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WO2009043093A1 - Inhibition de hif - Google Patents

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Publication number
WO2009043093A1
WO2009043093A1 PCT/AU2008/001454 AU2008001454W WO2009043093A1 WO 2009043093 A1 WO2009043093 A1 WO 2009043093A1 AU 2008001454 W AU2008001454 W AU 2008001454W WO 2009043093 A1 WO2009043093 A1 WO 2009043093A1
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Prior art keywords
unsubstituted
hif
substituted
compound
cycloalkylalkyl
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Mohammad Hossein Pourgholami
David L. Morris
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NewSouth Innovations Pty Ltd
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NewSouth Innovations Pty Ltd
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Priority claimed from AU2007905443A external-priority patent/AU2007905443A0/en
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Publication of WO2009043093A1 publication Critical patent/WO2009043093A1/fr
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to methods for the treatment of conditions associated with abnormal levels of Hypoxia Inducible Factor (HIF).
  • HIF Hypoxia Inducible Factor
  • hypoxia or low oxygen tension
  • Oxygen is only able to diffuse 100-180 ⁇ m from a capillary to cells before it is metabolized. Therefore, any cell located greater than this distance from a blood vessel will be hypoxic.
  • Hypoxia may occur when aberrant blood vessels are shutdown by becoming compressed or obstructed by tissue growth, a feature commonly observed during the rapid growth of tumours. This is a characteristic feature of most solid tumours and has been associated with poor treatment response.
  • hypoxia is an important cancer-aggravating factor because it contributes to the progression of a more malignant phenotype, and to the acquisition of resistance to radiotherapy and chemotherapy.
  • tumour cells lying far from the nearest functional blood vessel experience chronic hypoxia. Tumours may also become hypoxic because new blood vessels they develop are aberrant and have poor blood flow. Furthermore, because the diffusion distances of glucose and many other critical nutrients are similar to those of oxygen, these cells also experience nutritional deficiencies. In a normal vascular bed, there is regular, sequential flow of blood through arteries, arterioles, capillaries, post-capillary venules, and veins. However, tumour vascular beds are highly heterogeneous and often disorganized.
  • hypoxia is toxic to both cancer cells and normal cells
  • cancer cells undergo genetic and adaptive changes that allow them to survive and even proliferate in a hypoxic environment. These processes contribute to the malignant phenotype and to aggressive tumour behaviour.
  • Convincing evidence of the importance of hypoxia in human cancers has shown that low oxygen tension in tumours is associated with increased metastasis and poor survival.
  • Cells undergo a variety of biological responses in response to hypoxic conditions.
  • HIF-1 hypoxia-inducible transcription factor 1
  • HIF-1 is a heterodimer that consists of the hypoxic response factor HIF-1 ⁇ and the constitutively expressed HIF-1 ⁇ .
  • HREs hypoxia-response elements
  • Over-expression of HIF- 1 ⁇ in colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate and renal carcinomas have been reported.
  • Several studies have associated HIF-1 expression with human cancer progression.
  • HIF-1 ⁇ intracellular HIF-1 ⁇
  • histological analyses have shown that an increased level of intracellular HIF-1 ⁇ is associated with poor prognosis and resistance to therapy in head and neck cancer, ovarian cancer and oesophageal cancer.
  • animal studies using xenografted human tumors have shown that the over-expression of HIF-1 ⁇ enhances tumour growth and angiogenesis.
  • Increased HIF-1 ⁇ levels are detectable in the cytoplasm and the nucleus of cells in various solid tumours.
  • hypoxia responses is production of growth factors that induce angiogenesis (new blood vessel formation).
  • HIF-1 is a major regulator of the molecular mechanisms involved in the response to hypoxia, has been shown to be over-expressed in colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinoma. Histological analyses have shown that an increased level of intracellular HIF-1 ⁇ activity is associated with poor prognosis and resistance to therapy in patients with head and neck, ovarian, and other types of cancer. Thus, HIF-1 plays a role in tumour growth, progression, and resistance.
  • the present invention is predicated on the inventors' surprising finding that benzimidazole carbamates, such as albendazole, have a potent effect on HIF levels in human cancer cells in vivo and exhibit significant inhibitory effects on tumour growth.
