Purine inhibitors of fructose 1,6-bisphosphatase

Novel purine compounds of the following structure and their use as fructose-1,6-bisphosphatase inhibitors is described. ##STR1## wherein PA1 A is selected from the group consisting of --NR.sup.8.sub.2, --NHSO.sub.2 R.sup.3, --OR.sup.5, --SR.sup.5, halo, lower alkyl, --CON(R.sup.4).sub.2, guanidino, amidino, --H, and perhaloalkyl; PA1 E is selected from the group consisting of --H, halo, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, --CN, and --NR.sup.7.sub.2 ; PA1 X is selected from the group consisting of -alk-NR--, alkylene, alkenylene, alkynylene, arylene, heteroarylene, -alk-NR-alk-, -alk-O-alk-, -alk-S-alk-, -alk-S--, alicyclicene, heteroalicyclicene, 1,1-dihaloalkylene, --C(O)-alk-, --NR--C(O)--NR'--, -alk-NR--C(O)--, -alk-C(O)--NR--, --Ar-alk-, and -alk-Ar--, all optionally substituted, wherein each R and R' is independently selected from --H and lower alkyl, and wherein each "alk" and "Ar" is an independently selected alkylene or arylene, respectively; PA1 Y is selected from the group consisting of --H, alkyl, alkenyl, alkynyl, aryl, alicyclic, heteroalicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, --C(O)R.sup.3, --S(O).sub.2 R.sup.3, --C(O)--OR.sup.3, --CONHR.sup.3, --NR.sup.2.sub.2, and --OR.sup.3, all except H are optionally substituted; and PA1 pharmaceutically acceptable prodrugs and salts thereof.

FIELD OF THE INVENTION
 This invention relates to novel purine compounds that are inhibitors of
 Fructose-1,6-bisphosphatase at the AMP site. The invention also relates to
 the preparation and use of these purine analogs in the treatment of
 diabetes, and other diseases where the inhibition of gluconeogenesis,
 control of blood glucose levels, reduction in glycogen stores, or
 reduction in insulin levels is beneficial.
 BACKGROUND AND INTRODUCTION TO THE INVENTION
 Diabetes mellitus (or diabetes) is one of the most prevalent diseases in
 the world today. Diabetes patients have been divided into two classes,
 namely type I or insulin-dependent diabetes mellitus and type II or
 non-insulin dependent diabetes mellitus (NIDDM). Non-insulin-dependent
 diabetes mellitus (NIDDM) accounts for approximately 90% of all diabetics
 and is estimated to affect 12-14 million adults in the U.S. alone (6.6% of
 the population). NIDDM is characterized by both fasting hyperglycemia and
 exaggerated postprandial increases in plasma glucose levels. NIDDM is
 associated with a variety of long-term complications, including
 microvascular diseases such as retinopathy, nephropathy and neuropathy,
 and macrovascular diseases such as coronary heart disease. Numerous
 studies in animal models demonstrate a causal relationship between long
 term complications and hyperglycemia. Recent results from the Diabetes
 Control and Complications Trial (DCCT) and the Stockholm Prospective Study
 demonstrate this relationship for the first time in man by showing that
 insulin-dependent diabetics with tighter glycemic control are at
 substantially lower risk for development and progression of these
 complications. Tighter control is also expected to benefit NIDDM patients.
 Current therapies used to treat NIDDM patients entail both controlling
 lifestyle risk factors and pharmaceutical intervention. First-line therapy
 for NIDDM is typically a tightly-controlled regimen of diet and exercise
 since an overwhelming number of NIDDM patients are overweight or obese
 (.apprxeq.67%) and since weight loss can improve insulin secretion,
 insulin sensitivity and lead to normoglycemia. Normalization of blood
 glucose occurs in less than 30% of these patients due to poor compliance
 and poor response. Patients with hyperglycemia not controlled by diet
 alone are subsequently treated with oral hypoglycemics or insulin. Until
 recently, the sulfonylureas were the only class of oral hypoglycemic
 agents available for NIDDM. Treatment with sulfonylureas leads to
 effective blood glucose lowering in only 70% of patients and only 40%
 after 10 years of therapy. Patients that fail to respond to diet and
 sulfonylureas are subsequently treated with daily insulin injections to
 gain adequate glycemic control.
 Although the sulfonylureas represent a major therapy for NIDDM patients,
 four factors limit their overall success. First, as mentioned above, a
 large segment of the NIDDM population do not respond adequately to
 sulfonylurea therapy (i.e. primary failures) or become resistant (i.e.
 secondary failures). This is particularly true in NIDDM patients with
 advanced NIDDM since these patients have severely impaired insulin
 secretion. Second, sulfonylurea therapy is associated with an increased
 risk of severe hypoglycemic episodes. Third, chronic hyperinsulinemia has
 been associated with increased cardiovascular disease although this
 relationship is considered controversial and unproven. Last, sulfonylureas
 are associated with weight gain, which leads to worsening of peripheral
 insulin sensitivity and thereby can accelerate the progression of the
 disease.
 Recent results from the U.K. Diabetes prospective study also showed that
 patients undergoing maximal therapy of a sulfonylurea, metformin, or a
 combination of the two, were unable to maintain normal fasting glycemia
 over the six year period of the study. U.K. Prospective Diabetes Study 16.
 Diabetes, 44:1249-158 (1995). These results further illustrate the great
 need for alternative therapies. Three therapeutic strategies that could
 provide additional health benefits to NIDDM patients beyond the currently
 available therapies, include drugs that would: (i) prevent the onset of
 NIDDM; (ii) prevent diabetic complications by blocking detrimental events
 precipitated by chronic hyperglycemia; or (iii) normalize glucose levels
 or at least decrease glucose levels below the threshold reported for
 microvascular and macrovascular diseases.
 Hyperglycemia in NIDDM is associated with two biochemical abnormalities,
 namely insulin resistance and impaired insulin secretion. The relative
 roles of these metabolic abnormalities in the pathogenesis of NIDDM has
 been the subject of numerous studies over the past several decades.
 Studies of offspring and siblings of NIDDM patients, mono- and dizygotic
 twins, and ethnic populations with high incidence of NIDDM (e.g. Pima
 Indians) strongly support the inheritable nature of the disease.
 Despite the presence of insulin resistance and impaired insulin secretion,
 fasting blood glucose (FBG) levels remain normal in pre-diabetic patients
 due to a state of compensatory hyperinsulinemia. Eventually, however,
 insulin secretion is inadequate and fasting hyperglycemia ensues. With
 time insulin levels decline. Progression of the disease is characterized
 by increasing FBG levels and declining insulin levels.
 Numerous clinical studies have attempted to define the primary defect that
 accounts for the progressive increase in FBG. Results from these studies
 indicate that excessive hepatic glucose output (HGO) is the primary reason
 for the elevation in FBG with a significant correlation found for HGO and
 FBG once FBG exceeds 140 mg/dL. Kolterman, et al., J. Clin. Invest.
 68:957, (1981); DeFronzo Diabetes 37:667 (1988).
 HGO comprises glucose derived from breakdown of hepatic glycogen
 (glycogenolysis) and glucose synthesized from 3-carbon precursors
 (gluconeogenesis). A number of radioisotope studies and several studies
 using .sup.13 C-NMR spectroscopy have shown that gluconeogenesis
 contributes between 50-100% of the glucose produced by the liver in the
 postabsorptive state and that gluconeogenesis flux is excessive (2- to
 3-fold) in NIDDM patients. Magnusson, et al. J. Clin. Invest. 90:1323-1327
 (1992); Rothman, et al., Science 254: 573-76 (1991); Consoli, et al.
 Diabetes 38:550-557 (1989).
 Gluconeogenesis from pyruvate is a highly regulated biosynthetic pathway
 requiring eleven enzymes (FIG. 1). Seven enzymes catalyze reversible
 reactions and are common to both gluconeogenesis and glycolysis. Four
 enzymes catalyze reactions unique to gluconeogenesis, namely pyruvate
 carboxylase, phosphoenolpyruvate carboxykinase,
 fructose-1,6-bisphosphatase and glucose-6-phosphatase. Overall flux
 through the pathway is controlled by the specific activities of these
 enzymes, the enzymes that catalyzed the corresponding steps in the
 glycolytic direction, and by substrate availability. Dietary factors
 (glucose, fat) and hormones (insulin, glucagon, glucocorticoids,
 epinephrine) coordinatively regulate enzyme activities in the
 gluconeogenesis and glycolysis pathways through gene expression and
 post-translational mechanisms.
 Of the four enzymes specific to gluconeogenesis,
 fructose-1,6-bisphosphatase (hereinafter "FBPase") is the most suitable
 target for a gluconeogenesis inhibitor based on efficacy and safety
 considerations. Studies indicate that nature uses the FBPase/PFK cycle as
 a major control point (metabolic switch) responsible for determining
 whether metabolic flux proceeds in the direction of glycolysis or
 gluconeogenesis. Claus, et al., Mechanisms of Insulin Action, Belfrage, P.
 editor, pp.305-321, Elsevier Science 1992; Regen, et al. J. Theor. Biol.,
 111:635-658 (1984); Pilkis, et al. Annu. Rev. Biochem, 57:755-783 (1988).
 FBPase is inhibited by fructose-2,6-bisphosphate in the cell.
 Fructose-2,6-bisphosphate binds to the substrate site of the enzyme. AMP
 binds to an allosteric site on the enzyme.
 Synthetic inhibitors of FBPase have also been reported. McNiel reported
 that fructose-2,6-bisphosphate analogs inhibit FBPase by binding to the
 substrate site. J. Am. Chem. Soc. 106:7851 (1984); U.S. Pat. No. 4,968,790
 (1984). These compounds, however, were relatively weak and did not inhibit
 glucose production in hepatocytes presumably due to poor cell penetration.
 Gruber reported that some nucleosides can lower blood glucose in the whole
 animal through inhibition of FBPase. These compounds exert their activity
 by first undergoing phosphorylation to the corresponding monophosphate. EP
 0 427 799 B1.
 Gruber et al. U.S. Pat. No. 5,658,889 described the use of inhibitors of
 the AMP site of FBPase to treat diabetes.
 European patent application EP 0 632 048 A1 discloses certain ethyl
 phosphonates of purine derivatives for use as antiviral and antineoplastic
 agents. These structures differ from the claimed compounds because they
 have no substitution on the C-8 of the purine. There is no suggestion that
 these compounds are inhibitors of FBPase.

SUMMARY OF THE INVENTION
 The present invention is directed towards novel purine compounds which bind
 the AMP site and are potent FBPase inhibitors. In another aspect, the
 present invention is directed to the preparation of these novel purine
 compounds and to the in vitro and in vivo FBPase inhibitory activity of
 these compounds. Another aspect of the present invention is directed to
 the clinical use of the novel FBPase inhibitors as a method of treatment
 or prevention of diseases responsive to inhibition of gluconeogenesis and
 in diseases responsive to lowered blood glucose levels.
 Gruber et al. U.S. patent application Ser. No. 08/355,836, now issued U.S.
 Pat. No 5,658,889, described the use of inhibitors of the AMP site of
 FBPase to treat diabetes.
 The compounds are also useful in treating or preventing excess glycogen
 storage diseases and insulin dependent diseases such as cardiovascular
 diseases including atherosclerosis.
 The invention comprises the novel purine analogs as specified below in
 formula 1. Also included in the scope of the present invention are
 prodrugs of the compounds of formula 1.
 ##STR2##
 Since these compounds may have asymmetric centers, the present invention is
 directed not only to racemic mixtures of these compounds, but also to
 individual stereoisomers. The present invention also includes
 pharmaceutically acceptable and/or useful salts of the compounds of
 formula 1, including acid addition salts and basic salts. The present
 inventions also encompass prodrugs of compounds of formula 1.
 Definitions
 In accordance with the present invention and as used herein, the following
 terms are defined with the following meanings, unless explicitly stated
 otherwise.
 The term "aryl" refers to aromatic groups which have at least one ring
 having a conjugated pi electron system and includes carbocyclic aryl,
 heterocyclic aryl and biaryl groups, all of which may be optionally
 substituted.
 Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic
 ring are carbon atoms. Carbocyclic aryl groups include monocyclic
 carbocyclic aryl groups and polycyclic or fused compounds such as
 optionally substituted naphthyl groups.
 Heterocyclic aryl groups are groups having from 1 to 4 heteroatoms as ring
 atoms in the aromatic ring and the remainder of the ring atoms being
 carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen.
 Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl,
 N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl,
 and the like, all optionally substituted.
 The term "biaryl" represents aryl groups containing more than one aromatic
 ring including both fused ring systems and aryl groups substituted with
 other aryl groups.
 The term "alicyclic" means compounds which combine the properties of
 aliphatic and cyclic compounds and include but are not limited to
 aromatic, cycloalkyl and bridged cycloalkyl compounds. The cyclic compound
 includes heterocycles. Cyclohexenylethyl, cyclohexanylethyl, and norbornyl
 are suitable alicyclic groups. Such groups may be optionally substituted.
 The term "optionally substituted" or "substituted" includes groups
 substituted by one to four substituents, independently selected from lower
 alkyl, lower aryl, lower aralkyl, lower alicyclic, hydroxy, lower alkoxy,
 lower aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy,
 heteroarylalkyl, heteroaralkoxy, azido, amino, guanidino, halogen, lower
 alkylthio, oxo, ketone, carboxy esters, carboxyl, carboxamido, nitro,
 acyloxy, alkylamino, aminoalkyl, alkylaminoaryl, alkylaryl,
 alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, phosphonate,
 sulfonate, carboxamidoalkylaryl, carboxamidoaryl, hydroxyalkyl, haloalkyl,
 alkylaminoalkylcarboxy, aminocarboxamidoalkyl, cyano, lower alkoxyalkyl,
 and lower perhaloalkyl.
 The term "aralkyl" refers to an alkyl group substituted with an aryl group.
 Suitable aralkyl groups include benzyl, picolyl, and the like, and may be
 optionally substituted.
 The term "lower" referred to herein in connection with organic radicals or
 compounds respectively defines such as with up to and including 10,
 preferably up to and including 6, and advantageously one to four carbon
 atoms. Such groups may be straight chain, branched, or cyclic.
 The terms "arylamino" (a), and "aralkylamino" (b), respectively, refer to
 the group --NRR' wherein respectively, (a) R is aryl and R' is hydrogen,
 alkyl, aralkyl or aryl, and (b) R is aralkyl and R' is hydrogen or
 aralkyl, aryl, alkyl.
 The term "acyl" refers to --C(O)R where R is alkyl and aryl.
 The term "carboxy esters" refers to --C(O)OR where R is alkyl, aryl,
 aralkyl, and alicyclic, all optionally substituted.
 The term "oxa" refers to .dbd.O in an alkyl group.
 The term "alkylamino" refers to --NRR' where R and R' are independently
 selected from hydrogen or alkyl.
 The term "carbonylamine" or "carbonylamino" refers to --CONR.sub.2 where
 each R is independently hydrogen or alkyl.
 The term "halogen" or "halo" refers to --F, --Cl, --Br and --I.
 The term "oxyalkylamino" refers to --O-alk-NR--, where "alk" is an alkylene
 group and R is H or alkyl.
 The term "alkylaminoalkylcarboxy" refers to the group -alk-NR-alk-C(O)--O--
 where "alk" is an alkylene group, and R is a H or lower alkyl.
 The term "alkylaminocarbonyl" refers to the group -alk-NR--C(O)-- where
 "alk" is an alkylene group, and R is a H or lower alkyl.
 The term "oxyalkyl" refers to the group --O-alk- where "alk" is an alkylene
 group.
 The term "alkylcarboxyalkyl" refers to the group -alk-C(O)--O-alkyl where
 each alk is independently an alkylene group.
 The term "alkyl" refers to saturated aliphatic groups including
 straight-chain, branched chain and cyclic groups. Alkyl groups may be
 optionally substituted.
 The term "bidentate" refers to an alkyl group that is attached by its
 terminal ends to the same atom to form a cyclic group. For example,
 propylene imine contains a bidentate propylene group.
 The term "cyclic alkyl" refers to alkyl groups that are cyclic.
 The term "heterocyclic" and "heterocyclic alkyl" refer to cyclic alkyl
 groups containing at least one heteroatom. Suitable heteroatoms include
 oxygen, sulfur, and nitrogen. Heterocyclic groups may be attached through
 a heteroatom or through a carbon atom in the ring.
 The term "alkenyl" refers to unsaturated groups which contain at least one
 carbon-carbon double bond and includes straight-chain, branched-chain and
 cyclic groups. Alkene groups may be optionally substituted.
 The term "alkynyl" refers to unsaturated groups which contain at least one
 carbon-carbon triple bond and includes straight-chain, branched-chain and
 cyclic groups. Alkyne groups may be optionally substituted.
 The term "alkylene" refers to a divalent straight chain, branched chain or
 cyclic saturated aliphatic radical.
 The term "acyloxy" refers to the ester group --O--C(O)R, where R is H,
 alkyl, alkenyl, alkynyl, aryl, aralkyl, or alicyclic.
 The term "alkylaryl" refers to the group -alk-aryl- where "alk" is an
 alkylene group. "Lower alkylaryl" refers to such groups where alkylene is
 lower alkyl.
 The term "alkylamino" refers to the group -alk-NR-- wherein "alk" is an
 alkylene group.
 The term "alkyl(carboxyl)" refers to carboxyl substituted off the alkyl
 chain. Similarly, "alkyl(hydroxy)", "alkyl(phosphonate)", and
 "alkyl(sulfonate)" refers to substituents off the alkyl chain.
 The term "alkylaminoalkyl" refers to the group -alk-NR-alk- wherein each
 "alk" is an independently selected alkylene, and R is H or lower alkyl.
 "Lower alkylaminoalkyl" refers to groups where each alkylene group is
 lower alkyl.
 The term "alkylaminoaryl" refers to the group -alk-NR-aryl- wherein "alk"is
 an alkylene group. In "lower alkylaminoaryl", the alkylene group is lower
 alkyl.
 The term "alkyloxyaryl" refers to an alkylene group substituted with an
 aryloxy group. In "lower alkyloxyaryl", the alkylene group is lower alkyl.
 The term "alkylacylamino" refers to the group -alk-N--(COR)-- wherein alk
 is alkylene and R is lower alkyl. In "lower alkylacylamino", the alkylene
 group is lower alkyl.
 The term "alkoxyalkylaryl" refers to the group -alk-O-alk-aryl- wherein
 each "alk" is independently an alkylene group. "Lower alkoxalkylaryl"
 refers to such groups where the alkylene group is lower alkyl.
 The term "alkylacylaminoalkyl" refers to the group -alk-N--(COR)-alk- where
 each alk is an independently selected alkylene group. In "lower
 alkylacylaminoalkyl" the alkylene groups are lower alkyl.
 The term "alkoxy" refers to the group -alk-O-- wherein alk is an alkylene
 group.
 The term "alkoxyalkyl" refers to the group -alk-O-alk- wherein each alk is
 an independently selected alkylene group. In "lower alkoxyalkyl", each
 alkylene is lower alkyl.
 The term "alkylthio" refers to the group -alk-S-- wherein alk is alkylene
 group.
 The term "alkylthioalkyl" refers to the group -alk-S-alk- wherein each alk
 is an independently selected alkylene group. In "lower alkylthioalkyl"
 each alkylene is lower alkylene.
 The term "aralkylamino" refers to an amine substituted with an aralkyl
 group.
 The term "alkylcarboxamido" refers to the group -alk-C(O)N(R)-- wherein alk
 is an alkylene group and R is H or lower alkyl.
 The term "alkylcarboxamidoalkyl" refers to the group -alk-C(O)N(R)-alk-
 wherein each alk is an independently selected alkylene group and R is
 lower alkyl. In "lower alkylcarboxamidoalkyl" each alkylene is lower
 alkyl.
 The term "alkylcarboxamidoalkylaryl" refers to the group -alk.sub.1
 -C(O)--NH-alk.sub.2 Ar-- wherein alk.sub.1 and alk.sub.2 are independently
 selected alkylene groups and alk.sub.2 is substituted with an aryl group,
 Ar. In "lower alkylcarboxamidoalkylaryl", each alkylene is lower alkyl.
 The term "hteteroalicyclic" refers to an alicyclic group having 1 to 4
 heteroatoms in the ring selected from nitrogen, sulfur, phosphorus and
 oxygen.
 The term "aminocarboxamidoalkyl" refers to the group --NH--C(O)--N(R)--R
 wherein each R is an independently selected alkyl group. "Lower
 aminocarboxamidoalkyl" refers to such groups wherein each R is lower
 alkyl.
 The term "heteroarylalkyl" refers to an alkyl group substituted with a
 heteroaryl group.
 The term "perhalo" refers to groups wherein every C--H bond has been
 replaced with a C-halo bond on an aliphatic or aryl group. Suitable
 perhaloalkyl groups include --CF.sub.3 and --CFCl.sub.2.
 The term "guanidino" refers to both --NR--C(NR)--NR.sub.2 as well as
 --N.dbd.C(NR.sub.2).sub.2 where each R group is independently selected
 from the group of --H, alkyl, alkenyl, alkynyl, aryl, and alicyclic, all
 optionally substituted.
 The term "amidino" refers to --C(NR)--NR.sub.2 where each R group is
 independently selected from the group of --H, alkyl, alkenyl, alkynyl,
 aryl, and alicyclic, all optionally substituted.
 The term "pharmaceutically acceptable salt" includes salts of compounds of
 formula 1 and its prodrugs derived from the combination of a compound of
 this invention and an organic or inorganic acid or base.
 The term "prodrug" as used herein refers to any compound that when
 administered to a biological system generates the "drug" substance either
 as a result of spontaneous chemical reaction(s) or by enzyme catalyzed or
 metabolic reaction(s). Reference is made to various prodrugs such as acyl
 esters, carbonates, and carbamates, included herein. The groups
 illustrated are exemplary, not exhaustive, and one skilled in the art
 could prepare other known varieties of prodrugs. Such prodrugs of the
 compounds of formula 1, fall within the scope of the present invention.
 The term "prodrug ester" as employed herein includes, but is not limited
 to, the following groups and combinations of these groups:
 [1] Acyloxyalkyl esters which are well described in the literature
 (Farquhar et al., J. Pharm. Sci. 72, 324-325 (1983)) and are represented
 by formula A
 ##STR3##
 wherein
 R, R', and R" are independently H, alkyl, aryl, alkylaryl, and alicyclic;
 (see WO 90/08155; WO 90/10636).
 [2] Other acyloxyalkyl esters are possible in which an alicyclic ring is
 formed such as shown in formula B. These esters have been shown to
 generate phosphorus-containing nucleotides inside cells through a
 postulated sequence of reactions beginning with deesterification and
 followed by a series of elimination reactions (e.g. Freed et al., Biochem.
 Pharm. 38: 3193-3198 (1989)).
 ##STR4##
 wherein
 R is --H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio,
 alkylamino, arylamino, cycloalkyl, or alicyclic.
 [3] Another class of these double esters known as alkyloxycarbonyloxymethyl
 esters, as shown in formula A, where R is alkoxy, aryloxy, alkylthio,
 arylthio, alkylamino, and arylamino; R', and R" are independently H,
 alkyl, aryl, alkylaryl, and alicyclic, have been studied in the area of
 .beta.-lactam antibiotics (Tatsuo Nishimura et al. J. Antibiotics, 1987,
 40(1), 81-90; for a review see Ferres, H., Drugs of Today, 1983,19, 499.).
