James L. Kelley

Novel 3-phenylprop-2-ynylamines as inhibitors of mammalian squalene epoxidase

The synthesis of a novel series of 3-phenylprop-2-ynylamines as selective mammalian squalene epoxidase inhibitors is described. Structure activity relationship studies led to the discovery of compound 19, 1-[3-(3,5-dichlorophenyl)-prop-2-ynyl]-3- methylpiperidine hydrochloride with an IC50 of 2.8 +/- 0.6 microM against rat liver squalene epoxidase. Against 23 strains of fungal squalene epoxidase compound 19 was found to be inactive.

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.

Chapter 15. Antiviral Agents

Publisher Summary Important advances in antiviral chemotherapy have been made with the food and drug administration (FDA) approval of idoxuridine, vidarabine, and trifluridine for the topical treatment of herpetic keratitis and of amantadine for oral treatment of all influenza A virus infections. Acyclovir, with its unique mechanism of action, although it was possible to share to some degree by a number of new antiviral pyrimidine nucleosides, may mark the beginning of a period of development of drugs with selective antiviral activity against several classes of viruses. This chapter discusses both new and old compounds with activity against DNA viruses and includes a brief update of the advances in the RNA area. Of the DNA viruses, the herpes group is the source of the most common viral illnesses in man. The family consists of herpes simplex virus (HSV) types 1 and 2 (cause of “cold sores,” encephalitis, eye, and genital infections), varicella zoster (VZV) (chickenpox and shingles), cytomegalovirus (CMV) (pneumonia, CNS diseases, and disseminated infections especially in neonates), and Epstein-Barr virus (EBV) (mononucleosis). All the herpesviruses share the characteristic of undergoing periods of dormancy. During that, they reside either in ganglionic sites or, in the case of EBV and possibly CMV, in lymphocytes. For reasons that are not well understood, these latent viruses may be reactivated to initiate recurrent or new forms of illness. Significant progress has also been made in the clinical use and development of agents active against RNA viruses. Clinical efficacy with both amantadine and rimantadine for the treatment of influenza A infections has been further substantiated. Ribovirin appears to be effective against influenza when administered by the inhalation of a small-particle aerosol through a face mask. A new compound, sodium 5-aminosulfonyl-2,4-dichlorobenzoateI has good in vitro activity against several strains of influenza virus and has been effective in reducing mortality in mice. Several other agents have been reported with potent in vitro activity against rhinovirus.

Synthesis and anti-viral activity of 6-amino- and 6-dimethylamino-9-(aminoacylamidobenzyl) purines

Abstract Several aminoacylamido derivatives of 9-benzyladenine and of 9-benzyl-6-dimethylaminopurine were synthesized for evaluation in anti-viral and anti-bacterial screens and in tests for inhibition of protein synthesis. The 9-(aminoacylamidobenzyl)purines were synthesized in two steps from the appropriate 9-(aminobenzyl)adenine 3 or 9-(aminobenzyl)-6-dimethylaminopurine 4 . Amines 3 and 4 were acylated with an N -carbobenzoxyamino acid via the mixed anhydride method to give the 9-( N -carbobenzoxyaminoacylamidobenzyl)purines 5–10 . The N -carbobenzoxy groups were removed by catalytic hydrogenolysis or with hydrogen bromide in acetic acid to give 9-(aminoacylamidobenzyl)purines 11–16 . Against rhinovirus serotype 1B, 6-dimethylamino-9-(3-phenylalanylamidobenzyl)-9 H -purine 16b had in vitro activity with an IC 50 = 17 μM.

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.

Design and synthesis of a chiral hapten for a radioimmunoassay of the antidepressant (2S, 3S, 5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol hydrochloride

Abstract The synthesis of a hapten for a radioimmunoassay of the antidepressant (2S, 3S, 5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol hydrochloride is described.

Chapter 12. Antiviral Agents

Publisher Summary This chapter discusses the agents with activity primarily against RNA viruses. The communicable diseases of the respiratory tract are probably the most common cause of symptomatic human infections. The viruses that are causative agents for human respiratory disease comprise the five taxonomically distinct families: orthomyxoviridae, paramyxoviridae, picornaviridae, coronaviridae, and adenoviridae. The influenza viruses, which consist of types A, B, and C, belong to the family orthomyxoviridae. Types A and B have been associated with significant increases in mortality during epidemics. The disease may be asymptomatic or cause symptoms ranging from the common cold to fatal pneumonia. Immunization against influenza has been recommended for high-risk groups and antiviral chemotherapy (amantadine) is available for the treatment and prophylaxis of all influenza A infections. There is both a great need for and interest in developing a chemotherapeutic agent for the treatment of these two viral, respiratory tract pathogens. The family picornaviridae contains the genus Rhinovirus that is composed of over a hundred distinct serotypes. Amantadine and rimantadine are specifically active against influenza A virus infections. The amantadine recipients reported a higher incidence of side effects largely attributed to the central nervous system (CNS) symptoms. This difference in side effects may be a pharmacokinetic phenomenon that results in higher plasma concentrations of amantadine. Significant progress continues to be made in the clinical use and development of agents active against DNA viruses. Acyclovir (9-(2-h droxyethoxymethyl)guanine) has been the subject of several reviews and of a syrnposium. Considerable progress has been made in evaluating the clinical promise of acyclovir; however, there remains much to be learned concerning the best use of this drug in clinical practice. Significant strides have been made in the development of clinically useful antiviral agents, especially against the DNA viruses of the herpes family. Most of these agents are directed against viral nucleic acid synthesis and require activation by a virus-induced thymidine kinase. Researchers have begun to focus on other strategies that may produce broader spectrum anti-viral agents with different mechanisms of action.

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.