  • a method for inhibiting HIF production in a subject comprising administering to the subject an effective amount of a compound selected from the group comprising a benzimidazole carbamate, a 2- aminobenzimidazole, a benzoxazole or any combination thereof.
  • the HIF is selected from the group comprising HIF-1 ⁇ , HIF-1 ⁇ , HIF- 1 ⁇ /H!F-1 ⁇ complex or a combination thereof
  • the benzimidazole carbamate may be selected from the group comprising albendazole, albendazole sulphoxide, mebendazole, flubendazole, triclabendazole, oxfenbendazole, luxabendazole, cambendazole, oxibendazole, parbendazole, thiabendazole, cyclobendazole, dribendazole, etibendazole and fenbendazole or a metabolites, derivatives or analogues thereof.
  • the compound is albendazole, or a metabolite, derivative or analogue thereof.
  • Ri is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, -SR 7 , -SORs 1 - SO 2 Rg, -SCN, B'(CH 2 )nBRio, -C(O)-Rn Or-ORi 2 , COOR13, -NO 2 , NRi 3 aCOORi3b, isothiocyanato, or -CN where R7 to Ri3b are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, B and B' are independently selected from
  • R3 is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, 5- or 6- membered heterocyclic ring the heteroatom(s) of which are selected from one or more of O, S and/or N, -OR15, -SOR16, -SO2R17, -SCN, -C(O)-Ri 8 , -OR19, NR20COOR21, where Ri 5 to R21 are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or arylalkyl; or a metabolite, derivative or analogue
  • the compound may be a compound of Formula II:
  • Ri is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, -SR7, -SORs, - SO2R9, -SCN, B'(CH 2 ) n BRio, -C(O)-Rn or -OR12, COOR13, -NO 2 , NRi 3 aCOORi 3 b, isothiocyanato, or -CN where R 7 to Ri3b are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, B and B' are independently selected
  • R21 is H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloakenylalkyl, aryl or arylalkyl.
  • the compound may be a compound of Formula III:
  • Ri is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, -SR 7 , -SORs, - SO2R9, -SCN, B'(CH 2 )nBRio, -C(O)-Rn or -OR12, COOR13, -NO 2 , NRi 3 aCOORi 3 b, isothiocyanato, or -CN where R 7 to Ri3b are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, B and B' are independently selected
  • the HIF may be produced by a tumour cell.
  • the tumour cell may be an ovarian, colorectal, liver, pancreatic, gastric, endometrial, renal or other primary or metastatic tumour cell.
  • the HIF production may be associated with an accumulation of fluid in a body cavity, such as ascites or pleural effusion.
  • a method for treating or preventing a condition associated with abnormal levels of HIF in a subject comprising administering to the subject an effective amount of a compound selected from the group comprising a benzimidazole carbamate, a 2-aminobenzimidazole, a benzoxazole or any combination thereof.
  • the benzimidazole carbamate may be selected from the group comprising group consisting of albendazole, albendazole sulphoxide, mebendazole, flubendazole, triclabendazole, oxfenbendazole, luxabendazole, cambendazole, oxibendazole, parbendazole, thiabendazole, cyclobendazole, dribendazole, etibendazole and fenbendazole or a metabolites, derivatives or analogues thereof.
  • Ri is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, -SR 7 , -SORs, - SO 2 Rg 1 -SCN, B'(CH 2 )nBRi 0 , -C(O)-Rn or -OR12, COOR13, -NO 2 , NRi 3a COORi3b, isothiocyanato, or -CN where R 7 to Ri3b are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, B and B' are independently selected from
  • R 2 is selected from H, or substituted or unsubstituted alkyl
  • R3 is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, 5- or 6- membered heterocyclic ring the heteroatom(s) of which are selected from one or more of O, S and/or N, -OR15, -SOR16, -SO2R17, -SCN, -C(O)-RiS, -OR19, NR 20 COOR 2 I, where R15 to R 2 i are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl,
  • the compound is albendazole, or a metabolite, derivative or analogue thereof.
  • the condition may be one associated with increased vascular permeability.
  • the condition may be selected from the group consisting of: cancer, ascites, cirrhosis, pleural effusion, cerebral oedema, pulmonary oedema, cardiovascular disease, ischaemic heart disease, chronic obstructive pulmonary disease, cerebrovascular disorders, macular degeneration, proliferative retinopathy, diabetic retinopathy, retinopathy of prematurity, psoriasis, endometriosis and arthritis, such as rheumatoid arthritis.
