WO2013019169A1 - Promédicaments du phosphate - Google Patents

Promédicaments du phosphate Download PDF

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Publication number
WO2013019169A1
WO2013019169A1 PCT/US2011/001359 US2011001359W WO2013019169A1 WO 2013019169 A1 WO2013019169 A1 WO 2013019169A1 US 2011001359 W US2011001359 W US 2011001359W WO 2013019169 A1 WO2013019169 A1 WO 2013019169A1
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WIPO (PCT)
Prior art keywords
substituted
compound
alkyl
diarrhea
aryl
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PCT/US2011/001359
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English (en)
Inventor
Tue Nguyen
Eugenio De Hostos
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Institute For Oneworld Health
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Priority to PCT/US2011/001359 priority Critical patent/WO2013019169A1/fr
Publication of WO2013019169A1 publication Critical patent/WO2013019169A1/fr

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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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/653—Five-membered rings
    • C07F9/65306—Five-membered rings containing two nitrogen atoms
    • C07F9/65318—Five-membered rings containing two nitrogen atoms having the two nitrogen atoms in positions 1 and 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • This technology is related to phosphate-containing prodrug derivatives of active agents, which active agents inhibit the transport of ions (e.g., chloride ions) across cell membranes expressing the cystic fibrosis transmembrane conductance regulator (CFTR) protein.
  • ions e.g., chloride ions
  • CFTR cystic fibrosis transmembrane conductance regulator
  • prodrug derivatives that, in certain aspects, contain a phosphate or a phosphonate moiety covalently bonded to a hydroxyl group, either directly or via a linker.
  • the hydroxyl group is a phenolic hydroxyl group.
  • the linker is a traceless linker.
  • the linker is a substituted or unsubstituted aliphatic hydrocarbyl group such as alkylene.
  • the aliphatic hydrocarbyl group further includes heteroatoms such as nitrogen, oxygen, and sulfur.
  • Other linkers bearing aryl, such as phenyl, moieties are also present.
  • the prodrug derivative provided herein is of formula:
  • the prodrug derivative provided herein is of formula:
  • prodrug derivatives provided herein.
  • the prodrug derivatives provided herein are also referred to as
  • a compound described herein includes an isomer, a tautomer, and a solvate of the compound, and a solvate of the isomer and the tautomer of the compound.
  • pharmaceutical formulations of, and methods of using the, compounds and their pharmaceutically acceptable salts are also provided herein.
  • the present technology provides a method for treating a secretory disease, such as, diarrhea, in an animal in need thereof comprising, or alternatively consisting essentially of, or yet further consisting of, administering to the animal an effective amount of a compound, or a composition or formulation provided herein, thereby treating the secretory disease, such as diarrhea.
  • the administration is performed orally, intraluminally or by suppository.
  • the compound, pharmaceutical composition or formulation is administered as a sustained release formulation.
  • the compounds are useful in the treatment of diseases suffered by animal populations, e.g., a human patient or other animal.
  • diarrhea is secretory diarrhea.
  • the diarrhea is infectious diarrhea, inflammatory diarrhea, or diarrhea associated with chemotherapy.
  • the method further comprises administering an effective amount of an oral glucose-electrolyte solution or an effective amount of a micronutrient to the animal.
  • the present technology provides a method for treating polycystic kidney disease (PKD) in an animal in need thereof, comprising administering to the animal an effective amount of a compound provided herein or a composition provided herein, thereby treating PKD.
  • PPD polycystic kidney disease
  • the present technology provides a method of treating a disease in an animal, which disease is responsive to inhibiting of functional cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide, comprising
  • CFTR cystic fibrosis transmembrane conductance regulator
  • the compound inhibits halide ion transport by CFTR.
  • the disease is secretory diarrhea, inflammatory diarrhea, inflammatory bowel disease, infectious diarrhea, polycystic kidney disease (PKD), cardiac arrhythmia, male infertility or an disorder associated with neovascularization.
  • the present technology provides a method for inhibiting the transport of a halide ion across a mammalian cell membrane expressing functional cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide, comprising contacting the CFTR polypeptide with an effective amount of the compound provided herein or a composition of provided herein, thereby inhibiting the transport of the halide ion.
  • the halide ion is at least one of F " , CI " or Br " .
  • the halide ion is CI " .
  • the functional CFTR is wild-type full length CFTR.
  • the mammalian cell is an epithelial cell, luminal epithelial cell or a kidney cell.
  • the mammalian cell is an intestinal epithelial cell or a colon epithelial cell.
  • FIG. 2 graphically depicts the efficacy of prodrug derivatives 6 and 8 to inhibit cholera toxin (CTX) induced secretion in comparison with active agent.
  • CTX cholera toxin
  • FIG. 3 is an ⁇ -NMR spectrum of compound 6 recorded in DMSO-d 6 .
  • FIG. 4 is an ⁇ -NMR spectrum of compound 8 recorded in DMSO-c ⁇ .
  • a cell includes a plurality of cells, including mixtures thereof.
  • compositions and methods include the recited elements, but not exclude others.
  • Consisting essentially of when used to define compositions and methods shall mean excluding other elements of any essential significance to the combination.
  • a composition consisting essentially of the elements as defined herein would not exclude trace contaminants, e.g., from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like.
  • Consisting of shall mean excluding more than trace elements of other ingredients. Embodiments defined by each of these transition terms are within the scope of this technology.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl
  • Alkynyl refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (-C ⁇ C-) unsaturation.
  • alkynyl groups include acetylenyl (-C ⁇ CH), and propargyl (-CH 2 C ⁇ CH).
  • Substituted alkyl refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamiiio, acyloxy, amino, substituted amino, aminocarbonyl,
  • aminothiocarbonyl aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted
  • heterocyclyloxy heterocyclylthio, substituted heterocyclylthio, nitro, S0 3 H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.
  • Substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents, and. preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,
  • aminothiocarbonyl aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted
  • Substituted alkynyl refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,
  • aminothiocarbonyl aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted
  • Alkylene refers to divalent saturated aliphatic hydrocarbyl groups preferably having from 1 to 6 and more preferably 1 to 3 carbon atoms that are either straight-chained or branched. This term is exemplified by groups such as methylene (-CH 2 -), ethylene
  • Substituted alkylene refers to an alkylene group having from 1 to 3 hydrogens replaced with substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and oxo wherein said substituents are defined herein.
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.
  • Substituted alkoxy refers to the group -0-(substituted alkyl) wherein substituted alkyl is defined herein.
  • “Acyl” refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted
  • Acyl includes the "acetyl" group CH 3 C(0)-.
  • Acylamino refers to the groups -NR 47 C(0)alkyl, -NR 47 C(0)substituted alkyl, -NR 47 C(0)cycloalkyl, -NR 47 C(0)substituted cycloalkyl, -NR 47 C(0)cycloalkenyl,
  • R 47 is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl
  • alkyloxy refers to the groups alkyl-C(0)0-, substituted alkyl-C(0)0-,
  • an "animal” or “patient” of diagnosis or treatment refers to an animal such as a mammal, or a human, ovine, bovine, feline etc.
  • Non-human animals subject to diagnosis or treatment include, for example, simians, murine, such as, rat, mice, canine, leporid, livestock, sport animals, and pets.
  • Amino refers to the group -NH 2 .
  • Substituted amino refers to the group -NR 48 R 49 where R 48 and R 49 are
  • alkyl independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SC -alkyl, -S0 2 -substituted alkyl,
  • R 48 and R 49 are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R 48 and R 49 are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • R 48 is hydrogen and R 49 is alkyl
  • the substituted amino group is sometimes referred to herein as alkylamino.
  • R 48 and R 49 are alkyl
  • the substituted amino group is sometimes referred to herein as dialkylamino.
  • a monosubstituted amino it is meant that either R 48 or R 49 is hydrogen but not both.
  • a disubstituted amino it is meant that neither R nor R 49 are hydrogen.
  • Aminocarbonyl refers to the group -C(O)NR 50 R 51 where R 50 and R 51 are
  • Aminothiocarbonyl refers to the group -C(S)NR 50 R 51 where R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl
  • Aminocarbonylamino refers to the group -NR 47 C(O)NR 50 R 51 where R 47 is hydrogen or alkyl and R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and where R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted substituted alky
  • heterocyclic and substituted heterocyclic are as defined herein.
  • Aminothiocarbonylamino refers to the group -NR 47 C(S)NR 50 R 51 where R 47 is hydrogen or alkyl and R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
  • cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic where R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Aminocarbonyloxy refers to the group -O-C(O)NR 50 R 51 where R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, ary
  • Aminosulfonyl refers to the group -SO 2 NR 50 R 51 where R 50 and R 51 are
  • Aminosulfonyloxy refers to the group -O-SO 2 NR 50 R 51 where R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted cyclo
  • Aminosulfonylamino refers to the group -NR 47 SO 2 NR 50 R 51 where R 47 is hydrogen or alkyl and R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
  • Aryl refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring ⁇ e.g., phenyl) or multiple condensed rings ⁇ e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic ⁇ e.g., 2-benzoxazolinone, 2H-l ,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom.
