WO2009075826A1 - Methods for increasing white blood cells - Google Patents

Methods for increasing white blood cells Download PDF

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Publication number
WO2009075826A1
WO2009075826A1 PCT/US2008/013517 US2008013517W WO2009075826A1 WO 2009075826 A1 WO2009075826 A1 WO 2009075826A1 US 2008013517 W US2008013517 W US 2008013517W WO 2009075826 A1 WO2009075826 A1 WO 2009075826A1
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Prior art keywords
compound
carbonyl
hydroxy
amino
acetic acid
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PCT/US2008/013517
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French (fr)
Inventor
Stephen J. Klaus
Ingrid Langsetmo Parobok
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Fibrogen, Inc.
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Priority to US12/734,890 priority Critical patent/US20110039879A1/en
Priority to EP08860233A priority patent/EP2231156A1/en
Publication of WO2009075826A1 publication Critical patent/WO2009075826A1/en

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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4743—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having sulfur as a ring hetero atom
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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

Definitions

  • the present invention relates to methods and compounds useful for increasing white blood cell levels in blood and bone marrow. Methods and compounds for increasing hematopoietic progenitor cells are also provided.
  • White blood cells or leukocytes are cells of the immune system that defend the body against both infectious disease and foreign agents. Different and diverse types of white blood cells exist, including neutrophils, eosinophils, basophils, lymphocytes (including B cells and T cells), monocytes, and macrophages. Despite their diversity, all white blood cells are produced and derived from a multipotent cell in the bone marrow known as a hematopoietic progenitor (or precursor) cell.
  • Leukopenia is a reduction in the number of white blood cells. Leukopenia may affect the overall white blood cell count or one of the specific populations of white blood cells. For example, neutropenia and lymphopenia refer to low numbers of neutrophils and lymphocytes, respectively.
  • Known causes of low white blood cell count include infections (e.g., viral infections, HIV, bacterial infections, and fungal infections), autoimmune disorders (e.g., lupus), various medications (e.g., chemotherapeutic agents, antibiotics, corticosteroids, and immunosuppressive drugs), radiation therapy, and certain bone marrow diseases (e.g., leukemia and myelodysplastic syndromes).
  • Increased white blood cell levels in the clinic currently are achieved by administration of recombinant growth factors, such as recombinant G-CSF, or by bone marrow transplantation.
  • recombinant growth factors such as recombinant G-CSF
  • the present invention provides novel methods and compounds useful for increasing white blood cell levels and for increasing hematopoietic precursor cell levels.
  • the present invention also provides methods for increasing white blood cell levels in a subject.
  • the invention provides a method for increasing white blood cell levels in blood in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits HIF prolyl hydroxylase enzyme activity, thereby increasing white blood cell levels in blood in the subject.
  • the invention provides a method for increasing white blood cell levels in bone marrow in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits HIF prolyl hydroxylase enzyme activity, thereby increasing white blood cell levels in bone marrow in the subject.
  • the present invention provides a method for increasing hematopoietic precursor cell levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing hematopoietic progenitor cell levels in the subject.
  • the present invention provides methods for increasing white blood cell mobilization in a subject.
  • the invention provides a method for increasing mobilization of white blood cells in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing the mobilization of white blood cells in the subject.
  • the mobilization of white blood cells in a subject is mobilization of white blood cells from the bone marrow to the blood.
  • the present invention provides methods for increasing neutrophils, monocytes, macrophages, basophils, eosinophils, or lymphocytes in a subject.
  • the invention provides a method for increasing neutrophil levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing neutrophil levels in the subject.
  • the invention provides a method for increasing macrophage levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing macrophage levels in the subject.
  • the invention provides a method for increasing monocyte levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing monocyte levels in the subject.
  • the invention provides a method for increasing basophil levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing basophil levels in the subject.
  • the invention provides a method for increasing eosinophil levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing eosinophil levels in the subject.
  • the invention provides a method for increasing lymphocyte levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing lymphocyte levels in the subject.
  • a subject suitable for treatment with the present methods and compounds is a subject who has or is at risk for having decreased or reduced levels of white blood cell, including decreased or reduced levels of neutrophils, basophils, monocytes, macrophages, lymphocytes, or eosinophils.
  • a subject suitable for treatment with the present methods and compounds is a subject who has or is a risk for having decreased or reduced levels of hematopoietic progenitor cells.
  • a subject suitable for treatment with the present methods and compounds is a subject undergoing or about to undergo chemotherapy or radiation therapy.
  • the present methods are useful for treating or preventing various disorders associated with reduced white blood cell levels, including, for example, leukopenia, neutropenia, or lymphocytopenia. Therefore, in some embodiments, the present invention provides methods for treating or preventing leukopenia, neutropenia, or lymphocytopenia, the methods comprising administering to a subject an effective amount of a compound that inhibits HIF prolyl hydroxylase enzyme activity, thereby providing treatment of leukopenia, neutropenia, or lymphocytopenia. In some aspects, the leukopenia, neutropenia, or lymphocytopenia is associated with chemotherapy.
  • the compound used in the present methods is a structural mimetic of 2-oxoglutarate, wherein the compound inhibits the target HIF prolyl hydroxylase enzyme competitively with respect to 2-oxoglutarate and noncompetitively with respect to iron.
  • compounds of the present invention include heterocyclic carboxamides, phenanthrolines, and hydroxamates.
  • a heterocyclic carboxamide of the present invention is a pyridine carboxamide, a quinoline carboxamide, an isoquinoline carboxamide, a quinolone carboxamide, a cinnoline carboxamide, or a beta-carboline carboxamide.
  • compounds of the present invention include variously substituted 3-hydroxy- pyridine-2-carbonyl-glycines, 4-hydroxy-pyridazine-3-carbonyl-glycines, 3-hydroxy-quinoline-2- carbonyl-glycines, 4-hydroxy-2-oxo-l ,2-dihydro-quinoline-3-carbonyl-glycines, 4-hydroxy-2-oxo-l ,2- dihydro-naphthyridine-3-carbonyl-glycines, S-hydroxy- ⁇ -oxo- ⁇ -dihydro-pyridopyrazine-V-carbonyl- glycines, 4-hydroxy-isoquinoline-3 -carbonyl -glycines, 4-hydroxy-cinnoline-3 -carbonyl-glycines, 7- hydroxy-thienopyridine-6-carbonyl-glycines, 4-hydroxy-thienopyridine-5-carbonyl-glycines, 7-hydroxy-hydroxy-hydroxy-
  • the compound of the present invention is [4-Hydroxy-7-(4-methoxy- phenoxy)-isoquinoline-3-carbonyl]-amino ⁇ -acetic acid (Compound A), [(4-Hydroxy-l -methyl -7- phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound B), [l-Cyano-6-(2,6-dimethyl- phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino ⁇ -acetic acid (Compound C), ⁇ [l-Cyano-6-(4- fluoro-phenoxy)-4-hyd ⁇ oxy-isoquinoline-3-carbonyl]-amino ⁇ -acetic acid (Compound D), ⁇ [l-Cyano-6- (2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino ⁇ -acetic acid (Compound A), [(
  • a compound for use in the present methods and medicaments is a pyridine-2- carboxamide, a pyridazine-3-carboxamide, a quinoline-2-carboxamide, an isoquinoline-3-carboxamide or ester thereof as described in European Patent Nos. EP0650960 and EP0650961.
  • a compound for use in the present methods and medicaments is a pyridine-2-carboxamide as described in U.S. Patent Application Publication No. 2007/0299086.
  • a compound for use in the present methods and medicaments is a pyridine-2-carboxamidoester, a pyridazine-3- carboxamidoester, or an isoquinoline-3-carboxamidoester as described in U.S. Patent No. 5,658,933.
  • a compound for use in the present methods and medicaments is a pyridine-2- carboxamide, a pyridizine-3-carboxamide, or a quinoline-2-carboxamide as described in U.S. Patent No. 5,620,995.
  • a compound for use in the methods and medicaments of the present invention is a 3-hydroxypyridine-2-carboxamidoester as described in U.S. Patent No. 6,020,350; a sulfonamidocarbonylpyridine ⁇ -carboxamide as described in U.S. Patent No. 5,607,954; or a sulfonamidocarbonyl-pyridine-2-carboxamide or a sulfonamidocarbonyl-pyridine-2-carboxamide ester as described in U.S. Patent Nos. 5,610,172 and 5,620,996.
  • a compound for use in the present methods and medicaments is a quinoline-2-carboxamide as described in U.S. Patent Nos. 5,719,164 and 5,726,305.
  • a compound for use in the present methods and medicaments is an isoquinoline-3- carboxamide as described in U.S. Patent No. 6,093,730 and 7,323,475.
  • a compound for use in the present methods and medicaments is an isoquinoline-3-carboxamide as described in U.S. Patent Application Publication No. 2007/0298104.
  • a compound for use in the present methods and medicaments is a beta-carboline-3-carboxamide, a pyrrolo[3,2-c]pyridine- 6-carboxamide, a pyrrolo[2,3-c]pyridine-5-carboxamide, a thiazolo[4,5-c]pyridine-6-carboxamide, or a thiazolo[5,4-c]pyridine-6-carboxamide as described in U.S. Patent Application Publication No. 2008/0004309.
  • a compound for use in the present methods and medicaments is a thieno[3,2- c]pyridine-6-carboxamide or a thieno[2,3-c]pyridine-5-carboxamide as described in U.S. Patent Application Publication No. 2006/0199836.
  • a compound for use in the present methods and medicaments is a 2,4-dioxo-l,2,3,4-tetrahydro-pyrimidine-5-carboxamide or a 4-oxo-2- thioxo-l,2,3,4-tetrahydro-pyrimidine-5-carboxamide as described in International Publication No. WO 2007/150011.
  • a compound for use in the present methods and medicaments is a 6-oxo-l,6-dihydro-pyrimidine-5-carboxamide as described in U.S. Patent Application Publication No. 2008/0171756.
  • a compound for use in the present methods and medicaments is a 2-oxo-l,2- dihydro-quinoline-3-carboxamide as described in International Publication No. WO 2007/038571 and U.S. Patent Application Publication No. 2007/0249605.
  • a compound for use in the present methods and medicaments is a 2-oxo-l,2-dihydro-[l,8]naphthyridine-3-carboxamide, a 2-oxo-l,2- dihydro-[l,6]naphthyridine-3-carboxamide, or a 6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazine-7-carboxamide as described in International Publication Nos. WO 2007/103905, WO 2008/076425, and WO 2008/130527.
  • a compound for use in the present methods and medicaments is a 6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxamide, a 5-oxo-4,5-dihydro-thieno[3,2-b]pyridine- 6-carboxamide, or a 6-oxo-6,7-dihydro-pyrazolo[3,4-b]pyridine-5-carboxamide as described in International Publication No. WO 2007/136990.
  • a compound for use in the present methods and medicaments is a 3-oxo-2,3-dihydro- pyridazine-4-carboxamide as described in U.S. Patent Application Publication No. 2008/0214549.
  • a compound for use in the present methods and medicaments is a 3-oxo-3,4-dihydro- naphthalene-2-carboxamide, a 7-oxo-7,8-dihydro-quinoline-6-carboxamide, or a 7-oxo-7,8-dihydro- isoquinoline-6-carboxamide as described in International Publication No. WO 2008/076427.
  • a compound for use in the present methods and medicaments is a 3 -hydroxy- 1-oxo- IH- indene-2-carboxamide as described in International Publication No. WO 2008/130508.
  • a compound for use in the present methods and medicaments is a 4-oxo-[l,10]- phenanthroline as described in U.S. Patent Nos. 5,916,898 and 6,200,974, and International Publication No. WO 99/21860.
  • a 4-oxo-[l,10]-phenanthroline is 4-oxo-l,4-dihydro- [l,10]phenanthroline-3-carboxylic acid (see, e.g., Seki et al. (1974) Chem Abstracts 81:424, No. 21).
  • a compound for use in the present methods and medicaments is a hydrozone as described in U.S. Patent No. 6,660,737.
  • a compound for sue in the present methods and medicaments is a dihydropyrazole or a dihydropyrozolone as described in U.S. Patent No. 6,878,729 and International Publication No. WO 2008/049539.
  • a compound for use in the present methods and medicaments is a dipyridyl dihyropyrazones as described in International Publication No. WO 2006/114213.
  • a compound for use in the present methods and medicaments is a spiroindalone as described in International Publication No. WO 2008/144266.
  • compounds for use in the present invention are selected from the group consisting of 2-oxoglutarate mimetics, iron chelators, and proline analogs.
  • the compound used in the methods and medicaments of the present invention is a 2-oxoglutarate structural mimetic.
  • the compound used in the methods and medicaments of the present invention is a 2-oxoglutarate structural mimetic that inhibits HIF prolyl hydroxylase competitively with respect to 2-oxoglutarate and noncompetitively with respect to iron.
  • a compound for use in the methods and medicaments of the present invention is, in various embodiments, a cyclic carboxamide.
  • the cyclic carboxamide is a carbonyl glycine, hi other aspects of the present embodiment, the carboxamide is replaced by a carbonyl proprionic acid.
  • the compound used in the methods and medicaments of the present invention is a carbocyclic carboxamide.
  • cyclic carboxamides suitable for use in the present invention are heterocyclic carboxamides.
  • a compound of the present invention is a heterocyclic carboxamide having a heterocyclic group selected from the group consisting of: azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, furan, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimi
  • the heterocyclic group is a single ring selected from the group consisting of a pyridine, a pyridinone, a pyradizine, a pyridazinone, a pyrimidine, and a pyrimidinone ring.
  • the heterocyclic group is a multiple condensed ring selected from the group consisting of an isoquinoline, an isoquinolone, a naphthyridinone, a pyrrolopyridine, a pyrrolopyridinone, a pyrozolopyridinone, a pyrrolopyridizinone, a quinoline, a quinolone, a chromenone, a thiochromenone, a thienopyridine, a thienopyridinone, a thiazolopyridine, and a thiazolopyridinone.
  • a compound for use in the methods and medicaments of the present invention is selected from the group consisting of an isoquinoline carboxamide, a pyrrolopyridine carboxamide, a thienopyridine carboxamide, a pyrrolopyridizanone carboxamide, and a thiochromenone carboxamide.
  • a particularly preferred compound of the present invention is a heterocyclic carbonyl glycine.
  • the heterocyclic carbonyl glycine suitable for use in the present invention is a heterocyclic carbonyl glycine having a heterocyclic group that is selected from the following list: azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, furan, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazin
  • the heterocyclic carbonyl glycine suitable for use in the present invention is a heterocyclic carbonyl glycine having a heterocyclic group, wherein the heterocyclic group is a single ring selected from the following list: a pyridine, a pyridinone, a pyradizine, a pyridazinone, a pyrimidine, and a pyrimidinone ring.
  • the heterocyclic carbonyl glycine suitable for use in the present invention is a heterocyclic carbonyl glycine having a heterocyclic group, wherein the heterocyclic group is a multiple condensed ring selected from the group consisting of an isoquinoline, an isoquinolone, a naphthyridinone, a pyrrolopyridine, a pyrrolopyridinone, a pyrozolopyridinone, a pyrrolopyridizinone, a quinoline, a quinolone, a chromenone, a thiochromenone, a thienopyridine, a thienopyridinone, a thiazolopyridine, and a thiazolopyridinone.
  • the heterocyclic group is a multiple condensed ring selected from the group consisting of an isoquinoline, an isoquinolone, a naphthyridinone, a pyrrolopyridine,
  • a compound for use in the present methods and medicaments is a heterocyclic carbonyl glycine selected from the group consisting of an isoquinoline carbonyl glycine, a pyrrolopyridine carbonyl glycine, a thienopyridine carbonyl glycine, a pyrrolopyridizanone carbonyl glycine, and a thiochromenone carbonyl glycine.
  • a compound for use in the present methods and medicaments is an isoquinoline- 3-carbonyl-glycine.
  • a compound for use in the present methods and medicaments is a 4-hydroxy-isoquinoline-3-carbonyl-glycine.
  • a compound for use in the present methods and medicaments is [(l-Chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound S); [ ⁇ -Bromo ⁇ -hydroxy-isoquinoline ⁇ -carbonyO-aminol-acetic acid (Compound T); ⁇ [4- Hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino ⁇ -acetic acid (Compound A); ⁇ [7-(4- Fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino ⁇ -acetic acid (Compound U); [(4-Hydroxy-l- methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound B); ⁇ [7-(3,4-Difluoro- phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino ⁇
  • a compound for use in the present methods and medicaments is a pyrrolopyridine carbonyl glycine.
  • a compound for use in the present methods and medicaments is a pyrrolo[2,3-c]pyridine-5-carbonyl-glycine.
  • a compound for use in the present methods and medicaments is a pyrrolo[2,3-c]pyridine-5-carbonyl-glycine or a 4- hydroxy-pyrrolo[2,3-c ⁇ pyridine-5-carbonyl-glycine.
  • a compound of the present methods and medicaments is [(l-Benzyl-3-chloro-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine- 5-carbonyl)-amino]-acetic acid (Compound F); ⁇ [7-Cyano-l-(4-fluoro-benzyl)-4-hydroxy-lH- pyrrolo[2,3-c]pyridine-5-carbonyl]-amino ⁇ -acetic acid (Compound O); ⁇ [3-Chloro-7-cyano-l-(4-fluoro- benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino ⁇ -acetic acid (Compound P); ⁇ [(R)-2,3- Dichloro-7-cyano-4-hydroxy- 1 -( 1 -phenyl -ethyl)- 1 H-pyrrolo[2,3-c]pyridine-5-carbonyl
  • a compound for use in the present methods and medicaments is a thienopyridine carbonyl glycine.
  • the compound is a thieno[3,2-c]pyridine-6- carbonyl-glycine.
  • the compound is a 7-hydroxy-thieno[3,2-c]pyridine-6-carbonyl- glycine.
  • the compound is [(4-Cyano-7-hydroxy-thieno[3,2-c]pyridine-6-carbonyl)- amino]-acetic acid (Compound AA).
  • a compound for use in the present methods and medicaments is a pyrrolopyridizinone carbonyl glycine, a 2-oxo-pyrrolo[l,2-b]pyridazine-3-carbonyl-glycine, or a 4-hydroxy-2-oxo- pyrrolo[l,2-b]pyridazine-3-carbonyl-glycine.
  • a compound for use in the present methods and medicaments is ⁇ [4-Hydroxy-2-oxo-l-(4-trifluoromethyl -benzyl)- 1, 2 -dihydro- pyrrolo[l,2-b]pyridazine-3-carbonyl ⁇ -amino ⁇ -acetic acid (Compound BG).
  • a compound for use in the present methods and medicaments is a thiochromenone carbonyl glycine.
  • a compound for use in the present methods and medicaments is a 2-oxo-thiochromenone-3-carbonyl-glycine.
  • a compound for use in the present methods and medicaments is a 4-hydroxy-2-oxo-thiochromenone-3 -carbonyl -glycine.
  • a compound for use in the present methods and medicaments is [(4-Hydroxy-2-oxo-2H- thiochromene-3-carbonyl)-amino]-acetic acid (Compound BF).
  • a compound for use in the methods and medicaments of the present invention is a HIF prolyl hydroxylase inhibitor compound of Formula I:
  • prolyl hydroyxlase inhibitors include, but are not limited to, variously substituted pyridine-2-carbonyl-glycines, pyridazine-3-carbonyl-glycines, quinoline-2-carbonyl-glycines, 2-oxo-l,2-dihydro-quinoline-3-carbonyl- glycines, 2-oxo-l ⁇ -dihydro-naphthyridine-S-carbonyl-glycines, 6-oxo-4,6-dihydro-pyridopyrazine-7- carbonyl-glycines, isoquinoline-S-carbonyl-glycines, cinnoline-S-carbonyl-carbonyl-
  • a compound for use in the methods and medicaments of the present invention is a compound of Formula II:
  • R 1 , R 2 , R 3 , R 4 and R 5 are identical or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl; (C 1 -C 20 )- alkyl, (C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkoxy, (C 6 -C 12 )-aryl, (C 7 -C 16 )-aralkyl, (C 7 -C 16 )-aralkenyl, (C 7 -C 16 )-aralkynyl, (C 2 -C 2O )-alkenyl, (C 2 -C 20 )-alkynyl, (C 1 - C 20 )-alkoxy, (C 2 -C 20 )-alkenyloxy, (C 2 -C 20 )-alkynyloxy, retinyloxy, (C 6
  • a compound of the present invention is a compound of Formula II wherein: R 1 is selected from hydrogen, halo, (Ci-C 3 )-alkyl, or cyano; R 2 is selected from hydrogen or aryloxy, wherein the aryl is optionally substituted with halo, (C r C 3 )-alkyl, or (Ci-C 3 )-alkoxy; R 3 is hydrogen or aryloxy, wherein the aryl is optionally substituted with one or two halo,
  • R 4 is selected from hydrogen, halo, (Ci-C 3 )-alkoxy, aryloxy, wherein the aryl is optionally substituted with one or two halo, (Ci-C 3 )-alkyl, or (C r C 3 )-alkoxy or heteroaryloxy optionally substituted with (Ci-C 3 )-alkyl; and R 5 is selected from hydrogen or aryloxy optionally substituted with halo.
  • a compound suitable for use in the present methods and medicaments is a compound of Formula II wherein:
  • R 1 is selected from hydrogen, chloro, methyl, or cyano
  • R 2 is selected from hydrogen, phenoxy, 4-fluorophenoxy, 3-chlorophenoxy, 4- chlorophenoxy, 4-methoxy-phenoxy, 3-methylphenoxy, 4-methylphenoxy;
  • R 3 is hydrogen, phenoxy, 4-fluoro-phenoxy, 2,6-dimethyl-phenoxy, 4-chloro-2,6- dimethyl-phenoxy;
  • R 4 is selected from hydrogen, chloro, bromo, isopropoxy, phenoxy, 2,6-dimethyl- phenoxy, 3-methoxy-phenoxy, 4-methoxy-phenoxy, 4-fluorophenoxy, 3,4- difluorophenoxy, 3-chloro-4-fluorophenoxy, or 2-methyl-benzothiazol-6-yloxy; and
  • R 5 is selected from hydrogen, phenoxy, or 4-fluorophenoxy.
  • a compound for use in the methods and medicaments of the present invention is a compound of Formula III
  • R 6 is selected from the group consisting of hydrogen, halo, cyano, (C r C 3 )-alkyl, and aryl
  • R 7 is selected from the group consisting of hydrogen, halo, cyano, (Ci-C 6 )-alkyl, and aryl, wherein the aryl is optionally substituted by one or two halo;
  • R 8 is selected from the group consisting of hydrogen, halo, cyano, (Ci-C 6 )-alkyl, trifiuoromethyl, and aryl optionally substituted with halo;
  • R 9 is selected from the group consisting of hydrogen, (Ci-Cio)-alkyl, (C 1 -C 3 ⁇ aIkVl-(C 1 - C,o)-alkyl, (C,-C 3 )-alkoxy-(Ci-C 6 )-alkyl, (C 4 -C 6 )-cycloalkyl, (C 4 -C 6 )-cycloalkyl- (Ci-C 3 )-alkyl, aryl, (C 7 -Ci 2 )-aralkyl, aryl-aralkyl, and heteroaralkyl; where in each case an aryl or heteroaryl may be optionally substituted by one or two halo, trifiuoromethyl, or (C]-C 4 )-alkoxy; or pharmaceutically acceptable salts, single stereoisomers, mixtures of stereoisomers, esters, or prodrugs thereof.
  • a compound of the present invention is a compound of Formula III wherein:
  • A C(R 7 )-
  • B is -N(R 9 )-
  • R 6 is cyano
  • R 7 is selected from hydrogen or halogen
  • R 8 is selected from hydrogen, halo, or trifiuoromethyl
  • R 9 is selected from (C r Cio)-alkyl, (Ci-C 3 )-alkyl-(Ci-C 10 )-alkyl, (C 1 -C 3 ⁇ aIkOXy-(C 1 -C 6 )- alkyl, (C 7 -C 12 )-aralkyl or aryl-aralkyl, wherein each aryl is optionally substituted with halo, (C 1 -C 3 ) ⁇ aIkOXy, or trifiuoromethyl.
  • a compound of the present invention is a compound of Formula III wherein:
  • R 6 is cyano
  • R 7 is selected from hydrogen, chloro, or bromo.
  • R 8 is hydrogen, chloro, trifiuoromethyl
  • R 9 is selected from methyl-butyl, hexyl, methoxy-methyl, naphthalen-2-yl-methyl, benzyl, 4-fluorobenzyl, 1-phenyl-ethyl, 4-methoxy-benzyl, 2-fluoro-benzyl, 2- trifluoromethyl-benzyl, biphenyl-4-yl-methyl, or 4-isopropoxy-benzyl.
  • a compound for use in the claimed methods and medicaments is a compound of Formula IV
  • R 10 is selected from the group consisting of hydrogen, bromo, cyano, (Ci-C 4 )-alkyl, (C 1 -
  • R 11 is selected from hydrogen or 4-fluorophenyl
  • R 12 is selected from hydrogen, methyl, (E)-styryl, 2-(trifluoromethyl)-phenyl, 3-
  • a compound of the present invention is a compound of Formula IV wherein:
  • R 10 is cyano
  • R 11 and R 12 are hydrogen.
  • a compound suitable for use in the claimed methods and medicaments is a compound of Formula V
  • R 13 is (C 7 -C i 2 )-aralkyl optionally substituted on the aryl with one or two substituents selected from the group consisting of halo, trifluoromethyl, and (d-C 3 )-alkoxy; and R 14 , R 15 , and R 16 are hydrogen.
  • a compound for use in the present invention is a compound of Formula V wherein: R 13 is aralkyl optionally substituted on the aryl with trifluoromethyl; R 14 is hydrogen; R 15 is hydrogen; and R 16 is hydrogen.
  • a compound for use in the present invention is a compound of Formula V wherein:
  • R 13 is 4-trifluoromethyl-benzyl
  • R 14 is hydrogen
  • R 15 is hydrogen
  • R 16 is hydrogen
  • a compound for use in the present methods and medicaments is a compound of Formula VI
  • R 17 is hydrogen
  • R 18 is hydrogen, halo, or (Ci-C 3 )-alkoxy
  • R 19 is hydrogen, halo, (Ci -C 3 )-alkyl, (Ci-C 6 )-alkoxy, aryl optionally substituted with one or two substituents selected from the group consisting of halo, (C ! -C 3 )-alkoxy, and trifluoromethyl; heteroaryl optionally substituted with halo; or aralkoxy; and
  • R 20 is hydrogen or (C,-C 3 )-alkyl.
  • a compound for use in the present invention is a compound of Formula VI wherein R 17 is hydrogen; R 18 is hydrogen; R 19 is hydrogen; and R 20 is hydrogen.
  • a compound of the present invention is a compound of Formula VI wherein: R 17 , R 18 , R 19 , and R 20 are hydrogen.
  • Pharmaceutical compositions or medicaments effective for use in any of the present methods are provided herein.
  • the compositions comprise an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase and an acceptable carrier.
  • the methods and compounds of the present invention are used in combination with administration of one or more other therapeutic agents.
  • Other therapeutic agents for use in the present methods include white blood cell stimulating factors, such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and stem cell factor (SCF).
  • G-CSF granulocyte colony-stimulating factor
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • SCF stem cell factor
  • Other therapies for use in combination with the present methods and compounds include chemotherapy and radiation therapy. These therapeutic agents can be administered in subsequent or coordinate fashion.
  • a HIF prolyl hydroxylase enzyme may include a plurality of such enzymes; a reference to a “compound that inhibits the activity of a hypoxia-inducible factor prolyl hydroxylase enzyme” may be a reference to one or more compounds that inhibits the activity of a hypoxia-inducible factor prolyl hydroxylase enzyme, and so forth.
  • the present invention provides methods and compounds for increasing white blood cell levels in a subject.
  • the present invention provides a method for increasing white blood cell levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing white blood cell levels in the subject.
  • the invention also provides compounds for use in manufacturing a medicament for increasing white blood cell levels in a subject, wherein the compound inhibits the activity of a HIF prolyl hydroxylase enzyme.
