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WO2004085448A2 - Inhibiteurs du transport de phosphate comprenant un groupe phosphinyl-phosphonate insature - Google Patents

Inhibiteurs du transport de phosphate comprenant un groupe phosphinyl-phosphonate insature Download PDF

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WO2004085448A2
WO2004085448A2 PCT/US2004/008038 US2004008038W WO2004085448A2 WO 2004085448 A2 WO2004085448 A2 WO 2004085448A2 US 2004008038 W US2004008038 W US 2004008038W WO 2004085448 A2 WO2004085448 A2 WO 2004085448A2
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substituted
alkyl group
group
independently
polymer
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WO2004085448A3 (fr
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Chad C. Huval
Angeles Dios
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Genzyme Corp
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Genzyme Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C07F9/4012—Esters of acyclic acids which can have further substituents on alkyl substituted by B, Si, P or a metal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • C07F9/3821—Acyclic saturated acids which can have further substituents on alkyl substituted by B, Si, P or a metal

Definitions

  • 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.
  • the unsaturated phosphinyl phosphonate compounds shown in Table 1 inhibit phosphate transport, several with an IC5 0 below 10 ⁇ M 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.
  • 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 (111): or a pharmaceutically acceptable salt or a prodrug thereof.
  • R 3 is a substituted or unsubstituted hydrocarbyl group optionally interrupted by one or more nitrogen, oxygen or sulfur atoms.
  • Each R b is independently -H, a substituted or unsubstituted alkyl group, or a phosphate protecting group.
  • X is a covalent bond, -CHY-, -CY 2 -, -C(O)-, -OC(O)-, -S-, -S(O)-, -S(O) 2 -, -NR ⁇ - ; -O-, -C(S)-, -SC(O)-, -SC(S)-, -NHC(O)NH-, or -NHC(NH)NH-.
  • Y is a halogen or lower alkyl group.
  • R x 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.
  • the alkenylene phosphinyl phosphonate or alkynylene phosphinyl phosphonate groups are represented by Structural Formula (IV), (V), or (VI):
  • 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.
  • 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
  • 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.
  • a phosphate transport inhibitor disclosed herein compound or polymer comprising one or more pendant phosphinyl phosphate groups
  • 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.
  • 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.
  • small molecule and polymer inhibitors of phosphate transport 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 (I), (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 inliibitors also comprise unsaturated phosphinyl phosphonate groups, which can be pendant from the polymer backbone or integral to the polymer backbone.
  • Ri and R 2 in Structural Formulas (I)-(VI) can independently be an electron withdrawing group.
  • Preferred values of R 1 and R 2 are -H, an electron withdrawing group (e.g., a halogen), or a substituted or unsubstituted alkyl group; more preferably Ri and R 2 are -H or -F.
  • t and R 5 in Structural Formulas (I)-(VI) are typically -H, a halogen, a substituted or unsubstituted alkyl group, -C(O)R x , -C(O)OR x , or -C(O)N(R x ) 2 ; and are preferably independently -H or a halogen, particularly -F.
  • Ri and R 2 are independently -H or -F and and R 5 are independently -H or -F.
  • R b in Structural Formulas (I)-(VI) is typically independently -H or a lower alkyl group.
  • Rb has these values, then R l5 R 2 , R 4 , and R 5 preferably have the values described in the previous paragraph.
  • R 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.
  • R b is a phosphate protecting group
  • R l3 R 2 , R 4; and R 5 preferably have the values described in the previous paragraph.
  • X in Structural Formulas (I)-(V ⁇ ) is selected to be a covalent bond, -S-, -S(O) 2 -, -NR X - or -O-; and R 1? R , R 4 , R 5 and R b are as described in the previous paragraph.
  • X is a covalent bond, -S-, or -S(O) 2 -.
  • Rb is preferably -H.
  • Ri and R 2 are -H or -F and R 4 and R 5 are each -H.
  • X is preferably a covalent bond.
  • R 3 in Structural Formulas (I)-(III) is a substituted or unsubstituted C 6 -C 18 alkyl group, but is more preferably unsubstituted.
  • Compounds where R 3 is an unsubstituted C 8 -C 12 alkyl group have been found to have particularly desirable properties.
  • the alkyl group represented by R 3 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 R 3 can be perhalogenated, specifically perfluorinated.
  • R 3 has these values, preferred values for X, R l5 R 2 , R 4 , R 5 , and R b are those described in the prior paragraph.
  • the R 3 group is a straight chained hydrocarbyl group optionally interrupted by one or more nitrogen, oxygen or sulfur atoms.
  • preferred values for X, R ls R 2 , R 4 , R 5 , and R b 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 O, -NH 2 -NH(R'), -N(R') 2 . -C(O)OR', -C(O)NH 2 , -C(O)NHR', -C(O)N(R')2, -SH, -S(R'), an aliphatic group, an aryl group and a heteroaryl group.
  • R' is independently -H, an alkyl group or an aryl group.
  • R 3 is a straight chained hydrocarbyl group optionally interrupted by one or more nitrogen or sulfur atoms.
  • R can additionally be a substituted or unsubstituted aryl group, which is either carbocyclic or heteroaryl.
  • R 3 is an aryl group, it is often a phenyl group.
  • R 3 has these values, preferred values for X, R l5 R 2 , i, R 5 , and R b are those described in the prior paragraph.
  • X is a covalent bond and R 3 is represented by the following structural formula:
