WO2014200773A2 - Compositions and methods for treating anemia - Google Patents

Compositions and methods for treating anemia Download PDF

Info

Publication number
WO2014200773A2
WO2014200773A2 PCT/US2014/040889 US2014040889W WO2014200773A2 WO 2014200773 A2 WO2014200773 A2 WO 2014200773A2 US 2014040889 W US2014040889 W US 2014040889W WO 2014200773 A2 WO2014200773 A2 WO 2014200773A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
level
formula
patient
anemia
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.)
Ceased
Application number
PCT/US2014/040889
Other languages
English (en)
French (fr)
Other versions
WO2014200773A3 (en
Inventor
Robert Shalwitz
Charlotte HARTMAN
Akshay BUCH
Isaiah SHALWITZ
John JANUSZ
Joseph Gardner
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.)
Akebia Therapeutics Inc
Original Assignee
Akebia Therapeutics 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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=52022903&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2014200773(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Akebia Therapeutics Inc filed Critical Akebia Therapeutics Inc
Priority to CA2914662A priority Critical patent/CA2914662C/en
Priority to FIEP14811317.8T priority patent/FI3007695T3/fi
Priority to NZ714963A priority patent/NZ714963A/en
Priority to CN202111479746.1A priority patent/CN114404414A/zh
Priority to MA38670A priority patent/MA38670B2/fr
Priority to KR1020217011294A priority patent/KR102461176B1/ko
Priority to DK14811317.8T priority patent/DK3007695T3/da
Priority to RS20240271A priority patent/RS65341B1/sr
Priority to RU2016100363A priority patent/RU2705206C2/ru
Priority to CN202111479723.0A priority patent/CN114404413A/zh
Priority to LTEPPCT/US2014/040889T priority patent/LT3007695T/lt
Priority to MX2020006963A priority patent/MX391198B/es
Priority to SG11201509998WA priority patent/SG11201509998WA/en
Priority to BR112015031027A priority patent/BR112015031027A2/pt
Priority to EP24156067.1A priority patent/EP4360706A3/en
Priority to SM20240092T priority patent/SMT202400092T1/it
Priority to KR1020167000558A priority patent/KR102373245B1/ko
Priority to SI201432066T priority patent/SI3007695T1/sl
Priority to HRP20240319TT priority patent/HRP20240319T1/hr
Priority to MYPI2019003537A priority patent/MY204336A/en
Priority to JP2016519543A priority patent/JP2016521747A/ja
Priority to ES14811317T priority patent/ES2974273T3/es
Priority to KR1020227037446A priority patent/KR102660040B1/ko
Priority to CN201480045048.2A priority patent/CN105451739A/zh
Priority to MX2015017229A priority patent/MX378150B/es
Priority to HK16104721.0A priority patent/HK1216844B/en
Priority to EP14811317.8A priority patent/EP3007695B1/en
Priority to PE2020000452A priority patent/PE20201496A1/es
Priority to PL14811317.8T priority patent/PL3007695T3/pl
Priority to KR1020247012967A priority patent/KR20240055172A/ko
Priority to MA43609A priority patent/MA43609B1/fr
Priority to US14/897,849 priority patent/US11857543B2/en
Priority to AU2014278543A priority patent/AU2014278543B2/en
Publication of WO2014200773A2 publication Critical patent/WO2014200773A2/en
Publication of WO2014200773A3 publication Critical patent/WO2014200773A3/en
Priority to PH12015502738A priority patent/PH12015502738B1/en
Priority to IL24304715A priority patent/IL243047B/en
Priority to ZA2015/09024A priority patent/ZA201509024B/en
Priority to CR20150660A priority patent/CR20150660A/es
Anticipated expiration legal-status Critical
Priority to IL270335A priority patent/IL270335B/en
Priority to AU2020200903A priority patent/AU2020200903B2/en
Priority to PH12020551705A priority patent/PH12020551705A1/en
Priority to IL281058A priority patent/IL281058B2/en
Priority to AU2022200570A priority patent/AU2022200570B2/en
Priority to US18/511,042 priority patent/US20240335434A1/en
Priority to NO2024025C priority patent/NO2024025I1/no
Priority to NL301278C priority patent/NL301278I2/nl
Priority to FR24C1025C priority patent/FR24C1025I2/fr
Priority to FIC20240023C priority patent/FIC20240023I1/fi
Priority to LTPA2024521C priority patent/LTPA2024521I1/lt
Priority to AU2024205219A priority patent/AU2024205219A1/en
Ceased legal-status Critical Current

Links

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1816—Erythropoietin [EPO]
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P7/06—Antianaemics

