Indian Patents
Title of Invention

AN ARYL PHOSPHONATES
Abstract Novel FBPase inhibitors of formula (I)n are useful in the treatment of diabetes and other associated with elevated blood glucose.
Full Text FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS RULES, 2003 COMPLETE SPECIFICATION
[See Section 10; rule 13]
"AN ARYL PHOSPHONATES"
METABASIS THERAPEUTICS, INC., of 9390 Towne Centre Drive, San Diego, California 92121, United States of America,
The following specification particularly describes the invention and the manner in which it is to be performed:


GRANTED
25-9-2007



ORIGINAL
IN/PCT/02/1219/MUM 25-SEP-2007

The present invention relates to an aiyl phosphonates.
Related Application
" Tie present application claims the benefit of priority to U.S. Provisional
Application No. 60/187,750,- filed on Marcli 8, 2000 and is incorporated by reference in its
entirety.
Field of the Invention
This invention ^elates to novel aiyl containing compounds that possess a phosphonate group that ar^ inhibitors of Fructose-l,6-bispliospiiatase. Itie invention also relates to the preparation and use of these compounds in the treatment of diabetes, and other diseases where the inhibition of gluconeogenesis, control of blood glucose levels, reduction in glycogen storage, or reduction in insulin levels is beneficial.
Backgyouiid and Introduction to the Invention
■The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to be, or to describe, prior art to the invention. All cited pubHcations are incorporated by reference herein in their entirety.

Diabetes melHtus (or diabetes) is one of the most prevalent diseases in the world today. Diabetic patients have been divided into two classes, namely type I or insnlin-dependent diabetes jnellitu^ and type H or non-insulin dependent diabetes melhtus (NIDDM). NIDDM accounts for approximately 90% of all diabetics and is estimated to affect 12-14 million adults in. theU. S. alone {6.6% of thepopnlation). NEDDM is characterized by both fasting hyperglycerhia and exaggerated postprandial increases in " plasma glucose levels. NEDDM 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 hyperglycemia and complications. Results fi-omthe Diabetes Control and Complications Trial (DCCT) and the StocMiokn Prospective Study demonstrate this.Telationship for the first time in jnan by showing that insulin-dependent diabetics with tighter glycemic control are at substantially lower risk for the development and progression of these complications. Titter control is also expected to benefit NIDDM patients..


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Current therapies used to treat NIDDM patients entail both controIling lifestyle risk factors and pharmaceutical intervention. First-hne therapy for NIDDM is typically a tightly-controlled regimen of diet, and exercise since" an overwhelming number of NIDDM patients are overweight or obese (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 insuhn. 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 insuUn iajections to gain adequate glycemic control.
Although the sulfonylureas represent a major therapy for NIDDM patients, four factors hmit 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 becorhe 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 hyperinsuhnemia 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.
Results from the U.K. Diabetes Prospective Study also showed thit 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 fiirther illustrate the great need for alternative therapies.
Gluconeogenesis from pyruvate and other 3-carbon precursors is a highly regulated biosynthetic pathway requiring eleven enzymes. Seven enzymes catalyze reversible reactions and are common to both gluconedgenesis and glycolysis. Four enzymes catalyze reactions unique to gluconeogenesis, namely pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-l,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.

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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-l,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. Clans, et al., Mechanisms of Insulin Action, Belfrage, P: editor, pp.305-321, Elsevier Science 1992; Regen, et al. L Theor. BioL, 111:635-658 (1984); Pilkis, et al. Annu. Rev. Biochem. 57:755-7"83 (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 fiructose-2,6-bisphosphate analogs inhibit FBPase by binding to the substrate site. J. Am. Chem. Soc. 106:7851-7853 (1984)-U.S. Patent No. 4,968,790 (1984). These compounds, however, were relatively weak and did not inhibit glucose production ia 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 Bl.
Gruber et al. U.S. Patent No. 5,658,889 described the use of inhibitors of the AMP site,of FBPase to treat diabetes. WO 98/39344, WO 98/39343, WO 98/39342 and WO 00/14095 describe specific inhibitors of FBPase to treat diabetes.
Summary of the Invention
The present invention is directed towards novel aryl compounds containing a phosphonate or phosphoramidate group and are potent FBPase inhibitors. In another aspect, the present invention is directed to the preparation of this type of compound 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 these 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.

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The compounds are also useful in treating or preventing excess glycogen storage diseases and diseases such as cardiovascular diseases including atherosclerosis, myocardial ischemic injury, and diseases such as metabolic disorders such as hypercholesterolemia, hyperhpidemia which are exacerbated by hyperinsulinema and hyperglycemia.
The invention also comprises the novel compounds and methods of using them as specified below in formula I. Also included in the scope of the present invention are prodrugs of the compounds of formula I.

Formula I
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 phaimaceutically acceptable and/or useful salts of the compounds of formula I, including acid addition salts. The present inventions also encompass prodrugs of compounds of formula I.
Detailed Description Definitions
In accordance with the present invention and as used herein, the following temis are defined with the following meanings, unless explicitly stated otherwise.
L group nomenclature as used herein in formula I begins with the group attached to the phosphorous and ends with the group attached to the axyl ring. For example, when L is -alkylcarbonylamino-, the following structure is intended:
P(O)(YR1)2-alk:-C(O)-NR-(aromaticring)
For J2,J3,j4,J5, and J6 groups and other substituents of the R5 aromatic ring, the substituents are described in such a way that the term ends with the group attached to the aromatic ring. Generally, substituents are named such that the term ends with the group at the point of attachment. For example, when J2 is alkylaryl, the intended structure is alkyl-aryl-G2 in the ring.

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The term "aryl" refers to aromatic groupswhich have.5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which maybe optionally substituted. Suitable aryl groups include phenyl and furan"-2,5-diyI.
Carbocyclic aryl groups axe groups wherein the ring atoms on the aromatic ring are carbon, atoms. Carbocyclic aryl. groups include monocyclic cairbocyclic aryl groups and polycyclic or fused compounds such as optionally substitutednaphthyl groups.
Heterocyclic aryl or heteroaryl 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, nitrogen, and selenium. Suitable heteroaryl groups include ftiranyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyirolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the Iike, 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. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl.
The term "alicyclic" means compounds which combine the properties of aliphatic and cyclic compounds. Such cyclic compounds include but are not limited to, aromatic, cycloalkyl and bridged cycloalkyl compounds. The cyclic coinpound includes heterocycles. Cyclohexenylethyl and cyclohexylethyl 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 ahcyclic, heterocyclic alkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, guanidino, amidino, halo, lower "fflkylthio, oxo, acylalkyi, carboxy esters, carboxyl, -carboxamido, nitro, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, aUcoxyaryl, arylamino, aralkylainino, phosphono, sulfonyl, -carboxamidoalkylaryl, -carboxamido aryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-, aminocarboxamidoalkyl-, cyano, lower alkoxyalkyl, lower perhaloaUcyl, and arylalkyloxyalkyl. These optional substituents may not be optionally substituted. "Substituted axyl" and "substituted heteroaryl" refers to aryl and heteroaryl groups substituted with 1-3 substituents. In one aspect, suitable substituents are selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino. "Substituted" when describing an R5 group does not include annulation.

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The terra "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 tern "-aralkyl-" refers to a divalent group -aryl-alkylene-. Thus, "aralkyl" is synonymous with "aralkylene." "Heteroaryialkyr" refers to an alkylene group substituted with a heteroaryl group.
The term "-alkylaryl-" refers to the group -alk-aiyl- where "alk" is an alkylene group. Thus, "-alkylaryl-" is synonymous with "ralkyleneaiyl-." "Lower-alkylaryl-" refers to such groups where alkylene is lower alkylene.
The term "lower" referred to herein in connection with organic radicals or compounds respectively defines such as with up to and including 10, or up to and including 6, or 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(0)R where R is alkyl or aryl. The term "carboxy esters" refers to -C(O)OR where R is alkyl, aryl, aralkyl, or alicyclic, all optionally substituted.
The term "carboxyl" refers to -C(O)OH. The term "oxo" refers to =0 in an alkyl group.
The term "amino" refers to.-NRR" where R and R" are independently selected from hydrogen, alkyl, aryl, aralkyl and alicyclic, all except H are optionally substituted; and.R and R"can form a cychc ring system.
The term "carbonylamino" and "-carbonylamino-" refers to RCONR- and -CONR-, respectively, where each R is independently hydrogen or aUcyl. The terra "halogen" or "halo" refers to -F, -CI, -Br and -I.
The term "-oxyalkylamino-" refers to -O-alk-NR-, where "alk" is an alkylene group and R is H or alkyl. Thus, "-oxyalkylamino-" is synonymous with "-oxyalkyleneamino-."
The term "-alkyiaminpalkylcarboxy-" refers to the group -alk-NR-alk-C(O)-O-where "alk" is an alkylene group, and R is a H or lower alkyl. Thus, "-alkylaiuinoalkylcarboxy-" is synonymous with "-alkyleneaminoalkylenecarboxy-."
The term "-alkylaminocarbonyl-" refers to the group -alk-lSIR-G(O)- where "alk" is an alkylene groupj and R is a H or lower alkyl. Thus, "-alkylaminocarbonyl-" is synonymous with "-aUcyleneaminocarbonyl-."


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The term "-oxyalkyl-" refers to &e group -O-alk- where "alic" is an atkylene group. Thus, "-oxyalkyl-" is synonymous with "-oxyalkcylene-."
The term "-alkylcarhoxyalkyl-" refers to the group -alk-C(O)-O-ark- where each alk is independently an alkylene group. Thus, "-alkylcarboxyalkyl-" is synonymous with "-alkylenecarboxyalkylene-."
The tenn "alkyl" refers to .saturated aliphatic groups including straight-chain,-branched chain and cychc groups. Alkyl groups maybe optionally substituted. Suitable alkyl groups include methyl, isopropyl, and cyclopropyl.
The term "cyclic alkyl" or "cycloalkyl" refers to alkyl groups that are cyclic groups of 3 to 6 or 3 to 10 atoms. Suitable cyclic groups include norbomyl and cyclopropyl. Such groups may be substituted.
The term "heterocyclic" and "heterocyclic alkyl" refer to cyclic groups of 3 to 6 atoms, or 3 to 10 atoms, containing at least one heteroatom. In one aspect, these groups contain 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocychc groups may be attached through a nitrogen or through a carbon atom in the ring. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl. Such groups may be substituted.
The term "phosphono" refers to -PO3R2, where R is selected from the group
consisting of-H, alkyl, aryl, aralkyl, and alicyclic. . -
The term "sulphonyl" or "sulfonyl" refers to -S(O)2OR, where R is selected from the group of H, alkyl, aryl, aralkyl,. or alicyclic.
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," Alkenyl groups may be optionally substihited. Suitable alkenyl groups include allyl. "1- -alkenyl" refers to alkenyl groups where the double bond is between the first and second carbon atom. If the 1-alkenyl igroup is attached to another group, e.g. it is a W substituent attached to the cyclic phosphonate or phosphoramidate, it is attached at the first carbon.
" 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. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl. "1-alkynyl" refers to alknyl groups where the triple bond is between the first and second carbon atom. If the 1-alkynyl group is attached to another group, e.g. it is a W substituent attached to the cyclic phosphonate or phosphoramidate, it is attached at the first carbon. The term "alkylene" refers to a divalent straight chain, branched chain or cycHc saturated aliphatic group.

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The term "-cycloalkylene-GOOR3" refers to a divalent cychc alkyl group or heterocyclic group containing 4 to 6 atoms in the ring, with 0-1 heteroatoms selected from. O, N, and S. The cychc alkyl or heterocycHc group is substituted with -COOR^.
The teim "acyloxy" refers to the ester group -O-C(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or alicyclic.
The term "aminoalkylT" refers to the group NR2-alk- wherein "alk" is an alkylene group and R is selected from the group of H, alkyl, aryl, aralkyl, and ahcyclic.
The term "alkylaminoalkyl-" refers to the group alkyl-NR-alk- wherein each "alk" is an independently selected alkylene, and R is H or lower alkyl. Thus, "alkylaminoalkyl-" is synonymous with "alkylaminoalkylene-." "Lower alkylaminoalkyl-" refers to groups . where each alkylene group is lower alkylene. .
The term "aryraminoalkyl-" refers to the group aryl-NR-alk- wherein, "alk" is an alkylene group and R is H, alkyl, aryl, aralkyl, and alicyclic. Thus, "arylaminoalkyl-" is synonymous with "arylaminoalkylene-." hi "lower arylaminoalkyl-", the alkylene group is lower alkylene.
The term "alkylaminoaryl-" refers to the group alkyl-NR-aryl- wherein "aryl" is a divalent group and R is H, alkyl, aralkyl, and ahcyclic. In "lower alkylaminoaryl-", the alkyl group is lower alkyl.
The term "alkyloxyaryl-" refers to an aryl group substituted with an alkyloxy group. In "lower alkyloxyaryl-", the alkyl group is lower alkyl.
. The term "aryloxyalkyl-" refers to an alkyl group substituted with an aryloxy group. Thus, "aryloxyalkyl-" is synonymous with "aryloxyalkylene-."
The term "aralkyloxyalkyl-" refers to. the group aryl-alk-0-alk- wherein "alk" is an alkylene group. Thus, "aralkyloxyalkyl-" is synonymous with "aralkyloxyalkylene-." "Lower aralkyloxyalkyl-" refers to such groups where the alkylene groups are lower alkylene.
The term "-alkoxy-" or "-alkyloxy-" refers to the group -alk-0- wherein "alk" is an alkylene group. Thus, "-alkoxy-" and "-alkyloxy-" are synonymous with "-alkyleneoxy-." The term "alkoxy-" refers to the group aIkyl-0-.
The term "-alkoxyalkyl-" or "-alkyloxyalkyl-" refer to the group -alk-O-alk-wherein each "alk" is an independently selected alkylene group. Thus, "-alkoxyalkyl-" and "-alkyloxyalkyl-" are synonymous with "-aUcylenebxyalkylene-." In "lower -alkoxyaUcyl-", each alkylene is lower alkylene.


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The terms "alkylthio-" and "-alkylthio-" refer to the groups alkyl-S-, and -alk-S-, respectively, wherein "allc" is allcylene group. Thus, "-alkylthio-" is synonymous with "-aliylenethio-."
The term "-alkylthioalkyl-" refers to the group -alk-S-alk- wherein each "alk" is an ■ independently selected alkylene group-. Thus, "-alkylthioalkyl-" is synonymous with "- . alkylenethioalkylene-." In "lower -alkylthioalkyl-" each alkylene is lower alkylene. The term "alkoxycarbonyloxy-" refers to alkyl-O-C(O)-O-. The tenn "aryloxycarbonyloxy-" refers to aryl-O-C(O)-O-. The term "alkylthiocarbonyloxy-" refers to alkyl-S-C(O)-O-, The term "-alkoxycarbonylamino-" refers to ralk-0-C(0)-NR"-,where "alk" is alkylene andR" includes -H, alkyl, aryl, alicychc, and araJkyl. Thus, "-alkoxycarbonylamino-" is synonymous with "-alkyleneoxycarbonylaraino-."
The term "-alkylaminocarbonylamino-" refers to -an:-NE."-C(O)-NR"-, where "alk" is alkylene and R1 is independently selected from H, alkyl, aryl, aralkyi, and alicycHc. Thus, "-alkylaminocarbonylainino-"is synonymous with "-alkyleneanunocarbonylamino-." The terms "amido" or "carboxamido" refer to NR2-C(0)- and RC(0)-NR"-, where R and R" include H, alkyl, aryl, aralkyi, and alicyclic.- The term does not include urea, -NR-C(0)-NR-
The terms "carboxamidoalkylaryr" and "carboxamidoaryl" refer to an ar-alk-NR1-C(0)-, and ar-NR"-C(O)-, respectively, where "ar" is aryl, and "alk" is alkylene, R" and R include H, alkcyl, aryl, aralkyi, and alicyclic. Thus, "carboxamidoalkylaryl" is synonymoiis with "carboxamidoalkylenearyl."
The term "-alkylcarboxamido-" or "-alkylcarbonylaminor" refers to the group -alk- • C(0)N(R)- wherein "alk" is an alkylene group and R is H or lower alkyl. Thus, "-alkylcarboxamido-" and "-alkylcaxbonylamino-" are synonymous with "-alkylenecarboxamido-" and "-alkcylenecarbonylamino-," respectively.
The term "-alkylaminocarbonyl-" refers to the group -alk-NR-C(O)- wherein "alk" is an alkylene group and R is H or lower alkyl. Thus, "-alkylaminocarbonyl-" is synonymous with "-alkyleneaminocarbonyl-."
The term "aminocarboxamidoalkyl-" refers to the group NR2-C(O)-N(R)-alk-wherein R is an alkyl group or H and "alk" is an alkylene group. Thus, "aminocarboxamidoalkyl-" is synonymous with "aminocarboxamidoalkylene-." "Lower aminocarboxamidoalkyl-" refers to such groups wherein "alk" is lower alkylene.
The term "thiocarbonate" refers to -O-C(S)-O- either in a chain or in a cyclic group.