 More recently Cathy, M. S., et al. (Abstract from AAPS Western Regional
 Meeting, April, 1997) showed that these alkyloxycarbonyloxymethyl ester
 prodrugs on (9-[(R)-2-phosphonomethoxy)propyl]adenine (PMPA) are
 bioavailable up to 30% in dogs.
 [4] Aryl esters have also been used as phosphonate prodrugs (e.g. Erion,
 DeLambert et al., J. Med. Chem. 37: 498, 1994; Serafinowska et al., J.
 Med. Chem. 38: 1372, 1995). Phenyl as well as mono and poly-substituted
 phenyl phosphonate ester prodrugs have generated the parent phosphonic
 acid in studies conducted in animals and in man (Formula C). Another
 approach has been described where Y is a carboxylic ester ortho to the
 phosphate. Khamnei and Torrence, J. Med. Chem.; 39:4109-4115 (1996).
 ##STR5##
 wherein
 Y is H, alkyl, aryl, alkylaryl, alkoxy, acetoxy, halogen, amino,
 alkoxycarbonyl, hydroxy, cyano, alkylamino, and alicyclic.
 [5] Benzyl esters have also been reported to generate the parent phosphonic
 acid. In some cases, using substituents at the para-position can
 accelerate the hydrolysis. Benzyl analogs with 4-acyloxy or 4-alkyloxy
 group [Formula D, X.dbd.H, OR or O(CO)R or O(CO)OR] can generate the
 4-hydroxy compound more readly through the action of enzymes, e.g.
 oxidases, esterases, etc. Examples of this class of prodrugs are described
 by Mitchell et al., J. Chem. Soc. Perkin Trans. I 2345 (1992); Brook, et
 al. WO 91/19721.
 ##STR6##
 wherein
 X and Y are independently H, alkyl, aryl, alkylaryl, alkoxy, acetoxy,
 hydroxy, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl; and
 R' and R" are independently H, alkyl, aryl, alkylaryl, halogen, and
 alicyclic.
 [6] Thio-containing phosphonate ester prodrugs have been described that are
 useful in the delivery of FBPase inhibitors to hepatocytes. These
 phosphonate ester prodrugs contain a protected thioethyl moiety as shown
 in formula E. One or more of the oxygens of the phosphonate can be
 esterified. Since the mechanism that results in de-esterification requires
 the generation of a free thiolate, a variety of thiol protecting groups
 are possible. For example, the disulfide is reduced by a
 reductase-mediated process (Puech et al., Antiviral Res., 22: 155-174
 (1993)). Thioesters will also generate free thiolates after
 esterase-mediated hydrolysis. Benzaria, et al., J. Med. Chem., 39:4958
 (1996). Cyclic analogs are also possible and were shown to liberate
 phosphonate in isolated rat hepatocytes. The cyclic disulfide shown below
 has not been previously described and is novel.
 ##STR7##
 wherein
 Z is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, or
 alkylthio.
 Other examples of suitable prodrugs include proester classes exemplified by
 Biller and Magnin (U.S. Pat. No. 5,157,027); Serafinowska et al. (J. Med.
 Chem. 38,1372 (1995)); Starrett et al. (J. Med. Chem. 37,1857 (1994));
 Martin et al. J. Pharm. Sci. 76,180 (1987); Alexander et al., Collect.
 Czech. Chem. Commun, 59, 1853 (1994)); and EPO patent application 0 632
 048 A1. Some of the structural classes described are optionally
 substituted, including fused lactones attached at the omega position and
 optionally substituted 2-oxo-1,3-dioxolenes attached through a methylene
 to the phosphorus oxygen such as:
 ##STR8##
 wherein
 R is --H, alkyl, cycloalkyl, or alicyclic; and
 wherein Y is --H, alkyl, aryl, alkylaryl, cyano, alkoxy, acetoxy, halogen,
 amino, alkylamino, alicyclic, and alkoxycarbonyl.
 [7] Propyl phosphonate ester prodrugs can also be used to deliver FBPase
 inhibitors into hepatocytes. These phosphonate ester prodrugs may contain
 a hydroxyl and hydroxyl group derivatives at the 3-position of the propyl
 group as shown in formula F. The R and X groups can form a cyclic ring
 system as shown in formula F. One or more of the oxygens of the
 phosphonate can be esterified.
 ##STR9##
 wherein
 R is alkyl, aryl, heteroaryl;
 X is hydrogen, alkylcarbonyloxy, alkyloxycarbonyloxy; and
 Y is alkyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, halogen,
 hydrogen, hydroxy, acetoxy, amino.
 [8] The cyclic propyl phosphonate esters as in Formula G are shown to
 activate to phosphonic acids. The activation of prodrug can be
 mechanistically explained by in vivo oxidation and elimination steps.
 These prodrugs inhibit glucose production in isolated rat hepatocytes and
 are also shown to deliver FBPase inhibitors to the liver following oral
 administration.
 ##STR10##
 wherein
 V and W are independently selected from the group consisting of hydrogen,
 aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl,
 1-alkynyl, and --R.sup.9 ; or
 together V and Z are connected to form a cyclic group containing 3-5 atoms,
 optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarboxy,
 or aryloxycarboxy attached to a carbon atom that is three atoms from an
 oxygen attached to the phosphorus; or
 together V and W are connected to form a cyclic group containing 3 carbon
 atoms substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy,
 hydroxymethyl, and aryloxycarboxy attached to a carbon atom that is three
 atoms from an oxygen attached to the phosphorus;
 Z is selected from the group consisting of --CH.sub.2 OH, --CH.sub.2
 OCOR.sup.3, --CH.sub.2 OC(O)SR.sup.3, --CH.sub.2 OCO.sub.2 R.sup.3,
 --SR.sup.3, --S(O)R.sup.3, --CH.sub.2 N.sub.3, --CH.sub.2 NR.sup.2.sub.2,
 --CH.sub.2 Ar, --CH(Ar)OH, --CH(CH.dbd.CR.sup.2 R.sup.2)OH,
 --CH(C.ident.CR.sup.2)OH, and --R.sup.2 ;
 with the provisos that:
 a) V, Z, W are not all --H; and
 b) when Z is --R.sup.2, then at least one of V and W is not --H or
 --R.sup.9 ;
 R.sup.2 is selected from the group consisting of R.sup.3 and --H;
 R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic,
 and aralkyl; and
 R.sup.9 is selected from the group consisting of alkyl, aralkyl, and
 alicyclic.
 [9] Phosphoramidate derivatives have been explored as potential phosphonate
 prodrugs (e.g. McGuigan et al., Antiviral Res. 1990, 14: 345; 1991, 15:
 255. Serafinowska et al., J. Med. Chem., 1995, 38,1372). Most
 phosphoramidates are unstable under aqueous acidic conditions and are
 hydrolyzed to the corresponding phosphonic acids. Cyclic phosphoramidates
 have also been studied as phosphonate prodrugs because of their potential
 for greater stability compared to non cyclic phosphoramidates (e.g.
 Starrett et al., J. Med. Chem., 1994, 37: 1857).
 Other prodrugs are possible based on literature reports such as substituted
 ethyls for example, bis(trichloroethyl)esters as disclosed by McGuigan, et
 al. Bioorg Med. Chem. Lett., 3:1207-1210 (1993), and the phenyl and benzyl
 combined nucleotide esters reported by Meier, C. et al. Bioorg. Med. Chem.
 Lett., 7:99-104 (1997).
 X group nomenclature as used herein in formula 1 describes the group
 attached to the phosphonate and ends with the group attached to the
 6-position of the purine ring. For example, when X is alkylamino, the
 following structure is intended:
EQU (OR.sup.1).sub.2 (O)P-alk-NR--(purine ring)
 Y group nomenclature likewise ends with the group attached to the ring.
 DETAILED DESCRIPTION OF THE INVENTION
 Novel Purine Compounds
 Preferred compounds of the present invention are inhibitors of the AMP site
 of FBPase of the following formula (1):
 ##STR11##
 wherein
 A is selected from the group consisting of --NR.sup.8.sub.2, NHSO.sub.2
 R.sup.3, --OR.sup.5, --SR.sup.5, halogen, lower alkyl,
 --CON(R.sup.4).sub.2, guanidine, amidine, --H, and perhaloalkyl;
 E is selected from the group consisting of --H, halogen, lower alkylthio,
 lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower
 alkoxy, --CN, and --NR.sup.7.sub.2 ;
 X is selected from the group consisting of alkylamino, alkyl, alkenyl,
 alkynyl, alkyl(carboxyl), alkyl(hydroxy), alkyl(phosphonate),
 alkyl(sulfonate), aryl, alkylaminoalkyl, alkoxyalkyl, alkylthioalkyl,
 alkylthio, alicyclic, 1,1-dihaloalkyl, carbonylalkyl, aminocarbonylamino,
 alkylaminocarbonyl, alkylcarbonylamino, aralkyl, and alkylaryl, all
 optionally substituted; or together with Y forms a cyclic group including
 cyclic alkyl, heterocyclic, and aryl;
 Y is selected from the group consisting of --H, alkyl, alkenyl, alkynyl,
 aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, --C(O)R.sup.3,
 --S(O).sub.2 R.sup.3, --C(O)--OR.sup.3, --CONHR.sup.3, --NR.sup.2.sub.2,
 and --OR.sup.3, all except H are optionally substituted; or together with
 X forms a cyclic group including aryl, cyclic alkyl, and heterocyclic;
 R.sup.1 is independently selected from the group consisting of --H, alkyl,
 aryl, alicyclic where the cyclic moiety contains a carbonate or
 thiocarbonate, --C(R.sup.2).sub.2 -aryl, alkylaryl, --C(R.sup.2).sub.2
 OC(O)NR.sup.2.sub.2, --NR.sup.2 --C(O)--R.sup.3, --C(R.sup.2).sub.2
 --OC(O)R.sup.3, C(R.sup.2).sub.2 --O--C(O)OR.sup.3, --C(R.sup.2).sub.2
 OC(O)SR.sup.3, alkyl-S--C(O)R.sup.3, alkyl-S--S-alkylhydroxy, and
 alkyl-S--S--S-alkylhydroxy, or together R.sup.1 and R.sup.1 are
 -alkyl-S--S-alkyl to form a cyclic group, or together R.sup.1 and R.sup.1
 are
 ##STR12##
 wherein
 V and W are independently selected from the group consisting of hydrogen,
 aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl,
 1-alkynyl, and --R.sup.9 ; or
 together V and Z are connected to form a cyclic group containing 3-5 atoms,
 optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarboxy,
 or aryloxycarboxy attached to a carbon atom that is three atoms from an
 oxygen attached to the phosphorus; or
 together V and W are connected to form a cyclic group containing 3 carbon
 atoms substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy,
 hydroxymethyl, and aryloxycarboxy attached to a carbon atom that is three
 atoms from an oxygen attached to the phosphorus;
 Z is selected from the group consisting of --CH.sub.2 OH, --C H.sub.2
 OCOR.sup.3, --CH.sub.2 OC(O)SR.sup.3, --CH.sub.2 OCO.sub.2 R.sup.3,
 --SR.sup.3, --S(O)R.sup.3, --CH.sub.2 N.sub.3, --CH.sub.2 NR.sup.2.sub.2,
 --CH.sub.2 Ar, --CH(Ar)OH, --CH(CH.dbd.CR.sup.2 R.sup.2)OH,
 --CH(CH.ident.CR.sup.2)OH, and --R.sup.2 ;
 with the provisos that:
 a) V, Z, W are not all --H; and
 b) when Z is --R.sup.2, then at least one of V and W is not --H or
 --R.sup.9 ;
 R.sup.2 is selected from the group consisting of R.sup.3 and --H;
 R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic,
 and aralkyl;
 R.sup.4 is independently selected from the group consisting of --H, lower
 alkyl, lower alicyclic, lower aralkyl, and lower aryl;
 R.sup.5 is selected from the group consisting of lower alkyl, lower aryl,
 lower aralkyl, and lower alicyclic;
 R.sup.6 is independently selected from the group consisting of --H, and
 lower alkyl;
 R.sup.7 is independently selected from the group consisting of --H, lower
 alkyl, lower alicyclic, lower aralkyl, lower aryl, and --C(O)R.sup.10 ;
 R.sup.8 is independently selected from the group consisting of --H, lower
 alkyl, lower aralkyl, lower aryl, lower alicyclic, --C(O)R.sup.10, or
 together they form a bidendate alkyl;
 R.sup.9 is selected from the group consisting of alkyl, aralkyl, and
 alicyclic;
 R.sup.10 is selected from the group consisting of --H, lower alkyl,
 --NH.sub.2, lower aryl, and lower perhaloalkyl;
 R.sup.11 is selected from the group consisting of alkyl, aryl, --OH,
 --NH.sub.2 and --OR.sup.3 ; and
 pharmaceutically acceptable prodrugs and salts thereof.
 Preferred Compounds of Formula 1
 Suitable alkyl groups include groups having from 1 to about 20 carbon
 atoms. Suitable aryl groups include groups having from 1 to about 20
 carbon atoms. Suitable aralkyl groups include groups having from 2 to
 about 21 carbon atoms. Suitable acyloxy groups include groups having from
 1 to about 20 carbon atoms. Suitable alkylene groups include groups having
 from 1 to about 20 carbon atoms. Suitable alicyclic groups include groups
 having 3 to about 20 carbon atoms. Suitable heteroaryl groups include
 groups having from 1 to about 20 carbon atoms and from 1 to 5 heteroatoms,
 preferably independently selected from nitrogen, oxygen, phosphorous, and
 sulfur. Suitable heteroalicyclic groups include groups having from 2 to
 about twenty carbon atoms and from 1 to 5 heteroatoms, preferably
 independently selected from nitrogen, oxygen, phosphorous, and sulfur.
 Preferred A groups include --NR.sup.8.sub.2, lower alkyl, lower
 perhaloalkyl, lower alkoxy, and halogen. Particularly preferred are
 --NR.sup.8.sub.2, and halogen. Especially preferred is --NR.sup.8.sub.2.
 Most preferred is --NH.sub.2.
 Preferred E groups include --H, halogen, lower perhaloalkyl, --CN, lower
 alkyl, lower alkoxy, and lower alkylthio. Particularly preferred E groups
 include --H, --SMe, --Et, and --Cl. Especially preferred is --H and
 --SCH.sub.3.
 Preferred X groups include alkylamino, alkyl, alkynyl, alkoxyalkyl,
 alkylthio, aryl, 1,1-dihaloalkyl, carbonylalkyl, heteroaryl,
 alkylcarbonylamino, and alkylaminocarbonyl. Particularly preferred is
 alkyl substituted with 1 to 3 substituents selected from halogen,
 phosphonate, --CO.sub.2 H, --SO.sub.3 H, and --OH. Particularly preferred
 are alkylaminocarbonyl, alkoxyalkyl, and heteroaryl. Preferred alkoxyalkyl
 groups include methoxymethyl. Preferred heteroaryl groups include furanyl,
 optionally substituted.
 Preferred Y groups include aralkyl, alicyclic, alkyl, and aryl, all
 optionally substituted. Particularly preferred is lower alkyl.
 Particularly preferred Y groups include (2-naphthyl)methyl,
 cyclohexylethyl, phenylethyl, nonyl, cyclohexylpropyl, ethyl,
 cyclopropylmethyl, cyclobutylmethylphenyl, (2-methyl)propyl, neopentyl,
 cyclopropyl, cyclopentyl, (1-imidozolyl)propyl, 2-ethoxybenzyl,
 1-hydroxy-2,2-dimethylpropyl, 1-chloro-2,2-dimethylpropyl,
 2,2-dimethylbutyl , 2-(spiro-3,3-dimethylcyclohex-4-enyl)propyl, and
 1-methyineopentyl. Especially preferred is neopentyl and isobutyl.
 Preferred R.sup.4 and R.sup.7 groups are --H, and lower alkyl. Particularly
 preferred are --H, and methyl.
 Preferred R.sup.1 groups include --H, alkyl, aryl, alicyclic where the
 cyclic moiety contains a carbonate or thiocarbonate, --C(R.sup.2).sub.2
 -aryl, alkylaryl, --C(R.sup.2).sub.2 OC(O)NR.sup.2.sub.2, --NR.sup.2
 --C(O)--R.sup.3, --C(R.sup.2).sub.2 --OC(O)R.sup.3, C(R.sup.2).sub.2
 --O--C(O)OR.sup.3, --C(R.sup.2).sub.2 OC(O)SR.sup.3, alkyl-S--C(O)R.sup.3,
 alkyl-S--S-alkylhydroxy, and alkyl-S--S--S-alkylhydroxy, or together
 R.sup.1 and R.sup.1 are -alkyl-S--S-alkyl to form a cyclic group, or
 together R.sup.1 and R.sup.1 are
 ##STR13##
 wherein
 V and W are independently selected from the group consisting of hydrogen,
 aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl,
 1-alkynyl, and --R.sup.9 ; or
 together V and Z are connected to form a cyclic group containing 3-5 atoms,
 optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarboxy,
 or aryloxycarboxy attached to a carbon atom that is three atoms from an
 oxygen attached to the phosphorus; or
 together V and W are connected to form a cyclic group containing 3 carbon
 atoms substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy,
 hydroxymethyl, and aryloxycarboxy attached to a carbon atom that is three
 atoms from an oxygen attached to the phosphorus;
 Z is selected from the group consisting of --CH.sub.2 OH, --CH.sub.2
 OCOR.sup.3, --CH.sub.2 OC(O)SR.sup.3, --CH.sub.2 OCO.sub.2 R.sup.3,
 --SR.sup.3, --S(O)R.sup.3, --CH.sub.2 N.sub.3, --CH.sub.2 NR.sup.2.sub.2,
 --CH.sub.2 Ar, --CH(Ar)OH, --CH(CH.dbd.CR.sup.2 R.sup.2)OH,
 --CH(C.ident.OCR.sup.2)OH, and --R.sup.2 ;
 with the provisos that:
 a) V, Z, W are not all --H; and
 b) when Z is --R.sup.2, then at least one of V and W is not --H or
 --R.sup.9 ;
 R.sup.2 is selected from the group consisting of R.sup.3 and --H;
 R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic,
 and aralkyl; and
 R.sup.9 is selected from the group consisting of alkyl, aralkyl, and
 alicyclic.
 Preferred R.sup.1 groups include --H, alkylaryl, aryl, --C(R.sup.2).sub.2
 -aryl, and --C(R.sup.2).sub.2 --OC(O)R.sup.3. Preferred such R.sup.1
 groups include optionally substituted phenyl, optionally substituted
 benzyl, --H, --C(R.sup.2).sub.2 OC(O)OR.sup.3, and --C(R.sup.2).sub.2
 OC(O)R.sup.3. Preferably, said alkyl groups are greater than 4 carbon
 atoms. Another preferred aspect is where at least one R.sup.1 is aryl or
 --C(R.sup.2).sub.2 -aryl. Also particularly preferred are compounds where
 R.sup.1 is alicyclic where the cyclic moiety contains carbonate or
 thiocarbonate. Another preferred aspect is when at least one R.sup.1 is
 --C(R.sup.2).sub.2 --OC(O)R.sup.3, --C(R.sup.2).sub.2 --OC(O)OR.sup.3 or
 --C(R.sup.2).sub.2 --OC(O)SR.sup.3. Also particularly preferred is when
 R.sup.1 and R.sup.1 together are optionally substituted, including fused,
 lactone attached at the omega position or are optionally substituted
 2-oxo-1,3-dioxolenes attached through a methylene to the phosphorus
 oxygen. Also preferred is when at least one R.sup.1 is
 -alkyl-S--S-alkylhydroxyl, -alkyl-S--C(O)R.sup.3, and
 -alkyl-S--S--S-alkylhydroxy, or together R.sup.1 and R.sup.1 are
 -alkyl-S--S-alkyl- to form a cyclic group. Also preferred is where R.sup.1
 and R.sup.1 together are
 ##STR14##
 to form a cyclic group,
 wherein
 V and W are independently selected from the group consisting of hydrogen,
 aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl,
 1-alkynyl, and --R.sup.9 ; or
 together V and Z are connected to form a cyclic group containing 3-5 atoms,
 optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarboxy,
 or aryloxycarboxy attached to a carbon atom that is three atoms from an
 oxygen attached to the phosphorus; or
 together V and W are connected to form a cyclic group containing 3 carbon
 atoms substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy,
 hydroxymethyl, and aryloxycarboxy attached to a carbon atom that is three
 atoms from an oxygen attached to the phosphorus;
 Z is selected from the group consisting of --CH.sub.2 OH, --CH.sub.2
 OCOR.sup.3, --CH.sub.2 OC(O)SR.sup.3, --CH.sub.2 OCO.sub.2 R.sup.3,
 --SR.sup.3, --S(O)R.sup.3, --CH.sub.2 N.sub.3, --CH.sub.2 NR.sup.2.sub.2,
 --CH.sub.2 Ar, --CH(Ar)OH, --CH(CH.dbd.CR.sup.2 R.sup.2)OH,
 --CH(C.ident.CR.sup.2)OH, and --R.sup.2 ;
 with the provisos that:
 a) V, Z, W are not all --H; and
 b) when Z is --R.sup.2, then at least one of V and W is not --H or
 --R.sup.9 ;
 R.sup.2 is selected from the group consisting of R.sup.3 and --H;
 R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic,
 and aralkyl; and
 R.sup.9 is selected from the group consisting of alkyl, aralkyl, and
 alicyclic.
 Particularly preferred are such groups wherein V and W both form a
 6-membered carbocyclic ring substituted with 0-4 groups, selected from the
 group consisting of hydroxy, acyloxy, alkoxycarbonyl, and alkoxy; and Z is
 R.sup.2. Also particularly preferred are such groups wherein V and W are
 hydrogen; and Z is selected from the group consisting of hydroxyalkyl,
 acyloxyalkyl, alkyloxyalkyl, and alkoxycarboxyalkyl. Also particularly
 preferred are such groups wherein V and W are independently selected from
 the group consisting of hydrogen, optionally substituted aryl, and
 optionally substituted heteroaryl, with the proviso that at least one of V
 and W is optionally substituted aryl or optionally substituted heteroaryl.
 In one preferred aspect, R.sup.1 is not lower alkyl of 1-4 carbon atoms.
 In another preferred aspect, A is --NR.sup.8.sub.2 or halogen, E is --H,
 halogen, --CN, lower alkyl, lower perhaloalkyl, lower alkoxy, or lower
 alkylthio, X is alkylamino, alkyl, alkoxyalkyl, alkynyl, 1,1-dihaloalkyl,
 carbonylakyl, alkyl(OH), alkyl(sulfonate), alkylcarbonylamino,
 alkylaminocarbonyl, alkylthio, aryl, or heteroaryl, and R.sup.4 and
 R.sup.7 is --H or lower alkyl. Particularly preferred are such compounds
 where Y is aralkyl, aryl, alicyclic, or alkyl. Especially preferred are
 such compounds where R.sup.1 and R.sup.1 together are
 ##STR15##
 wherein
 V and W are independently selected from the group consisting of hydrogen,
 aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl,
 1-alkynyl, and --R.sup.9 ; or
 together V and Z are connected to form a cyclic group containing 3-5 atoms,
 optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarboxy,
 or aryloxycarboxy attached to a carbon atom that is three atoms from an
 oxygen attached to the phosphorus; or
 together V and W are connected to form a cyclic group containing 3 carbon
 atoms substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy,
 hydroxymethyl, and aryloxycarboxy attached to a carbon atom that is three
 atoms from an oxygen attached to the phosphorus;
 Z is selected from the group consisting of --CH.sub.2 OH, --CH.sub.2
 OCOR.sup.3, --CH.sub.2 OC(O)SR.sup.3, --CH.sub.2 OCO.sub.2 R.sup.3,
 --SR.sup.3, --S(O)R.sup.3, --CH.sub.2 N.sub.3, --CH.sub.2 NR.sup.2.sub.2,
 --CH.sub.2 Ar, --CH(Ar)OH, --CH(CH.dbd.CR.sup.2 R.sup.2)OH,
 --CH(C.ident.CR.sup.2)OH, and --R.sup.2 ;
 with the provisos that:
 a) V, Z, W are not all --H; and
 b) when Z is --R.sup.2, then at least one of V and W is not --H or
 --R.sup.9 ;
 R.sup.2 is selected from the group consisting of R.sup.3 and --H;
 R.sup.3 is selected from the group consisting of alkyl, aryl, alicyclic,
 and aralkyl; and
 R.sup.9 is selected from the group consisting of alkyl, aralkyl, and
 alicyclic.