Definitions

  • the present disclosure relates to uses of a HIF prolyl hydroxylase inhibitor in treating or preventing anemia, such as anemia secondary to or associated with chronic kidney disease, anemia associated with or resulting from chemotherapy, or anemia associated with AIDS.
  • anemia such as anemia secondary to or associated with chronic kidney disease, anemia associated with or resulting from chemotherapy, or anemia associated with AIDS.
  • the present disclosure relates to HIF prolyl hydroxylase inhibitor compounds and pharmaceutically acceptable salts thereof, compositions comprising the HIF prolyl hydroxylase inhibitor compounds, and to methods for treating or preventing diseases such as, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, hypoxia and anemia.
  • diseases such as, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, hypoxia and anemia.
  • the present disclosure relates to specific doses of, and dosing regimens for, uses of a HIF prolyl hydroxylase inhibitor in treating or preventing anemia, such as anemia secondary to or associated with chronic kidney disease, anemia associated with or resulting from chemotherapy, or anemia associated with AIDS.
  • anemia such as anemia secondary to or associated with chronic kidney disease, anemia associated with or resulting from chemotherapy, or anemia associated with AIDS.
  • Hypoxia-inducible factor is a transcription factor that is a key regulator of responses to hypoxia.
  • hypoxic conditions i.e., reduced oxygen levels in the cellular environment
  • HIF upregulates transcription of several target genes, including those encoding erythropoietin.
  • HIF is a heteroduplex comprising an alpha and beta subunit. While the beta subunit is normally present in excess and is not dependent on oxygen tension, the HIF-alpha subunit is only detectable in cells under hypoxic conditions.
  • HIF-alpha is regulated primarily by hydroxylation at two proline residues by a family of prolyl hydroxylases known as HIF prolyl hydroxylases, wherein hydroxylation of one or both of the proline residues leads to the rapid degradation of HIF-alpha. Accordingly, inhibition of HIF
  • BOI-38503vl prolyl hydroxylase results in stabilization and accumulation of HIF-alpha (i.e., the degradation of HIF-alpha is reduced), thereby leading to an increase in the amount of HIF-alpha available for formation of the HIF heterodimer and upregulation of target genes, such as the Erythropoietin gene.
  • activation of HIF prolyl hydroxylase results in destabilization of HIF-alpha (i.e., the degradation of HIF-alpha is increased), thereby leading to a decrease in the amount of HIF-alpha available for formation of the HIF heterodimer and downregulation of target genes, such as VEGF.
  • hypoxia inducible factors includes HIF-1 -alpha, HIF-2-alpha, and HIF-3 - alpha.
  • a new class of prolyl hydroxylase inhibitors and their use to treat or prevent diseases ameliorated by modulation of hypoxia-inducible factor (HIF) prolyl hydroxylase are described in U.S. Patent No. 7,811,595, which is incorporated herein by reference in its entirety.
  • the synthesis of such prolyl hydroxylase inhibitors is described in U.S. Patent Publication No.
  • EPO erythropoietin
  • HIF regulates transcription of several target genes, including those encoding proteins involved in iron metabolism.
  • iron is considered to be essential for living cells, excess iron accumulation is associated with formation of toxic free radicals and progressive tissue damage. An excess of iron may also lead to a higher risk for cardiovascular events and thromboembolic events.
  • Iron overload may be caused for example by blood transfusions or anemias that arise from ineffective erythropoiesis. A need exists for treatment of anemia without increasing the risk of iron overload.
  • Compound 12 Compound 13, Metabolite 1, and Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof are administered according to a specific dosing regimen to modulate HIF prolyl hydroxylase, thereby stabilizing HIF-alpha, and thereby treating anemia (e.g. anemia secondary to chronic kidney disease). See Section 5.2 for a description of these formulae and compounds. Further disclosed herein are specific doses and unit dosage forms of a
  • BOI-38503vl compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,
  • the compound is ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid.
  • the compound is a pharmaceutically acceptable salt of Compound 1.
  • the compound is a solvate of Compound 1.
  • the compound is a hydrate of Compound 1.
  • described herein are methods for treating or preventing a disease ameliorated by modulation of HIF prolyl hydroxylase comprising administering to a patient having a disease ameliorated by modulation of HIF prolyl hydroxylase an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound is Compound 1.
  • the compound is Compound 7.
  • a daily dose of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof for the uses described herein is about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about
  • the daily dose is 2mg/kg, 2.1mg/kg, 2.2mg/kg, 2.3mg/kg, 2.4mg/kg, 2.5mg/kg, 2.6mg/kg, 2.7mg/kg, 2.8mg/kg, 2.9mg/kg, 3mg/kg, 3.1mg/kg, 3.2mg/kg, 3.3mg/kg, 3.4mg/kg, 3.5mg/kg, 3.6mg/kg, 3.7mg/kg, 3.8mg/kg, 3.9mg/kg, or 4mg/kg.
  • anemia such as anemia secondary to chronic kidney disease
  • administering comprising administering to a patient having anemia an effective amount of an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • a daily dose a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof specifically a daily dose of Compound 1 is about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • the daily dose is 2mg/kg, 2.1mg/kg, 2.2mg/kg, 2.3mg/kg, 2.4mg/kg, 2.5mg/kg, 2.6mg/kg, 2.7mg/kg, 2.8mg/kg, 2.9mg/kg, 3mg/kg, 3.1mg/kg, 3.2mg/kg, 3.3mg/kg, 3.4mg/kg, 3.5mg/kg, 3.6mg/kg, 3.7mg/kg, 3.8mg/kg, 3.9mg/kg, or 4mg/kg.
  • a unit dosage form comprising a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4,
  • the unit dosage form is a tablet or capsule.
  • kits for maintaining the level of hemoglobin in a patient having anemia such as anemia secondary to chronic kidney disease, at a level of at least about 8.0 g/dL and at or below about 13.0 g/dL, at least about 8.5 g/dL and at or below 13.0 g/dL, at least about 9.0 g/dL and at or below 13.0 g/dL, at least about 9.5 g/dL and at or below 13.0 g/dL, or at least about 10.0 g/dL and at or below about 13.0 g/dL, comprising administering an effective amount of a compound having a structure of Formula (I), Formula
  • a patient having anemia having anemia at a level of at least about 11.0 g/dL, such as at least about 11.0 g/dL and at or below about 13.0 g/dL, comprising administering an effective amount of a compound having a structure of Formula (I), Formula (II), Formula
  • Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, specifically Compound 1, is about 150 mg, about 300 mg, about 450 mg, about 600, or about 750 mg.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three
  • the daily dose is 2mg/kg, 2.1mg/kg, 2.2mg/kg, 2.3mg/kg, 2.4mg/kg, 2.5mg/kg, 2.6mg/kg, 2.7mg/kg, 2.8mg/kg, 2.9mg/kg, 3mg/kg, 3.1mg/kg, 3.2mg/kg, 3.3mg/kg, 3.4mg/kg, 3.5mg/kg, 3.6mg/kg, 3.7mg/kg, 3.8mg/kg, 3.9mg/kg, or 4mg/kg.
  • kits for increasing the level of hemoglobin in a patient having anemia such as anemia of chronic kidney disease, by at least about 0.1 g/dL, by at least about 0.2 g/dL, by at least about 0.3 g/dL, by at least about 0.4 g/dL, by at least about 0.5 g/dL, by at least about 0.6 g/dL, by at least about 0.7 g/dL, by at least about 0.8 g/dL, by at least about 0.9 g/dL, by at least about 1.0 g/dL, by at least about 1.1 g/dL, by at least about 1.2 g/dL, by at least about 1.3 g/dL, by at least about 1.4 g/dL, or by at least about 1.5 g/dL relative to a baseline hemoglobin level in a patient, comprising administering an effective amount a compound having a structure of Formula (I), Formula (II
  • such a daily dose is about 150 mg, about 300 mg, about 450 mg, about 600, or about 750 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • a method for treating or preventing anemia in a patient comprising administering to the patient a pharmaceutically effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 or a
  • BOI-38503vl effective amount is suitable to increase the level of hemoglobin by at least about 0.5 g/dL, by at least about 0.6 g/dL, by at least about 0.7 g/dL, by at least about 0.8 g/dL, by at least about 0.9 g/dL, by at least about 1.0 g/dL, by at least about 1.2 g/dL, or by at least about 1.5 g/dL relative to a baseline hemoglobin level in the patient while:
  • erythropoietin EPO
  • various methods for treating a disease or condition related to diminished endogenous production of erythropoietin comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer, so as to raise the level of hemoglobin relative to a baseline hemoglobin level in a patient, while mimicking the diurnal variation of serum EPO levels in healthy individuals, wherein the HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,
  • erythropoietin EPO
  • methods for treating a disease or condition related to diminished endogenous production of EPO comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the level of hemoglobin relative to a baseline hemoglobin level in a patient, wherein the time period between the administration of at least one of said successive
  • BOI-38503vl doses and the administration of the immediately preceding dose is a sufficient time period to permit the level of serum EPO in a patient to return to about baseline serum EPO level
  • the HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12,
  • erythropoietin EPO
  • methods for treating a disease or condition related to diminished endogenous production of erythropoietin comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the level of hemoglobin relative to a baseline hemoglobin level in a patient, wherein prior to the addition of one or more doses following the initial dose the level of serum EPO returns to about a baseline level, wherein the HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Met
  • erythropoietin EPO
  • methods for treating a disease or condition related to diminished endogenous production of erythropoietin comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the level of hemoglobin relative to a baseline hemoglobin level in a patient without significantly increasing the level of serum EPO relative to the baseline level of serum EPO, wherein the HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of
  • the cardiovascular side-effects and risk of thromboembolic events associated with administration of exogenous EPO are minimized.
  • the level of serum EPO returns to about baseline level within about one week, about six days, about five days, about four days, about three days, about two days, about twenty four hours, about eighteen hours, or about twelve hours of administering a dose of a HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer disclosed herein.
  • the level of serum EPO returns to within about 5 mlU/mL, about 4 mlU/mL, about 3 mlU/mL, about 2 mlU/mL, or about 1 mlU/mL of the baseline level of EPO.
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of one week relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.1 g/dL over a period of one week relative to the baseline hemoglobin level.
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of two weeks relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.1 g/dL over a period of two weeks relative to the baseline hemoglobin level.
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of three weeks relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.5 g/dL over a period of three weeks relative to the baseline hemoglobin level.
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of four weeks relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.6 g/dL over a period of four weeks relative to the baseline hemoglobin level.
  • the disease or condition is anemia. In certain such embodiments, the disease or condition is anemia.
  • the anemia is anemia secondary to chronic kidney disease (CKD).
  • CKD chronic kidney disease
  • the chronic kidney disease is stage 3, 4, or 5 chronic kidney disease. In certain such embodiments, the chronic kidney disease is pre-dialysis chronic kidney disease.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is administered once daily. In certain embodiments, the HIF prolyl hydroxylase inhibitor or HIF- alpha stabilizer is administered orally.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-N-(2-aminoethyl)-2-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe
  • Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-N-(2-aminoethyl)-2-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • EPO erythropoietin
  • TSAT transferrin saturation
  • a method of treating a disease or condition related to diminished endogenous production of erythropoietin comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the total iron binding capacity (TIBC) relative to a baseline TIBC in a patient, without significantly increasing the serum iron level relative to a baseline serum iron level.
  • EPO erythropoietin
  • a method for treating or preventing anemia in a subject comprises administering to the subject a pharmaceutically effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the pharmaceutically effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is suitable to raise TIBC at least about 10 ⁇ g/dL, at least about 20 ⁇ g/dL, at least about 30 ⁇ g/dL, at least about 40 ⁇ g/dL, at least about 50 ⁇ g/dL, or at least about 60 ⁇ g/dL relative to baseline TIBC and/or the level of hemoglobin by at least about 0.5 g/dL, by at least about 0.6 g/dL, by at least about 0.7 g/dL, by at least about 0.8 g/dL, by at least about
  • erythropoietin EPO
  • methods of treating a disease or condition related to diminished endogenous production of erythropoietin (EPO) while minimizing the cardiovascular side-effects and risk of thromboembolic events associated with increased serum iron levels comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the total iron binding capacity (TIBC) relative to a baseline TIBC in a patient, without significantly increasing the serum iron level relative to a baseline serum iron level.
  • TIBC total iron binding capacity
  • the transferrin saturation (TSAT) decreases relative to a baseline TSAT.
  • the serum iron level decreases relative to a baseline serum iron level.
  • the TIBC increases by at least about 10 ⁇ g/dL, at least about 20 ⁇ g/dL, at least about 30 ⁇ /dL, at least about 40 ⁇ /dL, at least about 50 ⁇ /dL, or at least about 60 ⁇ /dL relative to a baseline TIBC.
  • the TIBC increase relative to a baseline TIBC occurs over about 1 week, over about 2 weeks, over about 3 weeks, over about 4 weeks, over about 5 weeks, or over about 6 weeks.
  • the serum iron level increases by less than about 20 ⁇ /dL, less than about 15 ⁇ /dL, less than about 10 ⁇ /dL, or less than about 5 ⁇ /dL relative to a baseline serum iron level.
  • the disease or condition is anemia. In certain such embodiments, the disease or condition is anemia.
  • the anemia is anemia secondary to chronic kidney disease (CKD).
  • the chronic kidney disease is stage 3, 4, or 5 chronic kidney disease.
  • the chronic kidney disease is pre-dialysis chronic kidney disease.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is administered once daily.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is administered orally.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is a heterocyclic carboxamide.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is selected from a pyridine carboxamide, a quinoline carboxamide, and an isoquinoline carboxamide.
  • the HIF prolyl hydroxylase inhibitor or HIF- alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • BOI-38503vl disclosed in 5.5, specifically at a dose suitable to increase total iron binding capacity as described in Section 5.3.2.
  • hepcidin expression is similar to the expression in healthy adults and functions to regulate iron transport normally.
  • a method of treating a disease or condition selected from non-severe anemia secondary to chronic kidney disease, non-severe anemia secondary to congestive heart failure, and idiopathic anemia of aging comprising administering to a patient having non-severe anemia secondary to chronic kidney disease, non-severe anemia secondary to congestive heart failure, or idiopathic anemia of aging a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the serum hemoglobin levels relative to a baseline serum hemoglobin level in a patient, without significantly decreasing hepcidin expression relative to a baseline hepcidin expression level.
  • the serum hemoglobin level is raised by between about 0.1 and about 1.0 g/dL over a period of one week relative to the baseline hemoglobin level. In certain such embodiments, the serum hemoglobin level is raised by about 0.1 g/dL over a period of one week relative to the baseline hemoglobin level.
  • the serum hemoglobin level is raised by between about 0.1 and about 1.0 g/dL over a period of two weeks relative to the baseline hemoglobin level. In certain such embodiments, the serum hemoglobin level is raised by about 0.1 g/dL over a period of two weeks relative to the baseline hemoglobin level.
  • the serum hemoglobin level is raised by between about 0.1 and about 1.0 g/dL over a period of three weeks relative to the baseline hemoglobin level. In certain such embodiments, the serum hemoglobin level is raised by about 0.5 g/dL over a period of three weeks relative to the baseline hemoglobin level.
  • the serum hemoglobin level is raised by between about 0.1 and about 1.0 g/dL over a period of four weeks relative to the baseline hemoglobin level.
  • the serum hemoglobin level is raised by about 0.6 g/dL over a period of four weeks relative to the baseline hemoglobin level.
  • the serum hemoglobin level is raised by between about 0.1 and about 1.0 g/dL over a period of five weeks relative to the baseline hemoglobin level. In certain such embodiments, the serum hemoglobin level is raised by about 0.6 g/dL over a period of five weeks relative to the baseline hemoglobin level.
  • the serum hemoglobin level is raised by between about 0.1 and about 1.0 g/dL over a period of six weeks relative to the baseline hemoglobin level. In certain such embodiments, the serum hemoglobin level is raised by about 0.6 g/dL over a period of six weeks relative to the baseline hemoglobin level.
  • hepcidin expression decreases less than about 20%, less than about 15%, less than about 10%> relative to the baseline hepcidin expression level, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% relative to the baseline hepcidin expression level.
  • the disease or condition is non-severe anemia secondary to chronic kidney disease. In certain embodiments, the disease or condition is non-severe congestive heart failure. In certain embodiments, the disease or condition is idiopathic anemia of aging.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is administered once daily. In certain embodiments, the HIF prolyl hydroxylase inhibitor or HIF- alpha stabilizer is administered orally.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is a heterocyclic carboxamide.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is selected from a pyridine carboxamide, a quinoline carboxamide, and an isoquinoline carboxamide.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,
  • BOI-38503vl prolyl hydroxylase inhibitor or HIF-alpha stabilizer is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • hydroxylase inhibitor or HIF-alpha stabilizer is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • FIG. la shows the serum concentration of Compound 1 in healthy male adults over twenty-four hours.
  • FIG. lb shows the EPO response in healthy male adults over twenty-four hours after administration of Compound 1.
  • FIG. 2 shows the EPO levels over twenty four hours in patients with anemia secondary to chronic kidney disease after administration of Compound 1.
  • FIG. 3 shows the concentration of Compound 1 in patients with anemia secondary to chronic kidney disease over twenty- four hours.
  • FIG. 4 shows the change in hemoglobin from baseline in patients with anemia secondary to chronic kidney disease when Compound 1 is administered at various doses.
  • FIG. 5 shows the hemoglobin, reticulocyte, and EPO levels in patients with anemia secondary to chronic kidney disease over six weeks of treatment with Compound 1.
  • FIG. 6 shows the mean ( ⁇ SE) absolute change from the mean baseline for hemoglobin and ferritin in a dose escalation study in patients with anemia secondary to chronic kidney disease.
  • FIG. 7 shows an increase in total iron binding capacity in patients with anemia secondary to chronic kidney disease over six weeks, while also showing no significant increase in serum iron levels when treated with Compound 1.
  • FIG. 8 shows an increase in serum hemoglobin levels relative to baseline in patients with anemia secondary to chronic kidney disease over six weeks when treated with Compound 1.
  • FIG. 9 shows that at low doses, hepcidin expression does not decrease relative to baseline in patients with anemia secondary to chronic kidney disease over six weeks when treated with Compound 1.
  • a method for treating or preventing anemia in a patient comprising administering to the patient a pharmaceutically effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 or a
  • the pharmaceutically effective amount is suitable to increase the level of hemoglobin by at least about 0.2 g/dL, 0.3 g/dL, 0.4 g/dL, 0.5 g/dL, by at least about 0.6 g/dL, by at least about 0.7 g/dL, by at least about 0.8 g/dL, by at least about 0.9 g/dL, by at least about 1.0 g/dL, by at least about 1.2 g/dL, or by at least about 1.5 g/dL relative to a baseline hemoglobin level in the patient while: a) restoring or maintaining the diurnal pattern of EPO serum levels; and/or b) increasing the total iron binding capacity; and/or c) increasing the total iron binding capacity without increasing significantly the total iron levels; and/or c) not significantly decreasing hepcidin levels.
  • the word “comprise” and other forms of the word, such as “comprising” and “comprises,” means including but not limited to, and is not intended to exclude, for example, other additives, components, integers, or steps.
  • the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
  • reference to “a composition” includes mixtures of two or more such compositions.
  • “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not
  • an "alkyl” group is a saturated straight chain or branched non-cyclic hydrocarbon having, for example, from 1 to 12 carbon atoms, 1 to 9 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 2 to 6 carbon atoms.
  • alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while branched alkyls include -isopropyl, - sec-butyl, -z ' so-butyl, -tert-butyl, -z ' so-pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like.
  • Ci_6 alkyl units include the following non-limiting examples: methyl (Ci), ethyl (C 2 ), n- propyl (C 3 ), zso-propyl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), z ' so-butyl (C 4 ), tert-butyl (C 4 ), n-pentyl (C 5 ), tert-pentyl (C 5 ), neo-pentyl (C 5 ), z ' so-pentyl (C 5 ), sec-pentyl (C 5 ), 3-pentyl (C 5 ), n-hexyl (C 6 ), z ' so-hexyl (C 6 ), neo-hexyl (C 6 ), 3-methylpentyl (C 6 ), 4-methylpentyl (C 6 ), 3-methylpentan- 2-yl (Ci),
  • alkenyl is a partially unsaturated straight chain or branched non-cyclic hydrocarbon containing at least one carbon-carbon double bond and having, for example, from 1 to 6 carbon atoms.
  • Representative alkenyl groups include propenyl and the like.
  • an "alkynyl” group is a partially unsaturated straight chain or branched non-cyclic hydrocarbon containing at least one carbon-carbon triple bond and having, for example, from 2 to 6 carbon atoms.
  • Representative alkynyl groups include propynyl, butynyl and the like.
  • an "alkoxy” group is an alkyl-O- group in which the alkyl group is as defined herein.
  • Representative alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • an "cycloalkyl” group is a saturated cyclic alkyl group of from 3 to 6 carbon atoms having a single cyclic ring.
  • Representative cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclopentyl.
  • an "cycloalkenyl” group is a partially unsaturated cyclic alkyl group containing at least one carbon-carbon double bond and from 3 to 6 carbon atoms having a single cyclic ring.
  • Representative cycloalkenyl groups include cyclopropenyl and cyclobutenyl.
  • a "cycloalkoxy” group is a cycloalkyl-O- group in which the cycloalkyl group is as defined herein.
  • Representative cycloalkoxy groups include cyclopropyloxy, cyclobutyloxy and cyclopentyloxy.
  • a "haloalkyl” group is an alkyl group as defined herein above with one or more (e.g., 1 to 5) hydrogen atoms are replaced by halogen atoms.
  • Representative haloalkyl groups include CF 3 , CHF 2 , CH 2 F, CC1 3 , CF 3 CH 2 CH 2 and CF 3 CF 2 .
  • a "halocycloalkyl” group is a cycloalkyl group as defined herein above with one or more (e.g., 1 to 5) hydrogen atoms are replaced by halogen atoms.
  • Representative halocycloalkyl groups include 2,2-difluorocyclopropyl, 2,2-dichlorocyclopropyl, 2,2- dibromocyclopropyl, tetrafluorocyclopropyl, 3,3-difluorocyclobutyl and 2,2,3,3- tetrafluorocyclobutyl.
  • a "heterocycloalkyl” group is a saturated ring of 4 to 7 atoms, preferably 5 or 6 ring atoms, wherein 1 or 2 ring members are selected from the group consisting of O, S and NR' ' and the remaining atoms are carbon. There are no adjacent oxygen and/or sulfur atoms in the rings.
  • Representative heterocycloalkyl groups are piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1 ,4-dioxanyl, oxazolinyl,
  • an "aryl” group is an aromatic monocyclic or multi-cyclic ring system comprising 6 to 10 carbon atoms.
  • Representative aryl groups include phenyl and naphthyl.
  • heteroaryl is a single ring, bicyclic or benzofused heteroaromatic group of 5 to 10 atoms comprised of 2 to 9 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, provided that the rings do not include adjacent oxygen and/or sulfur atoms. N-oxides of the ring nitrogens are also included.
  • Representative single-ring heteroaryl groups include pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl.
  • Representative bicyclic heteroaryl groups are naphthyridyl (e.g., 1,5 or 1, 7), imidazopyridyl, pyridopyrimidinyl and 7-azaindolyl.
  • benzofused heteroaryl groups include indolyl, quinolyl, isoquinolyl, phthalazinyl, benzothienyl (i.e., thianaphthenyl), benzimidazolyl, benzo furanyl, benzoxazolyl, benzisoxazolyl,
  • composition of matter stand equally well for the HIF prolyl hydroxylase enzyme inhibitors described herein, including all enantiomeric forms, diastereomeric forms, salts, tautomers, and
  • the compounds disclosed herein include all salt forms, for example, salts of both basic groups, inter alia, amines, as well as salts of acidic groups, inter alia, carboxylic acids.
  • the following are non-limiting examples of anions that can form pharmaceutically acceptable salts with basic groups: chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, citrate, and the like.
  • anemia is art-recognized and is defined by hemoglobin threshold as follows:
  • Anemia may be chronic (e.g., anemia secondary to chronic kidney disease, anemia secondary to chronic heart failure, idiopathic anemia of aging, anemia of chronic disease, such as
  • BOI-38503vl fibrosis and other aplastic or dysplastic anemias
  • subacute e.g., chemotherapy induced anemia, such as chemotherapy for treating cancer, hepatitis C, or other chronic disease that reduces bone marrow production
  • acute e.g., blood loss from injury or surgery
  • nutrition related e.g., iron deficiency or vitamin B12 deficiency
  • hemaglobinpathies e.g., sickle cell disease, thalassemia, etc.
  • anemia due to prematurity or anemia due to autologous blood donation.
  • non-severe anemia refers to a patient having anemia wherein the hemoglobin is at least 9.0 g/dL. In certain such embodiments, non-severe anemia refers to anemia in a patient, wherein the patient does not require a transfusion.
  • dose(s) means a quantity of the compound or a
  • a dose may comprise a single unit dosage form, or alternatively may comprise more than a single unit dosage form (e.g., a single dose may comprise two tablets), or even less than a single unit dosage form (e.g., a single dose may comprise half of a tablet). Accordingly, if the compound is administered at a daily dose of 450 mg, once daily, then the dose of compound may be three tablets, each comprising 150 mg of compound administered once daily.