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The term "hydroxyalkyl" refers to an allcyl group substituted with one -OH.
The term "haloalkyl" refers to an allcyl group substituted v/ith one halo, selected from the group I, Cl;Br, F.
The term "cyano" refers to -CsN.
" The term, "nitro" refers to -NO2.
The term "acylalkyl" refers to an aIkyl-C(0)-alk-, where "alc" is alkylene. Thus, "acylalkyl" is synonymous with "acylalkylene."
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 -CF3 and-CFCl2.
The term "guanidiao" refers to both -NR-C(NR)-1SJR2 as well as -N=C(NR2)2 where each R. group is independently selected from the group of-H, alkyl, ■ aUcenyl, alkynyl, aryl, and alicyclic, all except -H are optionally substituted.
The term "amidino" refers to -C(NR)-NR2 where each R group is independently selected from the group of-H, alkyl, alkenyl, alkynyl, aryl, and alicyclic, all except -H are ■ optionally substituted.
The term "pharmaceutically acceptable salt" includes salts of compounds of formula I and its prodrugs derived from the combination of a compound of this invention and an organic or inorganic acid or base. Suitable acids include hydrochloric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and maleic acid.
The term "prodmg" as used herein refers to any compound that when administered to a biological system generates the "drug" substance (a biologically active compound) in or-more steps involving spontaneous chemical reaction(s), inzyme catalyzed chemical reaction(s), or both. Standard prodrugs are formed using groups attached to functionality, e.g. H0-, HS-, HOOC-, R2N-, associated with the FBPase inhibitor, that cleave in vivo. Prodrugs for these groups are well known in the art and are often used to enhance oral bioavailability or other properties beneficial to the formulation, deUvery, or activity of the drug. Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, araDcyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. Standard prodrugs of phosphonic acids are also included and may be represented by R" in formula I. The groups illusfrated are exemplary,


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not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs. Such prodrugs of the compounds of formula I fall within the scope of the present invention. Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active, In some cases, the prodrug is biologically active usually less than the drug itself, and serves to improve efScacy or safety through improved oral bioavailability, pharmacodynamic half-life, etc.
The term "prodrug ester" as employed herein refers to esters of phosphonic acids or phosphoramic acids and 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

Formula A
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 alicycHc 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: 31.93-3198 (1989)).


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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 alkyloxycarbbnyloxyraethyl esters, as shown in formula A, where R is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, and arylamino; R", andR" are independently H, alkyl, aryl, alkylaryl, and alicycUc, have been studied in the area of p-lactam-antibiotics (Tatsuo Nishimura et al. J. Antibiotics,. 1987, 40(1), 81-90; for a review see Fejxes, H., Dnigs of Today, 19S3,19, 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)propyi]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. Cbem. 38; 1372, 1995). Phenyl as well as mono and poly-substituted phenyl proesters 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 Toixence, J. Med. Chem.: 39:4109-4115 (1996).


Formula C
wherein: Y is H, alkyl, aiyl, alkylaryl, alkoxy, acyloxy, halogen, amino,
alkoxycarbonyl, hydroxy, cyano, 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 = H, OR or 0(CO)R or 0(CO)OR] can generate the 4-hydroxy compound more readily through the action of enzymes, e.g. oxidases, esterases, etc. Examples of this class of prodrugs are described in Mitchell et al, J, Chem. Soc. Perkm Trans. 12345 (1992); Brook, et al. WO 91/19721.

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Formula D
wherein X and Y are independently H, alkyl, aryl, alkylaiyl, alkoxy, acyloxy,
hydroxy, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl; and R and R are independently H, alkyl, aryl, alkylaryl, halogen, and ahcyclic.
[6] Thio-containing phosphonate proesters have been described that are useful in the delivery of FBPase inhibitors to hepatocytes. These proesters 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). Cyclicanalogs 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.

Formula-E
wherein Z is alkylcarbonyl, allcoxycarbonyl, arylcarbonyl, aryloxycarbonyl, or alkylthio.
Other examples of suitable prodrugs include proester classes exemplified by Biller and Magnin (U.S. Patent No. 5,157,027); Serafinowska et al (]. Med. Chem. 38, 1372 (1995)); Starrett et al. (J. Med. Chem. 37, 1857 (1994)); Martin et al. J. Pharm. Sci. 76, 180 (19S7)- Alexander et al. Collect. Czech. Chem. Commun. 59, 1853 (1994)); and




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The structure shown above (left) has an additional 3 carbon atoms that forms a five member cyclic group. -Such cychc groups must possess the listed substitution to be oxidized.
The phrase "together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V includes the following:



The phrase "together V and W are connected via an additional 3 carbon atoms to
form an optionally substituted cyclic group containing 6 carbon atoms and substituted with
one substituent selected from the group consisting of hydroxy, acyloxy,
alkoxycarbonyloxy, alkylthiocarbonyloxy,, and aryloxycarbonyloxy, attached to one of said
additional carbon atoms that is three atoms from a,Y attached to the phosphorus" includes
the following:
1

The structure above has an acyloxy substituent that is three carbon atoms from a Y, and an optional substituent, -CH3, on the new 6-membered ring. There has to be at least one hydrogen at each of the following positions: the carbon attached to Z; both carbons alpha to the carbon labeled "3"; and the carbon attached to "0C(0)CH3" above.



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The phrase "together W and W are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaiyl" includes the following:


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blood, tissues, or urine following oral administration compared to measurements following systemic administration.
The term "parent drug" refers to any compound which dehvers the same biologically active compound. The parent drug form is P(O(O)2-L-R5 and standard prodrugs, such as esters.
The term "drug metabolite" refers to any compound produced in vivo or in vitro from the parent drug, which can include the biologically active drug.
The term "biologically active drug or agent" refers to the chemical entity that produces a biological effect. Thus, active drugs or agents include compounds which as P(O(O)2-L-R5are biologically active.
The term "therapeutically effective amount" refers to an amount that has any . .
beneficial effect in treating a disease or condition.
Compounds of Formula I "
Suitable alkyl groups include groups haying 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 carbonatoms. Suitable acyloxy groups include groups having from 1 to about 20 carbon atoms. Suitable aUcylene groups include groups having from 1 to about 20 carbon atoms. Suitable alicyclic group include groups having 3 to about 20 carbon atoms. Suitable heteroaiyl groups include groups ■ having from 1 to about 20 carbon atoms and from 1 to 4 heteroatoms, independently selected from nitrogen, oxygen, phosphorous, and sulfur. Suitable"heteroaliycHc groups include groups having from 2 to about twenty carbon atoms and from 1 to 5 heteroatoms, independently selected from nifrogen, oxygen, phosphorous, and sulftir.
In the method claims, representative are the following compounds of formula (T):




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--^^


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or .
together V and Z are coimected via an additional 3-5 atoms to fonri a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V; or
together Z. and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or
W and W are independently selected from the group of-H, atkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and l-alkynyl and-R9; or-
together W and W are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or
b) V2, W2 and W" are independently selected from the group of-H, alkyl, aralkyl,
ahcyclic aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and l-alkynyl; .

together V2and Z2 are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally containing 1 heteroatom, and substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from a Y attached to phosphorus;
c) Z"is selected from the group of-OH,-OC(0)R3-OC02R3 and
-OC(OSR3;
D"is-H;


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D" is selected from the group of-H, alkyl -OR2OH, and -OC(OR3
each W"" is independently selected from the group consisting of-H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and l-alkynyl;
p is an integer 2 or 3;
with the provisos that: ,
a) V, Z, W, W are not all-H and V2^W2Ware not all-H; and
R2is selected from the group consisting of R^ and -H;
R3s selected from the group consisting of aUcyl, aiyl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of-H, alkyl, -alkylenearyl, and aryl, or together R4 and R4 are connected via 2-6 atoms, optionally including one heteroatom selected from the group consisting of O, N, and S;
R4is selected from the group consisting of-H, lower alkyl, acyloxyalkyi, aryl, aralkyl, alkoxycarbonyloxyalkyl, and lower acyl, or together with R12 is connected via 1-4 carbon atoms to form a cychc group;
R7is lower R3
each R9 is independently selected from the group consisting of-H, alkyl, aralkyl, and alicychc, or together R9 and R9 form a cyclic alkyl group;
R11is selected from the group consisting of alkyl, aryl, -NR22, and -OR2; and
each R12 and R13is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12 and R13 together are connected via a chain of 2-6 atom optionally including 1 heteroatom selected from the group consisting of O, N, and S, to form a cyclic group;
each R14 is independently selected from the group consisting of-OR17, -N(R17)2, -NHR17-SR17 and-NR2OR20;
R16 is selected from the group consisting of-H, lower aralkyl, lower aryl, lower aralkyl, or together with R16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
R16 is selected from, the group consisting of-(CR12R13)-C(O-R14 -H, lower alkyl, lower aryl, lower aralkyl, or together with R15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;












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a) V is selected firom the group of aryl, substituted aryl, heteroaryl, substituted heteroaryl, l-alkynyl and 1-alkenyl;

together V and Z are connected via an additional 3-5 atoms to form a cycUc group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V; or
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or
W and W are independently selected from the group of-H, alkyl, aralkyl, aUcyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl and-R^; or
together W and W are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 het6roatoms,.and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together V^ and Z^ are connected via an additional 3-5 atomsto form a cyclic group containing 5-7 ring atoms, optionally containing 1 heteroatom, and substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from a Y attached to phosphorus;


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c) Z" is sdlected from group of -OH, -OC(OR3-OCO2 and -OC(OSR3
D"is-H;
D" is selected from the group of -H, alkyl, -OR2-OH, and -OC(OR3
each W3is independently selected from the group consisting of-H, alkyl, aralkyi, alicyclicaryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W"are not all-H and V2W2Ware not all H and
R2is selected from the group consisting of R3and -H;
R3is selected from the group consisting of alky aryl, alicyclic, and aralkyl,
.each R4is independently selected from the group consisting,of-H, alkyl, -alkylenearyl, and aryl, or together R4and R4are connected via 2-6 atoms, optionally including one heteroatom selected from the group consisting of 0, N, and S;
R6is selected from the group consisting of-H, lower alkyl, acyloxyalkyl, aryl, aralkyi, alkycarbonyloxyalkyl, and lower acyl, or together with R is connected via 1-4 carbon atoms to form a cyclic group;
R7is lower R3
each R9is independently selected from the group consisting of-H, alkyl, aralkyi, and alicychc, or together R9and R9forma cyclic alky group;
R1is selected from the group consisting of alky], aryl, -NR22 and -OR2 and
each R"^ and R^^ is independently selected from the group consisting of H, lower alkyl ower aryl, lower aralkyi, all optionally substituted, or R^^ and R"^ together are connected via a chain of 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S, to form a cycUc group;
each R"* is independently selected from the group consisting of-OR^^, -N(R^")2, -NHR17SR17and-NR2R20
R15s selected from the group consisting of —H, lower aralkyi, lower aryl, lower aralkyi, or together with R16 connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;


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R16 is selected from the group consisting of-(CR12R13)n-C(O)-R"14,H lower alkyl, lower aryl, lower aralkyl, or together with R15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
each R17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower axalkyl, or together R17 and R17 on N is- connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
R18 is selected from the group consisting of-H and lower R ;
R19 is selected from the group consisting of —H, and lower acyl;
R20 is selected from the group consisting of-H, lower R3, and -C(O)-(lower R3);
n is an integer from 1 to 3;
with the provisos that:
1) when X3, X4, or X5 is N, then the respective J3, J4, or J5 is. null;
2) when L is not substituted furanyl, then at least one of J2 J3 J4 and J5 is not-H or null;
3) when L is not substituted ftiranyl, then at least two of J2, J3, J4, and J5 on formula 1(a) or J2, J3, J4, J5, and J6 on formula 1(b) are not -H or null;
4) when G2, G3, or G4 is O or S, then the respective J2, or J3 or J4 is null;
5) when G3 or G4 is N, then the respective J3 or j4 is not halogen or a group directly bonded to G or G via a heteroatom;
6) if both Y groups axe -NR6-, and R1 and R1 are not connected to form a cyclic phosphoramidate, then at least one R" is -(CR12-R13)nR14
7) when L is -alkylcarbonylamino- or -alkaminocarbonyl-, then X3 X4 and X5 are not all C;
8) when L is -alkoxyalkyl-, and X3X4 and X5are all C, then neither J3nor J5 can be substituted with an acylated amine;
9) when R5 s substituted phenyl, then J3 J4 and J5 not puriny purinylalkylene, deaza-purinyl, or deazfapuiinylalkylene;
10) R1can be lower alkyl only when the other YR1is -NR6C(R12RC(O-

WO 01/66553 PCT/US01/d7452
11) when R5 is substituted phenyl and L is 1,2-ethynyl, then J3 or J5 is not a
heterocyclic group;
12) when L is 1,2-ethynyl, then X3 or X5 cannot be N "
and pharmaceutically acceptable prodrugs and salts thereof.
In one aspect of the present invention compounds of formula are envisioned.
In one aspect of the present invention compounds of formula lb are envisioned. In one aspect of the present invention compounds of formula I are envisioned with the further proviso that when L is -alkoxyalkyl-, and R5 is substituted thienyl, substituted fiiranyl, or substituted phenyl, then J3, ]"4, or J5 is not halo or alkenyl.
In another aspect are compounds of formula I with the further proviso that when L is -alkoxyalkyl-, then R5 is not substituted thienyl, substituted furanyl, or substituted phenyl.
In yet another aspect are compounds of formula I with the further proviso that when L is -allcoxycarbonyl-, and X3, X4., and X5 are all C, then neither J2 nor J6 is a group attached through a nitrogen atom.
In another aspect are compounds of formula I with the further proviso that when L is -alkoxyalkyl- or-alcoxycarbonyl-, then R5 is not substituted phenyl.
In one aspect of the invention are compounds of formula I wherein said prodrug is a compound offonnula VI;

VI
wherein
V is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In another aspect are such compounds wherein V is selected from the group consisting of phenyl and substituted phenyl. In yet another aspect are such compounds wherein V is selected from the group consisting of 3.,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, 2-bromophenyl, S-bromophenyl, and 4-pyridyl.