  • the cancer may be liver, ovarian, colorectal, lung, small cell lung, breast, prostate, pancreatic, renal, gastric, endometrial, oesophageal, head or neck cancers, peritoneal carcinomatosis, lymphoma, sarcoma or secondary metastases thereof.
  • Administration of the compound may be systemic or regional depending on the nature of the condition to be treated. Administration may be intracavitary, intravesical, intramuscular, intraarterial, intravenous, subcutaneous, topical or oral. Intracavitary administration may be intraperitoneal or intrapleural.
  • the compound may be administered in the form of a composition together with one or more pharmaceutically acceptable carriers, adjuvants or diluents.
  • a composition for inhibiting HIF production by a cell wherein the composition comprises a benzimidazole carbamate, a 2-aminobenzimidazole, a benzoxazole or any combination thereof together with one or more pharmaceutically acceptable carriers, diluents or adjuvants.
  • compositions for the treatment or prevention of a condition associated with altered HIF production wherein the composition comprises a benzimidazole carbamate, a 2-aminobenzimidazole, a benzoxazole or any combination thereof together with one or more pharmaceutically acceptable carriers, diluents or adjuvants.
  • compositions for the treatment or prevention of a condition associated with altered HIF production wherein the composition comprises a benzimidazole carbamate, a 2-aminobenzimidazole, a benzoxazole or any combination thereof, together with at least one other chemotherapeutic agent and optionally with one or more pharmaceutically acceptable carriers, diluents or adjuvants.
  • the chemotherapeutic agent may be selected from the group comprising adriamycin, taxol, fluorouricil, melphaian, cisplatin, oxaliplatin, alpha interferon, vincristine, vinblastine, angioinhibins, TNP-470, pentosan polysulfate, platelet factor 4, angiostatin, LM-609, SU-101, CM-101, Techgalan, thalidomide, SP-PG and the like, alkylating agents such as nitrogen mustards including mechloethamine, melphan, chlorambucil, cyclophosphamide and ifosfamide, nitrosoureas including carmustine, lomustine, semustine and streptozocin; alkyl sulfonates including busulfan; triazines including dicarbazine; ethyenimines including thiotepa and hexamethylmelamine; folicin
  • isomers including stereoisomers and geometric isomers of the compounds of Formula I, Il and III, as well as tautomeric forms thereof.
  • inhibiting means preventing, reducing or otherwise ameliorating HIF production or activation. For example, depending on the circumstances, including the nature of the condition being treated, it may not be necessary that inhibition should mean completely blocking HIF production or activation, but reducing HIF production or activation to a sufficient degree to enable the desired effect to be achieved.
  • HIF refers to HIF-1 ⁇ and HIF-1 ⁇ either alone or in complex with each other or in complex with any other peptide, polypeptide, or nucleic acid such as a hypoxia response element (HRE).
  • HRE hypoxia response element
  • HIF also includes within its meaning modified forms of HIF such as the hydroxylated and ubiquitinated forms of HIF-1 ⁇ .
  • treating and “treatment” refer to any and all uses which remedy a
  • condition or symptoms prevent the establishment of a condition or disease, or otherwise prevent, hinder, retard, or reverse the progression of a condition or disease or other undesirable symptoms in any way whatsoever.
  • the term "effective amount” includes within its meaning an amount of an agent or compound sufficient to provide the desired effect. The exact amount required will vary from subject to subject depending on factors such as the species being treated, the age and general condition of the subject, the severity of the condition being treated, the particular agent being administered and the mode of administration and so forth. Thus, it is not possible to specify an exact “effective amount”. However, for any given case, an appropriate “effective amount” may be determined by one of ordinary skill in the art using only routine experimentation.
  • alkyl as used herein, includes within its meaning monovalent, saturated, straight and branched chain hydrocarbon radicals.
  • alkenyP as used herein, includes within its meaning, monovalent, straight and branched chain hydrocarbon radicals having at least one double bond.
  • aryl as used herein, includes within its meaning monovalent, single, polynuclear, conjugated and fused aromatic hydrocarbon radicals.
