US20160279155A1 - Novel formulations - Google Patents

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US20160279155A1
US20160279155A1 US15/035,006 US201415035006A US2016279155A1 US 20160279155 A1 US20160279155 A1 US 20160279155A1 US 201415035006 A US201415035006 A US 201415035006A US 2016279155 A1 US2016279155 A1 US 2016279155A1
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salt
tris
hydroxymethyl
alkyl
aminomethane
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Marc F. Pelletier
Paul Robert Mcguirk
George William Farr
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Aeromics Inc
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Aeromics Inc
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Definitions

  • Aquaporins are cell membrane proteins that act as molecular water channels to mediate the flow of water in and out of the cells. While there is some degree of passive diffusion or osmosis of water across cell membranes, the rapid and selective transport of water in and out of cells involves aquaporins. These water channels selectively conduct water molecules in and out of the cell, while blocking the passage of ions and other solutes, thereby preserving the membrane potential of the cell. Aquaporins are found in virtually all life forms, from bacteria to plants to animals. In humans, they are found in cells throughout the body.
  • Aquaporin inhibitors may be of utility in the treatment or control of diseases of water imbalance, for example edema (particularly edema of the brain and spinal cord), hyponatremia, and excess fluid retention, as well as diseases such as epilepsy, retinal ischemia and other diseases of the eye, myocardial ischemia, myocardial ischemia/reperfusion injury, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, and neuromyelitis optica, as well as migraines.
  • diseases of water imbalance for example edema (particularly edema of the brain and spinal cord), hyponatremia, and excess fluid retention, as well as diseases such as epilepsy, retinal ischemia and other diseases of the eye, myocardial ischemia, myocardial ischemia/reperfusion injury, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, and neuromyelitis optica, as well as migraines.
  • compositions comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate (Formula I).
  • kits comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate.
  • FIG. 1 depicts percent survival curves for the water toxicity mouse model using 0.76 mg/kg N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Compound 1).
  • a time course of edema formation is shown comparing no drug vs. N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Compound 1) at 0.76 mg/kg.
  • the first time point at 5.67 min coincides with the scan slice at the middle of the brain during the first post-injection scan. Other time points are placed in a similar manner.
  • the data is fitted to a single exponential equation:
  • FIG. 3 depicts the calcein fluorescence end-point assay used for high throughput screening.
  • FIG. 4 depicts hit validation using the Cell Bursting Aquaporin Assay; inset shows the structure of 5-chloro-N-(3,5-dichlorophenyl)-2-hydroxybenzamide (Compound 3).
  • FIG. 5 depicts reduction in intracranial pressure (ICP) in the mouse water toxicity model with N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Compound 1) at 0.76 mg/kg.
  • ICP intracranial pressure
  • FIG. 6 depicts plasma and serum levels of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Compound 1) converted from 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl phosphate bis ethanolamine salt.
  • FIG. 7 depicts mouse middle cerebral artery occlusion (MCAo) model of ischemic stroke.
  • FIG. 8 depicts relative change in hemispheric brain volume in the mouse middle cerebral artery occlusion (MCAo) model.
  • FIG. 9 depicts neurological outcome following MCAo in mice treated with saline (no drug, ⁇ ) or 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl phosphate disodium salt ( ⁇ ) (Compound 5).
  • FIG. 10 depicts plasma and serum levels of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Compound 1) converted from a solution of 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate and Tris-Base.
  • therapeutically effective amount refers to an amount effective, when administered to a human or non-human patient, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease.
  • the specific dose of substance administered to obtain a therapeutic benefit will, of course, be determined by the particular circumstances surrounding the case, including, for example, the specific substance administered, the route of administration, the condition being treated, and the individual being treated.
  • sodium phosphate refers to sodium dihydrogen phosphate (NaH 2 PO 4 ), disodium hydrogen phosphate (Na 2 HPO 4 ), and trisodium phosphate (Na 3 PO 4 ).
  • potassium phosphate refers to potassium dihydrogen phosphate (KH 2 PO 4 ), dipotassium hydrogen phosphate (K 2 HPO 4 ), and tripotassium phosphate (K 3 PO 4 ).
  • bolus refers to administration of a therapeutic agent in a single injection that lasts for a relatively short period of time, e.g., about 60 minutes or less, about 30 minutes or less, about 20 minutes or less, about 10 minutes or less, about 5 minutes or less, e.g., about 3 minutes or less.
  • a bolus may rapidly deliver a therapeutically effective amount of a therapeutic agent to the blood.
  • patient includes human or non-human (i.e., animal) patient.
  • the invention encompasses both human and nonhuman.
  • the invention encompasses nonhuman.
  • the term encompasses human.
  • fairly rapid with respect to onset of action means that the time it takes after a compound is administered for a response to be observed is 30 minutes or less, for example 20 minutes or less, for example 15 minutes or less, for example 10 minutes or less, for example 5 minutes or less, for example 1 minute or less.