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in one aspect of the invention are compounds of formula wherein said prodrug is a compound of formula VII



wherein
A ,■„
Z5is selected from the group consisting of -CHR2H, -CHR2C(0)R3 -CHR2C(S)R3 -CHR2OC02R3 -CHR2OC(0)SR3 -CHR20C(S)0R3 and-CH2aryl. In another aspect, are such compounds wherein Z2 is selected from the group consisting of -CHR2OH, -CHR2GC(O)R2 and -CHR2.OCO2R3 In yet another aspect are such compounds wherem R2 is -H.
In another aspect of the invention are compounds of formula I wherein said prodrug is a compound of formula VIII

VII
■ ■. *
wherein " ,
Z" is selected from the group consisting of -OH, -0C(O)R3 -OCO2 R3 and -OC(O)SR3
D"is-H;and
D" is selected from the group consisting of-H, alkyl,OH, and -OC(O)R3 .
In another aspect of the invention are compounds wherein W and Z are -H, W and V are both the same aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and both Y groups are the same -NR6, such that the phosphonate or phosphoramidate prodrug moiety:


WO /66553 PCT/USOl/07452


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or
together V and Z are connected via an additional 3-5 a:toms to form a cyclic group, optiona.lly containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V; or
together Z and W are. connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaiyl, or substituted heteroaryl; or .
W and W are independently selected firom the group of-H, alkyl, aralkyl, alicyclic,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-aIkdnyl and l~alkynyl and -R^;
or
together W and W are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
b) V2, W2 and W" are independently selected from the group of-H, alkyl, aralkyl,
alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;

Z2 is selected from the group of-CHR2OH, -CHR2OC(OR3-CHR2OC(S)R3-CHR2C02R3-CHR2C(0)SR3 -CHR2C(S)OR3-CH(aryl)OH, -CH(CH=CR22OH, -CH(C=CR2OH,-SR2CH2Haiyl,-CH2ryl; or
together V2and arecnnected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally containing 1 heteroatom, and substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy"attached to a carbon atom that is three atoms from a Y attached to phosphorus;
c) Z" is selected from the group of -OH -0C(OR3-OCO2R3 AND
-OC(OSR3
D"is-H;
D" is selected from the group of-H, alkyl, -OR2 -OH, and -OC(OR3



"

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a) V is selected from the group of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-aIkynyl and 1-alkenyl;
Z is selected from the group of-CHR2OH, -CHR2OC(0)R3 -CHB2OC(S)R3 -CHR2OC(S)OR3 -CHR20C(O)SR3 -CHR2OCO2R3 -OR2 -SR2 -CHR2N3, -CH2aryl, -CH(aryl)OH, -CH(CH=CR22)0H, -CH(C=CR2")0H, -R2 , -NR22, -OCOR3 -OCO2R3, -SCOR3 -SCO2R3 -NHCOR2 -NHCO2R3 -CH2NHaryl, -(CH2)p-OR19 and -(CH2)p-SR19; or
. together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 hetferoatom, said cyclic group is flised to an aryl group at the beta and gamma position to the Y adacent to V; or
together Z and W are connected via an additional 3-5 atoms to form a cyclic group,
optionally containing one heteroatoin, and V must be aryl, substituted aryl, heteroaryl, or
substituted heteroaryl; or.
W and W are independently selected from the group of-H, allcyl, aralkyl,- alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyI and l-alkynyl and -R9; or
together W and W are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
b) V2 , W2 and W" are independently selected from the group of -H, alkyl, aralkyl, ahcyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-aIkenyl, and 1-alkynyl;
Z2 is selected from the group of-CHR2OH, -CHR2OC(O)R3 -CHR2OC(S)R3 -CHR2OCO2R3 -CHR2OC(O)SR3 -CHR2OC(S)OR3 -CH(aryl)OH, -CH(CH=CR22)0H, -CH(C=CR2)OH, -SR2 -CH2NHaryl, -CH2; or
together V2and Z2 are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally containing 1 heteroatom, and substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarboiiyloxy attached to a carbon atom that is three atoms from a Y attached to phosphorus;







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L is selected from the group consisting of
i) 2,5-furanyl, 2,5-thienyl, 1,3-phenyl, 2,6-pyridyl,"2,5-oxazolyl, 5,2-
oxazolyl, 2,4-oxazolyl, 4;2-oxa2olyl, 2i4-imidazolyl, 2,6-pyiimidinyl, 2,6-pyrazinyl; ii) 1,2-ethynyi; and
iii) ai linking group having 3 atoms measured by the fewest number of atoms connecting the carbon of the aromatic ring and the phosphorus atom and is selected from the group consisting of alkylcarbonylamino-, -alkylaminocarbonyl-, -alkoxycarbonyl-, and -alkoxyalkyl-; when both Y groups are -0-, then R" is independently:selected from the group consisting of optionally substituted aryl, optionally substituted benzyl, -C(R2)20C(0)R3, -C(R2)2OC(O)OR3 and-H; or
when one Y is -0-, then R" attached to -O- is optionally substituted aryl; and the other Y is -NR6-, then R" attached to -NR6- is selected from the group consisting of -C(R4)2C(O)OR3 and-C(R2)2C(O)OR3 or
when Y is -O- or -NR6-, then together R1 and R1 are

wherein
a) V is selected from the group of aryl, substituted aryl, heteroaryl, substituted
heteroaryl, l-alkcynyl and l-alkenyl;
Z is selected from the group of-CHR2OH, -CHR2OC(O)R2 -CHR2OC(S)R3


WO 01/66553 PCT/USOl/07452.

or
together V and Z are connected via an additional 3-5 atoms to form a,cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V; or
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or
W and W are independently selected from the group .of-H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, l-alkenyl and 1-allkynyl and-R9; or
together W and W aire connected via an additional-2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
b) V2, W2 and W" are independently selected from the group of-H, akcyl, aralkyl,
alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, l-aUcenyl, and 1-aLkynyl;
Z2 is selected from the group of-CHR2OH, -CHR2OC(O)R3 -CHR2OC(S)R3 -CHR2OCO2R3 -CHR2OC(0)SR3--CHR2OC(S)OR3 -CH(aryl)OH, -CH(CH=CR22)0H, -CH(C=CR2)OH, -SR2-CH2NHaryl,-CH2aryl; or
together V2 and Z2 are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally containing 1 heteroatom, and substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from a Y attached to phosphorus;
c) Z" is selected from the group of-OH, -OC(O)R3 -OCO2R3.and
-OC(O)SR3;
D"is-H;








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d) V groups that contain groups that add to the α β-unsaturated ketone to
form a ring;
e) Z groups that from a stable ring via Michael addition to double bond; and
f): groups that enhance detoxification of the by-product by one or more of
the following characteristics: .
(i) confine to liver; and
(ii) make susceptible to detoxification reactions {e.g. ketone reduction); and
(6) capable of generating a pharmacologically active product, hi one aspect of the invention, V groups of formula VI are aryl, substituted aryl, heteroaiyl, and substituted heteroaiyl. Within such a group aryl and substituted aryl groups include phenyl, and phenyl substituted with 1-3 halogens. Within such a group are 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, 2-bromophenyl, and 3-bromophenyl. In another aspect of the invention, Y is-0-. Inyet another aspect of the invention V is selected from the group consisting o/monocycUc heteroaryl and monocychc substihited heteroaryl containing at least one nitrogen atom. Within such a group such a heteroaryl and substituted heteroaryl is 4-pyridyl and 3-bromopytidyl, respectively.
In yet another aspect of the invention, when together V and Z are connected via an additional 3-5 atoms to form a cychc group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma positions to the Y attached to phosphorus. In such compounds it is envisioned that said aryl group may be an optionally substituted monocychc aryl group and the connection between Z and the gamma position of the aiyl group is selected from the group consisting of O, CH2, CH2CH2, OCH2 or CH2O.
In another aspect, together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and monosubstituted with one substityent selected from the gi"oup consisting of hydroxy, acyloxy, alkoxycarbonyloxy, ahcylthiocarbonyloxy, and aryloxycarbonyloxy attached to one of said additional carbon atoms that is three atoms from a Y attached to the











WO 01/66553 PCT/USOl/07452
or P(O)(O )(NHR6)-L-R5 Within such a group, the Z" group is OH. Group D" may be hydrogen, alkyl, and-0R2,0C(0)R3
With regard to the foregoing aspect of the invention, the inventors contemplate any combination of the Markush groups as set forth above and the sub-Markush groups for any variable as described in the following Tables A - Q.






















































PCT/USOl/07452.







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In the following examples of compounds, the following prodrugs are envisioned;
Acyloxyalkyl esters;
Alkoxycarbonyloxyalkyl esters;
Axyl esters;
Benzyl and substituted benzyl esters;
Disulfide containing esters;
Substituted (l,3-dioxolen-2-one)methyl esters;
Substituted 3-phthalidyl esters;
Cyclic-[5-hydroxycyclohexan-1,3 -diyl) diesters and hydroxy protected forms; Cyclic"[2-hydroxymethylpropan-l,3-diyl] diesters and hydroxy protected forms;
CycUc-( 1-arylpropan-1,3-diyl);
Monoaryl ester N-substituted mono phosphoramidates;
Bis Omega substituted lactone esters; and all mixed esters resulted from possible combinations of above esters;
Also envisioned are the following: Bis-pivaloyloxymethyl esters; Bis-isobutyryloxymethyl esters; Cychc-[l-(3-chlorophenyl)propan-l,3-diyi]diesters; Cyclic-[l-(3,5"dichlorophenyl)propan-l,3-diyl]diester; Cyclic-[l-(3-bromo-4-fluorophenyl)propan-l,3-diyl]diester; Cyclic-[2-hydroxymethylpropan-l,3-diyl] diester; CycIic-[2-acetoxymethylpropan-1,3-diyl] diester; CycHc-[2-methyloxycarbonyloxymethylpropan-l,3-diyl] diester; Cyclic-[l-pheny}propan-l,3-diyl] diesters; CycHc-[l-(2-pyridyl)propan-l,3-diyl)] diesters; Cyclic-[l-(3~pyridyl)propan-l,3-diyl] diesters; Cyclic-[l-(4-pyridyl)propan-l,3-diyl] diesters;
Cyclic-[5-hydroxycyclohexan-l,3-diyl] diesters and hydroxy protected forms; Bis-benzoylthiomethyl esters; Bis-benzoylthdoethyl esters;


WO 01/66553 PCT/USOl/07452
Bis-benzoyloxymethyl esters;
Bis-p-fluorobenzoyloxymethyl esters;
Bis-6-chloronicotinoyloxymethyl esters;
Bis-5-bromonicotinoyloxymethyl esters;
Bis-thiophenecarbonyloxymethyl esters;
Bis-2-fiiroyloxyinethyl 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-(l-triazolophenyl) esters; Bis-(3-N,;N""-dimethylaminophenyl) esters; Bis-(1,2,3,4-tetrahydronapthalen-2-yl) esters; Bis-(3-chloro-4-methoxy)benzyl esters; Bis-(3-bromo-4-rriethoxy)ben2yl esters; . Bis-(3-cyano-4-methoxy)benzyl esters; Bis-(3-cliloro-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-drinethoxy-4-acetoxy)benzyl esters;

WO 01/66553 PCT/USOl/07452.
Bis-(3-methyl-4-acetoxy)b6nzyl esters; Bis-(benzyl)esters;
Bis-(3-niethoxy-4-acetoxy)benzyl esters; Bis-(6"-hydroxy-3",4"-dithia)hexyl esters; Bis-(6"-acetoxy-3",4"-ditliia)hexyl esters; (3,4-dithiahexan-l,6-diyl) esters; Bis-(5-methyl-l,3-dioxolen-2-one-4-yl)methyl esters; Bis-(5-ethyl-l,3-dioxolen-2-one-4-yl)nietliyl esters; Bis-(5-tert-butyl-l,3-dioxolen-2-one-4-yl)inethyl esters; Bis-3-(5,6,7-trimethoxy)ph.thalidyl esters; Bis-(cycloliexyloxycarbonyloxymethyl) esters; Bis-(isopropyloxycarbonyloxymethyl) esters; Bis-(ethyloxycarbonyloxymethyl) esters; Bis-(methyloxycarbonyloXymethyl) esters; Bis-(isopropylthi.ocarbonyloxymethyl) esters; Bis-(phenylpxycarbonyloxyniethyl) esters; Bis-(benzyloxycarbonyloxymethyl) esters; Bis-(phenylthiocarbonyloxymethyl) esters; Bis-(f-methoxyphenoxycarbonyloxymethyl) esters; Bis-(m-methoxyphenoxycarbonyloxymethyl) esters; Bis-(o-niethoxyphenoxycarbonyloxymethyl) esters; Bis-(o-niethylphenoxycarboiiyloxymethyl) esters; Bis-(p-chlorophenoxycaTbonyloxyinethyl) esters; Bis-(l,4-biph.enoxycarbonyloxymethyl) esters; Bis-[(2-phthaliniidoethyl)oxycarbonyloxymethyl]esters; Bis-(iV-phenyl-A^-metbylcarbamoyl6xymethyl) esters; Bis-(2,2,2-tricMoroethyI) esters; Bis-(2-bromoethyl) esters; Bis-(2-iodoetliyl) esters; Bis-(2-a2idoethyl) esters;


wo 01/66553 PCT/0SO1/O7452








wo 01/66553 PCT/USOl/07452.




WO 01/66553 PCT/USOl/07452,
0-(4-chlorophenyl)-[N-(ethoxycarbonyl)methyl]pliosphoramidates(-P(O)(OPh-4-Cl)(NH-
CH2C02Et) 0-(4-acetaniidophenyl)-[N-(ethoxycarbonyl)methyl]phosphoraniidates (-P(0)(0Ph-4-"
NHAc)(NH-CH2C02Et) 0-(2-ethoxycarbonylphenyl)-[N-(ethoxycarbonyl)meth.yl]phospliorainidates(-P(0)(OPh-2-
C02Et)(NH-CH2C02Et) • .
Examples of compounds of formula I include, but are not limited to pharmaceutically acceptable salts and prodrugs of the compounds named in Tables 1 and 2 as follows;





/^







wo 01/66553

, PCT/USOl/07452



wo 01/66553

PCT/USOl/07452.







wo 01/66553

PCT/USOl/07452,









WO 01/66553 PCT/USOl/07452.
incorporated from intermediate 2 is an aryl and the L fragment is -CH2KHC(O)-.
Similarly, substitution of diethyl alkylaminoalkylphosphonates in this method may
produce compounds with an L fragment represented by -R"C(R")N(R)C(O)-;
Altematively, for example, coupling of an aryl amine preferably-with
diethylphosphonoacetic acid can result in a compound of formula I whereia the ring
fragment incorporated from intermediate 2 is an aryl and the L fragment is -CH2C(O)NH-.
Compounds with an L fragment of-R"C(R")C(0)NR- may be prepared by extension of
this method. " ■
Known ester bond formation reactions can be used to produce compounds of • formula I wherein L is alkylcarboxy or alkoxycarbonyl (e.g. -CH2C(O)O- or "CH20C(O)-). For example, when compound 2 fragment is a hydroxy substituted aryl (e.g. a phenol derivative) it can be acylated with diethylphosphonoacetyl chloride in the presence of a bindered amine such as triethylaroine to produce compounds wherein L is -CH2C(0)0-. Additionally, aryl-acyl halides (e.g..aryl-acyl chlorides) can be coupled to dialkyl (hydroxyalkyl)phosphonates (e.g. diethyl (hydroxy)methylphosphonate) to produce compounds wherein L is -alkoxycarbonyl- (e.g. -CH20.C(0)-).
Known ether bond formation reactions can be used to produce compounds of ■formula I where L is an alkylene-0 or an alkylene-O-aUcylene group. For example^ the sodium salt of a phenol maybe alkylated with diethyl (iodomethyl)phosphonate or preferably diethylphosphonomethyl triflate to produce compounds of formula I wbere L is -alkylene-0. Likewise, aUcylation of the sodium salt of a aryhnethyl alcohol with diethyl (iodomethyl)phosphonate or preferably diethylphosphonomethyl triflate may produce compounds of formula I where L is -aUcylene-O-allcylene-. Altematively, freatment of diethyl hydroxymethylphosphonate with sodium hydride and reaction of this generated sodium salt with a haloalkylaryl compound can produce compounds of formula I where L is-alkylene-0-alkylene-.
For compounds of formula I wherein L is an alkyl group, the phosphonate group can be infroduced using other common phosphonate formation methods such as Michaelis-Arbuzov reaction (Bhattacharya et al., Chem. Rev., 1981, 81: 4.15), Michaelis-Becker reaction (Blackbum et al., J. Organomet. Chem., 1988, 348: 55), and addition reactions of