 In another preferred aspect, A is --NR.sup.8.sub.2, E is --H, Cl--, or
 methylthio, and X is optionally substituted furanyl, or alkoxyalkyl.
 Particularly preferred are such compounds where A is --NH.sub.2, X is
 2,5-furanyl, or methoxymethyl, and Y is lower alkyl. Most preferred are
 such compounds where E is H, X is 2,5-furanyl, and Y is neopentyl; those
 where E is --SCH.sub.3, X is 2,5-furanyl, and Y is isobutyl; and those
 where E is --H, X is 2,5-furanyl, and Y is
 1-(3-chloro-2,2-dimethyl)-propyl. Especially preferred are such compounds
 where R.sup.1 is --CH.sub.2 O--C(O)--C(CH.sub.3).sub.3.
 In the following examples of preferred compounds, the following prodrugs
 are preferred:
 Acyloxyalkyl esters;
 Alkoxycarbonyloxyalkyl esters;
 Aryl esters;
 Benzyl and substituted benzyl esters;
 Disulfide containing esters;
 Substituted (1,3-dioxolen-2-one)methyl esters;
 Substituted 3-phthalidyl esters;
 Cyclic-[2'-hydroxymethyl]-1,3-propanyl diesters and hydroxy protected
 forms;
 Lactone type esters; and all mixed esters resulted from possible
 combinations of above esters.
 Bis-pivaloyloxymethyl esters;
 Bis-isobutyryloxymethyl esters;
 Cyclic-[2'-hydroxymethyl]-1,3-propanyl diester;
 Cyclic-[2'-acetoxymethyl]-1,3-propanyl diester;
 Cyclic-[2'-methyloxycarbonyloxymethyl]-1,3-propanyl diester;
 Bis-benzoylthiomethyl esters;
 Bis-benzoylthioethyl esters;
 Bis-benzoyloxymethyl esters;
 Bis-p-fluorobenzoyloxymethyl esters;
 Bis-6-chloronicotinoyloxymethyl esters;
 Bis-5-bromonicotinoyloxymethyl esters;
 Bis-thiophenecarbonyloxymethyl esters;
 Bis-2-furoyloxymethyl esters;
 Bis-3-furoyloxymethyl esters;
 Diphenyl esters;
 Bis-(4-methoxyphenyl) esters;
 Bis-(2-methoxyphenyl) esters;
 Bis-(2-ethoxyphenyl) esters;
 Mono-(2-ethoxyphenyl) esters;
 Bis-(4-acetamidophenyl) esters;
 Bis-(4-acetoxyphenyl) esters;
 Bis-(4-hydroxyphenyl) esters;
 Bis-(2-acetoxyphenyl) esters;
 Bis-(3-acetoxyphenyl) esters;
 Bis-(4-morpholinophenyl) esters;
 Bis-[4-(1-triazolophenyl) esters;
 Bis-(3-N,N-dimethylaminophenyl) esters;
 Bis-(2-tetrahydronapthyl) esters;
 Bis-(3-chloro-4-methoxy)benzyl esters;
 Bis-(3-bromo-4-methoxy)benzyl esters;
 Bis-(3-cyano-4-methoxy)benzyl esters;
 Bis-(3-chloro-4-acetoxy)benzyl esters;
 Bis-(3-bromo-4-acetoxy)benzyl esters;
 Bis-(3-cyano-4-acetoxy)benzyl esters;
 Bis-(4-chloro)benzyl esters;
 Bis-(4-acetoxy)benzyl esters;
 Bis-(3,5-dimethoxy-4-acetoxy)benzyl esters;
 Bis-(3-methyl-4-acetoxy)benzyl esters;
 Bis-(benzyl)esters;
 Bis-(3-methoxy-4-acetoxy)benzyl esters;
 Bis-(3-chloro-4-acetoxy)benzyl esters;
 cyclic-(2,2-dimethylpropyl)phosphonoamidate;
 cyclic-(2-hydroxymethylpropyl) ester;
 Bis-(6'-hydroxy-3',4'-disulfide)hexyl esters;
 Bis-(6'-acetoxy-3',4'-disulfide)hexyl esters;
 (3',4'-Dithia)cyclononane esters;
 Bis-(5-methyl-1,3-dioxolen-2-one-4-yl)methyl esters;
 Bis-(5-ethyl-1,3-dioxolen-2-one-4-yl)methyl esters;
 Bis-(5-tert-butyl-1,3-dioxolen-2-one-4-yl)methyl esters;
 Bis-3-(5,6,7-trimethoxy)phthalidyl esters;
 Bis-(cyclohexyloxycarbonyloxymethyl) esters;
 Bis-(isopropyloxycarbonyloxymethyl) esters;
 Bis-(ethyloxycarbonyloxymethyl) esters;
 Bis-(methyloxycarbonyloxymethyl) esters;
 Bis-(isopropylthiocarbonyloxymethyl) esters;
 Bis-(phenyloxycarbonyloxymethyl) esters;
 Bis-(benzyloxycarbonyloxymethyl) esters;
 Bis-(phenylthiocarbonyloxymethyl) esters;
 Bis-(p-methoxyphenyloxycarbonyloxymethyl) esters;
 Bis-(m-methoxyphenyloxycarbonyloxymethyl) esters;
 Bis-(o-methoxyphenyloxycarbonyloxymethyl) esters;
 Bis-(o-methylphenyloxycarbonyloxymethyl) esters;
 Bis-(p-chlorophenyloxycarbonyloxymethyl) esters;
 Bis-(1,4-biphenyloxycarbonyloxymethyl) esters;
 Bis-[(2-phthalimidoethyl)oxycarbonyloxymethyl]esters;
 Bis-(N-Phenyl, N-methylcarbamoyloxymethyl) esters;
 Bis-(2-trichloroethyl) esters;
 Bis-(2-bromoethyl) esters;
 Bis-(2-iodoethyl) esters;
 Bis-(2-azidoethyl) esters;
 Bis-(2-acetoxyethyl) esters;
 Bis-(2-aminoethyl) esters;
 Bis-(2-N,N-diaminoethyl) esters;
 Bis-(2-aminoethyl) esters;
 Bis-(methoxycarbonylmethyl) esters;
 Bis-(2-aminoethyl) esters;
 Bis-[N,N-di(2-hydroxyethyl)]amidomethylesters;
 Bis-(2-aminoethyl) esters;
 Bis-(2-methyl-5-thiozolomethyl) esters;
 Bis-(bis-2-hydroxyethylamidomethyl) esters.
 Most preferred are the following:
 Bis-pivaloyloxymethyl esters;
 Bis-isobutyryloxymethyl esters;
 cyclic-(2-hydroxymethylpropyl) ester;
 cyclic-(2-acetoxymethylpropyl) ester;
 cyclic-(2-methyloxycarbonyloxymethylpropyl) ester;
 cyclic-(2-cyclohexylcarbonyloxymethylpropyl)ester;
 cyclic-(2-aminomethylpropyl)ester;
 cyclic-(2-azidomethylpropyl)ester;
 Bis-benzoylthiomethyl esters;
 Bis-benzoylthioethylesters;
 Bis-benzoyloxymethyl esters;
 Bis-p-fluorobenzoyloxymethyl esters;
 Bis-6-chloronicotinoyloxymethyl esters;
 Bis-5-bromonicotinoyloxymethyl esters;
 Bis-thiophenecarbonyloxymethyl esters;
 Bis-2-furoyloxymethyl esters;
 Bis-3-furoyloxymethyl esters;
 Diphenyl esters;
 Bis-(2-methyl)phenyl esters;
 Bis-(2-methoxy)phenyl esters;
 Bis-(2-ethoxy)phenyl esters;
 Bis-(4-methoxy)phenyl esters;
 Bis-(3-bromo-4-methoxy)benzyl esters;
 Bis-(4-acetoxy)benzyl esters;
 Bis-(3,5-dimethoxy-4-acetoxy)benzyl esters;
 Bis-(3-methyl-4-acetoxy)benzyl esters;
 Bis-(3-methoxy-4-acetoxy)benzyl esters;
 Bis-(3-chloro-4-acetoxy)benzyl esters;
 Bis-(cyclohexyloxycarbonyloxymethyl) esters;
 Bis-(isopropyloxycarbonyloxymethyl) esters;
 Bis-(ethyloxycarbonyloxymethyl) esters;
 Bis-(methyloxycarbonyloxymethyl) esters;
 Bis-(isopropylthiocarbonyloxymethyl) esters;
 Bis-(phenyloxycarbonyloxymethyl) esters;
 Bis-(benzyloxycarbonyloxymethyl) esters;
 Bis-(phenylthiocarbonyloxymethyl) esters;
 Bis-(p-methoxyphenyloxycarbonyloxymethyl) esters;
 Bis-(m-methoxyphenyloxycarbonyloxymethyl) esters;
 Bis-(o-methoxyphenyloxycarbonyloxymethyl) esters;
 Bis-(o-methylphenyloxycarbonyloxymethyl) esters;
 Bis-(p-chlorophenyloxycarbonyloxymethyl) esters;
 Bis-(1,4-biphenyloxycarbonyloxymethyl) esters;
 Bis-[(2-phthalimidoethyl)oxycarbonyloxymethyl]esters;
 Bis-(6'-hydroxy-3',4'-disulfide)hexyl esters; and
 (3',4'-Disulfide)cyclononane esters.
 Bis-(2-bromoethyl) esters;
 Bis-(2-aminoethyl) esters;
 Bis-(2-N,N-diaminoethyl) esters;
 Examples of preferred compounds include, but are not limited to those
 described in Table 1 including salts and prodrugs thereof:

furanyl
 154 NH2 H neopentyl
 3-fluoro-2,5-furanyl
 155 NH2 H neopentyl
 4-fluoro-2,5-furanyl
 156 NH2 H neopentyl
 CONHCH(CO2H)
 157 NH2 Me neopentyl
 2,5-furanyl
 158 NH2 Et neopentyl
 2,5-furanyl
 159 NH2 Pr neopentyl
 2,5-furanyl
 160 NH2 vinyl neopentyl
 2,5-furanyl
 161 NH2 acetylen neopentyl
 2,5-furanyl
 yl
 162 NH2 allyl neopentyl
 2,5-furanyl
 163 NH2 2- neopentyl
 2,5-furanyl
 furanyl
 164 NH2 3- neopentyl
 2,5-furanyl
 furanyl
 165 NH2 2- neopentyl
 2,5-furanyl
 thienyl
 166 NH2 3- neopentyl
 2,5-furanyl
 thienyl
 167 NH2 Ph neopentyl
 2,5-furanyl
 168 22.1 NH2 NH2 neopentyl
 2,5-furanyl
 169 NH2 NHMe neopentyl
 2,5-furanyl
 170 NH2 N(Me)2 neopentyl
 2,5-furanyl
 171 NH2 NHBn neopentyl
 2,5-furanyl
 172 NH2 I neopentyl
 2,5-furanyl
 173 NH2 Br neopentyl
 2,5-furanyl
 174 NH2 Cl neopentyl
 2,5-furanyl
 175 NH2 F neopentyl
 2,5-furanyl
 176 NH2 OMe neopentyl
 2,5-furanyl
 177 NH2 OEt neopentyl
 2,5-furanyl
 178 NH2 OPr neopentyl
 2,5-furanyl
 179 NH2 SO2Me neopentyl
 2,5-furanyl
 180 NH2 SEt neopentyl
 2,5-furanyl
 181 NH2 SPr neopentyl
 2,5-furanyl
 182 NH2 SBu neopentyl
 2,5-furanyl
 183 NH2 CN neopentyl
 2,5-furanyl
 184 NH2 CONH2 neopentyl
 2,5-furanyl
 185 NH2 2- neopentyl
 2,5-furanyl
 pyridyl
 186 NH2 3- neopentyl
 2,5-furanyl
 pyridyl
 187 NH2 4- neopentyl
 2,5-furanyl
 pyridyl
 188 5.4 NH2 H 1-(3-
 CH2OCH2
 cyclohexyl)propyl
 189 5.3 NH2 H 1-nonyl
 CH2OCH2
 190 5.2 NH2 H 2-cyclohexylethyl
 CH2OCH2
 191 5.1 NH2 H 2-phenethyl
 CH2OCH2
 192 10.2 NHMe H 2-phenethyl
 2,5-furanyl
 193 10.1 N(Me)2 H 2-phenethyl
 2,5-furanyl
 194 9.1 Cl H 2-phenethyl
 2,5-furanyl
 195 11.1 NH2 SMe isobutyl
 2,5-furanyl
 196 11.2 NH2 SO2Me isobutyl
 2,5-furanyl
 197 4.1 NH2 H D-ribosyl
 NHCH2CH2
 198 4.2 NH2 H 5'-deoxy-D-ribosyl
 NHCH2CH2
 199 NH2 H H
 NHCH2CH2
 200 3.1 NH2 H benzyl
 NHCH2CH2
 201 3.2 NH2 H 2-phenethyl
 NHCH2CH2
 202 3.3 NH2 H 2-naphthylmethyl
 NHCH2CH2
 203 6.2 NH2 H 2-phenethyl
 CH2CH2CH2
 204 3.4 NH2 H 2-cyclohexylethyl
 NHCH2CH2
 205 6.1 NH2 H 2-cyclohexylethyl
 CH2CH2CH2
 206 8.1 NH2 H 2-cyclohexylethyl
 SCH2
 207 7.1 NH2 H 2-phenethyl
 2,5-thienyl
 208 NH2 Me isobutyl
 2,5-furanyl
 209 NH2 Et isobutyl
 2,5-furanyl
 210 NH2 SEt isobutyl
 2,5-furanyl
 211 NH2 SPr isobutyl
 2,5-furanyl
 212 NH2 2- isobutyl
 2,5-furanyl
 furanyl
 213 NH2 2- isobutyl
 2,5-furanyl
 thienyl
 214 NH2 Pr isobutyl
 2,5-furanyl
 215 NH2 F isobutyl
 2,5-furanyl
 216 NH2 Cl isobutyl
 2,5-furanyl
 217 NH2 Br isobutyl
 2,5-furanyl
 218 NH2 H isobutyl
 2,5-furanyl
 219 NH2 Et isobutyl
 CONHCH2
 220 NH2 SEt isobutyl
 CONHCH2
 221 NH2 SPr isobutyl
 CONHCH2
 222 NH2 2- isobutyl
 CONHCH2
 furanyl
 223 NH2 2- isobutyl
 CONHCH2
 thienyl
 224 NH2 Pr isobutyl
 CONHCH2
 225 NH2 F isobutyl
 CONHCH2
 226 NH2 Cl isobutyl
 CONHCH2
 227 NH2 Br isobutyl
 CONHCH2
 228 NH2 Me isobutyl
 CONHCH2
 229 NH2 H isobutyl
 CONHCH2
 230 NH2 Et neopentyl
 acetylene
 231 NH2 SEt neopentyl
 acetylene
 232 NH2 SPr neopentyl
 acetylene
 233 NH2 2- neopentyl
 acetylene
 furanyl
 234 NH2 2- neopentyl
 acetylene
 thienyl
 235 NH2 Pr neopentyl
 acetylene
 236 NH2 F neopentyl
 acetylene
 237 NH2 Cl neopentyl
 acetylene
 238 NH2 Br neopentyl
 acetylene
 239 NH2 Me neopentyl
 acetylene
 240 NH2 Et neopentyl
 NHCOCH2
 241 NH2 SEt neopentyl
 NHCOCH2
 242 NH2 SPr neopentyl
 NHCOCH2
 243 NH2 2- neopentyl
 NHCOCH2
 furanyl
 244 NH2 2- neopentyl
 NHCOCH2
 thienyl
 245 NH2 Pr neopentyl
 NHCOCH2
 246 NH2 F neopentyl
 NHCOCH2
 247 NH2 Cl neopentyl
 NHCOCH2
 248 NH2 Br neopentyl
 NHCOCH2
 249 NH2 Me neopentyl
 NHCOCH2
 250 NH2 Et neopentyl
 CH2OCH2
 251 NH2 SEt neopentyl
 CH2OCH2
 252 NH2 SPr neopentyl
 CH2OCH2
 253 NH2 2- neopentyl
 CH2OCH2
 furanyl
 254 NH2 2- neopentyl
 CH2OCH2
 thienyl
 255 NH2 Pr neopentyl
 CH2OCH2
 256 NH2 F neopentyl
 CH2OCH2
 257 NH2 Cl neopentyl
 CH2OCH2
 258 NH2 Br neopentyl
 CH2OCH2
 259 NH2 Me neopentyl
 CH2OCH2
 260 NHBn H neopentyl
 2,5-furanyl
 261 NHPh H neopentyl
 2,5-furanyl
 262 NHBn SMe neopentyl
 2,5-furanyl
 263 NHPh SMe neopentyl
 2,5-furanyl
 264 NHPh-4-F H neopentyl
 2,5-furanyl
 265 NHPh-4-F SMe neopentyl
 2,5-furanyl
 266 NHNH2 F neopentyl
 2,5-furanyl
 267 NH2 Me cyclopropylmethyl
 2,5-furanyl
 268 NH2 SMe cyclopropylmethyl
 2,5-furanyl
 269 NH2 F cyclopropylmethyl
 2,5-furanyl
 270 NH2 Cl cyclopropylmethyl
 2,5-furanyl
 271 NH2 Br cyclopropylmethyl
 2,5-furanyl
 272 NH2 Et cyclopropylmethyl
 2,5-furanyl
 273 NH2 CN cyclopropylmethyl
 2,5-furanyl
 274 NH2 Me cyclopropylmethyl
 CONHCH2
 275 NH2 SMe cyclopropylmethyl
 CONHCH2
 276 NH2 F cyclopropylmethyl
 CONHCH2
 277 NH2 Cl cyclopropylmethyl
 CONHCH2
 278 NH2 Br cyclopropylmethyl
 CONHCH2
 279 NH2 Et cyclopropylmethyl
 CONHCH2
 280 NH2 CN cyclopropylmethyl
 CONHCH2
 281 NH2 Me cyclopropylmethyl
 NHCOCH2
 282 NH2 SMe cyclopropylmethyl
 NHCOCH2
 283 NH2 F cyclopropylmethyl
 NHCOCH2
 284 NH2 Cl cyclopropylmethyl
 NHCOCH2
 285 NH2 Br cyclopropylmethyl
 NHCOCH2
 286 NH2 Et cyclopropylmethyl
 NHCOCH2
 287 NH2 CN cyclopropylmethyl
 NHCOCH2
 288 2.18 NH2 H 3-(1-imidazolylpropyl)
 2,5-furanyl
 289 19.1 NH2 H neopentyl
 1,2-C.sub.6 H.sub.4 --O--
 290 21.1 NH2 H 2-phenethyl
 CONHCH2
 More preferred are the following compounds from Table 1 including salts and
 prodrugs thereof:
 1, 21, 22, 23, 29, 50, 57, 61, 62, 63, 66, 67, 72, 73, 89, 90, 107, 110,
 111, 112, 113, 114, 115, 119, 123, 125, 126, 129, 130, 131, 132, 133, 134,
 136, 137, 145, 148, 149, 151, 152, 153, 154, 155, 156, 158, 159, 163, 165,
 173, 174, 175, 180, 181, 182, 183, 209, 210, 212, 215, 216, 217, 219, 220,
 221, 230, 231, 234, 236, 237, 238, 240, 241, 246, 247, 248, 250, 251, 256,
 257, 258, 266, 268, 269, and 272.
 Most preferred are the following compounds and their salts and prodrugs:
 N.sup.9 -neopentyl-2-methylthio-8-phosphonomethylaminocarbonyladenine;
 N.sup.9 -neopentyl-2-methylthio-8-(2-(5-phosphono)furanyl)adenine;
 N.sup.9 -neopentyl-8-(2-(5-phosphono)furanyl)adenine;
 N.sup.9 -isobutyl-2-methylthio-8-(2-(5-phosphono)furanyl)adenine;
 N.sup.9 -isobutyl-8-(2-(5-phosphono)furanyl)adenine;
 N.sup.9 -cyclopropyl-8-(2-(5-phosphono)furanyl)adenine;
 N.sup.9 -(2-cyclohexyl)ethyl-8-(2-(5-phosphono)furanyl)adenine;
 N.sup.9
 -(1-(2,2-dimethyl-3-chloro)propyl)-8-(2-(5-phosphono)furanyl)adenine;
 N.sup.9 -(1-(3,3-dimethyl)butyl)-8-(2-(5-phosphono)furanyl)adenine;
 N.sup.9
 -(1,5,5-trimethyl-3-cyclohexen-1-yl)methyl-8-(2-(5-phosphono)furanyl)adeni
 ne;
 N.sup.9 -neopentyl-8-(2-phosphonoacetylene-1-yl)adenine;
 N.sup.9 -neopentyl-8-(1-(3-phosphono-3-sulfuryl)propyl)adenine;
 N.sup.9 -neopentyl-8-(1-(3-phosphono-3-carboxyl)propyl)adenine;
 N.sup.9 -neopentyl-8-(1-(3,3-diphosphono)propyl)adenine;
 N.sup.9 -neopentyl-2-chloro-8-(2-(5-phosphono)furanyl)adenine;
 2-Ethyl-N.sup.9 -neopentyl-8-(2-(5-phosphono)furanyl)adenine;
 2-Methylthio-N.sup.9 -isobutyl-8-(2-(5-phosphono)furanyl)adenine; and
 2-Methylthio-N.sup.9 -isobutyl-8-(phosphonomethoxymethyl)adenine.
 Synthesis of Compounds of Formula 1
 Synthesis of compounds encompassed by the present invention typically
 includes some or all of the following general steps: (1) preparation of
 phosphonate prodrug; (2) deprotection of phosphonate ester; (3)
 modification of C-8-substituted purine intermediates; (4) modification of
 purine at positions other than C-8; (5) construction of the purine ring
 system; and (6) preparation of 4,5-diaminopyrimidine and other coupling
 partners.
 ##STR17##
 (1) Preparation of Phosphonate Prodrugs
 Prodrug esters can be introduced at different stages of the synthesis.
 Because of their lability, prodrugs are often prepared from compounds of
 formula 1 where R.sup.1 is H. Advantageously, these prodrug esters can be
 introduced at an early stage, provided that it can withstand the reaction
 conditions of the subsequent steps.
 Compounds of formula 5 where R.sup.1 is H, can be alkylated with
 electrophiles (such as alkyl halides, alkyl sulfonates etc) under
 nucleophilic substitution reaction conditions to give phosphonate esters.