  • the methods and compounds of the present invention are effective at increasing white blood cell levels in a subject, wherein the subject has or is at risk for having reduced white blood cell levels.
  • Detection and quantitation of white blood cells can be performed by any method known or available to those skilled in the art. For example, detection of total white blood cells in a sample obtained from a subject is performed by complete blood count using a CellDyn cell analyzer (Abbott Laboratories) as previously described. (Kendall et al. (2003) Lab Hematol 9:143-52.) In addition to total white blood cell count, complete blood counts can identify and quantify neutrophil, basophil, lymphocyte, monocyte, and eosinophil levels in a sample. In human blood, a normal range of leukocytes (i.e.
  • white blood cells is about 4.3-10.8 x 10 3 / ⁇ l; a normal range of neutrophils is about 1.9-8.0 x 10 3 / ⁇ l or about 45-74% of white blood cells; a normal range of lymphocytes is about 0.7-4.9 x 10 3 / ⁇ l or about 16-45% of white blood cells; a normal range of monocytes is about 0.2-1.1 x 10 3 / ⁇ l or about 4-10% of white blood cells; a normal range of eosinophils is about 0-0.8 x 10 3 / ⁇ l or about 0-7% of white blood cells; and a normal range of basophils is about 0-0.2 x 10 3 / ⁇ l or about 0-2% of white blood cells.
  • the present invention provides methods and compounds for maintaining or achieving a normal range of white blood cell levels in a subject.
  • the present invention provides methods and compounds for maintaining or achieving a normal range of lymphocytes, monocytes, eosinophils, neutrophils, or basophils in a subject.
  • the methods and compounds of the present invention are useful for increasing white blood cell levels in blood in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing white blood cell levels in blood in the subject.
  • the methods and compounds of the present invention are useful for increasing white blood cell levels in bone marrow of a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing white blood cell levels in bone marrow in the subject.
  • the present invention provides methods for increasing the levels of specific types of white blood cells, including, for example, methods for increasing the levels of neutrophils, lymphocytes, basophiles, eosinophils, macrophages, or monocytes.
  • Complete blood counts can quantify the levels of neutrophils, lymphocytes, monocytes, macrophages, basophils, and eosinophils in a sample. (Kendall et al. (2003) Lab Hematol 9:143-52.)
  • Other methods are available to identify and quantify specific types of white blood cells.
  • neutrophils can be identified using flow cytometry, as well as other methods, by the presence of two characteristic and identifying neutrophil cell surface markers: Mac-1 and Gr-I (other aliases for Gr-I include CDl Ib). (Legasse et al (1996) J Immunol Methods 197:139-50).
  • the methods and compounds of the present invention are useful for increasing neutrophil levels, wherein the neutrophils are positive for expression of both Mac-1 and Gr-I cell-surface markers (i.e., double positive; Mac-1+/Gr-1+).
  • the present invention provides a method for increasing neutrophil levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing neutrophil levels in the subject.
  • the neutrophils are positive for Mac-1 and Gr-I expression.
  • Adult white blood cells derive primarily from bone marrow, and are mobilized from bone marrow to blood.
  • the methods and compounds of the present invention are useful for increasing mobilization of white blood cells in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing mobilization of white blood cells in the subject.
  • the mobilization of white blood cells is mobilization from bone marrow to blood.
  • the methods and compounds of the present invention are effective at increasing white blood cell mobilization in a subject, wherein the subject has or is at risk for having reduced white blood cell mobilization. In other embodiments, the methods and compounds of the present invention are effective at increasing white blood cell levels in a subject, wherein the subject has or is at risk for having reduced white blood cell levels.
  • the present methods are useful for treating or preventing various disorders associated with reduced white blood cell levels, including, for example, leukopenia, neutropenia, or lymphocytopenia. Therefore, in some embodiments, the present invention provides methods for treating or preventing leukopenia, neutropenia, or lymphocytopenia, the methods comprising administering to a subject an effective amount of a compound that inhibits HIF prolyl hydroxylase enzyme activity, thereby providing treatment of leukopenia, neutropenia, or lymphocytopenia. In some aspects, the leukopenia, neutropenia, or lymphocytopenia is associated with chemotherapy or radiation therapy.
  • the methods and compounds of the present invention are used in combination with administration of one or more other therapeutic agents.
  • Other therapeutic agents include, for example, white blood cell stimulating factors, such as G-CSF, GM-CSF, and SCF.
  • the present methods and compounds are useful for and effective at increasing white blood cell levels in a subject, wherein the white blood cells are functional white blood cells, i.e., a white blood cell that is able to differentiate into a mature white blood cell (e.g., a neutrophil, basophil, monocyte, eosinophil, or lymphocyte).
  • a white blood cell that is able to differentiate into a mature white blood cell (e.g., a neutrophil, basophil, monocyte, eosinophil, or lymphocyte).
  • Various cell culture methods are available to identify functional white blood cells. (See, e.g., Lu et al.
  • CFU-GM colony-forming unit granulocyte-macrophage
  • the present invention also provides a method for increasing hematopoietic progenitor cell levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing hematopoietic progenitor cell levels in the subject.
  • the hematopoietic progenitor cell is positive for Sca-1 and c-Kit expression (i.e., Sca-l+/c-Kit+).
  • the present invention relates to methods for increasing white blood cell mobilization and for increasing white blood cell levels in a subject by administration of an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme to the subject.
  • the invention is applicable to a variety of different organisms, including, for example, vertebrates, large animals, and primates.
  • the subject is a mammalian subject, and in a most preferred embodiment, the subject is a human subject.
  • medical applications with humans are clearly foreseen, veterinary applications are also envisaged herein.
  • a suitable subject is a subject that has low or reduced white blood cell levels, or is at risk for having low or reduced white blood cell levels.
  • a subject that has or is at risk for having low or reduced white blood cell levels is a subject having or at risk for having a condition or is a subject undergoing treatment with any of a number of agents associated with reduced white blood cell levels.
  • Such conditions or treatments include infections (e.g., viral infections, HIV, bacterial infections, and fungal infections), autoimmune disorders (e.g., lupus), various medications (e.g., chemotherapeutic agents, antibiotics, corticosteroids, and immunosuppressive drugs), radiation therapy, and certain bone marrow diseases (e.g., leukemia and myelodysplastic syndromes).
  • a suitable subject is a subject that has normal white blood cell levels
  • a suitable subject is a subject that has high or increased white blood cell levels.
  • a suitable subject for the present methods is a subject having or at risk for having leukopenia.
  • a suitable subject for the present methods is a subject having or at risk for having neutropenia. In yet other embodiments, a suitable subject for the present methods is a subject having or at risk for having lymphocytepenia. In various aspects, the leukopenia, the neutropenia, or the lymphocytopenia is associated with chemotherapy or radiation therapy.
  • Whether a subject has low (reduced), normal, or high (increased) white blood cell levels is determined by any measure accepted and utilized by those skilled in the art.
  • a suitable subject who would benefit by the compounds and methods of the present invention includes a subject having or at risk for having a hematopoietic disorder, such as a leukemia, a drug-induced leukopenia, and a leukopenic deficit resulting from chemotherapy or radiation therapy.
  • the method of the present invention is further useful for treating subjects who are immuno-compromised or whose immune system is otherwise impaired.
  • a suitable subject who would benefit by the compounds and methods of the present invention includes a subject infected with a retrovirus, such as human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • HIF prolyl hydroxylase refers to any enzyme that is capable of hydroxylating a proline residue within an alpha subunit of HIF.
  • HIF prolyl hydroxylases include protein members of the EGL-9 (EGLN) 2-oxoglutarate- and iron-dependent dioxygenase family described by Taylor (2001) Gene 275:125-132; and characterized by Aravind and Koonin (2001) Genome Biol 2:RESEARCH0007; Epstein et al.
  • HIF prolyl hydroxylases include human SM-20 (EGLNl) (GenBank Accession No. AAG33965; Dupuy et al. (2000) Genomics 69:348-54), EGLN2 isoform 1 (GenBank Accession No. CAC42510; Taylor, supra), EGLN2 isoform 2 (GenBank Accession No. NP_060025), and EGLN3 (GenBank Accession No. CAC4251); mouse EGLNl (GenBank Accession No. CAC42515), EGLN2 (GenBank Accession No.
  • HIF prolyl hydroxylase may include Caenorhabditis elegans EGL-9 (GenBank Accession No. AAD56365) and Drosophila melanogaster CGl 114 gene product (GenBank Accession No. AAF52O5O).
  • the term "HIF prolyl hydroxylase” also includes any active fragment of the foregoing full-length proteins.
  • a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme refers to any compound that reduces or otherwise modulates the activity of at least one HIF prolyl hydroxylase enzyme.
  • a compound may additionally show inhibitory activity toward one or more other 2-oxoglutarate- and iron-dependent dioxygenase enzymes, e.g. factor inhibiting HIF (FIH; GenBank Accession No. AAL27308), procollagen prolyl 4-hydroxylase (cP4H), etc.
  • compounds used in the present methods and medicaments provided herein are structural mimetics of 2-oxoglutarate, wherein the compound inhibits the target HIF prolyl hydroxylase enzyme competitively with respect to 2-oxoglutarate and noncompetitively with respect to iron. Examples of compounds that may be used in the methods and medicaments provided herein can be found, e.g., in Majamaa et al. (1984) Eur. J.
  • WO 03/049686 WO 02/074981, WO 03/080566, WO 2004/108681, WO 2006/094292, WO 2007/038571, WO 2007/090068, WO 2007/070359, WO 2007/103905, and WO 2007/115315.
  • heterocyclic carboxamides including pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, quinolone carboxamides, cinnoline carboxamides, or beta- carboline carboxamides
  • phenanthrolines hydroxamates
  • 3-hydroxy-pyridine- 2-carbonyl-glycines 4-hydroxy-pyridazine-3-carbonyl-glycines, 3-hydroxy-quinoline-2-carbonyl- glycines, 4-hydroxy-2 -oxo-1, 2-dihydro-quinoline-3-carbonyl-glycines, 4-hydroxy-2-oxo-l,2-dihydro- naphthyridine-3-carbonyl-glycines, 8-hydroxy-6-oxo-4,6-dihydro-pyridopyrazine-7-carbonyl-glycine
  • the compound is [4-Hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3- carbonyl] -amino ⁇ -acetic acid (Compound A), [(4-Hydroxy-l-methyl-7-phenoxy-isoquinoline-3- carbonyl)-amino] -acetic acid (Compound B), [l-Cyano-6-(2,6-dimethyl-phenoxy)-4-hydroxy- isoquinoline-3-carbonyl]-amino ⁇ -acetic acid (Compound C), ⁇ [l-Cyano-6-(4-fluoro-phenoxy)-4- hydroxy-isoquinoline-3-carbonyl]-amino ⁇ -acetic acid (Compound D), ⁇ [l-Cyano-6-(2,6-dimethyl- phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino ⁇ -acetic acid (Compound E), [(l-Benzyl)
  • Compounds for use in the present invention are compounds that inhibit HIF prolyl hydroxylase activity.
  • a compound that inhibits HIF prolyl hydroxylase activity is any compound that reduces or otherwise inhibits the activity of at least one HIF prolyl hydroxylase enzyme.
  • Various compounds that inhibit HIF prolyl hydroxylase have been identified and are suitable for use in the methods and medicaments as claimed in the present invention.
  • Exemplary pyridine-2-carboxamides, pyridazine-3-carboxamides, quinoline-2-carboxamides, isoquinoline-3-carboxamides and esters thereof are described in European Patent Nos. EP0650960 and EP0650961. All compounds listed in EP0650960 and EP0650961, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein. Additional pyridine-2-carboxamides are described in U.S. Patent Application Publication No. 2007/0299086. All compounds listed in U.S. Patent Application Publication No.
  • 2007/0299086 in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
  • exemplary pyridine-2-carboxamidoesters, pyridazine-3-carboxamidoesters, and isoquinoline-3- carboxamidoesters are described in U.S. Patent No. 5,658,933. All pyridine-2-carboxamidoesters, pyridazine-3-carboxamidoesters, and quinoline-2-carboxamidesters are listed in U.S. Patent No. 5,658,933, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
  • Exemplary isoquinoline-3-carboxamides are described in U.S. Patent No. 6,093,730 and 7,323,475. All compounds listed in U.S. Patent No. 6,093,730 and 7,323,475 , in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein. Particularly exemplary embodiments of isoquinoline-3- carboxamides are described in U.S. Patent Application Publication No. 2007/0298104. All compounds listed in U.S. Patent Application Publication No. 2007/0298104, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
  • Exemplary beta-carboline-3-carboxamides, pyrrolo[3,2-c]pyridine-6-carboxamides, pyrrolo[2,3- c]pyridine-5-carboxamides, thiazolo[4,5-c]pyridine-6-carboxamides, and thiazolo[5,4-c]pyridine-6- carboxamides are described in U.S. Patent Application Publication No. 2008/0004309. All compounds listed in U.S. Patent Application Publication No. 2008/0004309, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
  • Exemplary 2,4-dioxo-l,2,3,4-tetrahydro-pyrimidine-5-carboxamides and 4-oxo-2-thioxo- 1,2,3,4- tetrahydro-pyrimidine-5-carboxamides are described in International Publication No. WO 2007/150011. All compounds listed in the foregoing publication, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein. Exemplary 6-oxo-l,6-dihydro-pyrimidine-5-carboxamides are described in U.S. Patent Application Publication No. 2008/0171756. All compounds listed in U.S. Patent Application Publication No. 2008/0171756, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
  • Exemplary 2-oxo- 1 ,2-dihydro-[ 1 ,8]naphthyridine-3 -carboxamides, 2-oxo- 1 ,2-dihydro-[ 1 ,6]naphthyridine- 3-carboxamides, and 6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazine-7-carboxamides are described in International Publication Nos. WO 2007/103905, WO 2008/076425, and WO 2008/130527. All compounds listed in the foregoing publications, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
  • Exemplary 6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxamides, 5-oxo-4,5-dihydro-thieno[3,2- b]pyridine-6-carboxamides, 6-oxo-6,7-dihydro-pyrazolo[3,4-b]pyridine-5-carboxamides are described in International Publication No. WO 2007/136990. All compounds listed in the foregoing publications, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein. Exemplary 3-oxo-2,3-dihydro-pyridazine-4-carboxamides are described in U.S. Patent Application Publication No. 2008/0214549. All compounds listed in U.S. Patent Application Publication No. 2008/0214549, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
  • Exemplary 4-oxo-[l,10]-phenanthrolines are described in U.S. Patent Nos. 5,916,898 and 6,200,974, and International Publication No. WO 99/21860. All compounds listed in the foregoing patents and publication, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
  • An exemplary 4-oxo- [l,10]-phenanthroline is 4-oxo-l,4-dihydro-[l,10]phenanthroline-3-carboxylic acid (see, e.g., Seki et al. (1974) Chem Abstracts 81:424, No. 21).
  • Exemplary dihydropyrazoles and dihydropyrozolones are described in U.S. Patent No. 6,878,729 and International Publication No. WO 2008/049539, respectively. All compounds listed in U.S. Patent No. 6,878,729, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein. Exemplary dipyridyl dihyropyrazones are described in International Publication No. WO 2006/114213. All compounds listed in International Publication No. WO 2006/114213, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
  • compounds suitable for use in the present invention are selected from the group consisting of 2-oxoglutarate mimetics, iron chelators, and proline analogs.
  • the compound is a 2-oxoglutarate structural mimetic.
  • 2-oxoglutarate structural mimetics suitable for use in the claimed methods include structural mimetics of 2-oxoglutarate that inhibit HIF prolyl hydroxylase activity competitively with respect to 2-oxoglutarate.
  • the compound is a 2-oxoglutarate structural mimetic that inhibits HIF prolyl hydroxylase competitively with respect to 2-oxoglutarate and noncompetitively with respect to iron.
  • a compound of the present invention is, in various embodiments, a cyclic carboxamide.
  • the cyclic carboxamide is a carbonyl glycine.
  • the carboxamide is replaced by a carbonyl proprionic acid.
  • the compound of the present invention is a carbocyclic carboxamide.
  • Preferred cyclic carboxamides suitable for use in the present invention are heterocyclic carboxamides.
  • Such heterocyclic carboxamide compounds include heterocyclic carboxamides previously identified as inhibitors of HIF prolyl hydroxylase activity, and known and available to those of skill in the art.
  • a compound of the present invention is a heterocyclic carboxamide having a heterocyclic group selected from the group consisting of: azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, furan, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimi
  • the heterocyclic group is a single ring selected from the group consisting of a pyridine, a pyridinone, a pyradizine, a pyridazinone, a pyrimidine, and a pyrimidinone ring, hi other preferred embodiments, the heterocyclic group is a multiple condensed ring selected from the group consisting of an isoquinoline, an isoquinolone, a naphthyridinone, a pyrrolopyridine, a pyrrolopyridinone, a pyrozolopyridinone, a pyrrolopyridizinone, a quinoline, a quinolone, a chromenone, a thiochromenone, a thienopyridine, a thienopyridinone, a thiazolopyridine, and a thiazolopyridinone.
  • a particularly preferred heterocyclic carboxamide of the present invention is selected from the group consisting of an isoquinoline carboxamide, a pyrrolopyridine carboxamide, a thienopyridine carboxamide, a pyrrolopyridizanone carboxamide, and a thiochromenone carboxamide.
  • heterocyclic carboxamides suitable for use in the claimed methods are heterocyclic carbonyl glycines.
  • Preferred such heterocyclic carbonyl glycines include those represented by Formula I, infra.
  • the heterocyclic carbonyl glycine suitable for use in the present invention is a heterocyclic carbonyl glycine having a heterocyclic group that is selected from the following list: azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, furan, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, pipe
  • the heterocyclic carbonyl glycine suitable for use in the present invention is a heterocyclic carbonyl glycine having a heterocyclic group, wherein the heterocyclic group is a single ring selected from the following list: a pyridine, a pyridinone, a pyradizine, a pyridazinone, a pyrimidine, and a pyrimidinone ring.
  • the heterocyclic carbonyl glycine suitable for use in the present invention is a heterocyclic carbonyl glycine having a heterocyclic group, wherein the heterocyclic group is a multiple condensed ring selected from the group consisting of an isoquinoline, an isoquinolone, a naphthyridinone, a pyrrolopyridine, a pyrrolopyridinone, a pyrozolopyridinone, a pyrrolopyridizinone, a quinoline, a quinolone, a chromenone, a thiochromenone, a thienopyridine, a thienopyridinone, a thiazolopyridine, and a thiazolopyridinone.
  • the heterocyclic group is a multiple condensed ring selected from the group consisting of an isoquinoline, an isoquinolone, a naphthyridinone, a pyrrolopyridine,
  • heterocyclic carbonyl glycines suitable for use in the claimed methods heterocyclic carbonyl glycines selected from the group consisting of isoquinoline carbonyl glycines, pyrrolopyridine carbonyl glycines, thienopyridine carbonyl glycines, pyrrolopyridizanone carbonyl glycines, and thiochromenone carbonyl glycines.
  • Isoquinoline carbonyl glycines suitable for use in the present invention include isoquinoline-3 -carbonyl - glycines.
  • isoquinoline-3-carbonyl-glycines are 4-hydroxy-isoquinoline-3-carbonyl- glycines
  • exemplary such compounds include [(l-Chloro-4-hydroxy-isoquinoline-3-carbonyl)- amino]-acetic acid (Compound S); [(T-Bromo- ⁇ hydroxy-isoquinoline-S-carbonyty-aminoJ-acetic acid (Compound T); ⁇ [4-Hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino ⁇ -acetic acid (Compound A); ⁇ [7-(4-Fluoro-phenoxy)-4-hydroxy-isoquinoline-3 -carbonyl] -amino ⁇ -acetic acid (Compound U); [(4-Hydroxy-l-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound B); ⁇ [7-(2-
  • the present invention further contemplates the use of pyrrolopyridine carbonyl glycines.
  • Preferred pyrrolopyridine carbonyl glycines are pyrrolo[2,3-c]pyridine-5-carbonyl-glycines. More preferred pyrrolo[2,3-c]pyridine-5-carbonyl-glycines include 4-hydroxy-pyrrolo[2,3-c]pyridine-5-carbonyl- glycines.
  • Exemplary such compounds include, but are not limited to: [(l-Benzyl-3-chloro-7-cyano-4- hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound F); ⁇ [7-Cyano-l-(4- fluoro-benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino ⁇ -acetic acid (Compound O); ⁇ [3- Chloro-7-cyano-l-(4-fluoro-benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino ⁇ -acetic acid (Compound P); ⁇ [( ⁇ -Z ⁇ -Dichloro-T-cyano ⁇ -hydroxy-l ⁇ l-phenyl-ethyO-lH-pyrrolo ⁇ - c]pyridine-5-carbonyl] -amino ⁇
  • compounds suitable for use in the claimed methods and medicaments are thienopyridine carbonyl glycines. More preferred thienopyridine carbonyl glycines include thieno[3,2-c]pyridine-6-carbonyl-glycines. Most preferred thienopyridine carbonyl glycines are T-hydroxy-thieno ⁇ -cJpyridine- ⁇ -carbonyl-glycines. Exemplary such compounds include [(4-Cyano-7- hydroxy-thieno[3,2-c]pyridine-6-carbonyl)-amino]-acetic acid (Compound AA) and other compounds according to Formula IV, infra.
  • preferred compounds of the present invention include pyrrolopyridizinone carbonyl glycines; more preferred, 2-oxo-pyrrolo[l,2-b]pyridazrne-3-carbonyl-glycines; most preferred, 4- hydroxy-2-oxo-pyrrolo[l,2-b]pyridazine-3-carbonyl-glycines.
  • Exemplary such compounds include, but are not limited to, ⁇ [4-Hydroxy-2-oxo-l-(4-trifluoromethyl-benzyl)-l,2-dihydro-pyrrolo[l,2- b]pyridazine-3-carbonyl]-amino ⁇ -acetic acid (Compound BG) and other compounds of Formula V, infra.
  • thiochromenone carbonyl glycines include 2-oxo-thiochromenone-3-carbonyl-glycines. Most preferred thiochromenone carbonyl glycines are 4-hydroxy-2-oxo-thiochromenone-3 -carbonyl -glycines. Exemplary such compounds include but are not limited to [(4-Hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]- acetic acid (Compound BF) and compounds of Formula VI, infra.
  • a compound for use in the methods and medicaments of the present invention is a HIF prolyl hydroxylase inhibitor compound of Formula I:
  • prolyl hydroyxlase inhibitors include, but are not limited to, variously substituted pyridine-2-carbonyl-glycines, pyridazine-3-carbonyl-glycines, quinoline-2-carbonyl-glycines, 2-oxo-l,2-dihydro-quinoline-3-carbonyl- glycines, 2-oxo-l ,2-dihydro-naphthyridine-3-carbonyl-glycines, 6-oxo-4,6-dihydro-pyridopyrazine-7- carbonyl -glycines, isoquinoline-3 -carbonyl -glycines, cinnoline-3-carbonyl
  • R 1 , R 2 , R 3 , R 4 and R 5 are identical or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl; (Ci-C 20 )- alkyl, (C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkoxy, (C 5 -C 12 )-aryl, (C 7 -C 16 )-aralkyl, (C 7 -C 16 )-aralkenyl, (C 7 -C 16 )-aralkynyl, (C 2 -C 20 )-alkenyl, (C 2 -C 20 )-alkynyl, (C 1 - C 20 )-alkoxy, (C 2 -C 20 )-alkenyloxy, (C 2 -C 20 )-alkynyloxy, retinyloxy, (C 6 -C
  • a compound of the present invention is a compound of Formula II wherein: R 1 is selected from hydrogen, halo, (C 1 -C 3 )-alkyl, or cyano; R 2 is selected from hydrogen or aryloxy, wherein the aryl is optionally substituted with halo, (C,-C 3 )-alkyl, or (C,-C 3 )-alkoxy; R 3 is hydrogen or aryloxy, wherein the aryl is optionally substituted with one or two halo,
  • a compound suitable for use in the present methods and medicaments is a compound of Formula II wherein:
  • R 1 is selected from hydrogen, chloro, methyl, or cyano
  • R 2 is selected from hydrogen, phenoxy, 4-fluorophenoxy, 3-chlorophenoxy, 4- chlorophenoxy, 4-methoxy-phenoxy, 3-methylphenoxy, 4-methylphenoxy;
  • R 3 is hydrogen, phenoxy, 4-fluoro-phenoxy, 2,6-dimethyl-phenoxy, 4-chloro-2,6- dimethyl-phenoxy;
  • R 4 is selected from hydrogen, chloro, bromo, isopropoxy, phenoxy, 2,6-dimethyl- phenoxy, 3-methoxy-phenoxy, 4-methoxy-phenoxy, 4-fluorophenoxy, 3,4- difluorophenoxy, 3-chloro-4-fluorophenoxy, or 2-methyl-benzothiazol-6-yloxy; and
  • R 5 is selected from hydrogen, phenoxy, or 4-fluorophenoxy.
  • a compound for use in the methods and medicaments of the present invention is a compound of Formula III
  • R 6 is selected from the group consisting of hydrogen, halo, cyano, (CVCy-alkyl, and aryl;
  • R 7 is selected from the group consisting of hydrogen, halo, cyano, (Ci-C 6 )-alkyl, and aryl, wherein the aryl is optionally substituted by one or two halo;
  • R 8 is selected from the group consisting of hydrogen, halo, cyano, (Ci-C 6 )-alkyl, trifluoromethyl, and aryl optionally substituted with halo;
  • R 9 is selected from the group consisting of hydrogen, (Ci-Ci O )-alkyl, (C r C 3 )-alkyl-(Ci- C,o)-alkyl, (C,-C 3 )-alkoxy-(C,-C 6 )-alkyl, (C 4 -C 6 )-cycloalkyl, (C 4 -C 6 )-cycloalkyl- (Ci-C 3 )-alkyl, aryl, (C 7 -C ⁇ )-aralkyl, aryl-aralkyl, and heteroaralkyl; where in each case an aryl or heteroaryl may be optionally substituted by one or two halo, trifluoromethyl, or (C]-C 4 )-alkoxy; or pharmaceutically acceptable salts, single stereoisomers, mixtures of stereoisomers, esters, or prodrugs thereof.
  • a compound of the present invention is a compound of Formula III wherein:
  • A C(R 7 )-
  • B is -N(R 9 )-
  • R 6 is cyano
  • R 7 is selected from hydrogen or halogen
  • R 8 is selected from hydrogen, halo, or trifluoromethyl
  • R 9 is selected from (Ci-C 10 )-alkyl, (C,-C 3 )-alkyl-(Ci-Ci 0 )-alkyl, (C,-C 3 )-alkoxy-(Ci-C 6 )- alkyl, (C 7 -Ci 2 )-aralkyl or aryl-aralkyl, wherein each aryl is optionally substituted with halo, or trifluoromethyl.
  • a compound of the present invention is a compound of Formula III wherein:
  • R 6 is cyano
  • R 7 is selected from hydrogen, chloro, or bromo.
  • R 8 is hydrogen, chloro, trifluoromethyl
  • R 9 is selected from methyl-butyl, hexyl, methoxy-methyl, naphthalen-2-yl-methyl, benzyl, 4-fluorobenzyl, 1-phenyl-ethyl, 4-methoxy-benzyl, 2-fluoro-benzyl, 2- trifiuoromethyl-benzyl, biphenyl-4-yl-methyl, or 4-isopropoxy-benzyl.
  • a compound suitable for use in the claimed methods and medicaments can be a compound of Formula IV
  • R 10 is selected from the group consisting of hydrogen, bromo, cyano, (Ci-C 4 )-alkyl, (Q-
  • R 1 ' is selected from hydrogen or 4-fluorophenyl
  • R 12 is selected from hydrogen, methyl, (E)-styryl, 2-(trifluoromethyl)-phenyl, 3-
  • a compound of the present invention is a compound of Formula IV wherein:
  • R 10 is cyano
  • R 11 and R 12 are hydrogen.