  • the term "daily dose” means a quantity of the compound, or a pharmaceutically acceptable salt, solvate, or hydrate thereof that is administered in a 24 hour period. Accordingly, a daily dose may be administered all at once (i.e., once daily dosing) or alternatively the daily dosing may be divided such that administration of the compound is twice daily, three times daily, or even four times daily. When a daily dose is administered every day without interruption, the dosing is referred to as "continuous" dosing.
  • unit dosage form(s) includes tablets; caplets; capsules, such as soft elastic gelatin capsules; sachets; cachets; troches; lozenges; dispersions; powders;
  • solutions; gels; liquid dosage forms suitable for oral or mucosal administration to a patient including suspensions (e.g., aqueous or non-aqueous liquid suspensions), emulsions (e.g., oil-in- water emulsions, or a water-in-oil liquid emulsion), solutions, and elixirs; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for oral or parenteral administration to a patient.
  • the unit dosage form does not necessarily have to be administered as a single dose nor does a single unit dosage form necessarily constitute an entire dose.
  • an "effective amount” refers to that amount of a compound or a pharmaceutically acceptable salt, solvate or hydrate thereof sufficient to provide a therapeutic benefit in the treatment of the disease or to delay or minimize symptoms associated with the disease. Certain preferred effective amounts are described herein.
  • the compound is a compound disclosed herein.
  • the terms “prevent”, “preventing” and “prevention” are art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a compound provided herein or a pharmaceutically acceptable salt, solvate or hydrate thereof, which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
  • the compound is a compound that is not disclosed herein.
  • the condition is a disease or condition related to diminished endogenous production of erythropoietin (EPO) or a disease or condition related to deficiencies in endogenous hemoglobin production, such as anemia or anemia secondary to chronic kidney disease.
  • EPO erythropoietin
  • a disease or condition related to deficiencies in endogenous hemoglobin production such as anemia or anemia secondary to chronic kidney disease.
  • the terms “treat”, “treating” and “treatment” refer to the reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in manner to improve or stabilize a subject's condition.
  • the terms “treat” and “treatment” also refer to the eradication or amelioration of the disease or symptoms associated with the disease. In certain embodiments, such terms refer to minimizing the spread or worsening of the disease resulting from the administration of a compound provided herein or a pharmaceutically acceptable salt, solvate or hydrate thereof to a patient with such a disease.
  • the term "pharmaceutically acceptable salt” refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts for a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,
  • Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 include, but are not limited to, sodium, lithium, potassium, calcium, magnesium, zinc, bismuth, ammonium
  • BOI-38503vl including alkyl substituted ammonium, amino acids (e.g., lysine, ornithine, arginine, or glutamine), tromethamine, and meglumine.
  • Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid,
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the relevant active compound without causing clinically unacceptable biological effects or interacting in a deleterious manner with any of the other components of the
  • hydrate means a compound provided herein or a
  • pharmaceutically acceptable salt thereof that further includes a stoichiometric or non- stoichiometric amount of water bound by non-covalent intermolecular forces.
  • solvate means a compound provided herein or a
  • pharmaceutically acceptable salt thereof that further includes a stoichiometric or non- stoichiometric amount of a solvent, other than water, bound by non-covalent intermolecular forces.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. In certain embodiments, ranges can be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the
  • BOI-38503vl particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that when a value is disclosed, then “less than or equal to” the value, “greater than or equal to the value,” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan.
  • the term subject or patient can refer to a mammal, such as a human, mouse, dog, donkey, horse, rat, guinea pig, bird, or monkey.
  • a subject or a patient is a human subject or patient.
  • a compound provided herein is Compound 1, namely ⁇ [5-(3- chlorophenyl)-3-hydroxypyridin -2-carbonyl] amino ⁇ acetic acid having the structure
  • the compound may be ⁇ [5-(3-chlorophenyl)-3- hydroxypyridine-2-carbonyl]amino ⁇ acetic acid, while in certain alternative embodiments, the compound may be a pharmaceutically acceptable salt of ⁇ [5-(3-chlorophenyl)-3- hydroxypyridine-2-carbonyl]amino ⁇ acetic acid. In certain alternative embodiments, the compound may be a solvate of ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl] amino ⁇ acetic acid. In certain alternative embodiments, the compound may be a
  • the invention relates to the compound in its parent form (i.e., not a salt, solvate, or hydrate). In certain alternative preferred embodiments, the invention relates to the compound or a pharmaceutically acceptable salt thereof.
  • HIF prolyl hydroxylase is art-recognized and may be abbreviated as "PHD”.
  • HIF prolyl hydroxylase is also known as "prolyl hydroxylase domain- containing protein” which may be abbreviated as "PHD”.
  • PHD1 PHD2, and PHD3 also referred to as EGLN2, EGLN1, and EGLN3, or HPH3, HPH2, and HPH1, respectively.
  • HIF prolyl hydroxylase may refer to a particular target of the enzyme (e.g., HIF- ⁇ prolyl hydroxylase, HIF-2a prolyl hydroxylase, and/or HIF-3a prolyl hydroxylase).
  • a compound for use with the methods provided herein is a modulator of a HIF prolyl hydroxylase. In more specific embodiments, a compound for use with the methods provided herein is a modulator of a HIF-1 -alpha prolyl hydroxylase. In other, more specific embodiments, a compound for use with the methods provided herein is a modulator of a HIF-2-alpha prolyl hydroxylase.
  • a compound for use with the methods provided herein is a modulator of a HIF-2-alpha prolyl hydroxylase that is more active against HIF-2-alpha prolyl hydroxylase than HIF-1 -alpha prolyl hydroxylase by at least 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 100%, 125%, 150%, 175%, 200%), 250%), 500%), 750%), or at least 1000%).
  • a compound provided herein for use with the methods provided herein preferentially stabilizes HIF-2-alpha over HIF-1 -alpha.
  • the concentrations of HIF-1 -alpha and HIF-2-alpha in a subject with and without test compound can be determined using a HIF-1 -alpha and a HIF-2-alpha ELISA kit. Care should be taken that the primary antibodies in the respective kits are not cross-reactive with the other HIF (i.e., the primary antibody against HIF-1 -alpha reacts immunospecifically with HIF-1 -alpha and does not cross-react with HIF-2-alpha; the primary antibody against HIF-2-alpha reacts
  • a compound of the invention which is a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is a heterocyclic carboxamide.
  • heterocyclic carboxamide is selected from a pyridyl carboxamide, a quinoline carboxamide, and an isoquinoline carboxamide.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer has a structure of Formula (I):
  • R and R 1 are each independently:
  • said substitution selected from:
  • R 4 is a C 1 -C 4 alkyl or C 3 -C 4 cycloalkyl
  • R 5a and R 5b are each independently selected from:
  • R 5a and R 5b are taken together to form a ring having from 3 to 7 atoms;
  • R 2 is selected from:
  • R 6 is selected from hydrogen and C1-C4 alkyl or C3-C4 cycloalkyl
  • R 7a and R 7b are each independently selected from:
  • R 7a and R 7b are taken together to form a ring having from 3 to 7 atoms;
  • R 3 is selected from hydrogen, methyl, and ethyl;
  • L is a linking unit having a structure -[C(R 8a R 8b )] n -
  • R 8a and R 8b are each independently selected from hydrogen, methyl and ethyl
  • n is an integer from 1 to 3;
  • R 9 is selected from hydrogen and methyl.
  • R and R 1 are not both hydrogen.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer has a structure of Formula (II):
  • A is selected from the group consisting of CR', N, N + -0 " and N + (Ci-C 6 alkyl);
  • R' is selected from the group consisting of H, Ci-C 6 alkyl, C3-C6 cycloalkyl, C2-C6
  • R" is independently selected from the group consisting of Ci-C 6 alkyl, C3-C6 cycloalkyl, C4-C7 heterocycloalkyl, C 6 -Cio aryl and C5-C10 heteroaryl; and wherein Ci-C 6
  • BOI-38503vl alkyl, C3-C6 cycloalkyl, or C4-C7 heterocycloalkyl are optionally substituted with oxo, NH 2 , NHR", N(R") 2 , F, CI, Br, I, OH, OR", SH, SR", S(0)R", S(0) 2 R", S(0)NHR", S(0) 2 NHR", S(0)NR” 2 , S(0) 2 NR" 2 , C(0)R", C0 2 H, C0 2 R", C(0)NH 2 , C(0)NHR", C(0)NR” 2 , CN, CH 2 CN, CF 3 , CHF 2 , CH 2 F, NH(CN), N(CN) 2 , CH(CN) 2 , C(CN) 3 ; and wherein C 6 -Ci 0 aryl or C5-C10 heteroaryl are optionally substituted with Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alken
  • R 2 is selected from:
  • R a and R are each independently selected from:
  • R 7a and R 7b are taken together to form a ring having from 3 to 7 atoms.
  • the HIF stabilizer is a compound having a structure of Formula (III)
  • R is chosen from
  • R 3 are each independently selected from:
  • R 2 and R 3 can be taken together to form a ring having from 2 to 7 carbon atoms and from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulfur including the nitrogen atom to which R 2 and R 3 are bonded;
  • M 1 is a cation
  • R 4 is:
  • M 2 is a cation.
  • the HIF stabilizer is a compound having a structure of Formula (IV)
  • R is chosen from
  • R 1 is:
  • R 2 and R 3 are each independently selected from:
  • R 2 and R 3 can be taken together to form a ring having from 2 to 7 carbon atoms and from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulfur including the nitrogen atom to which R 2 and R 3 are bonded;
  • M 1 is a cation
  • R 4 is:
  • M 2 is a cation. .
  • HIF prolyl hydroxylase inhibitor compounds described herein are unsubstituted or substituted 3-hydroxy-pyridine-2-carboxamides, having the structure shown in Formula (V) below:
  • Formula (V) and pharmaceutically acceptable salts and tautomers thereof wherein: L is Ci_ 6 alkyl; and wherein R 1 and R 2 are independently H or Ci_ 6 alkyl.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is ⁇ [5 -(3 -chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino ⁇ acetic acid (Compound 1):
  • Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the HIF stabilizer is Compound 2 having the structure:
  • Compound 2 or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the HIF stabilizer is Compound 3 having a structure
  • the HIF stabilizer is Compound 4 having a structure
  • the HIF stabilizer is Compound 5 having the structure
  • Compound 5 or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the HIF stabilizer is Compound 6 having the structure
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is Compound 7 having the structure:
  • the HIF stabilizer is Compound 8 having the structure:
  • Compound 8 or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the HIF stabilizer is Compound 9 having a structure
  • BOI-38503vl or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the HIF stabilizer is Compound 10 having a structure
  • the HIF stabilizer is Compound 11 having the structure
  • the HIF stabilizer is Compound 12 having the structure
  • Compound 12 or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the HIF stabilizer is Compound 13 having the structure
  • Tautomers of Compound 13 include the following:
  • a metabolite of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, or Compound 13 can be used with the methods provided herein.
  • such a metabolite is a phenolic glucuronide or an acyl-glucuronide.
  • Compound 13 can be prepared using reagents and methods known in the art, including the methods provided in Chinese Patent Application Publication No. CN 85107182 A, published on April 8, 1987, and German Patent Application Publication No. DE 3530046 Al, published on March 13, 1986, the entire contents of each of which are incorporated herein by reference.
  • a method for treating and/or preventing anemia comprising administering to a patient having anemia an effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer, such as a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein a daily dose comprises about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • the daily dose is 2mg/kg, 2.1mg/kg, 2.2mg/kg, 2.3mg/kg, 2.4mg/kg, 2.5mg/kg, 2.6mg/kg, 2.7mg/kg, 2.8mg/kg, 2.9mg/kg, 3mg/kg, 3.1mg/kg, 3.2mg/kg, 3.3mg/kg, 3.4mg/kg, 3.5mg/kg, 3.6mg/kg, 3.7mg/kg, 3.8mg/kg, 3.9mg/kg, or 4mg/kg.
  • a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer such as a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for use in a method of treating anemia, such as anemia secondary to chronic kidney disease, comprising administering the HIF prolyl hydroxylase inhibitor of HIF-alpha stabilizer at a daily dose of about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about
  • BOI-38503vl 240 mg about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 600 mg, or about 750 mg of the compound, pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • the daily dose is 2mg/kg, 2.1mg/kg, 2.2mg/kg, 2.3mg/kg, 2.4mg/kg, 2.5mg/kg, 2.6mg/kg, 2.7mg/kg, 2.8mg/kg, 2.9mg/kg, 3mg/kg, 3.1mg/kg, 3.2mg/kg, 3.3mg/kg, 3.4mg/kg, 3.5mg/kg, 3.6mg/kg, 3.7mg/kg, 3.8mg/kg, 3.9mg/kg, or 4mg/kg.
  • the compound is 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In certain embodiments, the compound is a pharmaceutically acceptable salt of 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid. In certain embodiments, the compound is a solvate of 2-(5-(3- fluorophenyl)-3-hydroxypicolinamido)acetic acid. In certain embodiments, the compound is a hydrate of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid.
  • the daily dose comprises about 150 mg, about 300 mg, about 450 mg, or about 600 mg of the compound, pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the daily dose comprises about 150 mg. In certain embodiments, the daily dose comprises about 300 mg. In certain embodiments, the daily dose comprises about 450 mg. In certain embodiments, the daily dose comprises about 600 mg.
  • BOI-38503vl been previously treated for anemia, such as anemia secondary to chronic kidney disease.
  • the patient is refractory to treatment with recombinant erythropoietin.
  • the daily dose is administered continuously. In certain embodiments, the daily dose is administered indefinitely, such as for more than 42 consecutive days, or even more than 90 consecutive days. In certain alternative embodiments, the daily dose is administered for at least one week and up to 30 consecutive days, up to 35 consecutive days, or even up to 40 consecutive days. In certain embodiments, the daily dose is administered orally, once daily. In certain embodiments, the daily dose is administered orally as a divided dose administered twice daily. In certain embodiments, the daily dose is administered at a specific time of day. In even more specific embodiments, the daily dose is administered in the early afternoon.
  • administration of a compound provided herein results in an increase of the level of hemoglobin increases by at least about 0.1 g/dL, by at least about 0.2 g/dL, by at least about 0.3 g/dL, by at least about 0.4 g/dL, by at least about 0.5 g/dL, by at least about 0.6 g/dL, by at least about 0.7 g/dL, by at least about 0.8 g/dL, by at least about 0.9 g/dL, by at least about 1.0 g/dL, by at least about 1.1 g/dL, by at least about 1.2 g/dL, by at least about 1.3 g/dL, by at least about 1.4 g/dL, or by at least about 1.5 g/dL relative to a baseline hemoglobin level.
  • the compound is optionally administered in combination with another medicament.
  • the other medicament is an iron supplement,
  • BOI-38503vl such as ferrous sulfate, ferrous gluconate, or ferrous fumarate, which may be administered at least two hours following administration of the compound.
  • the iron supplement is administered in an amount such that ferritin is maintained at a level of between about 50 ng/mL and about 300 ng/mL.
  • the iron supplement is administered orally at a daily dose about 50 mg of elemental iron.
  • the iron supplement is administered on an as needed basis, whereas in certain alternative
  • the iron supplement is administered continuously and/or indefinitely.
  • the other medicament is an erythropoiesis stimulating agent (ESA), such as an erythropoietin mimetic.
  • ESA erythropoiesis stimulating agent
  • the other medicament is an rhEPO product, such as epoetin alfa, epoetin beta, darbepoetin, or peginesatide.
  • the ESA is administered as a rescue therapy, whereas in certain alternative embodiments, the ESA is administered continuously and/or indefinitely.
  • Compound 13 Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is adjusted during the course of treatment. Specifically, the treatment is monitored using routine tests such as for example blood pressure, hematocrit, hemoglobin levels, and/or red blood cell count. Depending on the result of these tests, the daily dose is adjusted, i.e., increased or decreased.
  • the daily dose is increased subsequently by about 50 mg, 100 mg, 150 mg, or 200 mg. In certain embodiments, the daily dose is decreased subsequently by about 50 mg, 100 mg, 150 mg, or 200 mg.
  • the compound is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the compound is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • anemia such as anemia secondary to chronic kidney disease
  • methods of treating anemia comprising administering to a patient having anemia a daily dose of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a
  • the hemoglobin level in the patient after an administration of the daily dose of the compound and then again a period of time later, wherein when the hemoglobin level in the patient is less than about 10.0 g/dL and the level of hemoglobin has decreased by less than about 0.5 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level in the patient is less than about 10.0 g/dL and the level of hemoglobin has changed by up to about 0.4 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level in the patient is between about 10.0 and about 10.9 g/dL and the level of hemoglobin has decreased by less than about 0.5 g/dL as compared to the level measured the period of time earlier; administering an adjusted daily dose of the compound that is 150 mg greater than the daily dose.
  • BOI-38503vl measured the period of time earlier; or when the hemoglobin level in the patient is between about 10.0 and about 10.9 g/dL and the level of hemoglobin has increased by greater than about 1.5 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level is between about 11.0 and about 12.2 g/dL and the level of hemoglobin has increased by between about 1.0 and about 1.4 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level is between about 12.3 and about 12.9 g/dL and the level of hemoglobin has decreased by up to about 0.4 g/dL or increased by up to about 0.4 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level in the patient is between about 12.3 and about 12.9 g/dL and the level of hemoglobin has increased by about 0.5 to about 0.9 g/dL as compared to the level measured the period of time earlier;
  • the daily dose of the compound is about 450 mg.
  • the compound is ⁇ [5 -(3 -chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino ⁇ acetic acid.
  • the compound is a pharmaceutically acceptable salt of ⁇ [5-(3- chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid.
  • the compound is a solvate of ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid.
  • the compound is a hydrate of ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-
  • the compound is 2-(5-(3-fluorophenyl)-
  • the compound is a
  • the compound is a solvate of 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid.
  • the compound is a hydrate of 2-(5-(3- fluorophenyl)-3-hydroxypicolinamido)acetic acid.
  • the period of time is from about one week to about eight weeks, such as from about two weeks to about seven weeks, about three weeks to about six weeks, or about four weeks.
  • BOI-38503vl a pharmaceutically acceptable salt, solvate, or hydrate thereof; measuring the hemoglobin level in the patient after an administration of the daily dose of the compound and then again a period of time later, wherein when the hemoglobin level in the patient is between about 11.0 and about 12.2 g/dL and the level of hemoglobin has increased by greater than about 1.5 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level in the patient is between about 12.3 and about 12.9 g/dL and the level of hemoglobin has increased by between about 1.0 and about 1.4 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level in the patient is between about 12.3 and about 12.9 g/dL and the level of hemoglobin has increased by greater than about 1.5 g/dL as compared to the level measured the period of time earlier; or administering an adjusted daily dose of the compound that is 300 mg less than the daily dose.
  • the compound is a hydrate of 2-(5-(3- fluorophenyl)-3-hydroxypicolinamido)acetic acid.
  • the period of time is from about one week to about eight weeks, such as from about two weeks to about seven weeks, about three weeks to about six weeks, or about four weeks.
  • the invention relates to a method for treating anemia, such as anemia secondary to chronic kidney disease, comprising administering to a patient having anemia a daily dose of a compound which is ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl] amino ⁇ acetic acid or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the daily dose is about 450 mg.
  • the chronic kidney disease is stage 3, 4, or 5 chronic kidney disease. In certain such embodiments, the chronic kidney disease is pre-dialysis chronic kidney disease. In certain embodiments, the patient has not been previously treated for anemia, such as anemia secondary to chronic kidney disease. In certain alternative embodiments, the patient has been previously treated for anemia, such as anemia secondary to chronic kidney disease.
  • the invention relates to a method of treating anemia, such as anemia secondary to chronic kidney disease, comprising administering to a patient having anemia a daily dose of a compound which is ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl] amino ⁇ acetic acid or a pharmaceutically acceptable salt, solvate, or hydrate thereof; measuring the hemoglobin level in the patient after an administration of the daily dose of the compound and then again a period of time later, wherein when the hemoglobin level in the patient is between about 11.0 and about 12.2 g/dL and the level of hemoglobin has increased by greater than about 1.5 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level in the patient is between about 12.3 and about 12.9 g/dL and the level of hemoglobin has increased by between about 1.0 and about 1.4 g/dL as compared to the level measured the period of time earlier; or when the hemoglobin level
  • Compound 1 a HIF prolyl hydroxylase inhibitor, was able to increase serum hemoglobin levels while serum EPO levels returned to approximately baseline levels within twenty- four hours after administration.
  • EPO erythropoietin
  • a disease or condition related to endogenous hemoglobin production such as anemia or anemia secondary to chronic kidney disease
  • a compound as disclosed herein such as Compound 1
  • Compound 1 so as to raise the level of hemoglobin relative to a baseline hemoglobin level in a patient, while simultaneously mimicking the diurnal variation of serum EPO levels in healthy individuals, and without significantly increasing the baseline level of serum erythropoietin (EPO).
  • kits for treating and/or preventing anemia in a subject comprises administering to the subject a pharmaceutically effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer, wherein the pharmaceutically effective amount is suitable to mimic the diurnal variation of serum
  • erythropoietin More specifically, administration of a pharmaceutically effective amount of a compound provided herein increases the trough levels of EPO mR A and/or EPO protein by about 0%, by at most 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or by at most 50% relative to the trough levels of EPO mRNA and/or EPO protein prior to the treatment and/or relative to trough levels of EPO mRNA and/or EPO protein in a subject without anemia, while at the same time increasing the peak levels of serum EPO during the circadian cycle by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, or at least 150% relative to the peak levels of serum EPO prior to treatment (or compared to a healthy, non-anemic subject).
  • the HIF prolyl hydroxylase inhibitor or the HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4,
  • the pharmaceutically effective amount is suitable to mimic the diurnal variation of serum erythropoietin without increasing serum erythropoietin above baseline levels, wherein the baseline levels is the diurnal baseline of EPO in a healthy volunteer without anemia.
  • EPO erythropoietin
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In a specific embodiment, the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain such embodiments, the cardiovascular side-effects and risk of thromboembolic events associated with administration of exogenous EPO are minimized.
  • administering is performed at a dose that increases the trough levels of EPO mRNA and/or EPO protein by about 0%, by at most 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or by at most 50% relative to the trough levels of EPO mRNA and/or EPO protein levels prior to the treatment and/or relative to trough levels of EPO mRNA and/or EPO protein in a subject without anemia, while at the same time increasing the peak levels of EPO mRNA and/or EPO protein during the circadian cycle be at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100% relative to the peak levels of EPO mRNA and/or EPO protein prior to the
  • EPO erythropoietin
  • BOI-38503vl a healthy volunteer without anemia.
  • the diurnal cycle is mimicked but the amplitude of the daily variation of serum EPO levels is increased.
  • EPO levels are increased by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or at least 95%), or 100%) during the peak period but the trough levels are not significantly increased.
  • the level of serum EPO returns to about baseline level within about one week, about six days, about five days, about four days, about three days, about two days, about twenty four hours, about eighteen hours, or about twelve hours of administering a dose of the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer.
  • the level of serum EPO returns to within about 5 mlU/mL, about 4 mlU/mL, about 3 mlU/mL, about 2 mlU/mL, or about 1 mlU/mL of the baseline level of EPO.
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of two weeks relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.1 g/dL over a period of two weeks relative to the baseline hemoglobin level.
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of three weeks relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.5 g/dL over a period of three weeks relative to the baseline hemoglobin level.
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of four weeks relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.6 g/dL over a period of four weeks relative to the baseline hemoglobin level.
  • the anemia is anemia secondary to chronic kidney disease (CKD).
  • the chronic kidney disease is stage 3, 4, or 5 chronic kidney disease.
  • the chronic kidney disease is pre-dialysis chronic kidney disease.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is administered once daily. In certain embodiments, the HIF prolyl hydroxylase inhibitor or HIF- alpha stabilizer is administered orally.
  • erythropoietin erythropoietin
  • methods for treating a disease or condition related to diminished endogenous production of erythropoietin comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the level of hemoglobin relative to a baseline hemoglobin level in a patient, wherein the time period between the administration of at least one of said successive doses and the administration of the immediately preceding dose is a sufficient time period to permit the level of serum EPO in a patient to return to about baseline serum EPO level.
  • erythropoietin EPO
  • the HIF prolyl hydroxylase inhibitor or the HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a
  • the HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. . In even more specific
  • the level of serum EPO returns to about baseline level within about one week, about six days, about five days, about four days, about three days, about two days, about twenty four hours, about eighteen hours, or about twelve hours of administering a dose of the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer.
