US20160279155A1 - Novel formulations - Google Patents

Novel formulations Download PDF

Info

Publication number
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
Authority
US
United States
Prior art keywords
salt
tris
hydroxymethyl
alkyl
aminomethane
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US15/035,006
Other languages
English (en)
Inventor
Marc F. Pelletier
Paul Robert Mcguirk
George William Farr
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aeromics Inc
Original Assignee
Aeromics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aeromics Inc filed Critical Aeromics Inc
Priority to US15/035,006 priority Critical patent/US20160279155A1/en
Assigned to AEROMICS, LLC reassignment AEROMICS, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PELLETIER, MARC F., MCGUIRK, PAUL ROBERT, FARR, GEORGE WILLIAM
Assigned to AEROMICS, INC. reassignment AEROMICS, INC. CERTIFICATE OF CONVERSION FROM A LIMITED LIABILITY COMPANY TO A CORPORATION Assignors: AEROMICS, LLC
Publication of US20160279155A1 publication Critical patent/US20160279155A1/en
Assigned to AEROMICS, INC. reassignment AEROMICS, INC. ASSIGNEE CHANGE OF ADDRESS Assignors: AEROMICS, INC.
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids

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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Cardiology (AREA)
  • Neurology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Neurosurgery (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Emergency Medicine (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Endocrinology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Reproductive Health (AREA)
  • Inorganic Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
US15/035,006 2013-11-06 2014-11-06 Novel formulations Abandoned US20160279155A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US15/035,006 US20160279155A1 (en) 2013-11-06 2014-11-06 Novel formulations

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201361900919P 2013-11-06 2013-11-06
US201361900946P 2013-11-06 2013-11-06
US201361900878P 2013-11-06 2013-11-06
PCT/US2014/064441 WO2015069956A2 (en) 2013-11-06 2014-11-06 Novel formulations
US15/035,006 US20160279155A1 (en) 2013-11-06 2014-11-06 Novel formulations

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2014/064441 A-371-Of-International WO2015069956A2 (en) 2013-11-06 2014-11-06 Novel formulations

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US16/236,817 Continuation US10894055B2 (en) 2013-11-06 2018-12-31 Pharmaceutical compositions, methods of making pharmaceutical compositions, and kits comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}4-chlorophenyl dihydrogen phosphate
US16/236,817 Division US10894055B2 (en) 2013-11-06 2018-12-31 Pharmaceutical compositions, methods of making pharmaceutical compositions, and kits comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}4-chlorophenyl dihydrogen phosphate

Publications (1)

Publication Number Publication Date
US20160279155A1 true US20160279155A1 (en) 2016-09-29

Family

ID=53042097

Family Applications (9)

Application Number Title Priority Date Filing Date
US15/035,006 Abandoned US20160279155A1 (en) 2013-11-06 2014-11-06 Novel formulations
US15/034,274 Active US9827253B2 (en) 2013-11-06 2014-11-06 Prodrug salts
US15/034,543 Active US9949991B2 (en) 2013-11-06 2014-11-06 Methods of treating aquaporin-mediated conditions
US15/792,707 Active US10258636B2 (en) 2013-11-06 2017-10-24 Prodrug salts
US16/236,817 Active US10894055B2 (en) 2013-11-06 2018-12-31 Pharmaceutical compositions, methods of making pharmaceutical compositions, and kits comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}4-chlorophenyl dihydrogen phosphate
US16/665,333 Active US11071744B2 (en) 2013-11-06 2019-10-28 Prodrug salts
US17/099,435 Active 2035-03-18 US11801254B2 (en) 2013-11-06 2020-11-16 Pharmaceutical compositions and methods of making pharmaceutical compositions comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate
US17/304,201 Active 2036-06-19 US12213987B2 (en) 2013-11-06 2021-06-16 Prodrug salts
US18/492,750 Active US12496308B2 (en) 2013-11-06 2023-10-23 Methods of administering a pharmaceutically acceptable salt of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate

Family Applications After (8)