  • a compound suitable for use in the claimed methods and medicaments is a compound of Formula V
  • R 13 is (C 7 -Ci 2 )-aralkyl optionally substituted on the aryl with one or two substituents selected from the group consisting of halo, trifluoromethyl, and (Ci-C 3 )-alkoxy; and R 14 , R 15 , and R 16 are hydrogen.
  • a compound for use in the present invention is a compound of Formula V wherein: R 13 is aralkyl optionally substituted on the aryl with trifluoromethyl; R 14 is hydrogen; R 15 is hydrogen; and R 16 is hydrogen.
  • a compound for use in the present invention is a compound of Formula V wherein:
  • R 13 is 4-trifluoromethyl-benzyl
  • R 14 is hydrogen
  • R 15 is hydrogen
  • R 16 is hydrogen.
  • Other preferred compounds, suitable for use in the present methods and medicaments, include compounds of Formula VI
  • R 17 is hydrogen
  • R 18 is hydrogen, halo, or (C r C 3 )-alkoxy
  • R 19 is hydrogen, halo, (Ci-C 3 )-alkyl, (Ci-C 6 )-alkoxy, aryl optionally substituted with one or two substituents selected from the group consisting of halo, (Q-C ⁇ -alkoxy, and trifluoromethyl; heteroaryl optionally substituted with halo; or aralkoxy; and
  • R 20 is hydrogen or (d-C 3 )-alkyl.
  • a compound for use in the present invention is a compound of Formula VI wherein R 17 is hydrogen; R 18 is hydrogen; R 19 is hydrogen; and R 20 is hydrogen.
  • a compound of the present invention is a compound of Formula VI wherein: R 17 , R 18 , R 19 , and R 20 are hydrogen.
  • hydroxy or "hydroxyl” refer to the group -OH.
  • halo or halogen refers to fluoro, chloro, bromo, and iodo.
  • cyano refers to the group -CN.
  • nitro refers to the group -NO 2 .
  • carboxyl refers to -COOH or salts thereof.
  • alkyl refers to saturated monovalent hydrocarbyl groups having from 1 to 10 carbon atoms; more particularly, from 1 to 5 carbon atoms; and, even more particularly, 1 to 3 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, wo-propyl, n-butyl, /-butyl, n-pentyl, and the like.
  • cycloalkyl refers to a saturated or an unsaturated, but nonaromatic, cyclic alkyl groups of from 3 to 10, 3 to 8, or 3 to 6 carbon atoms having single or multiple cyclic rings including, by way of example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, cyclohexenyl, and the like.
  • cycloalkoxy refers to an -O-cycloalkyl group.
  • aryl refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is the aryl group.
  • Preferred aryls include phenyl and naphthyl.
  • heterocyclic or “heterocyclyl” refer to a saturated or unsaturated ring system having a single ring or multiple condensed rings, from 1 to 10 carbon atoms, and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur, or oxygen within the ring.
  • heteroaryl refers to an aromatic heterocyclic group of from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, and 1 to 4 heteroatoms within the ring selected from the group consisting of oxygen, nitrogen, and sulfur.
  • Such heteroaryl groups can have a single ring (e.g., pyridinyl, furyl, or thienyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl), which condensed rings may or may not be aromatic provided the point of attachment is through a ring containing the heteroatom and that ring is aromatic.
  • the nitrogen can optionally be oxidized to provide for the N-oxide
  • the sulfur ring atoms can optionally be oxidized to provide for the sulfoxide and sulfone derivatives.
  • heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, furan, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, phthal
  • groups are exemplified by vinyl (ethen-1-yl), allyl, but-3-enyl, and the like.
  • alkynyl refers to acetylinic unsaturated monovalent hydrocarbyl groups having from 2 to 6, preferably from 2 to 3, carbon atoms and having at least 1, preferably from 1 to 2, sites of acetylenic (-C ⁇ C-) unsaturation. This group is exemplified by ethyn-1-yl, propyn-1-yl, propyn-2-yl, and the like.
  • alkoxy refers to the group “alkyl-O-,” which includes, by way of example, methoxy, ethoxy, n-propoxy, wo-propoxy, n-butoxy, f-butoxy, sec-butoxy, n-pentoxy, and the like.
  • alkenyloxy refers to the group “alkenyl-O-.”
  • alkynyloxy refers to the group “alkynyl-O-.”
  • aryloxy refers to the group aryl-O- that includes, by way of example, phenoxy, naphthoxy, and the like.
  • aralkyloxy refers to the group aralkyl-O- that includes, by way of example, benzyloxy, and the like.
  • aminoacyl or “amide”, or the prefixes “carbamoyl” or “carboxamide,” refer to the group -C(0)NR q R q where each R q is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocyclic; or where each R q is joined to form together with the nitrogen atom a heterocyclic wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • amino refers to the group -NH 2 .
  • alkylsulfanyl refers to the groups -S-alkyl where alkyl is as defined above.
  • sulfinyl refers to the group -S(O)-.
  • sulfonyl refers to the group -S(O) 2 -.
  • heterocyclyloxy refers to the group -O-heterocyclic.
  • cycloalkylene refers to divalent cycloalkyl groups as defined above.
  • cycloalkylthio or “cycloalkylsulfanyl” refer to the groups -S-cycloalkyl where cycloalkyl is as defined herein.
  • arylthio or “arylsulfanyl” refer to the group -S-aryl, where aryl is as defined herein.
  • heteroarylthio or “heteroarylsulfanyl” refer to the group -S-heteroaryl, where heteroaryl is as defined herein.
  • heterocyclicthio or “heterocyclicsulfanyl” refer to the group -S-heterocyclic, where heterocyclic is as defined herein.
  • alkyl alcohol refers to the group “alkyl-OH”. "Alkyl alcohol” is meant to include methanol, ethanol, 2-propanol, 2-butanol, butanol, etc.
  • acyl refers to the groups H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-, alkynyl-C(O)-, cycloalkyl- C(O)-, aryl-C(O)-, heteroaryl-C(O)-, and heterocyclic-C(O)-, provided that a nitrogen atom of the heterocyclic is not bound to the -C(O)- group, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • acyloxy refers to the groups alkyl-C(O)O-, alkenyl-C(O)O-, alkynyl-C(O)O-, aryl-C(O)O-, cycloalkyl-C(O)O-, heteroaryl-C(O)O-, and heterocyclic-C(O)O-, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • groups are exemplified by vinyl (ethen-1-yl), allyl, but-3-enyl and the like.
  • alkynyl refers to acetylinic unsaturated monovalent hydrocarbyl groups having from 2 to 6, preferably from 2 to 3, carbon atoms and having at least 1, preferably from 1 to 2, sites of acetylenic (-C ⁇ €-) unsaturation. This group is exemplified by ethyn-1-yl, propyn-1-yl, propyn-2-yl, and the like.
  • acylamino refers to the groups -NR'C(O)alkyl, -NR l C(O)cycloalkyl, -NR'C(O)alkenyl, -NR t C(O)alkynyl,-NR'C(O)aryl, -NR t C(O)heteroaryl, and -NR l C(O)heterocyclic where R' is hydrogen or alkyl, and wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic are defined herein.
  • carbonyloxyamino refers to the groups -NR u C(O)O-alkyl, -NR u C(O)O-alkenyl, -NR U C(O)O- alkynyl, -NR u C(O)O-cycloalkyl, -NR u C(O)O-aryl, -NR u C(O)O-heteroaryl, and -NR u C(0)0-heterocyclic, where R u is hydrogen or alkyl and wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • oxycarbonylamino refers to the groups -NR u C(O)O-alkyl, -NR u C(O)O-alkenyl, -NR 11 C(O)O- alkynyl, -NR u C(O)O-cycloalkyl, -NR u C(O)O-aryl, -NR u C(O)O-heteroaryl, and -NR u C(O)O-heterocyclic, where R u is hydrogen or alkyl, and wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • oxythiocarbonylamino refers to the groups -NR u C(S)O-alkyl,-NR u C(S)O-alkenyl, -NR u C(S)O-alkynyl, -NR u C(S)O-cycloalkyl, -NR u C(S)O-aryl, -NR u C(S)O-heteroaryl, and -NR U C(S)O- heterocyclic, where R u is hydrogen or alkyl, and wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • aminocarbonyloxy or the prefix “carbamoyloxy” refer to the groups -OC(O)NR V R V where each R v is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic; or where each R v is joined to form, together with the nitrogen atom, a heterocyclic, and wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, substituted heteroaryl, and heterocyclic are as defined herein.
  • aminocarbonylamino refers to the group -NR W C(O)N(R W ) 2 where each R w is independently selected from the group consisting of hydrogen and alkyl.
  • aminothiocarbonylamino refers to the group -NR W C(S)N(R W ) 2 where each R w is independently selected from the group consisting of hydrogen and alkyl.
  • aryloxyaryl refers to the group -aryl-O-aryl.
  • carboxyl ester refers to the groups -C(O)O-alkyl, -C(O)O-alkenyl, -C(O)O-alkynyl, -C(O)O- cycloalkyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-heteroaryl, -C(O)O-substituted heeteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic.
  • cycloalkylene refers to divalent cycloalkyl groups as defined above.
  • heteroaryloxy refers to the group -O-heteroaryl.
  • sulfonyl refers to the group -S(O) 2 -, and may be included in the groups -S(O) 2 H, -SO 2 -alkyl, -SO 2 -alkenyl, -SO 2 -alkynyl, -SO 2 -cycloalkyl, -SO 2 -cycloalkenyl, -SO 2 -aryl, -SO 2 -substituted aryl, -SO 2 -heteroaryl, and -SO 2 -heterocyclic, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • heterocyclyloxy refers to the group -O-heterocyclic.
  • arylthio or "arylsulfanyl” refer to the group -S-aryl.
  • heteroarylthio or “heteroarylsulfanyl” refer to the group -S-heteroaryl.
  • heterocyclicthio or “heterocyclicsulfanyl” refer to the group -S-heterocyclic. Conjugated terms refer to a linear arrangement of the separate substituents as each separate term is defined herein.
  • aralkyl refers to an aryl-alkyl group and includes, by way of example, benzyl; the term “aralkylcarbamoyl” refers to an aryl-alkyl-carbomoyl substituent wherein each term is as defined herein, etc.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups or a hydroxyl group alpha to ethenylic or acetylenic unsaturation.
  • impermissible substitution patterns are well known to the skilled artisan.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art, and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and, when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like.
  • stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters.
  • Stereoisomers include enantiomers (compounds are non-superimposable mirror images) and diastereomers (compounds having more than one stereogenic center that are non-mirror images of each other and wherein one or more stereogenic center differs between the two stereoisomers).
  • the compounds of the invention can be present as a mixture of stereoisomers or as a single stereoisomer.
  • prodrug refers to compounds that include chemical groups which, in vivo, can be converted into the carboxylate group and/or can be split off from the amide N-atom and/or can be split off from the R atom to provide for the active drug, a pharmaceutically acceptable salt thereof, or a biologically active metabolite thereof.
  • Suitable groups are well known in the art and particularly include: for the carboxylic acid moiety, a prodrug selected from, e.g., esters including, but not limited to, those derived from alkyl alcohols, substituted alkyl alcohols, hydroxy substituted aryls and heteroaryls and the like; amides, particularly amides derived from amines of the Formula HNR 200 R 210 where R 200 and R 210 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and the like; hydroxymethyl, aldehyde and derivatives thereof.
  • esters refers to compounds that include the group -COOR where R is alkyl, substituted alkyl, alkoxy, or substituted alkoxy.
  • excipient means an inert or inactive substance used in the production of pharmaceutical products or other tablets, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, parenteral, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • Binders include, e.g., carbopol, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc, honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams and lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g
  • Assays for hydroxylase activity are standard in the art. Such assays can directly or indirectly measure hydroxylase activity.
  • an assay can measure hydroxylated residues, e.g., proline, asparagine, etc., present in the enzyme substrate, e.g., a target protein, a synthetic peptide mimetic, or a fragment thereof. (See, e.g., Palmerini et al. (1985) J Chromatogr 339:285-292.)
  • a reduction in hydroxylated residue, e.g., proline or asparagine, in the presence of a compound is indicative of a compound that inhibits hydroxylase activity.
  • assays can measure other products of the hydroxylation reaction, e.g., formation of succinate from 2-oxoglutarate.
  • assays can measure other products of the hydroxylation reaction, e.g., formation of succinate from 2-oxoglutarate.
  • Kaule and Gunzler (1990; Anal Biochem 184:291-297) describe an exemplary procedure that measures production of succinate from 2-oxoglutarate. Procedures such as those described above can be used to identify compounds that modulate HIF hydroxylase activity.
  • Target protein may include HIF ⁇ or a fragment thereof, e.g., HIF(556-575).
  • Enzyme may include, e.g., HIF prolyl hydroxylase and active fragments thereof (see, e.g., GenBank Accession No. AAG33965, etc.) or HIF asparaginyl hydroxylase and active fragments thereof (see, e.g., GenBank Accession No. AAL27308, etc.), obtained from any source. Enzyme may also be present in a crude cell lysate or in a partially purified form.
  • compositions of the present invention can be delivered directly or in pharmaceutical compositions containing excipients, as is well known m the art.
  • the present methods of treatment involve administration of an effective amount of a compound of the present invention to a subject in need, wherein the subject has reduced or is at ⁇ sk for having reduced white blood cell levels, or wherein the subject would benefit by having increased white blood cell mobilization or increased white blood cell levels.
  • an effective amount, e.g., dose, of compound or drug can readily be determined by routine experimentation, as can an effective and convenient route of administration and an approp ⁇ ate formulation.
  • Various formulations and drug delivery systems are available in the art. (See, e.g., Gennaro, ed. (2000) Remington's Pharmaceutical Sciences, supra; and Hardman, Limbird, and Gilman, eds. (2001) The Pharmacological Basis of Therapeutics, supra.)
  • Suitable routes of administration may, for example, include oral, rectal, topical, nasal, pulmonary, ocular, intestinal, and parenteral administration.
  • Primary routes for parenteral administration include intravenous, intramuscular, and subcutaneous administration.
  • Secondary routes of administration include intraperitoneal, mtra-arte ⁇ al, infra-articular, intracardiac, intracisternal, intradermal, lntralesional, intraocular, intrapleural, intrathecal, intrauterine, and intraventricular administration.
  • the indication to be treated, along with the physical, chemical, and biological properties of the drug, dictate the type of formulation and the route of administration to be used, as well as whether local or systemic delivery would be preferred.
  • the compounds of the present invention are administered orally.
  • the invention provides for oral administration of [4-Hydroxy-7-(4-methoxy- phenoxy)-isoquinoline-3-carbonyl]-ammo ⁇ -acetic acid (Compound A), [(4-Hydroxy-l-methyl-7- phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound B), [l-Cyano-6-(2,6-dimethyl- phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino ⁇ -acetic acid (Compound C), ⁇ [l-Cyano-6-(4- fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino ⁇ -acetic acid (Compound D), ⁇ [l-Cyano-6- (2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-ammo ⁇ -acetic
  • Pharmaceutical dosage forms of a compound of the invention may be provided in an instant release, controlled release, sustained release, or target drug-delivery system.
  • Commonly used dosage forms include, for example, solutions and suspensions, (micro-) emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols, and lyophilized formulations.
  • special devices may be required for application or administration of the drug, such as, for example, syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks.
  • Pharmaceutical dosage forms are often composed of the drug, an excipient(s), and a container/closure system.
  • One or multiple excipients also referred to as inactive ingredients, can be added to a compound of the invention to improve or facilitate manufacturing, stability, administration, and safety of the drug, and can provide a means to achieve a desired drug release profile. Therefore, the type of excipient(s) to be added to the drug can depend on various factors, such as, for example, the physical and chemical properties of the drug, the route of administration, and the manufacturing procedure.
  • Pharmaceutically acceptable excipients are available in the art, and include those listed in various pharmacopoeias.
  • compositions of the present invention can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.
  • the composition may be formulated in aqueous solution, if necessary using physiologically compatible buffers, including, for example, phosphate, histidine, or citrate for adjustment of the formulation pH, and a tonicity agent, such as, for example, sodium chloride or dextrose.
  • physiologically compatible buffers including, for example, phosphate, histidine, or citrate for adjustment of the formulation pH
  • a tonicity agent such as, for example, sodium chloride or dextrose.
  • semisolid, liquid formulations, or patches may be preferred, possibly containing penetration enhancers.
  • penetration enhancers are generally known in the art.
  • the compounds can be formulated in liquid or solid dosage forms and as instant or controlled/sustained release formulations.
  • Suitable dosage forms for oral ingestion by a subject include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, slurries, suspensions, and emulsions.
  • the compounds may also be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • Solid oral dosage forms can be obtained using excipients, which may include, fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, antiadherants, cationic exchange resins, wetting agents, antioxidants, preservatives, coloring, and flavoring agents.
  • excipients may include, fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, antiadherants, cationic exchange resins, wetting agents, antioxidants, preservatives, coloring, and flavoring agents.
  • excipients can be of synthetic or natural source.
  • excipients examples include cellulose derivatives, citric acid, dicalcium phosphate, gelatine, magnesium carbonate, magnesium/sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinyl pyrrolidone, silicates, silicium dioxide, sodium benzoate, sorbitol, starches, stearic acid or a salt thereof, sugars (i.e. dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oils (hydrogenated), and waxes. Ethanol and water may serve as granulation aides.
  • coating of tablets with, for example, a taste-masking film, a stomach acid resistant film, or a release-retarding film is desirable.
  • Natural and synthetic polymers, in combination with colorants, sugars, and organic solvents or water, are often used to coat tablets, resulting in dragees.
  • the drug powder, suspension, or solution thereof can be delivered in a compatible hard or soft shell capsule.
  • the compounds of the present invention can be administered topically, such as through a skin patch, a semi-solid or a liquid formulation, for example a gel, a (micro)-emulsion, an ointment, a solution, a (nano/micro)-suspension, or a foam.
  • the penetration of the drug into the skin and underlying tissues can be regulated, for example, using penetration enhancers; the appropriate choice and combination of lipophilic, hydrophilic, and amphiphilic excipients, including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, emulsifiers; by pH adjustment; and use of complexing agents.
  • Other techniques, such as iontophoresis may be used to regulate skin penetration of a compound of the invention. Transdermal or topical administration would be preferred, for example, in situations in which local delivery with minimal systemic exposure is desired.
  • the compounds for use according to the present invention are conveniently delivered in the form of a solution, suspension, emulsion, or semisolid aerosol from pressurized packs, or a nebuliser, usually with the use of a propellant, e.g., halogenated carbons dervided from methane and ethane, carbon dioxide, or any other suitable gas.
  • a propellant e.g., halogenated carbons dervided from methane and ethane, carbon dioxide, or any other suitable gas.
  • hydrocarbons like butane, isobutene, and pentane are useful.
  • the appropriate dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin, for use in an inhaler or insufflator may be formulated. These typically contain a powder mix of the compound and a suitable powder base such as lactose or starch.
  • compositions formulated for parenteral administration by injection are usually sterile and, can be presented in unit dosage forms, e.g., in ampoules, syringes, injection pens, or in multi-dose containers, the latter usually containing a preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents, such as buffers, tonicity agents, viscosity enhancing agents, surfactants, suspending and dispersing agents, antioxidants, biocompatible polymers, chelating agents, and preservatives.
  • the vehicle may contain water, a synthetic or vegetable oil, and/or organic co-solvents.
  • the parenteral formulation would be reconstituted or diluted prior to administration.
  • Depot formulations providing controlled or sustained release of a compound of the invention, may include injectable suspensions of nano/micro particles or nano/micro or non- micronized crystals.
  • Polymers such as poly(lactic acid), poly(glycolic acid), or copolymers thereof, can serve as controlled/sustained release matrices, in addition to others well known in the art.
  • Other depot delivery systems may be presented in form of implants and pumps requiring incision.
  • Suitable carriers for intravenous injection for the molecules of the invention are well-known in the art and include water-based solutions containing a base, such as, for example, sodium hydroxide, to form an ionized compound, sucrose or sodium chloride as a tonicity agent, for example, the buffer contains phosphate or histidine.
  • a base such as, for example, sodium hydroxide
  • sucrose or sodium chloride as a tonicity agent
  • the buffer contains phosphate or histidine.
  • Co-solvents such as, for example, polyethylene glycols, may be added.
  • These water-based systems are effective at dissolving compounds of the invention and produce low toxicity upon systemic administration.
  • the proportions of the components of a solution system may be varied considerably, without destroying solubility and toxicity characteristics.
  • the identity of the components may be varied.
  • low-toxicity surfactants such as polysorbates or poloxamers
  • polyethylene glycol or other co-solvents polyethylene glycol or other co-solvents
  • biocompatible polymers such as polyvinyl pyrrolidone may be added, and other sugars and polyols may substitute for dextrose.
  • composition useful for the present methods of treatment a therapeutically effective dose can be estimated initially using a variety of techniques well-known in the art. Initial doses used in animal studies may be based on effective concentrations established in cell culture assays. Dosage ranges appropriate for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays.
  • a therapeutically effective dose or amount of a compound, agent, or drug of the present invention refers to an amount or dose of the compound, agent, or drug that results in amelioration of symptoms or a prolongation of survival in a subject.
  • Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50/ ED50. Agents that exhibit high therapeutic indices are preferred.
  • the effective amount or therapeutically effective amount is the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician, e.g., treatment of cancer, including induction of anti-tumor effects, etc.
  • Dosages preferably fall within a range of circulating concentrations that includes the ED50 with little or no toxicity. Dosages may vary within this range depending upon the dosage form employed and/or the route of administration utilized. The exact formulation, route of administration, dosage, and dosage interval should be chosen according to methods known in the art, in view of the specifics of a subject's condition.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety that are sufficient to achieve the desired effects, i.e., minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from, for example, in vitro data and animal experiments. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
  • effective doses for compounds of the invention include doses of 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, and 30 mg/kg, respectively.
  • effective treatment regimes for compounds of the invention include administration two or three times weekly.
  • the amount of agent or composition administered may be dependent on a variety of factors, including the sex, age, and weight of the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient.
  • a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass and rubber stoppers such as in vials.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Example 1 Increased Levels of Hematopoietic Progenitor Cells and Neutrophils in vivo
  • HPC hematopoietic progenitor cell
  • neutrophil levels Male Swiss-Webster mice were administered various compounds of the present invention via oral gavage using a ball-tipped gavage needle. Animals treated by oral gavage received a 10 ml/kg volume of either 0.5% carboxymethyl cellulose (CMC) with 0.1% Polysorbate 80 (vehicle control) or various doses (10-100 mg/kg) of a compound of the present invention in 0.5% CMC with 0.1% Polysorbate 80. Animals were dosed once daily for 3 or 4 days.
  • CMC carboxymethyl cellulose
  • Polysorbate 80 vehicle control
  • various doses (10-100 mg/kg) of a compound of the present invention in 0.5% CMC with 0.1% Polysorbate 80 Animals were dosed once daily for 3 or 4 days.
  • HPCs hematopoietic progenitor cells
  • neutrophils FACS analysis
  • the remaining cells were incubated for one hour with monoclonal antibodies directed against mouse Sca-1 and mouse c-Kit (cell surface markers for HPCs, BD Pharmingen), or mouse Mac-1 and mouse Gr-I (cell surface markers for murine neutrophils, BD Pharmingen).
  • monoclonal antibodies directed against mouse Sca-1 and mouse c-Kit (cell surface markers for HPCs, BD Pharmingen), or mouse Mac-1 and mouse Gr-I (cell surface markers for murine neutrophils, BD Pharmingen).
  • sort buffer PBS, 1% fetal bovine serum
  • Sort buffer containing 50 ⁇ g/ml of propidium iodide.
  • Samples were then analyzed for the presence and quantitation of HPCs and neutrophils by flow cytometry (FACS Calibur, Becton Dickinson). The cytometer was set to acquire 10 000 events.
  • Hematopoietic progenitor cells were determined as double positive Sca-l+/c-Kit+ cells and neutrophils were determined as double positive Mac- 1 +/Gr- 1+ cells.
  • Example 2 Increased Levels of Hematopoietic Progenitor Cells and Neutrophils in Bone Marrow
  • HPC hematopoietic progenitor cell
  • neutrophil levels in bone marrow Male Swiss- Webster mice were administered various compounds of the present invention via oral gavage using a ball- tipped gavage needle. Animals treated by oral gavage received a 10 ml/kg volume of either 0.5% carboxymethyl cellulose (CMC) with 0.1% Polysorbate 80 (vehicle control) or various doses (10-100 mg/kg) of a compound of the present invention in 0.5% CMC with 0.1% Polysorbate 80. Animals were dosed once daily for 3 or 4 days.
  • CMC carboxymethyl cellulose
  • Polysorbate 80 vehicle control
  • various doses (10-100 mg/kg) of a compound of the present invention in 0.5% CMC with 0.1% Polysorbate 80 Animals were dosed once daily for 3 or 4 days.
  • bone marrow samples were taken from one tibia of each animal and suspended in buffer (PBS with 1% fetal bovine serum). Bone marrow suspensions were then filtered through nylon filters to remove stromal cells. Following filtration, the remaining cells were counted manually using a hemocytometer. Detection and quantitation of HPCs and neutrophils were performed by FACS analysis as described above in Example 1.
  • mice administered various compounds of the present invention showed an increase in the percent of hematopoietic progenitor cells in bone marrow compared to that observed in bone marrow of non-treated control animals.
  • Example 3 Increased White Blood Cells in vivo
  • mice Male Swiss-Webster mice were administered various compounds of the present invention via oral gavage using a ball-tipped gavage needle. Animals treated by oral gavage received a 10 ml/kg volume of either 0.5% carboxymethyl cellulose (CMC) with 0.1% Polysorbate 80 (vehicle control) or various doses (10-100 mg/kg) of a compound of the present invention in 0.5% CMC with 0.1% Polysorbate 80. Animals were dosed once daily for 3 or 4 days. Six hours after the final dosing, 200 ⁇ l blood samples were collected and total white blood cell, neutrophil, and lymphocyte levels were measured by complete blood count (CBC) using a CellDyn cell analyzer (Abbott Laboratories).
  • CMC carboxymethyl cellulose
  • Polysorbate 80 vehicle control
  • CBC complete blood count
  • mice Male Swiss-Webster mice were administered various compounds (see Table 7 and Table 8) of the present invention via oral gavage using a ball-tipped gavage needle.
  • Animals treated by oral gavage received a 10 ml/kg volume of either 0.5% carboxymethyl cellulose (CMC) with 0.1% Polysorbate 80 (vehicle control) or various doses (10-100 mg/kg) of a compound of the present invention in 0.5% CMC with 0.1% Polysorbate 80.
  • CMC carboxymethyl cellulose
  • Polysorbate 80 vehicle control
  • Total WBC, neutrophil, lymphocyte, and monocyte levels were measured in mice as described above on day 8 following administration of compound on day 1, day 3, and day 5.
  • Blood samples (0.2 ml) were collected on day 4 as follows. Animals were anesthetized with isoflurane and 0.2 ml of blood was collected from the tail vein into a MICROTAINER EDTA-2K tube (Becton- Dickinson). Blood samples were processed to measure total white blood cell, neutrophil, and lymphocyte levels by CBC analysis as described above in Example 3.
  • administration of 5 mg/kg cisplatin reduced total white blood cell levels by 21%, compared to that in non-treated control animals at day 4.
  • Administration of Compound S or Compound B increased total white blood cell levels in the cisplatin-treated animals.
  • animals initially administered 5 mg/kg cisplatin and subsequently treated with Compound S or Compound B had white blood cell levels equal to or greater than white blood cell levels in non-treated control (i.e., no chemotherapeutic agent administration) animals.

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Abstract

The present invention relates to methods and compounds useful for increasing white blood cell levels in blood and bone marrow. Methods and compounds for increasing hematopoietic progenitor cells are also provided.

Description

METHODS FOR INCREASING WHITE BLOOD CELLS
FIELD OF THE INVENTION
The present invention relates to methods and compounds useful for increasing white blood cell levels in blood and bone marrow. Methods and compounds for increasing hematopoietic progenitor cells are also provided.