  • the level of serum EPO returns to within about 5 mlU/mL, about 4 mlU/mL, about 3 mlU/mL, about 2 mlU/mL, or about 1 mlU/mL of the baseline level of
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of one week relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.1 g/dL over a period of one week relative to the baseline hemoglobin level.
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of two weeks relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.1 g/dL over a period of two weeks relative to the baseline hemoglobin level.
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of three weeks relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.5 g/dL over a period of three weeks relative to the baseline hemoglobin level.
  • the disease or condition is anemia. In certain such embodiments, the disease or condition is anemia.
  • the anemia is anemia secondary to chronic kidney disease (CKD).
  • the chronic kidney disease is stage 3, 4, or 5 chronic kidney disease.
  • the chronic kidney disease is pre-dialysis chronic kidney disease.
  • kits for treating a disease or condition related to diminished endogenous production of erythropoietin comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the level of hemoglobin relative to a baseline hemoglobin level in a patient, wherein prior to the addition of one or more doses following the initial dose the level of serum EPO returns to about a baseline level.
  • the HIF prolyl hydroxylase inhibitor or the HIF-alpha stabilizer is a compound having a structure of
  • the level of serum EPO returns to about baseline level within about one week, about six days, about five days, about four days, about three days, about two days, about twenty four hours, about eighteen hours, or about twelve hours of administering a dose of the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer.
  • the level of serum EPO returns to within about 5 mlU/mL, about 4 mlU/mL, about 3 mlU/mL, about 2 mlU/mL, or about 1 mlU/mL of the baseline level of
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of one week relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.1 g/dL over a period of one week relative to the baseline hemoglobin level.
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of three weeks relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.5 g/dL over a period of three weeks relative to the baseline hemoglobin level.
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of four weeks relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.6 g/dL over a period of four weeks relative to the baseline hemoglobin level.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is administered once daily. In certain embodiments, the HIF prolyl hydroxylase inhibitor or HIF- alpha stabilizer is administered orally.
  • erythropoietin EPO
  • methods for treating a disease or condition related to diminished endogenous production of erythropoietin comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the level of hemoglobin relative to a baseline hemoglobin level in a patient without significantly increasing the level of serum EPO relative to the baseline level of serum EPO, wherein the HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,
  • the compound is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the level of serum EPO returns to about baseline level within about one week, about six days, about five days, about four days, about three days, about two days, about twenty four hours, about eighteen hours, or about twelve hours of administering a dose of the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer.
  • the level of serum EPO returns to within about 5 mlU/mL, about 4 mlU/mL, about 3 mlU/mL, about 2 mlU/mL, or about 1 mlU/mL of the baseline level of EPO.
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of one week relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.1 g/dL over a period of one week relative to the baseline hemoglobin level.
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of two weeks relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.1 g/dL over a period of two weeks relative to the baseline hemoglobin level.
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of three weeks relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.5 g/dL over a period of three weeks relative to the baseline hemoglobin level.
  • the level of hemoglobin is raised by between about 0.1 and about 1.0 g/dL over a period of four weeks relative to the baseline hemoglobin level. In certain such embodiments, the level of hemoglobin is raised by about 0.6 g/dL over a period of four weeks relative to the baseline hemoglobin level.
  • the disease or condition is anemia. In certain such embodiments, the disease or condition is anemia.
  • EPO erythropoietin
  • Serum EPO levels may be determined, for example using in vivo bioassays, in vitro bioassays and immunological assays.
  • the serum EPO levels described herein are determined using an immunological assay, such as an ELISA assay.
  • the provided herein is a method of treating a disease or condition related to diminished endogenous production of erythropoietin (EPO) or a disease or condition related to diminished production of hemoglobin, comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the level of hemoglobin relative to a baseline hemoglobin level in a patient, while mimicking the diurnal variation of serum EPO levels in healthy individuals.
  • EPO erythropoietin
  • provided herein is a method of treating a disease or condition related to diminished endogenous production of erythropoietin (EPO) or a disease or condition related to diminished production of hemoglobin while minimizing the cardiovascular side-effects and risk of thromboembolic events associated with administration of exogenous EPO.
  • EPO erythropoietin
  • the compound is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • erythropoietin EPO
  • a disease or condition related to diminished production of hemoglobin comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the level of hemoglobin relative to a baseline hemoglobin level in a patient, wherein the time period between the administration of at least one of said successive doses and the administration of the immediately preceding dose is a sufficient time period to permit the level of serum EPO in a patient to return to about baseline serum EPO level.
  • EPO erythropoietin
  • BOI-38503vl Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • kits for treating a disease or condition related to diminished endogenous production of erythropoietin (EPO) or a disease or condition related to diminished production of hemoglobin comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the level of hemoglobin relative to a baseline hemoglobin level in a patient, wherein prior to the addition of one or more doses following the initial dose the level of serum EPO returns to about a baseline level.
  • erythropoietin EPO
  • a disease or condition related to diminished production of hemoglobin comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the level of hemoglobin relative to a baseline hemoglobin level in a patient without significantly increasing the level of serum EPO relative to the baseline level of serum EPO.
  • erythropoietin EPO
  • a disease or condition related to diminished endogenous production of erythropoietin EPO
  • a disease or condition related to diminished production of hemoglobin while minimizing the cardiovascular side-effects and risk of thromboembolic events associated with administration of exogenous EPO.
  • the compound is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the level of serum EPO returns to about baseline level within one week, within six days, within five days, within four days within three days, within two days, within twenty four hours, within eighteen hours, or within twelve hours of administering a dose of the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer.
  • the level of serum EPO returns to within about 5 mlU/mL, about 4 mlU/mL, about 3 mlU/mL, about 2 mlU/mL, or about 1 mlU/mL of the baseline level of EPO.
  • the level of hemoglobin is raised by between about 0.1 and 1.0 g/dL, between about 0.1 and about 0.9 g/dL, about 0.1 and about 0.8 g/dL, about 0.1 and about 0.7 g/dL, about 0.1 and about 0.6 g/dL, or about 0.1 and about 0.5 g/dL over a period of time, such as about one week, about two weeks, about three weeks, or about four weeks, relative to the baseline hemoglobin level.
  • anemia e.g. , anemia secondary to or associated with chronic kidney disease, anemia secondary to chronic heart disease, idiopathic anemia of aging, anemia of chronic disease, myelodysplasia
  • BOI-38503vl syndrome bone marrow fibrosis, other aplastic or dysplastic anemias, chemotherapy induced anemia (including chemotherapy for treating cancer, hepatitis C, or other chronic drug therapy that reduces bone marrow production), anemia resulting from blood loss, anemia resulting from iron deficiency, anemia resulting from vitamin B 12 deficiency, sickle cell disease, or
  • thalassemia comprising administering to a patient having anemia an effective amount of a compound disclosed herein, such as Compound 1, wherein the diurnal pattern of EPO expression is mimicked in the patient in response to said administration as described above.
  • methods of treating anemia such as anemia secondary to chronic kidney disease, comprising administering to a patient having anemia an effective amount of a compound disclosed herein, such as Compound 1, wherein the diurnal pattern of EPO expression is mimicked in the patient in response to said administration as described above.
  • anemia secondary to chronic kidney disease comprising administering to a patient having anemia secondary to CKD an effective amount of a compound disclosed herein, such as Compound 1.
  • Such daily doses may be administered orally, preferably once daily.
  • the daily dose is administered once daily.
  • the CKD is stage 1, 2, 3, 4, or 5 chronic kidney disease.
  • the CKD is stage 3, 4, or 5 chronic kidney disease.
  • the CKD is stage 1 chronic kidney disease.
  • the CKD is stage 2 chronic kidney disease.
  • the CKD is stage 3 chronic kidney disease.
  • the CKD is stage 4 chronic kidney disease. In certain embodiments, the CKD is stage 5 chronic kidney disease. In certain embodiments, the chronic kidney disease is pre-dialysis chronic kidney disease. In certain embodiments, the patient is a dialysis patient and these patients may be referred to as having end stage renal disease (ESRD).
  • the anemia such as anemia secondary to CKD or ESRD may be refractory to treatment with an erythropoiesis stimulating agent, including a rhEPO product, such as, epoetin alfa, epoetin beta, darbepoetin, or peginesatide.
  • the patient has been previously treated for anemia, while in certain alternative embodiments, the patient has not previously been treated for anemia.
  • the patient is a patient having chronic kidney disease. In certain more specific embodiments, the patient does not have endogenous EPO circadian circulation expression patterns.
  • the compound ie, a compound dislcosed in
  • Phase 2a clinical trials showed that, in stage 3, 4, or 5 CKD patients, Compound 1, a HIF prolyl hydroxylase inhibitor, was able to increase TIBC levels, at 6 weeks post
  • a method of treating or preventing a disease or condition related to diminished endogenous production of erythropoietin comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a pharmaceutically effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer as disclosed herein, wherein the pharmaceutically effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is suitable to increase the total iron binding capacity in the patient by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50%.
  • EPO erythropoietin
  • the HIF prolyl hydroxylase inhibitor or the HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,
  • the HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the HIF prolyl hydroxylase inhibitor or a HIF- alpha stabilizer is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the pharmaceutically effective amount is suitable to increase the total iron binding capacity in the patient by at least 5%, 10%, 15%, 20%, 25%o, 30%), 35%), 40%), 45%, or at least 50%> while the total serum iron levels are not increased, or are increased by at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or at most
  • a method of treating or preventing an anemia in a patient comprising administering to the patient having anemia a pharmaceutically effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer as disclosed herein, wherein the pharmaceutically effective amount of a HIF prolyl hydroxylase inhibitor or a HIF- alpha stabilizer is suitable to increase the total iron binding capacity in the patient by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50%.
  • the pharmaceutically effective amount is suitable to increase the total iron binding capacity in the patient by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50% while the total serum iron levels are not increased, or are increased by at most 1%>, 2%>, 3%>, 4%>, 5%>, 6%>, 7%, 8%, 9%, 10%, 15%, 20%, or at most 25%.
  • the HIF prolyl hydroxylase inhibitor or the HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the anemia is, e.g., anemia secondary to or associated with chronic kidney disease, anemia secondary to chronic heart disease, idiopathic anemia of aging, anemia of chronic disease, myelodysplastic syndrome, bone marrow fibrosis, other aplastic or
  • BOI-38503vl dysplastic anemias include chemotherapy induced anemia (including chemotherapy for treating cancer, hepatitis C, or other chronic drug therapy that reduces bone marrow production), anemia resulting from blood loss, anemia resulting from iron deficiency, anemia resulting from vitamin B12 deficiency, sickle cell disease, or thalassemia.
  • the CKD is stage 5 chronic kidney disease.
  • the chronic kidney disease is pre-dialysis chronic kidney disease.
  • the patient is a dialysis patient and these patients may be referred to as having end stage renal disease (ESRD).
  • ESRD end stage renal disease
  • the anemia such as anemia secondary to CKD or ESRD may be refractory to treatment with an erythropoiesis stimulating agent, including a rhEPO product, such as, epoetin alfa, epoetin beta, darbepoetin, or peginesatide.
  • the patient has been previously treated for anemia, while in certain alternative embodiments, the patient has not previously been treated for anemia.
  • the disease or condition related to diminished endogenous EPO production is anemia, such as anemia secondary to chronic kidney disease.
  • the disease or condition that is treatable by increasing endogenous EPO production is anemia, such as anemia secondary to chronic kidney disease.
  • a method of treating or preventing a disease or condition related to diminished endogenous hemoglobin production in a patient comprising administering to the patient having disease or condition related to diminished endogenous hemoglobin production a pharmaceutically effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer as disclosed herein, wherein the pharmaceutically effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is suitable to increase the total iron binding capacity in the patient by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
  • the pharmaceutically effective amount is suitable to increase the total iron binding capacity in the patient by at least 5%, 10%, 15%, 20%, 25%o, 30%), 35%), 40%), 45%, or at least 50%> while the total serum iron levels are not increased, or are increased by at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or at most 25%.
  • the HIF prolyl hydroxylase inhibitor or the HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,
  • the HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the HIF prolyl hydroxylase inhibitor or a HIF- alpha stabilizer is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • a method of treating a disease or condition that is treatable by increasing endogenous hemoglobin production comprising administering to a patient having a disease or condition that is treatable by increasing endogenous hemoglobin production, a pharmaceutically effective amount of a HIF prolyl hydroxylase inhibitor or a HIF- alpha stabilizer as disclosed herein, wherein the pharmaceutically effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is suitable to increase the total iron binding capacity in the patient by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50%.
  • the pharmaceutically effective amount is suitable to increase the total iron binding capacity in the patient by at least 5%, 10%>, 15%, 20%>, 25%, 30%>, 35%), 40%), 45%), or at least 50%> while the total serum iron levels are not increased, or are increased by at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or at most 25%.
  • the HIF prolyl hydroxylase inhibitor or the HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,
  • the HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is Compound 1 or a pharmaceutically acceptable
  • the HIF prolyl hydroxylase inhibitor or a HIF- alpha stabilizer is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the disease or condition related to diminished endogenous hemoglobin production is anemia, such as anemia secondary to chronic kidney disease.
  • the disease or condition that may be treated by increasing endogenous hemoglobin production is anemia, such as anemia secondary to chronic kidney disease.
  • serum iron may be determined using a test based on the FerroZine method without deproteinization. Specimens are analyzed on the Roche Modular Instrument utilizing Roche Diagnostics Reagents. Under acidic conditions, iron is liberated from transferrin. The detergent clarifies lipemic samples. Ascorbate reduces the released Fe3+ ions to Fe2+ ions, which then react with FerroZine to form a colored complex. The color intensity is directly proportional to the iron concentration and can be measured photometrically.
  • unsaturated iron binding capacity may be determined by adding serum to an alkaline buffer/reductant solution containing a known concentration of iron to saturate the available binding sites on transferrin.
  • the Ferrozine chromogen reacts only with the Fe 2 +; therefore, an iron reductant is added to insure that all iron is present in the ferrous state.
  • the excess unbound divalent iron reacts with Ferrozine chromogen to form a magenta complex, which is measure spectrophotometrically.
  • the unsaturated iron binding capacity (UIBC) is equal to the difference measured in the concentrations of the added iron solution and the excess unbound iron.
  • Serum TIBC is equal to total serum iron plus UIBC and may therefore be calculated using the results of the UIBC and serum iron determinations.
  • Total iron binding capacity is a measure of the blood's capacity to bind iron with transferrin and is performed by drawing blood and measuring the maximum amount of iron that the blood can carry. Accordingly, the TIBC is representative of the amount of circulating transferrin, which contains two binding sites for transporting iron from iron storage sites to erythroid progenitor cells.
  • Serum iron level measurements determine how much iron is in the plasma. The amount of iron that is found in serum is dependent on the ability to mobilize the iron that is stored in cells. This process of iron mobilization is controlled by ferroportin and hepcidin which work in concert to regulate the amount of iron that is exported to the plasma. Ferroportin moves iron in and out of cells, while hepcidin regulates the action of ferroportin, thereby determining whether
  • BOI-38503vl iron is released into the plasma or retained in the cell. Accordingly, it is possible to have large amounts of iron stored in cells, but relatively low levels of serum iron depending on the activity of ferroportin and hepcidin.
  • a method of treating a disease or condition related to diminished endogenous production of erythropoietin (EPO), comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO, a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the TIBC relative to a baseline TIBC in a patient, without significantly increasing the serum iron level relative to a baseline.
  • provided herein are methods of treating a disease or condition related to diminished endogenous production of EPO while minimizing the cardiovascular side-effects and risk of thromboembolic events associated with increased serum iron levels.
  • the disease or condition is anemia, such as anemia secondary to chronic kidney disease.
  • a method of treating a disease or condition that is treatable by increasing endogenous erythropoietin (EPO) production comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO that is treatable by increasing endogenous EPO production, a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the TIBC relative to a baseline TIBC in a patient, without significantly increasing the serum iron level relative to a baseline.
  • EPO erythropoietin
  • provided herein are methods of treating a disease or condition that is treatable by increasing endogenous production of EPO while minimizing the cardiovascular side-effects and risk of thromboembolic events associated with increased serum iron levels.
  • the disease or condition is anemia, such as anemia secondary to chronic kidney disease.
  • the TIBC increases by about 10 ⁇ g/dL, about 20 ⁇ g/dL, about 30 ⁇ g/dL, about 40 ⁇ g/dL, about 50 ⁇ g/dL about 60 ⁇ g/dL, about 70 ⁇ g/dL, about 80 ⁇ g/dL, about 90 ⁇ g/dL or about 100 ⁇ g/dL relative to a baseline TIBC.
  • the TIBC increases by at least about 10 ⁇ g/dL, at least about 20 ⁇ g/dL, at least about 30 ⁇ g/dL, at least about 40 ⁇ g/dL, at least about 50 ⁇ g/dL, at least about 60 ⁇ g/dL, at least about 70 ⁇ g/dL, at least about 80 ⁇ g/dL, at least about 90 ⁇ g/dL or at least about 100 ⁇ g/dL.
  • the TIBC increases by between about 10 ⁇ g/dL and about 60 ⁇ g/dL, between
  • BOI-38503vl about 10 ⁇ g/dL and about 50 ⁇ /dL, between about 10 ⁇ /dL and about 40 ⁇ /dL, between about 10 ⁇ /dL and about 30 ⁇ /dL, or between about 10 ⁇ /dL and about 20 ⁇ g/dL.
  • the TIBC increases by between 20 ⁇ /dL and about 60 ⁇ /dL, between about 30 ⁇ g/dL and about 60 ⁇ /dL, between 40 ⁇ /dL and about 60 ⁇ /dL, or between about 50 ⁇ /dL and about 60 ⁇ g/dL.
  • the TIBC increase occurs over about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks relative to a baseline TIBC.
  • the serum iron level increases by less than about 20 ⁇ /dL, less than about 15 ⁇ /dL, less than about 10 ⁇ /dL, or less than about 5 ⁇ /dL relative to a baseline serum iron level. In certain embodiments, the serum iron level increases by between about 0 ⁇ g/dL and about 20 ⁇ /dL, between about 0 ⁇ /dL and about 15 ⁇ /dL, between about 0 ⁇ /dL and about 10 ⁇ /dL, or between about 0 ⁇ /dL and about 5 ⁇ g/dL.
  • Phase 2a clinical trials showed that, in stage 3, 4, or 5 CKD patients, Compound 1 , a HIF prolyl hydroxylase inhibitor, was able to increase serum hemoglobin levels, at 6 weeks post administration as compared to baseline and compared to placebo treated patients. Unexpectedly, the increase in hemoglobin levels was not associated with a decrease in hepcidin levels.
  • erythropoietin erythropoietin
  • methods of treating or preventing a disease or condition related to diminished endogenous production of erythropoietin (EPO) comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a pharmaceutically effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer, wherein the pharmaceutically effective amount is suitable to increase the peak levels of serum EPO during the circadian cycle by at least 10%, 15%, 20%>, 25%, 30%>, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 1 10%, 120%, 130%), 140%), or at least 150% relative to the trough levels of serum EPO without decreasing the serum levels of hepcidin by more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1%,
  • BOI-38503vl having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4,
  • kits for treating or preventing a disease or condition that is treatable by increasing endogenous production of erythropoietin (EPO), comprising administering to a patient having a disease or condition that is treatable by increasing endogenous production of EPO a pharmaceutically effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer, wherein the pharmaceutically effective amount is suitable to increase the peak levels of serum EPO during the circadian cycle by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, or at least 150% relative to the trough levels of serum EPO without decreasing the serum levels of hepcidin by more than 1%>, 2%>, 3%>, 4%>, 5%>, 6%>, 7%>, 8%>, 9%>,
  • the disease or condition that is treatable by increasing endogenous EPO production is anemia, such as non-severe anemia secondary to chronic kidney disease, non- severe anemia secondary to congestive heart failure, and idiopathic anemia of aging.
  • kits for treating or preventing a disease or condition related to endogenous hemoglobin production comprising administering to a patient having disease or condition related to endogenous hemoglobin production a pharmaceutically effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer, wherein the pharmaceutically effective amount is suitable to increase the peak levels of hemoglobin levels by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, or at least 20%, relative to hepcidin levels prior to the treatment without decreasing the serum levels of hepcidin by more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or by more than 20% relative to hepcidin levels prior
  • the HIF prolyl hydroxylase inhibitor or the HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4,
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the disease or condition that relates to diminished endogenous hemoglobin production is anemia, such as non-severe anemia secondary to chronic kidney disease, non- severe anemia secondary to congestive heart failure, and idiopathic anemia of aging.
  • kits for treating or preventing a disease or condition that is treatable by increasing endogenous hemoglobin production comprising administering to a patient having disease or condition that is treatable by increasing endogenous hemoglobin production a pharmaceutically effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer, wherein the pharmaceutically effective amount is suitable to increase the peak levels of hemoglobin levels by at least 2%>, 3%>, 4%>, 5%>, 6%>, 7%>, 8%>, 9%>,
  • BOI-38503vl 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, or at least 20%, relative to hepcidin levels prior to the treatment without decreasing the serum levels of hepcidin by more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or by more than 20% relative to hepcidin levels prior to administration of the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer.
  • the HIF prolyl hydroxylase inhibitor or the HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II),
  • HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the disease or condition that is treatable by increasing endogenous EPO production is anemia, such as non-severe anemia secondary to chronic kidney disease, non-severe anemia secondary to congestive heart failure, and idiopathic anemia of aging.
  • kits for treating or preventing an anemia in a patient comprising administering to the patient having the anemia a
  • a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer wherein the pharmaceutically effective amount is suitable to increase the peak levels of hemoglobin levels by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%), 15%), 16%), 17%), 18%), or at least 20%>, relative to hepcidin levels prior to the treatment without decreasing the serum levels of hepcidin by more than 1%>, 2%>, 3%>, 4%>, 5%>, 6%>, 7%>, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or by more than 20% relative to hepcidin levels prior to administration of the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer.
  • the HIF prolyl hydroxylase inhibitor or the HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the disease or condition that is treatable by increasing endogenous EPO production is anemia, such as non-severe anemia secondary to chronic kidney disease (CKD), non-severe anemia secondary to congestive heart failure, and idiopathic anemia of aging.
  • CKD chronic kidney disease
  • idiopathic anemia of aging idiopathic anemia of aging.
  • the anemia is, e.g., anemia secondary to or associated with chronic kidney disease, anemia secondary to chronic heart disease, idiopathic anemia of aging, anemia of chronic disease, myelodysplasia syndrome, bone marrow fibrosis, other aplastic or dysplastic anemias, chemotherapy induced anemia (including chemotherapy for treating cancer, hepatitis C, or other chronic drug therapy that reduces bone marrow production), anemia resulting from blood loss, anemia resulting from iron deficiency, anemia resulting from vitamin B 12 deficiency, sickle cell disease, or thalassemia).