WO 01/66353 PCT/USOl/07452
phosphorus to electrophiles (such as aldehydes, ketones, acyl halides, imines. and other carbonyl derivatives).
When feasible and sometimes advantageous, compounds of formula 3 can also be
prepared from an aryl componnd (2b) via the introdnction of a phosphonate moiety such as
a dialcylphosphono group (e.g. a diethylphosphono group). For example, compounds of
formula I wherein L is a 1,2-ethynyl can be prepared via the litktation of a terminal
arylaUcyne followed by reacting the anion with a phosphorylating agent (e.g. CIPO3R2) to
give an arylalkytiylphosphonate. The required arylalkynes are readily made using
conventional chemistry. For example, arylalkynes can be derived from reactions of aryl
halides (e.g. iodides, bromides) or triflates and trimethylsilylacetylene using Sonogashira
reactions (Sonogashira in"Comprehensive Organic Synthesis, Pergamon Press: New York,
1991, vol. 3, pp 521-549) followed by deprotection of the triinethylsilyl group to give "
terminal arylalkynes.
fb) Modification of the coupled molecule.
The coupled, molecule 3" can be modified in a variety of ways. Aryl halides (J2 -J6 each optionally e.g. Br, I or 0-triflate) are useful intermediates and .are often readily converted to other substituents such as aryls, olefins, alkyls, alkynyls, arylamines and aryloxy groups via transition metal assisted coupling reactions such as Stille, Suzuki, Heck, Sonogashira andi otherreactions (Farina, et al, Organic Reactions, Vol. 50; Wiley, New York, 1997; Mitchell,.Synthesis, 1992, 808; Suzuki in. Metal Catalyzed Cross-Coupling Reactions; Wiley VCH, 1998, pp 49-97; Heck Palladium Reagents in Organic Synthesis; Academic Press: San Diego, 1985; Sonogashira in Comprehensive Organic Synthesis, Pergamon Press: New York, 1991, vol. 3, pp 521-549, Buchwald J. Am. Chem. Sac. 1999,121, 4369-4378; Hartwig, J. Am. Chem. Soc. 1999,121, 3224-3225; Buchwald^cc. Chem.-Res. 1998,31, 805).
Compounds of formula I wherein J -J are each optionally is a carboxamido group can be made from then corresponding alkyl carboxylate esters via aminolysis using various amines, or by reaction of carboxylic acids with amines under standard amide bond formation reaction conditions (e.g.: DIC/HOBt mediated amide bond formation).

WO 01/66553 PCT/USOl/07452.
Compounds of fpnnula I wherein J2 -J6 are each optionally a carboxylate ester group can be made from the corresponding carboxylic acids by standard esterification reactions (.e.g. DIEA/DMF/alkyl iodide or EDCI, DMAP and an alcohol), or from the corresponding aiyl hahdes/trifl"ates via transition metal-catalyzed carbonylation reactions.
Compounds of formula I wherein J2-J6 are each optionally is an alkylaminoalkyi or arylainiaoalkyl group can be prepared from their corresponding aldehydes by standard reductive amination reactions (e.g. aryl or alkyl amine, TMOF, AcOH, DMSO, NaBH4).
(c) Deprotection of a phosphonate or phosphoramidate ester
. Compounds of formula 4 may be prepared from phosphonate esters using known phosphate and phosphonate ester cleavage conditions. Silyl hahdes are generally used to cleave various phosphonate esters. When required, acid scavengers (e.g. 1,1,1,3,3,3- . hexamethyldisilazane, 2,6-lutidine etc.) can be used for the synthesis of acid labile compounds. Such silyl hahdes include preferably bromotrimethylsilaue (McKenna, et al, -Tetrahedron Lett., 1977,155), chlorotrimethylsilane (Rabinowitz, J. Org. Chem., 1963, 28: 2975) and iodotrimethylsilane (Blackburn, .efal, /. Chem. Soc, Chem. Commun., . 1978, 870). Alternately, phosphonate esters can be cleaved under strong acidic conditions (e.g. HBr, HCl: Moffatt, et al, U.S. Patent 3,524.846,1970). Aryl and benzyl phosphonate esters can be cleaved under hydrogenolysis conditions (Lejczak, et si, Synthesis, 1982, 412; Elliott, et al, J. Med. Chem., 1985,28:1208; Baddiley, et al. Nature, 1953, 777, 76).
fd) Preparation of a phosphonate orphosphoramidate prodrug
The prodrug substitution can be introduced at different stages of the synthesis. Most often the prodrug is made from the phosphonio acid of fonnula.4 because of the instability of some of the. prodrugs. Advantageously, the prodmg can be introduced at an earlier stage, provided that it can withstand the reaction conditions of the subsequent steps. Bis-phosphoramidates, compounds of formula I wherein both Y"s are nitrogen.and R1 "s are identical groups derived from amino acids, can be prepared from compounds of formula 4 via the coupling of a suitably activated phosphonate (e.g. dichlorophosphonate) with an amino acid ester (e.g. alanine ethyl ester) with or without the presence of abase





wo 01/66553 PCT/USOl/07452
(e.g. N-methyltmidazole, 4-N,N-dimethylarniaopyridine). Alternatively, bis-phosphoramidates can be prepared-through reactions between compounds of formula 4
• with an amino acid ester (e.g. glycine ethyl ester) in the presence of triphenylphosphine and 2,2"-dipyridyl disulfide in pyridine as described in WO 95/07920 orMukaiyama, T. et al, J Am. Chem. Soc, 1972, 94, 8528. "
Mixed bis-phosphorairddates, compounds of formula I wherein both-Y"s are nitrogen and R^"s are different groups with one R" being derived from amino acids and the other R^ being either derived from amino acids or other groups (e.g. alkyl, aryl, arylaUcyl amines), can be prepared by the methods described above but with sequential addition of the different" amines (e.g. a glycine ethyl ester and an alanine ethyl ester) to a suitably activated phosphonates (e.g. dichlorophosphonate). It is anticipated that the mixed bis- ■ phosphoramidates may have to be"separated from other products (e.g. compounds of formula I wherein both Y"s are nifrogen and R^ "s are identical groups) using suitable purification techniques such as column chromatography, MPLC or cfystalUzation methods. Alternatively, mixed bis-phosphoramidates can be prepared in the following manner: coupling of an appropriate phosphonate monoester (e.g. phenyl esters or benzyl esters) with an amine (e.g. alanine ethyl ester or morpholine) via the chloridate method described
, above, followed by removal of the phosphonate ester (e.g. phenyl esters or benzyl esters) under conditions that the phosphoramidate bond is stable (e.g. suitable hydrogenation conditions), and the resulting mono-phosphoramidate can be coupled with a second amine (e.g. glycine ethyl ester) to give a mixed bis-phosphoramidate via the chloridate method described above. Mono esters of a phosphonic acid can be prepared using conventional methods (e.g.. hydrolysis of phosphonate diesters or procedures described in EP 481 214). Mono phosphoramidate mono esters, compounds of formula I wherein one Y is 0 and the other Y is N, can also be prepared using the sequential addition methods described above. For example, a dichloridate generated from compounds of formula 4 can be treated with 0.7 to 1 equivalent of an alcohol (e.g! phenol, benzyl alcohol, 2,2,2-trifluoroethanol) preferably in the presence of a suitable base (e.g. Hunig"s base, triethylamine). After the above reaction is completed, 2 to 10 equivalents of an amine (e.g. alanine ethyl ester) is added to the reaction to give compounds of formula I wherein one Y is O and the other Y

WO 01/66553 PCT/USOl/07452,
is N. Alternatively, selective hydrolysis (e.g. using lithium hydroxide) of a phosphonate diester (e.g. a diphenyl phosphonate) can also lead to a phosphonate mono ester (e.g. a phosphonate mono phenyl ester), and the phosphonate mono ester can be coupled with an amine (e.g. alanine ethyl ester) via the chloridate method described above for the preparation of mixed bis-phosphoramidates.
Compounds of formula 4, can be alkylated with electropbiles (such as alkyl halides, alkyl sulfonates, etc.) uiidernucleophilic substitution reaction conditions to give phosphonate esters. For example compounds of formula I, wherein R" are aeyloxyalkyl groups can be synthesized through direct alkylation of compounds of foimula 4 with an appropriate acyloxyalkyl halide (e.g. Cl, Br, I; Elhaddadi, et al Phosphorus Sulfur, 1990, 54(1-4): 143; Hoffinann, Synthesis, 1988, 62) in presence of a suitable base (e.g. N, N"-dicyclohexyl-4-morpholinecarboxamiduie, Hunig"s base etc.) (Starrett, et al, J. Med. Chem., 1994, 1857). The carboxylate component of these acyloxyalkyl halides can be, but is not limited to, acetate, propionate, 2-methylpropionate, pivalate, benzoate, and other carboxylates. When appropriate, further modifications are envisioned after the formation of acyloxyaUcyl phosphonate esters such as reduction of a nitro group. For example, compounds of formula 5 wherein J2 to J6 are each optionally a nitro group can be converted to compounds of formula 5 wherein J2 to J6 are each optionally an amino group under suitable reduction conditions (Dickson, et al, J. Med. Chem., 1996, 39: 661; Iyer, et al, Tetrahedron Lett., 1989, 30:7141; Srivastva, et al, Bioorg. Chem., 1984,12: 118). Compounds of formula I wherein R1 is a cyclic carbonate, a lactone or a phthalidyl group can also be synthesized via direct alkylation of compounds of formula 4 with appropriate electrophiles (e.g. halides) in the presence of a suitable base (e.g. NaH or diisopropylethylamine, Biller et al., US 5,157,027; Serafinowska et al, J. Med. Chem. 1995, 38: 1372; Staixett et al., J. Med. Chem. 1994, 37: 1857; Martin et al., J. Pharm. Set 1987, 76: 180; Alexander et al., Collect. Czech. Chem. Commun, 1994, 59: 1853; EPO 0632048A1). Other methods can also be used to alkylate compounds of formula 4 (e.g. using iV,iV-Dimethylformamide dialkyl acetals as alkylating reagents: Alexander, P., et al Collect. Czech. Chem. Commun., 1994, 59, 1853).


WO 01/66553 PCT/USOl/07452
Alternatively, these phosphonate prodrugs can-also be synthesized by reactions of the corresponding dichlorophosphonates with an alcohol (Alexander et al. Collect. Czech. Chein. Commun., 1994, 59: 1853). For example, reactions of a"dichlorophosphonate with substituted phen.ols,afylalkyl alcohols IB the presence of a suitable base (e.g. pyridine, triethylamine, etc) yield compounds"of formula I where R" is an aryl group (Khamnei et al, J. Med. Chem., 1996, 39: 4109; Serafinowska et al., J. Med.Chem., 1995, 38: 1372; ■. De Lombaert et al, J. Med. Chem., 1994,"37: 498) or an arylalkyl group (Mitchell et al., J.
Chem. Soc. Perkin Trans. 1,1992, 38: 2345) and Y is oxygen. The disulfide-containing prodrugs (Puech et al,. Antiviral Res., 1993, 22: 155) can also be prepared from a dichlorophosphonate and 2-hydroxyethyl disulfide under standard conditions. When applicable, these methods can be extended to the synthesis of other types of prodrugs, such as compounds of formula I wherein R1 is a 3-phthalidyl, a 2-oxo-4,5-didehydro-l,3-dioxolanemethyl, or a 2-oxotetrahydrofuran-5-yl group.
A dichlorophosphonate or a monochlorophosphonate derivative of compounds of ■ formula 4 can be generated from the corresponding phosphonic acids using a chlorinating agent (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, a dichlorophosphonate can also be generated from
.its corresponding disilyl phosphonate esters (Bhongle et al., Synth. Commun., 1987,17: 1071) or dialkyl phosphonate esters (Still et al.. Tetrahedron Lett, 1983, 24: 4405; Patois. et al. Bull Soc. Chim. Fr.,-1993,130: 485).
•Furthermore, when feasible some of these prodrugs can be prepared using
Mitsunobu reactions(Mitsunobu , Synthesis, 1981, 1; Campbell, J. Org. Chem., 1992, 52:
1
6331), and other coupKng reactions (e.g. using 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: 61 A3). In some cases R1" can also be introduced advantageously at an early stage of the synthesis provided that it is compatible with the subsequent reaction steps. For example, compounds of formula I where R" is an aryl group can be prepared by metalation of a 2-fiiranyl

WO 01/66553 PCT/USOl/07452
substituted heterocycle (e.g. using LDA) followed by trapping the anion with a diaryl chlorophosphate.
It is envisioned that compounds of formula I can be-mixed phosphonate esters (e.g. phenyl and benzyl esters, or phenyl and acyloxyalkyl esters) including the chemically combined mixed esters such as the phenyl and benzyl combined prodrugs reported by Meier, et al. Bioorg. Med. Chem. Lett, 1997, 7: 99.
The substituted cyclic propyl phosphonate or phosphoramidate esters can be synthesized by reactions of the corresponding dichlordphosphonate with a substituted 1,3-propanediol, 1,3-hydroxypropylamine, or 1,3-propanediamine. Some of the methods useful for preparations of a substituted 1,3-propanediol, for example, are discussed below.
Synthesis of a l,3-T3ropanedioh 1,3-hYdroxypropylamine and 1,3-propanediamine Various synthetic methods can be used to prepare numerous types of 1,3-propanediols: (i) 1-substituted, (ii) 2-substituted, (iii) 1,2- or 1,3-annulated 1,3-propanediols, (iv) 1,3-hydroxypropylaniine and 1,3-propanediamine. Substituents on the prodrug moiety of compounds of formula I (e.g. substituents on the 1,3-propanediol moiety) can be introduced or modified either during the synthesis of these diols,hydroxyamines, and diamines, or after the coupling of these compounds to the compounds of formula 4.
fi) 1-Substituted 1,3-propanediols. .
. 1,3-Propanediols useful for the synthesis of compounds in the present invention can be prepared using various synthetic methods. For example, additions of an aryl Grignard to a l-hydroxy-propan-3-al give 1-aryl substituted 1,3-propauediols (path a). This method is suitable for the conversion of various aryl hahdes to l-aryl substituted-1,3-propanediols (Coppi et. al, J. Org. Chem., 1988, 53, 911). Conversions of aiyl halides to 1-substituted 1,3-propanediols can also be achieved using Heck reactions (e.g. couplings with a l,3-diox-4-ene) followed by reductions and subsequent hydrolysis reactions (Sakamoto et. al.. Tetrahedron Lett., 1992, 33, 6845).. Various aromatic aldehydes can also be converted to l-substituted-l,3-propanediols using alkenyl Grignard addition reactions


WO 01/66553 PCT/USOl/07452


followed by hydroboration reactions (path b). Additions of a t-butyl acetate metal enolate to aromatic aldehydes followed by reduction of the ester (path e) are also useful for the synthesis of 1,3-propanediols (Turner., J. Org. Chem., 1990, 55 4744). in another method, epoxidations of cinnamyl alcohol derivatives using known methods (e.g. Sharpless epoxidations and other asymmetric epoxidation reactions) followed by a reduction reaction (e.g. using Red-Al) give various l,3-propan6diols (path c).: Alternatively, enautiomerically pure 1,3-propanediols can be obtained using chiral borane reduction reactions of hydroxyethyl aryl ketone derivatives (Ramachandran et. al., Tetrahedron Lett., 1997, 38 761). Propan-3-ols with a 1-heteroaryl substituent (e.g. apyridyl, a quinohnyl or an isoquinolinyl) can be oxygenated to give 1-substituted 1,3-propanediols using N-oxide formation reactions followed by a rearrangement reaction in acetic anhydride conditions (path d) (Yamamoto et. al., Tetrahedron , 1981, 37,1871). O-