  • Preferred aryl groups include phenyl and naphthyl.
  • Substituted aryl refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,
  • heterocyclyloxy heterocyclylthio, substituted heterocyclylthio, nitro, S0 3 H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.
  • Aryloxy refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.
  • Substituted aryloxy refers to the group -0-(substituted aryl) where substituted aryl is as defined herein.
  • Arylthio refers to the group -S-aryl, where aryl is as defined herein.
  • Substituted arylthio refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
  • Carboxyl or “carboxy” refers to -COOH or salts thereof.
  • Carboxyl ester or “carboxy ester” refers to the groups -C(0)0-alkyl
  • -C(0)0-substituted alkyl -C(0)0-alkenyl, -C(0)0-substituted alkenyl, -C(0)0-alkynyl, -C(0)0-substituted alkynyl, -C(0)0-aryl, -C(0)0-substituted aryl, -C(0)0-cycloalkyl, -C(0)0-substituted cycloalkyl, -C(0)0-cycloalkenyl, -C(0)0-substituted cycloalkenyl, -C(0)0-heteroaryl, -C(0)0-substituted heteroaryl, -C(0)0-heterocyclic, and
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • (Carboxyl ester)amino refers to the group -NR 47 C(0)0-alkyl
  • R 47 is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are
  • (Carboxyl ester)oxy refers to the group -0-C(0)0-alkyl, -0-C(0)0-substituted alkyl, -0-C(0)0-alkenyl, -0-C(0)0-substituted alkenyl, -0-C(0)0-alkynyl,
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Cyano refers to the group -CN.
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems.
  • the fused ring can be an aryl ring provided that the non aryl part is joined to the rest of the molecule.
  • suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
  • Substituted cycloalkyl and “substituted cycloalkenyl” refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl
  • cycloalkylthio cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted
  • heterocyclic heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, S0 3 H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.
  • Cycloalkyloxy refers to -O-cycloalkyl.
  • Substituted cycloalkyloxy refers to -0-(substituted cycloalkyl).
  • Cycloalkylthio refers to -S-cycloalkyl.
  • Substituted cycloalkylthio refers to -S-(substituted cycloalkyl).
  • Cycloalkenyloxy refers to -O-cycloalkenyl.
  • Substituted cycloalkenyloxy refers to -0-(substituted cycloalkenyl).
  • Cycloalkenylthio refers to -S-cycloalkenyl.
  • Substituted cycloalkenylthio refers to -S-(substituted cycloalkenyl).
  • Halo or "halogen” refers to fluoro, chloro, bromo and iodo.
  • Heteroaryl refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring.
  • Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g. , indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ 0), sulfinyl, or sulfonyl moieties.
  • Preferred heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
  • Substituted heteroaryl refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
  • Heteroaryloxy refers to -O-heteroaryl.
  • Substituted heteroaryloxy refers to the group -0-(substituted heteroaryl).
  • Heteroarylthio refers to the group -S-heteroaryl.
  • Substituted heteroarylthio refers to the group -S-(substituted heteroaryl).
  • Heterocycle or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems. In fused ring systems, one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, or sulfonyl moieties.
  • Substituted heterocyclic or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
  • Heterocyclyloxy refers to the group -O-heterocycyl.
  • Substituted heterocyclyloxy refers to the group -0-(substituted heterocycyl).
  • Heterocyclylthio refers to the group -S-heterocycyl.
  • Substituted heterocyclylthio refers to the group -S-(substituted heterocycyl).
  • heterocycle and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1 ,2,3,4-tetrahydroisoquinoline
  • thiamorpholinyl 1 , 1 -dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.
  • Neitro refers to the group -N0 2 .
  • Phenylene refers to a divalent aryl ring, where the ring contains 6 carbon atoms.
  • Substituted phenylene refers to phenylenes which are substituted with 1 to 4, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,
  • heterocyclyloxy heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.
  • Spirocycloalkyl and “spiro ring systems” refers to divalent cyclic groups from 3 to 10 carbon atoms having a cycloalkyl or heterocycloalkyl ring with a spiro union (the union formed by a single atom which is the only common member of the rings) as exemplified by the following structure:
  • Sulfonyl refers to the divalent group -S(0) 2 -.
  • Substituted sulfonyl refers to the group -S0 2 -alkyl, -S0 2 -substituted alkyl,
  • heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Substituted sulfonyl includes groups such as methyl-S0 2 -, phenyl-S0 2 -, and 4-methylphenyl-S0 2 -.
  • Substituted sulfonyloxy refers to the group -OS0 2 -alkyl, -OS0 2 -substituted alkyl, -OS0 2 -alkenyl, -OS0 2 -substituted alkenyl, -OS0 2 -cycloalkyl, -OS0 2 -substituted cylcoalkyl, -OS0 2 -cycloalkenyl, -OS0 2 -substituted cylcoalkenyl,-OS0 2 -aryl, -OS0 2 -substituted aryl, -OS0 2 -heteroaryl, -OS0 2 -substituted heteroaryl, -OS0 2 -heterocyclic, -OS0 2 -substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, substituted al
  • Thioacyl refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-, substituted
  • Thiol refers to the group -SH.
  • Alkylthio refers to the group -S-alkyl wherein alkyl is as defined herein.
  • Substituted alkylthio refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein.
  • “Isomer” refers to tautomerism, conformational isomerism, geometric isomerism, stereoisomerism and/or optical isomerism.
  • the compounds of the technology may include one or more chiral centers and/or double bonds and as a consequence may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, diasteromers, and mixtures thereof, such as racemic mixtures.
  • the compounds of the technology may exist in several tautomeric forms, including the enol form, the keto form, and mixtures thereof.
  • “Stereoisomer” or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • Linker refers to a divalent saturated or unsaturated aliphatic or aromatic
  • hydrocarbyl group which may include heteroatoms and are unsubstituted or substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cyclo
  • cycloalkylthio cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted
  • heterocyclic heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, S0 3 H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio.
  • linkers include without limitation -0-CH 2 -,
  • R Y is C]-C 6 alkyl
  • R B hydrogen or Ci-C 6 alkyl
  • a “traceless linker” refers to a linker which, for example upon hydrolysis
  • -0-CH 2 - is a traceless linker in the prodrug:
  • “Pharmaceutically acceptable salt” refers to salts of a compound, which salts are suitable for pharmaceutical use and are derived from a variety of organic and inorganic counter ions well known in the art and include, when the compound contains an acidic functionality, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate (see Stahl and Wermuth, eds., "HANDBOOK OF
  • pharmaceutically acceptable salts are those salts that retain substantially one or more of the desired pharmacological activities of the parent compound and which are suitable for administration to humans.
  • Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids.
  • Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalide acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1 ,2- ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, etc.), arylsulfonic acids (e.g.,
  • benzenesulfonic acid 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, etc.), 4-methylbicyclo[2.2.2]-oct-2-ene- l - carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.
  • Pharmaceutically acceptable salts also include salts formed when an acidic proton present in the parent compound is either replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or by an ammonium ion (e.g., an ammonium ion derived from an organic base, such as, ethanolamine, diethanolamine, triethanolamine, N- methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, triethylamine, and ammonia) .
  • a metal ion e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion
  • an ammonium ion e.g., an ammonium ion derived from an organic base, such as, ethanolamine, diethanolamine, triethanolamine, N- methylglucamine, morpholine, piperidine, dimethylamine, dieth
  • serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to no more than -substituted aryl-(substituted aryl)-substituted aryl-(substituted aryl).
  • an "effective amount” is an amount sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the route of administration, etc. It is understood, however, that specific dose levels of the therapeutic agents of the present technology for any particular subject depends upon a variety of factors including the activity of the specific compound employed, bioavailability of the compound, the route of administration, the age of the animal and its body weight, general health, sex, the diet of the animal, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration.
  • Treatment dosages generally may be titrated to optimize safety and efficacy.
  • dosage-effect relationships from in vitro and/or in vivo tests can provide useful guidance on the proper doses for patient administration.
  • Studies in animal models generally may be used for guidance regarding effective dosages for treatment of diseases such as diarrhea and polycystic kidney disease (PKD).
  • PPD polycystic kidney disease
  • one will desire to administer an amount of -the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vivo.
  • terapéuticaally effective amount is an amount sufficient to treat a specified disorder or disease or alternatively to obtain a pharmacological response such as inhibiting function CFTR.
  • treating or “treatment” of a disease in a patient refers to ( 1 ) preventing the symptoms or disease from occurring in an animal that is predisposed or does not yet display symptoms of the disease; (2) inhibiting the disease or arresting its
  • beneficial or desired results can include one or more, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of a condition (including a disease), stabilized (i.e., not worsening) state of a condition (including disease), delay or slowing of condition (including disease), progression, amelioration or palliation of the condition (including disease), states and remission (whether partial or total), whether detectable or undetectable.