 For example prodrugs of formula 1, where R.sup.1 is acyloxymethyl group
 can be synthesized through direct alkylation of the free phosphonic acid
 of formula 5, with the desired acyloxymethyl halide (e.g. Cl, Br, I;
 Elhaddadi, et al Phosphorus Sulfur, 1990, 54(1-4): 143; Hoffmann,
 Synthesis, 1988, 62) in presence of base e.g. N,
 N'-dicyclohexyl-4-morpholinecarboxamidine, Hunigs base etc. in polar
 aprotic solvents such as DMF (Starrett, et al, J. Med. Chem., 1994, 1857).
 These carboxylates include but not limited to acetate, propylate,
 isobutyrate, pivalate, benzoate, and other carboxylates. Alternately,
 these acyloxymethylphosphonate esters can also be synthesized by treatment
 of the nitrophosphonic acid (A is NO.sub.2 in formula 5; Dickson, et al,
 J. Med. Chem., 1996, 39: 661; lyer, et al, Tetrahedron Lett., 1989, 30:
 7141; Srivastva, et al, Bioorg. Chem., 1984, 12: 118). This can be
 extended to many other types of prodrugs, such as compounds of formula 1
 where R.sup.1 is 3-phthalidyl, 2-oxo-4,5-didehydro-1,3-dioxolanemethyl,
 and 2-oxotetrahydrofuran-5-yl groups, etc. (Biller and Magnin (U.S. Pat.
 No. 5,157,027); Serafinowska et al. (J. Med. Chem. 38: 1372 (1995));
 Starrett et al. (J. Med. Chem. 37: 1857 (1994)); Martin et al. J. Pharm.
 Sci. 76: 180 (1987); Alexander et al., Collect. Czech. Chem. Commun, 59:
 1853 (1994)); and EPO 0632048A1). N,N-Dimethylformamide dialkyl acetals
 can also be used to alkylate phosphonic acids (Alexander, P., et al
 Collect. Czech. Chem. Commun., 1994, 59,1853).
 Alternatively, these phosphonate prodrugs or phosphoramidates can also be
 synthesized, by reaction of the corresponding dichlorophosphonates and an
 alcohol or an amine (Alexander, et al, Collect. Czech. Chem. Commun.,
 1994, 59: 1853). For example, the reaction of dichlorophosphonate with
 phenols and benzyl alcohols in the presence of base (such as pyridine,
 triethylamine, etc) yields compounds of formula 1 where R.sup.1 is aryl
 (Khamnei, S., et al J. Med. Chem., 1996, 39: 4109; Serafinowska, H. T., et
 al J. Med. Chem., 1995, 38:1372; De Lombaert, S., et al J. Med. Chem.,
 1994, 37: 498) or benzyl (Mitchell, A. G., et al J. Chem. Soc. Perkin
 Trans. 1,1992, 38: 2345). The disulfide-containing prodrugs, reported by
 Puech et al., Antiviral Res., 1993, 22: 155, can also be prepared from
 dichlorophosphonate and 2-hydroxyethyl disulfide under the standard
 conditions.
 Such reactive dichlorophosphonate intermediates can be prepared from the
 corresponding phosphonic acids and the chlorinating agents e.g. thionyl
 chloride (Starrett, et al, J. Med. Chem., 1994, 1857), oxalyl chloride
 (Stowell, et al, Tetrahedron Lett., 1990, 31: 3261), and phosphorus
 pentachloride (Quast, et al, Synthesis, 1974, 490). Alternatively, these
 dichlorophosphonates can also be generated from disilyl phosphonate esters
 (Bhongle, et al, Synth. Commun., 1987, 17: 1071) and dialkyl phosphonate
 esters (Still, et al, Tetrahedron Lett., 1983, 24: 4405; Patois, et al,
 Bull. Soc. Chim. Fr., 1993, 130: 485).
 Furthermore, these prodrugs can be prepared from Mitsunobu reactions
 (Mitsunobu, Synthesis, 1981, 1; Campbell, J. Org. Chem., 1992, 52: 6331),
 and other acid coupling reagents include, but not limited to,
 carbodiimides (Alexander, et al, Collect. Czech. Chem. Commun., 1994,
 59:1853; Casara, et al, Bioorg. Med. Chem. Lett., 1992, 2:145; Ohashi, et
 al, Tetrahedron Lett., 1988, 29: 1189), and
 benzotriazolyloxytris-(dimethylamino)phosphonium salts (Campagne, et al,
 Tetrahedron Lett., 1993, 34: 6743). The prodrugs of formula 1 where
 R.sup.1 is the cyclic carbonate or lactone or phthalidyl can also be
 synthesized by direct alkylation of free phosphonic acid with desired
 halides in the presence of base such as NaH or diisopropylethylamine
 (Biller and Magnin U.S. Pat. No. 5,157,027; Serafinowska et al. J. Med.
 Chem. 38:1372 (1995); Starrett et al. J. Med. Chem. 37: 1857 (1994);
 Martin et al. J. Pharm. Sci. 76:180 (1987); Alexander et al., Collect.
 Czech. Chem. Commun, 59:1853 (1994); and EPO 0632048A1).
 R.sup.1 can also be introduced at an early stage of synthesis, when
 feasible. For example, compounds of formula 1 where R.sup.1 is phenyl can
 be prepared by phosphorylation of 2-furanylpurines via strong base
 treatment (e.g. LDA) followed by chlorodiphenylphosphonate, as shown in
 the following scheme. Alternatively, such compounds can be prepared by
 cyclization of 5-diphenylphosphono-2-furaldehyde with
 4,5-diaminopyrimidines as described in section 5.
 ##STR18##
 It is envisioned that compounds of formula 1 can be mixed phosphonate
 esters by combining the above described prodrugs (e.g. phenyl benzyl
 phosphonate esters, phenyl acyloxyalkyl phosphonate esters, etc.). For
 example, the chemically combined phenyl-benzyl prodrugs are reported by
 Meier et al. Bioorg. Med. Chem. Lett., 1997, 7: 99.
 The substituted cyclic propyl phosphonate esters of formula 5, can be
 synthesized by reaction of the corresponding dichlorophosphonate and the
 substituted 1,3-propanediol. The following are some of the methods to
 prepare the substituted 1,3-propanediols.
 Synthesis of the 1,3-Propanediols Used in the Preparation of Certain
 Prodrugs
 The discussion of this step includes various synthetic methods for the
 preparation of the following types of propane-1,3-diols: i) 1-substituted;
 ii) 2-substituted; and iii) 1,2- or 1,3-annulated. Different groups on the
 prodrug part of the molecule i.e., on the propanediol moiety can be
 introduced or modified either during the synthesis of the diols or after
 the synthesis of the prodrugs.
 i) 1-Substituted 1,3-Propanediols
 Propane-1,3-diols can be synthesized by several well known methods in the
 literature. Aryl Grignard additions to 1-hydroxypropan-3-al gives
 1-aryl-substituted propane-1,3-diols (path a). This method will enable
 conversion of various substituted aryl halides to
 1-arylsubstituted-1,3-propanediols (Coppi, et. al., J. Org. Chem., 1988,
 53, 911). Aryl halides can also be used to synthesize 1-substituted
 propanediols by Heck coupling of 1,3-diox-4-ene followed by reduction and
 hydrolysis (Sakamoto, et. al., Tetrahedron Lett., 1992, 33, 6845). A
 variety of aromatic aldehydes can be converted to
 1-substituted-1,3-propanediols by vinyl Grignard addition followed by
 hydroboration (path b). Substituted aromatic aldehydes are also utilized
 by lithium-t-butylacetate addition followed by ester reduction (path e)
 (Turner., J. Org. Chem., 1990, 55 4744). In another method, commercially
 available cinnamyl alcohols can be converted to epoxy alcohols under
 catalytic asymmetric epoxidation conditions. These epoxy alcohols are
 reduced by Red-Al to result in enantiomerically pure propane-1,3-diols
 (path c). Alternatively, enantiomerically pure 1,3-diols can be obtained
 by chiral borane reduction of hydroxyethyl aryl ketone derivatives
 (Ramachandran, et. al., Tetrahedron Lett., 1997, 38 761). Pyridyl,
 quinoline, and isoquinoline propan-3-ol derivatives can be oxygenated to
 1-substituted propan-1,3-diols by N-oxide formation followed by
 rearrangement under acetic anhydride conditions (path d) (Yamamoto, et.
 al., Tetrahedron, 1981, 37, 1871).
 ##STR19##
 ii) 2-Substituted 1,3-Propanediols:
 Various 2-substituted propane-1,3-diols can be made from commercially
 available 2-(hydroxymethyl)-1,3-propanediol. Triethyl
 methanetricarboxylate can be converted to the triol by complete reduction
 or diol-monocarboxylic acid derivatives can be obtained by partial
 hydrolysis and diester reduction (Larock, Comprehensive Organic
 Transformations, VCH, New York, 1989). Nitrotriol is also known to give
 the triol by reductive elimination (Latour, et. al., Synthesis, 1987, 8,
 742). The triol can be derivatized as a mono acetate or carbonate by
 treatment with alkanoyl chloride, or alkylchloroformate, respectively
 (Greene and Wuts, Protective Groups in Organic Synthesis, John Wiley, New
 York, 1990). Aryl substitution can be made by oxidation to the aldehyde
 followed by aryl Grignard additions and the aldehyde can also be converted
 to substituted amines by reductive amination reactions.
 iii) Annulated 1,3-Propanediols:
 Prodrugs of formula 1 where V-Z or V-W are fused by three carbons are made
 from cyclohexanediol derivatives. Commercially available cis,
 cis-1,3,5-cyclohexanetriol can be used for prodrug formation. This
 cyclohexanetriol can also be modified as described in the case of
 2-substituted propane-1,3-diols to give various analogues. These
 modifications can either be made before or after formation of prodrugs.
 Various 1,3-cyclohexanediols can be made by Diels-Alder methodology using
 pyrone as the diene (Posner, et. al., Tetrahedron Lett., 1991, 32, 5295).
 Cyclohexyl diol derivatives are also made by nitrile oxide
 olefin-additions (Curran, et. al., J. Am. Chem. Soc., 1985, 107, 6023).
 Alternatively, cyclohexyl precursors can be made from quinic acid (Rao,
 et. al., Tetrahedron Lett., 1991, 32, 547.)
 (2) Deprotection of Phosphonate Esters
 Compounds of formula 1 where R.sup.1 is H may be prepared from phosphonate
 esters using known phosphate and phosphonate ester cleavage conditions.
 For example, alkyl phosphonate esters are generally cleaved by reaction
 with silyl halides followed by hydrolysis of the intermediate silyl
 phosphonate esters. Depending on the stability of the products, these
 reactions are usually accomplished in the presence of acid scavengers such
 as 1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidine, etc. Various silyl
 halides can be used for this transformation, such as chlorotrimethylsilane
 (Rabinowitz J. Org. Chem., 1963, 28: 2975), bromotrimethylsilane (McKenna
 et al. Tetrahedron Lett., 1977, 155), iodotrimethylsilane (Blackburn et
 al. J. Chem. Soc., Chem. Commun., 1978, 870). Phosphonate esters can also
 be cleaved under strong acid conditions, such as hydrogen halides in
 acetic acid or water, and metal halides (Moffatt et al. U.S. Pat. No.
 3,524,846,1970). Phosphonate esters can also be converted to
 dichlorophosphonates with halogenating agents (e.g. PCl.sub.5, SOCl.sub.2,
 BBr.sub.3, etc. Pelchowicz et al. J. Chem. Soc., 1961, 238) and
 subsequently hydrolyzed to give phosphonic acids. Reductive reactions are
 useful in cleaving aryl and benzyl phosphonate esters. For example, aryl
 and benzyl phosphonate esters can be cleaved under hydrogenolysis
 conditions (Lejczak et al. Synthesis, 1982, 412; Elliott et al. J. Med
 Chem., 1985, 28: 1208.) or dissolving metal reduction conditions (Shafer
 et al. J. Am. Chem. Soc., 1977, 99: 5118). (Elliott et al. J. Med. Chem.,
 1985, 28: 1208). Electrochemical (Shono et al. J. Org. Chem., 1979, 44:
 4508) and pyrolysis (Gupta et al. Synth. Commun., 1980, 10: 299)
 conditions have also been used to cleave various phosphonate esters.
 (3) Modification of C-8-substituted Purine Intermediates
 8-Substituted purines are useful intermediates in the preparation of
 compounds of formula 1. 8-Halopurines, which are particularly useful
 intermediates, are readily prepared using chemistry well described in the
 literature. For example, N.sup.9 -alkyladenines are halogenated at the C-8
 position using known halogenating agents (e.g. Br.sub.2, NBS).
 8-Alkylpurine can be prepared through direct lithiation of purine followed
 by trapping with electrophiles (e.g. alkyl halides, Barton et al.
 Tetrahedron Lett., 1979, 5877).
 Functionaliztion of 8-halopurines can be accomplished under substitution
 reaction conditions with nucleophiles such as amines, alcohols, azides,
 sulfides, and alkylthiols. It is advantageous to have the phosphonate
 moiety as part of the nucleophiles. For example, substitution of
 8-bromopurine with aminoalkylphosphonates gives compounds of formula 1
 where X is alkylamino.
 8-Halopurines can also be transformed into other 8-substituted purines
 using palladium catalyzed reactions (Heck Palladium Reagents in Organic
 Synthesis; Academic Press: San Diego, 1985). For example, palladium
 catalyzed carbonylation reactions of 8-bromopurine in the presence of
 alcohol gives 8-alkoxycarbonylpurines. Using known chemistry, the
 8-carboxylate group can be converted into other functional groups, such as
 hydroxymethyl, halomethyl, formyl, carboxylic acid, carbamoyl, and
 thiocarbonyl groups. These functional groups are useful intermediates for
 the synthesis of compounds of formula 1. For example, 8-alkyl and
 8-arylpurines can be prepared from 8-halopurines via palladium catalyzed
 coupling reactions with organotin (Moriarty et al. Tetrahedron Lett.,
 1990, 41: 5877), organoborane (Yatagai, Bull. Chem. Soc. Jpn., 1980, 53:
 1670), and other reagents known to couple with aryl halides. When the
 coupling reagents contain the dialkylphosphonate group, the reaction is
 useful for preparation of compounds of formula 5 where X is alkyl,
 alkenyl, alkynyl, and aryl. For example, 8-bromopurine can be coupled with
 diethyl 1-tributylstannyl-3-allylphosphonate to give compounds of formula
 5 where X is --CH.dbd.CHCH.sub.2 --. Subsequent hydrogenation reaction
 gives compounds of formula 5 where X is --CH.sub.2 CH.sub.2 CH.sub.2 --.
 The phosphonate group can also be introduced by further modification of the
 8-substituents. Substitutions of 8-haloalkyl or 8-sulfonylalkylpurine with
 nucleophiles containing the phosphonate group are useful for the
 preparation of compounds of formula 5 where X is alkylaminoalkyl,
 alkoxyalkyl, and alkylthioalkyl. For example, compounds of formula 5 where
 X is --CH.sub.2 OCH.sub.2 -- can be prepared from 8-bromomethylpurine
 using hydroxymethylphosphonate esters and a suitable base. It is possible
 to reverse the nature of the nucleophiles and electrophiles for the
 substitution reactions, i.e. haloalkyl- and/or sulfonylalkylphosphonate
 esters can be substituted with purines containing a nucleophile at the C-8
 position (such as 8-hydroxyalkyl, 8-thioalkyl, and 8-aminoalkylpurines).
 For example, diethyl phosphonomethyltriflate can be substituted by
 alcohols such as 8-hydroxymethylpurine to give compounds of formula 5
 where X is --CH.sub.2 OCH.sub.2 -- (Phillion et al. Tetrahedron Lett.
 1986, 27: 1477). Known amide formation reactions are useful for the
 synthesis of compounds of formula 5 where X is alkylaminocarbonyl,
 alkoxycarbonyl, alkoxythiocarbonyl, and alkylthiocarbonyl. For example,
 coupling of 8-purinecarboxylic acids with aminoalkylphosphonate esters
 gives compounds of formula 5 where X is alkylaminocarbonyl. For compounds
 of formula 5 where X is alkyl, the phosphonate group can also be
 introduced using other common phosphonate formation methods, such as
 Michaelis-Arbuzov reaction (Bhattacharya et al. Chem. Rev., 1981, 81:
 415), Michaelis-Becker reaction (Blackburn et al. J. Organomet. Chem.,
 1988, 348: 55), addition reactions of phosphorus to electrophiles (such as
 aldehydes, ketones, acyl halides, imines and other carbonyl derivatives).
 8-Azidopurines are useful for the preparation for compounds of formula 5
 where X is alkylamino and alkylcarbonylamino groups. For example,
 carboxylic acids (e.g. (RO).sub.2 P(O)-alkyl-CO.sub.2 H) can be directly
 coupled to 8-azidopurines to give 8-alkylcarbonylaminopurines (Urpi et al.
 Tetrahedron Lett., 1986, 27: 4623). Alternatively, 8-azidopurines can also
 be converted to 8-aminopurines under reductive conditions, and
 subsequently converted to 8-alkylaminocarbonyl- and 8-alkylaminopurines
 using known chemistry.
 (4) Modification of Purines at Positions Other Than C-8
 Compounds of formula 5 can be further modified to give intermediates useful
 for the synthesis of compounds of formula 1. For example, substitution
 reactions of 6-chloropurine by ammonia or alkylamines are useful for the
 preparations of compounds of formula 5 where A is amino and alkylamino
 groups.
 E groups can be introduced by modifying existing 2-substituents of purine.
 For example, 2-halopurines, readily accessible from 2-aminopurines via
 chemistry well described in the literature, can be converted to other
 2-substituted purines by, for example, nucleophilic substitution
 reactions; transition metal catalyzed reactions, etc. (J. Med. Chem.,
 1993, 36: 2938; Heterocycles, 1990, 30: 435).
 E groups can also be introduced via metalation (e.g. lithiation, J. Org.
 Chem., 1997, 62(20), 6833) of the C-2-position and followed by addition of
 electrophiles which can be the desired E group or a substituent (e.g.
 tributylstannyl group) which can be converted to the desired E group using
 conventional chemistry.
 It is envisioned that N.sup.9 -substituted purines can be readily prepared
 from compounds of formula 5 where Y is H using, for example, standard
 alkylation reactions (with alkyl halide, or sulfonate), or Mitsunobu
 reactions. Further elaborations of substituents on Y are also possible.
 More importantly, combinatorial methods have been developed for synthesis
 of 2- and N-9-substituted purines on solid-phase which conceivably can be
 applied for the synthesis of purine FBPase inhibitors (Schultz, et al,
 Tetrahedron Lett., 1997, 38(7), 1161; J. Am. Chem. Soc., 1996, 118, 7430).
 (5) Construction of the Purine Ring System
 The purine ring system of compounds of formula 1 can be constructed using
 4,5-diaminopyrimidines and carboxylates or their derivatives (such as
 aldehydes, amides, nitrites, ortho esters, imidates, etc.) (Townsend
 Chemistry of Nucleosides and Nucleotides, Vol 1; Plenum Press, New York
 and London, page 156-158). For example, alkyl and aryl aldehydes can be
 cyclized with 4,5-diaminopyrimidines as shown below.
 ##STR20##
 Intramolecular cyclization reactions of pyrimidine derivatives can also be
 used to construct the purine ring system. For example,
 5-acylamino-4-alkylaminopyrimidines are treated with phosphorus
 oxychloride and cyclized under basic conditions to give purine
 derivatives. This transformation can also be achieved using other reagents
 (e.g. SiCl.sub.4 -Et.sub.3 N, Desaubry et al. Tetrahedron Lett., 1995, 36:
 4249). Imidazole derivatives are also useful for the construction of
 purine ring system via cyclization reactions to form the pyrimidine ring
 (Townsend Chemistry of Nucleosides and Nucleotides, Vol 1; Plenum Press,
 New York and London, page 148-156).
 (6) Preparation of Diaminopyrimidine and Other Coupling Partners
 Compounds of formula 4 are useful for the construction of purine ring
 systems, and such compounds can be readily synthesized using known
 chemistry. For example, the Y group can be introduced using a nucleophilic
 substitution reaction involving an amine and 4-halopyrimidines
 (Tetrahedron, 1984, 40: 1433). Alternatively, palladium catalyzed
 reactions (Wolfe et al. J. Am. Chem. Soc., 1996, 118: 7215) can also be
 used. Reductive amination reactions (Synthesis, 1975, 135) and alkylation
 with electrophiles (such as halides, sulfonates) are useful for the
 preparation of compounds of formula 4 from 4-aminopyrimidines. The 5-amino
 group can be introduced using amine formation reactions such as nitration
 followed by reduction (Dhainant et al. J. Med. Chem., 1996, 39: 4099),
 arylazo compound formation followed by reduction (Lopez et al. Nucleosides
 & Nucleotides, 1996, 15: 1335), azide formation followed by reduction, or
 by rearrangement of carboxylic acid derivatives (e.g. Schmidt, Curtius,
 and Beckmann reactions).
 Coupling of aromatic or aliphatic aldehydes, and carboxylic acid
 derivatives with attached phosphonate esters are particularly suited for
 the preparation of compounds of formula 1 as described in section 5. Such
 phosphonate esters are prepared by lithiation of the aromatic ring using
 methods well described in literature (Gschwend Org. React. 1979, 26: 1)
 followed by addition of phosphorylating agents (e.g. ClPO.sub.3 R.sub.2).
 Phosphonate esters can also be introduced by Arbuzov-Michaelis reaction
 (Brill Chem Rev., 1984, 84: 577) and transition metal catalyzed reaction
 with alkyl halides and aryl halides or triflates (Balthazar et al. J. Org.
 Chem., 1980, 45: 5425; Petrakis et al. J. Am. Chem. Soc., 1987, 109: 2831;
 Lu et al. Synthesis, 1987, 726). Alternatively, aryl phosphonate esters
 can be prepared from aryl phosphates under anionic rearrangement
 conditions (Melvin Tetrahedron Lett., 1981, 22: 3375; Casteel et al.
 Synthesis, 1991, 691). Aryl phosphate esters can also be used to prepare
 compounds of Formula 1 where X is an oxyaryl group. N-Alkoxy aryl salts
 with alkali metal derivatives of dialkyl phosphonate can be used to
 synthesize heteroaryl-2-phosphonate esters (Redmore J. Org. Chem., 1970,
 35: 4114).
 A second lithiation step can be used to incorporate the aldehyde
 functionality, although other methods known to generate aromatic aldehydes
 can be envisioned as well (e.g. Vilsmeier-Hack reaction, Reimar-Teimann
 reaction etc.). In the second lithiation step, the lithiated aromatic ring
 is treated with reagents that either directly generate an aldehyde (e.g.
 DMF, HCO.sub.2 R, etc.) or with reagents that lead to a group that
 subsequently is transformed into an aldehyde group using known chemistry
 (e.g. alcohol, ester, cyano, alkene, etc.). It is also envisioned that the
 sequence of these reactions can be reversed, i.e. the aldehyde moiety can
 be incorporated first followed by the phosphorylation reaction. The order
 of the reaction will depend on the reaction conditions and the protecting
 groups. Prior to the phosphorylation, it is also envisioned that it may be
 advantageous to protect the aldehydes using a number of well-known steps
 (hemiacetal, hemiaminal, etc.,). The aldehyde is then unmasked after
 phosphorylation. (Protective groups in Organic Synthesis, Greene, T. W.,
 1991, Wiley, New York).