  • chemotherapy induced anemia including chemotherapy for treating cancer, hepatitis C, or other chronic drug therapy that reduces bone marrow production
  • anemia resulting from blood loss anemia resulting from iron deficiency
  • anemia resulting from vitamin B 12 deficiency anemia resulting from vitamin B 12 deficiency
  • sickle cell disease or thalassemia
  • such daily doses may be administered orally, preferably once daily. In certain embodiments, the daily dose is administered once daily. In certain embodiments,
  • the anemia such as anemia secondary to CKD or ESRD may be refractory to treatment with an erythropoiesis stimulating agent, including a rhEPO product, such as, epoetin alfa, epoetin beta, darbepoetin, or peginesatide.
  • an erythropoiesis stimulating agent including a rhEPO product, such as, epoetin alfa, epoetin beta, darbepoetin, or peginesatide.
  • the patient has been previously treated for anemia, while in certain alternative embodiments, the patient has not previously been treated for anemia.
  • hepcidin expression may be determined, as described in Ganz, T. et al., "Immunoassay for human serum hepcidin” Blood 112: 4292-4297 (2008). Briefly, the
  • BOI-38503vl antibody to human hepcidin was purified on staphylococcal protein A columns according to the manufacturer's protocol; 96-well plates were coated with the antibody and incubated with 100 ⁇ , (standard samples) or 200 ⁇ , (samples with very low concentration of hepcidin) of 1 :20 dilution of serum or 1 : 10 dilution of urine in Tris-buffered saline containing 0.05% Tween-20 (TBS-Tween 20), with 10 ng/mL of biotinylated hepcidin-25 added as the tracer.
  • TBS-Tween 20 Tris-buffered saline containing 0.05% Tween-20
  • Standard curves were prepared by serial 2-fold dilution of synthetic hepcidin 4000 ng/mL in TBS-Tween 20 buffer containing the tracer. The integrity and bioactivity of synthetic hepcidin and biotinylated hepcidin were verified by mass spectrometry and by bioassay with ferroportin-green fluorescent protein expressing HEK-293 cells. After washing, the assay was developed with streptavidin-peroxidase and tetramethyl benzidine. The enzymatic reaction was stopped by sulfuric acid, and the plate was read at 450 nm on a DTX 880 microplate reader. Standard curves were fitted with 12-point fit using GraphPad Prism software. The fitted curve was then used to convert sample absorbance readings to hepcidin concentrations.
  • Serum hemoglobin levels may be determined, for example using standard approach CBC where red cells are lysed and potassium ferricyanide oxidizes hemoglobin to
  • methemoglobin which combines with potassium cyanide forming cyanmethemoglobin.
  • the brown color is measured spectrophotometrically and the corresponding hemoglobin reported.
  • kits for treating a disease or condition related to diminished endogenous production of erythropoietin comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO, a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the serum hemoglobin level relative to a baseline serum hemoglobin level, without significantly increasing hepcidin relative to a baseline level.
  • EPO erythropoietin
  • the disease or condition related to diminished endogenous EPO production is selected from non-severe anemia secondary to chronic kidney disease, non-severe anemia secondary to congestive heart failure, and idiopathic anemia of aging.
  • kits for treating a disease or condition that is treatable by increasing endogenous production of erythropoietin comprising administering to a patient having a disease or condition that is treatable by increasing EPO
  • the disease or condition is anemia, such as non- severe anemia secondary to chronic kidney disease, non-severe anemia secondary to congestive heart failure, or idiopathic anemia of aging.
  • the disease or condition that is treatable by increasing endogenous EPO production is selected from non-severe anemia secondary to chronic kidney disease, non-severe anemia secondary to congestive heart failure, and idiopathic anemia of aging.
  • the level of serum hemoglobin is raised by between about 0.1 and about 1.0 g/dL, between about 0.1 and about 0.9 g/dL, about 0.1 and about 0.8 g/dL, about 0.1 and about 0.7 g/dL, about 0.1 and about 0.6 g/dL, or about 0.1 and about 0.5 g/dL over a period of time, such as about one week, about two weeks, about three weeks, about four weeks, about five weeks, or about six weeks relative to the baseline hemoglobin level.
  • the level of hemoglobin is raised by at least about 0.1 g/dL, about 0.2 g/dL, about 0.3 g/dL, about 0.4 g/dL, about 0.5 g/dL, about 0.6 g/dL, about 0.7 g/dL, about 0.8 g/dL, about 0.9, or about 1.0 g/dL over a period of time, such as about one week, about two weeks, about three weeks, about four weeks, about five weeks, or about six weeks relative to the baseline hemoglobin level.
  • the level of hemoglobin is raised by about 0.1 g/dL over a period of one week relative to the baseline hemoglobin level. In certain embodiments, the level of hemoglobin is raised by about 0.1 g/dL over a period of two weeks relative to the baseline hemoglobin level. In certain embodiments, the level of hemoglobin is raised by about 0.5 g/dL over a period of three weeks relative to the baseline hemoglobin level. In certain embodiments, the level of hemoglobin is raised by about 0.6 g/dL over a period of four weeks relative to the baseline hemoglobin level.
  • the level of hemoglobin is raised by about 0.6 g/dL over a period of five weeks relative to the baseline hemoglobin level. In certain embodiments, the level of hemoglobin is raised by about 0.6 g/dL over a period of six weeks relative to the baseline hemoglobin level.
  • hepcidin expression decreases less than about 20%, less than about 15%), less than about 10%>, less than about 5%>, less than about 4%>, less than about 3%>, less than about 2%, or less than about 1% relative to the baseline hepcidin expression level. In certain embodiments, hepcidin expression decreases by between about 0%> and about 20%>,
  • BOI-38503vl between about 0% and about 15%, between about 0%> and about 10%>, or between about 0%> and about 5%>, between about 0%> and about 4%, between about 0%> and about 3%, between about 0%> and about 2%, or between about 0%> and about 1% relative to the baseline hepcidin expression level.
  • hepcidin expression decreases by about 20%, about 15%, about 10%), about 5%), about 4%, about 3%, about 2%, or about 1% relative to the baseline hepcidin expression level.
  • a method of treating a disease or condition selected from non-severe anemia secondary to chronic kidney disease, non-severe anemia secondary to congestive heart failure, and idiopathic anemia of aging comprising administering to a patient having non-severe anemia secondary to chronic kidney disease, non-severe anemia secondary to congestive heart failure, or idiopathic anemia of aging a sufficient number of successive doses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer so as to raise the serum hemoglobin levels relative to a baseline serum hemoglobin level in a patient, without significantly increasing erythroferrone expression relative to a baseline erythroferrone expression level.
  • the serum hemoglobin level is raised by between about 0.1 and about 1.0 g/dL over a period of one week relative to the baseline hemoglobin level. In certain such embodiments, the serum hemoglobin level is raised by about 0.1 g/dL over a period of one week relative to the baseline hemoglobin level.
  • the serum hemoglobin level is raised by between about 0.1 and about 1.0 g/dL over a period of two weeks relative to the baseline hemoglobin level. In certain such embodiments, the serum hemoglobin level is raised by about 0.1 g/dL over a period of two weeks relative to the baseline hemoglobin level.
  • the serum hemoglobin level is raised by between about 0.1 and about 1.0 g/dL over a period of three weeks relative to the baseline hemoglobin level. In certain such embodiments, the serum hemoglobin level is raised by about 0.5 g/dL over a period of three weeks relative to the baseline hemoglobin level.
  • the serum hemoglobin level is raised by between about 0.1 and about 1.0 g/dL over a period of four weeks relative to the baseline hemoglobin level.
  • the serum hemoglobin level is raised by about 0.6 g/dL over a period of four weeks relative to the baseline hemoglobin level.
  • the serum hemoglobin level is raised by between about 0.1 and about 1.0 g/dL over a period of five weeks relative to the baseline hemoglobin level. In certain such embodiments, the serum hemoglobin level is raised by about 0.6 g/dL over a period of five weeks relative to the baseline hemoglobin level.
  • the serum hemoglobin level is raised by between about 0.1 and about 1.0 g/dL over a period of six weeks relative to the baseline hemoglobin level. In certain such embodiments, the serum hemoglobin level is raised by about 0.6 g/dL over a period of six weeks relative to the baseline hemoglobin level.
  • erythroferrone transcription increases less than about 20%, less than about 15%, less than about 10% relative to the baseline erythroferrone transcription level, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% relative to the baseline erythroferrone transcription level, as measured by, for example, qRT-PCR of RNA (see SEQ ID NO: 3).
  • erythroferrone protein expression increases less than about 20%, less than about 15%, less than about 10% relative to the baseline erythroferrone expression level, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% relative to the baseline erythroferrone expression level, as measured by, for example, western blot of erythroferrone protein (see SEQ ID NO: 2).
  • the disease or condition is non-severe anemia secondary to chronic kidney disease. In certain embodiments, the disease or condition is non-severe congestive heart failure. In certain embodiments, the disease or condition is idiopathic anemia of aging.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is administered once daily. In certain embodiments, the HIF prolyl hydroxylase inhibitor or HIF- alpha stabilizer is administered orally.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is a heterocyclic carboxamide.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is selected from a pyridine carboxamide, a quinoline carboxamide, and an isoquinoline carboxamide.
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,
  • the HIF prolyl hydroxylase inhibitor or HIF-alpha stabilizer is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In a specific embodiment, the HIF prolyl
  • hydroxylase inhibitor or HIF-alpha stabilizer is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the present disclosures also relate to methods for treating and/or preventing and/or controlling, inter alia, Peripheral Vascular Disease (PVD); Coronary Artery Disease (CAD); heart failure; ischemia; anemia; wound healing; ulcers; ischemic ulcers; inadequate blood supply; poor capillary circulation; small artery atherosclerosis; venous stasis; atherosclerotic lesions (e.g., in coronary arteries); angina; myocardial infarction; diabetes; hypertension; Burgers disease; diseases associated with abnormal levels of VEGF, GAPDH, and/or EPO; Crohn's disease; ulcerative colitis; psoriasis; sarcoidosis; rheumatoid arthritis; hemangiomas; Osler- Weber-Rendu disease; hereditary hemorrhagic telangiectasia; solid or blood borne tumors and acquired immune deficiency syndrome; atrial arrhythmias; ischemic tissue damage
  • PVD Peripheral Vascular Disease
  • CAD Coronary Artery Disease
  • heart failure ischemia; anemia; wound healing; ulcers; ischemic ulcers; inadequate blood supply; poor capillary circulation; small artery atherosclerosis; venous stasis; atherosclerotic lesions (e.g., in coronary arteries); angina; myocardial infarction; diabetes; hypertension; Burgers disease; diseases associated with abnormal levels of VEGF, GAPDH, and/or EPO; Crohn's disease; ulcerative colitis; psoriasis; sarcoidosis; rheumatoid arthritis; hemangiomas; Osier- Weber-Rendu disease; hereditary hemorrhagic telangiectasia; solid or blood borne tumors and acquired immune deficiency
  • BOI-38503vl syndrome atrial arrhythmias; ischemic tissue damage in tissues such as: cardiac tissue, such as myocardium and cardiac ventricles, skeletal muscle, neurological tissue, such as from the cerebellum, internal organs, such as the stomach, intestine, pancreas, liver, spleen, and lung; and distal appendages such as fingers and toes, wherein the method comprises administering a pharmaceutically effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer, wherein the pharmaceutically effective amount is suitable to reduce the severity or frequency of at least one symptom of these diseases while:
  • Atherosclerotic PVD can present in three ways:
  • the present disclosures also relate to methods for regulating blood flow, oxygen delivery and/or energy utilization in ischemic tissues, wherein the methods can comprise administering to a human an effective amount of one or more compounds or pharmaceutically acceptable salts or tautomers thereof disclosed herein.
  • compositions effective as inhibitors of HIF prolyl hydroxylase thereby stimulating an angiogenic response in human tissue, thereby providing a method for increasing blood flow, oxygen delivery and energy utilization in ischemic tissues;
  • compositions effective as human protein HIF prolyl hydroxylase inhibitors and thereby increasing the concentration of HIF- 1 alpha leading to greater activation and sustaining the of various biological pathways that are the normal response to cellular hypoxia;
  • compositions effective in stimulating an EPO response in cells and thereby are provided.
  • BOI-38503vl enhancing the maintenance of red blood cells by controlling the proliferation and differentiation of erythroid progenitor cells into red blood cells
  • VEGF Vascular Endothelial Growth Factor
  • compositions that induce the production of soluble VEGF, an inhibitor of VEGF, in hypoxic cells thus increasing stimulus of important biological responses, inter alia, anti-angiogenic activities.
  • HIF prolyl hydroxylase inhibitors of the present disclosure which are capable of regulating blood flow, oxygen delivery and energy utilization in ischemic tissues that are caused by insufficient regulation of HIF prolyl hydroxylase.
  • HIF- 1 -alpha prolyl hydroxylase enzymes will have other positive medical effects on human tissue and the alleviation of symptoms and disease states other than those symptoms or diseases states that are specifically pointed out in the present disclosure.
  • these yet undisclosed or yet unknown conditions will be positively affected by compositions which stimulate the body own response to hypoxia and other low blood oxygen conditions.
  • kits for treating or preventing a disease or disorder ameliorated by modulation of HIF prolyl hydroxylase comprising administering to a patient having a disease ameliorated by modulation of HIF prolyl hydroxylase an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a
  • BOI-38503vl hydroxypicolinamido)acetic acid according to the dose and/or dosing regimen described herein.
  • the compound is administered from one to three, such as one, two or three times in the course of a 24 hour period.
  • provided herein are methods for treating or preventing a disease ameliorated by modulation of HIF prolyl hydroxylase comprising administering to a patient having a disease or disorder ameliorated by modulation of HIF prolyl hydroxylase an effective amount of ⁇ [5-(3-chlorophenyl)-3- hydroxypyridine-2-carbonyl]amino ⁇ acetic acid once daily.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of ⁇ [5- (3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid. In certain such embodiments,
  • kits for treating or preventing a disease ameliorated by modulation of HIF prolyl hydroxylase comprising administering to a patient having a disease or disorder ameliorated by modulation of HIF prolyl hydroxylase an effective amount of 2-(5-(3- fluorophenyl)-3-hydroxypicolinamido)acetic acid once daily.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 2- (5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • HIF prolyl hydroxylase e.g., PHDl , PHD2, and/or PHD3
  • administering comprising administering to a patient having a disease or disorder ameliorated by inhibiting HIF prolyl hydroxylase an effective amount of a compound having a structure of Formula (I),
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl] amino ⁇ acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3-
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • provided herein are methods of treating or preventing a disease or disorder ameliorated by inhibiting PHD1 , comprising administering to a patient having a disease or disorder ameliorated by inhibiting PHD 1 an effective amount of 5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl] amino ⁇ acetic acid according to the dose and/or dosing regimen described herein.
  • provided herein are methods of treating or preventing a disease or disorder ameliorated by inhibiting PHD 1 , comprising administering to a patient having a disease or disorder ameliorated by inhibiting PHD1 an effective amount of 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid according to the dose and/or dosing regimen described herein.
  • provided herein are methods of treating or preventing a disease or disorder ameliorated by inhibiting PHD2, comprising administering to a patient having a disease or disorder ameliorated by inhibiting PHD2 an effective amount of 5-(3-chlorophenyl)-3- hydroxypyridine-2-carbonyl] amino ⁇ acetic acid according to the dose and/or dosing regimen described herein. .
  • provided herein are methods of treating or preventing a disease or disorder ameliorated by inhibiting PHD2, comprising administering to a patient having a disease or disorder ameliorated by inhibiting PHD2 an effective amount of 2-(5- (3-fluorophenyl)-3-hydroxypicolinamido)acetic acid according to the dose and/or dosing regimen described herein.
  • provided herein are methods of treating or preventing a disease or disorder ameliorated by inhibiting PHD3, comprising administering to a patient having a disease or disorder ameliorated by inhibiting PHD3 an effective amount of 5- (3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid according to the dose and/or dosing regimen described herein.
  • provided herein are methods of treating or preventing a disease or disorder ameliorated by inhibiting PHD3, comprising administering to a patient having a disease or disorder ameliorated by inhibiting PHD3 an effective amount of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid according to the dose and/or dosing regimen described herein.
  • kits for treating or preventing a disease or disorder ameliorated by stabilizing HIF-alpha comprising administering to a patient having a disease or disorder ameliorated by
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl] amino ⁇ acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)- 3-hydroxypicolinamido)acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • methods of treating or preventing a disease or disorder ameliorated by stabilizing HIF- ⁇ comprising administering to a patient having a disease or disorder ameliorated by stabilizing HIF-1 -alpha an effective amount of 5-(3-chlorophenyl)-3- hydroxypyridine-2-carbonyl] amino ⁇ acetic acid according to the dose and/or dosing regimen described herein.
  • provided herein are methods of treating or preventing a disease or disorder ameliorated by stabilizing HIF-1 a, comprising administering to a patient having a disease or disorder ameliorated by stabilizing HIF-1 -alpha an effective amount of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid according to the dose and/or dosing regimen described herein.
  • provided herein are methods of treating or preventing a disease or disorder ameliorated by stabilizing HIF-2-alpha, comprising administering to a patient having a disease or disorder ameliorated by inhibiting HIF-2-alpha an effective amount of 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid according to the dose and/or dosing regimen described herein.
  • methods of treating or preventing a disease or disorder ameliorated by stabilizing HIF-2-alpha comprising administering to a patient having a disease or disorder
  • BOI-38503vl ameliorated by inhibiting HIF-2-alpha an effective amount of 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid according to the dose and/or dosing regimen described herein.
  • provided herein are methods of treating or preventing a disease or disorder ameliorated by stabilizing HIF-3-alpha, comprising administering to a patient having a disease or disorder ameliorated by stabilizing HIF-3 -alpha an effective amount of 5-(3- chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid according to the dose and/or dosing regimen described herein.
  • methods of treating or preventing a disease or disorder ameliorated by stabilizing HIF-3-alpha comprising administering to a patient having a disease or disorder ameliorated by stabilizing HIF-3 -alpha an effective amount of 5-(3- chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid according to the dose and/or dosing regimen described herein.
  • EPO erythropoietin
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl] amino ⁇ acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • anemia e.g. , anemia secondary to or associated with chronic kidney disease, anemia secondary to chronic heart disease, idiopathic anemia of aging, anemia of chronic disease, myelodysplasia
  • BOI-38503vl syndrome bone marrow fibrosis, other aplastic or dysplastic anemias, chemotherapy induced anemia (including chemotherapy for treating cancer, hepatitis C, or other chronic drug therapy that reduces bone marrow production), anemia resulting from blood loss, anemia resulting from iron deficiency, anemia resulting from vitamin B 12 deficiency, sickle cell disease, or
  • thalassemia comprising administering to a patient having anemia an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,
  • anemia such as anemia secondary to chronic kidney disease
  • methods of treating anemia comprising administering to a patient having anemia an effective amount of 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid.
  • anemia such as anemia secondary to chronic kidney disease
  • methods of treating anemia comprising administering to a patient having anemia an effective amount of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of ⁇ [5 -(3 -chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino ⁇ acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • CKD chronic kidney disease
  • administering comprising administering to a patient having anemia secondary to CKD an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily. In certain embodiments, the daily dose is administered once daily.
  • the CKD is stage 1, 2, 3, 4, or 5 chronic kidney disease. In certain such embodiments, the CKD is stage 3, 4, or 5 chronic kidney disease. In certain embodiments, the CKD is stage 1 chronic kidney disease.
  • the CKD is stage 2 chronic kidney disease. In certain embodiments, the CKD is stage 3 chronic kidney disease. In certain embodiments, the CKD is stage 4 chronic kidney disease. In certain embodiments, the CKD is stage 5 chronic kidney disease. In certain embodiments, the chronic kidney disease is pre- dialysis chronic kidney disease. In certain embodiments, the patient is a dialysis patient and these patients may be referred to as having end stage renal disease (ESRD).
  • ESRD end stage renal disease
  • the anemia such as anemia secondary to CKD or ESRD may be refractory to treatment with an erythropoiesis stimulating agent, including a rhEPO product, such as, epoetin alfa, epoetin beta, darbepoetin, or peginesatide.
  • an erythropoiesis stimulating agent including a rhEPO product, such as, epoetin alfa, epoetin beta, darbepoetin, or peginesatide.
  • the patient has been previously treated for anemia, while in certain alternative embodiments, the patient has not previously been treated for anemia.
  • angiogenesis-related disease or disorder comprising administering to a patient having angiogenesis-related disease or disorder an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12,
  • BOI-38503vl hydrate thereof (specifically, 5 -(3 -chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino ⁇ acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) according to the dose and/or dosing regimen described herein.
  • methods of regulating angiogenesis comprising administering to a patient an effective amount of 5-(3- chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid according to the dose and/or dosing regimen described herein.
  • kits for regulating angiogenesis comprising administering to a patient an effective amount of 2-(5-(3- fluorophenyl)-3-hydroxypicolinamido)acetic acid according to the dose and/or dosing regimen described herein.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl] amino ⁇ acetic acid.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • kits for treating or preventing disease or disorder affected by the level of VEGF or GAPDH comprising administering to a patient having a disease or disorder affected by the level of VEGF or GADPH an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • kits for promoting wound healing comprising administering to a patient having a wound an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of ⁇ [5- (3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of ⁇ [5- (3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • kits for enhancing the revascularization of damaged tissue or increasing vasculature comprising administering to a patient having damaged tissue an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, 5-(3- chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid) according to the dose and/or dosing regimen described herein.
  • provided herein are methods of vascularizing ischemic tissue, comprising administering to a patient having ischemic tissue an effective amount of 5-(3- chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid according to the dose and/or dosing regimen described herein. In certain embodiments, provided herein are methods of
  • BOI-38503vl vascularizing ischemic tissue comprising administering to a patient having ischemic tissue an effective amount of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid according to the dose and/or dosing regimen described herein.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of ⁇ [5-(3- chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • kits for promoting the growth of skin graft replacements comprising administering to a patient having a skin graft an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3,
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of ⁇ [5 -(3 -chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino ⁇ acetic acid.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • kits for promoting tissue repair in the context of guided tissue regeneration comprising administering to a patient an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a
  • BOI-38503vl pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, 5-(3-chlorophenyl)-3- hydroxypyridine-2-carbonyl]amino ⁇ acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid) according to the dose and/or dosing regimen described herein.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • a disease or disorder selected from diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, Eales' disease, Behcet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, trauma post-laser complications, diseases associated with rubeosis, and proliferative
  • BOI-38503vl about 450 mg, about 600 mg, or about 750 mg of ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl] amino ⁇ acetic acid.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer for the prevention and/or treatment of various diseases and disorders as described in Section 5.4, such as anemia (e.g., anemia secondary to chronic kidney disease).
  • This section provides several specific doses for such uses of a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer.
  • a dose is the initial dose at the beginning of a treatment.
  • such a dose is the adjusted dose at a later time during the course of treatment.
  • the HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the compound is Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • anemia such as anemia secondary to chronic kidney disease
  • methods for treating anemia comprising administering to a patient having anemia, a daily dose of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, ⁇ [5-(3- chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid) which is between about 100 mg and about 1,200 mg, about