  • alkyl is a saturated hydrocarbon moiety, preferably having one to six carbon atoms, preferably having one to four carbon atoms, which may be linear or branched.
  • a “C 1-4 -alkyl” is an alkyl having one to four carbon atoms.
  • alkylene is a saturated hydrocarbon moiety, preferably having one to six carbon atoms, preferably having one to four carbon atoms, which may be linear or branched and which has two points of attachment.
  • a C 1-4 -alkylene is an alkylene having from one to four carbon atoms.
  • C 1 -alkylene is methylene (—CH 2 —).
  • alkoxy is an alkyl ether radical, alkyl-O—, wherein the term alkyl is as defined above.
  • a “C 1-4 -alkoxy” is an alkoxy having one to four carbon atoms.
  • aryl is a mono or polycyclic (e.g., bicyclic) aromatic hydrocarbon, preferably phenyl, which may be optionally substituted, e.g., optionally substituted with one or more groups independently selected from C 1-6 alkyl (e.g., methyl), halogen (e.g., Cl or F), C 1-6 -haloalkyl (e.g., trifluoromethyl), hydroxy, and carboxy.
  • aryl in addition to being substituted with the groups disclosed herein, is further substituted with an aryl or a heteroaryl to form, e.g., biphenyl or pyridylphenyl.
  • heteroaryl is an mono or polycyclic (e.g., bicyclic) aromatic moiety wherein one or more of the atoms making up the aromatic ring is sulfur or nitrogen rather than carbon, e.g., pyridyl or thiadiazolyl, which may be optionally substituted, e.g., optionally substituted with one or more groups independently selected from C 1-6 alkyl (e.g., methyl), halogen (e.g., Cl or F), C 1-6 -haloalkyl (e.g., trifluoromethyl), hydroxy, and carboxy.
  • C 1-6 alkyl e.g., methyl
  • halogen e.g., Cl or F
  • C 1-6 -haloalkyl e.g., trifluoromethyl
  • hydroxy is —OH.
  • halogen as used herein is F, Cl, Br, or I.
  • haloalkyl is a saturated hydrocarbon moiety, preferably having one to six carbon atoms, preferably having one to four carbon atoms, which may be linear or branched, and is mono-, di- or tri-substituted with halogen.
  • the halogens may be the same (e.g., dichloromethyl) or different (e.g., chlorofluoromethyl).
  • Aquaporin-4 is upregulated in animal models of trauma, stroke and water intoxication, as well as around human malignant brain tumors. Aquaporin-4 (AQP4) has been shown to play a critical role in the development of cerebral and spinal cord edema. AQP4 provides the primary route for water movement across the blood-brain barrier (BBB) and glia limitans. AQP4 knockout mice, without the APQ4 gene, have improved survival compared to wild-type mice in models of ischemic stroke, water toxicity, bacterial meningitis, and spinal cord compression.
  • BBB blood-brain barrier
  • AQP4 knockout mice without the APQ4 gene, have improved survival compared to wild-type mice in models of ischemic stroke, water toxicity, bacterial meningitis, and spinal cord compression.
  • Cerebral edema may be generally divided into 2 major categories: vasogenic and cytotoxic.
  • Vasogenic cerebral edema may occur when a breach in the BBB allows water and solutes to diffuse into the brain. It has been reported that AQP4-null mice have increased brain edema in a model of subarachnoid hemorrhage, suggesting that AQP4 may be required for the clearance of water collected in intercellular space.
  • cytotoxic cerebral edema may be initiated by ischemia which may result in reduced plasma osmolality rather than a disrupted BBB.
  • Ischemia may lead to a drop in ATP levels, which is thought to slow the Na—K ATPase pump resulting in an uptake of Na + and Cl ⁇ through leakage pathways.
  • the net effect may be a cellular osmotic imbalance, drawing H 2 O into cells—astrocytes more so than neurons—and leading to increased intracranial pressure (ICP).
  • ICP intracranial pressure
  • Mouse models for ischemic stroke, water toxicity, bacterial meningitis, and spinal-cord compression fall into this category.
  • AQP4-null mice have been reported to have reduced CE pointing to AQP4 as the central pathway for water movement into the brain during the formation of cytotoxic CE.
  • cytotoxic and vasogenic edema are not sharply divided categories; an injury that initially causes cytotoxic edema may be followed later, e.g., within the next hours to days, by vasogenic edema. This may suggest different treatments for cerebral edema at different times.
  • AQP4 inhibitors may be of further utility for certain ailments where control of AQP4-medited water movement may augment neuroexcitation (by alteration of neuronal potassium homeostasis) and prove beneficial by reducing neuronal excitation, for example ailments such as fibromyalgia, multiple sclerosis, migraines and seizures (in particular but not limited to seizures associated with epilepsy).