  • Phosphate refers to the moiety:
  • each R x is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • one of the R" is H.
  • both the R x groups are H.
  • Phosphonate refers to the moiety:
  • each R x is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • the R x that is part of -OR x is H.
  • Prodrug refers to art recognized modifications to one or more functional groups which functional groups are metabolized in vivo to provide an active agent or an active metabolite thereof.
  • Such functional groups are well known in the art including acyl or thioacyl groups for hydroxyl and/or amino substitution, conversion of one or more hydroxyl groups to the mono-, di- and tri-phosphate wherein optionally one or more of the pendent hydroxyl groups of the mono-, di- and tri-phosphate have been converted to an alkoxy, a substituted alkoxy, an aryloxy or a substituted aryloxy group, and the like.
  • the prodrug derivative is contemplated to demonstrate various pharmacologically desirable properties, such as increased aqueous solubility, increased bioavailability, etc. and/or reduced activity of the active agent.
  • an active agent is a compound that is useful for the purposes disclosed herein.
  • Such prodrugs may, but need not, be pharmacologically inactive until converted into their active drug form.
  • the compounds disclosed herein can include prodrug derivatives that are hydrolyzed or otherwise cleaved under the conditions of use.
  • suitable prodrug derivatives include, without limitation, active agents where a hydroxyl, amino, thiol or a carboxyl group is derivatized to form the prodrug.
  • a hydroxyl functional group including phenolic and aliphatic hydroxyl groups, can be masked as a phosphate, phosphonate, sulfonate, ester, or with a carbonate containing promoiety.
  • the promoiety is a group that is bonded to an active agent to provide a prodrug derivative.
  • These prodrugs can be hydrolyzed in vivo to provide the hydroxyl group.
  • An amino functional group can be masked as an amide, carbamate, imine, urea, phosphenyl, phosphoryl, or sulfenyl promoiety.
  • These prodrugs can be hydrolyzed in vivo to provide the amino group.
  • a carboxyl group can be masked as an ester (including silyl esters and thioesters), amide, or oxadiazole promoiety. These prodrugs can be hydrolyzed in vivo to provide the carboxyl group.
  • prodrug derivatives bearing phosphate groups that differed by as little as an -0-CH 2 - linker demonstrated different levels of enhanced solubility (compared to a common active agent), in different pH ranges. See, Table 1.
  • the prodrugs can increase the water solubility of the prodrug compared to the active agent.
  • the progroup(s) such as for example a phosphate or a phosphonate moiety, or a linker containing a phosphate or a phosphonate moiety, may include or can be one or more groups suitable for imparting drug molecules with improved water solubility.
  • groups are well-known and include, by way of example and not limitation, hydrophilic groups such as a phosphate or a phosphonate or an alkyl, aryl, and arylalkyl, or
  • cycloheteroalkyl group substituted with one or more of a phosphorous acid (i.e., a phosphate or a phosphonate), an amine, alcohol, a carboxylic acid, a sulfoxide, a sugar, an amino acid, a thiol, a polyol, an ether, a thioether, and a quaternary amine salt.
  • a phosphorous acid i.e., a phosphate or a phosphonate
  • ester groups including phosphates or phosphonates, commonly undergo acid-catalyzed hydrolysis to yield the parent hydroxyl group when exposed to the acidic conditions of the stomach or base-catalyzed hydrolysis when exposed to the basic conditions of the intestine or blood.
  • ester moieties when administered to a subject orally, compounds that include ester moieties can be considered prodrugs of their corresponding hydroxyl, regardless of whether the ester form is pharmacologically active.
  • Prodrugs can cleave chemically in the stomach to the active compounds, and can employ progroups including such esters.
  • the progroups can be designed to metabolize in the presence of enzymes such as phosphatases, esterases, amidases, lipolases, including ATPases and kinases, etc.
  • Progroups including linkages capable of metabolizing in vivo are well known and include, by way of example and not limitation, ethers, thioethers, silylethers, silylthioethers, esters, thioesters, carbonates, thiocarbonates, carbamates, thiocarbamates, ureas, thioureas, and carboxamides.
  • a prodrug may also be metabolized under the desired conditions of use, for example, under the acidic conditions found in the stomach and/or by enzymes found in vivo, to yield a biologically active group, e.g. , the compounds as described herein.
  • a biologically active group e.g. , the compounds as described herein.
  • the progroup can comprise virtually any known or later-discovered hydroxyl, amine or thiol protecting group.
  • suitable protecting groups can be found, for example, in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, Greene & Wuts, 2nd Ed., John Wi ley & Sons, New York, 1991 .
  • the identity of the progroup(s) can also be selected to impart the prodrug with desirable characteristics.
  • hydrophilic groups can be used to increase water solubility.
  • prodrugs specifically tailored for selected modes of administration can be obtained.
  • the prodrug may also assist, for example, in improved passive intestinal absorption, improved transport-mediated intestinal absorption, protection against fast metabolism (slow-release prodrugs), tissue-selective delivery, passive enrichment in target tissues, and targeting-specific transporters.
  • Various groups described in these references can be utilized in the prodrugs described herein.
  • L A is -(alk) p -NR 2 CO-, -L B -(alk) p -, or -C(OH)R A -; alk is alkylene or heteroalkylene;
  • L B is O, S, NR 2 , -NR 2 CO-, -CONR 2 -, -C(0)0-, or -OC(O)-; p is 0, 1 , 2, or 3;
  • R A and R 1 independently are alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, aryloxy, or substituted aryloxy;
  • R 2 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl; or when p is 0, R 1 and R 2 together with the atoms bound thereto, form a heterocycle or substituted heterocycle; is a substituted or unsubstituted 5 membered heteroaryl group;
  • R 3 and R 4 are each independently halo
  • R 5 is hydrogen or hydroxy!
  • R 6 is an -L-R 61 moiety containing a phosphate or a phosphonate moiety
  • L is a bond or a linker
  • R 61 is phosphate or phosphonate.
  • the compound is a compound of Formula II:
  • the compound is a compound of Formula III:
  • R 1 1 is phenyl or a substituted phenyl group
  • L 1 is -O-, -S(0) m , or -NR 12 -;
  • n 0, 1 , or 2;
  • R 12 is hydrogen, C 1-C3 alkyl, or substituted C1 -C3 alkyl
  • L 2 is a phenylene or substituted phenylene group; and R 2 is H, C1 -C3 alkyl, or substituted C
  • heteroaryl containing 1 , 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur.
  • the heteroaryl contains 1 heteroatom.
  • the heteroaryl contains 2 heteroatoms. In a yet further embodiment, the heteroaryl contains 3 heteroatoms.
  • R A is C 1-C3 alkyl or substituted C1-C3 alkyl
  • Y A is CH or N.
  • R is hydrogen. In a yet further embodiment, R 5 is hydroxy. [0133] Also provided herein is a compound of Formula IV:
  • Formula IV or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, halo, amino, substituted amino, C1 -C3 alkoxy, substituted C 1-C3 alkoxy, C1 -C3 alkyl, or substituted C 1-C3 alkyl, r is 1 , 2, or 3, R 2 is H, C,-C 3 alkyl, or substituted C C 3 alkyl, and R 2 , R 3 , R 4 , and R 6 are defined as in any aspect or embodiment herein. In one embodiment, r is 1 .
  • R 2 is hydrogen.
  • R 2 is C1-C3 alkyl or substituted C1-C3 alkyl.
  • R 3 and R 4 are independently the same or different and are chloro or bromo.
  • L is a bond or a linker, such as a traceless linker.
  • a non-limiting example of a traceless linker is -0-CH 2 - wherein the carbon atom is bonded to the phosphate or the phosphonate moiety.
  • R 61 is phosphate or phosphonate.
  • R 6 contains a phosphate moiety or a phosphonate moiety.
  • R 13 is hydrogen.
  • the compound is of formula:
  • the compound is of formula:
  • non-limiting examples of pharmaceutically acceptable salts include, salts having alkali metal, alkaline earth metal, ammonium cations.
  • R 1 , R 3 -R 5 , p, and A are defined as in any aspect or embodiment herein, and R p is a protecting group suitable for protecting a phosphate group.
  • a prodrug derivative of the present technology containing a linker is synthesized as shown below.
  • R 1 , R 3 -R 5 , p, A, and R p are defined as in any aspect or embodiment herein.
  • the method comprises contacting a compound of formula (i) with a phosphorylating agent to provide a compound of formula (IA).
  • the method further comprises deprotecting the compound of formula (IA) to provide a compound of formula (IB).
  • the method comprises contacting a compound of formula (i) with a haloalkylphosphate to provide a compound of formula (IC).
  • the method further comprises deprotecting the compound of formula (IC) to provide a compound of formula (ID).
  • Exemplary reagents and conditions for performing these reactions are provided in the Examples below. Other examples of such protecting groups, R p , are described in Greene & Wuts, supra.