  • BOI-38503vl 200 mg and about 1,000 mg, about 400 mg and about 800 mg, or about 450 mg and about 600 mg, or about 300 mg and about 600 mg.
  • pharmaceutically acceptable salt, solvate, or hydrate thereof is between about 150 mg and about 600 mg.
  • the daily dose of the compound is between about 150 mg and about 300 mg, about 300 and about 600 mg, or between about 600 mg and about 750 mg.
  • the daily dose is about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,050 mg, 1,100 mg, 1,150 mg, or even about 1,200 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, ⁇ [5- (3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid).
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. In certain embodiments, the daily dose is not 240 mg, 370 mg, 500 mg or 630 mg of Compound 1. In certain embodiments, the daily dose is
  • BOI-38503vl about 240 mg, 370 mg, 500 mg or about 630 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, ⁇ [5 -(3 -chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino ⁇ acetic acid or 2-(5-(3- fluorophenyl)-3 -hydroxypicolinamido)acetic acid) .
  • anemia such as anemia secondary to chronic kidney disease
  • methods for treating anemia comprising administering to a patient having anemia daily dose of a compound which is a compound having a structure of Formula (I),
  • a daily dose of about 450 mg comprises three unit dosage forms, such as three tablets, each comprising about
  • Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof may be decreased by about 300 mg, such that the daily dose of the compound is about 150 mg.
  • the daily dose may be increased or decreased by about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.
  • the daily dose may be increased or decreased by an amount between about 75 mg and 300 mg, about 100 mg and about 300 mg, about 125 mg and about 300 mg, about 150 mg and about 300 mg, about 175 mg and about 300
  • the daily dose may be increased or decreased by an amount between about 75 mg and about 250 mg, about 100 mg and about 225 mg, or about 125 mg and about 200 mg. In certain such embodiments, the daily dose does not exceed about 600 mg or about 750 mg.
  • anemia such as anemia secondary to chronic kidney disease
  • methods for treating anemia comprising administering to a patient having anemia an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound
  • a daily dose of the compound is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • anemia such as anemia secondary to chronic kidney disease
  • methods for treating anemia comprising administering to a patient having anemia an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, ⁇ [5-a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, ⁇ [5-
  • hemoglobin levels of a patient are maintained at a level of at least about 10.0 g/dL and at or below about 13.0 g/dL.
  • the hemoglobin levels are maintained at a level of at least about 11.0 g/dL and at or below about 13.0 g/dL.
  • the hemoglobin levels are maintained at a level of at least about 11.0 g/dL and at or below about 12.0 g/dL.
  • a daily dose of the compound is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • anemia such as anemia secondary to chronic kidney disease
  • methods for treating anemia comprising administering to a patient having anemia an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, ⁇ [5- (3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid), wherein level of hemoglobin of a patient are increased at least about 1.2 g/dL relative to a baseline hemoglobin level.
  • a daily dose of the compound is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • hemoglobin levels are monitored and the dose of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4,
  • pharmaceutically acceptable salt, solvate, or hydrate thereof may be adjusted based on the level of hemoglobin and/or the change in level of hemoglobin.
  • the dose may be adjusted by either increasing or reducing the amount of a compound having a structure of Formula (I), Formula (I), Formula (I), Formula (I), Formula (I), Formula (I), Formula (I), Formula (I), Formula (I), Formula (I), Formula (I), Formula (I), Formula (I), Formula (I), Formula (I), Formula (I), Formula (I), Formula
  • BOI-38503vl 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof may be increased after a period of time, beginning on the day a patient is given a daily dose of the compound.
  • the period of time is from about one week to about eight weeks, such as from about two weeks to about seven weeks, about three weeks to about six weeks, or about four weeks.
  • the period of time is from about one week to about eight weeks, such as from about two weeks to about seven weeks, about three weeks to about six weeks, or about four weeks
  • anemia such as anemia secondary to chronic kidney disease
  • administering to a patient having anemia a daily dose of a compound which is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13,
  • the compound is administered once daily and may be administered orally.
  • the daily dose is about 450 mg, such that when the daily dose is increased by about 150 mg, the adjusted daily dose is about 600 mg.
  • the period of time is from about one week to about eight weeks, such as from about two weeks to about seven weeks, about three weeks to about six weeks, or about four weeks.
  • the daily dose may be increased or decreased by about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.
  • the daily dose may be increased or decreased by an amount between about 75 mg and 300 mg, about 100 mg and about 300 mg, about 125 mg and about 300 mg, about 150 mg and about 300 mg, about 175 mg and about 300 mg, about 200 mg and about 300 mg, about 225 mg and about 300 mg, about 250 mg and about 300 mg, or about 275 mg and about 300 mg. In certain embodiments, the daily dose may be increased or decreased by an amount between about 75 mg and about 250 mg, about 100 mg and about 225 mg, or about 125 mg and about 200 mg. In certain embodiments, the adjusted daily dose does not exceed 600 mg or 750 mg.
  • anemia such as anemia secondary to chronic kidney disease
  • methods for treating anemia comprising administering to a patient having anemia a daily dose of a compound which is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from
  • the compound is administered once daily and may be administered orally.
  • the daily dose is about 450 mg, such that when the daily dose is decreased by about 150 mg, the adjusted daily dose is about 300 mg.
  • the period of time is from about one week to about eight weeks, such as from about two weeks to about seven weeks, about three weeks to about six weeks, or about four weeks.
  • the daily dose may be increased or decreased by about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.
  • the daily dose may be increased or decreased by an amount between about 75 mg and 300 mg, about 100 mg and about 300 mg, about 125 mg and about 300 mg, about 150 mg and about 300 mg, about 175 mg and about 300 mg, about 200 mg and about 300 mg, about 225 mg and about 300 mg, about 250 mg and about 300 mg, or about 275 mg and about 300 mg. In certain embodiments, the daily dose may be increased or decreased by an amount between about
  • BOI-38503vl 75 mg and about 250 mg, about 100 mg and about 225 mg, or about 125 mg and about 200 mg. In certain embodiments, the adjusted daily dose does not exceed 600 mg or 750 mg.
  • anemia such as anemia secondary to chronic kidney disease
  • methods of treating anemia comprising administering to a patient having anemia a daily dose of a compound which is a compound having a structure of Formula (I), Formula (II),
  • the compound is administered once daily and may be administered orally.
  • the daily dose is 450 mg, such that when the initial daily dose is decreased by about 300 mg, the adjusted daily dose is about 150 mg.
  • the period of time is from about one week to about eight weeks, such as from about two weeks to about seven weeks, about three weeks to about six weeks, or about four weeks.
  • the daily dose may be increased or decreased by about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.
  • the daily dose may be increased or decreased by an amount between about 75 mg and 300 mg, about 100 mg and about 300 mg, about 125 mg and about 300 mg, about 150 mg and about 300 mg, about 175 mg and about 300 mg, about 200 mg and about 300 mg, about 225 mg and about 300 mg, about 250 mg
  • the daily dose may be increased or decreased by an amount between about 75 mg and about 250 mg, about 100 mg and about 225 mg, or about 125 mg and about 200 mg. In certain embodiments, the adjusted daily dose does not exceed 600 mg or 750 mg.
  • kits for treating anemia related to CKD in a patient undergoing hemodialysis comprising administering to the patient a pharmaceutically effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 at about 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour, or at about between 7 hours to 8 hours, 6 hours to 7 hours, 5 hours to 6 hours, 4 hours to 5 hours, 3 hours to 4 hours, 2 hours to 3 hours, 1 hour to 2 hours, or up to about 1 hour prior to starting a hemodialysis session.
  • kits for treating anemia related to CKD in a patient undergoing hemodialysis comprising administering to the patient a pharmaceutically effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 at about 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour, or at about between 7 hours to 8 hours, 6 hours to 7 hours, 5 hours to 6 hours, 4 hours to 5 hours, 3 hours to 4 hours, 2 hours to 3 hours, 1 hour to 2 hours, or up to about 1 hour after completing a hemodialysis session.
  • a method provided herein further comprises a monitoring step wherein the serum concentration of a metabolite of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 is determined.
  • BOI-38503vl having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4,
  • Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 is determined.
  • the serum concentration of the phenolic-glucuronide and/or the acyl-glucuronide of Compound 1, i.e., Metabolite 1 or Metabolite 2 is determined.
  • the daily dose is adjusted in accordance with the serum concentration of the metabolite.
  • anemia such as anemia secondary to chronic kidney disease
  • administering a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,
  • Compound 12 Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl] amino ⁇ acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) in combination with another medicament.
  • Such combination therapy may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment.
  • a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer such as a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,
  • Compound 12 Compound 13, Metabolite 1, or Metabolite 2or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, compound disclosed herein, such as Compound 1), wherein the compound is administered continuously and/or indefinitely, and wherein the compound is administered with another medicament.
  • anemia such as anemia secondary to chronic kidney disease
  • administering a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,
  • Compound 12 Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl] amino ⁇ acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) to a patient having anemia, wherein the compound is optionally administered in combination with an iron supplement, such as ferrous sulfate, ferrous gluconate, or ferrous fumarate.
  • the iron supplement is administered at least one hour, at least two hours, at least three hours, at least four hours, or even at least six hours following administration of the compound.
  • the iron supplement is administered in an amount such that
  • BOI-38503vl ferritin is maintained at a level of between about 50 ng/mL and about 300 ng/mL.
  • the iron supplement is administered orally at a daily dose of at least about 50 mg of elemental iron.
  • the iron supplement is administered orally at a dose of about 50 mg of elemental iron.
  • the iron supplement is administered intravenously.
  • the iron supplement is administered continuously and/or indefinitely, such as for more than 42 consecutive days.
  • the iron supplement is administered on an as needed basis such that ferritin is maintained at a level of between about 50 ng/mL and about 300 ng/mL.
  • the daily dose of the compound is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3,
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • anemia such as anemia secondary to chronic kidney disease
  • administering a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11,
  • Compound 12 Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl] amino ⁇ acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) to a patient having anemia, wherein the compound is optionally administered in combination with an erythropoiesis stimulating agent (ESA), such as an erythropoietin mimetic.
  • ESA erythropoiesis stimulating agent
  • the ESA is an rfiEPO product, including, but not limited to, epoetin alfa, epoetin beta, darbepoetin, or peginesatide.
  • the ESA is administered as a rescue therapy. In certain alternative embodiments, the ESA is administered continuously and/or
  • the daily dose is of the compound is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • anemia such as anemia secondary to chronic kidney disease (CKD)
  • administering comprising administering to a patient having anemia an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound
  • the patient is at least 50 years old, at least 60 years old, at least 65 years old, at least 70 years old, or even at least 80 years old.
  • the patient is a geriatric patient. In certain embodiments, the patient is less than 18 years old.
  • the patient is a pediatric patient. In certain embodiment, the patient is at least 18 years old. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • anemia such as anemia secondary to chronic kidney disease (CKD)
  • administering to a patient having anemia an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, 5-(3- chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid) according to the dose and/or dosing regimen described herein, wherein, the patient is a member of a subpopulation selected from White, Hispanic, Black, and Asian.
  • the patient is a member of a subpopulation selected from male and female.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I),
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • anemia such as anemia secondary to chronic kidney disease (CKD)
  • administering comprising administering to a patient having anemia an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound
  • BOI-38503vl Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof specifically, 5-(3- chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid) according to the dose and/or dosing regimen described herein, wherein, the patient has an additional disease or condition selected from cancer, AIDS, congestive heart failure, left ventricular hypertrophy, diabetes, hypertension, dyslipidemia, chronic heart failure, stroke, fatigue, depression, and cognitive impairment, or any combination thereof.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, ⁇ [5- (3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid).
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • anemia such as anemia secondary to CKD
  • methods for treating anemia comprising administering to a patient having anemia an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a
  • the ESA is an rhEPO product, including, but not limited to, epoetin alfa, epoetin beta, darbepoetin, or peginesatide.
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • anemia such as anemia secondary to CKD
  • methods for treating anemia comprising administering to a patient having anemia an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I),
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • anemia such as anemia secondary to CKD
  • methods for treating anemia comprising administering to a patient having anemia an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3,
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • anemia such as anemia secondary to CKD
  • methods for treating anemia comprising administering to a patient having anemia an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I), Formula (II),
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • anemia such as anemia secondary to CKD
  • methods for treating anemia comprising administering to a patient having anemia an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.
  • Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • anemia such as anemia secondary to CKD
  • methods for treating anemia comprising administering to a patient having anemia an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound
  • BOI-38503vl 10 Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, 5-(3-chlorophenyl)-3- hydroxypyridine-2-carbonyl]amino ⁇ acetic acid or 2-(5-(3-fluorophenyl)-3- hydroxypicolinamido)acetic acid) according to the dose and/or dosing regimen described herein, wherein the patient has had a red blood cell transfusion within 11 weeks or 12 weeks of initiation of treatment with the compound. In certain alternative embodiments, the patient has not had a red blood cell transfusion within 11 weeks or 12 weeks of initiation of treatment with the compound. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound having a structure of Formula (I),
  • the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.
  • kits for treating non-severe anemia secondary to chronic kidney disease, non-severe anemia secondary to congestive heart failure, and idiopathic anemia of aging comprising administering to a patient having anemia daily dose a compound disclosed herein, such as Compound 1, wherein the compound is administered continuously and/or indefinitely.
  • kits for treating and/or preventing iron overload in a patient comprising administering to the patient an effective amount of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10,
  • said administering step is performed according to the dose and/or dosing regimen described herein.
  • compositions may be used in the preparation of individual, single unit dosage forms.
  • Pharmaceutical compositions and dosage forms provided herein comprise a compound as provided herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof ⁇ e.g., the parent compound).
  • Pharmaceutical compositions and dosage forms can further comprise one or more excipients.
  • compositions and dosage forms comprise one or more excipients.
  • excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient.
  • oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form.
  • the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water.
  • Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition. Consequently, provided are pharmaceutical compositions and dosage forms that contain little, if any, lactose other mono- or disaccharides.
  • lactose-free means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
  • Lactose-free compositions can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) 25 NF20 (2002).
  • lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
  • anhydrous pharmaceutical compositions and dosage forms since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%)
  • BOI-38503vl is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80.
  • water and heat accelerate the decomposition of some compounds.
  • the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
  • anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are, in one embodiment, packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients.
  • compositions that are suitable for oral administration can be provided as discrete dosage forms, such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids ⁇ e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's The Science and Practice of Pharmacy, 21st Ed.,
  • Oral dosage forms provided herein are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or
  • BOI-38503vl aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • oral dosage forms are tablets or capsules, in which case solid excipients are employed.
  • tablets can be coated by standard aqueous or non-aqueous techniques.
  • Such dosage forms can be prepared by any of the methods of pharmacy.
  • pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
  • Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101 , AVICEL-PH-103 AVICEL RC-581 , AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof.
  • a specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103TM and Starch 1500 LM.
  • Other suitable forms of microcrystalline cellulose include, but are not limited to, silicified microcrystalline cellulose,
  • BOI-38503vl such as the materials sold as PROSOLV 50, PROSOLV 90, PROSOLV HD90, PROSOLV 90 LM, and mixtures thereof.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • talc calcium carbonate
  • microcrystalline cellulose e.g., powdere., powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • compositions is, in one embodiment, present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • fillers may include, but are not limited to block copolymers of ethylene oxide and propylene oxide.
  • block copolymers may be sold as POLOXAMER or PLURONIC, and include, but are not limited to POLOXAMER 188 NF, POLOXAMER 237 NF, POLOXAMER 338 NF, POLOXAMER 437 NF, and mixtures thereof.
  • fillers may include, but are not limited to isomalt, lactose, lactitol, mannitol, sorbitol xylitol, erythritol, and mixtures thereof.
  • Disintegrants may be used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients may be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. In one embodiment, pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, or from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, povidone, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium stearyl
  • Additional lubricants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), CAB-O-SIL (a pyrogenic colloidal silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants may be used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • an oral dosage form comprises the compound, silicified microcrystalline cellulose, sodium starch glycolate, a block copolymer of ethylene oxide and propylene oxide, sodium stearyl fumarate and colloidal silicon dioxide.
  • an oral dosage form comprises the compound in an amount of about 5% to about 75% by weight, silicified microcrystalline cellulose in an amount of about 15% to about 85%, sodium starch glycolate in an amount of about 2% to about 10%, block copolymer of ethylene oxide and propylene oxide in an amount of about 2% to about 10%, sodium stearyl fumarate in an amount of 0.2% to about 2%, and colloidal silicon dioxide in an amount of about 0.2% to about 2% by weight of the oral dosage form.
  • an oral dosage form comprises the compound, microcrystalline cellulose, isomalt, sodium starch glycolate, sodium lauryl sulfate, povidone, colloidal silicon dioxide, and magnesium stearate.
  • an oral dosage form comprises the compound in an amount of about 40% to about 50%, microcrystalline cellulose in an amount of about 40% to about 50%, isomalt in an amount of 0% to about 5%, sodium starch glycolate in an amount of about 5% to about 10%, sodium lauryl sulfate in an amount of 0.2% to about 2%, povidone in an amount of about 2% to about 10%, colloidal silicon dioxide in an amount of 0.1% to about 1%, and magnesium stearate in an amount of about 0.1% to about 1% by weight of the oral dosage form.
  • unit dosage forms that comprise between about 100 mg and about 1,200 mg, about 200 mg and about 1,000 mg, about 400 mg and about 800 mg, or about 450 mg and about 600 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound
  • unit dosage forms that comprise about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,050 mg, 1,100 mg, 1,150, or even about 1,200 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, ⁇ [5-(3- chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid or 2-(5-(3-fluorophenyl
  • the unit dosage form comprises about 40 mg, about 120 mg, about 150 mg, about 185 mg, about 200 mg, about 250 mg, about 300 mg, or even about 315 mg of a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or of Formula (V), or a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound
  • the unit dosage form is a capsule comprising about 40 mg, about 120 mg, about 185 mg, about 200 mg, about 200, about 250 mg, or even about 300 mg of the compound.
  • the unit dosage form is a tablet comprising about 150 mg of the compound.
  • the unit dosage form is a tablet comprising about 315 mg of the compound.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene
  • BOI-38503vl glycol 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof.
  • oils in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils
  • glycerol tetrahydrofuryl alcohol
  • polyethylene glycols polyethylene glycols
  • fatty acid esters of sorbitan and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.
  • Suspensions in addition to the active inhibitor(s) may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • GFR Glomerular Filtration Rate
  • Subjects are assigned to a Study Group based on their ESA (erythropoiesis stimulating agent) status at Screening (Naive, Previously Treated, or Actively Treated). Using a central randomization system, subjects are assigned in a double-blind fashion in a 2:1 ratio within each Study Group to either 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid or placebo and initiate dosing at three (3) tablets of 150 mg each, once daily for a total dose of 450 mg administered orally once daily.
  • ESA erythropoiesis stimulating agent
  • Subjects will be randomized to maintain balance between placebo and 5 -(3 -chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino ⁇ acetic acid treated subjects with respect to : 1) CKD status (GFR categories G3a/b, G4, or G5); and 2) whether or not they have diabetes mellitus.
  • Study medication is taken once daily on an outpatient basis for 20 consecutive weeks. Hemoglobin (HGB) is monitored at each study visit during dosing and is used to determine if the dose of study medication should be adjusted. Hemoglobin concentration (Hb) is reported as
  • hemoglobin is measured using the cyanmethemoglobin method, wherein a lysing agent is added to a sample of diluted blood. The lysing agent disrupts all the red cells in the sample and releases the hemoglobin into the fluid so that the sample is then a solution of hemoglobin. The hemoglobin is converted to a form called
  • cyanomethemoglobin and the concentration is read by a spectrophotometer with the wavelength set at the peak absorbance of cyanomethemoglobin. The concentration of hemoglobin is then calculated from the optical density of the solution.
  • hemoglobin concentration may be determined using a HemoCue® device which can measure hemoglobin concentration in capillary, venous or arterial whole blood.
  • the reaction in the HemoCue® cuvette is a modified azidemethemoglobin reaction.
  • the erythrocyte membranes are disintegrated by sodium deoxycholate, releasing the hemoglobin.
  • Sodium nitrite converts the hemoglobin iron from the ferrous to the ferric state to form methemoglobin, which then combines with azide to form azidmethemoglobin.
  • the photometer uses a double wavelength measuring method, 570 nm and 880 nm, for compensation of turbidity.
  • hemoglobin concentration may be determined using a non-invasive method such as the Masimo Total Hemoglobin (SpHb®) which allows non-invasive and continuous monitoring of hemoglobin.
  • SpHb® Masimo Total Hemoglobin
  • the dose is adjusted in accordance with the Dose Adjustment Guidelines (see below). Iron supplementation is prescribed as needed during the study to maintain ferritin levels of between 50 ng/mL and 300 ng/mL.
  • This study will include evaluations of specified neurocognitive and PRO measures to assess for the impact on cognition, depressed mood, and fatigue.
  • Patients with anemia secondary to CKD experience a number of adverse symptoms that may be minimized and/or alleviated with efficacious treatment. These include symptoms of cognitive impairment, depressed mood, fatigue, and others.
  • Subjects are selected for the study based on the following inclusion and exclusion criteria.
  • liver dysfunction aspartate transaminase (AST) or alanine transaminase (ALT) > 1.8x upper limit of normal (ULN), alkaline phosphatase > 2x ULN, or total bilirubin > 1.5x ULN);
  • BOI-38503vl 16 Any history of active malignancy or treatment of malignancy in the previous 2 years except for curative resected basal cell carcinoma of skin, squamous cell carcinoma of skin, cervical carcinoma in situ, or resected benign colonic polyps;
  • Age-related macular degeneration AMD
  • diabetic macular edema or active diabetic proliferative retinopathy that is likely to require treatment during the trial (disease itself is not exclusionary);