  • Aquaporin-2 is the primary route of water movement at the collecting duct in the kidney. Blocking this water channel would lower water reabsorption without incurring electrolyte imbalances or interfering with vasopressin receptor-mediated signaling. Evidence that an AQP2 blocker would not produce electrolyte imbalances, and instead be an effective treatment for hyponatremia, comes from patients with diabetes insipidus who lack functional AQP2. They exhibit chronic aquaresis but—if normal hydration is maintained—do not demonstrate any other consequence of their long-term loss of AQP2 function.
  • an IV infusion or IV bolus may be preferred.
  • rapid achievement of therapeutically effective amounts of a therapeutic agent may be important to a successful therapeutic outcome.
  • best practices are to administer drugs via IV.
  • a therapeutic agent with only a limited solubility in water and/or physiological media and/or limited stability may make parenteral administration, e.g., intravenous, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, or intracerebral, of the therapeutic agent challenging.
  • parenteral administration e.g., intravenous, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, or intracerebral
  • parenteral administration e.g., intravenous, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, or intracerebral
  • parenteral administration e.g., intravenous, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, or intracerebral
  • N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide is an aquaporin inhibitor
  • its solubility in water is 3.8 ⁇ g/ml.
  • a prodrug salt form of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide does show improved solubility—specifically, the solubility of 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl phosphate disodium salt in water is 1 mg/ml.
  • prodrug salt forms of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide may revert to N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide even in the solid state.
  • stable pharmaceutical compositions which may allow rapid achievement of therapeutically effective amounts of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide are needed.
  • novel formulations of 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate which may allow rapid achievement of therapeutically effective amounts of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide.
  • composition I comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate (Formula I) and a pharmaceutically acceptable excipient.
  • composition I as follows:
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate when 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, is provided as a solid that is to be admixed with a solvent, e.g., a sterile solution, to provide a pharmaceutically acceptable liquid, it is typically provided as a powder and admixed immediately or shortly before administration to the patient.
  • a solvent e.g., a sterile solution
  • the powdered 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate may be packaged in a container, for example, in a vial to which is added the solvent, e.g., the sterile solution.
  • the solvent e.g., the sterile solution.
  • the contents of the vial may be added to the solvent, e.g., the sterile solution, in a separate container.
  • the powdered 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate is packaged in a sachet, such as a foil package, that can be opened and the contents added to the solvent, e.g., the sterile solution.
  • the powdered 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate is formulated as a tablet that dissolves when it is added to the solvent, e.g., the sterils solution.
  • a pharmaceutical composition comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, e.g., Composition I, e.g., composition 1.1-1.124, is prepared by admixing 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate with a pharmaceutically acceptable excipient.
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate and the pharmaceutically acceptable excipient are milled together.
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate is crystalline. In some embodiments, 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate is amorphous. In some embodiments, 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate is lyophilized.
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate and the pharmaceutically acceptable excipient e.g., Composition I, e.g., composition 1.1-1.124, are lyophilized.
  • a pharmaceutical composition comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, e.g., Composition I, e.g., composition 1.1-1.124, is prepared by admixing 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate with a sterile solution, e.g., sterile water for injection or a sterile solution comprising sodium chloride (e.g., 0.9% sodium chloride injection), to form a pharmaceutically acceptable liquid.
  • a sterile solution e.g., sterile water for injection or a sterile solution comprising sodium chloride (e.g., 0.9% sodium chloride injection
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate is admixed with the sterile solution immediately or shortly before administration.
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate is admixed with a base, e.g., sodium citrate, sodium phosphate (e.g., Na 2 HPO 4 ), tris(hydroxymethyl)aminomethane, and/or a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate) prior to admixture with the sterile solution, e.g., sterile water for injection or a sterile solution comprising sodium chloride (e.g., 0.9% sodium chloride injection).
  • a base e.g., sodium citrate, sodium phosphate (e.g., Na 2
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate is admixed with a base, e.g., sodium citrate, sodium phosphate (e.g., Na 2 HPO 4 ), tris(hydroxymethyl)aminomethane, and/or a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate) and/or a bulking agent, e.g., dextran (e.g., dextran 40), prior to admixture with the sterile solution, e.g., sterile water for injection or a sterile solution comprising sodium chloride (e.g., 0.9% sodium chloride injection).
  • a base e.g., sodium citrate, sodium phosphate (e.g., Na 2 HPO 4 ), tris(hydroxymethyl)aminomethane, and/or a tris(hydroxymethyl)amin
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate admixed with the base and/or the bulking agent is lyophilized. In some embodiments, 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate admixed with the base and/or the bulking agent are milled together.
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate is admixed with a sterile solution comprising a base, e.g., sodium citrate, sodium phosphate (e.g., Na 2 HPO 4 ), tris(hydroxymethyl)aminomethane, and/or a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate).
  • a base e.g., sodium citrate, sodium phosphate (e.g., Na 2 HPO 4 ), tris(hydroxymethyl)aminomethane, and/or a tris(hydroxymethyl)aminomethane salt (e.g., tris acetate).