Application Number Title Priority Date Filing Date
US15/034,274 Active US9827253B2 (en) 2013-11-06 2014-11-06 Prodrug salts
US15/034,543 Active US9949991B2 (en) 2013-11-06 2014-11-06 Methods of treating aquaporin-mediated conditions
US15/792,707 Active US10258636B2 (en) 2013-11-06 2017-10-24 Prodrug salts
US16/236,817 Active US10894055B2 (en) 2013-11-06 2018-12-31 Pharmaceutical compositions, methods of making pharmaceutical compositions, and kits comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}4-chlorophenyl dihydrogen phosphate
US16/665,333 Active US11071744B2 (en) 2013-11-06 2019-10-28 Prodrug salts
US17/099,435 Active 2035-03-18 US11801254B2 (en) 2013-11-06 2020-11-16 Pharmaceutical compositions and methods of making pharmaceutical compositions comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate
US17/304,201 Active 2036-06-19 US12213987B2 (en) 2013-11-06 2021-06-16 Prodrug salts
US18/492,750 Active US12496308B2 (en) 2013-11-06 2023-10-23 Methods of administering a pharmaceutically acceptable salt of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate

Country Status (14)

Country Link
US (9) US20160279155A1 (enExample)
EP (3) EP3065728A4 (enExample)
JP (4) JP6535338B2 (enExample)
KR (1) KR20160079109A (enExample)
CN (3) CN106163506A (enExample)
AU (2) AU2014346682B2 (enExample)
CA (1) CA2929821A1 (enExample)
ES (1) ES2834131T3 (enExample)
HK (1) HK1224228A1 (enExample)
IL (1) IL245420B (enExample)
MX (2) MX386250B (enExample)
RU (1) RU2691951C2 (enExample)
SG (1) SG11201604153UA (enExample)
WO (3) WO2015069948A1 (enExample)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9827253B2 (en) 2013-11-06 2017-11-28 Aeromics, Inc. Prodrug salts
US11084778B2 (en) 2012-05-08 2021-08-10 Aeromics, Inc. Methods of treating cardiac edema, neuromyelitis optica, and hyponatremia
US11117909B2 (en) 2016-05-13 2021-09-14 Aeromics, Inc. Crystals

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021023226A (ja) * 2019-08-06 2021-02-22 学校法人慶應義塾 アクアポリン活性調節剤候補のハイスループットスクリーニング方法
CN110790787B (zh) * 2019-11-12 2022-06-14 广东药科大学 一类水溶性前药、其制备方法及其作为药物的用途
BR112023002129A2 (pt) * 2020-08-05 2023-04-18 Jiangsu Simcere Pharm Co Ltd Composição farmacêutica de inibidor de aquaporina e método de preparação da mesma
CN117105810B (zh) * 2023-10-23 2024-02-09 中国农业大学 一种具有广谱抗菌活性的化合物及其抗菌组合物
CN118178653A (zh) * 2024-03-22 2024-06-14 山东第一医科大学附属省立医院(山东省立医院) 跨膜水交换蛋白aqp4抑制剂在制备抗肿瘤药物上的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060094718A1 (en) * 2002-06-06 2006-05-04 Susumu Muto O-substituted hydroxyaryl derivatives