  • Q is a covalent bond, 1,3-phenylene, 1,4-phenylene, -C(O)O-, -C(O)NR x -, -C(O)-, -O-, or -NR X -;
  • R X is the same as defined above for Structural Formulas (I)-(VI).
  • the symbol “*” represents where the illustrated group is attached to the remainder of the molecule.
  • 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)NR x -, -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 R 6 and R is attached).
  • a carbonyl moiety e.g., -C(O)NR x -, -C(O)O-
  • L is a covalent bond
  • n is zero
  • m is from 8 to 12
  • Q is -C(O)O- or -C(O)NR x - (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 (XLLX).
  • polymers of the present invention comprise pendant unsaturated phosphinyl phosphonate groups.
  • pendant unsaturated phosphinyl phosphonate groups are represented by Structural Formulas (IV)-(VI) and (XXVII)-(XXXV) and (LVIH):
  • R l5 R 2 , R , R4, R 5 , b and X are as defined above for Structural Formulas (I)- (III).
  • Ri and R 2 are independently -H or -F.
  • Preferred values of R 3 , R 4 , R 5 , R b and X are as described above for Structural Formulas (I)-(ILT).
  • polymer backbone connects to the unsaturated phosphinyl phosphonate group via an inert linking group attached to X.
  • polymers of this type comprise repeat units represented by Structural Formulas (VII), (VIII) and (XXXVI):
  • M is -NR x -, -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R x ) 2 -, -NR x C(O)-, -(CH 2 ) q -, phenylene, or phenylene-O-;
  • A is a covalent bond or inert spacer group
  • Ri, R 2 , R 3 , R 4 , R 5 , R b and X are as defined above for Structural Formulas (I)- (III).
  • Ri, R 2j R 4 , and R 5 are preferably -H or -F. More preferably, R h R 2 , R 4 and R 5 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; R l5 R , t and R 5 are independently -H or -F; and X is a covalent bond, -S-, -S(O) 2 -, -NR X -, or -O-.
  • A is an allcylene group
  • R l5 R 2 , ; and R 5 are independently -H or -F
  • X is a covalent bond, -S-, -S(O) 2 -, -NR X -, or -O-
  • 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
  • R ls R 2 , R 3 , Ri, R 5 , R b , and X are as defined above for Structural Formulas (I)-(m).
  • unsaturated phosphinyl phosphonate groups represented by Structural Formulas (LX)-(XXII) and (L)-(LVI) are characterized by one or more of the following features: (1) Ri and R 2 are independently -H or -F, (2) R 3 is a substituted or unsubstituted alkyl group, (3) R and R 5 are independently -H or -F, and (4) R b is -H or a lower alkyl group.
  • the unsaturated phosphinyl phosphonate groups represented by Structural Formulas (LX)-(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).
  • pendant hydroxyl groups e.g., polyvinylalcohol, polyallylalcohol
  • terminal hydroxyl groups polyalkylene glycols such as polyethylene glycol and polypropylene glycol
  • 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):
  • each R DP is independently a diol or a polyol, which contain 2 or more or 3 or more hydroxyl groups, respectively.
  • diols and polyols are listed in the prior paragraph.
  • Other examples include sugars such as glucose and diols ⁇ such as 1,3-dihydroxypropane.
  • R ls R 2 , R 3s RA, R 5 , R b , and X are as defined above for Structural Formulas (I)-( ⁇ i).
  • Preferred values of R ls R 2 , R 3 , R 4 , R 5 , R b , and X are also as described above for Structural Formulas (I)-(III).
  • the following alkenylene phosphoninyl phosphonates represented by Structural Formulas (XXV) and (XXVI) are excluded from the present invention:
  • R e is -H, methyl, ethyl or phenyl
  • R d is -H or -F
  • 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).
  • 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.
  • a co-polymer or ter-polymer comprises a monomer or repeat unit without an unsaturated phosphinyl phosphonate group.
  • hydrophilic monomer or repeat units examples include hydrophilic monomer or repeat units, which comprise a hydrophilic group such as an alcohol, amine, carboxylate, or carboxamide in the side chain.
  • hydrophilic monomer or repeat units examples include polyallylamine, polydiallylamine, polyallylalcohol and polyvinylalcohol. Additional examples include: where R 13 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.
  • 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.
  • condensation polymers 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.
  • the unsaturated phosphinyl phosponate groups can be connected to amide nitrogens in the polymer backbone by an inert spacer group.
  • the unsaturated phosphinyl phosphonate group can be connected by an inert spacer group attached to a carbon atom in the backbone.
  • 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.
  • a poly(acrylamide) polymer is said to have a pory(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.
  • spacer group 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 Cl to C15 group, and even more preferably, a Cl to C8 alkylene group.
  • 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.
  • 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:
  • 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 (XXXVH)-(XLVIII):
  • A is as defined above for Structural Formulas (VII), (VIII) and (XXXVI). Preferred values of X, Ri, R 2 , R 3 , R ⁇ R 5 , and Rb are as described above for Structural Formulas (I)-(III).
  • A is an inert linking group, such as a substituted or unsubstituted alkylene group. X, Ri, R 2 , R 3 , *, R 5 , and R b are independently chosen, such that the dimers are either symmetrical or asymmetrical.
  • the dimer is symmetrical. If any of one the corresponding X, Ri, R 2 , R 3 , ⁇ R 5 , and R b 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., -(CH 2 ) Z - or -(CH 2 ) Z C 6 H 4 (CH 2 ) Z -, 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.
