a benzyl halide or by amination of a 6-chloro-9-benzylpurine with an aniline. Compounds with a variety of para -benzyl substituents had activity against rhinovirus serotype 1B. The 6-(3-fluoroanilino)-9-(3-fluorobenzyl)-2-trifluoromethylpurine 15 had good activity (IC 50 s = 0.4–13 μM) against 80% of the 47 serotypes tested, but pharmacokinetic studies indicated poor oral bioavailability.

Acyclic Nucleosides. Synthesis and Antiherpetic Activity of 9-[[[2-Hydroxy-1-(Hydroxymethyl)Ethyl]Thio]Methyl]Guanine and 1-[[[2-Hydroxy-1-(Hydroxymethyl)Ethyl]Thio]Methyl]Cytosine

Abstract The synthesis and antiherpetic activity of 9-[[[2-hydroxy-1-(hydroxymethyl)ethyl]thio]methy1]guanine (4) and 1-[[[2-hydroxy-1-(hydroxymethyl)ethyl]thio]methy]cytosine (6), the side-chain thio analogues of ganciclovir (3) and BW A1117U (5), are described. The sidechain synthon 1,3-bis(benzyloxy)-2-[(chloromethyl)thio]propane (11) was prepared in four steps from 1,3-bis(benzyloxy)-2-propanol (7). Alkylation of 2-amino-6-chloro-9H-purine with 11 provided the intermediate 9-substituted-2-amino-6-chloropurine 12, which was conveniently converted to 4 in two steps. Reaction of a fivefold excess of cytosine with 11 provided the desired 1-isomer 14, which was debenzylated to give 6. In contrast with ganciclovir (3) and BW A1117U (5), neither 4 nor 6 had significant in vitro activity against human cytomegalovirus.

Synthesis of C-1′-Branched Acyclic Nucleosides

Abstract Two C-1′-branched acyclic thymine derivatives, 1-[2-hydroxy-1-(2-hydroxyethoxy)ethyl]thymine and 1-[3-hydroxy-1-(2-hydroxyethoxy)-propyl]thymine were synthesized by a novel iodine-activated reaction of a tolylthio derivative with ethylene glycol. This synthetic method provides a potentially versatile synthetic entry to C-1′-branched acyclic nucleosides.