60/456,084, filed on March 19,2003. The entire teachings of the above application are incorporated herein by reference.

BACKGROUND OF THE INVENTION People with inadequate renal function, hypoparathyroidism, or certain other medical conditions often have hyperphosphatemia, or elevated serum phosphate levels (over 6 mg/dL). Hyperphosphatemia, especially if present over extended periods of time, leads to severe abnormalities in calcium and phosphorus metabolism, often manifested by hyperparathyroidism, bone disease and calcification in joints, lungs, eyes and vasculature. For patients who exhibit renal insufficiency, elevation of serum phosphorus within the normal range has been associated with progression of renal failure and increased risk of cardiovascular events. The progression of kidney disease can be slowed by reducing phosphate retention. Thus, for renal failure patients who are hyperphosphatemic and for chronic kidney disease patients whose serum phosphate is within the normal range or is only slightly elevated, therapy to reduce phosphate retention is beneficial.

For patients experiencing hyperphosphatemia, calcium salts have been widely used to bind intestinal phosphate and prevent its absorption. Different types of calcium salts including calcium carbonate, acetate, citrate, alginate, and ketoacid salts have been utilized for phosphate binding. The major problem with all of these therapeutics is the hypercalcemia that often results from absorption of high amounts of ingested calcium. Hypercalcemia causes serious side effects such as cardiac arrhythmias, renal failure, and skin and visceral calcification. Frequent monitoring of serum calcium levels is required during therapy with calcium-based phosphate binders. Other calcium and aluminum-free phosphate binders have drawbacks including the amount and frequency of dosing required to be therapeutically active.

An alternative approach to the prevention of phosphate absorption from the intestine in patients with elevated phosphate serum levels is through inhibition of the intestinal transport system, which mediates phosphate uptake in the intestine. It is understood that phosphate absorption in the upper intestine is mediated at least in part by a carrier-mediated mechanism that couples the absorption of phosphate to that of sodium in an energy-dependent fashion. Inhibition of intestinal phosphate transport will reduce serum phosphate levels. This would be particularly advantageous in patients susceptible to hyperphosphatemia as a result of renal insufficiency or in patients that have a disease that is treatable by inhibiting the uptake of phosphate from the intestines. Inhibition of phosphate reabsorption from the urine by the kidneys would also be advantageous for treating chronic renal failure. Furthermore, inhibition of phosphate transport may slow the progression of renal failure and reduce risk of cardiovascular events.

SUMMARY OF THE INVENTION It has now been found that certain unsaturated phosphinyl phosphonate compounds, which have a double or triple bond directly adjacent to the phosphinyl phosphonate moiety, are effective inhibitors of phosphate transport proteins. An alkenylene phosphinyl phosphonate has a double bond directly adjacent to the phosphinyl phosphonate moiety and an alkynylene phosphinyl phosphonate group has a triple bond directly adjacent to the phosphinyl phosphonate moiety. An allenylene phosphinyl phosphonate has an allene group adjacent to the phosphinyl phosphonate moiety and is considered herein to be a type of alkenylene phosphinyl phosphonate. For example, the unsaturated phosphinyl phosphonate compounds shown in Table 1 inhibit phosphate transport, several with an ICSO below 10 p1M in an in vitro rabbit intestinal Brush Border Membrane assay (see Example 10). Based on this discovery, methods of treating a subject with chronic kidney disease, a disease associated with disorders of phosphate metabolism or a disease mediated by impaired phosphate-transport function are disclosed. Also, novel phosphate transport inhibiting polymers and compounds are disclosed.

In one embodiment, the present invention is a compound having a double bond or triple bond directly adjacent to a phosphinyl phosphate group, such as those represented by Structural Formulas (I), (II) or (III):

or a pharmaceutically acceptable salt or a prodrug thereof.

Ri and R2 are independently-H,-ORx,-N (RX) 2, =0, =NRx, an electron withdrawing group or a substituted or unsubstituted alkyl group.

R3 is a substituted or unsubstituted hydrocarbyl group optionally interrupted by one or more nitrogen, oxygen or sulfur atoms.

R4 and R5 are independently-H, a halogen, a substituted or unsubstituted alkyl group, -C (O) Rx, -C (O) ORx, -C (O) N (Rx) 2,-ORx,-SRx,-S (O) OR.,-S (O) ORx, - S(O)N(Rx)2, -S(O)2ORx, -S(O)2N(Rx)2, -N(Rx)2, -N=N-Rx, -CN, or -NO2.

Preferably, when X is a covalent bond, R4 and R5 are a halogen, an alkyl group substituted with an electron withdrawing group,-C (O) Rx,-C (O) ORx,-C (O) N (Rx) 2, -ORx,-SRx,-S (O) ORx, -S (O) ORx,-S (O) N (Rx) 2,-S (0) 20Rx,-S (0) 2N (Rx) 2,-N (Rx) 2,- N=N-Rx,-CN, or -NO2.

Each Rb is independently-H, a substituted or unsubstituted alkyl group, or a phosphate protecting group.

X is a covalent bond,-CHY-,-CY2-,-C (O)-,-OC (O)-,-S-,-S (O)-, -S (0) 2-, -NRx-, -O-, -C (S) -,-SC (O)-,-SC (S) -,-NHC (O) NH-, or-NHC (NH) NH-.

Y is a halogen or lower alkyl group.

Rx is independently-H, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group.

The present invention also includes a polymer comprising one or more pendant alkenylene phosphinyl phosphonate or alkynylene phosphinyl phosphonate groups or a pharmaceutically acceptable salt thereof or ester thereof. In one example, the alkenylene phosphinyl phosphonate or alkynylene phosphinyl phosphonate groups are represented by Structural Formula (IV), (V), or (VI):

or a pharmaceutically acceptable salt thereof, where X, Rl, R2, R4, R5 and Rb are as defined above for Structural Formulas (I)- (III).

Another embodiment of the present invention is a method of inhibiting phosphate transport in a subject in need of phosphate transport inhibition. The method comprises the step of administering to the subject an effective amount of an alkenylene phosphinyl phosphonate or alkynylene phosphinyl phosphonate, or a polymer that comprises one or more alkenylene phosphinyl phosphonate or alkynylene phosphinyl phosphonate groups.

The phosphate transport inhibitors disclosed herein can be used for the manufacture of a medicament for inhibiting phosphate transport in a subject in need of such treatment, e. g. , for treating or preventing disorders of phosphate metabolism or impaired phosphate transport function such as hyperphosphatemia, hyperparathyroidism, uremic bone disease, soft tissue calcification (e. g., cardiovascular calcification), progression of renal failure, cardiovascular events and osteoporosis. The invention also relates to the disclosed unsaturated phosphinyl phosphonate compounds and unsaturated phosphinyl phosphonate containing polymers for use in inhibiting phosphate transport in a subject in need of such treatment, e. g. , for treating or for preventing chronic renal failure or a disease associated with hyperphosphatemia.

Another embodiment of the present invention is a pharmaceutical composition comprising a phosphate transport inhibiting compound or polymer of the present invention and a pharmaceutically acceptable carrier, diluent or excipient.

The pharmaceutical compositions can be used in therapy, such as for treatment of one of the diseases or conditions disclosed herein.