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Physiology (AREA)
  • Nutrition Science (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)
  • Pyridine Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
PCT/US2014/040889 2013-06-13 2014-06-04 Compositions and methods for treating anemia Ceased WO2014200773A2 (en)

Priority Applications (49)

Application Number Priority Date Filing Date Title
CA2914662A CA2914662C (en) 2013-06-13 2014-06-04 Compositions and methods for treating anemia
FIEP14811317.8T FI3007695T3 (fi) 2013-06-13 2014-06-04 Koostumuksia ja menetelmiä anemian hoitamiseksi
NZ714963A NZ714963A (en) 2013-06-13 2014-06-04 Compositions and methods for treating anemia
CN202111479746.1A CN114404414A (zh) 2013-06-13 2014-06-04 用于治疗贫血症的组合物和方法
MA38670A MA38670B2 (fr) 2013-06-13 2014-06-04 Compositions et méthodes de traitement de l'anémie
KR1020217011294A KR102461176B1 (ko) 2013-06-13 2014-06-04 빈혈 치료용 조성물 및 치료방법
DK14811317.8T DK3007695T3 (da) 2013-06-13 2014-06-04 Sammensætninger og fremgangsmåder til behandling af anæmi
RS20240271A RS65341B1 (sr) 2013-06-13 2014-06-04 Kompozicije i postupci za lečenje anemije
RU2016100363A RU2705206C2 (ru) 2013-06-13 2014-06-04 Композиции и способы лечения анемии
CN202111479723.0A CN114404413A (zh) 2013-06-13 2014-06-04 用于治疗贫血症的组合物和方法
LTEPPCT/US2014/040889T LT3007695T (lt) 2013-06-13 2014-06-04 Kompozicijos ir būdai, skirti anemijos gydymui
MX2020006963A MX391198B (es) 2013-06-13 2014-06-04 Composiciones y metodos para tratar anemia
SG11201509998WA SG11201509998WA (en) 2013-06-13 2014-06-04 Compositions and methods for treating anemia
BR112015031027A BR112015031027A2 (pt) 2013-06-13 2014-06-04 Uso de um composto, método in vitro, composição farmacêutica e forma de dosagem única
EP24156067.1A EP4360706A3 (en) 2013-06-13 2014-06-04 Compositions and methods for treating anemia
SM20240092T SMT202400092T1 (it) 2013-06-13 2014-06-04 Composizioni e metodi per il trattamento dell'anemia
KR1020167000558A KR102373245B1 (ko) 2013-06-13 2014-06-04 빈혈 치료용 조성물 및 치료방법
SI201432066T SI3007695T1 (sl) 2013-06-13 2014-06-04 Sestavki in metode za zdravljenje anemije
HRP20240319TT HRP20240319T1 (hr) 2013-06-13 2014-06-04 Pripravci i postupci za liječenje anemije
MYPI2019003537A MY204336A (en) 2013-06-13 2014-06-04 Compositions and methods for treating anemia
JP2016519543A JP2016521747A (ja) 2013-06-13 2014-06-04 貧血治療のための組成物及び方法
ES14811317T ES2974273T3 (es) 2013-06-13 2014-06-04 Composiciones y métodos para tratar la anemia
KR1020227037446A KR102660040B1 (ko) 2013-06-13 2014-06-04 빈혈 치료용 조성물 및 치료방법
CN201480045048.2A CN105451739A (zh) 2013-06-13 2014-06-04 用于治疗贫血症的组合物和方法
MX2015017229A MX378150B (es) 2013-06-13 2014-06-04 Composiciones y metodos para tratar anemia.
HK16104721.0A HK1216844B (en) 2013-06-13 2014-06-04 Compositions and methods for treating anemia
EP14811317.8A EP3007695B1 (en) 2013-06-13 2014-06-04 Compositions and methods for treating anemia
PE2020000452A PE20201496A1 (es) 2013-06-13 2014-06-04 Composiciones y metodos para tratar anemia
PL14811317.8T PL3007695T3 (pl) 2013-06-13 2014-06-04 Kompozycje i sposoby leczenia niedokrwistości
KR1020247012967A KR20240055172A (ko) 2013-06-13 2014-06-04 빈혈 치료용 조성물 및 치료방법
MA43609A MA43609B1 (fr) 2013-06-13 2014-06-04 Compositions et méthodes de traitement de l'anémie
US14/897,849 US11857543B2 (en) 2013-06-13 2014-06-04 Compositions and methods for treating anemia
AU2014278543A AU2014278543B2 (en) 2013-06-13 2014-06-04 Compositions and methods for treating anemia
PH12015502738A PH12015502738B1 (en) 2013-06-13 2015-12-07 Compositions and methods for treating anemia
IL24304715A IL243047B (en) 2013-06-13 2015-12-10 Compositions and methods for treating anemia
ZA2015/09024A ZA201509024B (en) 2013-06-13 2015-12-10 Compositions and methods for treating anemia
CR20150660A CR20150660A (es) 2013-06-13 2015-12-11 Composiciones y metodos para tratar anemia
IL270335A IL270335B (en) 2013-06-13 2019-10-31 Compositions and methods for treating anemia
AU2020200903A AU2020200903B2 (en) 2013-06-13 2020-02-07 Compositions and methods for treating anemia
PH12020551705A PH12020551705A1 (en) 2013-06-13 2020-10-15 Compositions and methods for treating anemia
IL281058A IL281058B2 (en) 2013-06-13 2021-02-23 Compositions and methods for treating anemia
AU2022200570A AU2022200570B2 (en) 2013-06-13 2022-01-28 Compositions and methods for treating anemia
US18/511,042 US20240335434A1 (en) 2013-06-13 2023-11-16 Compositions and methods for treating anemia
NO2024025C NO2024025I1 (no) 2013-06-13 2024-05-29 Vadadustat
NL301278C NL301278I2 (nl) 2013-06-13 2024-06-03 vadadustat
FR24C1025C FR24C1025I2 (fr) 2013-06-13 2024-06-07 Compositions et méthodes de traitement de l'anémie
FIC20240023C FIC20240023I1 (fi) 2013-06-13 2024-06-25 Vadadustaatti
LTPA2024521C LTPA2024521I1 (enExample) 2013-06-13 2024-06-26
AU2024205219A AU2024205219A1 (en) 2013-06-13 2024-07-30 Compositions and methods for treating anemia

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US201361834808P 2013-06-13 2013-06-13
US61/834,808 2013-06-13
US201361889478P 2013-10-10 2013-10-10
US61/889,478 2013-10-10
US201361898890P 2013-11-01 2013-11-01
US201361898885P 2013-11-01 2013-11-01
US61/898,885 2013-11-01
US61/898,890 2013-11-01
US201361912185P 2013-12-05 2013-12-05
US61/912,185 2013-12-05

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US14/897,849 A-371-Of-International US11857543B2 (en) 2013-06-13 2014-06-04 Compositions and methods for treating anemia
US18/511,042 Continuation US20240335434A1 (en) 2013-06-13 2023-11-16 Compositions and methods for treating anemia

Publications (2)

Publication Number Publication Date
WO2014200773A2 true WO2014200773A2 (en) 2014-12-18
WO2014200773A3 WO2014200773A3 (en) 2015-03-05

Family

ID=52022903

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2014/040889 Ceased WO2014200773A2 (en) 2013-06-13 2014-06-04 Compositions and methods for treating anemia

Country Status (37)

Country Link
US (2) US11857543B2 (enExample)
EP (2) EP3007695B1 (enExample)
JP (6) JP2016521747A (enExample)
KR (4) KR102461176B1 (enExample)
CN (3) CN114404413A (enExample)
AU (4) AU2014278543B2 (enExample)
BR (1) BR112015031027A2 (enExample)
CA (2) CA3151685A1 (enExample)
CL (2) CL2015003602A1 (enExample)
CY (2) CY1126699T1 (enExample)
DK (1) DK3007695T3 (enExample)
DO (1) DOP2015000297A (enExample)
EC (1) ECSP20058592A (enExample)
ES (1) ES2974273T3 (enExample)
FI (2) FI3007695T3 (enExample)
FR (1) FR24C1025I2 (enExample)
HR (1) HRP20240319T1 (enExample)
HU (2) HUE066123T2 (enExample)
IL (3) IL243047B (enExample)
LT (2) LT3007695T (enExample)
MX (3) MX378150B (enExample)
MY (1) MY204336A (enExample)
NL (1) NL301278I2 (enExample)
NO (1) NO2024025I1 (enExample)
NZ (3) NZ753904A (enExample)
PE (2) PE20201496A1 (enExample)
PH (2) PH12015502738B1 (enExample)
PL (1) PL3007695T3 (enExample)
PT (1) PT3007695T (enExample)
RS (1) RS65341B1 (enExample)
RU (2) RU2019134558A (enExample)
SG (2) SG11201509998WA (enExample)
SI (1) SI3007695T1 (enExample)
SM (1) SMT202400092T1 (enExample)
TW (5) TWI856464B (enExample)
WO (1) WO2014200773A2 (enExample)
ZA (1) ZA201509024B (enExample)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016161094A1 (en) * 2015-04-01 2016-10-06 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US9701636B2 (en) 2013-11-15 2017-07-11 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US10150734B2 (en) 2015-01-23 2018-12-11 Akebia Therapeutics, Inc. Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof
WO2019028150A1 (en) * 2017-08-01 2019-02-07 Akebia Therapeutics, Inc. COMPOSITIONS FOR USE IN METHODS OF TREATING HEMOGLOBINOPATHIES
US10246416B2 (en) 2011-06-06 2019-04-02 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides
WO2021087144A1 (en) 2019-10-31 2021-05-06 Akebia Therapeutics, Inc. Therapeutic methods using vadadustat
WO2021186356A1 (en) * 2020-03-17 2021-09-23 Cadila Healthcare Limited Formulation comprising hif prolyl hydroxylase inhibitors
WO2021257800A1 (en) 2020-06-19 2021-12-23 Akebia Therapeutics, Inc. Modulation of drug-drug interactions of vadadustat
WO2022150623A1 (en) 2021-01-08 2022-07-14 Akebia Therapeutics, Inc. Compounds and composition for the treatment of anemia
WO2022150621A1 (en) 2021-01-08 2022-07-14 Akebia Therapeutics, Inc. Therapeutic methods using vadadustat
US11426393B2 (en) 2006-06-26 2022-08-30 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
WO2022187142A1 (en) 2021-03-01 2022-09-09 Akebia Therapeutics, Inc. Modulation of drug-drug interactions of vadadustat
US11524939B2 (en) 2019-11-13 2022-12-13 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid
US11713298B2 (en) 2018-05-09 2023-08-01 Akebia Therapeutics, Inc. Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid
US11857543B2 (en) 2013-06-13 2024-01-02 Akebia Therapeutics, Inc. Compositions and methods for treating anemia

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014170832A1 (en) 2013-04-16 2014-10-23 Koninklijke Philips N.V. System and method for biventricular pacemaker pulse detection in surface ecg
CN108401429A (zh) * 2016-12-06 2018-08-14 深圳市塔吉瑞生物医药有限公司 一种取代的杂芳基酰胺化合物及包含该化合物的组合物及其用途
AU2021263829A1 (en) * 2020-04-29 2022-12-15 BioAge Labs, Inc. Hypoxia-inducible factor prolyl hydroxylase inhibitors for treating aging-related conditions

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070299086A1 (en) 2006-06-26 2007-12-27 The Procter & Gamble Company Prolyl hydroxylase inhibitors and methods of use

Family Cites Families (126)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3655679A (en) 1969-06-25 1972-04-11 Merck & Co Inc Certain aryl pyridine carboxylic acid derivatives
US3703582A (en) 1970-04-20 1972-11-21 Merck & Co Inc Aryl pyridine carboxylic acids in the treatment of inflammation
US3894920A (en) 1971-12-21 1975-07-15 Sagami Chem Res Process for preparing alkyl-substituted 3,6-dihydro-o-dioxin derivatives
US4016287A (en) 1972-07-17 1977-04-05 Boehringer Ingelheim Gmbh Dermatological compositions containing an acylamino-carboxylic acid or an alkyl ester thereof
CA1261335A (en) 1984-08-29 1989-09-26 Hoffmann-La Roche Limited/Hoffmann-La Roche Limitee Ethylenediamine monoamide derivatives
CN1023479C (zh) 1985-09-27 1994-01-12 弗·哈夫曼-拉罗切有限公司 乙二胺的单酰胺衍生物的制备方法
TW219933B (enExample) 1990-02-26 1994-02-01 Lilly Co Eli
US5405613A (en) 1991-12-11 1995-04-11 Creative Nutrition Canada Corp. Vitamin/mineral composition
TW352384B (en) 1992-03-24 1999-02-11 Hoechst Ag Sulfonamido- or sulfonamidocarbonylpyridine-2-carboxamides, process for their preparation and their use as pharmaceuticals
DE4219158A1 (de) 1992-06-11 1993-12-16 Thomae Gmbh Dr K Biphenylderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
EP0650961B1 (de) 1993-11-02 1997-03-05 Hoechst Aktiengesellschaft Substituierte heterocyclische Carbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel
ES2101420T3 (es) 1993-11-02 1997-07-01 Hoechst Ag Esteres-amidas de acidos carboxilicos heterociclicos sustituidos, su preparacion y su utilizacion como medicamentos.
CA2138929A1 (en) 1993-12-30 1995-07-01 Klaus Weidmann Substituted heterocyclic carboxamides, their preparation and their use as pharmaceuticals
DE4410480A1 (de) 1994-03-25 1995-09-28 Hoechst Ag Sulfonamidocarbonylpyridin-2-carbonsäureesteramide sowie ihre Pyridin-N-oxide, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
DE4410423A1 (de) 1994-03-25 1995-09-28 Hoechst Ag Sulfonamidocarbonylpyridin-2-carbonsäureamide sowie ihre Pyridin-N-oxide, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US5789426A (en) 1995-01-20 1998-08-04 Cornell Research Foundation, Inc. Method for the treatment of fibroproliferative disorders by application of inhibitors of protein hydroxylation
DE19535571A1 (de) * 1995-09-14 1997-03-20 Boehringer Mannheim Gmbh Pharmazeutische Kombinationspräparate und deren Verwendung zur Behandlung von Hämodialysepatienten
IL135495A (en) 1995-09-28 2002-12-01 Hoechst Ag Intermediate compounds for the preparation of quinoline-converted amines - 2 - carboxylic acid
JPH09221476A (ja) 1995-12-15 1997-08-26 Otsuka Pharmaceut Co Ltd 医薬組成物
JP2000509047A (ja) 1996-04-30 2000-07-18 ヘキスト・アクチエンゲゼルシヤフト ３―アルコキシピリジン―２―カルボキサミドエステル類、その製法および薬剤としてのその使用
DE19620041A1 (de) 1996-05-17 1998-01-29 Merck Patent Gmbh Adhäsionsrezeptor-Antagonisten
DE19650215A1 (de) 1996-12-04 1998-06-10 Hoechst Ag 3-Hydroxypyridin-2-carbonsäureamidester, ihre Herstellung und ihre Verwendung als Arzneimittel
US6420427B1 (en) 1997-10-09 2002-07-16 Ono Pharmaceutical Co., Ltd. Aminobutyric acid derivatives
DE19746287A1 (de) 1997-10-20 1999-04-22 Hoechst Marion Roussel De Gmbh Substituierte Isochinolin-2-Carbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel
EP1080075B1 (en) 1998-03-23 2004-08-11 Aventis Pharmaceuticals Inc. Piperididinyl and n-amidinopiperidinyl derivatives
GB9809213D0 (en) 1998-04-29 1998-07-01 Glaxo Group Ltd Pharmaceutical compositions
WO1999063970A1 (en) 1998-06-11 1999-12-16 Pharmacia & Upjohn Company Delavirdine tablet formulation
US6159379A (en) 1999-05-04 2000-12-12 Baker Hughes Incorporated Organic ammonium salts for the removal of water soluble organics in produced water
JP2001048786A (ja) 1999-08-05 2001-02-20 Yamanouchi Pharmaceut Co Ltd 三環式ヘテロアリール誘導体
US6589758B1 (en) 2000-05-19 2003-07-08 Amgen Inc. Crystal of a kinase-ligand complex and methods of use
MXPA03006217A (es) 2001-01-12 2004-10-15 Sun Pharmaceutical Ind Ltd Sistema de administracion espaciada de farmacos.
US6849718B2 (en) 2001-03-20 2005-02-01 Dana Farber Cancer Institute, Inc. Muteins of hypoxia inducible factor alpha and methods of use thereof
US6855510B2 (en) 2001-03-20 2005-02-15 Dana Farber Cancer Institute, Inc. Pharmaceuticals and methods for treating hypoxia and screening methods therefor
US20040146964A1 (en) 2001-03-21 2004-07-29 Maxwell Patrick Henry Assays, methods and means
SE0101327D0 (sv) 2001-04-12 2001-04-12 Astrazeneca Ab New crystalline forms
US6566088B1 (en) 2001-10-04 2003-05-20 Board Of Regents, The University Of Texas System Prolyl-4-hydroxylases
GB0124941D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
WO2003053997A2 (en) 2001-12-06 2003-07-03 Fibrogen, Inc. Methods of increasing endogenous erythropoietin (epo)
EP1556033A4 (en) 2002-05-17 2006-05-31 Celgene Corp METHODS AND COMPOSITIONS USING CYTOKINE INHIBITOR SELECTIVE MEDICAMENTS FOR THE TREATMENT AND MANAGEMENT OF CANCERS AND OTHER DISEASES
WO2003101431A1 (en) * 2002-06-04 2003-12-11 J.B. Chemicals & Pharmaceuticals Ltd. Pharmaceutical composition for controlled drug delivery system
WO2004019868A2 (en) 2002-08-29 2004-03-11 Merck & Co., Inc. N-biarylmethyl aminocycloalkanecarboxamide derivatives
MXPA05004033A (es) 2002-10-16 2005-06-08 Isis Innovation Hidroxilasas de asparaginil y moduladores de las mismas.
CA2506799A1 (en) 2002-11-21 2004-06-10 Eli Lilly And Company Mixed lineage kinase modulators
US8124582B2 (en) 2002-12-06 2012-02-28 Fibrogen, Inc. Treatment of diabetes
US7618940B2 (en) 2002-12-06 2009-11-17 Fibrogen, Inc. Fat regulation
US7183287B2 (en) 2003-04-03 2007-02-27 Pharmacia Corporation Substituted pyrimidinones
DE602004031114D1 (de) 2003-06-06 2011-03-03 Fibrogen Inc Stickstoffhaltige heteroarylverbindungen und deren verwendungen zur erhoehung des gehaltes von endogenem erythropoietin
US8614204B2 (en) 2003-06-06 2013-12-24 Fibrogen, Inc. Enhanced erythropoiesis and iron metabolism
US20060251638A1 (en) 2003-06-06 2006-11-09 Volkmar Guenzler-Pukall Cytoprotection through the use of hif hydroxylase inhibitors
GB0314129D0 (en) 2003-06-18 2003-07-23 Astrazeneca Ab Therapeutic agents
JP2008500834A (ja) 2004-05-28 2008-01-17 ファイブローゲン、インコーポレーテッド Ｈｉｆプロリルヒドロキシラーゼ活性アッセイ
TW200609218A (en) 2004-05-31 2006-03-16 Tanabe Seiyaku Co Bicyclic compounds
EA200700243A1 (ru) 2004-07-14 2007-08-31 ПиТиСи ТЕРАПЬЮТИКС, ИНК. Способы лечения гепатита с
TW200616969A (en) 2004-09-17 2006-06-01 Tanabe Seiyaku Co Imidazole compound
WO2006084210A2 (en) 2005-02-04 2006-08-10 Regents Of The University Of California, San Diego Hif modulating compounds and methods of use thereof
DE102005019712A1 (de) 2005-04-28 2006-11-09 Bayer Healthcare Ag Dipyridyl-dihydropyrazolone und ihre Verwendung
US20060276477A1 (en) 2005-06-06 2006-12-07 Fibrogen, Inc. Treatment method for anemia
JP5410751B2 (ja) 2005-06-15 2014-02-05 ファイブローゲン、インコーポレーテッド がん治療のための化合物および方法
PT1928409E (pt) 2005-09-12 2012-11-27 Actelion Pharmaceuticals Ltd Composição farmacêutica estável que compreende uma pirimidina-sulfamida
US20070154482A1 (en) 2005-09-12 2007-07-05 Beth Israel Deaconess Medical Center Methods and compositions for the treatment and diagnosis of diseases characterized by vascular leak, hypotension, or a procoagulant state
WO2007038571A2 (en) 2005-09-26 2007-04-05 Smithkline Beecham Corporation Prolyl hydroxylase antagonists
WO2007047194A2 (en) 2005-10-11 2007-04-26 Dana-Farber Cancer Institute, Inc. Methods for treating mitf-related disorders
AU2006326662B2 (en) 2005-12-09 2011-07-28 Amgen Inc. Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, and compositions, and uses thereof
MX2008008608A (es) 2006-01-09 2009-03-04 Btg Int Ltd Moduladores de factor i inducible por hipoxia y usos relacionados.
EP1983823A1 (en) 2006-01-17 2008-10-29 VIB vzw Inhibitors of prolyl-hydroxylase 1 for the treatment of skeletal muscle degeneration
EP1979353A2 (en) 2006-01-19 2008-10-15 OSI Pharmaceuticals, Inc. Fused heterobicyclic kinase inhibitors
JP4801451B2 (ja) 2006-01-19 2011-10-26 株式会社日立ハイテクノロジーズ 走査電子顕微鏡等に用いる電子銃の制御装置及び制御方法
ITMI20060179A1 (it) 2006-02-02 2007-08-03 Abiogen Pharma Spa Procedimento per la risoluzione di miscele racemiche e complesso diastereoisomerico di un agente risolvente e di unantiomero di interesse
WO2007101204A1 (en) 2006-02-27 2007-09-07 Alcon Research, Ltd. Method of treating glaucoma
TW200808793A (en) 2006-03-07 2008-02-16 Smithkline Beecham Corp Prolyl hydroxylase inhibitors
US7588924B2 (en) 2006-03-07 2009-09-15 Procter & Gamble Company Crystal of hypoxia inducible factor 1 alpha prolyl hydroxylase
US20090176825A1 (en) 2006-05-16 2009-07-09 Fitch Duke M Prolyl hydroxylase inhibitors
KR100798730B1 (ko) * 2006-06-12 2008-01-29 신풍제약주식회사 록소프로펜 또는 잘토프로펜 함유 제어방출성 제제 및 그의제조방법
AR061570A1 (es) 2006-06-23 2008-09-03 Smithkline Beecham Corp Compuesto de glicina sustituido en el n heteroaromatico composicion farmaceutica que lo comprende, su uso para preparar un medicamento, procedimientos para preparar dicha composicion farmaceutica y para preparar el compuesto
CA2563690C (en) 2006-10-12 2014-10-07 Pharmascience Inc. Pharmaceutical compositions comprising intra- and extra- granular fractions
GB2444904B (en) 2006-12-05 2008-11-05 Michael Hilary Burke A Process For The Preparation of an Orally Administrable Unit Dose Tablet
TW200845994A (en) 2007-01-12 2008-12-01 Smithkline Beecham Corp N-substituted glycine derivatives: prolyl hydroxylase inhibitors
TW200845991A (en) 2007-01-12 2008-12-01 Smithkline Beecham Corp N-substituted glycine derivatives: hydroxylase inhibitors
WO2008125388A1 (en) 2007-04-17 2008-10-23 Ratiopharm Gmbh Pharmaceutical compositions comprising irbesartan
AU2008241503A1 (en) 2007-04-18 2008-10-30 Merck Sharp & Dohme Corp. Novel 1,8-naphthyridine compounds
ES2446418T3 (es) 2007-04-18 2014-03-07 Amgen, Inc Derivados de indanona que inhiben la prolil hidroxilasa
US8030346B2 (en) 2007-05-04 2011-10-04 Amgen Inc. Heterocyclic quinolone derivatives that inhibit prolyl hydroxylase activity
US8309544B2 (en) 2007-05-16 2012-11-13 Merck Sharp & Dohme Corp. Spiroindalones
WO2008141731A2 (en) 2007-05-18 2008-11-27 Bayer Healthcare Ag Inhibitors of hypoxia inducible factor (hif) useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
CN101868251B (zh) 2007-08-06 2012-10-10 千寿制药株式会社 含有HIF-1α和HIF-2α表达抑制物质的药物
TW200908984A (en) 2007-08-07 2009-03-01 Piramal Life Sciences Ltd Pyridyl derivatives, their preparation and use
KR20100045480A (ko) 2007-08-10 2010-05-03 크리스탈지노믹스(주) 피리딘 유도체 및 이들의 사용방법
WO2009035534A2 (en) 2007-09-07 2009-03-19 The Cleveland Clinic Foundation Treatment of ischemic eye disease by the systematic pharmaceutical activation of hypoxia inducible factor (hif)
WO2009039321A1 (en) 2007-09-19 2009-03-26 Smithkline Beecham Corporation Prolyl hydroxylase inhibitors
WO2009039323A1 (en) 2007-09-19 2009-03-26 Smithkline Beecham Corporation Prolyl hydroxylase inhibitors
WO2009043093A1 (en) 2007-10-04 2009-04-09 Newsouth Innovations Pty Limited Hif inhibition
WO2009049112A1 (en) 2007-10-10 2009-04-16 Smithkline Beecham Corporation Prolyl hydroxylase inhibitors
WO2009067790A1 (en) 2007-11-26 2009-06-04 Uti Limited Partnership STIMULATION OF HYPOXIA INDUCIBLE FACTOR -1 ALPHA (HIF-1α) FOR THE TREATMENT OF CLOSTRIDIUM DIFFICILE ASSOCIATED DISEASE (CDAD), FOR INTESTINAL MOTILITY AND FOR DETECTING INFECTION
WO2009073497A2 (en) 2007-11-30 2009-06-11 Smithkline Beecham Corporation Prolyl hydroxylase inhibitors
JP2011505367A (ja) 2007-11-30 2011-02-24 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー プロリルヒドロキシラーゼ阻害剤
WO2009073669A1 (en) 2007-12-03 2009-06-11 Fibrogen, Inc. Isoxazolopyridine derivatives for use in the treatment of hif-mediated conditions
WO2009086044A1 (en) 2007-12-19 2009-07-09 Smith Kline Beecham Corporation Prolyl hydroxylase inhibitors
US20110003013A1 (en) 2008-01-04 2011-01-06 Garvan Institute Of Medical Research Method of increasing metabolism
US8952160B2 (en) 2008-01-11 2015-02-10 Fibrogen, Inc. Isothiazole-pyridine derivatives as modulators of HIF (hypoxia inducible factor) activity
PL2268618T3 (pl) 2008-03-03 2015-11-30 Novartis Ag Związki i kompozycje jako modulatory aktywności receptorów TLR
ES2383273T3 (es) 2008-07-23 2012-06-19 F. Hoffmann-La Roche Ag Compuestos heterocíclicos antivíricos
TW201006473A (en) * 2008-08-13 2010-02-16 Orient Pharma Co Ltd Bi-layer medicine tablet containing Zaleplon
CA2736732A1 (en) 2008-09-15 2010-03-18 Kasina Laila Innova Pharmaceuticals Private Limited Anti-cancer drugs and uses relating thereto for metastatic malignant melanoma and other cancers
HU230877B1 (hu) * 2008-09-30 2018-11-29 EGIS Gyógyszergyár NyR Stabil kombinációs gyógyszerkészítmény
CN105037323A (zh) 2008-11-14 2015-11-11 菲布罗根有限公司 作为hif羟化酶抑制剂的苯并噻喃衍生物
US8137666B2 (en) * 2008-11-22 2012-03-20 Academia Sinica Nattokinase for degrading and reducing amyloid fibrils—associated with alzheimer's disease, prion diseases and other amyloidoses
EP3708163A1 (en) 2009-03-31 2020-09-16 Ligand Pharmaceuticals, Inc. Use of sparsentan for the treatment of chronic inflammatory diseases
KR101772963B1 (ko) 2009-03-31 2017-08-31 깃세이 야쿠힌 고교 가부시키가이샤 인돌리진 유도체 및 그 의약용도
HRP20140705T1 (hr) 2009-07-17 2014-09-12 Japan Tobacco, Inc. Spoj triazolopiridina i njegovo djelovanje kao inhibitora prolil hidroksilaze i induktora proizvodnje eritropoetina
RS54010B1 (sr) 2009-11-06 2015-10-30 Aerpio Therapeutics Inc. Inhibitori prolil hidroksilaze
US20140171465A1 (en) 2011-01-13 2014-06-19 Fibrogen, Inc. Methods For Increasing Reticulocyte Hemoglobin Content
CA2837560C (en) 2011-06-06 2017-02-14 Akebia Therapeutics Inc. Compounds and compositions for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer
NO2686520T3 (enExample) 2011-06-06 2018-03-17
WO2012174256A2 (en) 2011-06-17 2012-12-20 The Regents Of The University Of Michigan Dna methylation profiles in cancer
JP6099644B2 (ja) 2011-07-22 2017-03-22 ベイジン ベータ ファーマシューティカルズ カンパニー， リミテッド プロリルヒドロキシラーゼ阻害剤としての化合物の多形体、およびその使用
JP2016519684A (ja) 2013-04-08 2016-07-07 デニス エム ブラウン 準最適に投与された薬物療法の有効性を改善するための及び／又は副作用を低減するための方法および組成物
HUE066123T2 (hu) 2013-06-13 2024-07-28 Akebia Therapeutics Inc Készítmények és módszerek anémia kezelésére
CN105979779A (zh) 2013-08-16 2016-09-28 俄亥俄州国家创新基金会 调整dna甲基化的组合物和方法
AU2014348523B2 (en) 2013-11-15 2019-01-03 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
JP2017503835A (ja) 2014-01-23 2017-02-02 アケビア セラピューティクス インコーポレイテッドＡｋｅｂｉａ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｉｎｃ． 眼球疾患治療のための組成物及び方法
CA2974691A1 (en) 2015-01-23 2016-07-28 Akebia Therapeutics, Inc. Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof
AU2016235534A1 (en) 2015-03-20 2017-10-12 Akebia Therapeutics, Inc. Deuterium-enriched hypoxia-inducible factor prolyl hydroxylase enzyme inhibitors
MX374909B (es) 2015-04-01 2025-03-06 Akebia Therapeutics Inc El uso del inhibidor de propil hidrolasa del factor inducible de hipoxia (hif) para el tratamiento o prevención de la anemia.
WO2019028150A1 (en) 2017-08-01 2019-02-07 Akebia Therapeutics, Inc. COMPOSITIONS FOR USE IN METHODS OF TREATING HEMOGLOBINOPATHIES
KR20210100594A (ko) 2018-10-03 2021-08-17 아케비아 테라퓨틱스 인코포레이티드 염증성 장애의 치료에 사용하기 위한 벤조이미다졸 유도체
US11524939B2 (en) * 2019-11-13 2022-12-13 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070299086A1 (en) 2006-06-26 2007-12-27 The Procter & Gamble Company Prolyl hydroxylase inhibitors and methods of use