Family Cites Families (91)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE615511A (enExample) 1961-03-25
NL292958A (enExample) 1962-05-29 1900-01-01
GB8809205D0 (en) 1988-04-19 1988-05-25 Nye P C G Treatment of oedema
US5137871A (en) 1989-07-28 1992-08-11 Regents Of The University Of California Treatment to reduce edema for brain and musculature injuries
DE4010536A1 (de) * 1990-04-02 1991-10-10 Boehringer Mannheim Gmbh Pharmazeutische waessrige loesung von 4-(2-(benzolsulfonylamino)-ethyl)-phenoxyessigsaeure
US5486530A (en) 1991-04-27 1996-01-23 Boehringer Mannheim Gmbh Use of torasemide for the treatment of brain oedemas
DE4113820A1 (de) 1991-04-27 1992-10-29 Boehringer Mannheim Gmbh Verwendung von torasemid zur behandlung von hirnoedemen
US5858702A (en) 1991-12-13 1999-01-12 The Johns Hopkins University Isolation, cloning and expression of transmembrane water channel Aquaporin 5 (AQP5)
US5741671A (en) 1991-12-12 1998-04-21 The Johns Hopkins University Isolation cloning and expression of transmembrane water channel aquaporin 1(AQP1)
US5519035A (en) 1993-07-02 1996-05-21 Cornell Research Foundation, Inc. Treatment of stroke or in anticipation of the occurrence of brain ischemia
US20060167110A1 (en) 1995-01-13 2006-07-27 Blume Cherly D Methods for treating cerebrovascular disease by administering desmethylselegiline
WO1998021951A1 (en) 1996-11-18 1998-05-28 Emisphere Technologies, Inc. Methods and compositions for inducing oral tolerance in mammals
JP2001513503A (ja) 1997-08-06 2001-09-04 スミスクライン・ビーチャム・コーポレイション 心臓血管系の疾病の治療に用いられるマクロファージスカベンジャー受容体アンタゴニスト
US5905090A (en) 1998-04-29 1999-05-18 Italfarmaco S.P.A. Analogues of the active metabolite of leflunomide
CO5180581A1 (es) 1999-09-30 2002-07-30 Pfizer Prod Inc Compuestos para el tratamiento de la isquemia ciones farmaceuticas que los contienen para el tratamiento de la isquemia
US6500809B1 (en) 1999-11-12 2002-12-31 Neuron Therapeutics, Inc. Hyperoncotic artificial cerebrospinal fluid and method of treating neural tissue edema therewith
ATE257479T1 (de) 1999-12-10 2004-01-15 Pfizer 5-ring heteroarylsubstituierte 1,4- dihydropyridine als bradykinin antagonisten
UA82827C2 (en) 2000-12-18 2008-05-26 Inhibitors against the production and release of inflammatory cytokines
US8980952B2 (en) 2002-03-20 2015-03-17 University Of Maryland, Baltimore Methods for treating brain swelling with a compound that blocks a non-selective cation channel
US7872048B2 (en) 2004-09-18 2011-01-18 University Of Maryland, Baltimore Methods for treating spinal cord injury with a compound that inhibits a NCCa-ATP channel
JP4485806B2 (ja) 2002-03-20 2010-06-23 ユニヴァーシティ オブ メリーランド，ボルチモア 神経系細胞の非選択的陽イオンチャネルおよび脳腫脹を治療する方法
TWI280876B (en) 2002-06-05 2007-05-11 Inst Med Molecular Design Inc Therapeutic drug for diabetes
AU2003242131A1 (en) 2002-06-05 2003-12-22 Institute Of Medicinal Molecular Design, Inc. Immunity-related protein kinase inhibitors
CA2487891A1 (en) 2002-06-05 2003-12-18 Institute Of Medicinal Molecular Design, Inc. Inhibitors against the activation of ap-1 and nfat
CN1658872B (zh) 2002-06-06 2010-09-22 株式会社医药分子设计研究所 抗过敏药
TW200307535A (en) 2002-06-10 2003-12-16 Inst Med Molecular Design Inc Therapeutic agent for cancer
EA010470B1 (ru) * 2002-06-10 2008-08-29 Инститьют Оф Медисинал Молекьюлар Дизайн. Инк. ИНГИБИТОРЫ АКТИВАЦИИ NF-kB
JP4635130B2 (ja) 2002-06-11 2011-02-16 株式会社医薬分子設計研究所 神経変性疾患治療剤
EP1542699A4 (en) 2002-07-15 2009-03-25 Myriad Genetics Inc COMPOUNDS, COMPOSITIONS AND METHODS OF USE THEREOF
DK1590458T3 (da) 2003-02-06 2013-02-04 Univ Belfast Bradykinin B2-receptorantagonistpeptid fra amfibiehud
NZ543201A (en) 2003-05-01 2007-05-31 Innogene Kalbiotech Pte Ltd Lactate containing pharmaceutical composition and uses thereof