BACKGROUND
White blood cells or leukocytes are cells of the immune system that defend the body against both infectious disease and foreign agents. Different and diverse types of white blood cells exist, including neutrophils, eosinophils, basophils, lymphocytes (including B cells and T cells), monocytes, and macrophages. Despite their diversity, all white blood cells are produced and derived from a multipotent cell in the bone marrow known as a hematopoietic progenitor (or precursor) cell.
Leukopenia is a reduction in the number of white blood cells. Leukopenia may affect the overall white blood cell count or one of the specific populations of white blood cells. For example, neutropenia and lymphopenia refer to low numbers of neutrophils and lymphocytes, respectively. Known causes of low white blood cell count include infections (e.g., viral infections, HIV, bacterial infections, and fungal infections), autoimmune disorders (e.g., lupus), various medications (e.g., chemotherapeutic agents, antibiotics, corticosteroids, and immunosuppressive drugs), radiation therapy, and certain bone marrow diseases (e.g., leukemia and myelodysplastic syndromes). Individuals with low white blood cell levels are at increased risk of serious infection, as the body's ability to defend itself against infectious disease and foreign agents is greatly reduced. Additionally, complications associated with low white blood cell count are the most common causes of dose reductions or delay in chemotherapy, adversely affecting treatment for individuals undergoing or in need of chemotherapy.
Increased white blood cell levels in the clinic currently are achieved by administration of recombinant growth factors, such as recombinant G-CSF, or by bone marrow transplantation. The present invention provides novel methods and compounds useful for increasing white blood cell levels and for increasing hematopoietic precursor cell levels.
SUMMARY OF THE INVENTION
The present invention also provides methods for increasing white blood cell levels in a subject. In one embodiment, the invention provides a method for increasing white blood cell levels in blood in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits HIF prolyl hydroxylase enzyme activity, thereby increasing white blood cell levels in blood in the subject. In another embodiment, the invention provides a method for increasing white blood cell levels in bone marrow in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits HIF prolyl hydroxylase enzyme activity, thereby increasing white blood cell levels in bone marrow in the subject.
In one embodiment, the present invention provides a method for increasing hematopoietic precursor cell levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing hematopoietic progenitor cell levels in the subject.
The present invention provides methods for increasing white blood cell mobilization in a subject. In one embodiment, the invention provides a method for increasing mobilization of white blood cells in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing the mobilization of white blood cells in the subject. In certain aspects, the mobilization of white blood cells in a subject is mobilization of white blood cells from the bone marrow to the blood.
In other embodiments, the present invention provides methods for increasing neutrophils, monocytes, macrophages, basophils, eosinophils, or lymphocytes in a subject. In one embodiment, the invention provides a method for increasing neutrophil levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing neutrophil levels in the subject. In another embodiment, the invention provides a method for increasing macrophage levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing macrophage levels in the subject. In another embodiment, the invention provides a method for increasing monocyte levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing monocyte levels in the subject. In yet another embodiment, the invention provides a method for increasing basophil levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing basophil levels in the subject. In another embodiment, the invention provides a method for increasing eosinophil levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing eosinophil levels in the subject. In yet another embodiment, the invention provides a method for increasing lymphocyte levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing lymphocyte levels in the subject. In certain embodiments, a subject suitable for treatment with the present methods and compounds is a subject who has or is at risk for having decreased or reduced levels of white blood cell, including decreased or reduced levels of neutrophils, basophils, monocytes, macrophages, lymphocytes, or eosinophils. In other embodiments, a subject suitable for treatment with the present methods and compounds is a subject who has or is a risk for having decreased or reduced levels of hematopoietic progenitor cells. In further embodiments, a subject suitable for treatment with the present methods and compounds is a subject undergoing or about to undergo chemotherapy or radiation therapy.
In other embodiments, the present methods are useful for treating or preventing various disorders associated with reduced white blood cell levels, including, for example, leukopenia, neutropenia, or lymphocytopenia. Therefore, in some embodiments, the present invention provides methods for treating or preventing leukopenia, neutropenia, or lymphocytopenia, the methods comprising administering to a subject an effective amount of a compound that inhibits HIF prolyl hydroxylase enzyme activity, thereby providing treatment of leukopenia, neutropenia, or lymphocytopenia. In some aspects, the leukopenia, neutropenia, or lymphocytopenia is associated with chemotherapy.
In certain embodiments, the compound used in the present methods is a structural mimetic of 2-oxoglutarate, wherein the compound inhibits the target HIF prolyl hydroxylase enzyme competitively with respect to 2-oxoglutarate and noncompetitively with respect to iron. In some embodiments, compounds of the present invention include heterocyclic carboxamides, phenanthrolines, and hydroxamates. In other embodiments, a heterocyclic carboxamide of the present invention is a pyridine carboxamide, a quinoline carboxamide, an isoquinoline carboxamide, a quinolone carboxamide, a cinnoline carboxamide, or a beta-carboline carboxamide.
In other embodiments, compounds of the present invention include variously substituted 3-hydroxy- pyridine-2-carbonyl-glycines, 4-hydroxy-pyridazine-3-carbonyl-glycines, 3-hydroxy-quinoline-2- carbonyl-glycines, 4-hydroxy-2-oxo-l ,2-dihydro-quinoline-3-carbonyl-glycines, 4-hydroxy-2-oxo-l ,2- dihydro-naphthyridine-3-carbonyl-glycines, S-hydroxy-ό-oxo-^ό-dihydro-pyridopyrazine-V-carbonyl- glycines, 4-hydroxy-isoquinoline-3 -carbonyl -glycines, 4-hydroxy-cinnoline-3 -carbonyl-glycines, 7- hydroxy-thienopyridine-6-carbonyl-glycines, 4-hydroxy-thienopyridine-5-carbonyl-glycines, 7-hydroxy- thiazolopyridine-6-carbonyl-glycines, 4-hydroxy-thiazolopyridine-5 -carbonyl-glycines, 7-hydroxy- pyrrolopyridine-6-carbonyl-glycines, and 4-hydroxy-pyrrolopyridine-5-carbonyl-glycines.
In particular embodiments, the compound of the present invention is [4-Hydroxy-7-(4-methoxy- phenoxy)-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound A), [(4-Hydroxy-l -methyl -7- phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound B), [l-Cyano-6-(2,6-dimethyl- phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound C), {[l-Cyano-6-(4- fluoro-phenoxy)-4-hydτoxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound D), {[l-Cyano-6- (2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound E), [(l-Benzyl-3-chloro-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound F), {[l-Cyano-5-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound G), [(l-Cyano-4-hydroxy-7-isopropoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound H), {[7-Cyano-l-(2-fluoro-benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]- amino}-acetic acid (Compound I), {[6-(4-Chloro-2,6-dimethyl-phenoxy)-l-cyano-4-hydroxy- isoquinoline-3-carbonyl]-amino}-acetic acid (Compound J), {[5-(4-Chloro-phenoxy)-l-cyano-4-hydroxy- isoquinoline-3-carbonyl] -amino} -acetic acid (Compound K), {[(R)-2,3-Dichloro-7-cyano-4-hydroxy-l- (l-phenyl-ethyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound L), {[7-Cyano-4- hydroxy- 1 -(3-methoxy-benzyl)- 1 H-pyrrolo[2,3 -c]pyridine-5-carbonyl]-amino} -acetic acid (Compound M), { [ 1 -Cyano-4-hydroxy-5 -(4-methoxy-phenoxy)-isoquinoline-3 -carbonyl] -amino } -acetic acid (Compound N), {[7-Cyano-l-(4-fluoro-benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]- aminoj-acetic acid (Compound O), {[3-Chloro-7-cyano-l-(4-fluoro-benzyl)-4-hydroxy-lH-pytτolo[2,3- c]pyridine-5-carbonyl]-amino}-acetic acid (Compound P), [(l-Benzyl-2,3-dichloro-7-cyano-4-hydroxy- lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound Q), [(7-Cyano-4-hydroxy-l- naphthalen-2-ylmethyl-lH-pyrrolo[2,3-c]pyridme-5-carbonyl)-amino]-acetic acid (Compound R), [(1- Chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound S), [(7-Bromo-4-hydroxy- isoquinoline-3-carbonyl)-amino}-acetic acid (Compound T), {[7-(4-Fluoro-phenoxy)-4-hydroxy- isoquinoline-3 -carbonyl] -amino} -acetic acid (Compound U), {[7-(3,4-Difluoro-phenoxy)-4-hydroxy- isoquinoline-3-carbonyl]-amino}-acetic acid (Compound V), {[7-(3-Chloro-4-fluoro-phenoxy)-4- hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound W), {[4-Hydroxy-7-(2 -methyl - benzothiazol-6-yloxy)-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound X), [(7-Chloro-4- hydroxy-l-methyl-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound Y), [(l-Cyano-4-hydroxy-7- phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound Z), [(4-Cyano-7-hydroxy-thieno[3,2- c]pyridine-6-carbonyl)-amino]-acetic acid (Compound AA), [(4-Hydroxy-8-phenoxy-isoquinoline-3- carbonyl)-amino] -acetic acid (Compound AB), [(4-Hydroxy-l-methyl-8-phenoxy-isoquinoline-3- carbonyl)-amino] -acetic acid (Compound AC), [(l-Cyano-4-hydroxy-8-phenoxy-isoquinoline-3- carbonyl)-amino] -acetic acid (Compound AD), {[8-(4-Fluoro-phenoxy)-4-hydroxy-l-methyl- isoquinoline-3-carbonyl]-amino}-acetic acid (Compound AE), {[l-Cyano-8-(4-fluoro-phenoxy)-4- hydroxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound AF), [(l-Cyano-4-hydroxy-6-phenoxy- isoquinoline-3-carbonyl)-amino] -acetic acid (Compound AG), [(l-Cyano-4-hydroxy-5-phenoxy- isoquinoline-3-carbonyl)-amino] -acetic acid (Compound AH), {[l-Cyano-7-(2,6-dimethyl-phenoxy)-4- hydroxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound AI), {[3-Bromo-7-cyano-4-hydroxy-l- (4-methoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AJ), {[2,3- Dichloro-7-cyano-4-hydroxy-l-(4-methoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}- acetic acid (Compound AK), {[(S)-2,3-Dichloro-7-cyano-4-hydroxy-l-(l-phenyl-ethyl)-lH-pyrrolo[2,3- c]pyridine-5-carbonyl] -amino} -acetic acid (Compound AL), {[3-Chloro-7-cyano-4-hydroxy-l-(4- methoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AM), {[3- Chloro-7-cyano-l-(2-fluoro-benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AN), {[3-Chloro-7-cyano-4-hydroxy-l-(3-methyl-butyl)-lH-pyrrolo[2,3-c]pyridine-5- carbonyl] -amino} -acetic acid (Compound AO), [(2,3-Dichloro-7-cyano-4-hydroxy-l-naphthalen-2- ylmethyl-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AP), {[7-Cyano-l-(2- fluoro-benzyl)-4-hydroxy-2-trifluoromethyl-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -acetic acid (Compound AQ), [(l-Benzyl-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AR), [(3-Chloro-7-cyano-l-hexyl-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)- amino]-acetic acid (Compound AS), {[3-Chloro-7-cyano-4-hydroxy-l-(2-trifluoromethyl-benzyl)-lH- pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -acetic acid (Compound AT), [(l-Biphenyl-4-ylmethyl-7- cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AU), [(1- Biphenyl-4-ylmethyl-2,3-dichloro-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]- acetic acid (Compound AV), [(l-Biphenyl-4-ylmethyl-3-chloro-7-cyano-4-hydroxy-lH-pyrrolo[2,3- c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AW), {[2,3-Dichloro-7-cyano-4-hydroxy-l-(4- isopropoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AX), {[1- Cyano-4-hydroxy-5-m-tolyloxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound AY), {[7- Cyano-4-hydroxy-l-(4-isopropoxy-benzyl)-3a,7a-dihydro-lH-pyrrolo[2,3-c]pyridine-5-carbonyl}- aminoj-acetic acid (Compound AZ), [(l-Cyano-4-hydroxy-5-p-tolyloxy-isoquinoline-3-carbonyl)- amino]-acetic acid (Compound BA), {[5-(3-Chloro-phenoxy)-l-cyano-4-hydroxy-isoquinoline-3- carbonyl]-amino} -acetic acid (Compound BB), {[3-Chloro-7-cyano-4-hydroxy-l-(4-isopropoxy-benzyl)- lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound BC), (S)-2-{[2,3-Dichloro-7- cyano-4-hydroxy-l-(4-isopropoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -propionic acid (Compound BD), {[l-Cyano-4-hydroxy-7-(3-methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound BE), [(4-Hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (Compound BF), or { [4-Hydroxy-2-oxo- 1 -(4-trifluoromethyl-benzyl)- 1 ,2-dihydro-pyrrolo[ 1 ,2-b]pyridazine-3- carbonyl] -amino} -acetic acid (Compound BG).
In one embodiment, a compound for use in the present methods and medicaments is a pyridine-2- carboxamide, a pyridazine-3-carboxamide, a quinoline-2-carboxamide, an isoquinoline-3-carboxamide or ester thereof as described in European Patent Nos. EP0650960 and EP0650961. In another embodiment, a compound for use in the present methods and medicaments is a pyridine-2-carboxamide as described in U.S. Patent Application Publication No. 2007/0299086. In yet another embodiment, a compound for use in the present methods and medicaments is a pyridine-2-carboxamidoester, a pyridazine-3- carboxamidoester, or an isoquinoline-3-carboxamidoester as described in U.S. Patent No. 5,658,933. In some embodiments, a compound for use in the present methods and medicaments is a pyridine-2- carboxamide, a pyridizine-3-carboxamide, or a quinoline-2-carboxamide as described in U.S. Patent No. 5,620,995. In another embodiment, a compound for use in the methods and medicaments of the present invention is a 3-hydroxypyridine-2-carboxamidoester as described in U.S. Patent No. 6,020,350; a sulfonamidocarbonylpyridine^-carboxamide as described in U.S. Patent No. 5,607,954; or a sulfonamidocarbonyl-pyridine-2-carboxamide or a sulfonamidocarbonyl-pyridine-2-carboxamide ester as described in U.S. Patent Nos. 5,610,172 and 5,620,996. In yet another embodiment, a compound for use in the present methods and medicaments is a quinoline-2-carboxamide as described in U.S. Patent Nos. 5,719,164 and 5,726,305.
In other embodiments, a compound for use in the present methods and medicaments is an isoquinoline-3- carboxamide as described in U.S. Patent No. 6,093,730 and 7,323,475. In another embodiment, a compound for use in the present methods and medicaments is an isoquinoline-3-carboxamide as described in U.S. Patent Application Publication No. 2007/0298104. In still another embodiment, a compound for use in the present methods and medicaments is a beta-carboline-3-carboxamide, a pyrrolo[3,2-c]pyridine- 6-carboxamide, a pyrrolo[2,3-c]pyridine-5-carboxamide, a thiazolo[4,5-c]pyridine-6-carboxamide, or a thiazolo[5,4-c]pyridine-6-carboxamide as described in U.S. Patent Application Publication No. 2008/0004309.
In one embodiment, a compound for use in the present methods and medicaments is a thieno[3,2- c]pyridine-6-carboxamide or a thieno[2,3-c]pyridine-5-carboxamide as described in U.S. Patent Application Publication No. 2006/0199836. In another embodiment, a compound for use in the present methods and medicaments is a 2,4-dioxo-l,2,3,4-tetrahydro-pyrimidine-5-carboxamide or a 4-oxo-2- thioxo-l,2,3,4-tetrahydro-pyrimidine-5-carboxamide as described in International Publication No. WO 2007/150011. In yet another embodiment, a compound for use in the present methods and medicaments is a 6-oxo-l,6-dihydro-pyrimidine-5-carboxamide as described in U.S. Patent Application Publication No. 2008/0171756.
In some embodiments, a compound for use in the present methods and medicaments is a 2-oxo-l,2- dihydro-quinoline-3-carboxamide as described in International Publication No. WO 2007/038571 and U.S. Patent Application Publication No. 2007/0249605. In other embodiments, a compound for use in the present methods and medicaments is a 2-oxo-l,2-dihydro-[l,8]naphthyridine-3-carboxamide, a 2-oxo-l,2- dihydro-[l,6]naphthyridine-3-carboxamide, or a 6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazine-7-carboxamide as described in International Publication Nos. WO 2007/103905, WO 2008/076425, and WO 2008/130527. In yet another embodiment, a compound for use in the present methods and medicaments is a 6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxamide, a 5-oxo-4,5-dihydro-thieno[3,2-b]pyridine- 6-carboxamide, or a 6-oxo-6,7-dihydro-pyrazolo[3,4-b]pyridine-5-carboxamide as described in International Publication No. WO 2007/136990.
In one embodiment, a compound for use in the present methods and medicaments is a 3-oxo-2,3-dihydro- pyridazine-4-carboxamide as described in U.S. Patent Application Publication No. 2008/0214549. In other embodiments, a compound for use in the present methods and medicaments is a 3-oxo-3,4-dihydro- naphthalene-2-carboxamide, a 7-oxo-7,8-dihydro-quinoline-6-carboxamide, or a 7-oxo-7,8-dihydro- isoquinoline-6-carboxamide as described in International Publication No. WO 2008/076427. In another embodiment, a compound for use in the present methods and medicaments is a 3 -hydroxy- 1-oxo- IH- indene-2-carboxamide as described in International Publication No. WO 2008/130508.
In another embodiment, a compound for use in the present methods and medicaments is a 4-oxo-[l,10]- phenanthroline as described in U.S. Patent Nos. 5,916,898 and 6,200,974, and International Publication No. WO 99/21860. In one aspect, a 4-oxo-[l,10]-phenanthroline is 4-oxo-l,4-dihydro- [l,10]phenanthroline-3-carboxylic acid (see, e.g., Seki et al. (1974) Chem Abstracts 81:424, No. 21).
In one embodiment, a compound for use in the present methods and medicaments is a hydrozone as described in U.S. Patent No. 6,660,737. In other embodiments, a compound for sue in the present methods and medicaments is a dihydropyrazole or a dihydropyrozolone as described in U.S. Patent No. 6,878,729 and International Publication No. WO 2008/049539. In another embodiment, a compound for use in the present methods and medicaments is a dipyridyl dihyropyrazones as described in International Publication No. WO 2006/114213. In other embodiments, a compound for use in the present methods and medicaments is a spiroindalone as described in International Publication No. WO 2008/144266.
In various embodiments, compounds for use in the present invention are selected from the group consisting of 2-oxoglutarate mimetics, iron chelators, and proline analogs. In preferred embodiments, the compound used in the methods and medicaments of the present invention is a 2-oxoglutarate structural mimetic. In particular embodiments, the compound used in the methods and medicaments of the present invention is a 2-oxoglutarate structural mimetic that inhibits HIF prolyl hydroxylase competitively with respect to 2-oxoglutarate and noncompetitively with respect to iron.
A compound for use in the methods and medicaments of the present invention is, in various embodiments, a cyclic carboxamide. In one aspect of the present embodiment, the cyclic carboxamide is a carbonyl glycine, hi other aspects of the present embodiment, the carboxamide is replaced by a carbonyl proprionic acid. In some embodiments of the present invention, the compound used in the methods and medicaments of the present invention is a carbocyclic carboxamide. In one embodiment, cyclic carboxamides suitable for use in the present invention are heterocyclic carboxamides. In certain embodiments, a compound of the present invention is a heterocyclic carboxamide having a heterocyclic group selected from the group consisting of: azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, furan, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), piperidinyl, pyrrolidine, and tetrahydrofuranyl. In preferred embodiments, the heterocyclic group is a single ring selected from the group consisting of a pyridine, a pyridinone, a pyradizine, a pyridazinone, a pyrimidine, and a pyrimidinone ring. In other preferred embodiments, the heterocyclic group is a multiple condensed ring selected from the group consisting of an isoquinoline, an isoquinolone, a naphthyridinone, a pyrrolopyridine, a pyrrolopyridinone, a pyrozolopyridinone, a pyrrolopyridizinone, a quinoline, a quinolone, a chromenone, a thiochromenone, a thienopyridine, a thienopyridinone, a thiazolopyridine, and a thiazolopyridinone.
In other embodiments, a compound for use in the methods and medicaments of the present invention is selected from the group consisting of an isoquinoline carboxamide, a pyrrolopyridine carboxamide, a thienopyridine carboxamide, a pyrrolopyridizanone carboxamide, and a thiochromenone carboxamide.
A particularly preferred compound of the present invention is a heterocyclic carbonyl glycine. In successive embodiments, the heterocyclic carbonyl glycine suitable for use in the present invention is a heterocyclic carbonyl glycine having a heterocyclic group that is selected from the following list: azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, furan, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), piperidinyl, pyrrolidine, and tetrahydrofuranyl. In certain preferred embodiments, the heterocyclic carbonyl glycine suitable for use in the present invention is a heterocyclic carbonyl glycine having a heterocyclic group, wherein the heterocyclic group is a single ring selected from the following list: a pyridine, a pyridinone, a pyradizine, a pyridazinone, a pyrimidine, and a pyrimidinone ring. In other preferred embodiments, the heterocyclic carbonyl glycine suitable for use in the present invention is a heterocyclic carbonyl glycine having a heterocyclic group, wherein the heterocyclic group is a multiple condensed ring selected from the group consisting of an isoquinoline, an isoquinolone, a naphthyridinone, a pyrrolopyridine, a pyrrolopyridinone, a pyrozolopyridinone, a pyrrolopyridizinone, a quinoline, a quinolone, a chromenone, a thiochromenone, a thienopyridine, a thienopyridinone, a thiazolopyridine, and a thiazolopyridinone. In certain embodiments, a compound for use in the present methods and medicaments is a heterocyclic carbonyl glycine selected from the group consisting of an isoquinoline carbonyl glycine, a pyrrolopyridine carbonyl glycine, a thienopyridine carbonyl glycine, a pyrrolopyridizanone carbonyl glycine, and a thiochromenone carbonyl glycine.
In another embodiment, a compound for use in the present methods and medicaments is an isoquinoline- 3-carbonyl-glycine. In other embodiments, a compound for use in the present methods and medicaments is a 4-hydroxy-isoquinoline-3-carbonyl-glycine. In particular embodiments, a compound for use in the present methods and medicaments is [(l-Chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound S); [^-Bromo^-hydroxy-isoquinoline^-carbonyO-aminol-acetic acid (Compound T); {[4- Hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound A); {[7-(4- Fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound U); [(4-Hydroxy-l- methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound B); {[7-(3,4-Difluoro- phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound V); {[7-(3-Chloro-4- fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound W); {[4-Hydroxy- 7-(2-methyl-benzothiazol-6-yloxy)-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound X); [(7- Chloro-4-hydroxy-l-methyl-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound Y); [(l-Cyano-4- hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound Z); [(4-Hydroxy-8- phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound AB); [(4-Hydroxy-l-methyl-8- phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound AC); [(l-Cyano-4-hydroxy-8-phenoxy- isoquinoline-3-carbonyl)-amino] -acetic acid (Compound AD); {[8-(4-Fluoro-phenoxy)-4-hydroxy-l- methyl-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound AE); {[l-Cyano-8-(4-fluoro-phenoxy)- 4-hydroxy-isoquinoline-3 -carbonyl] -amino} -acetic acid (Compound AF); [(l-Cyano-4-hydroxy-6- phenoxy-isoquinoline-3-carbonyl)-amino] -acetic acid (Compound AG); {[l-Cyano-6-(4-fluoro-phenoxy)- 4-hydroxy-isoquinoline-3 -carbonyl] -amino} -acetic acid (Compound D); {[l-Cyano-6-(2,6-dimethyl- phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound E); [(l-Cyano-4-hydroxy- 5 -phenoxy-isoquinoline-3-carbonyl)-amino] -acetic acid (Compound AH); [(l-Cyano-4-hydroxy-7- isopropoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound H); {[l-Cyano-5-(4-fluoro- phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound G); {[l-Cyano-7-(2,6- dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound AI); {[6-(4- Chloro-2,6-dimethyl-phenoxy)-l-cyano-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound J); {[5-(4-Chloro-phenoxy)-l-cyano-4-hydroxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound K); {[1 -Cyano-4-hydroxy-5-(4-methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound N); {[l-Cyano-4-hydroxy-5-m-tolyloxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound AY); [(l-Cyano-4-hydroxy-5-p-tolyloxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound BA); { [5 -(3 -Chloro-phenoxy)- 1 -cyano^-hydroxy-isoquinoline-S -carbonyl] -amino } -acetic acid (Compound BB); or {[l-Cyano-4-hydroxy-7-(3-methoxy-phenoxy)-isoquinoline-3-carbonyl]- amino} -acetic acid (Compound BE).
In one embodiment, a compound for use in the present methods and medicaments is a pyrrolopyridine carbonyl glycine. In one aspect of the present embodiment, a compound for use in the present methods and medicaments is a pyrrolo[2,3-c]pyridine-5-carbonyl-glycine. In other embodiments, a compound for use in the present methods and medicaments is a pyrrolo[2,3-c]pyridine-5-carbonyl-glycine or a 4- hydroxy-pyrrolo[2,3-c}pyridine-5-carbonyl-glycine. In particular embodiments, a compound of the present methods and medicaments is [(l-Benzyl-3-chloro-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine- 5-carbonyl)-amino]-acetic acid (Compound F); {[7-Cyano-l-(4-fluoro-benzyl)-4-hydroxy-lH- pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound O); {[3-Chloro-7-cyano-l-(4-fluoro- benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound P); {[(R)-2,3- Dichloro-7-cyano-4-hydroxy- 1 -( 1 -phenyl -ethyl)- 1 H-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -acetic acid (Compound L); {[3-Bromo-7-cyano-4-hydroxy-l-(4-methoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5- carbonyl]-amino} -acetic acid (Compound AJ); {[2,3-Dichloro-7-cyano-4-hydroxy-l-(4-methoxy-benzyl)- lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AK); {[(S)-2,3-Dichloro-7-cyano- 4-hydroxy-l -(I -phenyl-ethyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -acetic acid (Compound AL); {[3-Chloro-7-cyano-4-hydroxy-l-(4-methoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]- amino}-acetic acid (Compound AM); {[7-Cyano-l-(2-fluoro-benzyl)-4-hydroxy-lH-pyrrolo[2,3- c]pyridine-5-carbonyl]-amino}-acetic acid (Compound I); {[7-Cyano-4-hydroxy-l-(3-methoxy-benzyl)- lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound M); {[3-Chloro-7-cyano-l-(2- fluoro-benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -acetic acid (Compound AN); {[3-Chloro-7-cyano-4-hydroxy-l-(3-methyl-butyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -acetic acid (Compound AO); [(2,3-Dichloro-7-cyano-4-hydroxy-l-naphthalen-2-ylmethyl-lH-pyrrolo[2,3- c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AP); [(7-Cyano-4-hydroxy-l-naphthalen-2- ylmethyl-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound R); {[7-Cyano-l-(2- fluoro-benzyl)-4-hydroxy-2-trifluoromethyl-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AQ); [(l-Benzyl-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AR); [(3-Chloro-7-cyano-l-hexyl-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)- amino]-acetic acid (Compound AS); {[3-Chloro-7-cyano-4-hydroxy-l-(2-trifluoromethyl-benzyl)-lH- pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AT); [(l-Biphenyl-4-ylmethyl-7- cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AU); [(I - Biphenyl-4-ylmethyl-2,3-dichloro-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]- acetic acid (Compound AV); [(l-Biphenyl-4-ylmethyl-3-chloro-7-cyano-4-hydroxy-lH-pyrrolo[2,3- c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AW); {[2,3-Dichloro-7-cyano-4-hydroxy-l-(4- isopropoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -acetic acid (Compound AX); {[7- Cyano-4-hydroxy-l-(4-isopropoxy-benzyl)-3a,7a-dihydro-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]- amino}-acetic acid (Compound AZ); {[3-Chloro-7-cyano-4-hydroxy-l-(4-isopropoxy-benzyl)-lH- pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound BC); (S)-2-{[2,3-Dichloro-7-cyano-4- hydroxy- 1 -(4-isopropoxy-benzyl)- lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -propionic acid (Compound BD); or [(l-Benzyl-2,3-dichloro-7-cyano-4-hydroxy-lH-pyrτolo[2,3-c]pyridine-5-carbonyl)- amino] -acetic acid (Compound Q).