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate is admixed with a sterile solution comprising a base, e.g., sodium citrate, sodium phosphate (e.g., Na 2 HPO 4 ), tris(hydroxymethyl)aminomethane base, and/or a tris(hydroxymethyl)aminomethane salt (e.g., tris(hydroxymethyl)aminomethane acetate) and/or a bulking agent.
  • a base e.g., sodium citrate, sodium phosphate (e.g., Na 2 HPO 4 )
  • tris(hydroxymethyl)aminomethane base e.g., Na 2 HPO 4
  • tris(hydroxymethyl)aminomethane salt e.g., tris(hydroxymethyl)aminomethane acetate
  • the admixture of 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate and the sterile solution is agitated, e.g., any mode of agitation that results in a clear liquid, e.g., mechanical agitation, sonication, conventional mixing, conventional stirring and the combinations thereof.
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate admixed with the sterile solution is lyophilized.
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate admixed with the sterile solution is crystalline. In some embodiments, 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate admixed with the sterile solution is amorphous.
  • Composition I e.g., composition 1.1-1.124, is prepared by admixing 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate with a solvent, e.g., a sterile water for injection or a sterile solution comprising sodium chloride (e.g., 0.9% sodium chloride injection).
  • a solvent e.g., a sterile water for injection or a sterile solution comprising sodium chloride (e.g., 0.9% sodium chloride injection).
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate is admixed with a base, e.g., sodium citrate, sodium phosphate (e.g., Na 2 HPO 4 ), tris(hydroxymethyl)aminomethane, and/or a tris(hydroxymethyl)aminomethane salt (e.g., tris(hydroxymethyl)aminomethane acetate) and/or a bulking agent, e.g., dextran (e.g., dextran 40), prior to admixture with the solvent, e.g. an aqueous solution.
  • a base e.g., sodium citrate, sodium phosphate (e.g., Na 2 HPO 4 ), tris(hydroxymethyl)aminomethane, and/or a tris(hydroxymethyl)aminomethane salt (e.g., tris(hydroxymethyl)aminome
  • the solvent e.g., the aqueous solution
  • the solvent comprises a base, e.g., sodium citrate, sodium phosphate (e.g., Na 2 HPO 4 ), tris(hydroxymethyl)aminomethane, and/or a tris(hydroxymethyl)aminomethane salt (e.g., tris(hydroxymethyl)aminomethane acetate) and/or a bulking agent, e.g., dextran (e.g., dextran 40).
  • a base e.g., sodium citrate, sodium phosphate (e.g., Na 2 HPO 4 )
  • tris(hydroxymethyl)aminomethane e.g., tris(hydroxymethyl)aminomethane acetate
  • a bulking agent e.g., dextran (e.g., dextran 40).
  • the admixture of 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate and the solvent, e.g., the aqueous solution is agitated after admixture, e.g., by any mode of agitation that results in a clear liquid, e.g., mechanical agitation, sonication, conventional mixing, conventional stirring and the combinations thereof.
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate is lyophilized.
  • the admixture of 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate and the base and/or bulking agent is lyophilized. In some embodiments, the admixture of 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate and the base and/or bulking agent is milled together.
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate is admixed with the solvent, e.g., the sterile solution, immediately or shortly before administration.
  • compositions disclosed herein e.g., Composition I, e.g., composition 1.1-1.124, may be contained in a sterilized vessel such as syringes, vials or ampoules of various sizes and capacities.
  • a sterilized vessel such as syringes, vials or ampoules of various sizes and capacities.
  • composition I e.g., composition 1.1-1.124
  • a metal hydroxide salt e.g., NaOH and/or KOH, e.g., NaOH
  • the base is a solid.
  • the bases used herein may form a buffer with the 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate. If a solution of the base described herein and bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate is too basic, the phosphate group may be cleaved. On the other hand, if the solution is too acidic, the solubility of 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate may decrease.
  • base is any inorganic or organic Bronsted base.
  • a method for increasing the stability of a solid state formulation comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, wherein the method comprises milling 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate with a base, e.g., with tris(hydroxymethyl)aminomethane for later reconstitution as an aqueous solution for injection.
  • a method for lessening the potential for precipitation of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide and allows for IV administration comprising comprises milling 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate with a base, e.g., with tris(hydroxymethyl)aminomethane and reconstituting as an aqueous solution for injection.
  • a free base e.g., tris(hydroxymethyl)aminomethane, e.g., meglumine.
  • a free base e.g., tris(hydroxymethyl)aminomethane, e.g., meglumine.
  • Method I of making a pharmaceutical composition comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, e.g., Composition I, e.g., composition 1.1-1.124, wherein the method comprises admixing 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate and a pharmaceutically acceptable excipient.