 Formulations
 Compounds of the invention are administered orally in a total daily dose of
 about 0.1 mg/kg/dose to about 100 mg/kg/dose, preferably from about 0.3
 mg/kg/dose to about 30 mg/kg/dose. The most preferred dose range is from
 0.5 to 10 mg/kg (approximately 1 to 20 nmoles/kg/dose). The use of
 time-release preparations to control the rate of release of the active
 ingredient may be preferred. The dose may be administered in as many
 divided doses as is convenient. When other methods are used (e.g.
 intravenous administration), compounds are administered to the affected
 tissue at a rate from 0.3 to 300 nmol/kg/min, preferably from 3 to 100
 nmoles/kg/min. Such rates are easily maintained when these compounds are
 intravenously administered as discussed below.
 For the purposes of this invention, the compounds may be administered by a
 variety of means including orally, parenterally, by inhalation spray,
 topically, or rectally in formulations containing pharmaceutically
 acceptable carriers, adjuvants and vehicles. The term parenteral as used
 here includes subcutaneous, intravenous, intramuscular, and intraarterial
 injections with a variety of infusion techniques. Intraarterial and
 intravenous injection as used herein includes administration through
 catheters. Oral administration is generally preferred.
 Pharmaceutical compositions containing the active ingredient may be in any
 form suitable for the intended method of administration. When used for
 oral use for example, tablets, troches, lozenges, aqueous or oil
 suspensions, dispersible powders or granules, emulsions, hard or soft
 capsules, syrups or elixirs may be prepared. Compositions intended for
 oral use may be prepared according to any method known to the art for the
 manufacture of pharmaceutical compositions and such compositions may
 contain one or more agents including sweetening agents, flavoring agents,
 coloring agents and preserving agents, in order to provide a palatable
 preparation. Tablets containing the active ingredient in admixture with
 non-toxic pharmaceutically acceptable excipient which are suitable for
 manufacture of tablets are acceptable. These excipients may be, for
 example, inert diluents, such as calcium or sodium carbonate, lactose,
 calcium or sodium phosphate; granulating and disintegrating agents, such
 as maize starch, or alginic acid; binding agents, such as starch, gelatin
 or acacia; and lubricating agents, such as magnesium stearate, stearic
 acid or talc. Tablets may be uncoated or may be coated by known techniques
 including microencapsulation to delay disintegration and adsorption in the
 gastrointestinal tract and thereby provide a sustained action over a
 longer period. For example, a time delay material such as glyceryl
 monostearate or glyceryl distearate alone or with a wax may be employed.
 Formulations for oral use may be also presented as hard gelatin capsules
 where the active ingredient is mixed with an inert solid diluent, for
 example calcium phosphate or kaolin, or as soft gelatin capsules wherein
 the active ingredient is mixed with water or an oil medium, such as peanut
 oil, liquid paraffin or olive oil.
 Aqueous suspensions of the invention contain the active materials in
 admixture with excipients suitable for the manufacture of aqueous
 suspensions. Such excipients include a suspending agent, such as sodium
 carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,
 sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and
 dispersing or wetting agents such as a naturally occurring phosphatide
 (e.g., lecithin), a condensation product of an alkylene oxide with a fatty
 acid (e.g., polyoxyethylene stearate), a condensation product of ethylene
 oxide with a long chain aliphatic alcohol (e.g.,
 heptadecaethyleneoxycetanol), a condensation product of ethylene oxide
 with a partial ester derived from a fatty acid and a hexitol anhydride
 (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may
 also contain one or more preservatives such as ethyl or n-propyl
 p-hydroxy-benzoate, one or more coloring agents, one or more flavoring
 agents and one or more sweetening agents, such as sucrose or saccharin.
 Oil suspensions may be formulated by suspending the active ingredient in a
 vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil,
 or in a mineral oil such as liquid paraffin. The oral suspensions may
 contain a thickening agent, such as beeswax, hard paraffin or cetyl
 alcohol. Sweetening agents, such as those set forth above, and flavoring
 agents may be added to provide a palatable oral preparation. These
 compositions may be preserved by the addition of an antioxidant such as
 ascorbic acid.
 Dispersible powders and granules of the invention suitable for preparation
 of an aqueous suspension by the addition of water provide the active
 ingredient in admixture with a dispersing or wetting agent, a suspending
 agent, and one or more preservatives. Suitable dispersing or wetting
 agents and suspending agents are exemplified by those disclosed above.
 Additional excipients, for example sweetening, flavoring and coloring
 agents, may also be present.
 The pharmaceutical compositions of the invention may also be in the form of
 oil-in-water emulsions. The oily phase may be a vegetable oil, such as
 olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a
 mixture of these. Suitable emulsifying agents include naturally-occurring
 gums, such as gum acacia and gum tragacanth, naturally occurring
 phosphatides, such as soybean lecithin, esters or partial esters derived
 from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and
 condensation products of these partial esters with ethylene oxide, such as
 polyoxyethylene sorbitan monooleate. The emulsion may also contain
 sweetening and flavoring agents.
 Syrups and elixirs may be formulated with sweetening agents, such as
 glycerol, sorbitol or sucrose. Such formulations may also contain a
 demulcent, a preservative, a flavoring or a coloring agent.
 The pharmaceutical compositions of the invention may be in the form of a
 sterile injectable preparation, such as a sterile injectable aqueous or
 oleaginous suspension. This suspension may be formulated according to the
 known art using those suitable dispersing or wetting agents and suspending
 agents which have been mentioned above. The sterile injectable preparation
 may also be a sterile injectable solution or suspension in a non-toxic
 parenterally acceptable diluent or solvent, such as a solution in
 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable
 vehicles and solvents that may be employed are water, Ringer's solution
 and isotonic sodium chloride solution. In addition, sterile fixed oils may
 conventionally be employed as a solvent or suspending medium. For this
 purpose any bland fixed oil may be employed including synthetic mono- or
 diglycerides. In addition, fatty acids such as oleic acid may likewise be
 used in the preparation of injectables.
 The amount of active ingredient that may be combined with the carrier
 material to produce a single dosage form will vary depending upon the host
 treated and the particular mode of administration. For example, a
 time-release formulation intended for oral administration to humans may
 contain 20 to 2000 .mu.mol (approximately 10 to 1000 mg) of active
 material compounded with an appropriate and convenient amount of carrier
 material which may vary from about 5 to about 95% of the total
 compositions. It is preferred that the pharmaceutical composition be
 prepared which provides easily measurable amounts for administration. For
 example, an aqueous solution intended for intravenous infusion should
 contain from about 0.05 to about 50 .mu.mol (approximately 0.025 to 25 mg)
 of the active ingredient per milliliter of solution in order that infusion
 of a suitable volume at a rate of about 30 mL/hr can occur.
 As noted above, formulations of the present invention suitable for oral
 administration may be presented as discrete units such as capsules,
 cachets or tablets each containing a predetermined amount of the active
 ingredient; as a powder or granules; as a solution or a suspension in an
 aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a
 water-in-oil liquid emulsion. The active ingredient may also be
 administered as a bolus, electuary or paste.
 A tablet may be made by compression or molding, optionally with one or more
 accessory ingredients. Compressed tablets may be prepared by compressing
 in a suitable machine the active ingredient in a free flowing form such as
 a powder or granules, optionally mixed with a binder (e.g., povidone,
 gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent,
 preservative, disintegrant (e.g., sodium starch glycolate, cross-linked
 povidone, cross-linked sodium carboxymethyl cellulose) surface active or
 dispersing agent. Molded tablets may be made by molding in a suitable
 machine a mixture of the powdered compound moistened with an inert liquid
 diluent. The tablets may optionally be coated or scored and may be
 formulated so as to provide slow or controlled release of the active
 ingredient therein using, for example, hydroxypropyl methylcellulose in
 varying proportions to provide the desired release profile. Tablets may
 optionally be provided with an enteric coating, to provide release in
 parts of the gut other than the stomach. This is particularly advantageous
 with the compounds of formula 1 when such compounds are susceptible to
 acid hydrolysis.
 Formulations suitable for topical administration in the mouth include
 lozenges comprising the active ingredient in a flavored base, usually
 sucrose and acacia or tragacanth; pastilles comprising the active
 ingredient in an inert base such as gelatin and glycerin, or sucrose and
 acacia; and mouthwashes comprising the active ingredient in a suitable
 liquid carrier.
 Formulations for rectal administration may be presented as a suppository
 with a suitable base comprising for example cocoa butter or a salicylate.
 Formulations suitable for vaginal administration may be presented as
 pessaries, tampons, creams, gels, pastes, foams or spray formulations
 containing in addition to the active ingredient such carriers as are known
 in the art to be appropriate.
 Formulations suitable for parenteral administration include aqueous and
 non-aqueous isotonic sterile injection solutions which may contain
 antioxidants, buffers, bacteriostats and solutes which render the
 formulation isotonic with the blood of the intended recipient; and aqueous
 and non-aqueous sterile suspensions which may include suspending agents
 and thickening agents. The formulations may be presented in unit-dose or
 multi-dose sealed containers, for example, ampoules and vials, and may be
 stored in a freeze-dried (lyophilized) condition requiring only the
 addition of the sterile liquid carrier, for example water for injections,
 immediately prior to use. Injection solutions and suspensions may be
 prepared from sterile powders, granules and tablets of the kind previously
 described.
 Preferred unit dosage formulations are those containing a daily dose or
 unit, daily sub-dose, or an appropriate fraction thereof, of a fructose
 1,6-bisphosphatase inhibitor compound.
 It will be understood, however, that the specific dose level for any
 particular patient will depend on a variety of factors including the
 activity of the specific compound employed; the age, body weight, general
 health, sex and diet of the individual being treated; the time and route
 of administration; the rate of excretion; other drugs which have
 previously been administered; and the severity of the particular disease
 undergoing therapy, as is well understood by those skilled in the art.
 Utility
 FBPase inhibitors at the AMP site may be used to treat diabetes mellitus,
 lower blood glucose levels, and inhibit gluconeogenesis.
 FBPase inhibitors at the AMP site may also be used to treat excess glycogen
 storage diseases. Excessive hepatic glycogen stores are found in patients
 with some glycogen storage diseases. Since the indirect pathway
 contributes significantly to glycogen synthesis (Shulman, G. I. Phys. Rev.
 1992. 72, 1019-1035), inhibition of the indirect pathway (gluconeogenesis
 flux) is expected to decrease glycogen overproduction.
 FBPase inhibitors at the AMP site may also be used to treat or prevent
 diseases associated with increased insulin levels.
 Increased insulin levels are associated with an increased risk of
 cardiovascular complications and atherosclerosis (Folsom, et al., Stroke,
 1994, 25, 66-73; Howard, G. et al., Circulation 1996, 93, 1809-1817).
 FBPase inhibitors are expected to decrease postprandial glucose levels by
 enhancing hepatic glucose uptake. This effect is postulated to occur in
 individuals that are non-diabetic (or pre-diabetic, i.e. without elevated
 HGO or fasting blood glucose levels). Increased hepatic glucose uptake
 will decrease insulin secretion and thereby decrease the risk of diseases
 or complications that arise from elevated insulin levels.
 The compounds of this invention and their preparation can be understood
 further by the examples which illustrate some of the processes by which
 these compounds are prepared. These examples should not, however, be
 construed as specifically limiting the invention and variations of the
 invention, now known or later developed, are considered to fall within the
 scope of the present invention as hereinafter claimed.
 EXAMPLES
 Example 1
 Preparation of 5-diethylphosphono-2-furaldehyde (1)
 Step A. A solution of 2-furaldehyde diethyl acetal (1 mmol) in THF was
 treated with nBuLi (1 mmol) at -78.degree. C. After 1 h, diethyl
 chlorophosphate (1.2 mmol) was added and the reaction was stirred for 40
 min. Extraction and evaporation gave a brown oil.
 Step B. The resulting brown oil was treated with 80% acetic acid at
 90.degree. C. for 4 h. Extraction and chromatography gave compound 1 as a
 clear yellow oil.
 Alternatively this aldehyde can be prepared from furan as described below.
 Step C. A solution of furan (1 mmol) in diethyl ether was treated with
 TMEDA (N,N,N'N'-tetramethylethylenediamine) (1 mmol) and nBuLi (2 mmol) at
 -78.degree. C. The solution was stirred for 0.5 h. at -78.degree. C. and
 diethyl chlorophosphate was added and stirred for another 1 h. Extraction
 and distillation produced diethyl 2-furanphosphonate as a clear oil.
 Step D. A solution of diethyl 2-furanphosphonate (1 mmol) in THF
 (tetrahydrofuran) was treated with LDA (1.12 mmol, lithium
 N,N-diisopropylamide) at -78.degree. C. for 20 min. Methyl formate (1.5
 mmol) was added and the reaction was stirred for 1 h. Extraction and
 chromatography gave compound 1 as a clear yellow oil.
 Preferably this aldehyde can be prepared from 2-furaldehyde as described
 below.
 Step E. A solution of 2-furaldehyde (1 mmol) and N,N'-dimethylethylene
 diamine (1 mmol) in toluene was refluxed with a Dean-Stark trap to collect
 the resulting water. After 2 h the solvent was removed in vacuo and the
 residue was distilled to give furan-2-(N,N'-dimethylimidazolidine) as a
 clear colorless oil, bp 59-61.degree. C. (3 mm Hg).
 Step F. A solution of furan-2-(N,N'-dimethylimidazolidine) (1 mmol) and
 TMEDA (1 mmol) in THF was treated with nBuLi (1.3 mmol) at -40 to
 -48.degree. C. The reaction was stirred at 0.degree. C. for 1.5 h and then
 cooled to -55.degree. C. and treated with a solution of
 diethylchlorophosphate (1.1 mmol) in THF. After stirring at 25.degree. C.
 for 12 h the reaction mixture was evaporated and subjected to extraction
 to give 5-diethylphosphono-furan-2-(N,N'-dimethylimidazolidine) as a brown
 oil.
 Step G. A solution of
 5-diethylphosphonofuran-2-(N,N'-dimethyl-imidazolidine) (1 mmol) in water
 was treated with concentrated sulfuric acid until pH=1. Extraction and
 chromatography gave compound 1 as a clear yellow oil.
 Example 2
 Preparation of N.sup.9 -substituted-8-(2-(5-phosphono)furanyl)adenines
 The preparation of N.sup.9 -(2-phenethyl)-8-(2-(5-phosphono)furanyl)adenine
 is given as an example:
 Step A. A solution of 5-amino-4,6-dichloropyrimidine (1 mmol) in nBuOH was
 treated with Et.sub.3 N (1.2 mmol) and phenethylamine (1.05 mmol) at
 80.degree. C. After 12 h, the cooled reaction mixture was evaporated under
 vacuum and the residue was chromatographed to give
 6-chloro-5-amino-4-(phenethylamino)-pyrimidine as a yellow solid. mp
 156-157.degree. C.; TLC: R.sub.f =0.41, 50% EtOAc-hexane.
 Step B. The 6-chloro-5-amino-4-(2-phenethylamino)pyrimidine (1 mmol) in
 DMSO was treated with 2-furaldehyde (1.5 mmol) and FeCl.sub.3 -silica (2.0
 mmol) at 80.degree. C. After 12 h, the cooled reaction mixture was
 filtered and the filtrate was evaporated under vacuum. Chromatography
 afforded 6-chloro-N.sup.9 -(2-phenethyl)-8-(2-furanyl)purine as a yellow
 solid. TLC: Rf=0.62, 50% EtOAc-hexane. Anal. calcd. for C.sub.17 H.sub.13
 N.sub.4 OCl: C: 62.87; H: 4.03; N: 17.25. Found: C: 62.66; H: 3.96; N:
 17.07.
 Step C. The 6-chloro-N.sup.9 -(2-phenethyl)-8-(2-furanyl)purine (1 mmol) in
 THF was treated with LDA (1.5 mmol) at -78.degree. C. After 1 h, diethyl
 chlorophosphate (5 mmol) was added and the reaction was stirred at
 -78.degree. C. for 2 h and then quenched with saturated NH.sub.4 Cl.
 Extraction and chromatography gave 6-chloro-N.sup.9
 -(2-phenethyl)-8-(2-(5-diethylphosphono)-furanyl)purine as a yellow solid.
 TLC: Rf=0.34,100% EtOAc.
 Alternatively this type of compound can be prepared as follows:
 Step D. A solution of 6-chloro-5-amino-4-(2-phenethylamino)pyrimidine (1
 mmol) in DMSO was treated with 5-diethylphosphono-2-furaldehyde (1, 1.5
 mmol), and FeCl.sub.3 -silica (2.0 mmol) at 80.degree. C. After 12 h., the
 cooled reaction mixture was filtered and the filtrate was evaporated under
 vacuum. Chromatography afforded 6-chloro-N.sup.9
 -(2-phenethyl)-8-(2-(5-diethyl-phosphono)furanyl)purine as a yellow solid.
 TLC: Rf=0.34, 100% EtOAc.
 Step E. 6-Chloro-N.sup.9
 -(2-phenethyl)-8-(2-(5-diethylphosphono)furanyl)-purine (1 mmol) in
 THF-DMSO was treated with liquid ammonia (2 mL) in a steel bomb. After 12
 h, the reaction was evaporated under vacuum and the residue was purified
 through chromatography to give N.sup.9
 -(2-phenethyl)-8-(2-(5-diethylphosphono)furanyl)adenine as a yellow solid.
 TLC: Rf=0.12, 5% MeOH --CH.sub.2 Cl.sub.2.
 Step F. A solution of N.sup.9
 -(2-phenethyl)-8-(2-(5-diethylphosphono)furanyl)-adenine (1 mmol) in
 acetonitrile was treated with bromotrimethylsilane (10 mmol). After 12 h,
 the reaction was evaporated under vacuum and the residue was treated with
 a mixture of water and acetonitrile. The solid was collected through
 filtration to give N.sup.9
 -(2-phenethyl)-8-(2-(5-phosphono)furanyl)adenine (2.1). mp
 242-2440.degree. C.; Anal. calcd. for C.sub.17 H.sub.16 N.sub.5 O.sub.4
 P+1.37H.sub.2 O: C: 50.16; 4.64; N: 17.21. Found: C: 48.95; H: 4.59; N:
 16.80.
 The following compounds were prepared according to above procedures:
 2.2: N.sup.9 -(2-cyclohexylethyl)-8-(2-(5-phosphono)furanyl)adenine. mp
 194-195.degree. C.; Anal. calcd. for C.sub.17 H.sub.22 N.sub.5 O.sub.4 P+1
 H.sub.2 O: C: 49.90; H: 5.90; N: 17.10. Found: 50.20; H: 5.70; N: 17.10.
 2.3: N.sup.9 -(2-naphthylmethyl)-8-(2-(5-phosphono)furanyl)adenine. mp
 255-256.degree. C.; Anal. calcd. for C.sub.20 H.sub.16 N.sub.5 O.sub.4 P+1
 H.sub.2 O: C: 54.70; H: 4.10; N: 15.90. 54.30; H: 4.20; N: 15.90.
 2.4: N.sup.9 -(1-(2,2-diphenyl)ethyl)-8-(2-(5-phosphono)furanyl)adenine. mp
 220-221.degree. C.; Anal. calcd. for C.sub.23 H.sub.20 N.sub.5 O.sub.4
 P+0.25 H20: C: 59.29; H: 4.43; N: 15.03. Found: C: 59.35; H: 4.25; N:
 14.83.
 2.5: N.sup.9 -ethyl-8-(2-(5-phosphono)furanyl)adenine. mp &gt;230.degree. C.;
 Anal. calcd. for C.sub.11 H.sub.12 N.sub.5 O.sub.4 P+1 H.sub.2 O: C:
 40.38; H: 4.31; N: 21.40. Found: C: 40.45; H N: 21.44.
 2.6: N.sup.9 -isobutyl-8-(2-(5-phosphono)furanyl)adenine. mp &gt;230.degree.
 C.; Anal. calcd. for C.sub.13 H.sub.16 N.sub.5 O.sub.4 P: C: 46.30; H:
 4.78; N: 20.76. Found: C: 46.00; H: 4.61; N: 20.49.
 2.7: N.sup.9 -neopentyl-8-(2-(5-phosphono)furanyl)adenine. mp &gt;230.degree.
 C.; Anal. calcd. for C.sub.14 H.sub.18 N.sub.5 O.sub.4 P: C: 47.87; H:
 5.16; N: 19.94. Found: C: 47.59; H: 4.92; N: 19.53.
 2.8: N.sup.9 -adamentanemethyl-8-(2-(5-phosphono)furanyl)adenine. mp
 &gt;250.degree. C.; Anal. calcd. for C.sub.20 H.sub.24 N.sub.5 O.sub.4 P+0.5
 H.sub.2 O+0.25 MeOH: C: 54.48; H: 5.87; N: 15.69. Found: C: 54.62; H:
 5.52; N: 15.36.
 2.9: N.sup.9 -cyclopropyl-8-(2-(5-phosphono)furanyl)adenine. mp
 &gt;250.degree. C.; MS (M+H) calcd for C.sub.12 H.sub.13 N.sub.5 O.sub.4 P:
 322, found: 322.
 2.10: N.sup.9 -cyclopentyl-8-(2-(5-phosphono)furanyl)adenine. mp
 220.degree. C.(decomp); Anal. calcd. for C.sub.14 H.sub.16 N.sub.5 O.sub.4
 P+1 H.sub.2 O: C: 45.78; H: 4.94; N: 19.07. Found: C: 45.40; H: 4.79; N:
 18.73.
 2.11: N.sup.9 -((2-ethoxy)phenyl)methyl-8-(2-(5-phosphono)furanyl)-adenine.
 mp &gt;230.degree. C.; Anal. calcd. for C.sub.18 H.sub.18 N.sub.5 O.sub.5 P+2
 H.sub.2 O: C: 47.90; H: 4.91; N: C: 48.03; H: 4.53; N: 15.25.
 2.12: N.sup.9
 -(1-(3-N,N-dimethylamino-2,2-dimethyl)propyl)-8-(2-(5-phosphono)-furanyl)a
 denine. mp &gt;230.degree. C.; Anal. calcd. for C.sub.16 H.sub.23 N.sub.6
 O.sub.4 P+3 H.sub.2 O+0.5 HOAc+0.75 Na: C: 41.19; H: 6.30; N: 16.95.
 Found: C: 41.35; H: 6.04; N: 16.57.
 2.13: N.sup.9
 -(1-(3-hydroxyl-2,2-dimethyl)propyl)-8-(2-(5-phosphono)-furanyl)adenine.
 mp &gt;230.degree. C.; Anal. calcd. for C.sub.14 H.sub.18 N.sub.5 O.sub.5
 P+0.25 H.sub.2 O: C: 45.23; H: 5.02; N: 18.83. Found: C: 45.40; H: 5.02;
 N: 18.44.
 2.14: N.sup.9
 -(1-(3-chloro-2,2-dimethyl)propyl)-8-(2-(5-phosphono)-furanyl)adenine. mp
 &gt;230.degree. C.; Anal. calcd. for C.sub.14 H.sub.17 N.sub.5 O.sub.4
 PCl+0.125 CHCl.sub.3 +0.06 AcOEt: C: 42.50; H: 4.37; N: 17.25. Found: C:
 42.62; H: 3.99; N: 16.87.
 2.15: N.sup.9 -(1-(3,3-dimethyl)butyl)-8-(2-(5-phosphono)furanyl)-adenine.
 mp 230.degree. C.; Anal. calcd. for C.sub.15 H.sub.20 N.sub.5 O.sub.4
 P+1.25H.sub.2 O+0.13 AcOEt: C: 46.68; H: 5.94; N: 17.56. Found: C: 46.67;
 H: 5.78; N: 17.35.