In another embodiment, a compound for use in the present methods and medicaments is a thienopyridine carbonyl glycine. In one aspect of the present embodiment, the compound is a thieno[3,2-c]pyridine-6- carbonyl-glycine. In another aspect the compound is a 7-hydroxy-thieno[3,2-c]pyridine-6-carbonyl- glycine. In particular aspects, the compound is [(4-Cyano-7-hydroxy-thieno[3,2-c]pyridine-6-carbonyl)- amino]-acetic acid (Compound AA).
In one embodiment, a compound for use in the present methods and medicaments is a pyrrolopyridizinone carbonyl glycine, a 2-oxo-pyrrolo[l,2-b]pyridazine-3-carbonyl-glycine, or a 4-hydroxy-2-oxo- pyrrolo[l,2-b]pyridazine-3-carbonyl-glycine. In particular embodiments, a compound for use in the present methods and medicaments is {[4-Hydroxy-2-oxo-l-(4-trifluoromethyl -benzyl)- 1, 2 -dihydro- pyrrolo[l,2-b]pyridazine-3-carbonyl}-amino} -acetic acid (Compound BG).
In other embodiments, a compound for use in the present methods and medicaments is a thiochromenone carbonyl glycine. In one embodiment, a compound for use in the present methods and medicaments is a 2-oxo-thiochromenone-3-carbonyl-glycine. In another embodiment, a compound for use in the present methods and medicaments is a 4-hydroxy-2-oxo-thiochromenone-3 -carbonyl -glycine. In particular embodiments, a compound for use in the present methods and medicaments is [(4-Hydroxy-2-oxo-2H- thiochromene-3-carbonyl)-amino]-acetic acid (Compound BF).
In one embodiment, a compound for use in the methods and medicaments of the present invention is a HIF prolyl hydroxylase inhibitor compound of Formula I:
Figure imgf000012_0001
wherein X is an optionally substituted cyclic moiety and R' is hydrogen or (d-C4)-alkyl. In particular embodiments, the cyclic moiety is a hetercyclic moiety and R' is hydrogen. Such prolyl hydroyxlase inhibitors (PHIs) include, but are not limited to, variously substituted pyridine-2-carbonyl-glycines, pyridazine-3-carbonyl-glycines, quinoline-2-carbonyl-glycines, 2-oxo-l,2-dihydro-quinoline-3-carbonyl- glycines, 2-oxo-l ^-dihydro-naphthyridine-S-carbonyl-glycines, 6-oxo-4,6-dihydro-pyridopyrazine-7- carbonyl-glycines, isoquinoline-S-carbonyl-glycines, cinnoline-S-carbonyl-glycines, thienopyridine-6- carbonyl-glycines, thienopyridine-5 -carbonyl -glycines, thiazolopyridine-6-carbonyl-glycines, thiazolopyridine-5-carbonyl-glycines, hydroxy-pyrrolopyridine-β-carbonyl-glycines, and pyrrolopyridine- 5-carbonyl-glycines.
In another embodiment, a compound for use in the methods and medicaments of the present invention is a compound of Formula II:
Figure imgf000013_0001
wherein:
R1, R2, R3, R4 and R5 are identical or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl; (C1-C20)- alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkoxy, (C6-C12)-aryl, (C7-C16)-aralkyl, (C7-C16)-aralkenyl, (C7-C16)-aralkynyl, (C2-C2O)-alkenyl, (C2-C20)-alkynyl, (C1- C20)-alkoxy, (C2-C20)-alkenyloxy, (C2-C20)-alkynyloxy, retinyloxy, (C6-Ci2)- aryloxy, (C7-C 16)-aralkyloxy, (C,-C16)-hydroxyalkyl, -O-[CH2]xCfH(2f+1-g)Fg, - OCF2Cl, -OCF2-CHFCl, (C,-C20)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C6-C12)-arylcarbonyl, (C7-Ci6)-aralkylcarbonyl, cinnamoyl, (C2-C20)- alkenylcarbonyl, (C2-C20)-alkynylcarbonyl, (Ci-C20)-alkoxycarbonyl, (C6-Ci2)- aryloxycarbonyl, (C7-C]6)-aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2- C20)-alkenyloxycarbonyl, retinyloxycarbonyl, (C2-C20)-alkynyloxycarbonyl, (C1- Ci2)-alkylcarbonyloxy, (C3-C8)-cycloalkylcarbonyloxy, (C6-C12)- arylcarbonyloxy, (C7-C 16)-aralkylcarbonyloxy, cinnamoyloxy, (C2-C12)- alkenylcarbonyloxy, (C2-Ci2)-alkynylcarbonyloxy, (CrCi2)-alkoxycarbonyloxy, (C6-Ci2)-aryloxycarbonyloxy, (C7-C16)-aralkyloxycarbonyloxy, (C3-C8)- cycloalkoxycarbonyloxy, (C2-C12)-alkenyloxycarbonyloxy, (C2-C12)- alkynyloxycarbonyloxy, carbamoyl, N-(Ci-Ci2)-alkylcarbamoyl, N,N-di-(Cr C12)-alkylcarbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N,N-dicyclo-(C3-C8)- alkylcarbamoyl, N-(C1-C10)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-((C3-C8)- cycloalkyl-(C1-C6)-alkyl)-carbamoyl, N-(+)-dehydroabietylcarbamoyl, N-(Ci- C6)-alkyl-N-(+)-dehydroabietylcarbamoyl, N-(C6-Ci2)-arylcarbamoyl, N-(C7- C,6)-aralkylcarbamoyl, N-(C1-C1o)-alkyl-N-(C6-C,6)-arylcarbamoyl, N-(C1-C10)- alkyl-N-(C7-Ci6)-aralkylcarbamoyl, carbamoyloxy, N-(C1-C12)- alkylcarbamoyloxy, N,N-di-(C1-C12)-alkylcarbamoyloxy, N-(C3-C8)- cycloalkylcarbamoyloxy, N-(C6-C 12)-arylcarbamoyloxy, N-(C7-C16)- aralkylcarbamoyloxy, N-(Ci -C10)-alkyl-N-(C6-C12)-arylcarbamoyloxy, N-(C1 - C 10)-alkyl-N-(C7-C ] 6)-aralkylcarbamoyloxy , N-((C ] -C] 0)-alkyl)-carbamoyloxy , N-(C1-C10)-alkyl-N-((C7-C]6)-aralkyloxy-(C1-C1o)-alkyl)-carbamoyloxyamino, (C1-Ci2)-alkylamino, (Ii-(C1 -C12)-alkylamino, (C3-C8)-cycloalkylamino, (C3-C12)- alkenylamino, (C3-Ci2)-alkynylamino, N-(C6-C 12)-arylamino, N-(C7-C11)- aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C1-C12)-alkoxyamino, (C1-C12)-alkoxy-N-(Ci-C10)-alkylamino, (CrCi2)-alkanoylamino, (C3-C8)- cycloalkanoylamino, (C6-C 12)-aroylamino, (C7-C16)-aralkanoylamino, (C1-C12)- alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cycloalkanoyl-N-(C]-C10)-alkylammo, (C6-C12)-aroyl-N-(C1-C1o)-alkylamino, (C7-C1,)-aralkanoyl-N-(C1-C10)- alkylamino, amino-(C i-C10)-alkyl, (Q-C^-alkylmercapto, (C]-C20)-alkylsulfinyl, (CrC20)-alkylsulfonyl, (C6-C12)-arylmercapto, (C6-C12)-arylsulfmyl, (C6-C]2)- arylsulfonyl, (C7-C16)-aralkylmercapto, (C7-C16)-aralkylsulfϊnyl, (C7-C16)- aralkylsulfonyl, sulfamoyl, N-(C]-C10)-alkylsulfamoyl, N5N-(U-(C1-C10)- alkylsulfamoyl, (C3-C8)-cycloalkylsulfamoyl, N-(C6-C12)-arylsulfamoyl, N-(C7- C16)-aralkylsulfamoyl, N-(C1-Cio)-alkyl-N-(C6-Ci2)-arylsulfamoyl, N-(Ci-C10)- alkyl-N-(C7-C16)-aralkylsulfamoyl,
Figure imgf000014_0001
(C7-C16)- aralkylsulfonamido, and N-((Ci-C10)-alkyl-(C7-Ci6)-aralkylsulfonamido, (C6- C12)-heteroaryl, (C7-C]6)-heteroaralkyl; where an aryl or heteroaryl radical may be substituted by 1 to 5 substituents selected from hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (C2-Ci6)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)- cycloalkoxy, (C6-C12)-aryl, (C7-C,6)-aralkyl, (C2-Ci6)-alkenyl, (C2-C ]2)-alkynyl, (CrCi6)-alkoxy, (C!-C16)-alkenyloxy, (C6-Ci2)-aryloxy, (C7-C, 6)-aralkyloxy, (C1- C8)-hydroxyalkyl, -O-[CH2]xC,H(2f+1.g)Fg, -OCF2Cl, and -OCF2-CHFCl; x is 0 to 3; f is 1 to 8; and g is 0 or 1 to (2f+l); or a pharmaceutically acceptable salt, single stereoisomer, mixture of stereoisomers, ester, or prodrug thereof. In one embodiment, a compound of the present invention is a compound of Formula II wherein: R1 is selected from hydrogen, halo, (Ci-C3)-alkyl, or cyano; R2 is selected from hydrogen or aryloxy, wherein the aryl is optionally substituted with halo, (CrC3)-alkyl, or (Ci-C3)-alkoxy; R3 is hydrogen or aryloxy, wherein the aryl is optionally substituted with one or two halo,
(CrC3)-alkyl, or (CrC3)-alkoxy; R4 is selected from hydrogen, halo, (Ci-C3)-alkoxy, aryloxy, wherein the aryl is optionally substituted with one or two halo, (Ci-C3)-alkyl, or (CrC3)-alkoxy or heteroaryloxy optionally substituted with (Ci-C3)-alkyl; and R5 is selected from hydrogen or aryloxy optionally substituted with halo.
In another embodiment, a compound suitable for use in the present methods and medicaments is a compound of Formula II wherein:
R1 is selected from hydrogen, chloro, methyl, or cyano;
R2 is selected from hydrogen, phenoxy, 4-fluorophenoxy, 3-chlorophenoxy, 4- chlorophenoxy, 4-methoxy-phenoxy, 3-methylphenoxy, 4-methylphenoxy;
R3 is hydrogen, phenoxy, 4-fluoro-phenoxy, 2,6-dimethyl-phenoxy, 4-chloro-2,6- dimethyl-phenoxy;
R4 is selected from hydrogen, chloro, bromo, isopropoxy, phenoxy, 2,6-dimethyl- phenoxy, 3-methoxy-phenoxy, 4-methoxy-phenoxy, 4-fluorophenoxy, 3,4- difluorophenoxy, 3-chloro-4-fluorophenoxy, or 2-methyl-benzothiazol-6-yloxy; and
R5 is selected from hydrogen, phenoxy, or 4-fluorophenoxy.
In yet another embodiment, a compound for use in the methods and medicaments of the present invention is a compound of Formula III
Figure imgf000015_0001
wherein: one of A or B is =C(R7)- and the other is -N(R9)-;
— independently represents a single or a double bond;
R6 is selected from the group consisting of hydrogen, halo, cyano, (CrC3)-alkyl, and aryl; R7 is selected from the group consisting of hydrogen, halo, cyano, (Ci-C6)-alkyl, and aryl, wherein the aryl is optionally substituted by one or two halo;
R8 is selected from the group consisting of hydrogen, halo, cyano, (Ci-C6)-alkyl, trifiuoromethyl, and aryl optionally substituted with halo; and
R9 is selected from the group consisting of hydrogen, (Ci-Cio)-alkyl, (C1 -C3^aIkVl-(C1- C,o)-alkyl, (C,-C3)-alkoxy-(Ci-C6)-alkyl, (C4-C6)-cycloalkyl, (C4-C6)-cycloalkyl- (Ci-C3)-alkyl, aryl, (C7-Ci2)-aralkyl, aryl-aralkyl, and heteroaralkyl; where in each case an aryl or heteroaryl may be optionally substituted by one or two halo, trifiuoromethyl, or (C]-C4)-alkoxy; or pharmaceutically acceptable salts, single stereoisomers, mixtures of stereoisomers, esters, or prodrugs thereof.
m one embodiment, a compound of the present invention is a compound of Formula III wherein:
A is =C(R7)-;
B is -N(R9)-;
R6 is cyano;
R7 is selected from hydrogen or halogen;
R8 is selected from hydrogen, halo, or trifiuoromethyl; and
R9 is selected from (CrCio)-alkyl, (Ci-C3)-alkyl-(Ci-C10)-alkyl, (C1-C3^aIkOXy-(C1-C6)- alkyl, (C7-C 12)-aralkyl or aryl-aralkyl, wherein each aryl is optionally substituted with halo, (C1-C3)^aIkOXy, or trifiuoromethyl..
In another embodiment, a compound of the present invention is a compound of Formula III wherein:
R6 is cyano;
R7 is selected from hydrogen, chloro, or bromo.
R8 is hydrogen, chloro, trifiuoromethyl; and
R9 is selected from methyl-butyl, hexyl, methoxy-methyl, naphthalen-2-yl-methyl, benzyl, 4-fluorobenzyl, 1-phenyl-ethyl, 4-methoxy-benzyl, 2-fluoro-benzyl, 2- trifluoromethyl-benzyl, biphenyl-4-yl-methyl, or 4-isopropoxy-benzyl. In other embodiments, a compound for use in the claimed methods and medicaments is a compound of Formula IV
Figure imgf000017_0001
wherein:
R10 is selected from the group consisting of hydrogen, bromo, cyano, (Ci-C4)-alkyl, (C1-
C4)-alkynyl, heterocyclycl, heteroaryl, and aryl optionally substituted with halo. R11 is selected from hydrogen or 4-fluorophenyl; R12 is selected from hydrogen, methyl, (E)-styryl, 2-(trifluoromethyl)-phenyl, 3-
(trifluoromethyl)-phenyl, 4-(trifiuoromethyl)-phenyl, 4-fluorophenyl, 4- methoxyphenyl, 4-phenoxyphenyl, bromo, phenethyl, phenoxy, phenyl, phenylsulfanyl and pharmaceutically acceptable salts, single stereoisomers, mixtures of stereoisomers, esters, and prodrugs thereof.
In one embodiment, a compound of the present invention is a compound of Formula IV wherein:
R10 is cyano; and
R11 and R12 are hydrogen.
In one aspect of the present invention, it is contemplated that a compound suitable for use in the claimed methods and medicaments is a compound of Formula V
Figure imgf000017_0002
wherein:
R13 is (C7-C i2)-aralkyl optionally substituted on the aryl with one or two substituents selected from the group consisting of halo, trifluoromethyl, and (d-C3)-alkoxy; and R14, R15, and R16 are hydrogen. In one embodiment, a compound for use in the present invention is a compound of Formula V wherein: R13 is aralkyl optionally substituted on the aryl with trifluoromethyl; R14 is hydrogen; R15 is hydrogen; and R16 is hydrogen.
In another embodiment, a compound for use in the present invention is a compound of Formula V wherein:
R13 is 4-trifluoromethyl-benzyl;
R14 is hydrogen;
R15 is hydrogen; and
R16 is hydrogen.
In other embodiments, a compound for use in the present methods and medicaments is a compound of Formula VI
Figure imgf000018_0001
wherein:
R17 is hydrogen
R18 is hydrogen, halo, or (Ci-C3)-alkoxy;
R19 is hydrogen, halo, (Ci -C3)-alkyl, (Ci-C6)-alkoxy, aryl optionally substituted with one or two substituents selected from the group consisting of halo, (C!-C3)-alkoxy, and trifluoromethyl; heteroaryl optionally substituted with halo; or aralkoxy; and
R20 is hydrogen or (C,-C3)-alkyl.
In some embodiments, a compound for use in the present invention is a compound of Formula VI wherein R17 is hydrogen; R18 is hydrogen; R19 is hydrogen; and R20 is hydrogen.
In other embodiments, a compound of the present invention is a compound of Formula VI wherein: R17, R18, R19, and R20 are hydrogen. Pharmaceutical compositions or medicaments effective for use in any of the present methods are provided herein. In various embodiments, the compositions comprise an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase and an acceptable carrier.
It is further contemplated that, in various embodiments, the methods and compounds of the present invention are used in combination with administration of one or more other therapeutic agents. Other therapeutic agents for use in the present methods include white blood cell stimulating factors, such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and stem cell factor (SCF). Other therapies for use in combination with the present methods and compounds include chemotherapy and radiation therapy. These therapeutic agents can be administered in subsequent or coordinate fashion.
These and other embodiments of the present invention will readily occur to those of skill in the art in light of the disclosure herein, and all such embodiments are specifically contemplated.
DESCRIPTION OF THE INVENTION
Before the present compositions and methods are described, it is to be understood that the invention is not limited to the particular methodologies, protocols, cell lines, assays, and reagents described, as these may vary. It is also to be understood that the terminology used herein is intended to describe particular embodiments of the present invention, and is in no way intended to limit the scope of the present invention as set forth in the appended claims.
It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless context clearly dictates otherwise. Thus, for example, a reference to "a HIF prolyl hydroxylase enzyme" may include a plurality of such enzymes; a reference to a "compound that inhibits the activity of a hypoxia-inducible factor prolyl hydroxylase enzyme" may be a reference to one or more compounds that inhibits the activity of a hypoxia-inducible factor prolyl hydroxylase enzyme, and so forth.
Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All publications cited herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing the methodologies, reagents, and tools reported in the publications that might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
The practice of the present invention will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, molecular biology, cell biology, genetics, immunology and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., Gennaro, A.R., ed. (1990) Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co.; Hardman, J.G., Limbird, L.E., and Gilman, A.G., eds. (2001) The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill Co.; Colowick, S. et al., eds., Methods In Enzymology, Academic Press, Inc.; Weir, D.M., and Blackwell, CC, eds. (1986) Handbook of Experimental Immunology, VoIs. I-IV, Blackwell Scientific Publications; Maniatis, T. et al., eds. (1989) Molecular Cloning: A Laboratory Manual, 2nd edition, VoIs. I-III, Cold Spring Harbor Laboratory Press; Ausubel, F.M. et al., eds. (1999) Short Protocols in Molecular Biology, 4th edition, John Wiley & Sons; Ream et al., eds. (1998) Molecular Biology Techniques: An Intensive Laboratory Course, Academic Press; Newton, CR., and Graham, A., eds. (1997) PCR (Introduction to Biotechniques Series), 2nd ed., Springer Verlag.
The section headings are used herein for organizational purposes only, and are not to be construed as in any way limiting the subject matter described herein.
Methods
The present invention provides methods and compounds for increasing white blood cell levels in a subject. In one embodiment, the present invention provides a method for increasing white blood cell levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing white blood cell levels in the subject. The invention also provides compounds for use in manufacturing a medicament for increasing white blood cell levels in a subject, wherein the compound inhibits the activity of a HIF prolyl hydroxylase enzyme. In certain aspects, the methods and compounds of the present invention are effective at increasing white blood cell levels in a subject, wherein the subject has or is at risk for having reduced white blood cell levels.
Detection and quantitation of white blood cells can be performed by any method known or available to those skilled in the art. For example, detection of total white blood cells in a sample obtained from a subject is performed by complete blood count using a CellDyn cell analyzer (Abbott Laboratories) as previously described. (Kendall et al. (2003) Lab Hematol 9:143-52.) In addition to total white blood cell count, complete blood counts can identify and quantify neutrophil, basophil, lymphocyte, monocyte, and eosinophil levels in a sample. In human blood, a normal range of leukocytes (i.e. white blood cells) is about 4.3-10.8 x 103/μl; a normal range of neutrophils is about 1.9-8.0 x 103/μl or about 45-74% of white blood cells; a normal range of lymphocytes is about 0.7-4.9 x 103/μl or about 16-45% of white blood cells; a normal range of monocytes is about 0.2-1.1 x 103/μl or about 4-10% of white blood cells; a normal range of eosinophils is about 0-0.8 x 103/μl or about 0-7% of white blood cells; and a normal range of basophils is about 0-0.2 x 103/μl or about 0-2% of white blood cells. (See Harrison et al., eds. (2001) Principles of Internal Medicine, 15th edition, McGraw-Hill.) In one aspect, the present invention provides methods and compounds for maintaining or achieving a normal range of white blood cell levels in a subject. In another aspect, the present invention provides methods and compounds for maintaining or achieving a normal range of lymphocytes, monocytes, eosinophils, neutrophils, or basophils in a subject.
In one embodiment, the methods and compounds of the present invention are useful for increasing white blood cell levels in blood in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing white blood cell levels in blood in the subject. In another embodiment, the methods and compounds of the present invention are useful for increasing white blood cell levels in bone marrow of a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing white blood cell levels in bone marrow in the subject.
The present invention provides methods for increasing the levels of specific types of white blood cells, including, for example, methods for increasing the levels of neutrophils, lymphocytes, basophiles, eosinophils, macrophages, or monocytes. Complete blood counts can quantify the levels of neutrophils, lymphocytes, monocytes, macrophages, basophils, and eosinophils in a sample. (Kendall et al. (2003) Lab Hematol 9:143-52.) Other methods are available to identify and quantify specific types of white blood cells. For example, neutrophils can be identified using flow cytometry, as well as other methods, by the presence of two characteristic and identifying neutrophil cell surface markers: Mac-1 and Gr-I (other aliases for Gr-I include CDl Ib). (Legasse et al (1996) J Immunol Methods 197:139-50).
Therefore, in certain embodiments, the methods and compounds of the present invention are useful for increasing neutrophil levels, wherein the neutrophils are positive for expression of both Mac-1 and Gr-I cell-surface markers (i.e., double positive; Mac-1+/Gr-1+). In one embodiment, the present invention provides a method for increasing neutrophil levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing neutrophil levels in the subject. In certain aspects, the neutrophils are positive for Mac-1 and Gr-I expression. Adult white blood cells derive primarily from bone marrow, and are mobilized from bone marrow to blood. It is an object of the present invention to provide methods and compounds that increase white blood cell mobilization. In one embodiment, the methods and compounds of the present invention are useful for increasing mobilization of white blood cells in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing mobilization of white blood cells in the subject. In certain aspects, the mobilization of white blood cells is mobilization from bone marrow to blood.
In various conditions or as a consequence of various exogenous stimuli, including, for example, infections (e.g., viral infections, HIV, bacterial infections, and fungal infections), autoimmune disorders (e.g., lupus), various medications (e.g., chemotherapeutic agents, antibiotics, corticosteroids, and immunosuppressive drugs), radiation therapy, and certain bone marrow diseases (e.g., leukemia and myelodysplasia syndromes), white blood cell mobilization and white blood cell levels are reduced. In certain embodiments, the methods and compounds of the present invention are effective at increasing white blood cell mobilization in a subject, wherein the subject has or is at risk for having reduced white blood cell mobilization. In other embodiments, the methods and compounds of the present invention are effective at increasing white blood cell levels in a subject, wherein the subject has or is at risk for having reduced white blood cell levels.
By increasing white blood cell levels, the present methods are useful for treating or preventing various disorders associated with reduced white blood cell levels, including, for example, leukopenia, neutropenia, or lymphocytopenia. Therefore, in some embodiments, the present invention provides methods for treating or preventing leukopenia, neutropenia, or lymphocytopenia, the methods comprising administering to a subject an effective amount of a compound that inhibits HIF prolyl hydroxylase enzyme activity, thereby providing treatment of leukopenia, neutropenia, or lymphocytopenia. In some aspects, the leukopenia, neutropenia, or lymphocytopenia is associated with chemotherapy or radiation therapy.
It is further contemplated that, in various embodiments, the methods and compounds of the present invention are used in combination with administration of one or more other therapeutic agents. Other therapeutic agents (administered in subsequent or coordinate fashion) for use in the present methods include, for example, white blood cell stimulating factors, such as G-CSF, GM-CSF, and SCF.
The present methods and compounds are useful for and effective at increasing white blood cell levels in a subject, wherein the white blood cells are functional white blood cells, i.e., a white blood cell that is able to differentiate into a mature white blood cell (e.g., a neutrophil, basophil, monocyte, eosinophil, or lymphocyte). Various cell culture methods are available to identify functional white blood cells. (See, e.g., Lu et al. (1985) Exp Hematol 13:989; Blazsek et al (1999) Bone Marrow Transplant 23:647- 657.) In these culture methods, adult peripheral blood mononuclear cells are plated on dishes in a methyl cellulose cloning media in the presence of GM-CSF. Colonies are counted after 8-14 days of incubation. Such colonies are referred to as colony-forming unit granulocyte-macrophage (CFU-GM) and represent functional white blood cells.
The present invention also provides a method for increasing hematopoietic progenitor cell levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme, thereby increasing hematopoietic progenitor cell levels in the subject. In certain aspects, the hematopoietic progenitor cell is positive for Sca-1 and c-Kit expression (i.e., Sca-l+/c-Kit+).
Subjects
The present invention relates to methods for increasing white blood cell mobilization and for increasing white blood cell levels in a subject by administration of an effective amount of a compound that inhibits the activity of a HIF prolyl hydroxylase enzyme to the subject.
The invention is applicable to a variety of different organisms, including, for example, vertebrates, large animals, and primates. In a preferred embodiment, the subject is a mammalian subject, and in a most preferred embodiment, the subject is a human subject. However, although medical applications with humans are clearly foreseen, veterinary applications are also envisaged herein.
The methods of the present invention are particularly suitable for subjects who would benefit from increased white blood cell mobilization or increased white blood cell levels. In some aspects, a suitable subject is a subject that has low or reduced white blood cell levels, or is at risk for having low or reduced white blood cell levels. In certain aspects, a subject that has or is at risk for having low or reduced white blood cell levels is a subject having or at risk for having a condition or is a subject undergoing treatment with any of a number of agents associated with reduced white blood cell levels. Such conditions or treatments include infections (e.g., viral infections, HIV, bacterial infections, and fungal infections), autoimmune disorders (e.g., lupus), various medications (e.g., chemotherapeutic agents, antibiotics, corticosteroids, and immunosuppressive drugs), radiation therapy, and certain bone marrow diseases (e.g., leukemia and myelodysplastic syndromes). In other aspects, a suitable subject is a subject that has normal white blood cell levels, hi yet other aspects, a suitable subject is a subject that has high or increased white blood cell levels. In some embodiments, a suitable subject for the present methods is a subject having or at risk for having leukopenia. In other embodiments, a suitable subject for the present methods is a subject having or at risk for having neutropenia. In yet other embodiments, a suitable subject for the present methods is a subject having or at risk for having lymphocytepenia. In various aspects, the leukopenia, the neutropenia, or the lymphocytopenia is associated with chemotherapy or radiation therapy.
Whether a subject has low (reduced), normal, or high (increased) white blood cell levels is determined by any measure accepted and utilized by those skilled in the art.
A suitable subject who would benefit by the compounds and methods of the present invention includes a subject having or at risk for having a hematopoietic disorder, such as a leukemia, a drug-induced leukopenia, and a leukopenic deficit resulting from chemotherapy or radiation therapy. The method of the present invention is further useful for treating subjects who are immuno-compromised or whose immune system is otherwise impaired. A suitable subject who would benefit by the compounds and methods of the present invention includes a subject infected with a retrovirus, such as human immunodeficiency virus (HIV). The method of the invention thus targets conditions characterized by a deficiency in white blood cell levels, or which would benefit from elevation of white blood cell levels.