  • salt solution I comprising a solvent, e.g., an aqueous solution, and a salt formed from a compound of Formula I
  • each R 8 is independently C 1-8 alkyl (e.g., C 1-6 -alkyl, e.g., C 1-4 -alkyl, e.g., —CH 2 CH 3 , e.g., —CH 3 ) and n is 0 or C 1-8 -alkyl (e.g., C 1-6 -alkyl, e.g., C 1-4 -alkyl, e.g., —CH 2 CH 3 , e.g., —CH 3 ) and n is 0 or C 1-8 -alkyl (e.g., C 1-6 -alkyl, e.g., C 1-4 -alkyl, e.g., —CH 2 CH 3 , e.g., —CH 3 ) and n is 0 or C 1-8 -alkyl (e.g., C 1-6 -alkyl, e.g., C 1-4 -alkyl,
  • Salt Solution I as follows:
  • a salt solution e.g., Salt Solution I, e.g., Salt Solution 1.1-1.46, comprising admixing a compound of Formula I
  • each R 8 is independently C 1-8 alkyl (e.g., C 1-6 -alkyl, e.g., C 1-4 -alkyl, e.g., —CH 2 CH 3 , e.g., —CH 3 ) and n is 0 or C 1-8 -alkylene
  • kit (Kit I) comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate.
  • Kit I as follows:
  • the kit is prepared by transferring a liquid comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate to a container, e.g., a vial, in a predetermined volume first and then subjecting the liquid to a lyophilization process.
  • a container e.g., a vial
  • liquid can be lyophilized in a large volume and then a predetermined amount of the lyophilized preparation can be placed in a container.
  • a method (Method A) of treating or controlling a disease or condition mediated by an aquaporin comprising administering to a patient in need thereof a pharmaceutical composition comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, e.g., Composition I, e.g., composition 1.1-1.124.
  • edema e.g. edema of the brain or spinal cord
  • cerebral edema e.g. cerebral edema consequent to head trauma, ischemic stroke, glioma, meningitis, acute mountain sickness, epileptic seizure, infection, metabolic disorder, hypoxia, water intoxication, hepatic failure, hepatic encephalopathy, diabetic ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob disease, lupus cerebritis, cardiac arrest, microgravity and/or radiation exposure, or invasive central nervous system procedures, e.g., neurosurgery, endovascular clot removal, spinal tap, aneurysm repair, or deep brain stimulation or, e.g., optic nerve edema, e.g., optic nerve edema consequent to microgravity and/or radiation exposure
  • optic nerve edema e.g., optic nerve edema consequent to microgravity and/
  • Method C of treating or controlling a condition selected from hyponatremia and excessive fluid retention, e.g., consequent to heart failure (HF), for example congestive heart failure, liver cirrhosis, nephrotic disorder, syndrome of inappropriate antidiuretic hormone secretion (SIADH), or infertility treatment, comprising administering a pharmaceutical composition comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, e.g., Composition I, e.g., composition 1.1-1.124, to a patient in need thereof.
  • HF heart failure
  • SIADH syndrome of inappropriate antidiuretic hormone secretion
  • infertility treatment comprising administering a pharmaceutical composition comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, e.g., Composition I, e.g
  • Method D of treating or controlling a condition selected from epilepsy, retinal ischemia or other diseases of the eye associated with abnormalities in intraocular pressure and/or tissue hydration, myocardial ischemia, myocardial ischemia/reperfusion injury, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, neuromyelitis optica, glioblastoma, fibromyalgia, multiple sclerosis, and a migraine comprising administering a pharmaceutical composition comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, e.g., Composition I, e.g., composition 1.1-1.124, to a patient in need thereof.
  • Composition I e.g., Composition 1.1-1.124
  • Method E of treating or controlling a disease or condition mediated by an aquaporin comprising administering to a patient in need thereof a pharmaceutical composition comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, e.g., Composition I, e.g., composition 1.1-1.124, in an amount effective to inhibit the aquaporin, for example
  • Method F of inhibiting an aquaporin in vivo comprising administering a pharmaceutical composition comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, e.g., Composition I, e.g., composition 1.1-1.124, in an amount effective to inhibit the aquaporin.
  • a pharmaceutical composition comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, e.g., Composition I, e.g., composition 1.1-1.124, in an amount effective to inhibit the aquaporin.
  • Method G to inhibit an aquaporin in a patient suffering from a disease or condition mediated by an aquaporin comprising administering an effective amount of a pharmaceutical composition comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, e.g., Composition I, e.g., composition 1.1-1.124, to inhibit the aquaporin.
  • a pharmaceutical composition comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, e.g., Composition I, e.g., composition 1.1-1.124, to inhibit the aquaporin.
  • Method H of treating or controlling a condition selected from fibromyalgia and multiple sclerosis comprising administering a pharmaceutical composition comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, e.g., Composition I, e.g., composition 1.1-1.124, to a patient in need thereof.
  • a pharmaceutical composition comprising 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate, e.g., Composition I, e.g., composition 1.1-1.124, to a patient in need thereof.
  • composition I e.g., composition 1.1-1.124, for use in treating or controlling a disease or condition mediated by an aquaporin.