 2.16: N.sup.9
 -(1,5,5-trimethyl-3-cyclohexenyl)methyl-8-(2-(5-phosphono)furanyl)-adenine
 . mp &gt;230.degree. C.; Anal. calcd. for C.sub.19 H.sub.24 N.sub.5 O.sub.4
 P+0.5 H.sub.2 O+0.13 AcOEt: C: 53.54; H: 5.99; N: 16.01. Found: C: 53.67;
 H: 5.69; N: 15.75.
 2.17: N.sup.9
 -(1-(1,2,2-trimethyl)propyl)-8-(2-(5-phosphono)-furanyl)adenine. mp
 &gt;250.degree. C.; Anal. calcd. for C.sub.15 H.sub.20 N.sub.5 O.sub.4 P+0.67
 H.sub.2 O+0.13AcO Et: C: 47.74; N: 18.56. Found: C: 47.99; H: 5.39; N:
 18.49.
 2.18: 6-Amino-9-(3-(1-imidazolyl) propyl)-8-(2-(5-phosphono)furanyl)purine.
 mp 182-186.degree. C.; Mass calcd. for C.sub.15 H.sub.16 N.sub.7 O.sub.4
 P: 389. Found: M+H.sup.+ =390.
 Examples 3
 Preparation of N.sup.9 -substituted-8-(2-phosphonoethylamino)adenines
 Step A. Adenine (1 mmol) in DMF was treated with sodium hydride (1.2 mmol)
 followed by benzyl bromide (1.2 mmol) at room temperature under nitrogen.
 The resulting mixture was warmed at 100.degree. C. for 2 h. The cooled
 reaction mixture was evaporated to dryness. Extraction and chromatography
 afforded N.sup.9 -benzyladenine.
 Step B. A solution of N.sup.9 -benzyladenine (1 mmol) in acetic acid buffer
 (pH=4) was treated with bromine (1 mmol) at room temperature for 12 h. The
 reaction was quenched with 10% sodium sulfite solution and extracted with
 dichloromethane. The combined extracts were dried (Na.sub.2 SO.sub.4) and
 evaporated to dryness. Chromatography afforded N.sup.9
 -benzyl-8-bromoadenine.
 Step C. A mixture of N.sup.9 -benzyl-8-bromoadenine (1 mmol),
 aminoethylphosphonate (2 mmol), and sodium hydroxide (2 mmol) in
 ethanol-water in a sealed tube was warmed at 110.degree. C. under
 nitrogen. After 24 h the cooled reaction mixture was purified through
 preparative HPLC to give N.sup.9 -benzyl-8-(2-phosphonoethylamino)adenine
 (3.1). Exact mass calculated for C.sub.14 H.sub.17 N.sub.6 O.sub.3
 P+H.sup.+ : 349.1178. Found: 349.1180.
 The following compounds were prepared according to this procedure:
 3.2: N.sup.9 -phenethyl-8-(2-phosphonoethylamino)adenine. mp
 159-160.degree. C.; Anal. calcd. for C.sub.15 H.sub.19 N.sub.6 O.sub.3
 P+1.25 H.sub.2 O: C: 46.81; H: 5.63; N: 21.84. Found: C: 47.05; H: 5.63;
 N: 21.48.
 3.3: N.sup.9 -(2-naphthylmethyl)-8-(2-phosphonoethylamino)adenine. mp
 189-190.degree. C.; Anal. calcd. for C.sub.18 H.sub.19 N.sub.6 O.sub.3
 P+1.5 H.sub.2 O: C: 50.82; H: 5.21; N: 19.76. Found: C: 50.71; H: 5.25; N:
 19.54.
 3.4: N.sup.9 -cyclohexylethyl-8-(2-phosphonoethylamino)adenine. mp
 &gt;250.degree. C.; Anal. calcd. for C.sub.15 H.sub.25 N.sub.6 O.sub.3 P+0.33
 H.sub.2 O: C: 48.12; H: 6.91; N: 22.44. Found: C: 48.12; H: 6.78; N:
 22.15.
 Example 4
 Preparation of 8-(2-phosphonoethylamino)adenosines
 A mixture of 8-bromoadenosine (1 mmol), aminoethylphosphonate (2 mmol), and
 sodium hydroxide (2 mmol) in ethanol-water in a sealed tube was warmed at
 110.degree. C. under nitrogen. After 24 h the cooled reaction mixture was
 purified through preparative HPLC to give
 8-(2-phosphonoethylamino)-adenosine (4.1). mp 175.degree. C.; Anal. calcd.
 for C.sub.12 H.sub.19 N.sub.6 O.sub.7 P+0.5 H.sub.2 O: C: 36.10; H: 5.05;
 N: 21.05; P: 7.76. Found: C: 36.08; H: 4.83; N: 20.36; P: 7.86.
 The following compound was prepared in this manner:
 4.2: 8-(2-Phosphonoethylamino)-5-deoxyadenosine as a white solid. mp
 220.degree. C.; Anal. calcd. for C.sub.12 H.sub.19 N.sub.6 O.sub.6 P+1.5
 H.sub.2 O: C: 35.92; H: 5.53; N: 20.94. Found: C: 36.15; H: 5.12; N:
 20.53.
 Examples 5
 Preparation of N.sup.9 -alkyl-8-(phosphonomethoxymethyl)adenines
 Step A. A mixture of N.sup.9 -phenethyl-8-bromoadenine (1 mmol), tetrakis
 (triphenylphosphine)palladium (0.05 mmol), and triethylamine (5 mmol) in
 DMF in a sealed tube was warmed at 110.degree. C. under 50 psi of carbon
 monoxide. After 24 h the cooled reaction mixture was evaporated and
 purified through chromatography to give N.sup.9
 -phenethyl-8-methoxycarbonyladenine as a yellow solid. TLC: Rf=0.12, 5%
 MeOH--CH.sub.2 Cl.sub.2.
 Step B. A solution of N.sup.9 -phenethyl-8-methoxycarbonyladenine (1 mmol)
 in tetrahydrofuran was treated with lithium aluminum hydride (1 mmol) at
 0.degree. C. for 1 h. Extraction and chromatography gave N.sup.9
 -phenethyl-8-hydroxymethyl-adenine as a white solid. TLC: Rf=0.31, 10%
 MeOH--CH.sub.2 Cl.sub.2.
 Step C. A solution of N.sup.9 -phenethyl-8-hydroxymethyladenine (1 mmol) in
 methylene chloride was treated with phosphorus tribromide (1 mmol) at
 25.degree. C. for 1 h. Extraction and chromatography gave N.sup.9
 phenethyl-8-bromomethyl-adenine as a white solid. TLC: R.sub.f =0.31,10%
 MeOH--CH.sub.2 Cl.sub.2.
 Step D. A solution of N.sup.9 -phenethyl-8-bromomethyladenine (1 mmol) in
 DMF was treated with a solution of diethyl hydroxymethylphosphonate sodium
 salt (1 mmol) in DMF at 25.degree. C. for 1 h. Extraction and
 chromatography gave N.sup.9
 -phenethyl-8-diethylphosphonomethoxymethyladenine as a white solid. TLC:
 R.sub.f =0.31,10% MeOH--CH.sub.2 Cl.sub.2.
 N.sup.9 -phenethyl-8-diethylphosphonomethoxymethyladenine was subjected to
 Step F in Example 2 to give N.sup.9
 -(2-phenethyl)-8-(phosphonomethoxymethyl)-adenine (5.1) as a white solid.
 mp &gt;250.degree. C.; Anal. calcd. for C.sub.19 H.sub.22 N.sub.5 O.sub.4
 P+0.75 H.sub.2 O: C: 56.93; H: 5.91; N: 10.48. Found: C: 56.97; H: 5.63;
 N: 10.28.
 The following compounds were prepared according to this procedure:
 5.2: N.sup.9 -(2-cyclohexylethyl)-8-(phosphonomethoxymethyl)adenine. mp
 &gt;250.degree. C.; Anal. calcd. for C.sub.15 H.sub.24 N.sub.5 O.sub.4 P+1
 H.sub.2 O: C: 46.51; H: 6.76; N: 18.08. Found: 46.47; H: 6.71; N: 17.91.
 5.3: N.sup.9 -(1-nanonyl)-8-(phosphonomethoxymethyl)adenine. mp
 195-210.degree. C.; Anal. calcd. for C.sub.16 H.sub.28 N.sub.5 O.sub.4 P+1
 H.sub.2 O: C: 47.64; H: 7.50; N: 17.36. Found: C: 47.33; H: 7.34; N:
 16.99.
 5.4: N.sup.9 -(3-cyclohexylpropyl)-8-(phosphonomethoxymethyl)adenine. mp
 230-250.degree. C.; Anal. calcd. for C.sub.19 H.sub.22 N.sub.5 O.sub.4
 P+0.9 H.sub.2 O+0.3 HBr: C: 45.34; 16.52. Found: C: 45.74; H: 6.39; N:
 16.18.
 Alternatively this type of compound can also be prepared according to the
 following procedure:
 Step E. A solution of 6-chloro-5-amino-4-(neopentylamino)pyrimidine (1
 mmol) in diethyl ether was treated with pyridine (3 mmol), and
 acetoxyacetyl chloride (1.2 mmol) at 25.degree. C. for 12 h. Extraction
 and chromatography afforded
 6-chloro-5-acetoxyacetyl-amino-4-neopentylaminopyrimidine as a yellow
 solid. TLC: R.sub.f =0.18, 30% EtOAc-hexane.
 Step F. A solution of
 6-chloro-5-acetoxyacetylamino-4-neopentyl-aminopyrimidine (1 mmol) in
 phosphorus oxychloride was heated at reflux for 6 h. The cooled reaction
 mixture was evaporated to dryness and the residue was dissolved in
 pyridine and stirred at 25.degree. C. for 20 h. Evaporation and
 chromatography afforded 6-chloro-8-acetoxymethyl-N.sup.9 -neopentylpurine
 as a yellow solid. TLC: R.sub.f =0.51, 50% EtOAc-hexane.
 Step G. A solution of 6-chloro-8-acetoxymethyl-N.sup.9 -neopentylpurine (1
 mmol) in THF-water was treated with aqueous sodium hydroxide (1.5 mmol) at
 0.degree. C. for 0.5 h. Extraction and chromatography afforded
 6-chloro-8-hydroxymethyl-N.sup.9 -neopentylpurine as a yellow gel. TLC:
 R.sub.f =0.38, 33% EtOAc-hexane.
 Step H. A solution of 6-chloro-8-hydroxymethyl-N.sup.9 -neopentylpurine (1
 mmol) in methylene chloride was treated with phosphorus tribromide (1
 mmol) at 25.degree. C. for 6 h. Extraction and chromatography afforded
 6-chloro-8-bromomethyl-N.sup.9 -neopentylpurine as a white solid. TLC:
 R.sub.f =0.64, 25% EtOAc-hexane.
 Step I. A solution of 6-chloro-8-bromomethyl-N.sup.9 -neopentylpurine (1
 mmol) in DMF was treated with a solution of sodium
 diethylphosphono-methoxide (1 mmol) at 25.degree. C. for 6 h. Extraction
 and chromatography afforded
 6-chloro-8-diethyl-phosphonomethoxymethyl-N.sup.9 -neopentylpurine as a
 white solid. TLC: R.sub.f =0.31, 50% EtOAc-hexane.
 Step J. A solution of 6-chloro-8-diethylphosphonomethoxymethyl-N.sup.9
 -neopentylpurine (1 mmol) in THF-DMSO was treated with liquid ammonia (10
 mmol) at 25.degree. C. for 6 h. Extraction and chromatography afforded
 8-diethylphosphonomethoxymethyl-N.sup.9 -neopentyladenine as a white
 solid. TLC: R.sub.f =0.44,25% MeOH-EtOAc.
 8-Diethylphosphonomethoxymethyl-N.sup.9 -neopentyladenine was subjected to
 Step F in Example 2 to give N.sup.9
 -neopentyl-8-(phosphonomethoxymethyl)-adenine (5.5) as a white solid. mp
 &gt;250.degree. C.; Anal. calcd. for C.sub.12 H.sub.20 N.sub.5 O.sub.4 P+1.5
 H.sub.2 O: C: 40.45; H: 6.51; N: 19.65. Found: C: 40.68; H: 6.35; N:
 19.40.
 Examples 6
 Preparation of N.sup.9 -substituted-8-(1-(3-phosphono)propyl)adenines
 Step A. A mixture of diethyl propargylphosphonate (1 mmol, prepared
 according to J. Org. Chem., 1993, 58(24), 6531.), tributyltin hydride
 (1.05 mmol), and AIBN (0.005 mmol) was heated at 60.degree. C. for 18 h.
 The cooled reaction mixture was purified through chromatography to give
 dimethyl (1-tributylstannyl)allyl-3-phosphonate as a yellow oil.
 Step B. A solution of N.sup.9 -(2-cyclohexylethyl)-8-bromoadenine (1 mmol),
 tetrakis(triphenylphosphine)palladium (0.1 mmol), and dimethyl
 (1-tributylstannyl)allyl-3-phosphonate (5 mmol) in DMF was warmed at
 90.degree. C. under nitrogen. After 2 h the cooled reaction mixture was
 evaporated and purified through chromatography to give N.sup.9
 -(2-cyclohexylethyl)-8-(3-dimethylphosphonopropene-1-yl)adenine as a
 yellow solid. TLC: R.sub.f =0.48, 10% MeOH--CH.sub.2 Cl.sub.2.
 Step C. A solution of N.sup.9
 -(2-cyclohexylethyl)-8-(3-dimethylphosphono-propene-1-yl)adenine in
 methanol-acetic acid was stirred at room temperature under 50 psi of
 H.sub.2 for 12 h. Filtration and chromatography afforded N.sup.9
 -(2-cyclohexylethyl)-8-(1-(3-dimethylphosphono)propyl)adenine as a yellow
 solid. TLC: R.sub.f =0.26,10% MeOH--CH.sub.2 Cl.sub.2.
 N.sup.9 -(2-cyclohexylethyl)-8-(1-(3-dimethylphosphono)propyl)adenine was
 subjected to Step F in Example 2 to give N.sup.9
 -(2-cyclohexylethyl)-8-(1-(3-phosphono)propyl)adenine (6.1) as a white
 solid: mp 122-125.degree. C.; Anal. calcd. for C.sub.16 H.sub.26 N.sub.5
 O.sub.3 P+0.25 AcOH: C: 51.83; H: 7.12; N: 18.31. Found: C: 51.87; H:
 6.96; N: 17.96.
 6.2: N.sup.9 -(2-phenethyl)-8-(1-(3-phosphono)propyl)adenine was also
 prepared in this manner as a solid. mp &gt;250.degree. C. Anal. calcd. for
 C.sub.16 H.sub.20 N.sub.5 O.sub.3 P+0.5 H.sub.2 O: C: 51.89; H: 5.71; N:
 18.91. Found: C: 51.81; H: 5.49; N: 18.66.
 Examples 7
 Preparation of N.sup.9 -(2-phenethyl)-8-(2-(5-phosphono)thienyl)adenine
 Step A. A solution of 2-thienyllithium in THF (1 mmol) was added to a
 solution of diethyl chlorophosphate (1 mmol) at -78.degree. C. under
 nitrogen. After 2 h the reaction was warmed to room temperature and
 quenched with brine. Extraction and chromatography afforded
 2-diethylphosphonothiophene as a yellow oil. TLC: R.sub.f =0.37, 50%
 EtOAc--hexane.
 Step B. A solution of 2-diethylphosphonothiophene (1 mmol) in THF was
 treated with nBuLi at -78.degree. C. for 1 h. Tributyltin chloride was
 added and stirred at -78.degree. C. for 2 h and the reaction was quenched
 with water and warmed to room temperature. Extraction and chromatography
 afforded diethyl 2-(5-tributylstannyl)thienylphosphonate as a yellow oil.
 TLC: R.sub.f =0.65, 50% EtOAc-hexane.
 Step C. A mixture of N.sup.9 -phenethyl-8-bromoadenine (1 mmol), tetrakis
 (triphenylphosphine)palladium (0.1 mmol), and diethyl
 2-(5-tributylstannyl)-thienylphosphonate (5 mmol) in DMF was warmed at
 80.degree. C. under nitrogen. After 21 h the cooled reaction mixture was
 evaporated to dryness. The dark oil was triturated with hexane and the
 residue was dissolved in CH.sub.2 Cl.sub.2 and filtered. The filtrate was
 evaporated to give N.sup.9
 -(2-phenethyl)-8-(2-(5-diethylphosphono)-thienyl)adenine as a yellow
 solid. TLC: R.sub.f =0.50, 10% MeOH--CH.sub.2 Cl.sub.2.
 N.sup.9 -(2-phenethyl)-8-(2-(5-diethylphosphono)thienyl)adenine was
 subjected to Step F in Example 2 to give N.sup.9
 -(2-phenethyl)-8-(2-(5-phosphono)-thienyl)adenine (7.1) as a white solid.
 mp &gt;250.degree. C.; Anal. calcd. for C.sub.17 H.sub.16 N.sub.5 O.sub.3
 SP+0.5H.sub.2 O: C: 49.76; H: 4.17; N: 17.07. Found: C: 50.07; H: N:
 17.45.
 N.sup.9 -(2-phenethyl)-8-(2-(5-phosphono)thienyl)adenine can also be made
 via a cyclization reaction between
 5-diethylphosphono-2-thiophene-carboxaldehyde (prepared from
 2-thienyllithium as described in Steps C and D of Example 1) as described
 in Example 2.
 Example 8
 Preparation of N.sup.9 -(2-cyclohexylethyl)-8-(phosphonomethylthio)-adenine
 Step A. A mixture of N.sup.9 -(2-cyclohexylethyl)-8-bromoadenine (1 mmol),
 and K.sub.2 S (4 mmol) in ethanol was warmed at 110.degree. C. for 7 h,
 and at 85.degree. C. for 12 h. The cooled reaction mixture was filtered,
 evaporated and purified through chromatography to give N.sup.9
 -(2-cyclohexylethyl)-8-thiohydroxyadenine as a yellow solid. TLC: R.sub.f
 =0.26, 5% MeOH--CH.sub.2 Cl.sub.2
 Step B. A mixture of N.sup.9 -(2-cyclohexylethyl)-8-thiohydroxyadenine (1
 mmol), K.sub.2 CO.sub.3 (4 mmol), and diethyl chloromethylphosphonate (3
 mmol) in DMF was stirred at room temperature for 48 h. Extraction and
 chromatography gave N.sup.9
 -(2-cyclohexylethyl)-8-diethylphosphono-methylthioadenine. TLC: R.sub.f
 =0.35, 10% MeOH--EtOAc.
 N.sup.9 -(2-Cyclohexylethyl)-8-diethylphosphonomethylthioadenine was
 subjected to Step F in Example 2 to give N.sup.9
 -(2-cyclohexylethyl)-8-(phosphonomethylthio)adenine (8.1) as a white
 solid. mp 240-243.degree. C.; Anal. Calcd. for C.sub.14 H.sub.22 N.sub.5
 O.sub.3 SP+1.25H.sub.2 O: C: 42.69; H: 5.95; N: 17.54. Found: C: 42.62; H:
 6.03; N: 17.80.
 Example 9
 Preparation of 6-chloro-9-phenethyl-8-(2-(5-phosphono)furanyl)purine
 6-Chloro-N.sup.9 -phenethyl-8-(2-(5-diehtylphosphono)furanyl)purine (Step C
 in Example 2) was subjected to procedure of Step F in Example 2 to give
 compound 9.1 as a yellow solid. mp &gt;200.degree. C.; Anal. calcd. for
 C.sub.17 H.sub.14 N.sub.4 O.sub.4 PCl+2 H.sub.2 O+0.28 HBr: C: 44.06; H:
 3.98; N: 12.09. Found: C: 43.86; H: 3.59; N: 12.02.
 Example 10
 Preparation of N.sup.6,N.sup.9
 -substituted-8-(2-(5-phosphono)furanyl)adenines
 A solution of 6-chloro-N.sup.9
 -substituted-8-(2-(5-diethylphosphono)furanyl)-purine (1 mmol) in DMSO was
 treated with alkylamine at 100.degree. C. for 12 h. Evaporation and
 chromatography gave N.sup.6,N.sup.9
 -substituted-8-(2-(5-diethyl-phosphono)furanyl)adenines.
 The title compounds were obtained by subjecting N.sup.6,N.sup.9
 -substituted-8-(2-(5-diethylphosphono)furanyl)adenines to the procedure of
 Step F in Example 2.
 The following compounds were prepared in this manner:
 10.1: 6-Dimethylamino-N.sup.9 -phenethyl-8-(2-(5-phosphono)furanyl)purine
 as a white solid. mp &gt;200.degree. C.; Anal. calcd. for C.sub.19 H.sub.20
 N.sub.5 O.sub.4 P: C: 55.2; H: 4.8; N: 16.9. Found: C: 54.9; H: 4.9; N:
 16.6.
 10.2: 6-Methylamino-N.sup.9 -phenethyl-8-(2-(5-phosphono)furanyl)purine as
 a white solid. mp 242.degree. C.; Anal. calcd. for C.sub.18 H.sub.18
 N.sub.5 O.sub.4 P+1 H.sub.2 O: C: 51.8; H: 4.8; N: 16.8. Found: C: 51.7;
 H: 4.8; N: 16.7.
 Example 11
 Preparation of
 2-methylthio-6-amino-N-isobutyl-8-(2-(5-phosphono)furanyl)purine and
 2-methylsulfonyl-6-amino-N.sup.9
 -isobutyl-8-(2-(5-phosphono)furanyl)purine
 Step A: 2-Methylthio-4,5,6-triaminopyrimidine and
 5-diethylphosphono-2-furaldehyde was subjected to the procedures of Step D
 in Example 2 to give
 6-amino-2-methylthio-8-(2-(5-diethylphosphono)furanyl)purine as a yellow
 solid. TLC: R.sub.f =0.27, 80% EtOAc--hexane.
 Step B: 6-Amino-2-methylthio-8-(2-(5-diethylphosphono)furanyl)purine was
 alkylated with isobutyl bromide following the procedures of Step A in
 Example 3 to give 6-amino-N.sup.9
 -isobutyl-2-methylthio-8-(2-(5-diethylphosphono)-furanyl)purine as a
 yellow solid. TLC: R.sub.f =0.27, 80% EtOAc--hexane.
 Step C: 6-Amino-N.sup.9
 -isobutyl-2-methylthio-8-(2-(5-diethyl-phosphono)-furanyl)purine was
 subjected to Step F in Example 2 to give 6-amino-N.sup.9
 -isobutyl-2-methylthio-8-(2-(5-phosphono)-furanyl)purine (11.1) as a white
 solid. mp 220.degree. C.; Anal. calcd. for C.sub.14 H.sub.18 N.sub.5
 O.sub.4 PS+0.25 HBr+0.25 EtOAc: C: 42.33; H: 4.8; N: 16.45. Found: C:
 42.42; H: 4.53; N: 16.39.
 Step D: A solution of 6-amino-N.sup.9
 -isobutyl-2-methylthio-8-(2-(5-diethyl-phosphono)furanyl)purine (1 mmol)
 in 50 mL of methanol was cooled to 0.degree. C. and treated with an
 acetone solution of Oxone (1.6 mmol). After stirring for 3 h at 25.degree.
 C. the reaction was extracted and then chromatographed to give
 6-amino-N.sup.9
 -isobutyl-2-methylsulfonyl-8-(2-(5-diethylphosphono)furanyl)purine as a
 white solid. TLC: R.sub.f =0.24,100% EtOAc.