WO 01/66553 PCT/USOl/07452
fiii) Annulated 1,3-propane diols:
Compounds of formula I wherein V and Z or V and W are connected by four carbons to form a ring can be prepared from a 1,3-cyclohexanediol. For example, cis, cis-1,3,5-cyclohexanetriol can be modified as described for 2-substituted 1,3-propanediols. It is envisioned that these modifications can be performed either before or after formation of a cychcphosphonate 1,3-propanediol ester. Various 1,3-cyclohexanediols caii also be prepared using Diels-Alder reactions (e.g. using a pyrone as the diene: Posner et. al., Tetrahedron Lett., 1991, 32, 5295). 1,3-Cyclohexanediol derivatives are also prepared via other cycloaddition reaction methodologies. For .example, cycloadditon of a nitrile oxide to an olefin followed by conversion of the resulting cycloadduct to a 2-ketoethanol derivative which can be converted to a 1,3-cylohexanediol using know chemistry (Curran, et. al., J. Am. Chem. Soc, 1985, J 07, 6023). Alternatively, precursors to r,3-cyclohexanediol can be made firom quinic acid (Rao, et. al., Tetrahedron Leff., 1991, 52, 547.)
(vi) Synthesis of chiral substituted 1,3-hydroxvamines and 1,3-diamuies:-
Enantiomerically pure 3-aryl-3-hydroxypropan-1 -amines are synthesized by CBS enantioselective catalytic reaction of 3-chloropropiophenone!followed by displacement of halo group to make secondary or primary amines as required:(Corey, et al. Tetrahedron Lett., 1989, 30, 5207). Chiral 3-aryl-3-amino propan-1-ol type of prodrug moiety maybe obtained by 1,3-dipolar addition of chirally pure olefin and substituted nitrone of arylaldehyde followed by redixction of resulting isoxazolidine (Koizumi, et al., /. Org. . Chem., 1982, 47,4005). Chiral induction in 1,3-polar additions to form substituted isoxazolidines is also attained by chiral phosphine palladium complexes resulting in enantioselective formation of S-amino alcohol (Hon, et al., /. Org. Chem., 1999, 64, 5017). Alternatively, optically pure l-aiyl substituted amino alcohols are obtained by selective ring opening of corresponding chiral epoxy alcohols with desired amines (Canas et al. Tetrahedron Lett., 1991, 32, 6931).
Several methods are known for diastereoselective synthesis of 1,3-disubstituted aminoalcohols. For example, treatment of (E)-N-cnmamyltrichloroacetaraide with hypochlorus acid results in trans-dihydrooxazine which is readily hydrolysed to erythroβ

WO 01/66553 PCT/USOl/07452-
chloro-a-hydroxy-5-phenylpropanamiae in high diastereoselectivity (Commercon et at, Tetrahedron Lett., 1990, 31, 3871). Diastereoselective foimation of 1,3-aminoalcohols is also achieved by reductive amination of optically pure 3-hydroxy ketones (Haddad et al.. Tetrahedron Lett., 1997, 38, 5981). In an alternate approach, 3-aminoketones are transformed to 1,3-disubstituted aminoalcohols in high stereoselectivity by a selective hydride reduction (Barluenga et al, J. Org. Chem., 1992, 57," 1219).
All the above mentioned methods can also be applied to prepare corresponding V-Z, V-W, or V -Z annulated chiral aminoalcohols. Furthermore, such optically pure amino alcohols are also a source to obtain optically pure diamines by the procedures described earlier in the section.
Formulations
Compovmds of the invention are administered orally in a total daily dose of about 0.01 mg/kg/dose to about 100 mg/kg/dose, preferably from about 0.1 mg/kg/dose to about 10 mg/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 admimstration), compounds are administered to the affected tissue at sL rate from 0.05 to 10 mg/kg/hour, preferably from 0.1 to 1 mg/kg/hour. 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, arid . intraarterial injections with a variety of inftision techniques. Intraarterial and intravenous injection as used herein includes adminisfration through catheters. Oral administration is generally preferred. .
Pharmaceutical compositions containing the active ingredient maybe in any form suitable for the intended method of administration. When used for oral use for example, tablets, froches, lozenges, aqueous or oil suspensions, dispersible powders or granules.


WO 01/66553 PCT/USOl/07452
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 pxcipient which are suitable for
manufacture of tablets are acceptable. These excipients may be, for example, inert
diluents, such as.calcium: or sodium carbonate, lactose, calcitmaor 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 diluisnt, 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 methylcellulose, sodium alginate, polyvinylpyrrohdone, gum tragacanth . and gum acacia, and dispersing or wetting agents such as a-naturally occuning 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-benzbate, one or more coloiiug

WO 01/66553 PCT/USOl/07452
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, hi addition,
sterile fixed oils may conventionally TDC employed as a solvent or suspending medium. Por
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 hrnnans may contain approximately 1 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. The pharmaceutical composition can be prepared to provide easily measurable amounts-for administration. For example, an aqueous solution intended for intravenous infusion should contain from about 3 to 330 |j,g 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-aq-ueous 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, electuarpripaste.
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, hydroxypropyhnethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e;g-., sodium starch glycolate, cross-linked povidone, eross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture

WO 01/66553 PCT/US()l/07452
of the powdered compound moistened with an inert liquid diluent. The tablets may
optionally be coated or scored and may be fonnulated 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 I 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 ah 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 hi 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 inclutie
suspending agents and thickening agents. The formulations may be presented in unit-dose
or multi-dose sealed containers, for example, ampoules and vials, and maybe 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. • .
Suitable 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.


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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 may be used to treat diabetes melhtus, lower blood glucose levels, and inhibit gluconeogenesis.
FBPase inhibitors 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. 72:1019-1035 (1992)) inhibition of the indirect pathway (gluconeogenesis flux) decreases glycogen overproduction.
FBPase inhibitors 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, 25:66-73 (1994); Howard, G. et al.. Circulation 93:1809-1817 (1996)). 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, z. e. without elevated hepatic glucose output "hereinafter 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.
One aspect of the invention is directed to the use of prodrugs of the novel aryl phosphonates or phosphoramidates which results in efficient conversion of the cyclic phosphonate or phosphoramidate. The cyclic 1,3-propanyl ester containing compounds are oxidized by p450 enzymes foimd in large amounts in the liver and other tissues containing these specific enzymes.-


WO 01/66553 PCT/USOl/07452,
In another aspect of the invention, these prodrugs can also be used to prolong-the • phannacodynamic half-life because the cyclic phosphonates or phosphoramidatess of the invention can prevent the action of enzymes which degrade the parent drug.
In another aspect of the invention, these prodrugs can be used to achieve sustained
delivery of the parent drug because various novel prodrugs are slowly oxidized in the liver
at different rates.
The novel cyclic 1,3-piopanyl esters of the present invention may also be used to increase the distribution of a particular drug to the liver which contains abundant amoimts of the p450 isozymes responsible for oxidizing the cyclic 1,3-propanyl ester of the present invention so that the free phosphonate or phosphoramidate is produced.
In another aspect of the invention, the cyclic phosphonate or phosphoramidate pro&ugs can increase the oral bioavailability of the drugs.
Theses aspects are described in greater detail below.
Evidence of the liver specifi.city can also be shown in vivo after both oral and I-.V. administration of the prodmgs as described in Examples G and H.
Prodrug Cleavage Mechanism of Cyclic l,3-propahyl esters .
The cyclic 1,3-propanyl ester prodrugs are rapidly cleaved in the presence of liver microsomes from rates and humans, by freshly isolated rat hepatocyles, and by cytochrome P450 inhibitors. It is beKeved that the isoenzyme cytochrome CYP3A4 is responsible for the "oxidation based on ketoconozole inhibition of drug formation. Inhibitors of c3d:ochroihe P450 family 1 and/or family 2 do not appear to inhibit prodrug cleavage. Furthermore, although these specific prodrugs appear to be cleaved by CYP3A4, other prodrugs in the class, may be substrates.for other P450s.



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Step B. A solution of diethyl 2-furanpHosphonate (1 nunol) in 2 mL THF was cooled to -78 °C and added.to a solution of lithium diisopropylamide (LDA) (1 mmol) in 5 mL THP at 78- °C oyer 20 min. The resulting mixture was stirred -78 °C for 20 min and added into a solution of tributyltin chloride (1 mmole) in 1 mL THF at -78 °C over 20 min. The mixture was then stirred at -78 °C for 15 min,. and at 25. °C for 1 h. Extraction and chromatography gave diethyl 5-tributylstannyl-2-furanphosphonate as a colorless oil.
Step C. A mixture of diethyl 5-tributylstannyl-2-furanphosphonate (1 mmol), 1-iodo-2,4-dinitrohenzene (1 mmol) and tetralcis(triphenylphosphine)palladium(0) (0.05 mmol) in 6 mL of dioxane was heated at 80 °C for 16 h. Evaporation of solvent and chromatography provided diethyl 5-(3,5-dinitrophenyl)-2-iuranphoSphonate as sohd foam.
Step D.. A mixture of diethyl 5-(3,5-dinitrophenyl)-2-furanphosphonate (1 mmol) and TMSBr (6 mmol) in 10 mL of CH2Cl2.was stirred at rt for 16 h and then evaporated. The residue was dissolved in 85/15 CHsCN/water and then the solvent evaporated. The residue was suspended in CH2CI2 and the title compound (no. 1.01) was collected as a pale yellow solid: HPLC Rt = 5.3 0 min; negative ion electrospray MS M-1 found: 313. The following reagents were coupled with diethyl 5-tributylstannyl-2-furanphosphonate and converted into the respective example compounds (noted in parentheses) by using Steps C and D as described in Example 1: 2-broino-4,6-dinitroaniline (for 1.02); cliloro-2-iodoanisole (for 1.03); 2,5-dichloro-l-iodobenzene (for 1.04); Nl-methyl-2-iodo-4-(trifluoromethyl)ben2ene-l-sulfonamide (for 1.05); Nl-methyl-4-chloro-2-iodobenzene-l-sulfonamide (for 1.06); Nl-methyl-2-iodobenzene-l-sulfonamide (for 1.07); Nl-propyl-4-chloro-2-iodobenzene-l-sulfonamide (for (1.08); 2-iodophenol (for 1.09); S-iodo-m-xylene (for 1.10); l-bromo-S-iodobenzene (for 1.11); 4-iodoaiuline (for 1-12); 2,5-dimethoxy-4-iodochlorobenzene (for 1.13); Nl-(4-chlorob"enzyl)-2-iodobenzamide (for 1.14); Nl-(4-chlorophenethyl)-2-iodobenzamide (for 1.15); Nl-benzyl-2-iodobenzene-l-sulfonamide (for 1.16); 2-iodobenzenesulfonamide (for 1.17); l-iodo-2,3,4,5,6-pentamethylbenzene (for 1.18); 3-iodophthalic acid (iodoethane and diisopropylamine included iu Step C, for 1.19); 4-iodo-2-methylacetanihde (for 1.20); 3,5-dichloro-2-iodotoluene (for 1.21); methyl 5-hydroxy-2-iodobenzoate (for 1.22); 2-iodo-5-methylbenzamide (for 1.23); 5-hydroxy-2-


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iodobenzoic acid (iodoethane and diisopropylamine included ia Step C, for 1.24); 1-iodo-4-nitrobezene (for 1.25); Nl-(2,4-difluorophenyl)-2-iodobenzamide (for 1.26); 3,5-dichloro-1-iodobenzene (1.27); 3-iodophenol (for 1.28); 3~bromo-5-iodobeiizoic acid (for . 1.29); 3-bromo-4,5-dimethoxybenzaldehyde (for 1.30); l-iodo-2-nitrobenzene (for 1.31); 2-iodobiplienyl (for 1.32); 2-iodobenzoic acid (iodoetbane and diisppropylamine included in Step C, for 1.33); l-l3romo-4-iodobenzene (for 1.34); 3"-bromopropiophenone (for .1.35); 3-bromo.-4-metlioxybenzonitrile (for 1.36); l-ethyl-2-ibdobenzene (for 1.37); 2-bromo-3-nitrotoluene (for 1.38); 4-iodoacetanilide (for 1.39); 2,3,4,5-tetramethyliodobenzene (for 1.40); 3-bromobiplienyl (for 1.41); 4-chloro-2-iodobenzenesulfonamide (for 1.42); Nl -(4-iodophenyl)-2-tetrah.ydro-1 H-pyirol-1 -ylacetamide (for 1.43); 3,4-dimethyliodobenzene (for 1.44); 2,4-dinitroiodoben2;ene (for 1.45); 3-iodobenzylaniLne (for 1.46); 2-fluoro-4-iodoaniline (for 1147); 3-iodobenzyI alcohol (for 1.48); 2-bromo-l-iodobenzene (for 1.49); 2-broinophenethyl alcohol (for 1.50); 4-iodobenzamide (for 1.51); 4-bronioben2onitrile (for 1.52); 3-bromobenzordtrile • (for 1.53); 2-bromobenzonitrile (for 1.54); 4-br6mo-2-nitroariiline (for 1.55); 2- \ iodoisopropylbenzene (for 1.56); 6-amino-2-cMop-3-bromopyridiae (derived from reaction of 6-amiao-2-chloroben2ene (1 mmol) with bromine (1 mmol) in acetic acid (4 mL) for 2h at rt. followed by evaporation and chrortiatography to provide 6-amino-2-chloro-3-bromopyridine) (for 1.57); 3-bromo-4-methylthiophene (for 1.58); 2-bromo-4-chloroaniline (for 1.59); l-bromo-3-chloro-5-fluoroaniline (for 1.60); 2-bromo-4-cyanoanisole (for 1.61); 2-bromo-4-nitrotoluene (for 1.62); 3-nitro-5-fluoro-l-iodobenzene (for 1.63); 2~iodo-4-carbomethoxyaniliae (for 1.64); 2-bromo-4-nitroanisol6 (for 1.65); 2-chloro-l-iodo-5-trifluoromethylbenzene (for 1.66) and l-brorno-2,5-bis-. (trifluoromethyl)ben2ene (for 1.67).
Example 2
Preparation of 5-(4-FIuorophenyl)-2-furanphosphonic Acid (Compound no. 2.01).
Step A. A solution of diethyl 2-furanphosphonate (prepared as described in .Step A, Example 1) (1 mmol) in 2 mL THF was cooled to —78 °C and added to a solution of lithium isopropylcyclohexylamide (LICA) (1 nunol) in 2 mL THF at -78 °C over 20inin.


WO 01/66553 PCT/USOl/07452
The resulting mixture was stirred -78 °C for 20 min and added into a solution of iodine (1 mmole) in 1 mL THF at -78-oC over 20 min. The mixture was then stirred at -78 °C for 20 min. Extraction and chromatography provided diethyl 5-iodo-2-furanphosphonate as a yellow oil.
Stiep B. A mixture of diethyl 5-iodo-2-furanphosphonate (1 mmol), 4-fluorophenylboromc acid (2 mmol), diisopropylethylamine (DIEA) (4 mmol) and bis(acetoiiitrile)dicliloropalladium(I[) (0.05 mmol) in 6 mL DMF was heated at 75 °C for 16 h. Extraction and chromatography provided diethyl 5-(4-fluorophenyl)-2-furanphosphonate as an oil.
Step C. Application of Step D, Example 1, to this material provided the title compound (no. 2.01) as a white solid. HPLC Rt = 5:09 mm; negative ion electrospray MS M-1 found: 241.
Substitution of 2,4-dichlorophenylboroiiic acid into this method provided compound no. 2;.02. Substitution of 3-amino-5-carbomethoxyphenylboronic acid into this method provided compound no. 2.03..
Example 3
Preparation of .S-H-Bromo-S-aminophenyl-2-furanphosphonic Acid (Compound
no.3.Ql>.
Step A. Reaction of 3--aminophenylboronic acid hydrochloride with diethyl 5-iodo-2-furanphosphonate as described in Step B of Example 2 provided diethyl 5-(3- , aminophenyl)~2-jEliranphosphonate as an oil.
Step B. A mixture of diethyl 5-(3-aminopheuyl)-2-furanphosphonate (1 mmol), NBS (0.9 mmol) and AIBN (0.1 mmol) in 30 mL of CCI4 was stirred at rt for 2 h. Extraction and chromatography provided diethyl 5-(4-bromo-3-aminophenyl)-2" furanphosphonate as an oil.
Step C. Application of Step D, Example 1, to this material provided the title,
compound no. 3.01) as a white sohd, HPLC Rt = 4.72 min; negative ion elechrospray MS
M-1 found: 316/318. .