CN100406006C (zh) 2003-07-16 2008-07-30 株式会社医药分子设计研究所 皮肤色素沉着的治疗剂
NZ546365A (en) 2003-10-08 2010-01-29 Vertex Pharma Modulators of ATP-binding cassette transporters containing cycloalkyl or pyranyl groups
US8467876B2 (en) 2003-10-15 2013-06-18 Rmx, Llc Breathing disorder detection and therapy delivery device and method
WO2005039556A1 (ja) 2003-10-29 2005-05-06 Institute Of Medicinal Molecular Design. Inc. 血行再建術後の再狭窄又は再閉塞の治療及び／又は予防のための医薬
US7378509B2 (en) 2003-12-02 2008-05-27 Anesiva, Inc. NF-kappaB oligonucleotide decoy molecules
US10583094B2 (en) 2004-09-18 2020-03-10 University Of Maryland Therapeutic methods that target the NCCA-ATP channel
US7601745B2 (en) 2004-09-27 2009-10-13 4Sc Ag Heterocyclic NF-kB inhibitors
KR20070111475A (ko) 2005-01-04 2007-11-21 노파르티스 아게 만성 변비 환자에서 테가세로드의 효능을 확인하기 위한바이오마커
TWI462745B (zh) * 2005-04-28 2014-12-01 Takeda Pharmaceutical 安定的乳化組成物
WO2007084464A2 (en) 2006-01-17 2007-07-26 The University Of North Carolina At Chapel Hill Water channel blockers and methods of use thereof
JP4273235B2 (ja) 2006-06-01 2009-06-03 国立大学法人 新潟大学 アクアポリン４阻害薬
US20080014196A1 (en) 2006-06-06 2008-01-17 Genentech, Inc. Compositions and methods for modulating vascular development
AU2007319672B2 (en) 2006-06-06 2011-06-30 Genentech, Inc. Anti-DLL4 antibodies and methods using same
US7671058B2 (en) 2006-06-21 2010-03-02 Institute Of Medicinal Molecular Design, Inc. N-(3,4-disubstituted phenyl) salicylamide derivatives
US10004703B2 (en) 2006-10-12 2018-06-26 Biogen Chesapeake Llc Treatment of alzheimer's disease using compounds that reduce the activity of non-selective CA++ activated ATP-sensitive cation channels regulated by SUR1 channels
WO2008046014A1 (en) 2006-10-12 2008-04-17 Remedy Pharmaceuticals, Inc. Treatment of alzheimer's disease using compounds that reduce the activity of non-selective ca++- activated atp-sensitive cation channels regulated by sur1 receptors
CA2669117A1 (en) 2006-10-26 2008-05-02 Gary A. Flynn Aquaporin modulators and methods of using them for the treatment of edema and fluid imbalance
US9316633B2 (en) * 2006-11-16 2016-04-19 The Regents Of The University Of California Methods for identifying inhibitors of solute transporters
US20080214486A1 (en) 2006-11-28 2008-09-04 Alcon Manufacturing, Ltd. RNAi-MEDIATED INHIBITION OF AQUAPORIN 4 FOR TREATMENT OF IOP-RELATED CONDITIONS
WO2008067373A2 (en) 2006-11-28 2008-06-05 Alcon Research, Ltd. RNAi-MEDIATED INHIBITION OF AQUAPORIN 1 FOR TREATMENT OF IOP-RELATED CONDITIONS
CA2674949A1 (en) 2007-01-12 2008-07-24 J. Marc Simard Targeting ncca-atp channel for organ protection following ischemic episode
TWI629058B (zh) 2007-01-16 2018-07-11 陳建宏 醫藥組成物及其用途
US20120183600A1 (en) * 2007-01-16 2012-07-19 Chien-Hung Chen Novel composition for treating metabolic syndrome and other conditions
EP2114160B1 (en) 2007-02-09 2016-11-16 University of Maryland, Baltimore Antagonists of a non-selective cation channel in neural cells
CA2678486C (en) 2007-02-17 2019-03-12 President And Fellows Of Harvard College Compositions and method for tissue preservation
TW200848063A (en) 2007-04-23 2008-12-16 Combinatorx Inc Methods and compositions for the treatment of neurodegenerative disorders
CA2691199C (en) 2007-06-22 2017-09-12 Marc J. Simard Inhibitors of ncca-atp channels for therapy
EP2178531A4 (en) * 2007-07-02 2012-01-11 Yu Ming METHODS AND COMPOSITIONS, TARGETS FOR COMBINED CANCER TREATMENTS
US20090239868A1 (en) 2007-10-23 2009-09-24 Institute Of Medical Molecular Design, Inc. Inhibitor of pai-1 production
CN101842093B (zh) * 2007-10-23 2012-08-22 株式会社医药分子设计研究所 Pai-1产生抑制剂
PL2868315T3 (pl) 2007-12-04 2018-06-29 Biogen Chesapeake Llc Udoskonalone preparaty i sposoby liofilizacji oraz uzyskiwane liofilizaty