  • Various other reagents and reaction conditions for performing a phosphorylation, alkylation, and the deprotection to produce the phosphate prodrug will be apparent to the skilled artisan in view of this disclosure.
  • composition comprising a compound and/or an intermediate for making the compound as provided herein and a carrier.
  • the composition is a pharmaceutical composition comprising a compound provided herein and a
  • the pharmaceutical composition is an immediate release or alternatively, a sustained release formulation.
  • Yet another aspect of the present technology relates to a method for inhibiting the transport of a halide ion across a mammalian cell membrane expressing functional CFTR protein comprising or alternatively consisting essentially of, or alternatively consisting of, contacting the CFTR protein with an effective amount of compound defined herein or compositions or formulations comprising these compounds, thereby inhibiting the transport of the halide ion by the CFTR protein.
  • the compounds disclosed herein are useful in the treatment of a condition, disorder or disease or symptom of such condition, disorder, or disease, where the condition, disorder or disease is responsive to inhibition of functional CFTR.
  • diseases or conditions include, but are not limited to the various forms of diarrhea, P D and male infertility.
  • the methods include administration of an effective amount of a compound, composition or formulation as described herein.
  • Applicants believe that the compounds of the technology treat these diseases by inhibiting ion transport, e.g. HCO 3 ' or halide ion, e.g. , chloride ion, transport by CFTR.
  • the compounds and compositions are administered or delivered to treat diarrhea and associated symptoms in an animal in need of such treatment.
  • the term "animal” is used broadly to include mammals such as a human patient or other farm animals in need of such treatment.
  • the animal is an infant (i.e., less than 2 years old, or alternatively, less than one year old, or alternatively, less than 6 months old, or alternatively, less than 3 months old, or alternatively, less than 2 months old, or alternatively, less than 1 one month old, or alternatively, less than 2 weeks old), a newborn (e.g.
  • a pediatric patient e.g., less than 18 years old or alternatively less than 16 years old
  • a geriatric patient e.g., greater than 65 years old
  • CFTR function has been associated with a wide spectrum of diseases (including secretory diarrhea, polycystic kidney disease (P D), cardiac arrhythmia, disorders associated with neovascularization, male infertility, chronic obstructive pulmonary disorders, pancreatic insufficiency, bacterial pulmonary conditions, and an abnormally concentrated sudoriparous secretion, chronic idiopathic pancreatitis, sinusitis, allergic bronchopulmonary aspergillosis (ABPA), asthma, primary sclerosing cholangitis, congenital bilateral absence of the vas deferens (CBAVD), hydrosalpinx, liver disease, bile duct injury, mucoviscidosis, etc.), administration of an effective amount of a compound, composition or formulation of this technology will treat such diseases when administered to an animal such as a human patient in need thereof.
  • diseases including secretory diarrhea, polycystic kidney disease (P D), cardiac arrhythmia, disorders associated with neovascularization, male
  • the technology relates to a method of treating a disease in an animal, where the disease is responsive to inhibition of functional CFTR and is selected from the group consisting of secretory diarrhea, polycystic kidney disease (PKD), cardiac arrhythmia and disorders associated with neovascularization, by administering an effective amount of a compound, composition or formulation as defined herein thereby treating the disease.
  • PPD polycystic kidney disease
  • cardiac arrhythmia and disorders associated with neovascularization
  • diseases responsive to inhibiting of functional CFTR polypeptide include, but are not limited to, chronic idiopathic pancreatitis, sinusitis, allergic bronchopulmonary aspergillosis (ABPA), asthma, primary sclerosing cholangitis, congenital bilateral absence of the vas deferens (CBAVD), hydrosalpinx, liver disease, bile duct injury, and mucoviscidosis.
  • ABPA allergic bronchopulmonary aspergillosis
  • CBAVD congenital bilateral absence of the vas deferens
  • hydrosalpinx liver disease
  • bile duct injury and mucoviscidosis.
  • the compounds, compositions and formulations of the technology are used in the treatment of the conditions associated with aberrantly increased intestinal secretion, particularly acute aberrantly increased intestinal secretion. Such intestinal secretion can result in intestinal inflammatory disorders and diarrhea, particularly secretory diarrhea.
  • the technology relates to a treatment of diarrhea by administering an effective amount of the compound, composition or formulation.
  • the technology relates to treatment of secretory diarrhea by administering an effective amount of the compound, composition or formulation.
  • the technology relates to the treatment of diarrhea by administering an effective amount of the compound, composition or formulation, where the diarrhea is for example, infectious diarrhea, inflammatory diarrhea or diarrhea associated with chemotherapy.
  • the technology relates to a treatment of secretory diarrhea which involves use of a compound, composition or formulation of the technology to inhibit the CFTR chloride channel.
  • diarrhea intends a medical syndrome which is characterized by the primary symptom of diarrhea (or scours in animals) and secondary clinical symptoms that may result from a secretory imbalance and without regard to the underlying cause and therefore includes exudative (inflammatory), decreased absorption (osmotic, anatomic derangement, and motility disorders) and secretory diarrhea.
  • exudative inflammatory
  • absorption osmotic, anatomic derangement, and motility disorders
  • secretory diarrhea As noted previously, all forms of diarrhea have a secretory component. Symptoms include, but are not limited to impaired colonic absorption, ulcerative colitis, shigellosis, and amebiasis. Osmotic diarrhea can occur as a result of digestive abnormalities such as lactose intolerance.
  • Anatomic derangement results in a decreased absorption surface caused by such procedures as subtotal colectomy and gastrocolic fistula.
  • Motility disorders result from decreased contact time resulting from such diseases as hyperthyroidism and irritable bowel syndrome.
  • Secretory diarrhea is characterized by the hypersecretion of fluid and electrolytes from the cells of the intestinal wall. In classical form, the hypersecretion is due to changes which are independent of the permeability, absorptive capacity and exogenously generated osmotic gradients within the intestine. However, all forms of diarrhea can manifest a secretory component.
  • the compounds, compositions or formulation of this technology can also treat PKD and associated diseases or disorders such as Autosomal Dominant Polycystic Kidney Disease (ADPKD), Autosomal Recessive Polycystic Kidney Disease and Acquired Cystic Kidney Disease.
  • ADPKD Autosomal Dominant Polycystic Kidney Disease
  • PKD Autosomal Recessive Polycystic Kidney Disease
  • Acquired Cystic Kidney Disease The major manifestation of PKD is the progressive cystic dilation of renal tubules which ultimately leads to renal failure in half of affected individuals.
  • PKD-associated renal cysts may enlarge to contain several liters of fluid and the kidneys usually enlarge progressively causing pain.
  • Other abnormalities such as hematuria, renal and urinary infection, renal tumors, salt and water imbalance and hypertension frequently result from the renal defect.
  • Cystic abnormalities in other organs, including the liver, pancreas, spleen and ovaries are commonly found in PKD.
  • Massive liver enlargement occasionally causes portal hypertension and hepatic failure.
  • Cardiac valve abnormalities and an increased frequency of subarachnoid and other intracranial hemorrhage have also been observed in PKD.
  • Patent No. 5,891 ,628 Biochemical abnormalities which have been observed have involved protein sorting, the distribution of cell membrane markers within renal epithelial cells, extracellular matrix, ion transport, epithelial cell turnover, and epithelial cell proliferation. The most carefully documented of these findings are abnormalities in the composition of tubular epithelial cells, and a reversal of the normal polarized distribution of cell membrane proteins, such as the Na + /K + ATPase. Carone, F.A. et al (1994) Lab. Inv. 70:437-448.
  • Diarrhea amenable to treatment using the compounds of the technology can result from exposure to a variety of pathogens or agents including, without limitation, cholera toxin ⁇ Vibrio cholera), E. coli (particularly enterotoxigenic (ETEC)), Salmonella, e.g.
  • Cryptosporidiosis e.g., rotavirus
  • food poisoning e.g., rotavirus
  • toxin exposure results in increased intestinal secretion mediated by CFTR.
  • diarrheas that can be treated by the compounds of the technology include diarrhea associated with AIDS ⁇ e.g., AIDS-related diarrhea), diarrheas caused by anti-AIDS medications such as protease inhibitors and inflammatory gastrointestinal disorders, such as ulcerative colitis, inflammatory bowel disease (IBD), Crohn's disease, chemotherapy, and the like.
  • IBD inflammatory bowel disease
  • intestinal inflammation modulates the expression of three major mediators of intestinal salt transport and may contribute to diarrhea in ulcerative colitis both by increasing transepithelial CI " secretion and by inhibiting the epithelial NaCl absorption. See, e.g. , Lohi et al. (2002) Am. J. Physiol. Gastrointest. Liver Physiol
  • the compounds and compositions can be administered alone or combined with other suitable therapy such as oral rehydration therapy (ORT), supportive renal therapy, administration of an antiviral, vaccine, or other compound to treat the underlying infection or by administering an effective amount of an oral glucose-electrolyte solution to the animal.