Compounds
Compounds for use in the methods or medicaments provided herein are inhibitors of HIF prolyl hydroxylase enzymes. The term "HIF prolyl hydroxylase," as used herein, refers to any enzyme that is capable of hydroxylating a proline residue within an alpha subunit of HIF. Such HIF prolyl hydroxylases include protein members of the EGL-9 (EGLN) 2-oxoglutarate- and iron-dependent dioxygenase family described by Taylor (2001) Gene 275:125-132; and characterized by Aravind and Koonin (2001) Genome Biol 2:RESEARCH0007; Epstein et al. (2001) Cell 107:43-54; and Bruick and McKnight (2001) Science 294:1337-1340. Examples of HIF prolyl hydroxylases include human SM-20 (EGLNl) (GenBank Accession No. AAG33965; Dupuy et al. (2000) Genomics 69:348-54), EGLN2 isoform 1 (GenBank Accession No. CAC42510; Taylor, supra), EGLN2 isoform 2 (GenBank Accession No. NP_060025), and EGLN3 (GenBank Accession No. CAC4251); mouse EGLNl (GenBank Accession No. CAC42515), EGLN2 (GenBank Accession No. CAC42511), and EGLN3 (SM-20) (GenBank Accession No. CAC42517); and rat SM-20 (GenBank Accession No. AAAl 9321). Additionally, HIF prolyl hydroxylase may include Caenorhabditis elegans EGL-9 (GenBank Accession No. AAD56365) and Drosophila melanogaster CGl 114 gene product (GenBank Accession No. AAF52O5O). The term "HIF prolyl hydroxylase" also includes any active fragment of the foregoing full-length proteins. A compound that inhibits the activity of a HIF prolyl hydroxylase enzyme refers to any compound that reduces or otherwise modulates the activity of at least one HIF prolyl hydroxylase enzyme. A compound may additionally show inhibitory activity toward one or more other 2-oxoglutarate- and iron-dependent dioxygenase enzymes, e.g. factor inhibiting HIF (FIH; GenBank Accession No. AAL27308), procollagen prolyl 4-hydroxylase (cP4H), etc. In particular embodiments, compounds used in the present methods and medicaments provided herein are structural mimetics of 2-oxoglutarate, wherein the compound inhibits the target HIF prolyl hydroxylase enzyme competitively with respect to 2-oxoglutarate and noncompetitively with respect to iron. Examples of compounds that may be used in the methods and medicaments provided herein can be found, e.g., in Majamaa et al. (1984) Eur. J. Biochem. 138:239-245; Majamaa et al. (1985) Biochem. J. 229: 127-133; Kivirikko, and Myllyharju (1998) Matrix Biol. 16:357- 368; Bickel et al. (1998) Hepatology 28:404-411; Friedman et al. (2000) Proc. Natl. Acad. Sci. USA 97:4736-4741; Franklin (1991) Biochem. Soc. Trans. 19):812-815; and Franklin et al. (2001) Biochem. J. 353:333-338. Additionally, compounds that inhibit HIF prolyl hydroxylase enzyme activity or stabilize HIFαhave been described in, e.g., International Publication Nos. WO 03/049686, WO 02/074981, WO 03/080566, WO 2004/108681, WO 2006/094292, WO 2007/038571, WO 2007/090068, WO 2007/070359, WO 2007/103905, and WO 2007/115315.
Examples of additional compounds that may be used in the methods and medicaments provided herein include, but are not limited to, heterocyclic carboxamides (including pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, quinolone carboxamides, cinnoline carboxamides, or beta- carboline carboxamides), phenanthrolines, hydroxamates, and variously substituted 3-hydroxy-pyridine- 2-carbonyl-glycines, 4-hydroxy-pyridazine-3-carbonyl-glycines, 3-hydroxy-quinoline-2-carbonyl- glycines, 4-hydroxy-2 -oxo-1, 2-dihydro-quinoline-3-carbonyl-glycines, 4-hydroxy-2-oxo-l,2-dihydro- naphthyridine-3-carbonyl-glycines, 8-hydroxy-6-oxo-4,6-dihydro-pyridopyrazine-7-carbonyl-glycines, 4- hydroxy-isoquinoline-3 -carbonyl-glycines, 4-hydroxy-cinnoline-3 -carbonyl-glycines, 7-hydroxy- thienopyridine-6-carbonyl-glycines, 4-hydroxy-thienopyridine-5 -carbonyl-glycines, 7-hydroxy- thiazolopyridine-6-carbonyl-glycines, 4-hydroxy-thiazolopyridine-5 -carbonyl-glycines, 7-hydroxy- pyrrolopyridine-6-carbonyl-glycines, and 4-hydroxy-pyrrolopyridine-5-carbonyl-glycines.
In particular embodiments, the compound is [4-Hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3- carbonyl] -amino} -acetic acid (Compound A), [(4-Hydroxy-l-methyl-7-phenoxy-isoquinoline-3- carbonyl)-amino] -acetic acid (Compound B), [l-Cyano-6-(2,6-dimethyl-phenoxy)-4-hydroxy- isoquinoline-3-carbonyl]-amino}-acetic acid (Compound C), {[l-Cyano-6-(4-fluoro-phenoxy)-4- hydroxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound D), {[l-Cyano-6-(2,6-dimethyl- phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound E), [(l-Benzyl-3-chloro-7- cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound F), {[1-Cyano- 5-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound G), [(1-Cyano- 4-hydτoxy-7-isopropoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound H), {[7-Cyano-l-(2- fluoro-benzyl)-4-hydroxy-lH-pyπOlo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound I), {[6- (4-Chloro-2,6-dimethyl-phenoxy)-l-cyano-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound J), {[5-(4-Chloro-phenoxy)-l-cyano-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound K), {[(R)-2,3-Dichloro-7-cyano-4-hydroxy-l-(l-phenyl-ethyl)-lH-pyrrolo[2,3-c]pyridine-5- carbonyl]-amino} -acetic acid (Compound L), {[7-Cyano-4-hydroxy-l-(3-methoxy-benzyl)-lH- pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound M), {[l-Cyano-4-hydroxy-5-(4- methoxy-phenoxy)-isoquinoline-3-carbonyl] -amino} -acetic acid (Compound N), {[7-Cyano-l-(4-fluoro- benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound O), {[3- Chloro-7-cyano- 1 -(4-fluoro-benzyl)-4-hydroxy- 1 H-pyrrolo[2,3-c]pyridine-5 -carbonyl]-amino} -acetic acid (Compound P), [(l-Benzyl-2,3-dichloro-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)- amino]-acetic acid (Compound Q), [(7-Cyano-4-hydroxy-l-naphthalen-2-ylmethyl-lH-pyrrolo[2,3- c]pyridine-5-carbonyl)-amino] -acetic acid (Compound R), [(l-Chloro-4-hydroxy-isoquinoline-3- carbonyl)-amino] -acetic acid (Compound S), [(7-Bromo-4-hydroxy-isoquinoline-3-carbonyl)-amino]- acetic acid (Compound T), {[7-(4-Fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound U), {[7-(3,4-Difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound V), { [7-(3-Chloro-4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound W), { [4-Hydroxy-7 -(2 -methyl -benzothiazol-6-yloxy)-isoquinoline-3-carbonyl]-amino} - acetic acid (Compound X), [(7 -Chloro-4-hydroxy-l-methyl-isoquinoline-3-carbonyl)-amino] -acetic acid (Compound Y), [(l-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound Z), [(4-Cyano-7-hydroxy-thieno[3,2-c]pyridine-6-carbonyl)-amino]-acetic acid (Compound AA), [(4-Hydroxy-8-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound AB), [(4- Hydroxy-l-methyl-δ-phenoxy-isoquinoline-S-carbonyty-aminoJ-acetic acid (Compound AC), [(1-Cyano- 4-hydroxy-8-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound AD), {[8-(4-Fluoro- phenoxy)-4-hydroxy-l-methyl-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound AE), {[1-Cyano- 8-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound AF), [(1- Cyano-4-hydroxy-6-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound AG), [(1-Cyano- 4-hydroxy-5-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound AH), {[l-Cyano-7-(2,6- dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl] -amino} -acetic acid (Compound AI), {[3-Bromo- 7-cyano-4-hydroxy-l-(4-methoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AJ), {^^-Dichloro^-cyano^-hydroxy-l^-methoxy-benzy^-lH-pyrroloP^-cJpyridine-S- carbonyl]-amino}-acetic acid (Compound AK), {[(S)-2,3-Dichloro-7-cyano-4-hydroxy-l-(l-phenyl- ethyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -acetic acid (Compound AL), {[3-Chloro-7-cyano- 4-hydroxy-l-(4-methoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AM), {[3-Chloro-7-cyano-l-(2-fluoro-benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}- acetic acid (Compound AN), {[3-Chloro-7-cyano-4-hydroxy-l-(3-methyl-butyl)-lH-pyrrolo[2,3- c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AO), [(2,3-Dichloro-7-cyano-4-hydroxy-l- naphthalen-2-ylmethyl-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AP), {[7- Cyano- 1 -(2-fluoro-benzyl)-4-hydroxy-2-trifluoromethyl- 1 H-pyrrolo [2,3 -c]pyridine-5 -carbonyl] -amino } - acetic acid (Compound AQ), [(l-Benzyl-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)- amino]-acetic acid (Compound AR), [(3-Chloro-7-cyano-l-hexyl-4-hydroxy-lH-pyrrolo[2,3-c]pyridine- 5 -carbonyl)-amino] -acetic acid (Compound AS), {[3-Chloro-7-cyano-4-hydroxy-l-(2-trifluoromethyl- benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AT), [(l-Biphenyl-4- ylmethyl-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AU), [(l-Biphenyl-4-ylmethyl-2,3-dichloro-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]- acetic acid (Compound AV), [(l-Biphenyl-4-ylmethyl-3-chloro-7-cyano-4-hydroxy-lH-pyrrolo[2,3- c]pyridine-5-carbonyl)-amino] -acetic acid (Compound AW), {[2,3-Dichloro-7-cyano-4-hydroxy-l-(4- isopropoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AX), {[1- Cyano-4-hydroxy-5-m-tolyloxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound AY), {[7- Cyano-4-hydroxy-l-(4-isopropoxy-benzyl)-3a,7a-dihydro-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]- amino} -acetic acid (Compound AZ), [(l-Cyano-Φhydroxy-S-p-tolyloxy-isoquinoline-S-carbonyl)- amino]-acetic acid (Compound BA), {[5-(3-Chloro-phenoxy)-l-cyano-4-hydroxy-isoquinoline-3- carbonyl] -amino} -acetic acid (Compound BB), {[3-Chloro-7-cyano-4-hydroxy-l-(4-isopropoxy-benzyl)- lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound BC), (S)-2-{[2,3-Dichloro-7- cyano-4-hydroxy-l-(4-isopropoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -propionic acid (Compound BD), {[1 -Cyano-4-hydroxy-7-(3-methoxy-phenoxy)-isoquinoline-3 -carbonyl]-amino} -acetic acid (Compound BE), [(4-Hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (Compound BF), or { [4-Hydroxy-2-oxo- 1 -(4-trifluoromethyl -benzyl)- 1 ,2-dihydro-pyrrolo[ 1 ,2-b]pyridazine-3 - carbonyl] -amino} -acetic acid (Compound BG).
Compounds for use in the present invention are compounds that inhibit HIF prolyl hydroxylase activity. A compound that inhibits HIF prolyl hydroxylase activity is any compound that reduces or otherwise inhibits the activity of at least one HIF prolyl hydroxylase enzyme. Various compounds that inhibit HIF prolyl hydroxylase have been identified and are suitable for use in the methods and medicaments as claimed in the present invention.
Exemplary pyridine-2-carboxamides, pyridazine-3-carboxamides, quinoline-2-carboxamides, isoquinoline-3-carboxamides and esters thereof are described in European Patent Nos. EP0650960 and EP0650961. All compounds listed in EP0650960 and EP0650961, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein. Additional pyridine-2-carboxamides are described in U.S. Patent Application Publication No. 2007/0299086. All compounds listed in U.S. Patent Application Publication No. 2007/0299086, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein. Additionally, exemplary pyridine-2-carboxamidoesters, pyridazine-3-carboxamidoesters, and isoquinoline-3- carboxamidoesters are described in U.S. Patent No. 5,658,933. All pyridine-2-carboxamidoesters, pyridazine-3-carboxamidoesters, and quinoline-2-carboxamidesters are listed in U.S. Patent No. 5,658,933, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
Additional pyridine-2-carboxamides, pyridizine-3-carboxamides, and quinoline-2-carboxamides are described in U.S. Patent No. 5,620,995. All compounds listed in U.S. Patent No. 5,620,995, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein. Exemplary 3-hydroxypyridine-2- carboxamidoesters are described in U.S. Patent No. 6,020,350; sulfonamidocarbonylpyridine-2- carboxamides are described in U.S. Patent No. 5,607,954; and sulfonamidocarbonyl-pyridine-2- carboxamides and sulfonamidocarbonyl-pyridine-2-carboxamide esters are described in U.S. Patent Nos. 5,610,172 and 5,620,996. All compounds listed in these patents, in particular, those compounds listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
Exemplary quinoline-2-carboxamides are described in U.S. Patent Nos. 5,719,164 and 5,726,305. All compounds listed in the foregoing patents, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
Exemplary isoquinoline-3-carboxamides are described in U.S. Patent No. 6,093,730 and 7,323,475. All compounds listed in U.S. Patent No. 6,093,730 and 7,323,475 , in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein. Particularly exemplary embodiments of isoquinoline-3- carboxamides are described in U.S. Patent Application Publication No. 2007/0298104. All compounds listed in U.S. Patent Application Publication No. 2007/0298104, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
Exemplary beta-carboline-3-carboxamides, pyrrolo[3,2-c]pyridine-6-carboxamides, pyrrolo[2,3- c]pyridine-5-carboxamides, thiazolo[4,5-c]pyridine-6-carboxamides, and thiazolo[5,4-c]pyridine-6- carboxamides are described in U.S. Patent Application Publication No. 2008/0004309. All compounds listed in U.S. Patent Application Publication No. 2008/0004309, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein. Exemplary thieno[3,2-c]pyridine-6-carboxamide and thieno[2,3-c]pyridine-5-carboxamides are described in U.S. Patent Application Publication No. 2006/0199836. All compounds listed in U.S. Patent Application Publication No. 2006/0199836, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
Exemplary 2,4-dioxo-l,2,3,4-tetrahydro-pyrimidine-5-carboxamides and 4-oxo-2-thioxo- 1,2,3,4- tetrahydro-pyrimidine-5-carboxamides are described in International Publication No. WO 2007/150011. All compounds listed in the foregoing publication, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein. Exemplary 6-oxo-l,6-dihydro-pyrimidine-5-carboxamides are described in U.S. Patent Application Publication No. 2008/0171756. All compounds listed in U.S. Patent Application Publication No. 2008/0171756, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
Exemplary 2-oxo-l,2-dihydro-quinoline-3-carboxamides are described in International Publication No. WO 2007/038571 and U.S. Patent Application Publication No. 2007/0249605. All compounds listed in the foregoing publications, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
Exemplary 2-oxo- 1 ,2-dihydro-[ 1 ,8]naphthyridine-3 -carboxamides, 2-oxo- 1 ,2-dihydro-[ 1 ,6]naphthyridine- 3-carboxamides, and 6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazine-7-carboxamides are described in International Publication Nos. WO 2007/103905, WO 2008/076425, and WO 2008/130527. All compounds listed in the foregoing publications, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
Exemplary 6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxamides, 5-oxo-4,5-dihydro-thieno[3,2- b]pyridine-6-carboxamides, 6-oxo-6,7-dihydro-pyrazolo[3,4-b]pyridine-5-carboxamides are described in International Publication No. WO 2007/136990. All compounds listed in the foregoing publications, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein. Exemplary 3-oxo-2,3-dihydro-pyridazine-4-carboxamides are described in U.S. Patent Application Publication No. 2008/0214549. All compounds listed in U.S. Patent Application Publication No. 2008/0214549, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
Exemplary 3-oxo-3,4-dihydro-naphthalene-2-carboxamides, 7-oxo-7,8-dihydro-quinoline-6- carboxamides, and 7-oxo-7,8-dihydro-isoquinoline-6-carboxamides are described in International Publication No. WO 2008/076427. All compounds listed in the foregoing publication, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
Exemplary 3-hydroxy-l-oxo-lH-indene-2-carboxamides are described in International Publication No. WO 2008/130508. All compounds listed in International Publication No. WO 2008/130508, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
Exemplary 4-oxo-[l,10]-phenanthrolines are described in U.S. Patent Nos. 5,916,898 and 6,200,974, and International Publication No. WO 99/21860. All compounds listed in the foregoing patents and publication, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein. An exemplary 4-oxo- [l,10]-phenanthroline is 4-oxo-l,4-dihydro-[l,10]phenanthroline-3-carboxylic acid (see, e.g., Seki et al. (1974) Chem Abstracts 81:424, No. 21).
Exemplary hydrozones are described in U.S. Patent No. 6,660,737. All compounds listed in U.S. Patent No. 6,660,737, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
Exemplary dihydropyrazoles and dihydropyrozolones are described in U.S. Patent No. 6,878,729 and International Publication No. WO 2008/049539, respectively. All compounds listed in U.S. Patent No. 6,878,729, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein. Exemplary dipyridyl dihyropyrazones are described in International Publication No. WO 2006/114213. All compounds listed in International Publication No. WO 2006/114213, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein. Exemplary spiroindalones are described in International Publication No. WO 2008/144266. All compounds listed in International Publication No. WO 2008/144266, in particular, those listed in the compound claims and the final products of the working examples, are hereby incorporated into the present application by reference herein.
Additional HIF prolyl hydroxylase inhibitors known to those of skill in the art are described in Dao et al. (2009, Anal Biochem 384(2):213-23), Frohn et al. (2008, Bioorg Med Chem Lett 18(18):5023-6), and Tegley et al. (2008, Bioorg Med Chem Lett 18(14):3925-8). All compounds listed in the foregoing publications are hereby incorporated into the present application by reference herein.
In various embodiments, compounds suitable for use in the present invention are selected from the group consisting of 2-oxoglutarate mimetics, iron chelators, and proline analogs. In preferred embodiments, the compound is a 2-oxoglutarate structural mimetic.
2-oxoglutarate structural mimetics suitable for use in the claimed methods include structural mimetics of 2-oxoglutarate that inhibit HIF prolyl hydroxylase activity competitively with respect to 2-oxoglutarate. In preferred embodiments, the compound is a 2-oxoglutarate structural mimetic that inhibits HIF prolyl hydroxylase competitively with respect to 2-oxoglutarate and noncompetitively with respect to iron.
A compound of the present invention is, in various embodiments, a cyclic carboxamide. In some embodiments, the cyclic carboxamide is a carbonyl glycine. In other embodiments, the carboxamide is replaced by a carbonyl proprionic acid. In some embodiments of the present invention, the compound of the present invention is a carbocyclic carboxamide.
Preferred cyclic carboxamides suitable for use in the present invention are heterocyclic carboxamides. Such heterocyclic carboxamide compounds include heterocyclic carboxamides previously identified as inhibitors of HIF prolyl hydroxylase activity, and known and available to those of skill in the art. In certain embodiments, a compound of the present invention is a heterocyclic carboxamide having a heterocyclic group selected from the group consisting of: azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, furan, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), piperidinyl, pyrrolidine, and tetrahydrofuranyl. In preferred embodiments, the heterocyclic group is a single ring selected from the group consisting of a pyridine, a pyridinone, a pyradizine, a pyridazinone, a pyrimidine, and a pyrimidinone ring, hi other preferred embodiments, the heterocyclic group is a multiple condensed ring selected from the group consisting of an isoquinoline, an isoquinolone, a naphthyridinone, a pyrrolopyridine, a pyrrolopyridinone, a pyrozolopyridinone, a pyrrolopyridizinone, a quinoline, a quinolone, a chromenone, a thiochromenone, a thienopyridine, a thienopyridinone, a thiazolopyridine, and a thiazolopyridinone.
A particularly preferred heterocyclic carboxamide of the present invention is selected from the group consisting of an isoquinoline carboxamide, a pyrrolopyridine carboxamide, a thienopyridine carboxamide, a pyrrolopyridizanone carboxamide, and a thiochromenone carboxamide.
In a series of embodiments, heterocyclic carboxamides suitable for use in the claimed methods are heterocyclic carbonyl glycines. Preferred such heterocyclic carbonyl glycines include those represented by Formula I, infra.
In successive embodiments, the heterocyclic carbonyl glycine suitable for use in the present invention is a heterocyclic carbonyl glycine having a heterocyclic group that is selected from the following list: azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, furan, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), piperidinyl, pyrrolidine, and tetrahydrofuranyl. In certain preferred embodiments, the heterocyclic carbonyl glycine suitable for use in the present invention is a heterocyclic carbonyl glycine having a heterocyclic group, wherein the heterocyclic group is a single ring selected from the following list: a pyridine, a pyridinone, a pyradizine, a pyridazinone, a pyrimidine, and a pyrimidinone ring. In other preferred embodiments, the heterocyclic carbonyl glycine suitable for use in the present invention is a heterocyclic carbonyl glycine having a heterocyclic group, wherein the heterocyclic group is a multiple condensed ring selected from the group consisting of an isoquinoline, an isoquinolone, a naphthyridinone, a pyrrolopyridine, a pyrrolopyridinone, a pyrozolopyridinone, a pyrrolopyridizinone, a quinoline, a quinolone, a chromenone, a thiochromenone, a thienopyridine, a thienopyridinone, a thiazolopyridine, and a thiazolopyridinone.
Most preferred heterocyclic carbonyl glycines suitable for use in the claimed methods heterocyclic carbonyl glycines selected from the group consisting of isoquinoline carbonyl glycines, pyrrolopyridine carbonyl glycines, thienopyridine carbonyl glycines, pyrrolopyridizanone carbonyl glycines, and thiochromenone carbonyl glycines. Isoquinoline carbonyl glycines suitable for use in the present invention include isoquinoline-3 -carbonyl - glycines. Further preferred isoquinoline-3-carbonyl-glycines are 4-hydroxy-isoquinoline-3-carbonyl- glycines, and exemplary such compounds include [(l-Chloro-4-hydroxy-isoquinoline-3-carbonyl)- amino]-acetic acid (Compound S); [(T-Bromo-Φhydroxy-isoquinoline-S-carbonyty-aminoJ-acetic acid (Compound T); {[4-Hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound A); {[7-(4-Fluoro-phenoxy)-4-hydroxy-isoquinoline-3 -carbonyl] -amino} -acetic acid (Compound U); [(4-Hydroxy-l-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound B); {[7-(3,4-Difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound V); {[7-(3-Chloro-4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound W); {[4-Hydroxy-7-(2-methyl-benzothiazol-6-yloxy)-isoquinoline-3-carbonyl]-amino} - acetic acid (Compound X); [(7-Chloro-4-hydroxy-l-methyl-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound Y); [(l-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound Z); [(4-Hydroxy-8-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound AB); [(4-Hydroxy-l-methyl-8-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound AC); [(I - Cyano-4-hydroxy-8-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound AD); {[8-(4- Fluoro-phenoxy)-4-hydroxy-l-methyl-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound AE); {[1- Cyano-8-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound AF); [(l-Cyano-4-hydroxy-6-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound AG); {[1- Cyano-6-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound D); {[l-Cyano-6-(2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound E); [(I -Cyano-4-hydroxy-5-phenoxy-isoquinoline-3-carbonyl)-amino] -acetic acid (Compound AH); [(l-Cyano-4-hydroxy-7-isopropoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound H); {[l-Cyano-5-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound G); {[l-Cyano-7-(2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound AI); {[6-(4-Chloro-2,6-dimethyl-phenoxy)-l-cyano-4-hydroxy-isoquinoline-3- carbonyl]-amino} -acetic acid (Compound J); {[5-(4-Chloro-phenoxy)-l-cyano-4-hydroxy-isoquinoline-3- carbonyl]-amino} -acetic acid (Compound K); {[l-Cyano-4-hydroxy-5-(4-methoxy-phenoxy)- isoquinoline-3-carbonyl]-amino} -acetic acid (Compound N); {[l-Cyano-4-hydroxy-5-m-tolyloxy- isoquinoline-3-carbonyl]-amino} -acetic acid (Compound AY); [(l-Cyano-4-hydroxy-5-p-tolyloxy- isoquinoline-3-carbonyl)-amino]-acetic acid (Compound BA); {[5-(3-Chloro-phenoxy)-l-cyano-4- hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound BB); {[l-Cyano-4-hydroxy-7-(3- methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound BE); and other compounds encompassed by Formula II, infra.
The present invention further contemplates the use of pyrrolopyridine carbonyl glycines. Preferred pyrrolopyridine carbonyl glycines are pyrrolo[2,3-c]pyridine-5-carbonyl-glycines. More preferred pyrrolo[2,3-c]pyridine-5-carbonyl-glycines include 4-hydroxy-pyrrolo[2,3-c]pyridine-5-carbonyl- glycines. Exemplary such compounds include, but are not limited to: [(l-Benzyl-3-chloro-7-cyano-4- hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound F); {[7-Cyano-l-(4- fluoro-benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound O); {[3- Chloro-7-cyano-l-(4-fluoro-benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -acetic acid (Compound P); {[(^-Z^-Dichloro-T-cyano^-hydroxy-l^l-phenyl-ethyO-lH-pyrrolo^^- c]pyridine-5-carbonyl] -amino} -acetic acid (Compound L); {[3-Bromo-7-cyano-4-hydroxy-l-(4-methoxy- benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AJ); {[2,3-Dichloro-7- cyano-4-hydroxy-l-(4-methoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AK); {[(S)-2,3-Dichloro-7-cyano-4-hydroxy-l-(l-phenyl-ethyl)-lH-pyrrolo[2,3-c]pyridine- 5 -carbonyl] -amino} -acetic acid (Compound AL); {[3-Chloro-7-cyano-4-hydroxy-l-(4-methoxy-benzyl)- lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AM); {[7-Cyano-l-(2-fluoro- benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -acetic acid (Compound I); {[7-Cyano- 4-hydroxy-l-(3-methoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound M); {[3-Chloro-7-cyano-l-(2-fluoro-benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}- acetic acid (Compound AN); {[3-Chloro-7-cyano-4-hydroxy-l-(3-methyl-butyl)-lH-pyrrolo[2,3- c]pyridine-5-carbonyl]-amino} -acetic acid (Compound AO); [(2,3-Dichloro-7-cyano-4-hydroxy-l- naphthalen-2-ylmethyl-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AP); [(7- Cyano-4-hydroxy-l-naphthalen-2-ylmethyl-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound R); {[7-Cyano-l-(2-fluoro-benzyl)-4-hydroxy-2-trifluoromethyl-lH-pyrrolo[2,3-c]pyridine- 5 -carbonyl] -amino} -acetic acid (Compound AQ); [(l-Benzyl-7-cyano-4-hydroxy-lH-pyrrolo[2,3- c]pyridine-5-carbonyl)-amino] -acetic acid (Compound AR); [(S-Chloro^-cyano-l-hexyM-hydroxy-lH- pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AS); {[3-Chloro-7-cyano-4-hydroxy- l-(2-trifluoromethyl-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AT); [(l-Biphenyl-4-ylmethyl-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AU); [(l-Biphenyl-4-ylmethyl-2,3-dichloro-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5- carbonyl)-amino] -acetic acid (Compound AV); [(l-Biphenyl-4-ylmethyl-3-chloro-7-cyano-4-hydroxy- lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AW); {[2,3-Dichloro-7-cyano-4- hydroxy-1 -(4-isopropoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -acetic acid (Compound AX); {[7-Cyano-4-hydroxy-l-(4-isopropoxy-benzyl)-3a,7a-dihydro-lH-pyrrolo[2,3-c]pyridine-5- carbonyl] -amino} -acetic acid (Compound AZ); {[3-Chloro-7-cyano-4-hydroxy-l-(4-isopropoxy-benzyl)- lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound BC); (S)-2-{[2,3-Dichloro-7- cyano-4-hydroxy-l-(4-isopropoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -propionic acid (Compound BD); and [(l-Benzyl-2,3-dichloro-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5- carbonyl)-amino]-acetic acid (Compound Q); and other compounds of Formula III, infra. In preferred embodiments of the present invention, compounds suitable for use in the claimed methods and medicaments are thienopyridine carbonyl glycines. More preferred thienopyridine carbonyl glycines include thieno[3,2-c]pyridine-6-carbonyl-glycines. Most preferred thienopyridine carbonyl glycines are T-hydroxy-thienoβ^-cJpyridine-ό-carbonyl-glycines. Exemplary such compounds include [(4-Cyano-7- hydroxy-thieno[3,2-c]pyridine-6-carbonyl)-amino]-acetic acid (Compound AA) and other compounds according to Formula IV, infra.