GB0724340D0 (en) 2007-12-13 2008-01-30 Univ Dundee Novel Therapeutic Agents
US8642660B2 (en) * 2007-12-21 2014-02-04 The University Of Rochester Method for altering the lifespan of eukaryotic organisms
US20110034560A1 (en) 2008-01-29 2011-02-10 Sven Jacobson Liquid formulations of compounds active at sulfonylurea receptors
US8211882B2 (en) * 2008-03-08 2012-07-03 Richard Delarey Wood Glutamate receptor modulators and therapeutic agents
WO2009139925A1 (en) 2008-05-16 2009-11-19 Panacea Pharmaceuticals, Inc. Methods for the treatment of brain edema
EP2719380A3 (en) 2008-09-16 2014-07-30 University of Maryland, Baltimore SUR1 inhibitors for therapy
US20120010178A1 (en) 2008-10-21 2012-01-12 President And Fellows Of Harvard College Methods and compounds for treatment of neurodegenerative disorders
GB0823366D0 (en) 2008-12-22 2009-01-28 Uni I Oslo Synthesis
EP2385935A4 (en) 2009-01-12 2014-11-05 Purapharm Company Ltd COMPOUNDS AND APPLICATIONS THEREFOR FOR TREATING INFLAMMATION AND FOR MODULATING IMMUNE REACTIONS
US20120039805A1 (en) 2009-02-20 2012-02-16 Pangea Biosciences, Inc. Therapeutics And Methods For Treating Neoplastic Diseases Comprising Determining The Level Of Caveolin-1 And/Or Caveolin-2 In A Stromal Cell Sample
MX2012010382A (es) 2010-03-10 2013-01-29 Univ Melbourne Modulacion de acuaporinas con relaxina.
JP6188021B2 (ja) 2010-07-19 2017-08-30 バイオジェン チェサピーク エルエルシー グリブリドおよび他の薬剤の静脈内投与方法
EP2598145A1 (en) * 2010-07-28 2013-06-05 Boehringer Ingelheim International GmbH Pharmaceutical composition for treatment of respiratory and inflammatory diseases
US20110052678A1 (en) 2010-11-05 2011-03-03 Shantha Totada R Method for treating age related macular degeneration
WO2012125749A2 (en) 2011-03-14 2012-09-20 Io Therapeutics, Inc. INFLAMMATION AND AUTOIMMUNE DISORDER TREATMENT USING RARα SELECTIVE AGONISTS
US9290765B2 (en) * 2011-05-02 2016-03-22 Vereniging Voor Christelijk Hoger Onderwijs, Wetenschappelijk Onderzoek En Patiëntenzorg Protection against endothelial barrier dysfunction through inhibition of the tyrosine kinase abl-related gene (ARG)
RU2461375C1 (ru) * 2011-05-19 2012-09-20 Учреждение Российской академии медицинских наук Научно-исследовательский институт онкологии Сибирского отделения Российской академии медицинских наук (НИИ онкологии СО РАМН) Способ комбинированного лечения больных местно-распространенным раком желудка
WO2013152313A1 (en) 2012-04-05 2013-10-10 The Regents Of The University Of California Compositions and methods for treating cancer and diseases and conditions responsive to growth factor inhibition
US9452973B2 (en) 2012-05-04 2016-09-27 The United States Of America, As Represented By The Secretary Department Of Health And Human Services Modulators of the relaxin receptor 1
CA2872012C (en) 2012-05-08 2017-06-20 Aeromics, Llc New methods
EP3045169B1 (en) 2013-09-13 2018-05-02 Akiko Itai Aqueous solution formulation, and manufacturing method for same
CN106163506A (zh) 2013-11-06 2016-11-23 埃罗米克斯公司 新配方
SI3080134T1 (sl) 2013-12-13 2018-11-30 Vertex Pharmaceuticals Incorporated Predzdravila piridon amidov uporabna kot modulatorji natrijevih kanalov
AU2015346076A1 (en) 2014-11-13 2017-06-15 Aeromics, Inc. Novel methods
CN108348567B (zh) 2015-05-29 2022-03-01 马里兰州立大学巴尔的摩分校 减少或预防由内皮细胞的机械刺激所致的内膜损伤的方法
MA45574A (fr) 2015-10-07 2019-05-15 Biogen Chesapeake Llc Procédés de traitement de lésions ou de pathologies liées à un dème du snc
JP2019521086A (ja) 2016-05-13 2019-07-25 エアロミクス・インコーポレイテッドＡｅｒｏｍｉｃｓ，Ｉｎｃ． 結晶
KR102646250B1 (ko) 2016-07-29 2024-03-11 레메디 파마슈티칼즈, 인크. Sur1-trpm4 통로 저해제를 이용하는 의학적 치료 방법
BR112023002129A2 (pt) 2020-08-05 2023-04-18 Jiangsu Simcere Pharm Co Ltd Composição farmacêutica de inibidor de aquaporina e método de preparação da mesma