  • ORT oral rehydration therapy
  • the compounds or compositions are co-administered with micronutrients, e.g. , zinc, iron, and vitamin A.
  • the therapies may be administered simultaneously or
  • Administration is by any appropriate route and varies with the disease or disorder to be treated and the age and general health of the animal or human patient.
  • the compounds of the technology can be administered on a mucosal surface of the gastrointestinal tract ⁇ e.g. , by an enteral route, such as oral, intraintestinal, intraluminally, rectal as a suppository, and the like) or to a mucosal surface of the oral or nasal cavities ⁇ e.g. , intranasal, buccal, sublingual, and the like).
  • the compounds disclosed herein are administered in a pharmaceutical formulation suitable for oral administration, intraluminally or intraperitoneal administration.
  • the compounds disclosed herein are administered in a pharmaceutical formulation suitable for sustained release.
  • the compounds of the technology can also find further use as male infertility drugs, by inhibition of CFTR activity in the testes.
  • the compound is administered in a sustained release formulation which comprises the compound and an effective amount of a pharmaceutical ly-acceptable polymer.
  • sustained release formulations provide a composition having a modified
  • the sustained release formulation provides decreased C max and increased T max without altering bioavailability of the drug.
  • the compound is admixed with about 0.2 % to about 5.0 % w/v solution of a pharmaceutically-acceptable polymer. In other embodiments, the amount of
  • pharmaceutically-acceptable polymer is between about 0.25% and about 5.0 %; between about 1 % and about 4.5%; between about 2.0% and about 4.0 %; between about 2.5% and about 3.5%; or alternatively about 0.2%; about 0.25%; about 0.3%; about 0.35%; about 0.4%; about 0.45%; about 0.5%, about 1.0%, about 2.0%, about 3.0%, or about 4.0%, of the polymer.
  • the therapeutic and prophylactic methods of this technology are useful to treat human patients in need of such treatment.
  • the methods are not to be limited only to human patient but rather can be practiced and are intended to treat any animal in need thereof.
  • animals will include, but not be limited to farm animals and pets such as cows, pigs and horses, sheep, goats, cats and dogs.
  • Diarrhea also known as scours, is a major cause of death in these animals.
  • Diarrhea in animals can result from any major transition, such as weaning or physical movement.
  • one form of diarrhea is the result of a bacterial or viral infection and generally occurs within the first few hours of the animal's life. Infections with rotavirus and coronavirus are common in newborn calves and pigs. Rotavirus infection often occurs within 12 hours of birth. Symptoms of rotaviral infection include excretion of watery feces, dehydration and weakness. Coronavirus which causes a more severe illness in the newborn animals, has a higher mortality rate than rotaviral infection. Often, however, a young animal may be infected with more than one virus or with a combination of viral and bacterial microorganisms at one time.
  • Yet another aspect of the present technology relates to a method for inhibiting the transport of a halide ion across a mammalian cell membrane expressing functional CFTR protein by contacting the cell expressing functional CFTR with an effective amount of the compound defined herein or compositions or formulations thereof, thereby inhibiting the transport of the halide ion.
  • the term "functional CFTR" intends the full length wild type CFTR protein, a functional equivalent, or a biologically active fragment thereof.
  • CFTR has been isolated, cloned and recombinantly expressed in a variety of cell types, which include but are not limited to Fischer rat thyroid (FRT) epithelial cells, Human colonic T84 cells, intestinal crypt cells, colonic epithelial cells, mouse fibroblast cells, bronchial epithelial, tracheobronchial epithelial, sero/mucous epithelial cells, kidney cells.
  • FRT Fischer rat thyroid
  • CFTR-expressing cell lines also are available from the American Type Culture Collection (ATCC).
  • ATCC American Type Culture Collection
  • the open reading frame and polypeptide sequence of wild-type CFTR has been previously described in U.S. Patent Nos. 6,984,487; 6,902,907; 6,730,777; and 6,573,073.
  • the delta 508 mutant is specifically (see U.S. Patent Nos. 7, 160,729 and 5,240,846) excluded as an equivalent polynucleotide or polypeptide.
  • Equivalents of function CFTR include, but are not limited to polynucleotides or proteins that have the same or similar activity to transport ions across the cell membrane. At the sequence or amino acid level, equivalent sequences are at least 90 % identical or alternatively at least 95 %, or yet further at least 98 % identical (homologous as determined when comparison is run under default parameters) to wild-type CFTR or those which hybridize under stringent conditions to the complement of these coding sequences.
  • Biologically active functional fragments are those having contiguous identity to wild-type CFTR but contain less than 1480 amino acids. Functional fragments have been described. See U.S. Patent Nos. 5,639,661 and 5,958,893.
  • Hybridization refers to a reaction in which one or more polynucleotides react to form a complex that is stabilized via hydrogen bonding between the bases of the nucleotide residues.
  • the hydrogen bonding may occur by Watson-Crick base pairing, Hoogstein binding, or in any other sequence-specific manner.
  • the complex may comprise two strands forming a duplex structure, three or more strands forming a multi-stranded complex, a single self-hybridizing strand, or any combination of these.
  • a hybridization reaction may constitute a step in a more extensive process, such as the initiation of a PCR reaction, or the enzymatic cleavage of a polynucleotide by a ribozyme.
  • Hybridization reactions can be performed under conditions of different "stringency.” In general, a low stringency hybridization reaction is carried out at about 40 °C in 10 x SSC or a solution of equivalent ionic strength/temperature. A moderate stringency hybridization is typically performed at about 50 °C in 6 x SSC, and a high stringency hybridization reaction is generally performed at about 60 °C in 1 x SSC.
  • a double-stranded polynucleotide can be any polynucleotide
  • “complementary” or “homologous” to another polynucleotide if hybridization can occur between one of the strands of the first polynucleotide and the second.
  • “Complementarity” or “homology” is quantifiable in terms of the proportion of bases in opposing strands that are expected to form hydrogen bonding with each other, according to generally accepted base-pairing rules.
  • a polynucleotide or polynucleotide region has a certain percentage (for example, 80%, 85%, 90%, or 95%) of "sequence identity" to another sequence when aligned, that percentage of bases (or amino acids) are the same in comparing the two sequences.
  • This alignment and the percent homology or sequence identity can be determined using software programs known in the art, for example those described in CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (F.M. Ausubel et al. , eds., 1987) Supplement 30, section 7.7.18, Table 7.7.1 .
  • default parameters are used for alignment.
  • a preferred alignment program is BLAST, using default parameters.
  • Non-limiting examples of these programs are BLAST family programs including BLASTN, BLASTP, BLASTX, TBLASTN, and TBLASTX (BLAST is available from the worldwide web at ncbi.nlm.nih.gov/BLAST/), FastA, Compare, DotPlot, BestFit, GAP, FrameAlign, ClustalW, and Pileup. These programs are obtained commercially available in a
  • sequence analysis software such as GCG Inc.'s Wisconsin Package.
  • Other similar analysis and alignment programs can be purchased from various providers such as DNA Star's MegAlign, or the alignment programs in GeneJockey.
  • sequence analysis and alignment programs can be accessed through the world wide web at sites such as the CMS Molecular Biology Resource at
  • Protein sequences corresponding to a gene or a segment thereof can be used for sequence analysis.
  • Commonly employed databases include but are not limited to GenBank, EMBL, DDBJ, PDB, SWISS-PROT, EST, STS, GSS, and HTGS.
  • Parameters for determining the extent of homology set forth by one or more of the aforementioned alignment programs are known. They include but are not limited to p value, percent sequence identity and the percent sequence similarity. P value is the probability that the alignment is produced by chance. For a single alignment, the p value can be calculated according to Karlin et al. (1990) PNAS 87:2246. For multiple alignments, the p value can be calculated using a heuristic approach such as the one programmed in BLAST. Percent sequence identify is defined by the ratio of the number of nucleotide or amino acid matches between the query sequence and the known sequence when the two are optimally aligned.
  • Equivalent polynucleotides also include polynucleotides that are greater than 75%, or 80%, or more than 90%, or more than 95% homologous to wild-type CFTR and as further isolated and identified using sequence homology searches.
  • the halide ion is at least one of ⁇ , CP, or Br " .
  • the halide ion is CP.
  • the functional CFTR is wild-type full length CFTR.
  • the mammalian cell is an epithelial cell or a kidney cell. In one preferred embodiment, the mammalian cell is an intestinal epithelial cell or a colon epithelial cell.
  • the compounds of the present technology can be administered singly, as mixtures of one or more compounds of the technology, or in mixture or combination with other agents useful for treating such diseases and/or the symptoms associated with such diseases.
  • the compounds of the present technology may also be administered in mixture or in combination with agents useful to treat other disorders or maladies, such as steroids, membrane stabilizers, 5 -lipoxygenase (5LO) inhibitors, leukotriene synthesis and receptor inhibitors, inhibitors of IgE isotype switching or IgE synthesis, IgG isotype switching or IgG synthesis, ⁇ -agonists, tryptase inhibitors, aspirin, cyclooxygenase (COX) inhibitors, methotrexate, anti-TNF drugs, retuxin, PD4 inhibitors, p38 inhibitors, PDE4 inhibitors, and antihistamines, to name a few.