Another embodiment of the present invention is the use of a phosphate transport inhibitor disclosed herein (compound or polymer comprising one or more pendant phosphinyl phosphate groups) in combination with a pharmaceutically acceptable compound which binds phosphate (a"phosphate sequestrant"). The pharmaceutically acceptable phosphate binder can be a calcium, aluminum or lanthanum-containing phosphate binder or, preferably, a phosphate-binding polymer such as those disclosed in U. S. Patent Nos. 5,496, 545,5, 667,775 and 6,083, 495, the contents of which are incorporated herein by reference in their entirety. Preferably, the phosphate-binding polymer is a polyallylamine such as sevelamer (e. g, sevelamer hydrochloride, sevelamer carbonate, sevelamer bicarbonate).

The compounds and polymers disclosed herein are effective inhibitors of phosphate transport and thus are useful for treatment of hyperphosphatemia, chronic renal failure, diseases associated with disorders of phosphate metabolism and impaired phosphate transport function. The beneficial aspects on chronic renal failure, disorders of phosphate metabolism or impaired phosphate transport function, e. g. , hyperparathyroidism, uremic bone disease, renal bone disease, soft tissue

calcification (e. g. , cardiovascular calcification), cardiovascular events, and osteoporosis, could be mediated by either an effect on the intestinal transporters and/or on transporters in other tissues, such as those present in bone, kidney or vasculature.

DETAILED DESCRIPTION OF THE INVENTION Disclosed herein are small molecule and polymer inhibitors of phosphate transport. These compounds are preferably used to inhibit (i. e. , reduce or prevent, in whole or in part) phosphate transport in the gastrointestinal tract and are therefore useful in treating conditions and diseases characterized by elevated phosphate levels, for example, hyperphosphatemia, renal failure and hypoparathyroidism. Many of the small molecule inhibitors are expected to be absorbed by the gastrointestinal tract and are therefore available systemically. As a consequence, they can inhibit phosphate transport in other organs such as the kidneys and can advantageously be used to treat chronic renal failure. The small molecule inhibitors are represented by Structural Formulas (1), (II) and (III) and comprise an unsaturated phosphinyl phosphonate group, where a double or triple bond is immediately adjacent to the phosphinyl phosphonate moiety. The polymer inhibitors also comprise unsaturated phosphinyl phosphonate groups, which can be pendant from the polymer backbone or integral to the polymer backbone.

Ri and R2 in Structural Formulas (I)- (VI) can independently be an electron withdrawing group. Preferred values of Rl and R2 are-H, an electron withdrawing group (e. g. , a halogen), or a substituted or unsubstituted alkyl group ; more preferably Rl and R2 are-H or-F.

R4 and Rs in Structural Formulas (I)- (VI) are typically-H, a halogen, a substituted or unsubstituted alkyl group, -C (O) Rx,-C (O) ORX, or-C (O) N (Rx) 2 ; and are preferably independently-H or a halogen, particularly-F. Preferably, Rl and R2 are independently-H or-F and R4 and R5 are independently-H or-F.

Rb in Structural Formulas (I)- (VI) is typically independently-H or a lower alkyl group. When Rb has these values, then Rl, R2, R4, and Rs preferably have the values described in the previous paragraph. Rb can also be a phosphate protecting group, where one, two or all three of the acidic oxygens (oxygen atoms singly

bonded to phosphorus) are protected. When Rb is a phosphate protecting group, Ri, R2, R4, and R5 preferably have the values described in the previous paragraph.

In a more preferred embodiment, X in Structural Formulas (I)- (VI) is selected to be a covalent bond,-S-,-S (0) 2-,-NRx-or-0- ; and Rl, R2, R4, R5 and Rb are as described in the previous paragraph. Preferably, X is a covalent bond, -S-, or - S (0) 2-. When X is a covalent bond, -S-, or-S (0) 2-, Rb is preferably-H. Even more preferably, Rl and R2 are-H or-F and R4 and R5 are each-H. For alkynyl phosphinyl phosphonates, X is preferably a covalent bond.

In one preferred embodiment, R3 in Structural Formulas (I)- (III) is a substituted or unsubstituted C6-Cz8 alkyl group, but is more preferably unsubstituted.

Compounds where R3 is an unsubstituted C8-Cl2 alkyl group have been found to have particularly desirable properties. The alkyl group represented by R3 is optionally interrupted by one or more nitrogen, sulfur or oxygen atoms (preferably oxygen). Suitable substituents particularly include halogens (e. g. , chlorine, bromine, iodine and preferably fluorine). The alkyl group represented by R3 can be perhalogenated, specifically perfluorinated. When R3 has these values, preferred values for X, Rl, R2, Rs, R5, and Rb are those described in the prior paragraph.

In another preferred embodiment, the R3 group is a straight chained hydrocarbyl group optionally interrupted by one or more nitrogen, oxygen or sulfur atoms. When R3 is straight chained, preferred values for X, Rl, R2, R4, R5, and Rb are those described in the prior paragraph. A straight chain hydrocarbyl group is preferably substituted with one or more groups selected from a halogen,-OC (O) R', -CN,-NO2,-COOH, =0,-NH2-NH (R'), -N (R') 2.-C (O) OR',-C (O) NH2, -C (O) NHR', -C (O) N (R') 2, -SH,-S (R'), an aliphatic group, an aryl group and a heteroaryl group. Each R'is independently-H, an allcyl group or an aryl group.

Alternatively, R3 is a straight chained hydrocarbyl group optionally interrupted by one or more nitrogen or sulfur atoms.

R3 can additionally be a substituted or unsubstituted aryl group, which is either carbocyclic or heteroaryl. When R3 is an aryl group, it is often a phenyl group. When R3 has these values, preferred values for X, Rl, R2, R4, Rs, and Rb are those described in the prior paragraph.

In another aspect of the invention, X is a covalent bond and R3 is represented by the following structural formula:

where: m is an integer from 1 to about 18 ; n is an integer from 0 to about 6, provided that n is 1 to about 6 when L is -OC (O)-,-NRxC (O)-,-NRx-or-O-and Q is-C (O) O-,-C (O) NRX-,-NRx-or-0-; R6 is -H or an alkyl group; R7 is-H or an alkyl group; L is a covalent bond, 1,3-phenylene, 1,4-phenylene,-OC (O)-,-NRxC (O) -, -C (O)-,-O-, or-NRx-; Q is a covalent bond, 1,3-phenylene, 1,4-phenylene,-C (O) O-,-C (O) NRX-, -C (O)-,-O-, or-NRx-; and Rx is the same as defined above for Structural Formulas (I)- (VI).

As used herein, the symbol"*"represents where the illustrated group is attached to the remainder of the molecule. In polymers, the symbol"*"represents where the illustrated group is attached to the repeat unit of the polymer (e. g. , the polymer backbone, a linker group that attaches to the polymer backbone).

The groups represented by L and Q can be present in either orientation (left- to-right or right-to-left) within a structure, but those containing a carbonyl moiety (e. g.,-C (O) NRx-,-C (O) O-) are preferably selected such that the carbonyl moiety of L is closest to the unsaturated phosphinyl phosphate group and the carbonyl moiety of Q is closest to the terminal double bond (to which R6 and R7 is attached).