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Example 4
Preparation of 5-(3-(furfurvlaminomethvI)phenvI)-2-furanphosphonic Acid
(Compound no. 4.01).
Step A. Reaction of 3-fonnylphenylboronic acid with diethyl 5-iodo-2-furanphosphonate as described in Step B of Example 2 provided diethyl 5-(3-formylphenyl)-2-furanphosphonate as an oil.
Step B. A tnixture of diethyl 5-(3-fonnylphenyl)-2-furanphosphonate(l mmol),
furfurylamine (4 mmol), trimethylorthoformate (5 mmol), acetic acid (2 mmol) in 10 mL
DMSO was stirred at rt for 5h and then NaBH4 (6 mmol) was added and stirring.continued
for a further 16 h. The solvents were evaporated and the crude product mixture containing
diethyl .5-(3-(furftiiylaminomethyl)phenyl)-2-furanphosphonate was used directly in the
next step. . . " -
Step C. The product mixture from Step B and TMSBt (6 mmol) in 10 mL of
CH2CI2 was stirred at rt for 16 h and then evaporated. The residue was dissolved in
85/15 CHaCN/Avater and then the solvent evaporated.. The mixture was dissolved in ■ •
methanol with diisopropylethylamine (2 mmol) and mixed with DOWEX® 1X8-400
formate resin for 1 h and then the mixture filtered. The resin was slurried for 15 min each
with"9:l DMSO/water, methanol, acetonitrile and 85:15 acetonitrile/water.. Then the resin
was mixed with 90:10 TFA/water for 1 h and then filtered, this filtrate was evaporated to
.provide the title compound no. 4.01) as a sohd. HPLC Rt = 4.10 min; negativeion
electrospray MS M-1. found: 332. "
In a similar manner the aldehydes: 3-formylphenylboronic acid, 2-meihoxy-5-fdrmylphenylboronic acid, 2-formylthiophene-3-borbnic acid, 2-fonnylfuran-5-boronic acid, 2-formylphenylboromc acid and 2-formyl-4-methoxyphenylboronic acid were used to prepare the following compounds with respective amines indicated in parentheses: 4.02, 4.03 and 4.04 (fiiriuiylamine); 4.05, 4.06 and 4.07 (phenethylamine); 4.08, 4.09, 4.10 and 4.11 (l-amino-2-propanol); 4.12 and 4.13 (n-propylamine); 4 l4, 4.15 and 4.16 (cyolopiopylamine); 4.17,4.18,4.19 and 4.20 (3-amino-l,2-propanediol); 4.21 and 4.22 (benzylamine); 4.23 and 4.24 (l-amino-S-propanol); 4.25 (h-pentylamme); 4.26, 4.27 and 4.28 (phenylpropylamine); 4.29 and 4.30 (n-hexylamine); 4.31 and 4.32

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(HOBt) (1.5 mcnol) in 8 mL of DMF was stiired for 16 h at rt. Extraction and chroniatographyprovided diethyl 5-{N-(2-(2-hydroxyethyl)phenyl)thiophene-2-carboxainide-3-yl)furanphosphonate as an oil.
Step E. Diethyl 5-(N-(2-(2-hydroxyethyl)phenyl)thiophene-2-carboxaniide-3-y])furanphosphonate was deesterified withTMSBr as described in Step D, Example l,to provide the title compound (no. 5.01) as a sohd. HPLC Rt = 5.17 min; negative ion electrosprayMSM-1 found: 392.
In a similar manner the carboxylic acids: 2-iodobenzoic acid, 3-iodobeuzoic acid, 4-iodobenzoic acid, 3-bromothiophene-2-carboxyhc acid, 5-bromo-2-furoic acid, 3-bromothiophene-2-carboxyhc acid, 5-bromothiophene-.2-carboxylic acid and 5-bromonicotinic .acid were used to prepare the following compounds with respective amines, indicated in parentheses: 5.02 (N-methylfurylamine); 5.03, 5.04, 5.05 (2-(2-1iydrQxyethyl)aniline); 5.06 and 5.07 (3-hydroxymethyIaniline); 5.08 (8-aminoquuioIine); 5.09 and 5.10 (3-aniinoquinoline); 5.11 (3-aminobenzamide); 5.12, 5.13 (4-anunophenoI); 5.14 and 5.15 (3,4-methyl6nedioxyaniline); 5.16 (4-aminobeiizamide); 5.17 (cyclopropyiamine); 5.18 (t-butylamine); 5.19, 5.20 (3,3-dimethylbutylamine); 5.21 (n-pentylamiae); 5.22 and 5.23 (n-hexylamine); 5.24 (benzylamine); 5.25, 5.26 (phenethylamine); 5.27 and 5.28 (phenpropylaraine); 5.29 and 5.30 (phenbutylamine); 5.31 and 5.32 (ethanolamine); 5.33 (2-(2-aminoefhoxy)ethanol); 5.34 (3-ethoxypropylamine); 5.35, 5.36 and 5.37 (ethylenediamine mono-boc amide); 5.38, 5.39 4-(2-aniinoethyl)morpholiae); 5.40, 5.41 and 5.42 (piperonylamine); 5".43, 5.44, 5.45, 5.46, 5.47 and 5.48 (tetrahydrofuifurylamine); 5.49 and 5,50 (cyclohexylamine); 5.51 (2-aminoacetamide); 5.52 (6-methyl-2-picolyhnethylamihe) and 5.53 (morpholiae).
Example 6
Preparation of l-f3-Bromophenvlcarbainoyl)-3-carboethoxv-6-(2-phosphonofuran-5-
vDbenzene (Compound no. 6.01).
Step A. A.mixture of 3-carboxy-5-nitrophenylboronic acid (1 mmol), diethyl 5-iodo-2-furanphosphonate (1.5 mmol) and tetrakistriphenylphosphinepalladium(O)

WO 01/66553 PCT/USOl/07452,
(0.05 mmol) were dissolved in 1.5 mL of 1,4-dioxane and 0.25 mL of DMF. After bubbling N2 into this solution for 5 min then 1.5 mL of 1 M aqueous K3PO4 were added. After N2 bubbling for 5 min the mixture was heated at 85 °C for 14 h and then cooled and diluted with EtOAc and water. The layers were separated, the EtOAc layer extracted with water. The aqueous layers were combined, pH. lowered to pH 2 and then extracted with EtOAc. The EtOAc extract was dried (MgSO4) and evaporated. Chromatography on silica gel provided l-nitro-3-carboxy-5-(diethyl 2-phosphonofuran-5-yl)benzene.
Step B. A mixture of l-nitro-3-carboxy-5-(diethyl 2-phDSphonofuran-5-yl)benzene (1 mmol), trimethylsilylethanol (1 mmol), EDCI (1.1 nomol) and DMAP (0.1 nrniol) were stirred in 2 roL of CH2CI2 at rt for 16 h. Extractive isolation provided l-nitro-3-carbotrimethylsilylethoxy-5-(diethyl2-phosphonofuran-5-yl)beirzene.
Step C. A mixture of l-nitrQ-3-carbotrimethylsilvlethoxy-5-(diethyl 2-phosphonofuran-5-yl)benzene (1 mmol) and 10% Pd/C (80 mg) in 10 mL of EtOAc and 5 mL of MeOH was stirred at rt under an atmosphere of hydrogen for 6 h. The mixture" was filtered over Celite and purified by silica gel chromatography to provide l-;amino-3-carbotrimethylsilylethoxy-5-(diethyl 2-phosphonofuran~5-yl)benzene.
Step D. A mixture of 1 -amino-3-carbotrimethylsilylethoxy-5-(diethyl 2-phosphonofuran-5-yl)benzene (1 mmol), 3-bromobenzoyl chloride (4 mmol) and triethylamine (4.5 mmol) in 30 mL of CH2CI2 was stirred at rt for 4 h. Then 5 mL of water was added and after stirring for 30 min the mixture was evaporated. The residue was dissolved in MeOH and slurried with 5 g of DOWEX 1X8-400 carbonate resin. The mixture was filtered and the solvent evaporated to provide l-(3-bromophenylcafbamoyl)-3-carbotrimethylsilylethoxy-5-(diethyl 2-phosphonofiu"an-5-yl)berr2:ene, .
Step E. A mixture of l-(3-bromophenylcafbamoyl)-3-carbotrimethylsilylethoxy-5-(diethyl 2-phosphonofiiran-5-yl)ben2ene (I mmol) and 4.5 xnL of a 1 M solution of Bu4NF . in THE were stirred in 10 mL of THF for 6 h at rt. To this mixture was added. 5 grams of DOWEX 50WX8-400 free acid and 5 grams of DOWEX 50WX:8-400 sodium salt. After slurrying this mixture for 14 h.the mixture was filtered and the filtrate evaporated to provide l-(3-bromophenylcarbamoyl)-3-cafboxy-5-(diethyl 2-phosphonofur.an-5-yl)benzene.














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Step C. This compound was deesterified with TMSBr as described in Step D, Example 1, to provide the title compound (no. 187) as a solid. ,HPLC Rt = 5.24 mm; negative ion electrospray MS M-1 found: 309/311.
■ Compound 13.02 was prepared similarly from 3,5-dinitrobenzyl alcohol.
Example 14
Preparation of 2,4-Dichloro-5-(phosphonomethoxvmethythiazole Compound no. 14.01).
Step A. To a solution of 2,4-dichloro-5-(hydroxyroethyl)thiazole(J.Chem Soc. Perkin 1(1992, 973) (1 mmol) in. dichloromethane at 0 °C was added IM phosphorus tribromide in dichloromethane (1;1 mmol) and the mixture allowed to stir at rt for 1 h. The product 2,4-dichloTo-5-(bromomethyl)thiazole was extracted and purified by column chromatography.
Step B. To a solution of di.ethyl hydroxymethylphosphonate (1.2 mmol) in THF ■ (10 mL) at 0 °C was added 60% sodium hydride (1.1 mmol) and allowed to stir for. "" 15 minutes before adding 2,4-dichIoro-5-(brDmomethyl)thiazole (1 nunol). The mixture was warmed to room temperature and allowed to stir for 3 h. The reaction was extracted and chromatographed to yield 2,4-dichloro-5-(diethylphosphonomethoxymethyl)thiazole.
Step C. 2,4-Dichloro-5-(diethylphosphonom.ethoxymethyI)thiazolewas deesterified with TMSBr as described in Step D, Example 1, to provide the title compound (no. 14.01) as a solid. HPLC Rt = 4.36 min; negative ion electrospray MS M-1 found: 276/278.
Example 15
Preparation of 2-Amino-4-tert-butvI-l-phosphonomethoxybenzene (Compound
no. 15.01).
Step A. A solution of 2-amino-4-tert-butylphenoi (1 mmole) inDMF was treated with sodium hydride (1.2 mmole) and trifluoromethanesulfonic acid 2-diethylphosphonomethyl ester (1.2 mmole) at room temperature for 6 h. Evaporation and , chromatography gave 2-amio-4-tert-butyl-l-diethylphosphonomethoxybenzene as an oil.


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Step B. The compound 2-amino-4-tert-butyl-l-diethylphosphonomethoxybenzene
was deesterified with TMSBr as described in Step D, Example 1, to provide the title
compound (no. 15.01) as a solid. HPLC R- 4.45 min; negative ion electrospray MS M-1
found: 258.
Example 16
Preparation of l-Phosphono-2-phenvlacetylene (Compound no. 16.01).
Step A. A solution of iodobenzene (1 mmole) in DMF (5 mL) was treated with trimethylsilylacetyiene (2 mmole), Pd(PPh3)2Cl2 (0.035 mmole), Cul (0.08 mmole) and triethylarnine (4 mmole), and the resulting reaction mixture was stirred under nitrogen at room temperature for 5 h. Evaporation followed by chromatography gave l-trimethylsilyl-. 2-phenylacetylene as a solid.
Step B. A solution of l-trmiethylsilyl-2-ph6nylacetylene (1 mmole) in anhydrous THF (5 mL) was treated with a solution of tetrabutylammomum fluoride (1.5 mmole) at 0 °C for 1 h. Extraction and chromatography gave phenylacetylene.
Step C. A solution of phenylacetylene (1 mmole) in anhydrous THF (5 mL) was treated with TMEDA (1.2 mmole) followed by n-BuLi (1.2 mmole) at -78 °C. After 30 min the reaction was treated with diethyl chlorophosphate, and the resulting solution was stirred at —78 °C for 1 h." The reaction was quenched with saturated ammonium chloride. Extraction and chromatography gave l-diethylphosphono-2-phenylacetylene as an oil.
Step D. l-Diethylphosphono-2-phenylacetylene was deesterified with TMSBr as described in Step D, Example 1, to provide the title compound (no. 16.01) as a soHd. HPLC R "= 3.75 min; negative ion electrospray MS M-1 found: 181.
Example 17
General procedure for preparation of bis~phosphoroamide prodrugs.
Step A. Dichloridate formation. To a suspension of 1 mmol of phosphonic acid in
5 mL of dichloroethane is added 0.1 mmol of pyridme (or 0.1 mmol of DMF) followed by
6 mmol of thionyl chloride and it is heated to reflux for 2.5 h. Solvent and excess thionyl chloride are removed under reduced pressure and dried to give the dichloridate.


WO 01/66553 PCT/USOl/07452
Step B. Coupling reaction. Method 1: To a solution of the crude"dichlondate in 5 mL of dry CH2CI2 is added 8 mmol of aminoacid ester at 0 °C. The resultant mixture is allowed to come to it where it is stirred for 16 h. The reaction mixture is subjected to extractive work up and chromatography to provide the target bisphosphoramide.
Method 2: To the crude dichlondate in 5 mL of dry CH2CI2 is added 4 mmol of aminoacid ester and 4 mmol of N-methylimidazole at 0 °C. The resultant mixture is allowed to come to rt where it is stirred for 16 h. The reaction mixture is subjected to extractive work up and chromatography to provide the target bisphosphoramide.
Example 18
General procedure for niixed bis-phosphoroamidate prodrugs.
To a solution of crude dichloridate (1 mmol, prepared as described in Step A in Example 15) in 5 mL of dry CH2CI2 is added an amine (1 mmol) followed by 4-; .. dimethylaminopyridine (3 mmol) at 0 °C. The resulting mixture is allowed to warm to room temperature and stir for 1 h. The reaction is cooled back to 0 °C before adding an -aminoacid ester (2 mmol) and then is left at room temperature for 16 h. The reaction mixture is subjected to extractive work up and the mixed bis-phosphoroamidate prodrugis purified by column chromatography.





WO 01/66553 PCT/USOl/07452.
BIOLOGICAL EXAMPLES
Example A: Inhibition of Human Liver FBPase
E. coli strain BL21 transformed with a human liver FBPase-encoding plasraid was obtained from Dr. M.R. El-Magtirabi at the State University of New York at Stony Brook. The enzyme was typically purified from 10 liters of recombinant E. coli culture as described (M. Gidh-Jain et al., 1994, The Journal of Biological Chemistry 269,-p-p 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 couphng enzymes. Reaction mixtures (200 p.!) were made up in 96-well niicrotibre plates, and consisted of 50 mM Tris-HCl, pH 7.4,100 mM KCl, 5 mM EGTA, 2 mM MgClz, 0.2 mM NADP, 1 mg/ml BSA, 1 ,mM MTT, 0.6,mM PMS, 1 unit/rQl phosphoglucose isomerase, 2 units/ml glucose 6-phosphate dehydrogenase, and 0.150 mM substrate (fructose~l,6-bisphosphate). Inhibitor concentrations were varied from 0.01 µM to 10 p.M. Reactions were started by the addition of 0.002 units of pure hlFBPase, and were monitored for 7 minutes at 590 run in a Molecular Devices Plate Reader (37 °C).
Table 3 below provides the IC50 values for several compounds prepared. The IC50 for AMP is 1µM.