Additionally preferred compounds of the present invention include pyrrolopyridizinone carbonyl glycines; more preferred, 2-oxo-pyrrolo[l,2-b]pyridazrne-3-carbonyl-glycines; most preferred, 4- hydroxy-2-oxo-pyrrolo[l,2-b]pyridazine-3-carbonyl-glycines. Exemplary such compounds, include, but are not limited to, {[4-Hydroxy-2-oxo-l-(4-trifluoromethyl-benzyl)-l,2-dihydro-pyrrolo[l,2- b]pyridazine-3-carbonyl]-amino} -acetic acid (Compound BG) and other compounds of Formula V, infra.
Other preferred compounds include thiochromenone carbonyl glycines. Preferred thiochromenone carbonyl glycines are 2-oxo-thiochromenone-3-carbonyl-glycines. Most preferred thiochromenone carbonyl glycines are 4-hydroxy-2-oxo-thiochromenone-3 -carbonyl -glycines. Exemplary such compounds include but are not limited to [(4-Hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]- acetic acid (Compound BF) and compounds of Formula VI, infra.
As discussed, supra, in one embodiment, a compound for use in the methods and medicaments of the present invention is a HIF prolyl hydroxylase inhibitor compound of Formula I:
Figure imgf000035_0001
wherein X is an optionally substituted cyclic moiety and R' is hydrogen or (Ci-C4)-alkyl. In particular embodiments, the cyclic moiety is a hetercyclic moiety and R' is hydrogen. Such prolyl hydroyxlase inhibitors (PHIs) include, but are not limited to, variously substituted pyridine-2-carbonyl-glycines, pyridazine-3-carbonyl-glycines, quinoline-2-carbonyl-glycines, 2-oxo-l,2-dihydro-quinoline-3-carbonyl- glycines, 2-oxo-l ,2-dihydro-naphthyridine-3-carbonyl-glycines, 6-oxo-4,6-dihydro-pyridopyrazine-7- carbonyl -glycines, isoquinoline-3 -carbonyl -glycines, cinnoline-3-carbonyl-glycines, thienopyridine-6- carbonyl -glycines, thienopyridine-5-carbonyl-glycines, thiazolopyridine-6-carbonyl-glycines, thiazolopyridine-5-carbonyl-glycines, hydroxy-pyrrolopyridine-6-carbonyl -glycines, and pyrrolopyridine- 5 -carbonyl -glycines. In another embodiment, a compound for use in the methods and medicaments of the present invention is a compound of Formula II:
Figure imgf000036_0001
wherein:
R1, R2, R3, R4 and R5 are identical or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl; (Ci-C20)- alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkoxy, (C5-C12)-aryl, (C7-C16)-aralkyl, (C7-C16)-aralkenyl, (C7-C16)-aralkynyl, (C2-C20)-alkenyl, (C2-C20)-alkynyl, (C1- C20)-alkoxy, (C2-C20)-alkenyloxy, (C2-C20)-alkynyloxy, retinyloxy, (C6-C12)- aryloxy, (C7-C16)-aralkyloxy, (C,-C16)-hydroxyalkyl, -O-[CH2]xCfH(2f+1.g)Fg, - OCF2Cl, -OCF2-CHFCl, (C,-C20)-alkylcarbonyl, (C3-C8)-cycloalkylcarbonyl, (C6-Ci2)-arylcarbonyl, (C7-Ci6)-aralkylcarbonyl, cinnamoyl, (C2-C20)- alkenylcarbonyl, (C2-C20)-alkynylcarbonyl, (CrC20)-alkoxycarbonyl, (C6-Ci2)- aryloxycarbonyl, (C7-C16)-aralkoxycarbonyl, (C3-C8)-cycloalkoxycarbonyl, (C2- C20)-alkenyloxycarbonyl, retinyloxycarbonyl, (C2-C20)-alkynyloxycarbonyl, (C1- Ci2)-alkylcarbonyloxy, (C3-C8)-cycloalkylcarbonyloxy, (C6-C12)- arylcarbonyloxy, (C7-Ci6)-aralkylcarbonyloxy, cinnamoyloxy, (C2-C12)- alkenylcarbonyloxy, (C2-C i2)-alkynylcarbonyloxy, (CrCi2)-alkoxycarbonyloxy, (C6-Ci2)-aryloxycarbonyloxy, (C7-Ci 6)-aralkyloxycarbonyloxy, (C3-C8)- cycloalkoxycarbonyloxy, (C2-C] 2)-alkenyloxycarbonyloxy, (C2-C12)- alkynyloxycarbonyloxy, carbamoyl, N-(C1-Ci2)-alkylcarbamoyl, N,N-di-(Ci- Ci2)-alkylcarbamoyl, N-(C3-C8)-cycloalkylcarbamoyl, N,N-dicyclo-(C3-C8)- alkylcarbamoyl, N-(C, -Cj 0)-alkyl-N-(C3-C8)-cycloalkylcarbamoyl, N-((C3-C8)- cycloalkyl-(CrC6)-alkyl)-carbamoyl, N-(+)-dehydroabietylcarbamoyl, N-(Cr C6)-alkyl-N-(+)-dehydroabietylcarbamoyl, N-(C6-Ci2)-arylcarbamoyl, N-(C7- Ci6)-aralkylcarbamoyl, N-(Ci-C10)-alkyl-N-(C6-C,6)-arylcarbamoyl, N-(C1-Ci0)- alkyl-N-(C7-Ci6)-aralkylcarbamoyl, carbamoyloxy, N-(Ci-C]2)- alkylcarbamoyloxy, N,N-di-(CrCi2)-alkylcarbamoyloxy, N-(C3-C8)- cycloalkylcarbamoyloxy, N-(C6-Ci2)-arylcarbamoyloxy, N-(C7-Ci6)- aralkylcarbamoyloxy, N-(Ci-C10)-alkyl-N-(C6-Ci2)-arylcarbamoyloxy, N-(Ci- Ci0)-alkyl-N-(C7-Ci6)-aralkylcarbamoyloxy, N-((Ci-Cio)-alkyl)-carbamoyloxy, N-(Ci-C 10)-alkyl-N-((C7-C , 6)-aralkyloxy-(C i -C10)-alkyl)-carbamoyloxyamino, (Ci-C12)-alkylamino, di-(C1-Ci2)-alkylamino, (C3-C8)-cycloalkylamino, (C3-C12)- alkenylamino, (C3-Ci2)-alkynylamino, N-(C6-C12)-arylamino, N-(C7-C11)- aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (Ci-C12)-alkoxyamino, (C1 -C 12)-alkoxy-N-(C ] -C ] 0)-alkylamino, (C i -C 12)-alkanoylamino, (C3-C8)- cycloalkanoylamino, (C6-C 12)-aroylamino, (C7-C16)-aralkanoylamino, (CrC12)- alkanoyl-N-(C1-C10)-alkylamino, (C3-C8)-cycloalkanoyl-N-(Ci-C10)-alkylamino, (C6-CI2)-aroyl-N-(C1-C10)-alkylamino, (C7-C11)-aralkanoyl-N-(C1-C10)- alkylamino, amino-(C1-Ci0)-alkyl, (Ci-C20)-alkylmercapto, (Ci-C20)-alkylsulfinyl, (CrC20)-alkylsulfonyl, (C6-Ci2)-arylmercapto, (C6-C12)-arylsulfinyl, (C6-C12)- arylsulfonyl, (C7-C 16)-aralkylmercapto, (C7-C 16)-aralkylsulfinyl, (C7-C16)- aralkylsulfonyl, sulfamoyl, N-(C1-C10)-alkylsulfamoyl, N,N-di-(CrCio)- alkylsulfamoyl, (C3-C8)-cycloalkylsulfamoyl, N-(C6-C12)-arylsulfamoyl, N-(C7- C16)-aralkylsulfamoyl, N-(C1-C10)-alkyl-N-(C6-Ci2)-arylsulfamoyl, N-(Ci-C10)- alkyl-N-(C7-Ci6)-aralkylsulfamoyl, (C1-C10)-alkylsulfonamido, (C7-C16)- aralkylsulfonamido, and N-((Ci-C10)-alkyl-(C7-Ci6)-aralkylsulfonamido, (C6- C12)-heteroaryl, (C7-C16)-heteroaralkyl; where an aryl or heteroaryl radical may be substituted by 1 to 5 substituents selected from hydroxyl, halogen, cyano, trifluoromethyl, nitro, carboxyl, (C2-C16)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)- cycloalkoxy, (C6-C12)-aryl, (C7-C 16)-aralkyl, (C2-C16)-alkenyl, (C2-C12)-alkynyl, (C1-C16)-alkoxy, (CrC|6)-alkenyloxy, (C6-C]2)-aryloxy, (C7-C16)-aralkyloxy, (C1- C8)-hydroxyalkyl, -O-[CH2]xCfH(2f+1.g)Fg, -OCF2Cl, and -OCF2-CHFCl; x is 0 to 3; f is 1 to 8; and g is 0 or 1 to (2f+l); or a pharmaceutically acceptable salt, single stereoisomer, mixture of stereoisomers, ester, or prodrug thereof. ent, a compound of the present invention is a compound of Formula II wherein: R1 is selected from hydrogen, halo, (C1-C3)-alkyl, or cyano; R2 is selected from hydrogen or aryloxy, wherein the aryl is optionally substituted with halo, (C,-C3)-alkyl, or (C,-C3)-alkoxy; R3 is hydrogen or aryloxy, wherein the aryl is optionally substituted with one or two halo,
(C,-C3)-alkyl, or (C,-C3)-alkoxy; R4 is selected from hydrogen, halo, (CrC3)-alkoxy, aryloxy, wherein the aryl is optionally substituted with one or two halo, (CrC3)-alkyl, or or heteroaryloxy optionally substituted with (Q-QJ-alkyl; and R5 is selected from hydrogen or aryloxy optionally substituted with halo. In another embodiment, a compound suitable for use in the present methods and medicaments is a compound of Formula II wherein:
R1 is selected from hydrogen, chloro, methyl, or cyano;
R2 is selected from hydrogen, phenoxy, 4-fluorophenoxy, 3-chlorophenoxy, 4- chlorophenoxy, 4-methoxy-phenoxy, 3-methylphenoxy, 4-methylphenoxy;
R3 is hydrogen, phenoxy, 4-fluoro-phenoxy, 2,6-dimethyl-phenoxy, 4-chloro-2,6- dimethyl-phenoxy;
R4 is selected from hydrogen, chloro, bromo, isopropoxy, phenoxy, 2,6-dimethyl- phenoxy, 3-methoxy-phenoxy, 4-methoxy-phenoxy, 4-fluorophenoxy, 3,4- difluorophenoxy, 3-chloro-4-fluorophenoxy, or 2-methyl-benzothiazol-6-yloxy; and
R5 is selected from hydrogen, phenoxy, or 4-fluorophenoxy.
It is also contemplated that, in one embodiment, a compound for use in the methods and medicaments of the present invention is a compound of Formula III
Figure imgf000038_0001
wherein: one of A or B is =C(R7)- and the other is -N(R9)-;
— independently represents a single or a double bond;
R6 is selected from the group consisting of hydrogen, halo, cyano, (CVCy-alkyl, and aryl;
R7 is selected from the group consisting of hydrogen, halo, cyano, (Ci-C6)-alkyl, and aryl, wherein the aryl is optionally substituted by one or two halo;
R8 is selected from the group consisting of hydrogen, halo, cyano, (Ci-C6)-alkyl, trifluoromethyl, and aryl optionally substituted with halo; and
R9 is selected from the group consisting of hydrogen, (Ci-CiO)-alkyl, (CrC3)-alkyl-(Ci- C,o)-alkyl, (C,-C3)-alkoxy-(C,-C6)-alkyl, (C4-C6)-cycloalkyl, (C4-C6)-cycloalkyl- (Ci-C3)-alkyl, aryl, (C7-Cπ)-aralkyl, aryl-aralkyl, and heteroaralkyl; where in each case an aryl or heteroaryl may be optionally substituted by one or two halo, trifluoromethyl, or (C]-C4)-alkoxy; or pharmaceutically acceptable salts, single stereoisomers, mixtures of stereoisomers, esters, or prodrugs thereof.
In one embodiment, a compound of the present invention is a compound of Formula III wherein:
A is =C(R7)-;
B is -N(R9)-;
R6 is cyano;
R7 is selected from hydrogen or halogen;
R8 is selected from hydrogen, halo, or trifluoromethyl; and
R9 is selected from (Ci-C10)-alkyl, (C,-C3)-alkyl-(Ci-Ci0)-alkyl, (C,-C3)-alkoxy-(Ci-C6)- alkyl, (C7-Ci2)-aralkyl or aryl-aralkyl, wherein each aryl is optionally substituted with halo,
Figure imgf000039_0001
or trifluoromethyl..
In another embodiment, a compound of the present invention is a compound of Formula III wherein:
R6 is cyano;
R7 is selected from hydrogen, chloro, or bromo.
R8 is hydrogen, chloro, trifluoromethyl; and
R9 is selected from methyl-butyl, hexyl, methoxy-methyl, naphthalen-2-yl-methyl, benzyl, 4-fluorobenzyl, 1-phenyl-ethyl, 4-methoxy-benzyl, 2-fluoro-benzyl, 2- trifiuoromethyl-benzyl, biphenyl-4-yl-methyl, or 4-isopropoxy-benzyl.
A compound suitable for use in the claimed methods and medicaments can be a compound of Formula IV
Figure imgf000039_0002
wherein:
R10 is selected from the group consisting of hydrogen, bromo, cyano, (Ci-C4)-alkyl, (Q-
C4)-alkynyl, heterocyclycl, heteroaryl, and aryl optionally substituted with halo. R1 ' is selected from hydrogen or 4-fluorophenyl; R12 is selected from hydrogen, methyl, (E)-styryl, 2-(trifluoromethyl)-phenyl, 3-
(trifluoromethyl)-phenyl, 4-(trifluoromethyl)-phenyl, 4-fluorophenyl, 4- methoxyphenyl, 4-phenoxyphenyl, bromo, phenethyl, phenoxy, phenyl, phenylsulfanyl and pharmaceutically acceptable salts, single stereoisomers, mixtures of stereoisomers, esters, and prodrugs thereof.
In one embodiment, a compound of the present invention is a compound of Formula IV wherein:
R10 is cyano; and
R11 and R12 are hydrogen.
In one aspect of the present invention, it is contemplated that a compound suitable for use in the claimed methods and medicaments is a compound of Formula V
Figure imgf000040_0001
wherein:
R13 is (C7-Ci2)-aralkyl optionally substituted on the aryl with one or two substituents selected from the group consisting of halo, trifluoromethyl, and (Ci-C3)-alkoxy; and R14, R15, and R16 are hydrogen.
In one embodiment, a compound for use in the present invention is a compound of Formula V wherein: R13 is aralkyl optionally substituted on the aryl with trifluoromethyl; R14 is hydrogen; R15 is hydrogen; and R16 is hydrogen.
In another embodiment, a compound for use in the present invention is a compound of Formula V wherein:
R13 is 4-trifluoromethyl-benzyl;
R14 is hydrogen;
R15 is hydrogen; and
R16 is hydrogen. Other preferred compounds, suitable for use in the present methods and medicaments, include compounds of Formula VI
Figure imgf000041_0001
wherein:
R17 is hydrogen
R18 is hydrogen, halo, or (CrC3)-alkoxy;
R19 is hydrogen, halo, (Ci-C3)-alkyl, (Ci-C6)-alkoxy, aryl optionally substituted with one or two substituents selected from the group consisting of halo, (Q-C^-alkoxy, and trifluoromethyl; heteroaryl optionally substituted with halo; or aralkoxy; and
R20 is hydrogen or (d-C3)-alkyl.
In some embodiments, a compound for use in the present invention is a compound of Formula VI wherein R17 is hydrogen; R18 is hydrogen; R19 is hydrogen; and R20 is hydrogen.
In other embodiments, a compound of the present invention is a compound of Formula VI wherein: R17, R18, R19, and R20 are hydrogen.
The terms "hydroxy" or "hydroxyl" refer to the group -OH.
The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
The term "cyano" refers to the group -CN.
The term "nitro" refers to the group -NO2.
The term "carboxyl" refers to -COOH or salts thereof.
The term "alkyl" refers to saturated monovalent hydrocarbyl groups having from 1 to 10 carbon atoms; more particularly, from 1 to 5 carbon atoms; and, even more particularly, 1 to 3 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, wo-propyl, n-butyl, /-butyl, n-pentyl, and the like. The term "cycloalkyl" refers to a saturated or an unsaturated, but nonaromatic, cyclic alkyl groups of from 3 to 10, 3 to 8, or 3 to 6 carbon atoms having single or multiple cyclic rings including, by way of example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, cyclohexenyl, and the like.
The term "cycloalkoxy" refers to an -O-cycloalkyl group.
The term "aryl" refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is the aryl group. Preferred aryls include phenyl and naphthyl.
The terms "heterocyclic" or "heterocyclyl" refer to a saturated or unsaturated ring system having a single ring or multiple condensed rings, from 1 to 10 carbon atoms, and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur, or oxygen within the ring.
The term "heteroaryl" refers to an aromatic heterocyclic group of from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, and 1 to 4 heteroatoms within the ring selected from the group consisting of oxygen, nitrogen, and sulfur. Such heteroaryl groups can have a single ring (e.g., pyridinyl, furyl, or thienyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl), which condensed rings may or may not be aromatic provided the point of attachment is through a ring containing the heteroatom and that ring is aromatic. The nitrogen can optionally be oxidized to provide for the N-oxide, and/or the sulfur ring atoms can optionally be oxidized to provide for the sulfoxide and sulfone derivatives.
Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, furan, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofiiranyl, and the like.
The term "alkenyl" refers to a vinyl unsaturated monovalent hydrocarbyl group having from 2 to 6, preferably from 2 to 4, carbon atoms, and having at least 1, preferably from 1 to 2, sites of vinyl (>C=C<) unsaturation. Such groups are exemplified by vinyl (ethen-1-yl), allyl, but-3-enyl, and the like.
The term "alkynyl" refers to acetylinic unsaturated monovalent hydrocarbyl groups having from 2 to 6, preferably from 2 to 3, carbon atoms and having at least 1, preferably from 1 to 2, sites of acetylenic (-C ≡C-) unsaturation. This group is exemplified by ethyn-1-yl, propyn-1-yl, propyn-2-yl, and the like. The term "alkoxy" refers to the group "alkyl-O-," which includes, by way of example, methoxy, ethoxy, n-propoxy, wo-propoxy, n-butoxy, f-butoxy, sec-butoxy, n-pentoxy, and the like.
The term "alkenyloxy" refers to the group "alkenyl-O-."
The term "alkynyloxy" refers to the group "alkynyl-O-."
The term "aryloxy" refers to the group aryl-O- that includes, by way of example, phenoxy, naphthoxy, and the like.
The term "aralkyloxy" refers to the group aralkyl-O- that includes, by way of example, benzyloxy, and the like.
The term "carbonyl" refers to C=O.
The term "carbonyloxy" refers to -C(=O)O-.
The terms "aminoacyl" or "amide", or the prefixes "carbamoyl" or "carboxamide," refer to the group -C(0)NRqRq where each Rq is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocyclic; or where each Rq is joined to form together with the nitrogen atom a heterocyclic wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
The term "amino" refers to the group -NH2.
The terms "thio" or "mercapto" refer to the group -SH.
The terms "alkylsulfanyl," "alkylthio," or "thioether" refer to the groups -S-alkyl where alkyl is as defined above.
The term "sulfinyl" refers to the group -S(O)-.
The term "sulfonyl" refers to the group -S(O)2-.
The term "heterocyclyloxy" refers to the group -O-heterocyclic.
The term "cycloalkylene" refers to divalent cycloalkyl groups as defined above. The terms "cycloalkylthio" or "cycloalkylsulfanyl" refer to the groups -S-cycloalkyl where cycloalkyl is as defined herein.
The terms "arylthio" or "arylsulfanyl" refer to the group -S-aryl, where aryl is as defined herein. The terms "heteroarylthio" or "heteroarylsulfanyl" refer to the group -S-heteroaryl, where heteroaryl is as defined herein.
The terms "heterocyclicthio" or "heterocyclicsulfanyl" refer to the group -S-heterocyclic, where heterocyclic is as defined herein.
The term "alkyl alcohol" refers to the group "alkyl-OH". "Alkyl alcohol" is meant to include methanol, ethanol, 2-propanol, 2-butanol, butanol, etc.
The term "acyl" refers to the groups H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-, alkynyl-C(O)-, cycloalkyl- C(O)-, aryl-C(O)-, heteroaryl-C(O)-, and heterocyclic-C(O)-, provided that a nitrogen atom of the heterocyclic is not bound to the -C(O)- group, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
The term "acyloxy" refers to the groups alkyl-C(O)O-, alkenyl-C(O)O-, alkynyl-C(O)O-, aryl-C(O)O-, cycloalkyl-C(O)O-, heteroaryl-C(O)O-, and heterocyclic-C(O)O-, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
The term "alkenyl" refers to a vinyl unsaturated monovalent hydrocarbyl group having from 2 to 6 carbon atoms, and preferably 2 to 4 carbon atoms, and having at least 1 , and preferably from 1 to 2 sites of vinyl (>C=C<) unsaturation. Such groups are exemplified by vinyl (ethen-1-yl), allyl, but-3-enyl and the like.
The term "alkynyl" refers to acetylinic unsaturated monovalent hydrocarbyl groups having from 2 to 6, preferably from 2 to 3, carbon atoms and having at least 1, preferably from 1 to 2, sites of acetylenic (-C ≡€-) unsaturation. This group is exemplified by ethyn-1-yl, propyn-1-yl, propyn-2-yl, and the like.
The term "acylamino" refers to the groups -NR'C(O)alkyl, -NRlC(O)cycloalkyl, -NR'C(O)alkenyl, -NRtC(O)alkynyl,-NR'C(O)aryl, -NRtC(O)heteroaryl, and -NRlC(O)heterocyclic where R' is hydrogen or alkyl, and wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic are defined herein.
The term "carbonyloxyamino" refers to the groups -NRuC(O)O-alkyl, -NRuC(O)O-alkenyl, -NRUC(O)O- alkynyl, -NRuC(O)O-cycloalkyl, -NRuC(O)O-aryl, -NRuC(O)O-heteroaryl, and -NRuC(0)0-heterocyclic, where Ru is hydrogen or alkyl and wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
The term "oxycarbonylamino" refers to the groups -NRuC(O)O-alkyl, -NRuC(O)O-alkenyl, -NR11C(O)O- alkynyl, -NRuC(O)O-cycloalkyl, -NRuC(O)O-aryl, -NRuC(O)O-heteroaryl, and -NRuC(O)O-heterocyclic, where Ru is hydrogen or alkyl, and wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein. The term "oxythiocarbonylamino" refers to the groups -NRuC(S)O-alkyl,-NRuC(S)O-alkenyl, -NRuC(S)O-alkynyl, -NRuC(S)O-cycloalkyl, -NRuC(S)O-aryl, -NRuC(S)O-heteroaryl, and -NRUC(S)O- heterocyclic, where Ru is hydrogen or alkyl, and wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
The term "aminocarbonyloxy" or the prefix "carbamoyloxy" refer to the groups -OC(O)NRVRV where each Rv is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic; or where each Rv is joined to form, together with the nitrogen atom, a heterocyclic, and wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, substituted heteroaryl, and heterocyclic are as defined herein.
The term "aminocarbonylamino" refers to the group -NRWC(O)N(RW)2 where each Rw is independently selected from the group consisting of hydrogen and alkyl.
The term "aminothiocarbonylamino" refers to the group -NRWC(S)N(RW)2 where each Rw is independently selected from the group consisting of hydrogen and alkyl.
The term "aryloxyaryl" refers to the group -aryl-O-aryl.
The term "carboxyl ester" refers to the groups -C(O)O-alkyl, -C(O)O-alkenyl, -C(O)O-alkynyl, -C(O)O- cycloalkyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-heteroaryl, -C(O)O-substituted heeteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic.
The term "cycloalkylene" refers to divalent cycloalkyl groups as defined above.
The term "heteroaryloxy" refers to the group -O-heteroaryl.
The term "sulfonyl" refers to the group -S(O)2-, and may be included in the groups -S(O)2H, -SO2-alkyl, -SO2-alkenyl, -SO2-alkynyl, -SO2-cycloalkyl, -SO2-cycloalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, and -SO2-heterocyclic, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclic are as defined herein.
The term "heterocyclyloxy" refers to the group -O-heterocyclic.
The terms "arylthio" or "arylsulfanyl" refer to the group -S-aryl.
The terms "heteroarylthio" or "heteroarylsulfanyl" refer to the group -S-heteroaryl.
The terms "heterocyclicthio" or "heterocyclicsulfanyl" refer to the group -S-heterocyclic. Conjugated terms refer to a linear arrangement of the separate substituents as each separate term is defined herein. For example, the term "aralkyl" refers to an aryl-alkyl group and includes, by way of example, benzyl; the term "aralkylcarbamoyl" refers to an aryl-alkyl-carbomoyl substituent wherein each term is as defined herein, etc.
It is understood that in all substituted and conjugated groups as defined herein, polymers arrived at by defining substituents with further substituents to themselves (e.g. , aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion herein. Also not included are infinite numbers of substituents, whether the substituents are the same or different. In such cases, the maximum number of such substituents is three.
Similarly, it is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups or a hydroxyl group alpha to ethenylic or acetylenic unsaturation). Such impermissible substitution patterns are well known to the skilled artisan.
The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art, and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and, when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like.
The terms "stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers (compounds are non-superimposable mirror images) and diastereomers (compounds having more than one stereogenic center that are non-mirror images of each other and wherein one or more stereogenic center differs between the two stereoisomers). The compounds of the invention can be present as a mixture of stereoisomers or as a single stereoisomer.
The term "tautomer" refers to alternate forms of a compound that differ in the position of a proton, such as enol, keto, and imine enamine tautomers, or the tautomeric forms of heteroaryl groups contining a ring atom attached to both a ring NH moiety and a ring =N moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
The term "prodrug," as used herein, refers to compounds that include chemical groups which, in vivo, can be converted into the carboxylate group and/or can be split off from the amide N-atom and/or can be split off from the R atom to provide for the active drug, a pharmaceutically acceptable salt thereof, or a biologically active metabolite thereof. Suitable groups are well known in the art and particularly include: for the carboxylic acid moiety, a prodrug selected from, e.g., esters including, but not limited to, those derived from alkyl alcohols, substituted alkyl alcohols, hydroxy substituted aryls and heteroaryls and the like; amides, particularly amides derived from amines of the Formula HNR200R210 where R200 and R210 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and the like; hydroxymethyl, aldehyde and derivatives thereof. The term "ester" refers to compounds that include the group -COOR where R is alkyl, substituted alkyl, alkoxy, or substituted alkoxy.
The term "excipient" as used herein means an inert or inactive substance used in the production of pharmaceutical products or other tablets, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, parenteral, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbopol, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc, honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams and lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; parenterals include, e.g., mannitol, povidone, etc.; plasticizers include, e.g., dibutyl sebacate, polyvinylacetate phthalate, etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.