More preferably in Structural Formula (XLIX), L is a covalent bond, n is zero, m is from 8 to 12, and Q is-C (O) O-or-C (O) NRx- (e. g. , with the carbonyl group closer to the terminal double bond) and the remainder of the variables are as described above for Structural Formula (XLIX).

In one embodiment, polymers of the present invention comprise pendant unsaturated phosphinyl phosphonate groups. Examples of pendant unsaturated phosphinyl phosphonate groups are represented by Structural Formulas (IV)- (VI) and (XXVII)- (XXXV) and (LVIII) :

where Ri, R2, R3, R4, R5, Rb and X are as defined above for Structural Formulas (I)- (III). Preferably, Rl and R2 are independently-H or-F. Preferred values of R3, R4, R5, Rb and X are as described above for Structural Formulas (I)- (III).

In one type of polymer disclosed herein, the polymer backbone connects to the unsaturated phosphinyl phosphonate group via an inert linking group attached to X. Specific examples of polymers of this type comprise repeat units represented by Structural Formulas (VII), (VIII) and (XXXVI) :

where: M is-NR.-,-0-,-C -NRx-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(Rx)2-, -NRxC(O)-, -(CH2)q-, phenylene, or phenylene-O- ; A is a covalent bond or inert spacer group; and Ri, R2, R3, R4, R5, Rb and X are as defined above for Structural Formulas (I)- (III).

For repeat units represented by Structural Formulas (VII), (VIII), and (XXXVI), Ri, R2, R4, and R5 are preferably-H or-F. More preferably, Rl, R2, R4 and R5 are independently-H or-F and A is a hydrocarbyl group optionally interrupted by one or more nitrogen, oxygen or sulfur atoms, such as an alkylene group. Even more preferably, A is an alkylene group; Rl, R2, R4 and R5 are independently-H or-F; and X is a covalent bond,-S-,-S (0) 2-,-NRX-, or-O-. Yet more preferably, A is an alkylene group; Rl, R2, R4 and R5 are independently-H or

-F ; X is a covalent bond,-S-,-S (0) 2-,-NRx-, or -O-; and Rb is independently-H or a lower alkyl group.

Another type of polymer of the present invention is where the polymer forms an ester with the unsaturated phosphinyl phosphonate group. An ester may be formed with one, two or three of the acidic oxygens in the phosphinyl phosphonate group. When two or three oxygen atoms are esterified, the ester linkages can be made to the same molecule or to two or three separate molecules. Examples of such unsaturated phosphinyl phosphonate groups are represented by Structural Formulas (IX)- (XXII) and (L)- (LVI) :

or a pharmaceutically acceptable salt thereof, where Rl, R2, R3, R4, R5, Rb, and X are as defined above for Structural Formulas (I)- (III).

Preferably, unsaturated phosphinyl phosphonate groups represented by Structural Formulas (IX)- (XXII) and (L)- (LVI) are characterized by one or more of the following features: (1) R1 and R2 are independently-H or-F, (2) R3 is a

substituted or unsubstituted alkyl group, (3) R4 and Rs are independently-H or-F, and (4) Rb is-H or a lower alkyl group. More preferably, the unsaturated phosphinyl phosphonate groups represented by Structural Formulas (IX)- (XXII) and (L)- (LVI) are characterized by Feature (1), Features (1) and (2), Features (1), (2) and (3), or Features (1), (2), (3) and (4).

Polymers capable of forming ester linkage (s) with the unsaturated phosphinyl phosphonate groups shown above contain one or more or two or more pendant hydroxyl groups (e. g. , polyvinylalcohol, polyallylalcohol), one or more or two or more terminal hydroxyl groups (polyalkylene glycols such as polyethylene glycol and polypropylene glycol), or a combination of at least one pendant hydroxyl group and at least one terminal hydroxyl group (e. g. , a polysaccharide, a branched polysaccharide).

Another type of polymer of the present invention includes unsaturated phosphinyl phosphonate groups as a part of the polymer backbone. Polymers of this type are represented by Structural Formulas (XXIII), (XXIV) and (LIX):

where each Rap is independently a diol or a polyol, which contain 2 or more or 3 or more hydroxyl groups, respectively. Some examples of diols and polyols are listed in the prior paragraph. Other examples include sugars such as glucose and diols such as 1,3-dihydroxypropane. Rl, R2, R3, R4, R5, Rb, and X are as defined above for Structural Formulas (I)-(III). Preferred values of R1, R2, R3, R4, R5, Rb, and X are also as described above for Structural Formulas (I)- (III).

In some aspects, the following alkenylene phosphoninyl phosphonates represented by Structural Formulas (XXV) and (XXVI) are excluded from the present invention:

and pharmaceutically acceptable salts thereof, where Rc is-H, methyl, ethyl or phenyl; Rd is-H or-F; and q is an integer from 0-2; R"is a hydrocarbyl group such as a substituted or unsubstituted alkyl group (e. g. , an unsubstituted C18 alkyl group); and each R"'is independently-H or an unsubstituted alkyl or aryl group (e. g. , methyl, ethyl, propyl, phenyl). Typically, the phosphinyl R"'is phenyl and the phosphonate R"'groups are ethyl.

The polymers of the present invention can be homopolymers, which have a uniform backbone composed of an unsaturated phosphinyl phosphonate containing monomers derived from a common polymerizable unit, such as unsaturated phosphinyl phosphonate functionalized acrylamide. Also included are copolymers and terpolymers, i. e. , polymers comprising a mixed backbone of two or three different monomer units, respectively, one or more of which contains an unsatuated phosphinyl phosphonate group. Optionally, a co-polymer or ter-polymer comprises a monomer or repeat unit without an unsaturated phosphinyl phosphonate group.

Examples of such monomer or repeat units are hydrophilic monomer or repeat units, which comprise a hydrophilic group such as an alcohol, amine, carboxylate, or carboxamide in the side chain. Examples include polyallylamine, polydiallylamine, polyallylalcohol and polyvinylalcohol. Additional examples include:

where R13 is-H or a lower alkyl group and p is an integer from 1 to 18.

The polymers of the present invention include addition polymers such as an unsaturated phosphinyl phosphonate functionalized polyacrylate, alkylpolyacrylate, polyacrylamide, alkylpolyacrylamide, poly (allylalcohol), poly (vinylalcohol), poly (vinylether), poly (vinylester), poly (vinylamine), poly (allylamine), poly (diallylamine) backbone or a substituted polystyrene backbone. Typically, these addition polymers have side chains comprising unsaturated phosphinyl phosponate groups. The side chains are typically inert spacer groups such as a straight chained hydrocarbyl group, optionally comprising one or more linking groups, which connect the unsaturated phosphinyl phosphonate group to the polymer backbone, for example, to carboxylate groups of a polyacrylate, to the amide nitrogens of a polyacrylamide, to the alcohols of a poly (vinylalcohol) or poly (allylalcohol), or to the amines of a poly (vinylamine,) a poly (allylamine) or a poly (diallylamine) or to a substituent on the phenyl ring of a polystyrene. Polyacrylamide, polymethacrylamide, polyacrylate and polymethacrylate are preferred polymers.

The present invention also includes condensation polymers, which are formed from reactions in which a small molecule such as water is released.