  • FIG. 1 Top Panel: Western blot of VEGF protein (46 kDa) from OVCAR-3 tumours from nude mice at 1 , 6, 24, 48 and 72 hours after the administration of a single dose of albendazole as compared to a control; taken before administration of albendazole.
  • Bottom Panel Beta-Actin loading control.
  • Figure 2. Northern blot of VEGF mRNA from OVCAR-3 tumours from nude mice at 1 , 6, 24,
  • FIG. 1 Western blot of HIF-1 ⁇ protein (12OkDa) from OVCAR-3 tumours from nude mice at 1 , 6, 24, 48 and 72 hours after the administration of a single dose of albendazole as compared to a control; taken before administration of albendazole.
  • Bottom Panel Beta-Actin loading control.
  • Figure 4 Top Panel: RT-PCR of HIF-1 ⁇ mRNA from OVCAR-3 tumours from nude mice at 1 , 6, 24, 48 and 72 hours after the administration of a single dose of albendazole as compared to a control; taken before administration of albendazole.
  • Figure 5 Top Panel: VEGF protein levels in OVCAR-3 cells in vitro after treatment with the indicated concentrations of albendazole ([ABZ]M) in the presence of 25 ⁇ M C0CI2. NTC is the non- treated control.
  • Botton Panel HIF-1 levels in OVCAR-3 cells treated with C0CI2 or C0CI2 and Albendazole. Lane 1: non-treated control. Lane 2: 25 ⁇ M C0CI2.
  • Lane 3 25 ⁇ M CoCI 2 and 10" 12 M albendazole. Lane 4: 25 ⁇ M C0CI2 and 10" 9 M albendazole. Lane 5: 25 ⁇ M C0CI2 and 1O 7 M albendazole. Lane 6:25 ⁇ M C0CI2 and 10" 6 M albendazole.
  • Benzimidazole carbamate compounds are broad-spectrum anthelmintic drugs, widely used for the control of helminth parasites in mammals, including humans.
  • One target of benzimidazole carbamates is believed to be tubulin.
  • One such benzimidazole carbamate is albendazole (methyl 5-propylthio-IH-benzimidazoie-2-yl carbamate).
  • benzimidazole carbamates include mebendazole, flubendazole, thiabendazole, oxfenbendazole, luxabendazole, cambendazole, oxibendazole, parbendazole, thiabendazole, cyclobendazole, dribendazole, etibendazole and fenbendazole.
  • albendazole has an anti -prol iterative effect on a range of cancer cell lines in vitro and on cancers in animal models and clinical studies (WO 02/076454, the disclosure of which is incorporated herein by reference). As disclosed herein, the present inventors have now demonstrated that albendazole has a potent effect on HIF production and activity in human ovarian cancer cells in vitro.
  • one aspect of the invention relates to a method for inhibiting HIF production in a subject, the method comprising administering to the subject an effective amount of a compound selected from the group comprising a benzimidazole carbamate, a 2-aminobenzimidazole, a benzoxazole or any combination thereof.
  • the benzimidazole carbamate may be selected from the group comprising group consisting of albendazole, albendazole sulphoxide, mebendazole, flubendazole, triclabendazole, oxfenbendazole, luxabendazole, cambendazole, oxibendazole, parbendazole, thiabendazole, cyclobendazole, dribendazole, etibendazole and fenbendazole or a metabolites, derivatives or analogues thereof.