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Example B: AMP Site Binding
To assess whether compounds bind to the allosteric AMP binding site of hlFBPase, the enzyme is incubated with radio-labeled AMP in the presence of a range of test compound concentrations. The reaction mixtures consist of 25 mM ^H-AMP (54 mCi/mmole) and 0 -1000 mM test compound.in 25 mM Tris-HCl, pH .7.4, 100 mM ■ KCl and 1 mM MgCl2- 1.45 mg of homogeneous FBPase "(=l nmole) is added last. After a 1 minute incubation, AMP bound to FBPase is separated from unboimd AMP by means of a centrifugal rdtrafiltration unit ("Ultrafi-ee-MC", Millipore) used according to the instructions of the manufacturer. The radioactivity in aliquots (100 µl) of the upper compartment of the unit (the retentate, which contains enzyme and label) and the lower compartment (the filtrate, which contains unbound label) is quantified using a Beckman liquid scintillation counter. The amount of AMP bound to the enzyme is estimated by comparing the counts in the filtrate (the unbound label) to the total counts in the retentate.
Example C: AMP Site/Enzyme Selectivitv
To determine the selectivity of compounds towards FBPase, effects of FBPase inhibitors on 5 key AMP binding enzymes is measured using the assays described below: Adenosine Kinase: Human adenosine kinase is purified from E. coli expression system as described by Spychala et al. (Spychala, J.,. Datta, N.S.,.Tak:abayashi,- K., Datta, M., Fox, I.H., Gribbin, T., and Mitchell, B.S. (1996) Proc. Natl Acad. Sci. USA 93,12324237). Activity was measured essentially as described by Yamada et al. (Yamada, Y., Goto, H.,. Ogasawara, N. (l988)Biochim. Biophys. Acta 660, 36-43.) with a fewminor modifications. Assay mixtures contain 50 mM TRIS-maleate buffer, pH 7.0, 0.1% BSA, 1 mM ATP 1 mM MgCls, 1.0 pM [U-14C] adenosme (400-600 mCi/mmol) and varying duphcate concentrations of inhibitor. """C-AMP was separated firom unreacted """C-adenosine by absorption to anion exchange paper (Whatman) and quantified by • scintillation counting.


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Adenosine Monophosphate Deaminase: Porcine heart AMPDA is purified essentially as described by Smiley et al. (Smiley, K.L., Jr, Berry, A.J., and Suelter, C.H. (1967) J. Biol Chem. 242, 2502-2506) through tbe phosphocellulose step. -Inhibition of AMPDA activity is determined at 37 °C in a 0.1 ml assay mixture containing inhibitor, ~0.005U AMPDA, 0.1% bovine serum albumin, 10 mM ATP, 250 mM KCl, and 50 mM MOPS at pH 6.5. The concentration of the substrate AMP is. varied from 0.125 ^ 10.0 mM.,Catalysis is initiated by the addition of enzyme to the otherwise complete reaction mixture, and terminated after 5 minutes by injection into an HPLC system.:Activities are determined ti"om the amount of IMP formed during 5 minutes. IMP is separated from AMP by HPLC using a Beckman Ultrasil-SAX anion exchange column (4.6 mm x 25 cm) with an isocratic buffer system (12.5 mM potassium phosphate,30 mMKCl, pH 3.5) and detected spectrophotometrically by absorbance at 254 run.
Phosphojructokinase: Enzyme (rabbit liver) is purchased from Sigma. Activity is ■ measured at 30 °C in reactions in which the formation of fructose-l,6-bisphosphate is coupled to the oxidation of NADH via the action of aldolase, triosephosphate isornerase, and a-glycerophosphate dehydrogenase. Reaction mixtures (200 }µ1) are made up in 96-well microtifre plates and were read at 340 nm in a Molecular Devices Microplate Reader. The mixtures consist of 200 mM Tris-HCl pH 7.0, 2 mM DTT, 2 mM MgCl2, 0.2 mM NADH, 0.2 MM ATP, 0.5 mM Fructose 6-phosphate, 1 unit aldolase/ml, 3 units/ml triosephosphate isomerase, and 4 units/ml a-glycerophosphate dehydrogenase. Test compound concentrations range from Ito 500 µM. Reactions are started by the addition of 0.0025 units of phosphofructokinaseand are monitored for 15 minutes.
Glycogen Phosphorylase: Enzyme (rabbit muscle) is purchased from Sigma. Activity is measured at 37 °C in reactions in which the formation of glucose 1-phosphate is coupled to the reduction of NADP via phosphoglucomutase and glucose 6-phospbate dehydrogenase. Assays are performed on 96-well micro titre plates and are read at 340 nm on a Molecular Devices Microplate Reader. Reaction mixtures consist of 20 mM imidazole, pH 7.4, 20 mM MgCl2, 150 mM potassium acetate, 5 roM potassium




WO 01/66553 PCTAJSOl/07452
Example E: Glucose Production Inhibition and Fructose-l,6-bisphosphate Accumulation in Rat Hepatocytes
Isolated rat hepatocytes are prepared as described in Example D and incubated under the identical conditions described. Reactions are terminated by removing an aliquot (250 µl) of cell suspension and spinning it through a layer of oil (0.8 ml siHcone/mineral oil, 4/1) mto a 10% perchloric acid layer (100 µl). After removal of the oil layer, the" acidic cell extract layer is neutralized by addition of l/3rd volume of 3 M KOH/3 M KHCO3. After thorough mixing and centrifagation, the supernatant is analyzed for glucose content as described in Example D, and also for fructose-l,6-bisphosphate. Fructose-l,6-bisphosphate is assayed spectrophotometrically by coupling its enzymatic conversion to glycerol 3-phosphate to the oxidation of NADH, which is monitored at 340-nm. Reaction mixtures (1 ml) consist of 200 mM Tris-HCl, pH 7.4, 0.3 mM NADH, 2 units/ml glycerol 3-phosphate dehydrogenase, 2 units/ml triosephosphate isomerase, and 50-100 yd cell extract. After a 30 minute preincubation at 37 °C,.l unit/ml of aldolase is: added and the change in absorbance measured imtil a stable value is obtained. 2 moles of NADH are oxidized in this reaction per mole of frutose-l,6-bisphosphate present in the cell extract.
A dose-dependent inhibition of glucose production accompanied by a dose-dependent accumulation of fructose-1,6 bisphosphate (the substrate of FBPase) is an indication that the target enzyme in the gluconeogenic pathway, FBPase, is inhibited.
Example F: Blood Glucose Lowering Following Intravenons Administration to Fasted Rats
Sprague Dawley rats (250-300 g) are fasted for 18 hours and then dosed intravenously either with saline or up to about 60 mg/kg of ah FBPase inhibitor. Inhibitors are dissolved in water and the solution adjusted to neutrality with NaOH. Blood samples are obtained from the tail vein of conscious animals just prior to injection and after 1 hour. Blood glucose is measured using a HemoCue Inc. glucose analyzer according to the instructions of the manufacturer.

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Example G: Analysis of Drug Levels and Liver Accumulation in Rats
Sprague-Dawley rats (250-300 g) are fasted for 18 hours and then dosed intravenously either with.saline up to about 60 mgs/kg of a compound of the invention. The compound is dissolved in water and the solution adjusted to neutrality with NaOH. One hour post injection rats are anesthetized with halothane and a liver biopsy (approx. , 1 g) is taken as well as a blood sample (2 ml) from the posterior vena cava. A heparin flushed syringe and needle are used for blood collection. The liver sample is immediately homogenized in ice-cold 10% perchloric acid (3 ml), centrifuged, and the supernatant neutralized with l/3rd volume of 3 M KOH/3 M KHCO3. Following centrifugation and filtration, 50 µl of the neutralized extract is analyzed for compound content by HPLC. A YMC ODS AQ Column (250 X 4.6 cm) is used and eluted with a gradient from 10 mM sodium phosphate"pH 5.5 to 75% acetonitrile. Absorbance is monitored at 310 - 325 nm. Plasma is prepared from the blood sample by centrifugation and extracted by addition of methanol to 60% (v/v). The methanoHc extract is clarified by centrifugation and filtration and then analyzed by HPLC,as described above.
Example H: Glucose Lowering Following Oral Administration to the Fasted Rat
Compounds are administered by oral gavage to 18-hour fasted, Sprague Dawley
rats (250-300g). Phosphonic acids are prepared in deioni"zed water, and the solution
adjusted to neutrality with sodium hydroxide. Prodrugs are dissolved in polyethylene
glycol (mw 400). Blood glucose is measured unmediately prior to dosing and at 1 hour
intervals thereafter "by means of aHemoCue glucose analyzer (HemoCue Inc., Mission
Viejo, CA). . .
Example I: Estimation of the Oral Bioavailability of Phosphonic Acids and Their Prodrugs
Phosphonic acids are dissolved in water, and the solution adjusted to neutrality
with sodium hydroxide. Prodrugs are dissolved in 10%> ethanol/90% polyethlene glycol
(mw 400). Compound is administered by oral gavage to 18-hour fasted Sprague-Dawley
rats (220-250 g) at doses ranging firom 10-60 mg/kg. The rats are .subsequently placed in
metabolic cages and uiine is collected for 24 hours. The quantity of phosphonic acid


WO 01/66553 . PCT/USOl/07452
excreted into urine is determined by HPLC analysis as described in Example G. In a separate study, urinary recovery is determined following intravenous (tail vein) adrninistration of compound (in the case of the prodrugs, the appropriate parent phosphonic acid is administered LV.). The percentage oral bioavailability is estimated by comparison of the recovery of compound in urine 24 hours following oral administration, to that recovered in urine 24 hours after intravenous administration.
Example J: Blood Glucose Lowering in Zucker Diabetic Fatty Rats, Oral
Zucker Diabetic Fatty rats are purchased from Genetics Models Inc. (Indianapohs, Indiana) at 8 weeks of age and fed"therecommended Purina 5008 diet. At the age of 12 weeks, 16 animals with fed blood glucose levels between 500 and 700 mg/dl are selected and divided into two groups (n=8) with statistically equivalent average blood glucose levels. A compound of the invention is administered at a dose of up to about 300 mg/kg by oral gavage to one group of animals at 1 p.m. The drug solution for this treatment is prepared in deionized water and adjusted to neutrality by. dropwise addition of 5 N NaOH. A second group of rats (n=8) is dosed orally with saline, iu-.parallel. Blood glucose is measured in each rat just prior to drug or saline adibinistration and 6 hours post administration. A HemoGue blood glucose analyzer (HemoGue Inc;, Mission Viejo, GA) is used for these measurements according to the manufachirer"s instructions.
Example K: Blood Glucose Lowering in Zucker Diabetic Fatty Rats, Intravenous
12-week old Zucker Diabetic Fatty rats (Genetics Models Inc., Indianapolis, Indiana) maintained on Puiina 5008 diet are instrumented with tail artery and tail vein catheters at 8 am on the day of the study. Food is removed for the remainder of the day.. Starting at 12 p.m., animals are infused for 6 hours via the tail vein catheter either with saline or compound of the invention at up to about 60 mg/kg/h. Blood samples are obtained from the tail artery catheter at the start of the infusions, and at hourly intervals thereafter. Glucose is measured in the samples by means of a HemoCue analyzer (HemoCue Inc., Mission Viejo, GA) according to the manufacturer"s instructions.


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ExampleL: Inhibition of Gluconeogenesis by FBPase Inhibitor in Zucker Diabetic Fatty Rats
Following a 6-hour infusion of a compound of the invention at up to about 60 mg/kg/h or saline to Zucker Diabetic Fatty rats (n=3/group) as described in Example K; a bolus of14C-bicarboriate (40 µCi/1 OOg body weight) is administered via the tail vein catheter. 20 minutes later, a blood sample (0.6 mL) is taken via the tail artery. Blood • (0.5 ml) is 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 is centrifuged (20 minutes, 1000 X g) and 5 mL of the resulting supernatant is 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 AG 1-X8, 100-200 mesh, acetate form) to separate 14-C-bicabonate Irom 14C-glucose. The slurry is shaken at room temperature for four hours and then allowed to settle. An ahquot of the supernatant (0.5 mL) is.then counted in 5 mL scintillation cocktail. The percentage inhibition of gluconeogenesis in drug-treated rats is calculated by dividing the average cpm" of 14C-glucose in samples from drug-treated animals by those from saline-injected animals.
Inhibition 14C-Glucose production provides evidence that the glucose lowering activity in the Zucker Diabetic Fatty rat (Example K) is due to the inhibition of gluconeogenesis.
Example M: BIood Glucose Lowering in the Streptozotocin-Treated Rat
Diabetes is induced in male Sprague-Dawley rats (250-300 g) by intraperitoneal injection of 55 mg/kg streptozotocin (Sigma Chemical Co.). Six days later, blood glucose is measured as described in Example F. Animals are selected with fed blood glucose values (8 am) between 350 and 600 mg/dl, and divided into two groups. One group is dosed orally with compound (up to about 300 mg/kg) and the second with an equivalent volume of saline; Food is removed from the animals. Blood glucose is measured again after 2 and 4 hours of drug/saline administration.
Example N: Oral Absorption Determinations of Prodrugs in the Rat


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Prodrugs of the iiivention are administered to normal, fed rats at 3 0 mg/kg both by intraperitoneal injection"and by oral gavage (n=3 rats/ compound/route of administration). Rats are subsequently placed in metabolic cages and urine collected for 24 hours. Parent compound, is quantitated in urine by reverse phase HPLC as described in Example G. By comparison of the amount of pareni; compormd excreted in urine following oral administration to that following intraperitoneal administration, the % oral absorption is calculated for each prodrug.
Example O: Chronic Oral Efficacy in the ZDF Rat
To determine the chronic glucose lowering effects of aprodrug of the-invention, ZDF are administered the drug orally for 3 weeks.
Methods: ZDF rats (10 weeks of age) are maintained either on powdered Purina . 5008 rat chow (n=10) or the same powdered chow supplemented with 1% of the drug (n=8). Blood glucose measurements are made as described in Example F at baseliQe;and-at weekly intervals thereafter for a total of 3 weeks. Statistical analysis is performed using the Studenf s t test.
Example P: Identification of the P450 Isozyme Involved in the Activation
Prodrugs are evaluated for human microsome-cafalyzed conversion to parent compound in the absence and presence of specific inhibitors of three major P450 isozymes: ketoconazole (CYP3A4), furafylline (CYP1A2), and sulfaphenazole (CYP2C9).
Methods: Reaction (0.5 ml @ 37°C) consist of 0.2 M KH2PO4, 13 mM glucose-6-phosphate, 2.2 mMNADP"^, 1 unit of glucose-6-phosphate dehydrogenase, 0-2.5 mg/ml human microsomal protein (En Vitro Technologies, In.), 250µ prodrug, and 0-100 µM; P450 isozyme inhibitor; Reactions are stopped by addition of methanol to a concentration of 60%, filtered (0.2 µM filter), and lyophilized. Samples are resuspended in HPLC buffer (10 mM phosphate pH 5.5, 2.5 mM octyl-triethylammonium), loaded onto a YMC C8 HPLC column (250 x 4.6 mm), and eluted with a methanol gradient to 80%. Foimuation of parent drug is confinned by co-elution with an authentic parent drug standard.

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Results: Prodrug is converted readily to parent drug in human liver microsomes.
Ketoconazole will inhibit the formation of parent drugs in. a dose-dependent fashion. The
other inhibitor, fusafylline and sulfaphenazole, will show no significant inhibition. The
results indicate that CYP3A4 is the primary P450 isoform responsible for activation of
prodrugs in human liver. " " .
While in accordance with the patent statures, description of the yaiious embodiments and processing conditions have been provided, the scope of the invention is not to be limited thereto or thereby. Modifications and alterations of the present invention will be apparent to those skilled in the art without departing firom the scope and spirit of the present invention.. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims, rather than by the specific examples which have been presented by way of example.