  • the compounds of the technology can be administered per se in the form of prodrugs or as pharmaceutical compositions, comprising an active compound or prodrug.
  • the method can be practiced in vitro or in vivo. When practiced in vitro, the method can be used to screen for compounds, compositions and methods that possess the same or similar activity. Activity is determined using the methods described below or others known to those of skill in the art and described in Verkmann and Galietta (2006) Progress in
  • Human colonic T84 cells can be acquired from the European Collection of Cell Cultures (ECACC) and grown in standard culture conditions as described by the supplier. On the day before assay 25,000 T84 cells per well are plated into standard black walled, clear bottom 384-well assay plates in standard growth medium consisting of
  • T84 cells are incubated with the FLIPR Red membrane potential dye for 45 minutes in the presence and absence of test compound before being transferred to a commercially available fluorescence imaging plate reader (FLIPR384, Molecular Devices Corporation). Fluorescence levels are monitored continuously every second for 150 seconds; after an initial 10 second baseline, CFTR channel activity is stimulated through the addition of 10 ⁇ forskolin in the presence of 100 ⁇ of the phosphodiesterase inhibitor iso-butyl-methylxanthine (IBMX). Addition of the forskolin leads to the activation of intracellular adenylyl cylase 1, elevating cAMP levels and results in the phosphorylation and opening of CFTR anion channels. CFTR channel opening causes chloride ion efflux and subsequent depolarization of the cells, which is measured by an increase in fluorescence. CFTR inhibitor compounds prevent cell depolarization and the associated increase in fluorescence.
  • FRT Fisher Rat Thyroid
  • FRT wildtype human CFTR
  • a reporter protein such as green fluorescent protein (GFP) or a mutant such as the yellow fluorescent protein-based C l 31 /I " halide sensor e.g. YFP-H148Q
  • GFP green fluorescent protein
  • a mutant such as the yellow fluorescent protein-based C l 31 /I " halide sensor e.g. YFP-H148Q
  • FRT- CFTR-YFP-H148Q cells in 96-well plates are washed three times with phosphate buffered saline (PBS) and then CFTR halide conductance is activated by incubation for 5 minutes with a cocktail containing 5 ⁇ , forskolin, 25 ⁇ apigenin and 100 ⁇ IBMX.
  • Test compounds at a final concentration of 10 ⁇ and 20 ⁇ are added five minutes prior to assay of iodide influx in which cells are exposed to a 100 mM inwardly-directed iodide gradient.
  • Baseline YFP fluorescence is recorded for two seconds followed by 12 seconds of continuous recording of fluorescence after rapid addition of the ⁇ containing solution, to create a ⁇ gradient.
  • Initial rates of ⁇ influx can be computed from the time course of decreasing fluorescence after the ⁇ gradient as known to those skilled in the art and described in Yang et al. (2002) J. Biol. Chem.: 35079-35085.
  • Activity of the CFTR channel can also be measured directly using
  • Electrodes are fabricated from 1 .7 mm capillary glass with resistances between 2 and 3 ⁇ using a Sutter P-97 puller.
  • the extracellular solution can contain (in mM) 1 50 NaCl, 1 CaCI 2 , 1 MgCl 2 , 10 glucose, 10 mannitol, and 10 TES (pH 7.4), and the intracellular (pipette) solution can contain 120 CsCl, MgCl 2 , 10 TEA-C1, 0.5 EGTA, 1 Mg-ATP and 10 HEPES (pH 7.3).
  • the CFTR channels are activated by forskolin (5 ⁇ ) in the extracellular solution.
  • the cells are held at a potential of 0 mV and currents are recorded by a voltage ramp protocol from -120 mV to +80 mV over 500 ms every 10 seconds. No leak subtraction was employed.
  • Compounds are superfused to individual cells using a Biologic MEV-9/EVH-9 rapid perfusion system.
  • mice (CD l strain, 25-35 g) are deprived of food prior to surgery and can be anaesthetized with any suitable agent such as intraperitoneal ketamine (40 mg/kg) and xylazine (8 mg/kg). Body temperature should be maintained at 36-38° C using a heating pad.
  • a small abdominal incision is made and 3 closed intestinal (ileal and/or duodenum/jejunum) loops (length 15-30 mm) proximal to the cecum are isolated by sutures. Loops are injected with 100 ⁇ , of PBS or PBS containing cholera toxin ( ⁇ g) with or without test compound at appropriate doses. The abdominal incision is closed with suture and mice are allowed to recover from anesthesia.
  • mice are anesthetized, intestinal loops are removed, and loop length and weight are measured to quantify net fluid secretion to be measured as g/cm of loop.
  • compositions are administered to the animals and therapeutic effect is noted.
  • the compounds of the present technology can be formulated in the pharmaceutical compositions per se, or in the form of a hydrate, solvate, N-oxide, or pharmaceutically acceptable salt, as described herein.
  • such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts having lower solubility than the corresponding free acids and bases may also be formed.
  • the present technology includes within its scope solvates of the compounds and salts thereof, for example, hydrates.
  • the compounds may have one or more asymmetric centers and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present technology.
  • this technology provides a pharmaceutical formulation comprising a compound selected from the compounds of the technology, or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient, diluent, preservative, stabilizer, or mixture thereof.
  • the methods can be practiced as a therapeutic approach towards the treatment of the conditions described herein.
  • the compounds of the technology can be used to treat the conditions described herein in animal subjects, including humans.
  • the methods generally comprise administering to the subject an amount of a compound of the technology, or a salt, or N-oxide thereof, effective to treat the condition.
  • the subject is a non-human mammal, including, but not limited to, bovine, horse, feline, canine, rodent, or primate. In another embodiment, the subject is a human.
  • the compounds of the technology can be provided in a variety of formulations and dosages.
  • the compounds are provided as non-toxic pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this technology include acid addition salts such as those formed with hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid.
  • Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alky], alkenyl, alkynyl, or substituted alkyl moiety.
  • suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g., sodium or potassium salts; and alkaline earth metal salts, e.g. , calcium or magnesium salts.
  • the pharmaceutically acceptable salts of the present technology can be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble or in a solvent such as water which is removed in vacuo, by freeze drying, or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
  • compositions comprising the compounds described herein can be manufactured by means of conventional mixing, dissolving, granulating, dragee-making levigating, emulsifying, encapsulating, entrapping, or lyophilization processes.
  • the compositions can be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or auxiliaries which facilitate processing of the compounds provided herein into preparations which can be used pharmaceutically.
  • the compounds of the technology can be administered by oral, parenteral ⁇ e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray nasal, vaginal, rectal, sublingual, urethral ⁇ e.g., urethral suppository) or topical routes of administration ⁇ e.g., gel, ointment, cream, aerosol, etc.) and can be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, excipients, and vehicles appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant
  • topical routes of administration e
  • this technology relates to a composition
  • a composition comprising a compound as described herein and a carrier.
  • this technology relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described herein and a pharmaceutically acceptable carrier.
  • this technology relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound as described herein and a pharmaceutically acceptable carrier.
  • compositions for the administration of the compounds can be conveniently presented in dosage unit form and can be prepared by any of the methods well known in the art of pharmacy.
  • the pharmaceutical compositions can be, for example, prepared by uniformly and intimately bringing the compounds provided herein into association with a liquid carrier, a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the compound provided herein is included in an amount sufficient to produce the desired therapeutic effect.
  • compositions of the technology may take a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, and vaginal, or a form suitable for administration by inhalation or insufflation.
  • topical administration the compounds can be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well-known in the art.
  • Systemic formulations include those designed for administration by injection (e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection) as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.
  • Useful injectable preparations include sterile suspensions, solutions, or emulsions of the compounds provided herein in aqueous or oily vehicles.
  • the compositions may also contain formulating agents, such as suspending, stabilizing, and/or dispersing agents.
  • the formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, and may contain added preservatives.
  • the injectable formulation can be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogen free water, buffer, and dextrose solution, before use.
  • a suitable vehicle including but not limited to sterile pyrogen free water, buffer, and dextrose solution, before use.
  • the compounds provided herein can be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.
  • the pharmaceutical compositions may take the form of, for example, lozenges, tablets, or capsules prepared by conventional means with
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate, talc, or silica
  • disintegrants e.g., potato starch or sodium starch glycolate
  • wetting agents e.g., sodium lauryl sulfate.
  • the tablets can be coated by methods well known in the art with, for example, sugars, films, or enteric coatings.
  • compositions intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the compounds provided herein in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents (e.g., corn starch or alginic acid); binding agents (e.g.
  • a time delay material such as glyceryl
  • monostearate or glyceryl distearate can be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256, 108; 4, 166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • the pharmaceutical compositions of the technology may also be in the form of oil-in-water emulsions.
  • Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups, or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (e.g., lecithin, or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, cremophoreTM, or fractionated vegetable oils); and preservatives (e.g., methyl or
  • propyl-p-hydroxybenzoates or sorbic acid may also contain buffer salts, preservatives, flavoring, coloring, and sweetening agents as appropriate.
  • Preparations for oral administration can be suitably formulated to give controlled release or sustained release of the compounds provided herein, as is well known.
  • the sustained release formulations of this technology are preferably in the form of a compressed tablet comprising an intimate mixture of compound of the technology and a partially neutralized pH-dependent binder that controls the rate of compound dissolution in aqueous media across the range of pH in the stomach (typically approximately 2) and in the intestine (typically approximately about 5.5).
  • one or more pH- dependent binders can be chosen to control the dissolution profile of the sustained release formulation so that the formulation releases compound slowly and continuously as the formulation is passed through the stomach and gastrointestinal tract.
  • the pH- dependent binders suitable for use in this technology are those which inhibit rapid release of drug from a tablet during its residence in the stomach (where the pH is-below about 4.5), and which promotes the release of a therapeutic amount of the compound of the technology from the dosage form in the lower gastrointestinal tract (where the pH is generally greater than about 4.5).
  • enteric binders and coating agents have a desired pH dissolution properties.
  • the examples include phthalic acid derivatives such as the phthalic acid derivatives of vinyl polymers and copolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates, hydroxyalkylcellulose acetates, cellulose ethers, alkylcellulose acetates, and the partial esters thereof, and polymers and copolymers of lower alkyl acrylic acids and lower alkyl acrylates, and the partial esters thereof.
  • One or more pH-dependent binders present in the sustained release formulation of the technology are in an amount ranging from about 1 to about 20 wt %, more preferably from about 5 to about 12 wt % and most preferably about 10 wt %.
  • pH-independent binders may be in used in oral sustained release formulation of the technology.
  • the pH-independent binders can be present in the formulation of this technology in an amount ranging from about 1 to about 10 wt %, and preferably in amount ranging from about 1 to about 3 wt % and most preferably about 2 wt %.
  • the sustained release formulation of the technology may also contain pharmaceutical excipients intimately admixed with the compound and the pH-dependent binder.
  • Pharmaceutically acceptable excipients may include, for example, pH-independent binders or film-forming agents such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate esters, starch, gelatin, sugars, carboxymethylcellulose, and the like.
  • Other useful pharmaceutical excipients include diluents such as lactose, mannitol, dry starch, microcrystalline cellulose and the like; surface active agents such as polyoxyethylene sorbitan esters, sorbitan esters and the like; and coloring agents and flavoring agents.
  • Lubricants such as talc and magnesium stearate
  • other tableting aids can also be optionally present.
  • the sustained release formulations of this technology have a compound of this technology in the range of about 50% by weight to about 95% or more by weight, and preferably between about 70% to about 90% by weight; a pH-dependent binder content of between 5% and 40%, preferably between 5% and 25%, and more preferably between 5% and 15%; with the remainder of the dosage form comprising pH-independent binders, fillers, and other optional excipients.
  • the compositions may take the form of tablets or lozenges formulated in the conventional manner.
  • the compounds provided herein can be formulated as solutions (for retention enemas), suppositories, or ointments containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds provided herein can be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer with the use of a suitable propellant (e.g.,
  • the dosage unit can be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension.
  • This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent.
  • the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the compounds may also be administered in the form of suppositories for rectal or urethral administration of the drug.
  • creams, ointments, jellies, gels, solutions, suspensions, etc., containing the compounds of the technology can be employed.
  • the compounds of the technology can be formulated for topical administration with polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • these formulations may optionally comprise additional pharmaceutically acceptable ingredients such as diluents, stabilizers, and/or adjuvants.
  • the devices which can be used to administer compounds of the technology are those well-known in the art, such as metered dose inhalers, liquid nebulizers, dry powder inhalers, sprayers, thermal vaporizers, and the like.
  • Other suitable technology for administration of particular compounds of the technology includes electrohydrodynamic aerosolizers.
  • electrohydrodynamic aerosolizers As those skilled in the art will recognize, the formulation of compounds, the quantity of the formulation delivered, and the duration of administration of a single dose depend on the type of inhalation device employed as well as other factors.
  • the frequency of administration and length of time for which the system is activated will depend mainly on the concentration of compounds in the aerosol.
  • shorter periods of administration can be used at higher concentrations of compounds in the nebulizer solution.
  • Devices such as metered dose inhalers can produce higher aerosol concentrations and can be operated for shorter periods to deliver the desired amount of compounds in some embodiments.
  • Devices such as dry powder inhalers deliver compounds provided herein until a given charge of agent is expelled from the device. In this type of inhaler, the amount of compounds in a given quantity of the powder determines the dose delivered in a single administration.
  • Formulations of compounds of the technology for administration from a dry powder inhaler may typically include a finely divided dry powder containing compounds, but the powder can also include a bulking agent, buffer, carrier, excipient, another additive, or the like.
  • Additives can be included in a dry powder formulation of compounds of the technology, for example, to dilute the powder as required for delivery from the particular powder inhaler, to facilitate processing of the formulation, to provide advantageous powder properties to the formulation, to facilitate dispersion of the powder from the inhalation device, to stabilize to the formulation (e.g., antioxidants or buffers), to provide taste to the formulation, or the like.
  • Typical additives include mono-, di-, and polysaccharides; sugar alcohols and other polyols, such as, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants, such as sorbitols, diphosphatidyl choline, or lecithin; and the like.
  • sugar alcohols and other polyols such as, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof
  • surfactants such as sorbitols, diphosphatidyl choline, or lecithin; and the like.
  • the compounds of the technology can be formulated as a depot preparation for administration by implantation or intramuscular injection.
  • the compounds provided herein can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
  • transdermal delivery systems manufactured as an adhesive disc or patch which slowly releases the compounds provided herein for percutaneous absorption can be used.
  • permeation enhancers can be used to facilitate transdermal penetration of the compounds provided herein. Suitable transdermal patches are described in, for example, U.S. Patent No. 5,407,713.; U.S.
  • Patent No. 5,352,456 U.S. Patent No. 5,332,213; U.S. Patent No. 5,336, 168; U.S. Patent No. 5,290,561 ; U.S. Patent No. 5,254,346; U.S. Patent No. 5, 164, 189; U.S. Patent No. 5, 163,899; U.S. Patent No. 5,088,977; U.S. Patent No. 5,087,240; U.S. Patent No. 5,008, 1 10; and U.S. Patent No. 4,921 ,475.
  • Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver compounds provided herein.
  • Certain organic solvents such as dimethylsulfoxide (DMSO) may also be employed, although usually at the cost of greater toxicity.
  • DMSO dimethylsulfoxide
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the compounds provided herein.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device can be accompanied by instructions for administration.
  • the compounds described herein, or compositions thereof will generally be used in an amount effective to achieve the intended result, for example, in an amount effective to treat or prevent the particular condition being treated.
  • the compound(s) can be administered therapeutically to achieve therapeutic benefit or prophylactically to achieve prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated and/or eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • administration of a compound to a patient suffering from an diarrhea provides therapeutic benefit not only when the diarrhea is eradicated or ameliorated, but also when the patient reports a decrease in the severity or duration of the symptoms associated with the diarrhea.
  • Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is realized.
  • the amount of compound administered will depend upon a variety of factors, including, for example, the particular condition being treated, the mode of administration, the severity of the condition being treated, the age and weight of the patient, the bioavailability of the particular compound provided herein. Determination of an effective dosage is well within the capabilities of those skilled in the art. As known by those of skill in the art, the preferred dosage of compounds of the technology will also depend on the age, weight, general health, and severity of the condition of the individual being treated. Dosage may also need to be tailored to the sex of the individual and/or the lung capacity of the individual, where administered by inhalation. Dosage and frequency of administration of the compounds will also depend on whether the compounds are formulated for treatment of acute episodes of a condition or for the prophylactic treatment of a disorder. A skilled practitioner will be able to determine the optimal dose for a particular individual.
  • the compound can be administered to a patient at risk of developing one of the previously described conditions. For example, if it is unknown whether a patient is allergic to a particular drug, the compound can be administered prior to administration of the drug to avoid or ameliorate an allergic response to the drug.
  • prophylactic administration can be applied to avoid the onset of symptoms in a patient diagnosed with the underlying disorder.
  • Effective dosages can be estimated initially from in vitro assays.
  • an initial dosage for use in animals can be formulated to achieve a circulating blood or serum concentration of compounds provided herein that is at or above an ICs 0 of the particular compound as measured in as in vitro assay.
  • Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound is well within the capabilities of skilled artisans.
  • the reader is referred to Fingl & Woodbury, "General Principles," GOODMAN AND GILMAN'S THE PHARMACEUTICAL BASIS OF THERAPEUTICS, Chapter 1 , pp. 1 -46, latest edition, Pergamon Press, and the references cited therein.