 Step E: 6-Amino-N.sup.9
 -isobutyl-2-methylsulfonyl-8-(2-(5-diethylphosphono)-furanyl)purine was
 subjected to Step F in Example 2 to give 6-amino-N.sup.9
 -isobutyl-2-methylsulfonyl-8-(2-(5-phosphono)furanyl)purine (11.2) as a
 white solid. mp 240.degree. C. (decomp); Anal. calcd. for C.sub.14
 H.sub.18 N.sub.5 O.sub.6 PS+0.5 H.sub.2 O: C: 39.62; H: 4.51; N: 16.5.
 Found: C: 39.77; H: 4.44; N: 16.12
 Example 12
 Preparation of 6-amino-N.sup.9
 -neopentyl-8-(2-(3.4-dichloro-5-phosphono)furanyl)purine
 Step A: A solution of 3,4-dichloro-2-furoic acid (1 mmol) in diethyl ether
 was treated with LDA (3 mmol) at -78.degree. C. for 30 min and then
 treated with diethyl chlorophosphate (3.5 mmol) at -78.degree. C. for 1 h.
 The reaction was quenched and extracted to give
 5-diethylphosphono-3,4-dichloro-2-furoic acid as a yellow foam.
 Step B: A solution of 5-diethylphosphono-3,4-dichloro-2-furoic acid (1
 mmol) in methylene chloride was treated with oxalyl chloride and DMF at
 25.degree. C. for 1 h. The reaction mixture was evaporated and the residue
 was dissolved in diethyl ether and treated with a solution of
 4-chloro-5-amino-6-neopentyl-aminopyrimidine (1 mmol) and pyridine (3
 mmol) in diethyl ether at 25.degree. C. for 16 h. Extraction and
 chromatography gave
 4-chloro-5-(2-(3,4-dichloro-5-diethylphosphono)furoyl)amino-6-neopentylami
 nopyrimidine as a yellow solid. TLC: R.sub.f =0.4, 50% EtOAc-hexane.
 Step C: A solution of
 4-chloro-5-(2-(3,4-dichloro-5-diethylphosphono)-furoyl)amino-6-neopentylam
 inopyrimidine (1 mmol) in dichloromethane was treated with silicone
 tetrachloride (2.5 mmol) and triethylamine (2.5 mmol) at 45.degree. C. for
 18 h. The cooled reaction mixture was subjected to extraction and
 chromatography to give 6-chloro-N.sup.9
 -neopentyl-8-(2-(3,4-dichloro-5-diethyl-phosphono)furanyl)purine as a
 yellow solid. TLC: R.sub.f =0.28, 50% EtOAc-hexane.
 Step D: 6-Chloro-N.sup.9
 -neopentyl-8-(2-(3,4-dichloro-5-diethylphosphono)-furanyl)purine was
 subjected to Steps E and F in Example 2 to give 6-amino-N.sup.9
 -neopentyl-8-(2-(3,4-dichloro-5-phosphono)furanyl)purine (12.1) as a white
 solid. mp &gt;250.degree. C.; Anal. calcd. for C.sub.14 H.sub.16 N.sub.5
 O.sub.4 PCl.sub.2 +0.5 H.sub.2 O+0.15 EtOAc: C: 39.64; H: 4.15; N: 15.83.
 Found: C: 39.82; H: 3.88; N: 15.46.
 Example 13
 Preparation of hydroxyethyldisulfidylethylphosphonate diester
 A suspension of 8-(2-(5-phosphono)furanyl)-N.sup.9 -phenethyladenine (1
 mmol) in thionyl chloride (5 mL) was warmed at reflux for 4 h. The cooled
 reaction mixture was evaporated to dryness and the resulting yellow
 residue was treated with a solution of 2-hydroxyethyl disulfide (4 mmol),
 pyridine (2.5 mmol) in methylene chloride. After stirring at 25.degree. C.
 for 4 h the reaction was subjected to extraction and chromatography to
 give two compounds:
 13.1: N.sup.9
 -phenethyl-8-(bis(6'-hydroxy-3',4'-disulfide)hexylphosphono)furanyl)-adeni
 ne. Anal. calcd for C.sub.25 H.sub.32 N.sub.5 O.sub.6 S.sub.4 P+0.5
 DMSO+1.5 H.sub.2 O: C: 43.15; H: 5.29; N: 9.68. Found: C: 43.38; H: 4.93;
 N: 9.34.
 13.2: N.sup.9
 -phenethyl-8-((3',4'-disulfide)nonacyclicphosphono)furanyladenine. Anal.
 calcd for C.sub.21 H.sub.22 N.sub.5 O.sub.4 S.sub.2 P+DMSO: C: 47.49; H:
 4.85; N: 12.04. Found: C: 47.93; H: 4.60; N: 11.76.
 Example 14
 Preparation of substituted benzyl phosphonate diesters
 A suspension of 8-(2-(5-phosphono)furanyl)-N.sup.9 -phenethyladenine (1
 mmol) in thionyl chloride (5 mL) was warmed at refluxing 4 h. The cooled
 reaction mixture was evaporated to dryness and a solution of the resulting
 yellow residue was added to a solution of the corresponding benzyl alcohol
 (4 mmol), and pyridine (2.5 mmol) in methylene chloride. After stirring at
 25.degree. C. for 4 h the reaction mixture was subjected to extraction and
 chromatography to give the title compounds.
 14.1: N.sup.9
 -phenethyl-8-(2-(5-(bis-(3-bromo-4-methoxy)benzyl)phosphono)-furanyl)adeni
 ne. Molecular mass calculated for C.sub.33 H.sub.30 N.sub.5 O.sub.6
 Br.sub.2 P+H.sup.+ : 784. Found: 784.
 14.2: N.sup.9
 -phenethyl-8-(2-(5-(bis-(3-cyano-4-methoxy)benzyl)phosphono)-furanyl)adeni
 ne. Anal. calcd. for C.sub.35 H.sub.30 N.sub.7 O.sub.6 P+0.5 H.sub.2 O: C:
 61.40; H: 4.56; N: 14.32. Found: C: 61.45; H: 4.51; N: 14.18.
 14.3: N.sup.9
 -neopentyl-8-(2-(5-(bis-(4-acetoxy)benzyl)phosphono)furanyl)adenine. Anal.
 calcd. for C.sub.32 H.sub.34 N.sub.5 O.sub.8 P+0.6 H.sub.2 O: C: 58.37; H:
 5.39; N: 10.64. Found: C: 58.11; H: 5.28; N: 10.42.
 N.sup.9
 -neopentyl-8-(2-(5-(bis-(3-phthalidyl-2-ethyl)phosphono)furanyl)-adenine
 is also prepared following the above described procedure using
 2-(3-phthalidyl)ethanol which was prepared from phthalide-3-acetic acid in
 Example 27.
 This reaction procedure can also be used to prepare diaryl ester prodrugs
 of phosphonates, such as substituted phenyl esters of phosphonate.
 Example 15
 Preparation of 6-amino-8-(2-(5-diphenylphosphono)furanyl)-N.sup.9
 -(2-phenyl)ethylpurine
 Step A. A suspension of 6-chloro-8-(2-furanyl)-N.sup.9 -phenethylpurine (1
 mmol) in THF at -78.degree. C. was treated with LDA (1.3 mmol) for 1 h.
 Then a solution of diphenyl chlorophosphate in THF was added and the
 reaction was stirred at -78.degree. C. for another hour. The reaction was
 warmed to 0.degree. C. and quenched with aqueous saturated sodium
 bicarbonate. Extraction and chromatography gave
 6-chloro-8-(2-(5-diphenylphosphono)furanyl)-N.sup.9 -phenethylpurine as a
 white solid. mp 117-118.degree. C.
 Step B. A solution of 6-chloro-8-(2-(5-diphenylphosphono)furanyl)-N.sup.9
 -phenethylpurine (1 mmol) in DMF was treated with sodium azide (4 mmol)
 and triphenylphosphine (4 mmol) at room temperature for 3 h. Filtration,
 evaporation of the filtrate followed by chromatography gave
 6-triphenyl-phosphonoimino-8-(2-(5-diphenylphosphono)furanyl)-N.sup.9
 -(2-phenyl)ethylpurine as a beige foam.
 Step C. A solution of
 6-triphenylphosphonoimino-8-(2-(5-diphenyl-phosphono)furanyl)-9-(2-phenyl)
 ethylpurine (1 mmol) in THF was treated with aqueous hydrogen chloride at
 room temperature for 24 h. Evaporation and chromatography gave
 6-amino-8-(2-(5-diphenylphosphono)furanyl)-N.sup.9 -(2-phenyl)ethylpurine
 (15.1) as a pale yellow solid. mp 196-197.degree. C.; Anal. calcd. for
 C.sub.29 H.sub.24 N.sub.5 O.sub.4 P: C: 64.80; H: 4.50; N: 13.03; P: 5.76.
 Found: C: 64.50; H: 4.47; N: 12.98; P: 5.46.
 Example 16
 Preparation of acyloxymethylphosphonate diesters
 A solution of 8-(2-(5-phosphono)furanyl)-N.sup.9 -phenethyladenine (1 mmol)
 in acetonitrile and N,N,N-diisopropylethylamine (5 mmol) was treated with
 acyloxymethyl iodide (4 mmol) at 0.degree. C. for 24 h. Extraction and
 chromatography gave the title compounds.
 The following compounds were prepared according to this procedure:
 16.1:
 6-Amino-9-phenethyl-8-(2-(5-diisobutyrylmethylphosphono)furanyl)-purine.
 Anal. calcd for C.sub.27 H.sub.32 N.sub.5 O.sub.8 P: C: 55.40; H: 5.50; N:
 12.00. Found: C: 55.60; H: 5.60; N: 11.80.
 16.2:
 6-Amino-9-(2-cyclohexylethyl)-8-(2-(5-diisobutyrylmethylphosphono)-furanyl
 )purine. Anal. calcd for C.sub.27 H.sub.38 N.sub.5 O.sub.8 P+0.7 H.sub.2 O:
 C: 53.70; H: 6.60; N: 11.60. Found: C: 54.00; H: 6.50; N: 11.20.
 16.3: 6-Amino-9-ethyl-8-(2-(5-diisobutyrylmethylphosphono)-furanyl)purine.
 Anal. calcd for C.sub.21 H.sub.28 N.sub.5 O.sub.8 P: C: 49.51; H: 5.54; N:
 13.75. Found: C: 49.75; H: 5.37; N: 13.76.
 16.4:
 6-Amino-9-neopentyl-8-(2-(5-diisobutyrylmethylphosphono)furanyl)-purine.
 Anal. calcd for C.sub.24 H.sub.34 N.sub.5 O.sub.8 P: C: 52.27; H: 6.21; N:
 12.70. Found: C: 52.40; H: 6.27; N: 12.41.
 16.5: 6-Amino-9-neopentyl-8-(2-(5-dipivaloxymethylphosphono)furanyl)purine.
 Anal. calcd for C.sub.26 H.sub.38 N.sub.5 O.sub.8 P+0.2 EtOAc: C: 53.90;
 H: 6.68; N: 11.73. Found: C: 54.10; H: 6.80; N: 11.42.
 6-Amino-9-phenethyl-8-(2-(5-bis-(3-(5,6,7-trimethoxy)phthalidyl)-phosphono)
 furanyl)purine (16.6) was also synthesized following this procedure using
 3-bromo-5,6,7-trimethoxyphthalide as the alkylating reagent to give the
 titled compound as a white solid after preparative HPLC purification. mp
 155-160.degree. C.; Anal. calcd. for C.sub.39 H.sub.36 N.sub.5 O.sub.14
 P+H.sub.2 O: C: 55.26; H: 4.52; Found: C: 54.89; H: 4.75; N: 8.21.
 Example 17
 Preparation of 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene
 A solution of 4,5-dimethyl-2-oxo-1,3-dioxolene (1 mmol) and selenium
 dioxide (2.5 mmol) in dioxane was heated at reflux for 1 h. Evaporation,
 extraction and chromatography gave
 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene as a yellow oil. TLC: R.sub.f
 =0.5, 5% MeOH-dichloromethane.
 Example 18
 Preparation of (5-substituted 2-oxo-1,3-dioxolen-4-yl)methyl phosphonate
 prodrugs
 A solution of N.sup.9 -neopentyl-8-(2-(5-phosphono)furanyl)adenine (1 mmol)
 in DMF and 2 mmol of sodium hydride is treated with
 5-methyl-4-bromomethyl-2-oxo-1,3-dioxolene (4 mmol, prepared according to
 Chem. Pharm. Bull. 1984, 32(6), 2241) at 25.degree. C. for 24 h.
 Extraction and chromatography gives N.sup.9
 -neopentyl-8-(2-(5-bis(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl
 phosphono)-furanyl)adenine.
 Alternatively, N.sup.9
 -neopentyl-8-(2-(5-bis(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl
 phosphono)-furanyl)adenine is prepared from N.sup.9
 -neopentyl-8-(2-(5-phosphono)furanyl)adenine and
 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene (prepared from
 4,5-dimethyl-2-oxo-1,3-dioxolene as described in Example 17) according to
 procedures of Example 14.
 Example 19
 Preparation of 2-(6-amino-N.sup.9 -neopentylpurin-8-yl)phenyl phosphonate
 Step A. Triethylamine (1.1 mmol) was added slowly to an ice-cooled solution
 of 6-chloro-N.sup.9 -neopentyl-8-(2-hydroxyphenyl)purine (1 mmol) and
 diethyl phosphite (1 mmol) in carbontetrachloride. The reaction was
 stirred at room temperature overnight. Triethylamine hydrochloride was
 precipitated as a white solid mass. Extraction and chromatography gave
 diethyl 2-(6-Chloro-N.sup.9 -neopentylpurin-8-yl)phenyl phosphate.
 Step B. Diethyl 2-(6-Chloro-N.sup.9 -neopentylpurin-8-yl)phenyl phosphate
 was subjected to Step E and F in Example 2 to give the title compound
 (19.1). mp &gt;250.degree. C.; Anal. calcd. for C.sub.16 H.sub.20 N.sub.5
 O.sub.4 P+1.25 H.sub.2 O: C: 48.06; H: 5.67; N: 17.51. Found: C:48.42; H:
 5.42; N: 17.15.
 Example 20
 Preparation of N.sup.9 -neopentyl-8-(1-(2-phosphono)imidazolemethyl)adenine
 Step A. A solution of 1-benzylimidazole (1.1 mmol) in THF was treated with
 LDA (1.1 mmol) at -78.degree. C. for 1 h, and followed by addition of
 diethyl chlorophosphate (2 mmol), and stirred for 2 h. Extraction and
 chromatography gave 1-benzyl-2-diethylphosphonoimidazole as a yellow oil.
 TLC: R.sub.f =0.35, 80% EtOAc-hexane.
 Step B. A solution of 1-benzyl-2-diethylphosphonoimidazole (1 mmol) in EtOH
 was treated with palladium on carbon (10%) at 25.degree. C. under 1
 atmosphere of hydrogen for 19 h. Filtration and evaporation gave
 2-diethyl-phosphonoimidazole as a white solid. TLC: R.sub.f =0.05, 80%
 EtOAc-hexane.
 Step C. A solution of 8-bromomethyl-6-chloro-N.sup.9 -neopentylpurine (1
 mmol, Step H of Example 5), 2-diethylphosphonoimidazole (2.5 mmol), and
 N,N,N-diisopropylethylamine (2.5 mmol) in acetonitrile was stirred at
 25.degree. C. for 48 h. Extraction and chromatography gave
 6-chloro-N.sup.9
 -neopentyl-8-(1-(2-diethylphosphono)imidazolemethyl)purine.
 Step D. 6-Chloro-N.sup.9
 -neopentyl-8-(1-(2-diethylphosphono)imidazole-methyl)purine was subjected
 to Steps E and F in Example 2 to give the title compound (20.1). mp
 &gt;250.degree. C.; MS (M+H) calcd. for C.sub.14 H.sub.20 N.sub.7 O.sub.3 P:
 366; found: 366.
 Example 21
 Preparation of N.sup.9 -phenethyl-8-(phosphonomethylaminocarbonyl)adenine
 Step A. N.sup.9 -phenethyl-8-(methoxycarbonyl)adenine (1 mmol, prepared as
 in Step A of Example 5) was treated with sodium hydroxide (1.2 mmol) in
 THF:MeOH:H.sub.2 O (3:2:1) at 25.degree. C. for 1.5 h. The reaction
 mixture was evaporated to dryness, and the residue was dissolved in DMF,
 treated with diethyl aminomethylphosphonate (1.5 mmol), EDCl
 (1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride, 1.3 mmol),
 HOBt (1-hydroxy-benzotriazole hydrate, 1.5 mmol), and stirred at
 25.degree. C. for 24 h. Extraction and chromatography gave N.sup.9
 -phenethyl-8-(diethylphosphonomethyl-aminocarbonyl)adenine as a white
 solid. TLC: R.sub.f =0.1, EtOAc.
 Step B. N.sup.9 -phenethyl-8-(diethylphosphonomethylaminocarbonyl)adenine
 (1 mmol) was subjected to Step F in Example 2 to give the title compound
 (21.1). mp &gt;250.degree. C.; Anal. calcd. for C.sub.15 H.sub.17 N.sub.6
 O.sub.4 P+0.17 Toluene: C: 47.32; H: 4.50; N: 20.45. Found: C:47.67; H:
 4.57; N: 20.78.
 Example 22
 Preparation of 2-substituted N.sup.9
 -neopentyl-8-(2-(5-phosphono)furanyl)adenine
 Step A. A solution of 2-amino-4,6-dichloropyremidine (1 mmol),
 neopentylamine (1.05 mmol), and triethylamine (2 mmol) in n-butanol was
 stirred at 110.degree. C. for 12 h. Extraction and chromatography gave
 2-amino-4-chloro-6-neopentylpyrimidine as a yellow solid. TLC: R.sub.f
 =0.2, 30% EtOAc-hexane.
 Step B. A mixture of 2-amino-4-chloro-6-neopentylpyrimidine (1 mmol),
 sodium acetate (14 mmol), acetic acid (86 mmol), and
 4-chlorobenzene-diazonium hexafluorophosphate (1.15 mmol) in water was
 stirred at 25.degree. C. for 12 h. Extraction and evaporation gave a
 yellow solid which was treated with zinc dust (10 mmol) and acetic acid
 (5.54 mmol) in EtOH-H.sub.2 O at 80.degree. C. for 1 h. Extraction and
 chromatography gave 4-chloro-2,5-diamino-6-neopentyl-pyrimidine as a
 yellow solid. TLC: R.sub.f =0.25, 50% EtOAc-hexane.
 Step C. 4-Chloro-2,5-diamino-6-neopentylpyrimidine was subjected to Step D,
 E, F in Example 2 to give 2,6-diamino-N.sup.9
 -neopentyl-8-(2-(5-phosphono)furanyl)purine (22.1) as a yellow solid. mp
 240.degree. C. (decomp); Anal. calcd. for C.sub.14 H.sub.19 N.sub.6
 O.sub.4 P+2.2 HBr+0.5 acetone: C: 32.47; H: 4.25; N: 14.66. Found:
 C:32.31; H: 4.51; N: 14.85.
 Similarly, 2-methylthio-N.sup.9
 -neopentyl-8-(2-(5-phosphono)furanyl)adenine
 (22.2) was also prepared from 4-amino-6-chloro-2-methylthiopyrimidine as a
 yellow solid. mp &gt;250; Anal. calcd. for C.sub.15 H.sub.20 N.sub.5 O.sub.4
 PS+0.2 CH.sub.2 Cl.sub.2 +0.1 toluene: C: 45.08; H: 5.04; N: 16.53. Found:
 C:45.27; H: 5.34; N: 16.24.
 Example 23
 Preparation of alkyloxycarbonyloxyalkyl phosphonate esters
 A solution of N.sup.9 -neopentyl-8-(2-(5-phosphono)furanyl)adenine (1 mmol)
 in 5 mL of anhydrous DMF is treated with
 N,N'-dicyclohexyl-4-morpholinecarboxamidine (5 mmol), and
 isopropyloxycarbonyloxymethyl iodide (5 mmol) which is prepared from the
 commercially available chloromethyl chloroformate according to the
 reported procedure, Nishimura et al. J. Antibiotics, 1987, 40(1), 81-90.
 The reaction mixture is stirred for 24 h at room temperature and the
 solvent is removed under reduced pressure. The resulting syrup is
 chromatographed on silica with 50%/50% EtOAc/Hexane to yield N.sup.9
 -neopentyl-8-(2-(5-diisopropyloxycarbonyloxymethyl phosphono)fu
 ranyl)adenine.
 Other alkyloxycarbonyloxymethyl, aryloxycarbonyloxymethyl , alkyl- and
 arylthiocarbonyloxymethyl phosphonate esters can also be prepared
 following the above described procedure.
 Example 24
 Preparation of 1-substituted-1,3-propanediol cyclic esters of purine
 phosphonates
 Step A(J. Org. Chem. 1 957. 22 589)
 To a solution of 2-pyridine propanol (72.9 mmol) in acetic acid (75 mL) was
 added 30% hydrogen peroxide slowly. The reaction mixture was heated to
 80.degree. C. for 16 h. The reaction was concentrated under vacuum and the
 residue was dissolved in acetic anhydride (100 mL) and heated at
 110.degree. C. overnight. Acetic anhydride was evaporated upon completion
 of reaction. Chromatography of the mixture by eluting with
 methanol-methylene chloride (1:9) resulted in 10.5 g of pure
 2-(1-(1,3-diacetoxy)propyl)pyridine.
 Step B. To a solution of 2-(1-(1,3-diacetoxy)propyl)pyridine (21.1 mmol) in
 methanol-water (3:1, 40 mL) was added potassium carbonate (105.5 mmol).
 After stirring for 3 h at room temperature, the reaction mixture was
 concentrated. The residue was chromatographed by eluting with
 methanol-methylene chloride (1:9) to give 2.2 g of crystalline
 2-(1-(1,3-dihydroxy)propyl)pyridine.
 Step C. A suspension of N.sup.9
 -neopentyl-8-(2-(5-phosphono)furanyl)adenine (1 mmol) in 5 mL of thionyl
 chloride was heated at reflux temperature for 4 h. The reaction mixture
 was cooled and evaporated to dryness. To the resulting residue was added a
 solution of 2-(1-(1,3-dihydroxy)propyl)pyridine (1 mmol) and pyridine (2.5
 mmol) in 3 mL of methylene chloride. After stirring at 25.degree. C. for 4
 h the reaction was subjected to work up and chromatography to give N.sup.9
 -neopentyl-8-(2-(5-(1-(2-pyridyl)propan-1,3-yl)phosphono)furanyl)adenine
 (24.1) as a sticky solid. Anal. Calcd. for C.sub.22 H.sub.25 N.sub.6
 O.sub.4 P+0.75 H.sub.2 O+1.0 HCl: C:50.97; H: 5.35; N: 16.21. Found:
 C:51.19, H: 5.02; N: 15.91.
 Following the above described procedures, other cyclic esters are also
 prepared, such as N.sup.9
 -neopentyl-8-(2-(5-(1-(4-pyridyl)propan-1,3-yl)phosphono)furanyl)adenine,
 N.sup.9
 -neopentyl-8-(2-(5-(1-(3-pyridyl)propan-1,3-yl)phosphono)furanyl)adenine,
 and N.sup.9
 -neopentyl-8-(2-(5-(1-phenylpropan-1,3-yl)phosphono)furanyl)adenine.