Examples include a polyamide, polyalkyleneimine or a polyester. The unsaturated phosphinyl phosphonate groups can be connected by an inert spacer group to amine or ammonium nitrogens in the backbone of a polyalkyleneimine. For polyamides, the unsaturated phosphinyl phosponate groups can be connected to amide nitrogens in the polymer backbone by an inert spacer group. For polyesters, the unsaturated phosphinyl phosphonate group can be connected by an inert spacer group attached to a carbon atom in the backbone.

The term"polymer backbone"or"backbone"refers to that portion of the polymer that is a continuous chain, comprising the bonds that are formed between

monomers upon polymerization. The composition of the polymer backbone can be described in terms of the identity of the monomers from which it is formed, without regard to the composition of branches, or side chains, off of the polymer backbone.

Thus, a poly (acrylamide) polymer is said to have a poly (acrylamide) backbone, without regard to the substituents on the acrylamide nitrogen atom, which are components of the polymer side chains. A poly (acrylamide-co-styrene) copolymer, for example, is said to have a mixed acrylamide/styrene backbone.

A"side-chain"refers to a branch off of the polymer backbone. An unsaturated phosphinyl phosphonate group in a side chain is therefore said be "pendent"from the polymer backbone.

The term"spacer group, "as used herein, refers to a polyvalent molecular fragment that is a component of a polymer side chain and connects a pendant moiety to the polymer backbone. A spacer group is"inert"when it contains no functionality that substantially interferes with the therapeutic activity of the polymer.

Inert spacer groups are preferably hydrocarbyl groups and are preferably a Cl to C30 alkylene group, more preferably a C1 to C15 group, and even more preferably, a Cl to C8 alkylene group.

Although molecular weight is not believed to be critical, the maximum molecular weight of polymers of the present invention is typically less than about 500,000 Daltons. The polymers are preferably large enough so that they are not absorbed by the gastrointestinal tract, about 1,000 Daltons. Polymers can weigh from about 1,000 Daltons to about 100,000 Daltons or more (e. g. , 500,000 Daltons), about 1,000 Daltons to about 50,000 Daltons, about 1,000 Daltons to about 10,000 Daltons or about 2,000 Daltons to about 10,000 Daltons.

Under circumstance when the unsaturated phosphinyl phosphonate group is sensitive to further reaction, the polymerizable portion of the monomer can be chosen to minimize damage of the unsaturated phosphinyl phosphonate group. One example is to use a monomer that can be polymerized by the ring opening metathesis polymerization (ROMP) technique, such as the ones shown below:

where the inert linking group and the unsaturated phosphinyl phosphonate are attached via **. Further information about the ROMP technique is located in "Synthesis of Norbornenyl Polymers with Bioactive Oliogpeptides by Ring-Opening Metathesis Polymerization, "by H. D. Maynard, et al., Macromolecules, 33 (17): 6239-6248 (2000) and"Highly Efficient Ring-Opening Metathesis Polymerization (ROMP) Using New Ruthenium Catalysis Containing N-Heterocyclic Carbene Ligands, "by C. W. Bielawski, et al., Angew. Chemin. Int. Ed., 39 (16): 2903-2906 (2000), the contents of which are incorporated herein by reference.

The present invention also includes molecules that contain two unsaturated phosphinyl phosphonate moieties, referred to herein as"dimers". Such dimers are represented by Structural Formulas (XXXVII)- (XLVIII) :

where X, Ri, R2, R3, R4, R5, and Rb are as defined above for Structural Formulas (I) - (III) and A is as defined above for Structural Formulas (VII), (VIII) and (XXXVI).

Preferred values of X, Rl, R2, R3, R4, Rs, and Rb are as described above for Structural Formulas (I)- (III). Preferably, A is an inert linking group, such as a substituted or unsubstituted alkylene group. X, RI, R2, R3, R4, R5, and Rb are independently chosen, such that the dimers are either symmetrical or asymmetrical.

If each corresponding X, Ri, R2, R3, R4, R5, and Rb are the same in both unsaturated phosphinyl phosphonate groups, the dimer is symmetrical. If any of one the corresponding X, RI, R2, R3, R4, R5, and Rb variables are not the same between the two phosphinyl phosphonate groups, then the dimer is asymmetrical. Preferably, the dimer is symmetrical.

A"hydrocarbyl group"is an aliphatic or arylene group, or a combination thereof, i. e.,- (CH2),- or- (CH2), C6H4 (CH2),-, where z is a positive integer (e. g., from 1 to about 30), preferably between 6 and about 30, more preferably between 6 and about 15, and even more preferably between about 8 and about 14. The hydrocarbyl group may be optionally interrupted with one or more nitrogen, oxygen or sulfur atoms, or a combination thereof, or can have a backbone of only carbon atoms. Examples of hydrocarbyl groups include butylene, pentylene, hexylene, heptylen, octylene, nonylene, decylene, dodecylene, 4-oxaoctylene, 4-azaoctylene, 4-thiaoctylene, 3,6-dioxaoctylene, 3,6-diazaoctylene, and 4, 9-dioxadodecane.

Arylene groups can be interrupted by a nitrogen, oxygen or sulfur atom to form a heteroarylene group. An aliphatic hydrocarbyl group (or an aliphatic portion thereof) can optionally be saturated or can optionally have one or more double or triple bonds, which can be arranged to form a conjugated series of bonds. The conjugated bonds may or may not include the double or triple bond in the unsaturated phosphinyl phosphonate group.

An"aliphatic group"is a straight chained, branched or cyclic non-aromatic hydrocarbon which is completely saturated or which contains one or more units of unsaturation. Typically, a straight chained or branched aliphatic group has from 1 to about 20 carbon atoms, preferably about 8 to about 14, and a cyclic aliphatic group has from 3 to about 10 carbon atoms, preferably from 3 to about 8. Examples of an aliphatic group include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert- butyl, pentyl, hexyl, heptyl and octyl. An alkyl group is a completely saturated

aliphatic group. A C1-C4 straight chained or branched alkyl group or a C3-C8 cyclic alkyl group is also referred to as a"lower alkyl"group.

The term"aryl group"refers to carbocyclic aromatic groups such as phenyl, naphthyl, and anthracyl, and heteroaryl groups such as imidazolyl, isoimidazolyl, thienyl, furanyl, pyridyl, pyrimidyl, pyranyl, pyrazolyl, pyrrolyl, pyrazinyl, thiazoyl, isothiazolyl, oxazolyl, isooxazolyl, 1,2, 3-trizaolyl, 1,2, 4-triazolyl, and tetrazolyl. An "arylene group"is analogous to an aryl group, but is divalent instead of monovalent.

Heteroaryl groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings. Examples include benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazolyl, benzoisothiazolyl, benzooxazolyl, benzoisooxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl and isoindolyl.

Suitable substituents for a hydrocarbyl group or an aryl group are those that do not significantly lower the phosphate transport inhibiting activity of the compound or polymer (e. g. , do not lower the activity by more than a factor of about two compared with the corresponding unsubstituted compound). Examples include -OH, a halogen (-Br,-Cl,-I and-F),-O (R'), -OC (O) R',-CN,-NO2,-COOH, =0, - NH2-NH (R'), -N (R') 2.-C (O) OR', -CONH2,-C (O) NHR', -C (O) N (R') 2,-SH, - S (R'), an aliphatic group, an aryl group and a heteroaryl group. Each R'is independently-H, an alkyl group or an aryl group. A substituted aliphatic group or aryl group can have more than one substituent.