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060094718A1 (en) * 2002-06-06 2006-05-04 Susumu Muto O-substituted hydroxyaryl derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Sodium Phosphate, Cold Spring Harb Protoc 2006, doi:10.1101/pdb.rec8303, available at http://cshprotocols.cshlp.org/content/2006/1/pdb.rec8303.full?text_only=true *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11084778B2 (en) 2012-05-08 2021-08-10 Aeromics, Inc. Methods of treating cardiac edema, neuromyelitis optica, and hyponatremia
US12503425B2 (en) 2012-05-08 2025-12-23 Aeromics, Inc. Methods of treating or controlling cytotoxic cerebral edema
US11873266B2 (en) 2012-05-08 2024-01-16 Aeromics, Inc. Methods of treating or controlling cytotoxic cerebral edema consequent to an ischemic stroke
US10894055B2 (en) 2013-11-06 2021-01-19 Aeromics, Inc. Pharmaceutical compositions, methods of making pharmaceutical compositions, and kits comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}4-chlorophenyl dihydrogen phosphate
US11071744B2 (en) 2013-11-06 2021-07-27 Aeromics, Inc. Prodrug salts
US9827253B2 (en) 2013-11-06 2017-11-28 Aeromics, Inc. Prodrug salts
US11801254B2 (en) 2013-11-06 2023-10-31 Aeromics, Inc. Pharmaceutical compositions and methods of making pharmaceutical compositions comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate
US10258636B2 (en) 2013-11-06 2019-04-16 Aeromics, Inc. Prodrug salts
US12213987B2 (en) 2013-11-06 2025-02-04 Aeromics, Inc. Prodrug salts
US12496308B2 (en) 2013-11-06 2025-12-16 Aeromics, Inc. Methods of administering a pharmaceutically acceptable salt of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate
US9949991B2 (en) 2013-11-06 2018-04-24 Aeromics, Inc. Methods of treating aquaporin-mediated conditions
US11117909B2 (en) 2016-05-13 2021-09-14 Aeromics, Inc. Crystals
US11725018B2 (en) 2016-05-13 2023-08-15 Aeromics, Inc. Crystals
US12091431B2 (en) 2016-05-13 2024-09-17 Aeromics, Inc. Crystals