  • Initial dosages can also be estimated from in vivo data, such as animal models.
  • Dosage amounts will typically be in the range of from about 0.01 mg/kg/day to about 50 mg/kg/day, but can be higher or lower, depending upon, among other factors, the activity of the compound, its bioavailability, the mode of administration, and various factors discussed above.
  • the dosage amount is about 0.01 mg/kg/day, about 0.05 mg/kg day, about 0.1 mg/kg/day, about 0.2 mg/kg/day, about 0.3 mg/kg/day, about 0.4 mg/kg/day, about 0.5 mg/kg/day, about 0.6 mg/kg/day, about 0.7 mg/kg/day, about 0.8 mg/kg/day, about 0.9 mg/kg/day, about 1 mg/kg/day, about 2 mg/kg/day, about 3 mg/kg/day, about 4 mg/kg/day, about 5 mg/kg/day, about 6 mg/kg/day, about 7 mg/kg/day, about 8 mg/kg/day, about 9 mg/kg/day, or about 10 mg/kg/day.
  • the dosage amount is about 0.01 mg/kg/day to about 1 mg/kg/day, about 1.5 mg/kg/day to about 5 mg/kg/day, or about 5.5 mg/kg/day to about 10 mg/kg/day. In another embodiment, the dosage amount is about 10 mg/kg/day to about 20 mg/kg/day, about 20 mg/kg/day to about 30 mg/kg/day, about 30 mg/kg/day to about 40 mg/kg/day, or about 40 mg/kg/day to about 50 mg/kg/day. Dosage amount and interval can be adjusted individually to provide plasma levels of the compound(s) which are sufficient to maintain therapeutic or prophylactic effect.
  • the compounds can be administered once per week, several times per week (e.g., every other day), once per day, or multiple times per day, depending upon, among other things, the mode of administration, the specific indication being treated, and the judgment of the prescribing physician.
  • the compounds are administered 2-3 times per day.
  • the effective local concentration of compounds provided herein may not be related to plasma concentration. Skilled artisans will be able to optimize effective local dosages without undue experimentation.
  • the compound(s) will provide therapeutic or prophylactic benefit without causing substantial toxicity.
  • Toxicity of the compound(s) can be determined using standard pharmaceutical procedures.
  • the dose ratio between toxic and therapeutic (or prophylactic) effect is the therapeutic index.
  • Compounds(s) that exhibit high therapeutic indices are preferred.
  • kits for administration of the compounds of the technology, or pharmaceutical formulations comprising the compound that may include a dosage amount of at least one compound or a composition comprising at least one compound, as disclosed herein.
  • Kits may further comprise suitable packaging and/or instructions for use of the compound.
  • Kits may also comprise a means for the delivery of the at least one compound or compositions comprising at least one compound of the technology, such as an inhaler, spray dispenser (e.g., nasal spray), syringe for injection, or pressure pack for capsules, tables, suppositories, or other device as described herein.
  • kits provide the compound and reagents to prepare a composition for administration.
  • the composition can be in a dry or lyophilized form or in a solution, particularly a sterile solution.
  • the reagent may comprise a pharmaceutically acceptable diluent for preparing a liquid formulation.
  • the kit may contain a device for administration or for dispensing the compositions, including, but not limited to, syringe, pipette, transdermal patch, or inhalant.
  • the kits may include other therapeutic compounds for use in conjunction with the compounds described herein. These compounds can be provided in a separate form or mixed with the compounds of the present technology.
  • the kits will include appropriate instructions for preparation and administration of the composition, side effects of the compositions, and any other relevant information.
  • the instructions can be in any suitable format, including, but not limited to, printed matter, videotape, computer readable disk, or optical disc.
  • this technology provides a kit comprising a compound selected from the compounds of the technology, packaging, and instructions for use.
  • kits for treating an individual who suffers from or is susceptible to the conditions described herein comprising a container comprising a dosage amount of a compound of this technology or composition, as disclosed herein, and instructions for use.
  • the container can be any of those known in the art and appropriate for storage and delivery of oral, intravenous, topical, rectal, urethral, or inhaled formulations.
  • Kits may also be provided that contain sufficient dosages of the compounds or composition to provide effective treatment for an individual for an extended period, such as a week, 2 weeks, 3, weeks, 4 weeks, 6 weeks, or 8 weeks or more.
  • RSD Relative standard deviation
  • BQL below quantitation limit
  • N/A Not Acquired.
  • Example 5 The pharmacokinetics of the active agent generation upon in vivo
  • the pharmacokinetic properties of compounds 6 and 8 were determined in rats.
  • the animals were administered the prodrugs at an amount of 1 mg/kg by intravenous (i.v.) administration, and at an amount of 3 and 30 mg/kg orally (p.o.), and plasma concentrations of the prodrug and the active agent were determined by LC-MS MS (FIGs. l a- I d).
  • Plasma concentrations of compounds 6 and 8 dropped after administration.
  • plasma concentrations fell below the limit of quantitation (BLQ, 3 nanograms (ng)/ml) by 4 hours after administration.
  • For compound 6 (FIG. l c) levels were BLQ within 30 minutes of administration.
  • Plasma levels of the active agent, compound 4, increased rapidly after administration of compounds 6 or 8 (FIGs. l b, I d), reaching a peak of over 18,000 ng/ml at 0.5-1 hour after for the 30 mg/kg p.o. dose.
  • Administering a ten-fold lower dose at 3 mg/kg p.o. resulted, as expected, in a lower level of the active agent, approximately 1 ,200 ng/ml of compound 4, within 30 minutes after dosing.
  • prodrug derivatives 6 and 8 were rapidly and efficiently converted to the active agent in vivo, after i.v. or p.o. dosing.
  • the prodrug derivatives which are soluble in aqueous media and thus easily formulated, gave rise to plasma exposure of the active agent, potentially by efficient absorption through gut and/or by conversion to the active agent followed by absorption of the active agent.
  • prodrugs which, as exemplified before, are easy to formulate and administer, and provide active agent exposure in plasma when administered orally, are effective for inhibiting cholera toxin induced secretion.
  • prodrugs are contemplated to be useful for treating diarrhea and related secretory disorders.

Abstract

La présente invention concerne des dérivés de promédicaments du phosphate et du phosphonate, par exemple de formule IV, dans laquelle p, A, LA et R1, R3 à R6 sont tels que définis ici, et qui peuvent être utilisés à des fins de traitement de divers troubles dont, notamment, la diarrhée.
PCT/US2011/001359 2011-08-01 2011-08-01 Promédicaments du phosphate WO2013019169A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014047212A1 (fr) * 2012-09-21 2014-03-27 De Hostos Eugenio L Compositions et procédés comprenant des dérivés d'oxadiazole
US8796321B2 (en) 2008-04-21 2014-08-05 Path Drug Solutions Compounds, compositions and methods comprising oxadiazole derivatives
EP3302466A4 (fr) * 2015-05-29 2018-12-26 Emory University Composés 3- (phényl)-n- (4-phénoxybenzyl) -1,2,4-oxadiazole-5-carboxamide pour la prise en charge de maladies médiées par la protéine cftr
US10555918B2 (en) 2015-05-29 2020-02-11 Emory University 2-amino-N′-benzylideneacetohydrazides and derivatives for the management of CFTR protein mediated diseases

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8796321B2 (en) 2008-04-21 2014-08-05 Path Drug Solutions Compounds, compositions and methods comprising oxadiazole derivatives
WO2014047212A1 (fr) * 2012-09-21 2014-03-27 De Hostos Eugenio L Compositions et procédés comprenant des dérivés d'oxadiazole
EP3302466A4 (fr) * 2015-05-29 2018-12-26 Emory University Composés 3- (phényl)-n- (4-phénoxybenzyl) -1,2,4-oxadiazole-5-carboxamide pour la prise en charge de maladies médiées par la protéine cftr
US10512636B2 (en) 2015-05-29 2019-12-24 Emory University 3-(phenyl)-N-(4-phenoxybenzyl)-1,2,4-oxadiazole-5-carboxamide compounds for the management of CFTR protein mediated diseases
US10555918B2 (en) 2015-05-29 2020-02-11 Emory University 2-amino-N′-benzylideneacetohydrazides and derivatives for the management of CFTR protein mediated diseases
US11020379B2 (en) 2015-05-29 2021-06-01 Emory University 3-(phenyl)-N-(4-phenoxybenzyl)-1,2,4-oxadiazole-5-carboxamide compounds for the management of CFTR protein mediated diseases
US11116736B2 (en) 2015-05-29 2021-09-14 Emory University 2-amino-N'-benzylideneacetohydrazides and derivatives for the management of CFTR protein mediated diseases
US11844785B2 (en) 2015-05-29 2023-12-19 Emory University 3-(phenyl)-N-(4-phenoxybenzyl)-1,2,4-oxadiazole-5-carboxamide compounds for the management of CFTR protein mediated diseases

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