The term"electron withdrawing group", as it is used herein, has the meaning commonly afforded the term in the art. Specifically, an electron withdrawing group is a substituent which results in a phenyl ring having less electron density when the group is present on the phenyl ring than when it is absent. Electron withdrawing groups have a Hammet sigma value greater than zero (see, for example, C. Hansch, A. Leo and D. Hoeckman,"Exploring QSAR Hydrophobic, Electronic and Steric Constants", American Chemical Society (1995), pages 217-32, the contents of which are incorporated herein by reference). Examples of electron withdrawing groups include halogens,-NO2,-CN,-CF3 and-OCF3. A halogen, particularly fluoride, is a preferred electron withdrawing group.

Also included in the present invention are pharmaceutically acceptable salts of the compounds and polymers described herein. Compounds and polymers disclosed herein which possess a sufficiently acidic functional group, a sufficiently basic functional group or both, can react with any of a number of organic or inorganic bases, and inorganic and organic acids, to form a salt. Unsaturated phosphinyl phosphonates contain three acidic protons and therefore readily form salts in the presence of base.

Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, amines and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, and the like.

Acids commonly employed to form acid addition salts from compounds with basic groups are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.

Examples of such salts include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1,6- dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma- hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

When the compound or polymer comprises an ammonium group, a pharmaceutically acceptable counteranion is also present. Examples include chloride, bromide, iodide, nitrate, sulfate, carbonate, and the like. A compound or polymer can have more than one type of counteranion when the overall number of positive charges is greater than one.

Unsaturated phosphinyl phosphonate groups can also form a salt with an appropriate, pharmaceutically acceptable polymer. Typically, such polymers contain basic groups, such as amine groups. Aliphatic amine polymers, such as polyallylamines (e. g. , sevelamer) are advantageously used as counterions to an unsaturated phosphinyl phosphonate group.

A"subject"is preferably a human, but can also be another animal in need of treatment with a phosphate transport inhibitor, e. g., companion animals (e. g. , dogs, cats, and the like), farm animals (e. g. , cows, pigs, horses and the like) and laboratory animals (e. g. , rats, mice, guinea pigs and the like).

Subjects"in need of phosphate transport inhibition"include subjects with diseases and/or conditions that can be treated with phosphate transport inhibitors to achieve a beneficial therapeutic and/or prophylactic result. A beneficial outcome includes a decrease in the severity of symptoms or delay in the onset of symptoms, increased longevity and/or more rapid or more complete resolution of the disease or condition. For example, a subject in need of treatment typically has elevated serum phosphate levels or hyperphosphatemia, resulting from, for example, impaired kidney function or hypoparathyroidism. Lower serum phosphate levels can be achieved, for example, by inhibiting phosphate transport in the intestines. A subject"in need of treatment"also includes a subject with chronic renal failure who may have serum phosphate levels within the normal range. Inhibition of phosphate transport in the intestine or kidneys can slow rate of renal deterioration in these subjects, and decrease the risk of cardiovascular events. Other examples of subjects in need of phosphate transport inhibitors include patients with a disease associated with disorders of phosphate metabolism or a disease mediated by impaired phosphate transport function. Examples of diseases and/or disorders of this type include soft tissue calcification, such as cardiovascular calcification, hyperparathyroidism, uremic bone disease, renal bone disease and osteoporosis.

An"effective amount"of a compound or polymer disclosed herein is a quantity that results in a beneficial clinical outcome of the condition being treated with the compound or polymer compared with the absence of treatment. The amount of compound or polymer administered will depend on the degree, severity, and type of the disease or condition, the amount of therapy desired, and the release

characteristics of the pharmaceutical formulation. It will also depend on the subject's health, size, weight, age, sex and tolerance to drugs. Typically, the compound or polymer is administered for a sufficient period of time to achieve the desired therapeutic effect. Typically between about 5 g per day and about 0.001 g per day of the compound or polymer (preferably between about 1 g per day and about 0.001 g per day) is administered to the subject in need of treatment.

The compounds and polymers can be administered by any suitable route. The compound or polymer is preferably administrated orally (e. g. , dietary) in capsules, suspensions or tablets. Methods for encapsulating compositions (such as in a coating of hard gelatin or cyclodextran) are known in the art (Baker, et al.,"Controlled Release of Biological Active Agents", John Wiley and Sons, 1986). The compound or polymer can be administered to the subject in conjunction with an acceptable pharmaceutical carrier as part of a pharmaceutical composition. The formulation of the pharmaceutical composition will vary according to the route of administration selected. Suitable pharmaceutical carriers may contain inert ingredients that do not interact with the compound. The carriers should be biocompatible, i. e. , non-toxic, non-inflammatory, non-immunogenic and devoid of other undesired reactions at the administration site. Examples of pharmaceutically acceptable carriers include, for example, saline, commercially available inert gels, or liquids supplemented with albumin, methyl cellulose or a collagen matrix. Standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.

For oral administration, the compounds and polymers can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds and polymers of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.

Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such

as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.

Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound or polymer doses.

Pharmaceutical preparations which can be used orally include push-fit capsules made of a suitable material, such as gelatin, as well as soft, sealed capsules made of a suitable material, for example, gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds or polymers can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.

Compounds and polymers of the present invention can be administered as prodrugs and formulated as described above. A prodrug is converted into the active drug substance in vivo, after administration to a subject. Typically, the acidic oxygens of an unsaturated phosphinyl phosphonate are blocked in the prodrug form, such as by an alkyl ester, and these blocking groups are released (e. g. , by hydrolysis) in vivo.

The blocking group can either be a small molecule or a polymer. The number and/or type of blocking groups can be varied in order to control the duration of the blocking effect and/or the conditions under which the blocking group is released.

Phosphate protecting groups are groups that are generally removed in vivo from the phosphinyl and phosphonate moieties, for example by hydrolysis in vivo,

thereby obtaining the free acid or salt form of the phosphinyl phosphonate. Phosphate protecting groups can be chosen so that they are removed at a desired rate or under desired conditions. One example of a phosphate protecting group is an ester formed from a simple alcohol (e. g. , ethanol), diols or polyols (e. g. , sugars such as glucose) or polymeric alcohols (e. g. , polyvinyl alcohol, polysaccharides). Phosphate groups can also be protected as phosphoramides by reaction with amines that are capable of forming a phosphorus-nitrogen bond. Alternatively, phosphates can be protected by reaction with an acid halide or other activated carboxylic acid, thereby forming an acid anhydride with the phosphinyl phosphonate group.

It will be understood that, certain compounds of the invention may be obtained as different stereoisomers (e. g. , diastereomers and enantiomers) and that the invention includes all isomeric forms and racemic mixtures of the disclosed compounds and a methods of treating a subject with both pure isomers and mixtures thereof, including racemic mixtures. In particular, the invention includes alkenyl phosphinyl phosphonates that have either an E-or Z-configuration at the double bond adjacent to the phosphinyl phosphonate group, unless otherwise specified. Stereoisomers can be separated and isolated using any suitable method, such as chromatography.