Also Published As

Publication number Publication date
US20160264604A1 (en) 2016-09-15
EP3065727A1 (en) 2016-09-14
KR20160079109A (ko) 2016-07-05
US20160346302A1 (en) 2016-12-01
MX386250B (es) 2025-03-18
EP3065727A4 (en) 2017-05-31
EP3065728A4 (en) 2017-06-07
US20220143048A1 (en) 2022-05-12
WO2015069961A1 (en) 2015-05-14
CN106163506A (zh) 2016-11-23
US9949991B2 (en) 2018-04-24
WO2015069956A3 (en) 2015-11-12
US20210275549A1 (en) 2021-09-09
JP2016535787A (ja) 2016-11-17
EP3065727B1 (en) 2020-08-26
JP2022003084A (ja) 2022-01-11
RU2691951C2 (ru) 2019-06-19
US20200297740A1 (en) 2020-09-24
US12213987B2 (en) 2025-02-04
WO2015069948A1 (en) 2015-05-14
EP3065728A1 (en) 2016-09-14
CA2929821A1 (en) 2015-05-14
JP6957557B2 (ja) 2021-11-02
BR112016010338A2 (pt) 2017-08-08
US11801254B2 (en) 2023-10-31
JP6535338B2 (ja) 2019-06-26
US20180169118A1 (en) 2018-06-21
RU2016121850A3 (enExample) 2018-08-08
US20190307779A1 (en) 2019-10-10
AU2014346682B2 (en) 2020-03-12
AU2014346682A1 (en) 2016-06-09
JP2016536370A (ja) 2016-11-24
HK1224228A1 (zh) 2017-08-18
US10894055B2 (en) 2021-01-19
MX2016006012A (es) 2016-12-09
US11071744B2 (en) 2021-07-27
WO2015069956A2 (en) 2015-05-14
EP3065729A4 (en) 2017-05-31
US12496308B2 (en) 2025-12-16
SG11201604153UA (en) 2016-07-28
CN112402434A (zh) 2021-02-26
RU2016121850A (ru) 2017-12-08
JP2019163314A (ja) 2019-09-26
EP3065729A2 (en) 2016-09-14
US9827253B2 (en) 2017-11-28
ES2834131T3 (es) 2021-06-16
IL245420B (en) 2020-10-29
AU2020203697A1 (en) 2020-06-25
CN112370456A (zh) 2021-02-19
MX2021008629A (es) 2021-08-19
US20240299425A1 (en) 2024-09-12
US10258636B2 (en) 2019-04-16
IL245420A0 (en) 2016-06-30

Similar Documents

Publication Publication Date Title
US12496308B2 (en) Methods of administering a pharmaceutically acceptable salt of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate
US12503425B2 (en) Methods of treating or controlling cytotoxic cerebral edema
JP2016536370A5 (enExample)
BR112016010338B1 (pt) Composição farmacêutica compreendendo um composto de diidrogenfosfato de 2-{[3,5-bis(trifluormetil)fenil]carbamoil}-4-clorofenila e uma ou mais bases de bronsted, kit compreendendo o dito composto e uso dos mesmos para tratar ou controlar edema
HK1208363B (en) Compounds for use in the treatment of aquaporin-mediated diseases
HK1228761A1 (en) Novel prodrug salts
HK1228761B (en) Novel prodrug salts

Legal Events

Date Code Title Description
AS Assignment

Owner name: AEROMICS, LLC, OHIO

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PELLETIER, MARC F.;MCGUIRK, PAUL ROBERT;FARR, GEORGE WILLIAM;SIGNING DATES FROM 20160227 TO 20160314;REEL/FRAME:038784/0873

AS Assignment

Owner name: AEROMICS, INC., OHIO

Free format text: CERTIFICATE OF CONVERSION FROM A LIMITED LIABILITY COMPANY TO A CORPORATION;ASSIGNOR:AEROMICS, LLC;REEL/FRAME:039241/0887

Effective date: 20160323

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: AEROMICS, INC., CONNECTICUT

Free format text: ASSIGNEE CHANGE OF ADDRESS;ASSIGNOR:AEROMICS, INC.;REEL/FRAME:065155/0526

Effective date: 20230813