  • hydrocarbyl groups examples include butylene, pentylene, hexylene, heptylene, 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.
  • 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, rc-propyl, wo-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.
  • 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.
  • -C(O)OR' -CONH 2 , -C(O)NHR', -C(O)N(R') 2 , -SH, -S(R'), an aliphatic group, an aryl group and a heteroaryl group.
  • R' is independently -H, an alkyl group or an aryl group.
  • a substituted aliphatic group or aryl group can have more than one substituent.
  • Electron withdrawing group 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).
  • electron withdrawing groups include halogens, -NO 2 , -CN, -CF 3 and -OCF 3 .
  • a halogen, particularly fluoride, is a preferred electron withdrawing group.
  • 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.
  • 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 -toluenesulfonic acid, methanesulfonic acid, oxalic acid, -bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as -toluenesulfonic acid, methanesulfonic acid, oxalic acid, -bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • 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-l,4-dioate, hexyne-1,6- dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate
  • 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.
  • such polymers typically 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).
  • 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).
  • Subj ects "in need of phosphate transport inhibition” include subj ects 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
  • 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.
  • 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 are known in the art (Baker, et al, "Controlled
  • 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.
  • 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.
  • 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).
  • PVP polyvinylpyrrolidone
  • 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.
  • suitable coatings 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.
  • compositions 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.
  • the active compounds or polymers can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • 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.
  • the acidic oxygens of an unsaturated phosphinyl phosphonate are blocked in the prodrug form, such as by an allcyl 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.
  • 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.
  • 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.
  • 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.
  • 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 33 PO 4 Uptake In Rabbit Intestinal BBMV High Throughput Screening (HTS) assay, as described in the Example 10.
  • suitable assays such as the 33 PO 4 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.
  • 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.
  • a suitable leaving group e.g., halogen, triflate, tosylate
  • 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.
  • a nucleophile e.g., an alcohol, a thioalcohol
  • 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. 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.
  • additional pharmacologically active agents 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.
  • 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 RENAGEL® (Gel Tex Pharmaceuticals, Inc., Waltham, MA).
  • a compound or polymer of the invention with one or more pharmaceutically acceptable metal ion sequestrants, such as a calcium sequestrant.
  • calcium sequestrants include small molecules such as ethylenediamine triacetic acid (EDTA), citrates and citric acid, carbonates, silicates.
  • EDTA ethylenediamine triacetic acid
  • 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.
  • 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.
  • diethyl chlorophosphite (5g, 31.9mmol, leq) 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.
  • 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.
  • 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-phosphinoylmethyl)-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 cis/trans isomer mixture.
  • Example 9 [(Dodecane-l-sulfonylethynyl)-hydroxy-phosphinoylmethyl]- phosphonic acid tri-sodium salt.
  • BBMV Rabbit Intestinal Brush Border Membrane Vesicles
  • 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 MgCl 2 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.
  • this pellet 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.
  • 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 transfened 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 ⁇ L 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.
  • the suspension was transfened 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.
  • 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 ⁇ L), from the Hot Stock Plate, and the compound solutions (2 ⁇ L), from the Compound Plate, dispensing into an empty 96-well V-bottom plate (Assay Plate), then immediately aspirating the BBMVs (19 ⁇ L), 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 ⁇ L 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 transfened to the filter plate under vacuum.
  • the filters were washed two times with 200 ⁇ L 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 ⁇ L 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 33 P 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 MLN controls on the same plate using the following formula.
  • Example 4 and Example 7 were found to have no measurable inhibition (> IO "4 M) of sodium-dependent glucose transport. The lack of glucose transport inhibition shows these compounds are specific to the phosphate transport mechanism.