  • the present invention also relates to a method for inhibiting HIF production or activity by a cell in a subject, the method comprising administering to the subject an effective amount of a compound of Formula I:
  • Ri is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, -SR 7 , -SORB, - SO 2 R 9 , -SCN, B'(CH 2 )nBRio, -C(O)-Rn or-ORi 2 , COOR13, -NO 2 , NRi 3a COORi3b, isothiocyanato, or -CN where R7 to Ri3b are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, B and B' are independently selected from
  • R 2 is selected from H, or substituted or unsubstituted alkyl
  • R3 is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, 5- or 6- membered heterocyclic ring the heteroatom(s) of which are selected from one or more of O, S and/or N, -OR15, -SOR16, -SCN, -SO2R17, -C(O)-RiS 1 -OR19, NR 2 oCOOR 2 i, where Ris to R 2 i are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or arylalkyl; or an analogue, metabol
  • Ri is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, -SR7, -SORs, - SO 2 R 9 , -SCN, B'(CH 2 ) n BRio, -C(O)-Rn or -ORi 2 , COOR13, -NO 2 , NRi 3 aCOORi 3 b, isothiocyanato, or -CN where R7 to Ri3b are each independently selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylaikyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, B and B
  • R 2 i is H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloakenylalkyl, aryl or arylalkyl, or of formula III
  • Ri is selected from H, substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyi, -SR7, -SORs, - SO 2 R 9 , -SCN, B'(CH 2 )nBRio, -C(O)-Rn or -OR12, COOR13, -NO 2 , NRi 3 aCOORi 3 b, isothiocyanato, or -CN where R7 to Ri3b are each independently selected from H 1 substituted or unsubstituted, straight or branch chain alkyl, alkenyl, alkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyi, B and B' are independently selected
  • isomers, including stereoisomers and geometric isomers, of the above described compounds may exists and the use of such isomers are included within the scope of the present invention.
  • tautomeric forms of the above compounds is also contemplated.
  • the substituted benzimidazole group may exist in a number of tautomeric forms, including where the Ri substituent is in any one of the 4 to 7 positions.
  • Albendazole or a metabolite, derivative or analogue thereof is one bezimidazole carbamate particularly useful in methods and compositions of the present invention.
  • bezimidazole carbamates may also be employed.
  • a compound as described above may act to inhibit the cellular production or activity of HIF by cells in the subject undergoing treatment. Accordingly, the present invention provides methods and compositions for the treatment or prevention of conditions associated with abnormal, typically increased, levels of HIF production or activity, using such compounds as described above.
  • Conditions to which methods and compositions of the invention are applicable include, but are not limited to cancer, ascites, cirrhosis, pleural effusion, cerebral oedema, pulmonary oedema, cardiovascular disease, ischaemic heart disease, chronic obstructive pulmonary disease, cerebrovascular disorders, macular degeneration, proliferative retinopathy, diabetic retinopathy, retinopathy of prematurity, psoriasis, endometriosis and arthritis, such as rheumatoid arthritis.
  • the cancer may be liver, ovarian, colorectal, lung, small cell lung, breast, prostate, pancreatic, renal, gastric, endometrial, oesophageal, head or neck cancers, peritoneal carcinomatosis, lymphoma, sarcoma or secondary metastases thereof.
  • compositions and routes of administration are provided.
  • Embodiments of the present invention contemplate compositions for inhibiting HIF production in a subject and for treating or preventing a condition associated with abnormal levels of production or secretion of HIF.
  • compounds and compositions may be administered by any suitable route, either systemically, regionally or locally.
  • the particular route of administration to be used in any given circumstance will depend on a number of factors, including the nature of the condition to be treated, the severity and extent of the condition, the required dosage of the particular compound to be delivered and the potential side-effects of the compound.
  • administration may be regional rather than systemic.
  • Regional administration provides the capability of delivering very high local concentrations of the desired compound to the required site and thus is suitable for achieving the desired therapeutic or preventative effect whilst avoiding exposure of other organs of the body to the compound and thereby potentially reducing side effects.
  • administration according to embodiments of the invention may be achieved by any standard routes, including intracavitary, intravesical, intramuscular, intraarterial, intravenous, intraocular, subcutaneous, topical or oral.
  • Intracavitary administration may be intraperitoneal or intrapleural.
  • the desired compound may be administered intra-peritoneally and for the treatment of pleural effusion administration may be intra-pleural.
  • suitable compositions may be prepared according to methods which are known to those of ordinary skill in the art and may include a pharmaceutically acceptable diluent, adjuvant and/or excipient.
  • diluents, adjuvants and excipients must be "acceptable” in terms of being compatible with the other ingredients of the composition, and not deleterious to the recipient thereof.