 Example 25
 Preparation of 2-substituted-1,3-propanediol cyclic esters of purine
 phosphonates
 Step A. To a solution of 2-(hydroxymethyl)-1,3-propanediol (1 g, 9.4 mmol)
 in pyridine (7.5 mL) at 0.degree. C. was added acetic anhydride (0.89 mL,
 9.4 mmol) slowly. The resulting solution was warmed to room temperature
 and stirred for 16 h. The reaction was concentrated under reduced pressure
 and chromatographed by eluting with methanol-dichloromethane (1:9) to give
 510 mg of pure 2-acetoxymethyl-1,3-propanediol.
 Step B. 2-Acetoxymethyl-1,3-propanediol was coupled to N.sup.9
 -neopentyl-8-(2-(5-phosphono)furanyl)adenine following Step C of Example
 24 to give N.sup.9
 -neopentyl-8-(2-(5-(2-(acetoxymethyl)propan-1,3-yl)phosphono)furanyl)adeni
 ne (25.1). mp=164-165.degree. C.; Anal. Calcd. for C.sub.20 H.sub.26
 N.sub.5 O.sub.6 P: C: 51.84; H: 5.65; N: 15.11. Found: C: 52.12; H: 5.77;
 N: 14.59.
 Following the above described procedures, other cyclic esters are also
 prepared, such as N.sup.9
 -neopentyl-8-(2-(5-(2-(methoxycarbonyloxymethyl)-propan-1,3-yl)phosphono)f
 uranyl)adenine, N.sup.9
 -neopentyl-8-(2-(5-(2-(hydroxymethyl)-propan-1,3-yl)phosphono)furanyl)aden
 ine, N.sup.9
 -neopentyl-8-(2-(5-(2,2-dihydroxymethylpropan-1,3-yl)phosphono)furanyl)ade
 nine, N.sup.9
 -neopentyl-8-(2-(5-(2-(methoxycarbonyloxymethyl)propan-1,3-yl)phosphono)-f
 uranyl)adenine is prepared by coupling N.sup.9
 -neopentyl-8-(2-(5-phosphono)-furanyl)adenine with
 2-(methoxycarbonyloxymethyl)-1,3-propanediol which was prepared as
 follows:
 To a solution of 2-(hydroxymethyl)-1,3-propanediol (9.4 mmol) in
 dichloromethane (20 mL) and pyridine (7.5 mL) at 0.degree. C. was added
 methyl chloroformate (9.4 mmol) slowly. The resulting solution was warmed
 to room temperature and stirred for 16 h. The reaction was concentrated
 under reduced pressure and chromatographed by eluting with
 methanol-dichloromethane (1:4) to give 650 mg of
 2-(methoxycarbonyloxymethyl)-1,3-propanediol.
 Example 26
 Preparation of 8-(2-(5-hydroxyl-1,3 cyclohexyl)phosphono)furanylpurines
 A suspension of N.sup.9 -neopentyl-8-(2-(5-phosphono)furanyl)adenine (1
 mmol) in 5 mL of thionyl chloride was heated at reflux temperature for 4
 h. The reaction mixture was cooled and evaporated to dryness. To the
 resulting residue was added a solution of cis,cis-1,3,5-cyclohexanetriol
 (1 mmol) and pyridine (2.5 mmol) in 3 mL of methylene chloride. After
 stirring at 25.degree. C. for 24 h the reaction was subjected to work up
 and chromatography to give N.sup.9 -neopentyl-8-(2-(5-(5-hydroxyl-1,3
 cyclohexyl)phosphono)furanyl)adenine, minor isomer (26.1). mp
 248-250.degree. C.; Anal. Cald. for C.sub.20 H.sub.26 N.sub.5 O.sub.5
 P+0.5 H.sub.2 O: C: 52.63; H: 5.96; N: 15.34. Found: C: 52.62; H: 5.70; N:
 15.32; major isomer (26.2). mp 225-230.degree. C.; Anal. Cald. for
 C.sub.20 H.sub.26 N.sub.5 O.sub.5 P+0.5 H.sub.2 O: C: 52.63; H: 5.96; N:
 15.34. Found: C: 52.74; H: 5.80; N: 15.32.
 Following the above described procedures, N.sup.9
 -phenethyl-8-(2-(5-(5-hydroxyl-1,3 cyclohexyl)phosphono)furanyl)adenine
 (26.3) was also prepared. Anal. Cald. for C.sub.23 H.sub.24 N.sub.5
 O.sub.5 P+0.15 H.sub.2 O: C: 57.06; H: 5.06; N: 14.47. Found: C: 56.84; H:
 4.83; N: 14.38.
 Example 27
 Preparation of 3-(2-hydroxyethyl)phthalide
 A solution of phthalide-3-acetic acid (1 mmol) in THF was treated with
 borane dimethylsulfide (1.5 mmol) at 0.degree. C. for 1h, and 25.degree.
 C. for 24 h. Extraction and chromatography gave 2-(3-phthalidyl)ethanol as
 a light yellow oil. TLC: R.sub.f =0.25, 50% EtOAc-hexane.
 Example 28
 Preparation of Purine Phosphonate Amine Salts
 A mixture of N.sup.9 -neopentyl-8-(2-(5-phosphono)furanyl)adenine (1 mmol)
 and tris(hydroxymethyl)aminomethane (1.05 mmol) in methanol is stirred at
 25.degree. C. for 24 h. Evaporation gives N.sup.9
 -neopentyl-8-(2-(5-phosphono)furanyl)adenine
 tris(hydroxymethyl)aminomethane salt.
 Examples of the methods of the present invention include the following. It
 will be understood that these examples are exemplary and that the method
 of the invention is not limited solely to these examples.
 For the purposes of clarity and brevity, chemical compounds in the
 following biological examples are referred to by synthetic example
 numbers.
 Besides the following Examples, assays that may be useful for identifying
 compounds which inhibit gluconeogenesis include the following animal
 models of Diabetes:
 i. Animals with pancreatic b-cells destroyed by specific chemical
 cytotoxins such as Alloxan or Streptozotocin (e.g. the
 Streptozotocin-treated mouse, -rat, dog, and -monkey). Kodama, H., Fujita,
 M., Yamaguchi, I., Japanese Journal of Pharmacology 1994, 66, 331-336
 (mouse); Youn, J. H., Kim, J. K., Buchanan, T. A., Diabetes 1994, 43,
 564-571 (rat); Le Marchand, Y., Loten, E. G., Assimacopoulos-Jannet, F.,
 et al., Diabetes 1978, 27, 1182-88 (dog); and Pitkin, R. M., Reynolds, W.
 A., Diabetes 1970, 19, 70-85 (monkey).
 ii. Mutant mice such as the C57BUKs db/db, C57BUKs ob/ob, and C57BU6J ob/ob
 strains from Jackson Laboratory, Bar Harbor, and others such as Yellow
 Obese, T-KK, and New Zealand Obese. Coleman, D. L., Hummel, K. P.,
 Diabetologia 1967, 3, 238-248 (C57BUKs db/db); Coleman, D. L.,
 Diabetologia 1978, 14,141-148 (C57BU6J ob/ob); Wolff, G. L., Pitot, H. C.,
 Genetics 1973, 73,109-123 (Yellow Obese); Dulin, W. E., Wyse, B. M.,
 Diabetologia 1970, 6, 317-323 (T-KK); and Bielschowsky, M., Bielschowsky,
 F. Proceedings of the University of Otago Medical School 1953, 31, 29-31
 (New Zealand Obese).
 iii. Mutant rats such as the Zucker fa/fa Rat rendered diabetic with
 Streptozotocin or Dexamethasone, the Zucker Diabetic Fatty Rat, and the
 Wistar Kyoto Fatty Rat. Stolz, K. J., Martin, R. J. Journal of Nutrition
 1982, 112, 997-1002 (Streptozotocin); Ogawa, A., Johnson, J. H., Ohnbeda,
 M., McAllister, C. T., Inman, L., Alam, T., Unger, R. H., The Journal of
 Clinical Investigation 1992, 90, 497-504 (Dexamethasone); Clark, J. B.,
 Palmer, C. J., Shaw, W. N., Proceedings of the Society for Experimental
 Biology and Medicine 1983, 173, 68-75 (Zucker Diabetic Fatty Rat); and
 Idida, H., Shino, A., Matsuo, T., et al., Diabetes 1981, 30,1045-1050
 (Wistar Kyoto Fatty Rat).
 iv. Animals with spontaneous diabetes such as the Chinese Hamster, the
 Guinea Pig, the New Zealand White Rabbit, and non-human primates such as
 the Rhesus monkey and Squirrel monkey. Gerritsen, G. C., Connel, M. A.,
 Blanks, M. C., Proceedings of the Nutrition Society 1981, 40, 237 245
 (Chinese Hamster); Lang, C. M., Munger, B. L., Diabetes 1976, 25, 434-443
 (Guinea Pig); Conaway, H. H., Brown, C. J., Sanders, L. L. eta I., Journal
 of Heredity 1980, 71, 179-186 (New Zealand White Rabbit); Hansen, B. C.,
 Bodkin, M. L., Diabetologia 1986, 29, 713-719 (Rhesus monkey); and
 Davidson, I. W., Lang, C. M., Blackwell, W. L., Diabetes 1967, 16, 395-401
 (Squirrel monkey).
 v. Animals with nutritionally induced diabetes such as the Sand Rat, the
 Spiny Mouse, the Mongolian Gerbil, and the Cohen Sucrose-Induced Diabetic
 Rat. Schmidt-Nielsen, K., Hainess, H. B., Hackel, D. B., Science 1964,
 143, 689-690 (Sand Rat); Gonet, A. E., Stauffacher, W., Pictet, R., et
 al., Diabetologia 1965, 1, 162-171 (Spiny Mouse); Boquist, L.,
 Diabetologia 1972, 8, 274-282 (Mongolian Gerbil); and Cohen, A. M.,
 Teitebaum, A., Saliternik, R., Metabolism 1972, 21, 235-240 (Cohen
 Sucrose-Induced Diabetic Rat).
 vi. Any other animal with one of the following or a combination of the
 following characteristics resulting from a genetic predisposition, genetic
 engineering, selective breeding, or chemical or nutritional induction:
 impaired glucose tolerance, insulin resistance, hyperglycemia, obesity,
 accelerated gluconeogenesis, increased hepatic glucose output.
 Example A
 Inhibition of Human Liver FBPase
 E. coli strain BL21 transformed with a human liver FBPase-encoding plasmid
 was obtained from Dr. M. R. El-Maghrabi at the State University of New
 York at Stony Brook. hIFBPase was typically purified from 10 liters of E.
 coli culture as described (M. Gidh-Jain et al., The Journal of Biological
 Chemistry 1994, 269, 27732-27738). Enzymatic activity was measured
 spectrophotometrically in reactions that coupled the formation of product
 (fructose 6-phosphate) to the reduction of
 dimethylthiazoldiphenyltetrazolium bromide (MTT) via NADP and phenazine
 methosulfate (PMS), using phosphoglucose isomerase and glucose 6-phosphate
 dehydrogenase as the coupling enzymes. Reaction mixtures (200 .mu.L) were
 made up in 96-well microtitre plates, and consisted of 50 mM Tris-HCl, pH
 7.4,100 mM KCl, 5 mM EGTA, 2 mM MgCl.sub.2, 0.2 mM NADP, 1 mg/mL BSA, 1 mM
 MTT, 0.6 mM PMS, 1 unit/mL phosphoglucose isomerase, 2 units/mL glucose
 6-phosphate dehydrogenase, and 0.150 mM substrate (fructose
 1,6-bisphosphate). Inhibitor concentrations were varied from 0.01 .mu.M to
 10 .mu.M. Reactions were started by the addition of 0.002 units of pure
 hIFBPase and were monitored for 7 minutes at 590 nm in a Molecular Devices
 Plate Reader (37.degree. C.).
 The following Table depicts the IC.sub.50 values for several compounds
 prepared in the Examples. AMP has an IC.sub.50 value of 1.0 .mu.M in this
 assay.

Compound IC50 Glucose Production, .mu.M
 2.2 90
 2.6 18
 2.10 24
 2.13 50
 2.14 7.5
 2.16 12
 16.4 3
 FPBase from rat liver is less sensitive to AMP than that from human liver.
 IC.sub.50 values are correspondingly higher in rat hepatocytes than would
 be expected in human hepatocytes.
 Example E
 Effect of Compound 2.7 on Gluconeogenesis From Dihydroxyacetone in Rat
 Hepatocytes: Glucose Production Inhibition and Fructose 1,6-bisphosphate
 Accumulation
 Isolated rat hepatocytes were prepared as described in Example D and
 incubated under the identical conditions described except that
 lactate/pyruvate was replaced by 10 mM dihydroxyacetone, a substrate which
 feeds into the gluconeogenic pathway at a step just prior to FBPase.
 Reactions were terminated by removing an aliquot (250 .mu.L) of cell
 suspension and spinning it through a layer of oil (0.8 mL silicone/mineral
 oil, 4/1) into a 10% perchloric acid layer (100 .mu.L). After removal of
 the oil layer, the acidic cell extract layer was neutralized by addition
 of 1/3rd volume of 3 M KOH/3 M KH.sub.2 CO.sub.3. After thorough mixing
 and centrifugation, the supernatant was analyzed for glucose content as
 described in Example D, and also for fructose-1,6-bisphosphate.
 Fructose-1,6-bisphosphate was assayed spectrophotometrically by coupling
 its enzymatic conversion to glycerol 3-phosphate to the oxidation of NADH,
 which was monitored at 340 nm. Reaction mixtures (1 mL) consisted of 200
 mM Tris-HCl, pH 7.4, 0.3 mM NADH, 2 units/mL glycerol 3-phsophate
 dehydrogenase, 2 units/mL triosephosphate isomerase, and 50-100 .mu.l cell
 extract. After a 30 minute preincubation at 37.degree. C., 1 unit/mL of
 aldolase was added and the change in absorbance measured until a stable
 value was obtained. 2 moles of NADH are oxidized in this reaction per mole
 of fructose-1,6-bisphosphate present in the cell extract.
 As shown in FIG. 4A, compound 2.7 inhibited glucose production from
 dihydroxyacetone in rat hepatocytes (IC.sub.50 approx. 5 .mu.M) as
 effectively as from lactate pyruvate (IC.sub.50 4.5 .mu.M, FIG. 5). This
 data confirms that the site of action of the compound is in the last four
 steps of the gluconeogenic pathway. The dose-dependent accumulation of
 fructose-1,6-bisphosphate (the substrate of FBPase) that occurs upon cell
 exposure to compound 2.7 (FIG. 4B) is consistent with the inhibition of
 FBPase, the second to last enzyme in the pathway.
 Example F
 Blood Glucose Lowering in Fasted Rats
 Sprague Dawley rats (250-300 g) were fasted for 18 hours and then dosed
 intraperitoneally either with saline or with 35, 45, and 60 mg/kg compound
 16.4, a prodrug of compound 2.7. The vehicle used for drug administration
 was dimethylsulfoxide. Blood samples were obtained from the tail vein of
 conscious animals just prior to injection and then at half-hourly
 intervals. Blood glucose was measured using a HemoCue Inc. glucose
 analyzer according to the instructions of the manufacturer.
 FIG. 6 shows the profound glucose lowering elicited by treatment with
 compound 16.4. The duration of action was dose-dependent and ranged from 2
 to 6 hours.
 Example G
 Analysis of Drug Levels and Liver Fructose-1,6-bisphosphate Accumulation in
 Rats
 Sprague-Dawley rats (250-300 g) were fasted for 18 hours and then dosed
 intraperitoneally either with saline (n=3) or 20 mgs/kg compound 2.7
 (n=4). The vehicle used for drug administration was 10 mM bicarbonate. One
 hour post injection rats were anesthetized with halothane and a liver
 biopsy (approx. 1 g) was taken as well as a blood sample (2 mL) from the
 posterior vena cava. A heparin flushed syringe and needle were used for
 blood collection. The liver sample was immediately homogenized in ice-cold
 10% perchloric acid (3 mL), centrifuged, and the supernatant neutralized
 with 1/3rd volume of 3 M KOH/3 M KH.sub.2 CO.sub.3. Following
 centrifugation and filtration, 50 .mu.L of the neutralized extract was
 analyzed for compound 2.7 content by HPLC. A reverse phase YMC ODS AQ
 column (250.times.4.6 cm) was used and eluted with a gradient from 10 mM
 sodium phosphate pH 5.5 to 75% acetonitrile. Absorbance was monitored at
 310 nm. The concentration of fructose-1,6-bisphosphate in liver was also
 quantified using the method described in Example E. Blood glucose was
 measured in the blood sample as described in Example F. Plasma was then
 quickly prepared by centrifugation and extracted by addition of methanol
 to 60% (v/v). The methanolic extract was clarified by centrifugation and
 filtration and then analyzed by HPLC as described above.
 Compound 2.7 lowered blood glucose from 82.+-.3 to 28.+-.9.9 mg/dL within
 one hour (FIG. 7). Drug levels measured in plasma and liver were 38.5.+-.7
 .mu.M and 51.3.+-.10 nmoles/g, respectively. As shown in FIG. 8, a 10-fold
 elevation of fructose-1,6-bisphosphate levels was found in the livers from
 the drug-treated group, consistent with the inhibition of glucose
 production at the level of FBPase in the gluconeogenic pathway.
 Example H
 Blood Glucose Lowering in Zucker Diabetic Fatty Rats
 Zucker Diabetic Fatty rats purchased at 7 weeks of age were used at age 16
 weeks in the 24-hour fasted state. The rats were purchased from Genetics
 Models Inc. and fed the recommended Purina 5008 diet (6.5% fat). Their
 fasting hyperglycemia at 24 hours ranged from 150 mg/dL to 310 mg/dL blood
 glucose.
 Compound 2.7 was administered at a dose of 50 mg/kg by intraperitoneal
 injection (n=6). The stock solution was made up at 25 mg/mL in deionized
 water and adjusted to neutratility by dropwise addition of 5 N NaOH. 5
 control animals were dosed with saline. Blood glucose was measured at the
 time of dosing and 2 hours post dose as described in Example F.
 As shown in FIGS. 9A and 9B, blood glucose was lowered in the drug-treated
 group by an average of almost 20% (p&lt;0.0001 relative to the control
 animals).
 Example I
 Inhibition of Gluconeogenesis in Zucker Diabetic Fatty Rats
 Three 20-week old Zucker Diabetic Fatty rats were dosed with compound 2.7
 and three with saline as described in Example H. Fifteen minutes
 post-injection, the animals were anesthetized with sodium pentobarbitol
 (30 mgs, i.p.) and .sup.14 C-bicarbonate (20 .mu.Ci/100 g of body weight)
 was administered via the tail vein. Blood samples (0.6 mL) were obtained
 by cardiac puncture 10 and 20 minutes post tracer injection. Blood (0.5
 mL) was diluted into 6 mL deionized water and protein precipitated by
 addition of 1 mL zinc sulfate (0.3 N) and 1 mL barium hydroxide (0.3 N ).
 The mixture was centrifuged (20 minutes, 1000.times.g) and 5 mL of the
 resulting supernatant was then combined with 1 g of a mixed bed ion
 exchange resin (1 part AG 50W-X8, 100-200 mesh, hydrogen form and 2 parts
 of AG 1-X8, 100-200 mesh, acetate form) to separate .sup.14 C-bicarbonate
 from .sup.14 C-glucose. The slurry was shaken at room temperature for four
 hours and then allowed to settle. An aliquot of the supernatant (0.5 mL)
 was then counted in 5 mL scintillation cocktail.
 As shown in FIG. 10, compound 2.7 reduced the incorporation of .sup.14
 C-bicarbonate into glucose by 75%; therefore gluconeogenesis was clearly
 inhibited by the drug.
 Example J
 Blood Glucose Lowering in Streptozotocin-treated Rats
 Diabetes is induced in male Sprague-Dawley rats (250-300g) by
 intraperitoneal injection of 55 mg/kg streptozotocin (Sigma Chemical Co.).
 Six days later, 24 animals are selected with fed blood glucose values (8
 am) between 350 and 600 mg/dL and divided into two statistically
 equivalent groups. Blood glucose is measured in blood obtained from a tail
 vein nick by means of a HemoCue Inc. (Mission Viejo, Calif.) glucose
 analyzer. One group of 12 will subsequently receive inhibitor (100 mg/kg
 intraperitoneally) and the other 12 ("controls") an equivalent volume of
 saline. Food is removed from the animals. Blood glucose is measured in
 each animal four hours after dosing, and a second dose of drug or saline
 is then administered. Four hours later, a final blood glucose measurement
 is made.
 Example K
 Evaluation of Compound 16.4 as a Prodrug in Rat Hepatocytes--Intracellular
 Delivery of Compound 2.7
 Rat hepatocytes were prepared and incubated as in Example D, except that
 the test compound, 16.4, was added to yield a final concentration of 10
 .mu.M. Aliquots of the cell suspension were taken at 0, 5, 10, 20, 30, 45,
 and 60 minutes after drug exposure. The cells were extracted and analyzed
 for compound 2.7 content by HPLC as described in Example L. Absorbance of
 the HPLC column eluate was monitored at 310 nm. Quantitation of
 intracellular compound 2.7 was done by comparison to authentic standards
 of known concentration. As shown in FIG. 11A, compound 16.4 rapidly
 delivered high levels of compound 2.7 into the hepatocytes; a
 concentration of approximately 80 nmoles/g was achieved within 10 minutes.
 These data indicate that compound 16.4 readily penetrates cells and is
 efficiently de-esterified to the parent compound, 2.7, intracellularly.
 Furthermore, as shown in FIG. 11B, compound 16.4 inhibited glucose
 production in rat hepatocytes.
 Example L
 Estimation of the Oral Bioavailability of Prodrugs of Phosphonic Acids
 Prodrugs were dissolved in 10% ethanol/90% polyethylene glycol (mw 400) and
 administered by oral gavage at doses of approximately 20 or 40 mg/kg
 parent compound equivalents to 6-hour fasted, Sprague Dawley rats (220-240
 g). The rats were subsequently placed in metabolic cages and urine was
 collected for 24 hours. The quantity of parent compound excreted into
 urine was determined by HPLC analysis. An ODS column eluted with a
 gradient from potassium phosphate buffer, pH 5.5 to acetonitrile was
 employed for these measurements. Detection was at 310-325 nm. The
 percentage oral bioavailability was estimated by comparison of the
 recovery in urine of the parent compound generated from the prodrug, to
 that recovered in urine 24 hours after intravenous administration of
 unsubstituted parent compound at approximately 10 mg/kg. Parent compounds
 were typically dissolved in dimethyl sulfoxide, and administered via the
 tail vein in animals that were briefly anesthetized with halothane.
 For compound 16.4, a prodrug of compound 2.7, 6.2% of an oral dose of
 approximately 20 mg/kg was recovered in urine. For compound 2.7, 76.8% of
 an intravenous dose of approximately 10 mg/kg was recovered. The oral
 bioavailability of compound 16.4 was therefore calculated to be 6.2/76.8,
 or approximately 8%. The oral bioavailability of compound 16.5 was also
 estimated following the above described protocol to be 5.3%.
 Example M
 Glucose Lowering Following Oral Administration of FBPase Inhibitors
 FBPase inhibitor was administered by oral gavage at doses of 30, 100 and
 250 mg/kg to 18-hour fasted, Sprague Dawley rats (250-300g; n=4-5/group).
 The compound was prepared in deionized water, adjusted to neutrality with
 sodium hydroxide, and brought into solution by sonication prior to
 administration. Blood glucose was measured immediately prior to dosing,
 and at 1 hour intervals thereafter. Blood samples were obtained from the
 tail vein, and measurments made by means of a Hemocue glucose analyzer
 (Hemocue Inc, Mission Viejo, Calif.) used according to the manufacturer's
 instructions.