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Abstract

L'invention concerne un procédé permettant d'inhiber le transport de phosphate chez un sujet nécessitant un tel traitement, qui comporte l'étape consistant à administrer au sujet une quantité efficace d'un composé contenant une liaison double ou triple directement adjacente à un groupe phosphinyl phosphonate. L'invention concerne aussi des composés contenant de tels groupes phosphinyl phosphonate insaturés et des procédés de préparation de ces composés.
PCT/US2004/008038 2003-03-19 2004-03-17 Inhibiteurs du transport de phosphate comprenant un groupe phosphinyl-phosphonate insature Ceased WO2004085448A2 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
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WO2007056405A3 (fr) * 2005-11-08 2007-11-08 Genzyme Corp POLYMERES CONTENANT DU MAGNESIUM POUR l'HYPERPHOSPHATEMIE
WO2010083613A1 (fr) * 2009-01-26 2010-07-29 Cytochroma Inc. Régulation de phosphate avec de petites molécules
WO2014029983A1 (fr) 2012-08-21 2014-02-27 Ardelyx, Inc. Composés et procédés d'inhibition d'un antiport à médiation par nhe dans le traitement de troubles associés à une rétention de fluide ou à une surcharge de sel et de troubles du tractus gastro-intestinal
WO2018129552A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Composés utiles pour le traitement de troubles du tractus digestif
WO2018129556A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Composés et procédés pour l'inhibition d'un antiport à médiation par échangeur sodium/proton (nhe) dans le traitement de troubles associés à une rétention d'eau ou à une surcharge en sel et de troubles du tractus gastro-intestinal
WO2018129557A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Inhibiteurs d'antiport à médiation par nhe
EP3351248A1 (fr) 2008-12-31 2018-07-25 Ardelyx, Inc. Composés et procédés d'inhibition d'un antiport à médiation par nhe dans le traitement de troubles associés à une rétention de fluide ou à une surcharge de sel et de troubles du tractus gastro-intestinal
US10272079B2 (en) 2013-04-12 2019-04-30 Ardelyx, Inc. NHE3-binding compounds and methods for inhibiting phosphate transport
US10376481B2 (en) 2012-08-21 2019-08-13 Ardelyx, Inc. Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders

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US4871721A (en) * 1988-01-11 1989-10-03 E. R. Squibb & Sons, Inc. Phosphorus-containing squalene synthetase inhibitors
CA2040865C (fr) * 1990-05-15 2002-07-23 James L. Bergey Methode visant a prevenir, stabiliser ou reduire l'atherosclerose et reposant sur l'utilisation conjointe d'un medicament a effet hypocholesterolemiant et d'un inhibiteur de l'enzyme de conversion
US5130333A (en) * 1990-10-19 1992-07-14 E. R. Squibb & Sons, Inc. Method for treating type II diabetes employing a cholesterol lowering drug
DE19902924A1 (de) * 1999-01-26 2000-08-03 Hassan Jomaa Verwendung von phosphororganischen Verbindungen zur prophylaktischen und therapeutischen Behandlung von Infektionen

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007056405A3 (fr) * 2005-11-08 2007-11-08 Genzyme Corp POLYMERES CONTENANT DU MAGNESIUM POUR l'HYPERPHOSPHATEMIE
EP3351248A1 (fr) 2008-12-31 2018-07-25 Ardelyx, Inc. Composés et procédés d'inhibition d'un antiport à médiation par nhe dans le traitement de troubles associés à une rétention de fluide ou à une surcharge de sel et de troubles du tractus gastro-intestinal
EP3939964A1 (fr) 2008-12-31 2022-01-19 Ardelyx, Inc. Combinaisons d'inhibition d'un antiport a mediation par nhe dans le traitement de troubles associes a une retention de fluide ou a une surcharge de sel et de troubles du tractus gastro-intestinal
WO2010083613A1 (fr) * 2009-01-26 2010-07-29 Cytochroma Inc. Régulation de phosphate avec de petites molécules
US9198923B2 (en) 2009-01-26 2015-12-01 Opko Ireland Global Holdings, Ltd. Phosphate management with small molecules
US10376481B2 (en) 2012-08-21 2019-08-13 Ardelyx, Inc. Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
WO2014029983A1 (fr) 2012-08-21 2014-02-27 Ardelyx, Inc. Composés et procédés d'inhibition d'un antiport à médiation par nhe dans le traitement de troubles associés à une rétention de fluide ou à une surcharge de sel et de troubles du tractus gastro-intestinal
US10272079B2 (en) 2013-04-12 2019-04-30 Ardelyx, Inc. NHE3-binding compounds and methods for inhibiting phosphate transport
US10940146B2 (en) 2013-04-12 2021-03-09 Ardelyx, Inc. NHE3-binding compounds and methods for inhibiting phosphate transport
WO2018129557A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Inhibiteurs d'antiport à médiation par nhe
WO2018129556A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Composés et procédés pour l'inhibition d'un antiport à médiation par échangeur sodium/proton (nhe) dans le traitement de troubles associés à une rétention d'eau ou à une surcharge en sel et de troubles du tractus gastro-intestinal
WO2018129552A1 (fr) 2017-01-09 2018-07-12 Ardelyx, Inc. Composés utiles pour le traitement de troubles du tractus digestif
US11147884B2 (en) 2017-01-09 2021-10-19 Ardelyx, Inc. Inhibitors of NHE-mediated antiport
US11242337B2 (en) 2017-01-09 2022-02-08 Ardelyx, Inc. Compounds useful for treating gastrointestinal tract disorders
US12281103B2 (en) 2017-01-09 2025-04-22 Ardelyx, Inc. Compounds useful for treating gastrointestinal tract disorders

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