The activity of compounds of the present invention can be assessed using suitable assays, such as the 33Po4 Uptake In Rabbit Intestinal BBMV High Throughput Screening (HTS) assay, as described in the Example 10. Compounds of the present invention can also be identified by virtue of their ability to inhibit the absorption of phosphate in vivo, for example, in the gastrointestinal tract of a laboratory animal.

The compounds disclosed herein can be prepared accordingly as shown in Examples 1-9. The schemes are described in greater detail below. Briefly, many alkynyl phosphinyl phosphonates can be synthesized in two steps using commercially available materials. A terminal alkyne is reacted with an alkyl ester of phosphorochloridus acid (e. g. , the methyl or ethyl ester). The product of the first reaction is reacted with a protected methyl phosphonic acid that has a suitable leaving group (e. g. , halogen, triflate, tosylate) to form the alkynyl phosphinyl phosphonate.

The alkynyl phosphinyl phosphonate can subsequently be reduced or reacted with a

nucleophile (e. g. , an alcohol, a thioalcohol) to form an alkenyl phosphinyl phosphonate.

The phosphate transport inhibitors of the present invention can be administered as a monotherapy (e. g. , as the sole active ingredient) or as a combination therapy. Examples of combination therapies are discussed below.

In certain instances it may be advantageous to co-administer one or more additional pharmacologically active agents along with a compound or polymer of the present invention. Examples include pharmaceutically active calcium, aluminum or lanthanum-containing phosphate binders or, more preferably, pharmaceutically active phosphate-binding polymers such as those disclosed in U. S. Patent Nos. 5,496, 545, 5,667, 775 and 6,083, 495; the contents of which are incorporated herein by reference in their entirety. Preferably the pharmacologically active agent is a polyallylamine phosphate-binding polymer. More preferably, the pharmacologically active agent is an epichlorohydrin-cross-linked poly (allylamine hydrochloride) resin, also referred to as sevelamer hydrochloride or sevelamer and marketed as RENAGELS (Gel Tex Pharmaceuticals, Inc., Waltham, MA).

In some instances, it may be advantageous to co-administer a compound or polymer of the invention with one or more pharmaceutically acceptable metal ion sequestrants, such as a calcium sequestrant. Examples of calcium sequestrants include small molecules such as ethylenediamine triacetic acid (EDTA), citrates and citric acid, carbonates, silicates. Calcium sequestrants can also be polymers with acid functional groups, including polyacrylates, lignosulfonates, poly (aspartic acid), polysuccinimide and polystyrene sulfonates. The calcium sequestrant can be co- administered with the phosphate binder, provided that the calcium sequestrant and the phosphate binder do not significantly antagonize the binding or sequestering function of the other.

The invention is illustrated by the following examples which are not intended to be limiting in any way.

EXEMPLIFICATION Example 1. (Dodec-1-ynyl-ethoxy-phosphinoylmethyl)-phosphonic acid diethyl ester

1-Dodecyne (5g, 30.1 mmol, leq) was dissolved in 30 ml of dry THF under a nitrogen atmosphere and the solution was cooled to-10°C. A 2.5 M solution of n- butyl lithium in hexane (14.4 mL, 36.1 mmol, 1.2 eq) was added dropwise. During the addition the temperature rose to-4°C and the mixture was stirred at that temperature for half an hour after addition of lithium reagent was complete. The reaction mixture was then cooled to-74°C and a solution of diethyl chlorophosphite (5. 2mL, 36. lmmol, 1. 2eq) in 10 mL of THF was added dropwise. After the addition of diethyl chlorophosphate was complete the reaction was warmed to 0°C and left to stir for 45 minutes. After removing the solvent with a rotary evaporator, the product was characterized by NMR and used in the next step without purification. The crude product was stored at 0°C under nitrogen atmosphere. 31p NMR (CDC13) #= 131. 86 (s) ; tH NMR (CDC13) 6= 0. 84 (t, 3H), 1.20-1. 25 (m, 20H), 1.260-1. 35 (m, 2H), 1.45-1. 54 (m, 2H), 2.29 (m, 2H) 3.93 (q, 2H). M/Z (M+H) + = 287.

A dry round-bottomed flask was placed under a nitrogen atmosphere.

(Dodec-1-ynyl)-phosphite diethyl ester (5g, 18mmol, 2eq) was added to the flask by syringe. Then, diethyl iodomethyl phosphonate (2. 5g, 9mmol, leq) was added to the flask by syringe. The reaction mixture was warmed to 60°C for 48 hours. The crude reaction mixture was purified by chromatography on silica gel (1/20 methanol/ethyl acetate) providing 1.6g (43% yield). 31p NMR (CDC13) 8= 19.17 (d, 1P) 9.51 (d, 1P) ; IH NMR (CDCl3) 6= 0.82 (t, 1H), 1.15-1. 35 (m, 23H), 1.44-1. 56 (m, 2H), 2.26-2. 32 (m, 2H), 2.53 (dd, 2H), 4.10-4. 22 (q, 6H). M/Z (M+) = 409. Example 2. (Dodec-l-ynyl-hydroxy-phosphinoylmethyl)-phosphonic acid tri- sodium salt

A. ((n-decyl) hydroxyphosphinyl) methylphosphonic acid trisodium salt.

Bromotrimethylsilane (2 mL, 15.15 mmol) was added dropwise to ( (n-decyl) ethoxyphosphinyl) methylphosphonic acid dimethyl ester (0.6 g, 1. 68 mmol) in a 30 ml vial. A large exotherm was noted which resulted in a clear solution that was stirred for 14-16 hours at ambient temperature. Excess bromotrimethylsilane was then removed by passing a steady stream of nitrogen over the solution for 2 hours. The solution was then placed under high vacuum for 3 hours to remove any residual bromotrimethylsilane. A tacky solid was obtained.

Tributylamine (0.936 g, 5.05 mmol), methanol (10 mL) and deionized water (0.5 mL) was then added to the vial and a clear solution was obtained. This solution was then added dropwise to a 0.5 M solution of NaI in acetone (10.1 mL, 5.05 mmol). A white solid precipitated immediately which was then washed with 20 mL of acetone.

The solid was filtered under vacuum and then washed several times with acetone.

The white solid recovered was placed under vacuum to dry for a period of 12-16 hours to give the desired product (0. 481g, 78% yield). 1H NMR (400 MHz D20) : 8 1.6 (m, 2H), 1.4 (m, 2H), 1.2 (m, 2H), 1.0 (m, 14H), 0.5 (t, 3H).

B. (Dodec-1-ynyl-hydroxy-phosphinoyhnethyl)-phosphonic acid tri-sodium salt (Dodec-1-ynyl-ethoxy-phosphinoyhnethyl)-phosphonic acid diethyl ester was hydrolyzed with bromotrimethylsilane and precipitated with NaI (0. 5M)

solution in acetone as described for the preparation of ((n-decyl) hydroxyphosphinyl) methylphosphonic acid tri-sodium salt. M/Z of (M-H)-= 323.