Methods for Identifying Compounds
Methods for identifying compounds of the invention are also provided. Assays for hydroxylase activity are standard in the art. Such assays can directly or indirectly measure hydroxylase activity. For example, an assay can measure hydroxylated residues, e.g., proline, asparagine, etc., present in the enzyme substrate, e.g., a target protein, a synthetic peptide mimetic, or a fragment thereof. (See, e.g., Palmerini et al. (1985) J Chromatogr 339:285-292.) A reduction in hydroxylated residue, e.g., proline or asparagine, in the presence of a compound is indicative of a compound that inhibits hydroxylase activity. Alternatively, assays can measure other products of the hydroxylation reaction, e.g., formation of succinate from 2-oxoglutarate. (See, e.g., Cunliffe et al. (1986) Biochem J 240:617-619.) Kaule and Gunzler (1990; Anal Biochem 184:291-297) describe an exemplary procedure that measures production of succinate from 2-oxoglutarate. Procedures such as those described above can be used to identify compounds that modulate HIF hydroxylase activity. Target protein may include HIFα or a fragment thereof, e.g., HIF(556-575). Enzyme may include, e.g., HIF prolyl hydroxylase and active fragments thereof (see, e.g., GenBank Accession No. AAG33965, etc.) or HIF asparaginyl hydroxylase and active fragments thereof (see, e.g., GenBank Accession No. AAL27308, etc.), obtained from any source. Enzyme may also be present in a crude cell lysate or in a partially purified form. For example, procedures that measure HIF hydroxylase activity are descπbed in Ivan et al (2001, Science 292:464-468; and 2002, Proc Natl Acad Sci USA 99: 13459-13464) and Hirsila et al (2003, J Biol Chem 278:30772-30780); additional methods are descπbed in International Publication No. WO 03/049686. Measuring and compaπng enzyme activity in the absence and presence of the compound will identify compounds that inhibit hydroxylation of HEFa.
Pharmaceutical Formulations and Routes of Administration
The compositions of the present invention can be delivered directly or in pharmaceutical compositions containing excipients, as is well known m the art. The present methods of treatment involve administration of an effective amount of a compound of the present invention to a subject in need, wherein the subject has reduced or is at πsk for having reduced white blood cell levels, or wherein the subject would benefit by having increased white blood cell mobilization or increased white blood cell levels.
An effective amount, e.g., dose, of compound or drug can readily be determined by routine experimentation, as can an effective and convenient route of administration and an appropπate formulation. Various formulations and drug delivery systems are available in the art. (See, e.g., Gennaro, ed. (2000) Remington's Pharmaceutical Sciences, supra; and Hardman, Limbird, and Gilman, eds. (2001) The Pharmacological Basis of Therapeutics, supra.)
Suitable routes of administration may, for example, include oral, rectal, topical, nasal, pulmonary, ocular, intestinal, and parenteral administration. Primary routes for parenteral administration include intravenous, intramuscular, and subcutaneous administration. Secondary routes of administration include intraperitoneal, mtra-arteπal, infra-articular, intracardiac, intracisternal, intradermal, lntralesional, intraocular, intrapleural, intrathecal, intrauterine, and intraventricular administration. The indication to be treated, along with the physical, chemical, and biological properties of the drug, dictate the type of formulation and the route of administration to be used, as well as whether local or systemic delivery would be preferred.
In preferred embodiments, the compounds of the present invention are administered orally. For example, in certain embodiments, the invention provides for oral administration of [4-Hydroxy-7-(4-methoxy- phenoxy)-isoquinoline-3-carbonyl]-ammo} -acetic acid (Compound A), [(4-Hydroxy-l-methyl-7- phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound B), [l-Cyano-6-(2,6-dimethyl- phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound C), {[l-Cyano-6-(4- fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound D), {[l-Cyano-6- (2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound E), [(l-Benzyl-3-chloro-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound F), {[l-Cyano-5-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound G), [(l-Cyano-4-hydroxy-7-isopropoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound H), {[7-Cyano-l -(2-fluoro-benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]- amino} -acetic acid (Compound I), {[6-(4-Chloro-2,6-dimethyl-phenoxy)-l-cyano-4-hydroxy- isoquinoline-3-carbonyl] -amino} -acetic acid (Compound J), {[5-(4-Chloro-phenoxy)-l-cyano-4-hydτoxy- isoquinoline-3-carbonyl]-amino}-acetic acid (Compound K), {[(R)-2,3-Dichloro-7-cyano-4-hydroxy-l- (l-phenyl-ethyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound L), {[7-Cyano-4- hydroxy-1 -(3-methoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -acetic acid (Compound M), {[l-Cyano-4-hydroxy-5-(4-methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound N), {[7-Cyano-l -(4-fluoro-benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]- aminoj-acetic acid (Compound O), {[3-Chloro-7-cyano-l-(4-fluoro-benzyl)-4-hydroxy-lH-pyrrolo[2,3- c}pyridine-5-carbonyl]-amino}-acetic acid (Compound P), [(l-Benzyl-2,3-dichloro-7-cyano-4-hydroxy- lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound Q), [(7-Cyano-4-hydroxy-l- naphthalen-2-ylmethyl-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound R), [(1- Chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound S), [(7-Bromo-4-hydroxy- isoquinoline-3-carbonyl)-amino] -acetic acid (Compound T), {[7-(4-Fluoro-phenoxy)-4-hydroxy- isoquinoline-3-carbonyl]-amino} -acetic acid (Compound U), {[7-(3,4-Difluoro-phenoxy)-4-hydroxy- isoquinoline-3-carbonyl]-amino}-acetic acid (Compound V), {[7-(3-Chloro-4-fluoro-phenoxy)-4- hydroxy-isoquinoline-3-carbonyl] -amino} -acetic acid (Compound W), {[4-Hydroxy-7 -(2 -methyl - benzothiazol-6-yloxy)-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound X), [(7-Chloro-4- hydroxy-l-methyl-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound Y), [(l-Cyano-4-hydroxy-7- phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (Compound Z), [(4-Cyano-7-hydroxy-thieno[3,2- c]pyridine-6-carbonyl)-amino]-acetic acid (Compound AA), [(4-Hydroxy-8-phenoxy-isoquinoline-3- carbonyl)-amino]-acetic acid (Compound AB), [(4-Hydroxy-l-methyl-8-phenoxy-isoquinoline-3- carbonyl)-amino]-acetic acid (Compound AC), [(l-Cyano-4-hydroxy-8-phenoxy-isoquinoline-3- carbonyl)-amino] -acetic acid (Compound AD), {[8-(4-Fluoro-phenoxy)-4-hydroxy-l-methyl- isoquinoline-3-carbonyl] -amino} -acetic acid (Compound AE), {[l-Cyano-8-(4-fluoro-phenoxy)-4- hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound AF), [(l-Cyano-4-hydroxy-6-phenoxy- isoquinoline-3-carbonyl)-amino]-acetic acid (Compound AG), [(l-Cyano-4-hydroxy-5-phenoxy- isoquinoline-3-carbonyl)-amino]-acetic acid (Compound AH), {[l-Cyano-7-(2,6-dimethyl-phenoxy)-4- hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid (Compound AI), {[3-Bromo-7-cyano-4-hydroxy-l- (4-methoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino} -acetic acid (Compound AJ), {[2,3- Dichloro-7-cyano-4-hydroxy-l-(4-methoxy-benzyl)-lH-pyiTolo[2,3-c]pyridine-5-carbonyl]-amino}- acetic acid (Compound AK), {[(S)-2,3-Dichloro-7-cyano-4-hydroxy-l-(l-phenyl-ethyl)-lH-pyrrolo[2,3- c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AL), {[3-Chloro-7-cyano-4-hydroxy-l-(4- methoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AM), {[3- Chloro-7-cyano-l-(2-fluoro-benzyl)-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AN), {[3-Chloro-7-cyano-4-hydroxy-l-(3-methyl-butyl)-lH-pyrrolo[2,3-c]pyridine-5- carbonyl]-amino} -acetic acid (Compound AO), [(2,3-Dichloro-7-cyano-4-hydroxy-l-naphthalen-2- ylmethyl-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AP), {[7-Cyano-l-(2- fluoro-benzyl)-4-hydroxy-2-trifluoromethyl-lH-pyττolo[2,3-c]pyridine-5-carbonyl]-amino} -acetic acid (Compound AQ), [(l-Benzyl-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AR), [(3-Chloro-7-cyano-l-hexyl-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)- amino]-acetic acid (Compound AS), {[3-Chloro-7-cyano-4-hydroxy-l-(2-trifluoromethyl-benzyl)-lH- pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AT), [(l-Biphenyl-4-ylmethyl-7- cyano-4-hydroxy-lH-pyτrolo[2,3-c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AU), [(1- Biphenyl-4-ylmethyl-2,3-dichloro-7-cyano-4-hydroxy-lH-pyrrolo[2,3-c]pyridine-5-carbonyl)-amino]- acetic acid (Compound AV), [(l-Biphenyl-4-ylmethyl-3-chloro-7-cyano-4-hydroxy-lH-pyrrolo[2,3- c]pyridine-5-carbonyl)-amino]-acetic acid (Compound AW), {[2,3-Dichloro-7-cyano-4-hydroxy-l-(4- isopropoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound AX), {[1- Cyano-4-hydroxy-5-m-tolyloxy-isoquinoline-3-carbonyl]-amino} -acetic acid (Compound AY), {[7- Cyano-4-hydroxy-l-(4-isopropoxy-benzyl)-3a,7a-dihydro-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]- amino}-acetic acid (Compound AZ), [(l-Cyano-4-hydroxy-5-p-tolyloxy-isoquinoline-3-carbonyl)- amino]-acetic acid (Compound BA), {[5-(3-Chloro-phenoxy)-l-cyano-4-hydroxy-isoquinoline-3- carbonyl] -amino} -acetic acid (Compound BB), {[3-Chloro-7-cyano-4-hydroxy-l-(4-isopropoxy-benzyl)- lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid (Compound BC), (S)-2-{[2,3-Dichloro-7- cyano-4-hydroxy-l-(4-isopropoxy-benzyl)-lH-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-propionic acid (Compound BD), {[l-Cyano-4-hydroxy-7-(3-methoxy-phenoxy)-isoquinolme-3-carbonyl]-amino} -acetic acid (Compound BE), [(4-Hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (Compound BF), or {[4-Hydroxy-2 -oxo-1 -(4-trifluoromethyl-benzyl)-l, 2-dihydro-pyrrolo[l, 2-b]pyridazine-3- carbonyl] -amino} -acetic acid (Compound BG)
Pharmaceutical dosage forms of a compound of the invention may be provided in an instant release, controlled release, sustained release, or target drug-delivery system. Commonly used dosage forms include, for example, solutions and suspensions, (micro-) emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols, and lyophilized formulations. Depending on route of administration used, special devices may be required for application or administration of the drug, such as, for example, syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks. Pharmaceutical dosage forms are often composed of the drug, an excipient(s), and a container/closure system. One or multiple excipients, also referred to as inactive ingredients, can be added to a compound of the invention to improve or facilitate manufacturing, stability, administration, and safety of the drug, and can provide a means to achieve a desired drug release profile. Therefore, the type of excipient(s) to be added to the drug can depend on various factors, such as, for example, the physical and chemical properties of the drug, the route of administration, and the manufacturing procedure. Pharmaceutically acceptable excipients are available in the art, and include those listed in various pharmacopoeias. (See, e.g., USP, JP, EP, and BP, FDA web page (www.fda.gov), Inactive Ingredient Guide 1996, and Handbook of Pharmaceutical Additives, ed. Ash; Synapse Information Resources, Inc. 2002.)
Pharmaceutical dosage forms of a compound of the present invention may be manufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, levigating, emulsifying, (nano/micro-) encapsulating, entrapping, or lyophilization processes. As noted above, the compositions of the present invention can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.
Proper formulation is dependent upon the desired route of administration. For intravenous injection, for example, the composition may be formulated in aqueous solution, if necessary using physiologically compatible buffers, including, for example, phosphate, histidine, or citrate for adjustment of the formulation pH, and a tonicity agent, such as, for example, sodium chloride or dextrose. For transmucosal or nasal administration, semisolid, liquid formulations, or patches may be preferred, possibly containing penetration enhancers. Such penetrants are generally known in the art. For oral administration, the compounds can be formulated in liquid or solid dosage forms and as instant or controlled/sustained release formulations. Suitable dosage forms for oral ingestion by a subject include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, slurries, suspensions, and emulsions. The compounds may also be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
Solid oral dosage forms can be obtained using excipients, which may include, fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, antiadherants, cationic exchange resins, wetting agents, antioxidants, preservatives, coloring, and flavoring agents. These excipients can be of synthetic or natural source. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatine, magnesium carbonate, magnesium/sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinyl pyrrolidone, silicates, silicium dioxide, sodium benzoate, sorbitol, starches, stearic acid or a salt thereof, sugars (i.e. dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oils (hydrogenated), and waxes. Ethanol and water may serve as granulation aides. In certain instances, coating of tablets with, for example, a taste-masking film, a stomach acid resistant film, or a release-retarding film is desirable. Natural and synthetic polymers, in combination with colorants, sugars, and organic solvents or water, are often used to coat tablets, resulting in dragees. When a capsule is preferred over a tablet, the drug powder, suspension, or solution thereof can be delivered in a compatible hard or soft shell capsule.
In one embodiment, the compounds of the present invention can be administered topically, such as through a skin patch, a semi-solid or a liquid formulation, for example a gel, a (micro)-emulsion, an ointment, a solution, a (nano/micro)-suspension, or a foam. The penetration of the drug into the skin and underlying tissues can be regulated, for example, using penetration enhancers; the appropriate choice and combination of lipophilic, hydrophilic, and amphiphilic excipients, including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, emulsifiers; by pH adjustment; and use of complexing agents. Other techniques, such as iontophoresis, may be used to regulate skin penetration of a compound of the invention. Transdermal or topical administration would be preferred, for example, in situations in which local delivery with minimal systemic exposure is desired.
For administration by inhalation, or administration to the nose, the compounds for use according to the present invention are conveniently delivered in the form of a solution, suspension, emulsion, or semisolid aerosol from pressurized packs, or a nebuliser, usually with the use of a propellant, e.g., halogenated carbons dervided from methane and ethane, carbon dioxide, or any other suitable gas. For topical aerosols, hydrocarbons like butane, isobutene, and pentane are useful. In the case of a pressurized aerosol, the appropriate dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin, for use in an inhaler or insufflator, may be formulated. These typically contain a powder mix of the compound and a suitable powder base such as lactose or starch.
Compositions formulated for parenteral administration by injection are usually sterile and, can be presented in unit dosage forms, e.g., in ampoules, syringes, injection pens, or in multi-dose containers, the latter usually containing a preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents, such as buffers, tonicity agents, viscosity enhancing agents, surfactants, suspending and dispersing agents, antioxidants, biocompatible polymers, chelating agents, and preservatives. Depending on the injection site, the vehicle may contain water, a synthetic or vegetable oil, and/or organic co-solvents. In certain instances, such as with a lyophilized product or a concentrate, the parenteral formulation would be reconstituted or diluted prior to administration. Depot formulations, providing controlled or sustained release of a compound of the invention, may include injectable suspensions of nano/micro particles or nano/micro or non- micronized crystals. Polymers such as poly(lactic acid), poly(glycolic acid), or copolymers thereof, can serve as controlled/sustained release matrices, in addition to others well known in the art. Other depot delivery systems may be presented in form of implants and pumps requiring incision.
Suitable carriers for intravenous injection for the molecules of the invention are well-known in the art and include water-based solutions containing a base, such as, for example, sodium hydroxide, to form an ionized compound, sucrose or sodium chloride as a tonicity agent, for example, the buffer contains phosphate or histidine. Co-solvents, such as, for example, polyethylene glycols, may be added. These water-based systems are effective at dissolving compounds of the invention and produce low toxicity upon systemic administration. The proportions of the components of a solution system may be varied considerably, without destroying solubility and toxicity characteristics. Furthermore, the identity of the components may be varied. For example, low-toxicity surfactants, such as polysorbates or poloxamers, may be used, as can polyethylene glycol or other co-solvents, biocompatible polymers such as polyvinyl pyrrolidone may be added, and other sugars and polyols may substitute for dextrose.
For composition useful for the present methods of treatment, a therapeutically effective dose can be estimated initially using a variety of techniques well-known in the art. Initial doses used in animal studies may be based on effective concentrations established in cell culture assays. Dosage ranges appropriate for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays.
A therapeutically effective dose or amount of a compound, agent, or drug of the present invention refers to an amount or dose of the compound, agent, or drug that results in amelioration of symptoms or a prolongation of survival in a subject. Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50/ ED50. Agents that exhibit high therapeutic indices are preferred.
The effective amount or therapeutically effective amount is the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician, e.g., treatment of cancer, including induction of anti-tumor effects, etc.
Dosages preferably fall within a range of circulating concentrations that includes the ED50 with little or no toxicity. Dosages may vary within this range depending upon the dosage form employed and/or the route of administration utilized. The exact formulation, route of administration, dosage, and dosage interval should be chosen according to methods known in the art, in view of the specifics of a subject's condition.
Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety that are sufficient to achieve the desired effects, i.e., minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from, for example, in vitro data and animal experiments. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
In some embodiments of the present invention, effective doses for compounds of the invention include doses of 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, and 30 mg/kg, respectively.
In additional embodiments, effective treatment regimes for compounds of the invention include administration two or three times weekly.
The amount of agent or composition administered may be dependent on a variety of factors, including the sex, age, and weight of the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.
The present compositions may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass and rubber stoppers such as in vials. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein. EXAMPLES
The invention is further understood by reference to the following examples, which are intended to be purely exemplary of the invention. The present invention is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of the invention only. Any methods that are functionally equivalent are within the scope of the invention. Various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications fall within the scope of the appended claims.
Example 1: Increased Levels of Hematopoietic Progenitor Cells and Neutrophils in vivo
To examine the effect of compounds and methods of the present invention on hematopoietic progenitor cell (HPC) and neutrophil levels, the following studies were performed. Male Swiss-Webster mice were administered various compounds of the present invention via oral gavage using a ball-tipped gavage needle. Animals treated by oral gavage received a 10 ml/kg volume of either 0.5% carboxymethyl cellulose (CMC) with 0.1% Polysorbate 80 (vehicle control) or various doses (10-100 mg/kg) of a compound of the present invention in 0.5% CMC with 0.1% Polysorbate 80. Animals were dosed once daily for 3 or 4 days.
Six hours after the final dosing, 200 μl blood samples were collected for detection of hematopoietic progenitor cells (HPCs) and neutrophils by FACS analysis using methods previously described. (See, e.g., Wang et al. (1997) J Leukoc Biol 62 503-9 and Legasse et al. (1996) J Immunol Methods 197:139- 50.) Briefly, leukocytes and progenitor cells were isolated from whole blood samples following erythrocyte depletion using red blood cell lysis buffer (eBioscience) according to the manufacturer's instructions. The remaining cells were incubated for one hour with monoclonal antibodies directed against mouse Sca-1 and mouse c-Kit (cell surface markers for HPCs, BD Pharmingen), or mouse Mac-1 and mouse Gr-I (cell surface markers for murine neutrophils, BD Pharmingen). Following incubation with the monoclonal antibodies, the cells were washed three times with sort buffer (PBS, 1% fetal bovine serum) and resuspended in sort buffer containing 50 μg/ml of propidium iodide. Samples were then analyzed for the presence and quantitation of HPCs and neutrophils by flow cytometry (FACS Calibur, Becton Dickinson). The cytometer was set to acquire 10 000 events. Two or three blood samples obtained from each animal were analyzed and the average recorded. Hematopoietic progenitor cells were determined as double positive Sca-l+/c-Kit+ cells and neutrophils were determined as double positive Mac- 1 +/Gr- 1+ cells.
As shown below in Table 1 , compounds of the present invention were effective at increasing both hematopoietic progenitor cell levels in blood and at increasing the percent of hematopoietic progenitor cells in blood. These results indicated that methods and compounds of the present invention are effective at increasing hematopoietic progenitor cell levels in blood. These results further showed that hematopoietic progenitor cell levels in blood increased following oral administration of various compounds of the present invention.
TABLE l
Figure imgf000056_0001
As shown below in Table 2, compounds of the present invention were effective at increasing both neutrophil levels in blood and at increasing the percent of neutrophils in blood. These results indicated that methods and compounds of the present invention are effective at increasing neutrophil levels in blood. These results further showed that neutrophil levels in blood increased following oral administration of various compounds of the present invention.
TABLE 2
Figure imgf000056_0002
Example 2: Increased Levels of Hematopoietic Progenitor Cells and Neutrophils in Bone Marrow
To examine the effect of compounds and methods of the present invention on hematopoietic progenitor cell (HPC) and neutrophil levels in bone marrow, the following studies were performed. Male Swiss- Webster mice were administered various compounds of the present invention via oral gavage using a ball- tipped gavage needle. Animals treated by oral gavage received a 10 ml/kg volume of either 0.5% carboxymethyl cellulose (CMC) with 0.1% Polysorbate 80 (vehicle control) or various doses (10-100 mg/kg) of a compound of the present invention in 0.5% CMC with 0.1% Polysorbate 80. Animals were dosed once daily for 3 or 4 days. Six hours after the final dosing, bone marrow samples were taken from one tibia of each animal and suspended in buffer (PBS with 1% fetal bovine serum). Bone marrow suspensions were then filtered through nylon filters to remove stromal cells. Following filtration, the remaining cells were counted manually using a hemocytometer. Detection and quantitation of HPCs and neutrophils were performed by FACS analysis as described above in Example 1.
As shown below in Table 3, animals administered various compounds of the present invention showed an increase in the percent of hematopoietic progenitor cells in bone marrow compared to that observed in bone marrow of non-treated control animals. These results indicated that methods and compounds of the present invention are effective at increasing hematopoietic progenitor cell levels in bone marrow.
TABLE 3
Figure imgf000057_0001
As shown below in Table 4, animals administered various compounds of the present invention showed an increase in the percent of neutrophils in bone marrow compared to that observed in bone marrow of non- treated control animals. These results indicated that methods and compounds of the present invention are effective at increasing neutrophil levels in bone marrow.
TABLE 4
Figure imgf000057_0002
Example 3: Increased White Blood Cells in vivo
To examine the effect of compounds and methods of the present invention on increasing white blood cells, the following studies were performed. In one series of experiments, male Swiss-Webster mice were administered various compounds of the present invention via oral gavage using a ball-tipped gavage needle. Animals treated by oral gavage received a 10 ml/kg volume of either 0.5% carboxymethyl cellulose (CMC) with 0.1% Polysorbate 80 (vehicle control) or various doses (10-100 mg/kg) of a compound of the present invention in 0.5% CMC with 0.1% Polysorbate 80. Animals were dosed once daily for 3 or 4 days. Six hours after the final dosing, 200 μl blood samples were collected and total white blood cell, neutrophil, and lymphocyte levels were measured by complete blood count (CBC) using a CellDyn cell analyzer (Abbott Laboratories).
As shown below in Table 5, compounds of the present invention were effective at increasing total white blood cell (WBC) levels in mice. These results showed that methods and compounds of the present invention are effective at increasing white blood cell levels in blood. These results further showed that white blood cell levels in blood increased following oral administration of various compounds of the present invention.
TABLE 5
Figure imgf000058_0001
As shown below in Table 6, compounds of the present invention were effective at increasing both neutrophil and lymphocyte levels in blood of mice. Taken together, there results showed that methods and compounds of the present invention are effective at increasing the levels of total white blood cells, and in particular at increasing the levels of neutrophils and lymphocytes in blood. These results further showed that neutrophil and lymphocyte levels in blood increased following oral administration of various compounds of the present invention. TABLE 6
Figure imgf000059_0001
In another series of experiments, male Swiss-Webster mice were administered various compounds (see Table 7 and Table 8) of the present invention via oral gavage using a ball-tipped gavage needle. Animals treated by oral gavage received a 10 ml/kg volume of either 0.5% carboxymethyl cellulose (CMC) with 0.1% Polysorbate 80 (vehicle control) or various doses (10-100 mg/kg) of a compound of the present invention in 0.5% CMC with 0.1% Polysorbate 80. Total WBC, neutrophil, lymphocyte, and monocyte levels were measured in mice as described above on day 8 following administration of compound on day 1, day 3, and day 5.
As shown below in Table 7, administration of various compounds resulted in increased total white blood cell (WBC) levels in blood in mice compared to that observed in non-treated control mice. These results showed that methods and compounds of the present invention are effective at increasing white blood cell levels in blood. These results further showed that white blood cell levels in blood increased following oral administration of various compounds of the present invention.
TABLE 7
Figure imgf000060_0001
Figure imgf000061_0001
As shown below in Table 8, compounds of the present invention were effective at increasing neutrophil, lymphocyte, and monocyte levels in mice. These results showed that methods and compounds of the present invention are effective at increasing various white blood cells, including neutrophils, lymphocytes, and monocytes, in blood. These results further showed that neutrophil, lymphocyte, and monocyte levels in blood increased following oral administration of various compounds of the present invention.
TABLE 8
Figure imgf000061_0002
n/a - indicates that monocytes were not detected in control samples Example 4: Treatment of Leukopenia Associated with Chemotherapy
The following study was performed to examine the effect of compounds and methods of the present invention on treatment of chemotherapy-induced leukopenia. Thirty-eight Sprague Dawley male rats (280-300 g) were obtained from Charles River Laboratories. Six rats served as healthy controls. On day 0, the remaining thirty-two rats were treated by intravenous injection (i.v.) with a single dose of cisplatin (CP) (Bedford Laboratories, Bedford OH) at 5mg/kg and by oral gavage with one of the following: Compound S at 60 mg/kg; Compound B at 40 mg/kg; or vehicle 2 ml/kg. Compound was administered on day 0, day 2, and day 4 with the first dose given two hours before the CP injection. Blood samples (0.2 ml) were collected on day 4 as follows. Animals were anesthetized with isoflurane and 0.2 ml of blood was collected from the tail vein into a MICROTAINER EDTA-2K tube (Becton- Dickinson). Blood samples were processed to measure total white blood cell, neutrophil, and lymphocyte levels by CBC analysis as described above in Example 3.
As shown in below in Table 9, administration of 5 mg/kg cisplatin reduced total white blood cell levels by 21%, compared to that in non-treated control animals at day 4. Administration of Compound S or Compound B, however, increased total white blood cell levels in the cisplatin-treated animals. Specifically, animals initially administered 5 mg/kg cisplatin and subsequently treated with Compound S or Compound B had white blood cell levels equal to or greater than white blood cell levels in non-treated control (i.e., no chemotherapeutic agent administration) animals.
TABLE 9
Figure imgf000062_0001
*indicates that the reduction in total WBC count was not statistically significant
These results showed that methods and compounds of the present invention increased white blood cell levels in cisplatin-treated animals. These results further showed that methods and compounds of the present invention enhanced hematopoietic recovery following chemotherapy-induced leukopenia. As cisplatin-treated animal develop leukopenia, and administration of various compounds of the present invention corrected the reduced levels of white blood cells associated with cisplatin-treatment, the present compounds and methods are useful for treating or preventing leukopenia associated with chemotherapy. Various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.
All references cited herein are hereby incorporated by reference herein in their entirety.

Claims

CLAIMSWHAT IS CLAIMED IS:
1. A method for increasing white blood cell levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a hypoxia-inducible factor (HIF) prolyl hydroxylase enzyme, thereby increasing white blood cell levels in the subject.
2. The method of claim 1, wherein the white blood cell is selected from the group consisting of a neutrophil, a lymphocyte, a monocyte, a macrophage, a basophil, and an eosinophil.
3. A method for increasing hematopoietic progenitor cell levels in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a hypoxia- inducible factor (HIF) prolyl hydroxylase enzyme, thereby increasing hematopoietic progenitor cell levels in the subject.
4. Use of a compound that inhibits HIF prolyl hydroxylase enzyme activity in the manufacture of a medicament for increasing white blood cell levels in a subject.
5. Use of a compound that inhibits HIF prolyl hydroxylase enzyme activity in the manufacture of a medicament for increasing hematopoietic progenitor cell levels in a subject.
6. A method for treating or preventing leukopenia, neutropenia, or lymphocytopenia in a subject, the method comprising administering to the subject an effective amount of a compound that inhibits the activity of a hypoxia-inducible factor (HIF) prolyl hydroxylase enzyme, thereby treating or preventing leukopenia, neutropenia, or lymphocytopenia.
7. The method of claim 6, wherein the leukopenia, neutropenia, or lymphocytopenia is associated with chemotherapy.
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