  • composition I e.g., composition 1.1-1.124, for use in any of Methods A, e.g., A.1-A.58, any of Methods B, e.g., B.1-B.41, any of Methods C, e.g., C.1-C.8, any of Methods D, e.g., D.1-D.19, any of Methods E, e.g., E.1-E.59, any of Methods F, e.g., F.1-F.5, any of Methods G, e.g., G.1-G.58, and any of Methods H, e.g., H.1-H.9.
  • Composition I e.g., composition 1.1-1.124
  • a dose or method of administration of the dose of the present disclosure is not particularly limited. Dosages employed in practicing the present disclosure will of course vary depending, e.g. on the particular disease or condition to be treated, the particular compound used, the mode of administration, and the therapy desired.
  • the pharmaceutical compositions may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation. In stroke or other severely debilitating diseases or conditions, for example where the patient may be unconscious or unable to swallow, an IV infusion and/or IV bolus may be preferred. In general, satisfactory results, e.g. for the treatment of diseases as hereinbefore set forth are indicated to be obtained on oral administration at dosages of the order from about 0.01 to 15.0 mg/kg.
  • an indicated daily dosage for oral administration will accordingly be in the range of from about 0.75 to 1000 mg per day, conveniently administered once, or in divided doses 2 to 3 times, daily or in sustained release form.
  • Unit dosage forms for oral administration thus for example may comprise from about 0.2 to 75 mg or 150 mg, e.g. from about 0.2 or 2.0 mg to 50, 75, 100, 125, 150 or 200 mg of 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate together with a pharmaceutically acceptable diluent or carrier therefor.
  • the dose may be 0.1 or 0.25 mg to 500 mg per day, e.g., from about 0.25 mg to 75 or 150 mg, e.g., from about 0.1 or 0.25 or 2.0 mg to 50, 75, 100, 125, 150, 200, 300, 400, or 500 mg, by bolus or if IV by bolus or infusion.
  • compositions as hereinbefore described for use in the methods of the invention may be used as a sole therapeutic agent, but may also be used in combination or for co-administration with other active agents, for example in conjunction with conventional therapies for cerebral edema, stroke, traumatic brain injury, glioma (e.g., glioblastoma), meningitis, acute mountain sickness, infection, metabolic disorder, hypoxia, water intoxication, hepatic failure, hepatic encephalopathy, diabetic ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob disease, lupus cerebritis, optic nerve edema, hyponatremia, fluid retention, ovarian hyperstimulation syndrome, epilepsy, retinal ischemia or other diseases of the eye associated with abnormalities in intraocular pressure and/or tissue hydration, myocardial ischemia, myocardial ischemia/reperfusion injury, myocardial infarction, myocardial hypoxia,
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate includes its polymorphs, hydrates, solvates and complexes.
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate may be made using the methods as described and exemplified herein and by methods similar thereto and by methods known in the chemical art. Such methods include, but not limited to, those described below. If not commercially available, starting materials for these processes may be made by procedures which are selected from the chemical art using techniques which are similar or analogous to the synthesis of known compounds.
  • 5-chloro salicylic acid (8.75 g, 50 mmol, 1 eq) is dissolved in toluene (300 mL) under N 2 atmosphere then phosphorus trichloride (2.2 mL, 25 mmol, 0.5 eq) is added dropwise followed by 3,5-bis(trifluoromethyl)aniline (10 g, 43.7 mmol, 0.87 eq).
  • the reaction mixture is stirred under reflux for 12 h then cooled to room temperature.
  • the reaction mixture is quenched with NaHCO 3 saturated solution and stirred for 10 min.
  • Step 2 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl) phosphate
  • N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (4.0 g, 0.01 mol, 1 eq) is dissolved in CH 3 CN (104 mL) then DMAP (0.08 g, 0.001 mol, 0.06 eq), Hunig's base (7.36 mL, 0.021 mol, 2 eq) and CCl 4 (8.02 g, 0.052 mol, 5 eq) are added in this order. The solution is cooled to 0° C.
  • Step 3 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate
  • a 95% pure lot of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate is purified as follows. 15 g is dissolved in 1.2 L of water with 120 mM of sodium hydroxide and extracted with 500 ml ethyl acetate to remove phenol and non acid impurities. The aqueous layer is acidified with concentrated HCl to pH 1.2 and extracted with ethyl acetate 1 L followed by 600 ml.
  • mice The in vivo efficacies of the compounds are tested using the mouse water toxicity model, where a mouse is injected with water at 20% of its body weight.
  • Manley, G. T. et al. Aquaporin -4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke . Nat Med 6, 159-163 (2000); Gullans, S. R. & Verbalis, J. G. Control of brain volume during hyperosmolar and hypoosmolar conditions. Annual Review of Medicine 44, 289-301 (1993).
  • the resulting euvolemic hyponatremia rapidly leads to CE, making this a practical model to test an inhibitor of the CNS aquaporin, AQP4b.
