Michael Raymond Harnden

Selection of an oral prodrug (BRL 42810; famciclovir) for the antiherpesvirus agent BRL 39123 [9-(4-hydroxy-3-hydroxymethylbut-l-yl)guanine; penciclovir].

The limited oral absorption in rodents of the antiherpesvirus agent 9-(4-hydroxy-3-hydroxymethylbut-l-yl)guanine (BRL 39123 [penciclovir; British approved name]) prompted a search for oral prodrugs. The 6-deoxy derivative of penciclovir (BRL 42359) and the corresponding diacetyl and dipropionyl 6-deoxy derivatives (BRL 42810 [famciclovir; British approved name] and BRL 43599) were tested as oral prodrugs. The in vivo absorption (dose, 0.2 mmol/kg) and the conversion to the active compound, penciclovir, were determined in rats. Compared with the sodium salt of penciclovir given intravenously, the bioavailabilities of penciclovir from orally administered penciclovir, BRL 42359, famciclovir, and BRL 43599 were 1.5, 9, 41, and 27%, respectively. These prodrugs and 6-deoxyacyclovir were tested for stability in rat duodenal contents and for metabolism in rat intestinal wall homogenate, liver homogenate, and blood and in the corresponding human fluids and tissues. Famciclovir was much more stable than BRL 43599 in human duodenal contents (half-lives, greater than 2 h and 7 min, respectively) yet was efficiently converted to penciclovir by the tissue homogenates. The major metabolic pathway was by deacetylation followed by oxidation at the 6 position. The rate of oxidation was comparable to that of 6-deoxyacyclovir, which is known to be converted efficiently to acyclovir in humans. Famciclovir was selected for further evaluation and progression to studies in humans. These subsequent studies confirmed that, after oral dosing with famciclovir, more than half the dose was absorbed and rapidly converted to penciclovir.

Synthesis of pyrrolidin-1-yl analogues of pyrimidine dideoxynucleosides

Abstract The synthesis is described of the first members of a new class of nucleoside analogues in which the tetrahydrofuran ring is replaced by a pyrrolidine ring linked to the base through an N-N bond: the pyrrolidinyl analogues of 2′,3′-dideoxycytidine ( 10 ), uridine ( 8 ), and thymidine ( 9 ) were prepared via construction of the base on a 1-aminopyrrolidine ( 15 ).

Synthesis of 9-(3-hydroxypropoxy)guanine, a novel antiviral acyclonucleoside

Abstract Synthetic approaches to 9-(3-hydroxypropoxy)guanine ( 2 ) involving the intermediacy of either a 1-alkoxyimidazole ( 7 ) or a 4-alkoxyaminopyrimidine ( 13 ) are described. This 9-alkoxyguanine ( 2 ) has potent and selective anti-herpesvirus activity and is the first reported member of a new series of antiviral acyclonucleosides.

Crystal and Molecular Structures of the Antiviral Acyclonucleoside 9-[4-Hydroxy-3-(hydroxymethyl)butyl]guanine (BRL 39123, Penciclovir) and its Prodrug 9-[4-Acetoxy-3-(acetoxymethyl)butyl]-2-aminopurine (BRL 42810, Famciclovir)

Abstract The crystal and molecular structures of two closely related antiviral purine derivatives are reported. In 9-[4-hydroxy-3-(hydroxymethyl)butyl]guanine (2) the plane of the acyclic N9 substituent is orthogonal to the purine ring. In crystals of 2 there is an extensive network of intermolecular hydrogen bonds. In 9-[4-acetoxy-3-(acetoxymethyl)butyl]-2-aminopurine (3) characteristic changes in the geometry of the pyrimidine ring in comparison with 2 are observed. In crystals of the 2-aminopurine derivative 3 there is an absence of major hydrogen bonding interactions and there are π-π interactions between parallel overlapping pyrimidine moieties.

Synthesis of 9-[2,2-bis(hydroxymethyl)cycloprop-1-yl]guanine as a potential antiviral agent

Abstract The synthesis and antiviral activity of a cyclopropyl analogue of the antiviral agent penciclovir is reported.

9-[2-(Phosphonomethoxy)alkoxy]purines, A New Series of Antiviral Acyclonucleotides

Abstract The synthesis and antiviral activities of a series of 9-[2-(phosphono-methoxy)alkoxy]purines are described. These compounds are the first reported acyclonucleotides in which a phosphonic acid bearing moiety is attached to N-9 of a purine via an N-0 bond. Some of them show potent activity against herpesviruses and others are potent and selective inhibitors of the replication of visna virus, a lentivirus.