Example 3. (Dodec-l-enyl-ethoxy-phosphinoyhnethyl)-phosphonic acid diethyl ester

In a dry reaction flask under nitrogen atmosphere, (dodec-1-ynyl)-phosphite diethyl ester (0.162 g, 0.4 mmol) was dissolved in anhydrous methanol (5 mL). To this was added Lindlar catylast (0.051 g) and the mixture was stirred under a hydrogen atmosphere for forty-five minutes. Filtration of the palladium catalyst onto a celite pad, followed by chromatographic separation (85/100 ethyl acetate/hexane) provided 0. 085 g (52% yield) of the desired product. One double bond isomer was formed almost exclusively. Coupling constants and chemical shifts suggest that it was the trans isomer. 31p NMR (CDC13) 8= 32. 82 (d, 1P) 20.97 (d, 1P) ; 1H NMR (CDC13) 8= 0. 82 (t, 1H), 1. 18-1. 32 (m, 23H), 1.34-1. 41 (m, 2H), 2.41 (dd, 2H), 2.53-2. 58 (m, 2H), 4.10-4. 22 (q, 6H), 5.71 (dd, 1H), 6.41-6. 60 (m, 1H). M/Z (M+H) + = 411.

Example 4. (Dodec-l-enyl-hydroxy-phosphinoylmethyl)-phosphonic acid tri- sodium salt

(Dodec-l-enyl-ethoxy-phosphinoylmethyl)-phosphonic acid diethyl ester was hydrolyzed with bromotrimethylsilane and the sodium salt was precipitated in a NaI (0. 5M) solution in acetone as described for the preparation of ( (n- decyl) hydroxyphosphinyl) methylphosphonic acid tri-sodium salt. M/Z of (M-H)-= 325.

Example 5. (Ethoxy-ethynyl-phosphinoylmethyl)-phosphonic acid diethyl ester

In a dry reaction flask under nitrogen, diethyl chlorophosphite (5g, 31. 9mmol, 1eq) was dissolved in THF (10 mL) and the reaction cooled to-10°C. A 0. 5 molar solution of ethynyl magnesium bromide in THF (64 ml, 31.9 mmol, 1 eq) was added dropwise. After the addition was complete the reaction was allowed to warm to room temperature and was stirred for two hours. Hexanes (50 mL) was added to the reaction mixture. Filtration followed by concentration on a rotary evaporator resulted in a pale yellow oil which was used in the next reaction without further purification. 31p NMR (CDC13) b=129. 76 (s, 1P) ; 1HNMR (CDC13) 8=1. 24 (t, 6H), 3.02 (1H), 3.95 (q, 4H).

In a dry round bottom flask under inert atmosphere (ethoxy-ethynyl)- phosphite diethyl ester (1 g, 6. 8 mmol, 2 eq) was mixed with diethyl iodomethyl phosphate (0.95 g, 3.4 mmol, 1 eq). The mixture was allowed to stir at room temperature for seventy-two hours. The crude reaction mixture was purified by chromatography on silica gel (1/20 methanol/ethyl acetate) to give product (0.46g, 51% yield). 31P NMR (CDC13) 8=1 . 05 (d, 1P) 8. 98 (d, 1P) ; lH NMR (CDC13) 6= 1.10-1. 22 (m, 9H), 2.41 (dd, 2H), 3.17 (d, 1H), 3.94-4. 10 (m, 6H). M/Z = 269 [M+H] +, 291 [M+Na] +. Example 6. (Dodecylsulfanylethynyl-ethoxy-phosphinoylmethyl)-phosphonic acid diethyl ester

1-Dodecanethiol (0.094mL, 0. 4mmol, 2eq) was placed in a dry reaction vessel with triethylamine (0.056mL, 0.4mmol, 2eq). To this solution was added (ethoxy-ethynyl-phosphinoyhnethyl)-phosphonic acid diethyl ester (0.053g, 0.2mmol, leq). The mixture was allowed to stir for four hours. The reaction mixture was then concentrated revealing the crude product as a yellowish oil. This was purified by column chromatography to give 0.043g (68% yield) of the trans isomer and 0. 018g (19% yield) of a cisltrans isomer mixture. 31p NMR (CDC13) 6= 32.13 (d, 1P), 20.95 (d, 1P) ; IHNMR (CDC13) 6=0. 82 (t, 3H), 1.18-1. 38 (m, 27H), 1.57- 1.65 (m, 2H), 2.41 (dd, 2H), 2.74 (t, 2H), 3.90-4. 14 (m, 6H), 5.75 (dd, 1H) 7.50 (dd, 1H). M/Z = 471 [M+H] +, 493 [M+Na] +.

Example 7. (Dodecylsulfanylethynyl-hydroxy-phosphinoyhnethyl)-phosphoni c acid tri-sodium salt [(2-Dodecylsulfanyl-vinyl)-ethoxy-phosphinoylmethyl]-phospho nic acid diethyl ester was hydrolyzed with bromotrimethylsilane and the sodium salt was precipitated in a NaI (0. 5M) solution in acetone as described for the preparation of ( (n-decyl) hydroxyphosphinyl) methylphosphonic acid tri-sodium salt. M/Z of (M- H)-= 385. Example 8. [ (Dodecane-l-sulfonylethynyl)-ethoxy-phosphinoylmethyl]-phosp honic acid diethyl ester

A cisltrans mixture of [ (2-Dodecylsulfanyl-vinyl)-ethoxy- phosphinoylmethyl]-phosphonic acid diethyl ester (0. 15g, 0. 32mmol, leq) was dissolved in methanol (10 mL) and cooled to 0°C. OXONE (potassium peroxymonosulfate; 0.3 g, 0.48 mmol, 1.5 eq) dissolved in water (10 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for twenty-four hours. The reaction mixture was then concentrated, re- dissolved in methylene chloride and washed twice with water and once with brine.

The organic phase was concentrated to give the product. 31p NMR (CDC13) 8= 29.00 (d, 1P), 28.81 (d, 1P), 19.56 (d, 1P) 18.70 (d, 1P) ; lH NMR (CDC13) b=0. 83 (t, 3H), 1.18-1. 36 (m, 27H), 1.70-1. 84 (m, 2H), 2.51 (dd, 1H), 2.75 (dd, 1H), 2.92-3. 07 (m, 1H), 3.38 (t, 1H), 4.40-4. 20 (m, 6H), 6.7-7. 32 (dd, dd, dd, 2H). M/Z = 503 [M+H] +.

Example 9. [(Dodecane-1-sulfonylethynyl)-hydroxy-phosphinoylmethyl]- phosphonic acid tri-sodium salt.

[(Dodecane-1-sulfonylethynyl)-ethoxy-phosphinoylmethyl]-phos phonic acid diethyl ester was hydrolyzed with bromotrimethylsilane and the sodium salt was precipitated in a NaI (0. 5M) solution in acetone as described for the preparation of ( (n-decyl) hydroxyphosphinyl) methylphosphonic acid tri-sodium salt. M/Z of (M- H)'= 417.

Example 10 PHOSPHATE TRANSPORTER INHIBITION IN VITRO TESTING The following example outlines the procedures required for ill vitro measurement of the inhibition of phosphate uptake by rabbit intestinal Brush Border Membrane Vesicles (BBMV).