  • mice The ability of mice to survive H 2 O toxicity is determined in three experiments using 10-12 mice each (16-19 weak old male/female). Deionized water is prepared for injection with either 0.39 mg/kg phenylbenzamide (placebo) or 0.76 mg/kg with test compound.
  • Percent survival of the N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide cohorts improves 3.2 fold and the time to 50% survival for animals treated with N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide is improved by roughly 52 min.
  • Mouse Water Toxicity Model Brain Volume by Magnetic Resonance Imaging (MRI): MRI is used to measure changes in brain volume in response to water shock, using the water toxicity model. As described for the survival and brain water content studies above, mice are injected, IP, with a water bolus alone or water bolus and test compound at 0.76 mg/kg, and changes in brain volume as detected by MRI are monitored. Mouse brain volumes are assessed using MRI scans collected with a 9.4T Bruker Biospec MRI scanner at the Case Center for Imaging Research at Case Western Reserve University. This imaging method is found to provide sufficient contrast and resolution to sensitively detect changes in total brain volume in the mouse water toxicity model for cerebral edema.
  • MRI Magnetic Resonance Imaging
  • Each scan contains twenty-five 0.7 mm contiguous imaging slices of which 14-15 slices contain a portion of the brain.
  • the cross sectional area of the brain in each imaging slice is measured by manual region-of-interest selection using ImageJ. Brain volumes are then calculated for each scan by summing the individual cross sectional brain areas and multiplying by the slice thickness (0.7 mm).
  • hypotonic shock in a 384 well plate format, we return osmolality to normal (300 mOsm) by adding 2 ⁇ concentrated phosphate buffered saline supplemented to 2 ⁇ M with a nonfluorescent acetoxymethyl derivative of calcein (calcein-AM) to each well.
  • Intact cells take up calcein-AM and convert it to the fluorescent dye calcein—giving a quantitative measure of the remaining intact cells. Burst cells do not convert the precursor to the dye. Water uptake by AQP4-expressing cells is relatively rapid, with most test cells bursting within 4 min of hypotonic shock, whereas most cells expressing CD81 remain viable after 8 min. Intracellular conversion of calcein-AM provides a strong and easily detectable signal at 535 nM in our assay ( FIG. 3 ).
  • the signal for the CD81 cells is ca. 5 ⁇ higher than the signal for the APQ4 cells, because by 5.5 mins, most of the AQP4 cells have burst, while most of the CD81 cells remain intact. Inhibition of AQP4 would therefore be expected to provide a higher signal, more like the CD81 cells.
  • This assay is applied in a pilot screen of the MicroSource GenPlus 960 and the Maybridge DiversityTM 20 k libraries (approximately 21,000 compounds tested, each compound at 10-20 ⁇ M).
  • Hits from the HTS are validated using the same assay using a different plating arrangement.
  • FIG. 4 we show this validation assay used to examine 5-chloro-N-(3,5-dichlorophenyl)-2-hydroxybenzamide.
  • CHO cells expressing CD81 are seeded in lanes 2-3 as a control, and CHO cells expressing AQP4, in lanes 4-23.
  • Cells are treated with 0.1% DMSO in 10% FBS, DMEM (even numbered columns) or 10 ⁇ M N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (odd number columns) in 0.1% DMSO, 10% FBS, DMEM for 30 minutes.
  • the cells are shocked with H 2 O for 5:30 minutes, then osmolality returned to 300 mOsm in the presence of 1 ⁇ M calcein-AM, as described above.
  • the cells are incubated at 37° C. for 30 minutes and the relative fluorescence measured (ex 495/em 535 nM) on a fluorescence multiplate reader.
  • ICP Intracranial Pressure
  • ICP is monitored using a Samba 420 Sensor, pressure transducer, with a Samba 202 control unit (Harvard Apparatus, Holliston, Mass.).
  • This ICP monitoring system consists of a 0.42 mm silicon sensor element mounted on an optical fiber.
  • a 20-gauge syringe needle is implanted through the cisterna magna to a depth of ⁇ 1 cm. The needle then acts as a guide for insertion of the Samba Sensor and the site of implantation and the open end of the needle are sealed with 100% silicone sealant.
  • a baseline ICP reading is established followed by a water bolus IP injection (20% weight of animal) with or without N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide. ICP is monitored until the animal expires from the water load.
  • Plasma or serum levels of 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate are measured by LC-MS/MS at the Mass Spectrometry II Core facility at the Lerner Research Institute of the Cleveland Clinic Foundation. Measurements are taken at 15 minutes and 24 hours after a 10 mg/kg i.p. loading dose and 1 mg/ml at 8 ⁇ l/h maintenance dose (delivered by an Alzet i.p.
  • the LC method is sufficient to separate N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Compound 1) from 5-chloro-N-(3,5-dichlorophenyl)-2-hydroxybenzamide and subsequent MRM gave reliable quantitation with a linear response from 0.004-0.4 ng of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Compound 1) for its most abundant daughter ion.