  • Examples of pharmaceutically acceptable diluents are demineralised or distilled water; saline solution; vegetable based oils such as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil, sesame oils such as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil, sesame oil, arachis oil or coconut oil; silicone oils, including polysiloxanes, such as methyl polysiloxane, phenyl polysiloxane and methylphenyl polysolpoxane; volatile silicones; mineral oils such as liquid paraffin, soft paraffin or squalane; cellulose derivatives such as methyl cellulose, ethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose or hydroxypropylmethylcellulose; lower alkanols, for example ethanol or iso-propanol; lower aralkanols; lower polyalkylene glycols or lower alkylene glycols, for example polyethylene glycol,
  • non-toxic parenteral ⁇ acceptable diluents or carriers can include, Ringer's solution, medium chain triglyceride (MCT), isotonic saline, phosphate buffered saline, ethanol and 1 ,2 propylene glycol.
  • suitable carriers, diluents, excipients and adjuvants for oral use include peanut oil, liquid paraffin, sodium carboxymethylcellulose, methylcellulose, sodium alginate, gum acacia, gum tragacanth, dextrose, sucrose, sorbitol, mannitol, gelatine and lecithin.
  • these oral formulations may contain suitable flavouring and colourings agents.
  • the capsules When used in capsule form the capsules may be coated with compounds such as glyceryl monostearate or glyceryl distearate which delay disintegration.
  • Adjuvants typically include emollients, emulsifiers, thickening agents, preservatives, bactericides and buffering agents.
  • Solid forms for oral administration may contain binders acceptable in human and veterinary pharmaceutical practice, sweeteners, disintegrating agents, diluents, flavourings, coating agents, preservatives, lubricants and/or time delay agents.
  • Suitable binders include gum acacia, gelatine, corn starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol.
  • Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine.
  • Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, guar gum, xanthan gum, bentonite, alginic acid or agar.
  • Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate.
  • Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring.
  • Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten.
  • Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
  • Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
  • Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
  • Liquid forms for oral administration may contain, in addition to the above agents, a liquid carrier.
  • suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof.
  • Suspensions for oral administration may further comprise dispersing agents and/or suspending agents.
  • Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, poly-vinyl-pyrrolidone, sodium alginate or acetyl alcohol.
  • Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono- or di-oleate, -stearate or -laurate, polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate and the like.
  • Emulsions for oral administration may further comprise one or more emulsifying agents.
  • Suitable emulsifying agents include dispersing agents as exemplified above or natural gums such as guar gum, gum acacia or gum tragacanth.
  • compositions may incorporate any suitable surfactant such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
  • suitable surfactant such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • compositions may also be administered in the form of liposomes.
  • Liposomes are generally derived from phospholipids or other lipid substances, and are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used.
  • the compositions in liposome form may contain stabilisers, preservatives, excipients and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
  • Combination regimens Therapeutic advantages may be realised through combination regimens.
  • the respective agents may be administered simultaneously, or sequentially in any order. Accordingly, methods of treatment according to the present invention may be applied in conjunction with conventional therapy, such as radiotherapy, chemotherapy, surgery, or other forms of medical intervention.
  • chemotherapeutic agents include adriamycin, taxol, fluorouricil, melphalan, cisplatin, oxaliplatin, alpha interferon, vincristine, vinblastine, angioinhibins, TNP-470, pentosan poiysulfate, platelet factor 4, angiostatin, LM-609, SU-101, CM-101, Techgalan, thalidomide, SP-PG and the like.
  • chemotherapeutic agents include alkylating agents such as nitrogen mustards including mechloethamine, melphan, chlorambucil, cyclophosphamide and ifosfamide, nitrosoureas including carmustine, lomustine, semustine and streptozocin; alkyl sulfonates including busulfan; triazines including dicarbazine; ethyenimines including thiotepa and hexamethylmelamine; folic acid analogues including methotrexate; pyrimidine analogues including 5-fluorouracil, cytosine arabinoside; purine analogues including 6-mercaptopurine and 6- thioguanine; antitumour antibiotics including actinomycin D; the anthracyclines including doxorubicin, bleomycin, mitomycin C and methramycin; hormones and hormone antagonists including tamoxifen and cortiosteroids and
  • Compounds and compositions disclosed herein may be administered either therapeutically or preventively.
  • compounds and compositions are administered to a patient already suffering from a condition, in an amount sufficient to cure or at least partially arrest the condition and its symptoms and/or complications.
  • the compound or composition should provide a quantity of the active compound sufficient to effectively treat the patient.
  • the effective dose level of the administered compound for any particular subject will depend upon a variety of factors including: the type of condition being treated and the stage of the condition; the activity of the compound employed; the composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of sequestration of compounds; the duration of the treatment; drugs used in combination or coincidental with the treatment, together with other related factors well known in medicine.