We Claim:
1. An aryl phosphonates compound of formula (I):
wherein R5 is selected from the group consisting of:


wherein:
G2 is selected from the group consisting of C, O, and S;
G3 and G4 are independently selected from the group consisting of C, N, O, and S;
wherein a) not more than one of G2, G3, and G4 may be O, or S; b) when
G2 is O or S, not more than one of G3 and G4 is N; c) at least one of G2,
G3, and G4 is C; and d) G2,
G3, and G4 are not all C;
X3, X4, and X5 are independently selected from the group consisting of C and N wherein no more than two of X3, X4, and X5 may be N;








b) V2, W2 and W" are independently selected from the group of -H,
alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, 1-alkenyl, and 1-alkymyl;
Z2 is selected from the group of-CHR20H, -CHR20C(0)R3, -CHR20C(S)R3, -CHR2OCO2R3, -CHR20C(0)SR3, -CHR20C(S)OR3, -CH(aryl)OH, -CH(CH=CR22)OH, -CH(C=CR2)OH, -SR2,0 -CH2NHaryl, -CH2aiyl; or
together V2 and Z2- are connected via an additional 3 to 5 atoms to form a
cyclic group containing 5 to 7 ring atoms, optionally containing 1
heteroatom, and substituted with hydroxy, acyloxy,
alkyleneoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from a Y attached to phosphorus;
c) Z" is selected from the group of -OH, -0C(0)R3, -OcO21R3, and
-0C(0)SR3;
D" is -H;
D" is selected from the group of -H, alkyl, -OR2, -OH, and -0C(0)R3;
each W3 is independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W are not all -H and V2, Z2, W2, W" are not all -H; and
R2 is selected from the group consisting of R3 and -H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of -H, alkylene, -alkylenearyl and aryl, or together R4 and R4 are connected via 2 to 6 atoms, optionally including one heteroatom selected from the group consisting of O, N, and S;


R6 is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, aryl, aralkyl, alkyloxycarbonyloxyalkyl, and lower acyl, or together with R12 is connected via 1 to 4 carbon atoms to form a cyclic group;
R7 is lower R3;
each R9 is independently selected from the group consisting of -H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
R11 is selected from the group consisting of alkyl, aryl, -NR22, and -OR2; and
each R12 and R13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12 and R13 together are connected via a chain of 2 to 6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S, to form a cyclic group;
each R14 is independently selected from the group consisting of -OR17, -N(R17)2, -NHR17, -SR17, and -NR2OR20;
R15 is selected from the group consisting of -H, lower aralkyl, lower aryl, lower aralkyl, or together with R16 is connected via 2 to 6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
R16 is selected from the group consisting of -(CR12R13)n-C(0)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or together with R15 is connected via 2 to 6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
each R17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, or together R17 and R17 on N is connected via 2 to 6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
RI8 is selected from the group consisting of -H and lower R3;
R19 is selected from the group consisting of -H, and lower acyl;










9. The compounds as claimed in claim 1 wherein L is selected from the group consisting of:
i) 2,5-furanyl, 2,5-thienyl, 2,6-p3rridyl, 2,5-oxazolyl, 5,2-
oxazolyl, 2,4-oxazolyl, 4,2-oxazolyl, 2,4-imidazolyl, 2,6-pyrimidinyl, 2,6- pyrazinyl 1,3-phenyl;
ii) l,2-eth5?nyl; and
iii) a linking group having 3 atoms measured by the fewest
number of atoms connecting the carbon of the aromatic ring
and the phosphorus atom and is selected from the group
consisting of -alkylenecarbonylamino-,
alkyleneaminocarbonyl-, -alkyleneoxycarbonyl-, and -alkyleneoxyalkylene-.








V is selected from the group of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl;
Z is selected from the group of -CHR2OH, -CHR20C(0)R3, -CHR20C(S)R3, -CHR20C(S)OR3, -CHR20C(0)SR3, -CHR2OCO2R3, -OR2, -SR2, -CHR2N3, -CH2aryl, -CH(aiyl)OH, -CH(CH=CR22)OH, -CH(C=CR2)OH, -R2 , -NR22, -OCOR3, -OCO2R3, -SCOR3, -SCO2R3, -NHCOR2, -NHCO2R3, -CH2NHaiyl, -(CH2)p-OR19, and -(CH2)p-SR19;
or
together V and Z are connected via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V; or
together Z and W are connected via an additional 3 to 5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or
W and W" are independently selected from the group of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl and -R9;
or
together W and W are connected via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
23. The compounds as claimed in claim 1 wherein R1 and R1 together are



V2, W2 and W" are independently selected from the group of -H, alkyl, aralkyl, alicyclic, atyl, substituted aryl, heteroaryl, substituted heteroaryl, l-alkenyl, and 1-alkynyl;
Z2 is selected from the group of -CHR20H, -CHR20C(0)R3, -CHR20C(S)R3, CHR2OCO2R3, -CHR20C(O)SR3, -CHR2OC(S)OR, -CH(aryl)OH, -CH(CH=CR22)OH, -CH(C=CR2)OH, -SR2, -CH2NHaryl, -CH2aryl; or
together V2 and Z2 are connected via an additional 3 to 5 atoms to form a
cyclic group containing 5 to 7 ring atoms, optionally containing 1
heteroatom, and substituted with hydroxy, acyloxy,
alkyleneoxcarbonyoxy or aryloxycarbonyloxy attached to a carbon atom that is three atoms from a Y attached to phosphorus.
24. The compounds as claimed in claim 1 wherein when both Y groups are -0-, then R1 attached to -o- is optionally substituted aryl.
25. The compounds as claimed in claim 1 wherein when both Y groups are -0-, then R1 is indepehdently selected from the group consisting of optionlly substituted aralkyl.
26. The compounds as claimed in claim 1 wherein both Y groups are -0-, and at least one R1 is selected from the group consisting of -C(R2)2-0C(0)R3, and -C(R2)2-OC(o)OR3.
27. The compounds as claimed in claim 1 wherein at least one Y is -0-, and together R1 and R1 are





or Z
or Z"
w

wherein
a) V is selected from the group of aryl, substituted aiyl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl;
Z is selected from the group of -CHR20H, -CHR20C(0)R3, -CHR20C(S)R3, -CHR20C(S)OR3, -CHR20C(0)SR3, -CHR2OCO2R3, -OR2, -SR2, -CHR2N3, -CH2aiyl, -CH(aiyl)OH, -CH(CH=CR22)OH, -CH(C=CR2)OH, -R2, -NR22, -OCOR3, -OCO2R3, -SCOR3, -SCO2R3, -NHCOR2, -NHCO2R3, -CH2NHaiyl, -(CH2)p-OR19, and -(CH12P-SR19
or
together V and Z are connected via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V; or
together Z and W are connected via an additional 3 to 5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or
W and W are independently selected from the group of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl and -R9
or
together W and W are connected via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;


b) V2, W2 and W" are independently selected from the group of -H,
alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, 1-alkenyl, and 1-alkynyl;
Z2 is selected from the group of -CHR^OH, -CHR20C(0)R3, -CHR20C(S)R3, -CHR2OCO2R3, -CHR20C(0)SR3, -CHR20C(S)OR3, -CH(aryl)OH, -CH(CH=CR22)OH, -CH(C-CR2)OH, -SR2, -CH2NHaryl, -CH2aryl; or
together V2 and Z2 are connected via an additional 3 to 5 atoms to form a
cyclic group containing 5 to 7 ring atoms, optionally containing 1
heteroatom, and substituted with hydroxy, acyloxy,
alkyleneoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from a Y attached to phosphorus;
c) Z" is selected from the group of -OH, -OC(O)R3, -OCO2R3, and
-0C(0)SR3;
D" is -H;
D" is selected from the group of -H, alkyl, -OR2, -OH, and -0C(0)R3;
each W3 is independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W are not all -H and V2, Z2, W2, W" are not all -H; and
b) both Y groups are not -NR^-;
R2 is selected from the group consisting of R3 and -H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;


R6 is selected from the group consisting of -H, and lower alkyl.
28. The compounds as claimed in claim 1 wherein one Y is -0-, and R1 is optionally substituted aryl; and the other Y is -NR6-, where R1 attached to said -NR6- is selected from the group consisting of-C(R4)2C(O)OR3, and -C(R2)2C(O)OR3.
29. The compounds as claimed in claim 1 wherein
J2, J3, J4 j5 and J6 are independently selected from the group consisting of -H, -NR42, -CONR42, -CO2R3, halo, -SO2NR42, lower alkyl, lower alkenyl, lower alkyleneaiyl, lower alkynyl, lower perhaloalkyl, lower haloalkyl, lower aryl, lower alkylene-OH, -O11, -CR22NR42, -CN, -C{S)NR42, -OR2, -SR2, -N3, -NO2, -NHC(S)NR42, -NRI8COR2, -CR22CN;
L is selected from the group consisting of
i) 2,5-furanyl, 2,5-thienyl, 1,3-phenyl, 2,6-pyridyl, 2,5-
oxazolyl, 5,2-oxazolyl, 2,4-oxazolyl, 4,2-oxazolyl, 2,4-imidazolyl, 2,6-p5nnmidinyl, 2,6-pyra2inyl;
ii) l,2-ethnyl; and
iii) a linking group having 3 atoms measured by the fewest
number of atoms connecting the carbon of the aromatic ring
and the phosphorus atom and is selected from the group
consisting of -alkylenecarbonylamino-,
alkyleneaminocarbonyl-, -alkyleneoxycarbonyl-, and -alkyleneoxyalkylene-;
when both Y groups are -O-, then R1 is independently selected from the group consisting of optionally substituted aryl, optionally substituted benzyl, -C(R2)20C(0)R3, -C(R2)20C(0)OR3, and -H; or
when one Y is -0-, then R1 attached to -O- is optionally substituted aryl; and
the other Y is -NR6-, then R1 attached to -NR6- is selected from the group consisting of -C(R4)2C(O)OR3, and -C(R2)2C(0=O)OR3; or


when Y is -O- or -NR6-, then together R1 and Ri are

wherein
a) V is selected from the group of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl;
Z is selected from the group of -CHR20H, -CHR20C(O)R3, -CHR20C(S)R3, -CHR20C(S)OR3, -CHR20C(0)SR3, -CHR2OCO2R3, -OR2, -SR2, -CHR2N3, -CH2aiyl, -CH(aryl)OH, -CH(CH=CR22)OH, -CH(C=CR2)OH, -R2, -NR22, -OCOR3, -OCO2R3, -SCOR3, -SCO2R3, .-NHCOR2, -NHCO2R3, -CHaNHaiyl, -(CH2)p-OR19, and -(CH2)p-SR19;
or
together V and Z are connected via an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta ad gamma position to the Y adjacent to V;or
together Z and W are connected via an additional 3 to 5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or
W and W" are independently selected from the group of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl and -R9;
or


together W and W" are connected via an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V must be aiyl, substituted aryl, heteroaryl, or substituted heteroaryl;
b) V2, W2 and W" are independently selected from the group of -H,
alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, 1-alkenyl, and 1-alkynyl;
Z2 is selected from the group of -CHR20H, -CHR20C(0)R3, -CHR2OC(S)R3, -CHR20C02R3, -CHR2OC(O)SR3, -CHR20C(S)OR3, -CH(aryl)OH, -CH{CH=CR22)OH, CH(C=CR2)OH, -SR2, -CH2NHaryI, -CH2aryl; or
together V2 and Z2- are connected via an additional 3 to 5 atoms to form a
cyclic group containing 5 to 7 ring atoms, optionally containing 1
heteroatom, and substituted with hydroxy, acyloxy,
alkyleneoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from a Y attached to phosphorus;
c) Z" is selected from the group of -OH, -0C(0)R3, -OCO2R3, and
-0C(0)SR3;
D" is -H;
D" is selected from the group of -H, alkyl, -OR2, -OH, and -0C(0)R3;
each W3 is independently selected from the group consisting of -H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W are not all -H and V2, Z2, W2, W" are not all -H; and alicyclic; and
b) both Y groups are not -NR6-;
R2 is selected from the group consisting of R3 and -H;

R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R6 is selected from the group consisting of -H, and lower alkyl.
30. The compounds as claimed in claim 2 wherein R6 is substituted
phenyl;
L is furan-2,5-diyl; J2, J3, J4, j5 and J6 are independently selected from the group consisting of -OR3, -SO2NHR4, -CN, -H, halo, -NR4 -(CH2)2aryl, -(CH2)NHaiyl, and -NO2; at least one Y group is -0-.
31. The compounds as claimed in claim 1 wherein
one Y is -NR6-, and R1 attached to it is -{CR12R13)„-C(0)-R14, then the other YR1 is selected from the group consisting of -NR15R16, -OR7, and NR6-(CR12R13)n.c(O)-R14.
32. The compounds as claimed in claim 22 wherein the other YR1 is -OR7.
33. The compounds as claimed in claim 1 that are of the formula:




Dated this 06/09/2002

[RAPWNA MEHTA-DUTT]
OF REMFRY & SAGAR
ATTORNEY FOR THE APPLICANT[S]

Documents:

in-pct-2002-1219-mum-abstract(25-09-2007).doc

in-pct-2002-1219-mum-abstract(25-09-2007).pdf

in-pct-2002-1219-mum-cancelled pages(06-09-2002).pdf

in-pct-2002-1219-mum-claims(granted)(25-09-2007).pdf

in-pct-2002-1219-mum-claims(granted)-(25-09-2007).doc

in-pct-2002-1219-mum-correspondence(25-09-2007).pdf

in-pct-2002-1219-mum-correspondence-(ipo)(04-02-2007).pdf

in-pct-2002-1219-mum-form 1(25-09-2007).pdf

in-pct-2002-1219-mum-form 13(25-09-2007).pdf

in-pct-2002-1219-mum-form 18(30-11-2005).pdf

in-pct-2002-1219-mum-form 1a(06-09-2002).pdf

in-pct-2002-1219-mum-form 2(granted)(25-09-2007).pdf

in-pct-2002-1219-mum-form 2(granted)-(25-09-2007).doc

in-pct-2002-1219-mum-form 3(06-09-2002).pdf

in-pct-2002-1219-mum-form 3(25-09-2007).pdf

in-pct-2002-1219-mum-form 5(06-09-2002).pdf

in-pct-2002-1219-mum-form pct-isa-210(06-09-2002).pdf

in-pct-2002-1219-mum-general power of authority(06-09-2002).pdf

in-pct-2002-1219-mum-general power of authority(25-09-2007).pdf

in-pct-2002-1219-mum-petition under rule-137(25-09-2007).pdf

in-pct-2002-1219-mum-petition under rule-138(25-09-2007).pdf


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Patent Number 216576
Indian Patent Application Number IN/PCT/2002/01219/MUM
PG Journal Number 13/2008
Publication Date 28-Mar-2008
Grant Date 17-Mar-2008
Date of Filing 06-Sep-2002
Name of Patentee METABASIS THERAPEUTICS INC
Applicant Address 9390 TOWNE CENTRE DRIVE, SAN DIEGO, CALIFORNIA 92121, USA
Inventors:
# Inventor's Name Inventor's Address
1 BRETT C. BOOKSER 4186 STRUGEON COURT, SAN DIEGO, CALIFORNIA 92130, USA
2 K. RAJA REDDY 4146 FEDERMAN LANE, SAN DIEGO, CALIFORNIA 92130
3 QUN DANG 7825 ROAN ROAD, SAN DIEGO, CALIFORNIA 92129
PCT International Classification Number C07F9/655
PCT International Application Number PCT/US01/07452
PCT International Filing date 2001-03-07
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/187,750 2000-03-08 U.S.A.