  • the dashed line in FIG. 6 is the relative effective plasma concentration of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Compound 1) observed in the mouse water toxicity model.
  • the solubility of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide in water is 3.8 ⁇ g/ml.
  • the solubility of 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl phosphate disodium salt in water is 1 mg/ml.
  • 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl phosphate bis ethanolamine salt is undetectable in plasma samples taken from mice injected IP with 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl phosphate bis ethanolamine salt.
  • N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide is detected at a concentration consistent with good bioavailability and near-complete conversion of 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl phosphate bis ethanolamine salt.
  • mice With 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl phosphate bis ethanolamine salt doses of 10 mg/kg and IP injection volumes in saline (0.5 ml for a 30 g mouse), that give serum concentrations of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide in excess of 400 ng/ml ( FIG. 6 ) can be used.
  • Key PK parameters in mice are: rate of absorption 0.12 min ⁇ 1 ; rate of elimination 0.017 min ⁇ 1 .
  • MCA middle cerebral artery occlusion
  • ECA external carotid artery
  • ICA internal carotid artery
  • FIG. 7 shows a single slice from a T2-weighted MR image depicting the center of the brain showing cerebral cortex, hippocampus, thalamus, amygdala and hypothalamus for a “Normal” mouse (left panels) and a mouse which receives MCAo for one hour followed by 24 hours of reperfusion (right panels). Dashed lines mark the midline of the brain and show a large shift in the MCAo brain due to cerebral edema. Solid line highlights the region of infarct in the MCAo brain.
  • Compound 5 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl phosphate disodium salt
  • mice are scored for neurological outcome on a simple 5 point scale described in Manley, G. T. et al., Aquaporin -4 Deletion in Mice Reduces Brain Edema After Acute Water Intoxication and Ischemic Stroke, Nature Medicine, 6, 159-163 (2000).
  • An improvement in neurological outcome is observed for animals given 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl phosphate disodium salt (Compound 5).
  • Step 2 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl) phosphate
  • N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (4.0 g, 0.01 mol, 1 eq) is dissolved in CH 3 CN (104 mL) then DMAP (0.08 g, 0.001 mol, 0.06 eq), Hunig's base (7.36 mL, 0.021 mol, 2 eq) and CCl 4 (8.02 g, 0.052 mol, 5 eq) are added in this order. The solution is cooled to 0° C.
  • Step 3 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate
  • 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl hydrogen phosphate mono sodium salt, 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl phosphate bis sodium salt, and 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl phosphate bis ethanolamine salt are made as follows: 2 mM of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate is dissolved in ethanol 50 ml and appropriate equivalents of each base are added. Evaporation gives salts which are dissolved in water and freeze dried.
  • 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl hydrogen phosphate mono ethanolamine salt is made as follows: 1 g of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate is dissolved in isopropanol and 1 eq ethanol amine is added. Evaporation gave 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl hydrogen phosphate mono ethanolamine salt.
  • 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate mono ethanolamine salt (“mono ethanolamine salt”) is made as in Example 8. Surprisingly, the mono ethanolamine salt only shows about 1% hydrolysis after 5 days at RT. Its solubility in water is about 5 mg/ml. Solubility is expected to be higher at higher pH.
  • Both prodrugs are insoluble in water and pH 7.4 water even after stirring for 4-5 hrs., as determined by HPLC analysis of filtrate.
  • HPLC conditions for assaying the stability of compositions formed from 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate and a base, e.g., tris(hydroxymethyl)aminomethane are as follows:
  • Solid state compositions of the invention falling under Composition I show about 1% of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide over a four month period at room temperature as measured under the HPLC conditions above.
  • compositions of the invention falling under Composition I show 1-2% degradation over a 24 hour period.
  • the 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate is dissolved at 10 mg/mL in 0.07% aqueous Tris-Base. This solution is then diluted to 5 mg/ml with water and used to fill an Alzet osmotic pump (DURECT, Corp., model 2001D, delivery at 8 ul/hr for 24 hrs). Surgery is performed on an anesthetized mouse under sterile conditions to implant the pump in the peritoneal cavity. Once the abdominal incision is closed with sutures, muscle layer followed by skin, an IP bolus of 10 mg/kg is given.
  • DURECT Alzet osmotic pump
  • the 10 mg/mL 2- ⁇ [3,5-bis(trifluoromethyl)phenyl]carbamoyl ⁇ -4-chlorophenyl dihydrogen phosphate solution is diluted to 1 mg/ml with water and the appropriate volume administered.
  • blood is drawn by tail laceration, serum prepared and stored at ⁇ 20 C for later processing.
  • an aliquot of the serum sample is diluted 4-fold with acetonitrile to precipitate proteins and ensure soluble release of the parent compound N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide.
  • the protein is removed by centrifugation and the supernatant diluted to 37.5% acetonitrile using water.
  • the dashed line in FIG. 10 is the relative effective plasma concentration of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Compound 1) observed in the mouse water toxicity model.

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