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 2012, PHARMACEUTICAL PRESS
"Remington's The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS
JENS T. CARSTENSEN: "Drug Stability: Principles & Practice", 1995, MARCEL DEKKER, pages: 379 - 80
KIDNEY DISEASE: IMPROVING GLOBAL OUTCOMES 2012 CLINICAL PRACTICE GUIDELINE FOR THE EVALUATION AND MANAGEMENT OF CHRONIC KIDNEY DISEASE
SHETA ET AL., ONCOGENE, vol. 20, no. 52, 15 November 2001 (2001-11-15), pages 7624 - 34

Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12478615B2 (en) 2006-06-26 2025-11-25 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US11426393B2 (en) 2006-06-26 2022-08-30 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US11883386B2 (en) 2006-06-26 2024-01-30 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US10246416B2 (en) 2011-06-06 2019-04-02 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides
US11267785B2 (en) 2011-06-06 2022-03-08 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides
US10738010B2 (en) 2011-06-06 2020-08-11 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides
EP3007695B1 (en) 2013-06-13 2024-02-07 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US11857543B2 (en) 2013-06-13 2024-01-02 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US10596158B2 (en) 2013-11-15 2020-03-24 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US11065237B2 (en) 2013-11-15 2021-07-20 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US10149842B2 (en) 2013-11-15 2018-12-11 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US11690836B2 (en) 2013-11-15 2023-07-04 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US12419877B2 (en) 2013-11-15 2025-09-23 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US9701636B2 (en) 2013-11-15 2017-07-11 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US10150734B2 (en) 2015-01-23 2018-12-11 Akebia Therapeutics, Inc. Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof
EP3995138A1 (en) 2015-04-01 2022-05-11 Akebia Therapeutics Inc. Compositions and methods for treating anemia
EP3277270A4 (en) * 2015-04-01 2018-10-31 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
EP3277270B1 (en) 2015-04-01 2021-10-27 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
JP2021181478A (ja) * 2015-04-01 2021-11-25 アケビア セラピューティクス インコーポレイテッドAkebia Therapeutics Inc. 貧血治療のための組成物及び方法
KR20170132865A (ko) * 2015-04-01 2017-12-04 아케비아 테라퓨틱스 인코포레이티드 빈혈 치료용 조성물 및 방법
KR102866021B1 (ko) * 2015-04-01 2025-09-30 아케비아 테라퓨틱스 인코포레이티드 빈혈 치료용 조성물 및 방법
US11324734B2 (en) 2015-04-01 2022-05-10 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
WO2016161094A1 (en) * 2015-04-01 2016-10-06 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
JP2018510178A (ja) * 2015-04-01 2018-04-12 アケビア セラピューティクス インコーポレイテッドＡｋｅｂｉａ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｉｎｃ． 貧血治療のための組成物及び方法
TWI881714B (zh) * 2015-04-01 2025-04-21 美商阿克比治療有限公司 用於治療貧血之組合物及方法
TWI718138B (zh) * 2015-04-01 2021-02-11 美商阿克比治療有限公司 用於治療貧血之組合物及方法
AU2023200252B2 (en) * 2015-04-01 2025-03-20 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
AU2020273282B2 (en) * 2015-04-01 2022-10-20 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
CN107645953B (zh) * 2015-04-01 2022-11-01 阿克比治疗有限公司 用于治疗贫血的组合物和方法
KR20240038132A (ko) * 2015-04-01 2024-03-22 아케비아 테라퓨틱스 인코포레이티드 빈혈 치료용 조성물 및 방법
TWI794725B (zh) * 2015-04-01 2023-03-01 美商阿克比治療有限公司 用於治療貧血之組合物及方法
JP7270688B2 (ja) 2015-04-01 2023-05-10 アケビア セラピューティクス インコーポレイテッド 貧血治療のための組成物及び方法
EA036920B1 (ru) * 2015-04-01 2021-01-15 Экебиа Терапьютикс, Инк. Композиции и способы для лечения анемии
TWI836883B (zh) * 2015-04-01 2024-03-21 美商阿克比治療有限公司 用於治療貧血之組合物及方法
US11844756B2 (en) 2015-04-01 2023-12-19 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
AU2016243700B2 (en) * 2015-04-01 2020-08-20 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
KR102647879B1 (ko) * 2015-04-01 2024-03-15 아케비아 테라퓨틱스 인코포레이티드 빈혈 치료용 조성물 및 방법
WO2019028150A1 (en) * 2017-08-01 2019-02-07 Akebia Therapeutics, Inc. COMPOSITIONS FOR USE IN METHODS OF TREATING HEMOGLOBINOPATHIES
US11713298B2 (en) 2018-05-09 2023-08-01 Akebia Therapeutics, Inc. Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid
US12269802B2 (en) 2018-05-09 2025-04-08 Akebia Therapeutics, Inc. Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino] acetic acid
WO2021087144A1 (en) 2019-10-31 2021-05-06 Akebia Therapeutics, Inc. Therapeutic methods using vadadustat
US11524939B2 (en) 2019-11-13 2022-12-13 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid
WO2021186356A1 (en) * 2020-03-17 2021-09-23 Cadila Healthcare Limited Formulation comprising hif prolyl hydroxylase inhibitors
WO2021257800A1 (en) 2020-06-19 2021-12-23 Akebia Therapeutics, Inc. Modulation of drug-drug interactions of vadadustat
WO2022150621A1 (en) 2021-01-08 2022-07-14 Akebia Therapeutics, Inc. Therapeutic methods using vadadustat
WO2022150623A1 (en) 2021-01-08 2022-07-14 Akebia Therapeutics, Inc. Compounds and composition for the treatment of anemia
WO2022187142A1 (en) 2021-03-01 2022-09-09 Akebia Therapeutics, Inc. Modulation of drug-drug interactions of vadadustat

Also Published As

Publication number Publication date
EP4360706A2 (en) 2024-05-01
PE20160194A1 (es) 2016-04-20
FR24C1025I2 (fr) 2025-06-20
RU2019134558A (ru) 2020-02-20
HRP20240319T1 (hr) 2024-05-24
IL243047B (en) 2019-11-28
KR20240055172A (ko) 2024-04-26
CN114404413A (zh) 2022-04-29
SG11201509998WA (en) 2016-01-28
NO2024025I1 (no) 2024-05-29
JP6612479B2 (ja) 2019-11-27
AU2024205219A1 (en) 2024-09-19
EP3007695B1 (en) 2024-02-07
IL270335B (en) 2021-03-25
CN114404414A (zh) 2022-04-29
CA3151685A1 (en) 2014-12-18
KR20210043760A (ko) 2021-04-21
CY2024016I1 (el) 2025-05-09
US11857543B2 (en) 2024-01-02
KR20220151008A (ko) 2022-11-11
IL281058B1 (en) 2023-04-01
CA2914662A1 (en) 2014-12-18
BR112015031027A2 (pt) 2017-08-29
PT3007695T (pt) 2024-03-07
TW201534302A (zh) 2015-09-16
RS65341B1 (sr) 2024-04-30
AU2020200903A1 (en) 2020-02-27
JP2020033369A (ja) 2020-03-05
AU2014278543B2 (en) 2019-11-14
LT3007695T (lt) 2024-03-25
MY204336A (en) 2024-08-23
JP2021191773A (ja) 2021-12-16
EP4360706A3 (en) 2024-07-10
KR102660040B1 (ko) 2024-04-24
LTPA2024521I1 (enExample) 2024-07-10
MX2015017229A (es) 2016-04-19
JP2023145717A (ja) 2023-10-11
MX2022003510A (es) 2022-05-16
FI3007695T3 (fi) 2024-03-13
MX391198B (es) 2025-03-21
US20160143891A1 (en) 2016-05-26
EP3007695A4 (en) 2017-05-31
AU2020200903B2 (en) 2021-11-04
MX2020006963A (es) 2022-03-30
TWI650126B (zh) 2019-02-11
TW202339743A (zh) 2023-10-16
AU2022200570B2 (en) 2024-05-02
NZ714963A (en) 2020-07-31
EP3007695A2 (en) 2016-04-20
SMT202400092T1 (it) 2024-05-14
SG10201910773VA (en) 2020-01-30
TW201922244A (zh) 2019-06-16
CN105451739A (zh) 2016-03-30
CL2018002372A1 (es) 2018-12-28
ZA201509024B (en) 2019-05-29
TW202446394A (zh) 2024-12-01
JP7672455B2 (ja) 2025-05-07
NZ753905A (en) 2020-07-31
AU2022200570A1 (en) 2022-02-17
CY2024016I2 (el) 2025-05-09
HK1216844A1 (en) 2016-12-09
HUS2400023I1 (hu) 2024-07-28
TWI791177B (zh) 2023-02-01
AU2014278543A1 (en) 2016-01-07
FR24C1025I1 (fr) 2024-07-26
TWI856464B (zh) 2024-09-21
ECSP20058592A (es) 2020-10-30
RU2016100363A (ru) 2017-07-18
KR20160023773A (ko) 2016-03-03
JP2016521747A (ja) 2016-07-25
IL281058B2 (en) 2023-08-01
RU2016100363A3 (enExample) 2018-05-15
RU2705206C2 (ru) 2019-11-06
PL3007695T3 (pl) 2024-07-01
WO2014200773A3 (en) 2015-03-05
ES2974273T3 (es) 2024-06-26
CY1126699T1 (el) 2025-05-09
JP2019163293A (ja) 2019-09-26
JP2025114609A (ja) 2025-08-05
DK3007695T3 (da) 2024-03-18
JP7328291B2 (ja) 2023-08-16
SI3007695T1 (sl) 2024-04-30
TW202133843A (zh) 2021-09-16
KR102373245B1 (ko) 2022-03-17
NL301278I2 (nl) 2024-08-01
PH12015502738A1 (en) 2016-03-07
CL2015003602A1 (es) 2016-07-29
PE20201496A1 (es) 2020-12-29
NZ753904A (en) 2020-07-31
CA2914662C (en) 2022-05-31
JP6937812B2 (ja) 2021-09-22
IL281058A (en) 2021-04-29
PH12020551705A1 (en) 2021-11-15
MX378150B (es) 2025-03-10
TWI712411B (zh) 2020-12-11
KR102461176B1 (ko) 2022-11-01
HUE066123T2 (hu) 2024-07-28
US20240335434A1 (en) 2024-10-10
FIC20240023I1 (fi) 2024-06-25
PH12015502738B1 (en) 2021-12-10
DOP2015000297A (es) 2016-03-15

Similar Documents

Publication Publication Date Title
AU2022200570B2 (en) Compositions and methods for treating anemia
HK40109871A (en) Compositions and methods for treating anemia
HK1216844B (en) Compositions and methods for treating anemia

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201480045048.2

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14811317

Country of ref document: EP

Kind code of ref document: A2

ENP Entry into the national phase

Ref document number: 2914662

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 12015502738

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: P1642/2015

Country of ref document: AE

WWE Wipo information: entry into national phase

Ref document number: 243047

Country of ref document: IL

Ref document number: IDP00201508375

Country of ref document: ID

Ref document number: 38670

Country of ref document: MA

ENP Entry into the national phase

Ref document number: 2016519543

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 002603-2015

Country of ref document: PE

Ref document number: CR2015-000660

Country of ref document: CR

Ref document number: MX/A/2015/017229

Country of ref document: MX

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112015031027

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2014278543

Country of ref document: AU

Date of ref document: 20140604

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20167000558

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2014811317

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2016100363

Country of ref document: RU

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 16006928

Country of ref document: CO

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14811317

Country of ref document: EP

Kind code of ref document: A2

ENP Entry into the national phase

Ref document number: 112015031027

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20151210

WWR Wipo information: refused in national office

Ref document number: 515370271

Country of ref document: SA

WWE Wipo information: entry into national phase

Ref document number: P-2024/0271

Country of ref document: RS