BUFFER SOLUTION PREPARATION 300 MET 50 mL 300 mM mannitol 2.73 g 5 mM EGTA 117 mg 12 mM Tris base 73 mg pH 7. 1 (w/HCl) 60 MET 250 mL 60 mM mannitol 2.73g 5 mM EGTA 585 mg 12 mM Tris base 363 mg pH 7. 1 (w/HCl) Na Uptake buffer 50 mL 100 mM NaCl 292 mg 50 mM HEPES 596 mg 100 mM mannitol 911 mg 100 uM KH2PO4 50 mL 0.1 M stock pH 7.4 (w/NaOH) STOP buffer 1000 mL 100 mM mannitol 18.22 g 20 mM HEPES: Tris 20 mL total of 1 M stocks 20 mM MgS04 4.93 g

100 mM choline Cl 13.96 g 5 mM KH2PO4 681 mg 280 MH 250 mL 280 mM mannitol 12.75 g 20 mM HEPES 5 mL of 1 M stock pH 7.4 (w/KOH) K Uptake buffer 50 mL 100 mM KC1 373 mg 50 mM HEPES 596 mg 100 mM mannitol 911 mg 100 mM KH2PO4 50 mL 0.1 M stock PH 7. 4 (w/KOH) BBMV ISOLATION Rabbit Intestinal Brush Border Membrane Vesicles (BBMV) were isolated from mucosal scrapings of the upper small intestine (duodenum) of male New Zealand White rabbits. The scrapings were divided into 2 g aliquots in cryopreservation vials, frozen in liquid nitrogen, and stored at-80 °C.

The following procedure was performed for each 2 g sample of BBMV mucosal scraping. Buffer volumes and container sizes were adjusted appropriately for the number of 2 g samples used. The entire preparation was performed on ice, unless otherwise stated.

Mucosal scrapings (2 g per tube) were thawed in a 37 °C water bath for 3 minutes and then placed on ice. The scrapings were suspended with a total of 7.5 mL of 300 MET, and transferred to a 250 mL Corning tube on ice. To the suspension was added 30 mL cold (4 °C) deionized water (dH20). The suspension was homogenized with a tissue homogenizer (Polytron) on high speed for two minutes. A stir bar and MgCl2 (81. 3 mg) was added. The suspension was mixed well by inverting the closed tube. The suspension was stirred on ice, ensuring that a good vortex is achieved with the stir bar, for 40 minutes. The suspension was

transferred to a chilled centrifuge tube and spun at 4000 x g for 15 minutes. The supernatant was transferred to a new chilled centrifuge tube and spun at 32000 x g for 30 minutes. The supernatant was discarded and the pellet was re-suspended with 34 mL cold 60 MET. The suspension was homogenized with a Dounce homogenizer with 8 strokes. The suspension was transferred to a fresh 250 mL Corning tube. A stir bar and 69.1 mg Mec12 were added. The suspension was stirred well on ice for 10 minutes. The suspension was transferred to a chilled centrifuge tube and spun at 4000 x g for 15 minutes. The supernatant was transferred to a new chilled centrifuge tube and spun at 32000 x g for 30 minutes.

The supernatant was discarded. At this stage, the preparation could be continued or this pellet (P4) could be frozen in liquid nitrogen and stored at-80 °C. When needed, this pellet could be allowed to thaw at room temperature for 5 minutes.

Continuing the preparation, the pellet was re-suspended with 34 mL cold 280 MH The suspension was homogenized in a Dounce homogenize with 8 strokes. The suspension was transferred to a new chilled centrifuge tube and spun at 32000 x g for 30 minutes. The supernatant was discarded. To the pellet was added 500 AL 280 MH and the pellet was re-suspended very carefully with a 1 mL tuberculin syringe with a 25-gauge needle with care not to create bubbles. Once the entire pellet was suspended, the suspension was transferred to a chilled 1.5 mL microfuge tube. The suspension was evenly dispersed by bringing the suspension up into the syringe through the 25-gauge needle, and back out again eight times with care not to create bubbles. The total protein concentration was determined by performing a Bradford Protein Assay. Using that value, the BBMV were diluted with 280 MH to reach approximately 0.5-2. 0 mg/mL. The solution was used as soon as possible for uptake studies.

HIGH THROUGHPUT SCREENING (HTS) 33Po4 UPTAKE IN RABBIT INTESTINAL BBMV The following experiment was performed using a Beckman Multimek 96-tip robotic pipettor. The following outlines the preparation required to screen one 96-

well plate of compounds. However, multiple plates could be screened in one experiment.

To the"Uptake Buffers"was added 33PO4 to reach 200,000 CPM/19/L. The buffer solutions were stored at room temperature. The following control solutions were prepared and placed into appropriate wells of a polypropylene, 96-well V- bottom plate ("Hot Stock Plate") : a. Maximum activity (MAX) -Na Uptake buffer + 33PO4 at 200,000 CPM/l9 gL b. Midline activity (MID) - MAX + 100 uM KH2PO4, pH 7.4 c. Minimum activity (MIN) - K Uptake buffer + 33PO4 at 200,000 CPM/19 µL In the remaining wells, used for compound containing reactions, are placed MAX Control Buffer. The Hot Stock Plate was stored at room temperature. To each well of an appropriate 96-well filter plate was added approximately 200 AL Stop Buffer to pre-wet the filters for at least 15 minutes prior to assay. The"Compound Plate" was set-up by loading appropriate wells of a 96-well, polypropylene, V-bottom plate with compound solutions. This could be for testing inhibition at a single "screening"concentration, or to measure the potency of compounds by dose- response analysis at the appropriate concentrations. A"BBMV Plate"was set up by loading a 96-well, polypropylene, V-bottom plate with BBMVs at 0.5-2. 0 mg/mL (prepared as described above). The BBMV Plate was kept on ice until just prior to the assay. The reaction was initiated by aspiration of the hot uptake buffers (19 9, uL), from the Hot Stock Plate, and the compound solutions (2 µL), from the Compound Plate, dispensing into an empty 96-well V-bottom plate (Assay Plate), then immediately aspirating the BBMVs (19 gL), from the BBMV Plate and dispensing into the same Assay Plate. The addition of the BBMVs to the assay plate marked the reaction start time. After 15 minutes, the reaction was quenched by addition of 200, uL of STOP buffer from a reservoir. The Stop Buffer was aspirated by vacuum from the wells, through the filters, of the pre-soaked filter plate using a filter plate manifold. The quenched reactions were aspirated and transferred to the filter plate under vacuum. The filters were washed two times with 200 yL STOP buffer under vacuum. The filter plate was removed, dried, and the bottom of the filter plate was sealed. To each well of the filter plate was added 50 p1L of scintillant

(Microscint-20). A top seal was then applied to the filter plate. The plate was incubated for approximately 20 minutes before reading for 33P CPM on a scintillation counter (i. e. , TopCount-Packard Instruments). Percent inhibition was calculated by comparing the CPM values from compound containing wells to the MAX and MIN controls on the same plate using the following formula.

1- ( (CPM-MIN)/ (MAX-MIN)) ICso values were calculated from non-linear regression analysis within an appropriate software package (i. e., Prism GraphPad). The results are shown below in Table 1: TABLE 1 Compound ICso Example 2 3. 7 iM Example 3>100M Example 4 5. 2 iM Example 7 1. 3, uM Example 9 0. 49/, tM The compounds of Example 4 and Example 7 were found to have no measurable inhibition (> 10-4 M) of sodium-dependent glucose transport. The lack of glucose transport inhibition shows these compounds are specific to the phosphate transport mechanism.

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.