Synthesis of [3-(phosphonomethoxy)pyrrolidin-1-yl] derivatives of pyrimidines and purines : analogues of 2',3'-dideoxynucleotides

Pyrrolidin-1-yl derivatives of pyrimidines and purines, incorporating the phosphonomethoxy group as a phosphate mimic, were prepared as analogues of 2′,3′-dideoxynucleotides. The heterocyclic bases uracil, thymine, cytosine, adenine and hypoxanthine were constructed upon the primary amino group of the N-aminopyrrolidine 7, which was prepared by reaction of the dibromide 6 with hydrazine.

C-nucleoside studies. Part 21. Synthesis of some hydroxyalkylated pyrroloand thieno-[3,2-d]pyrimidines related to known antiviral acyclonucleosides

Treatment of (S)-4,5-isopropylidenedioxypentanonitrile 17 with ethyl formate and sodium hydride gave a hydroxymethylene derivative which interacted with aminoacetonitrile to give 3-cyanomethyleneamin-2-[(S)-isopropylidenedioxypropyl]acrylonitrile 19; this was elaborated via 3-amino-2-cyano-4-[(S)-2,3-isopropylidenedioxypropyl]pyrrole 22 into 4-amino-7-[(S)-2,3-dihydroxypropyl]pyrrolo[3,2-d]pyrimidine 9. Treatment of the hydroxymethylene derivative of 17 with methanesulphonyl chloride, followed by acetylthioacetonitrile and sodium carbonate in ethanol gave 3-amino-2-cyano-4-[(S)-2,3-isopropylidenedioxypropyl]thiophene 25, convertible in two steps into 4-amino-7-[(S)-2,3-dihydroxypropyl]thieno[3,2-d]pyrimidine 10.Similar chemistry was employed for the conversion of 5,6-isopropylidenedioxyhexanonitrile 30 into the higher homologues 4-amino-7-(3,4-dihydroxybutyl)pyrrol- and thieno-[3,2-d]pyrimidine 11 and 12, and for the preparation of 4-amino-7-(4-hydroxy-3-hydroxymethylbutyl)pyrrolo[3,2-d]pyrimidine 13d from 6-benzylox-5-benzyloxymethylhexanonitrile 41. The hydroxyalkylated products 9–13 are C-nucleoside analogues of known antiviral agents, but did not display antiviral activity.

Analogues of the antiviral acyclonucleoside 9-(4-hydroxy-3-hydroxymethylbutyl)guanine. Part 3. Modification of a 3′-hydroxymethyl group

Syntheses of 3′-hydroxymethyl modified analogues of the potent antiviral agent 9-(4-hydroxy-3-hydroxymethylbutyl)guanine (1c) are described. These include methyl homologues (7a, b), chain-extended compounds such as the methylene homologue (16) and hydroxyalkyl ethers (26b, c), and methoxy (26a), bromo (28), azido (29), amino (30), and formamido (31) substituted analogues. Compounds (7a, b), (16), and (26a–c) were prepared by construction of an appropriately functionalised alkyl unit followed by purine alkylation and deprotection, whereas compounds (28)–(31) were prepared by selective modification of (1c). The formamido analogue (31) showed moderate anti-herpes virus activity and compounds (16), (26b), and (29) weak activity.

Pyrrolidine analogues of 2',3'-dideoxynucleosides : synthesis via 9-aminopurines and 1-aminopyrimidines

Analogues of 2′,3′-dideoxynucleosides in which the tetrahydrofuran ring is replaced by a pyrrolidine ring linked to the base through an N–N bond have been prepared. The adenine 26, guanine 25 and hypoxanthine 27 compounds were synthesised via 9-aminopurines. Corresponding derivatives of 5-iodouracil 31, 5-chlorouracil 33 and 5-chlorocytosine 35 were prepared by substitution at the 5-position of hydroxy protected uracil derivatives. Enantiomers, 40a and 40b, of the pyrrolidine analogue of dideoxycytidine were prepared from 1-aminocytosine. The novel N-aminobases 9-aminoadenine 10, 1-aminocytosine 13 and 1-aminothymine 15 are described.