  • One skilled in the art would be able, by routine experimentation, to determine an effective, non-toxic dosage which would be required to treat applicable conditions. These will most often be determined on a case-by-case basis.
  • an effective dosage is expected to be in the range of about 0.0001 mg to about IOOOmg per kg body weight per 24 hours; typically, about 0.001 mg to about 750mg per kg body weight per 24 hours; about 0.01 mg to about 500mg per kg body weight per 24 hours; about 0.1 mg to about 500mg per kg body weight per 24 hours; about 0.1 mg to about 250mg per kg body weight per 24 hours; or about 1.Omg to about 250mg per kg body weight per 24 hours. More typically, an effective dose range is expected to be in the range of about 10mg to about 200mg per kg body weight per 24 hours.
  • an effective dosage may be up to about 5000mg/m 2 .
  • an effective dosage is expected to be in the range of about 10 to about 5000mg/m 2 , typically about 10 to about 2500mg/m 2 , about 25 to about 2000mg/m 2 , about 50 to about 1500mg/m 2 , about 50 to about 1000mg/m 2 , or about 75 to about 600mg/m 2 .
  • the optimal quantity and spacing of individual dosages will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the nature of the particular individual being treated. Also, such optimum conditions can be determined by conventional techniques.
  • mice 6-8 week old female nude athymic BaIb C nu/nu mice (Animal Resources Centre, Perth, Western Australia) were used. They were kept under specific pathogen-free conditions and fed autoclaved pellets and sterile water ad libitum. The health status of each animal was monitored daily. This work had institutional animal ethics committee approval.
  • Cell preparation for inoculation Cells were collected from the ascites of carrier mice inoculated with human ovarian carcinoma cell line OVCAR-3. These cells were originally obtained from the American Type Culture Collection (ATCC), and prepared for in vivo growth as previously described.
  • ATCC American Type Culture Collection
  • mice were inoculated i.p. with 10 x 10 6 OVCAR-3 cells isolated from the ascites of carrier mice and suspended in 1 ml of medium. Three weeks later, these animals were randomly assigned to one of the 8 treatment groups (8 mice/group). Groups 1 - 3 were treated with the vehicle (1mL of 0.5% CMC given i.p.) and sacrificed immediately (group 1) or 1 and 72 h post injection (groups 2 and 3 respectively). Groups 4-8 were treated with ABZ (1 mL of ABZ 150 mg/kg given i.p.) and euthanized at 1 , 6, 24, 48 or 72 hours.
  • mice were treated with the vehicle or the drug and then euthanized at the predetermined time. Prior to euthanasia, mice were anaesthetized and blood was collected through cardiac puncture. Immediately following euthanasia, peritoneal tumors were excised and snap frozen in liquid nitrogen.
  • Ovcar-3 cells (3 million- cells obtained from ascites fluid) seeded in 75 cm 2 were left for 72 hours in the growth medium (RPMI containing 10% FBS) to grow to 75% confluency. Following this, cells were treated for 4 h with a medium (5% FBS RPMI) containing 25 ⁇ M C0CI2 in the absence or presence of ABZ (0, 10" 12 , 10" 9 , 10" 6 M). A control group was treated with the medium only solution
  • compositions are outlined below. The following are to be construed as merely illustrative examples of compositions and not as a limitation of the scope of the present invention in any way.
  • a composition for parenteral injection could be prepared to contain 0.05 mg to 5 g of a benzimidazole carbamate, for example a compound of formula I (such as albendazole) in 10 mis to 2 litres of 1% carboxymethylcellulose.
  • a composition for intravenous infusion may comprise 250 ml of sterile Ringer's solution, and 0.05 mg to 5 g of a compound of formula I.
  • a composition suitable for administration by injection may also be prepared by mixing 1% by weight of the compound in 10% by volume propylene glycol and water.
  • the solution can be sterilised by filtration.
  • a composition of a benzimidazole carbamate for example a compound of formula I in the form of a capsule may be prepared by filling a standard two-piece hard gelatin capsule with 500 mg of the compound, in powdered form, 100 mg of lactose, 35 mg of talc and 10 mg of magnesium stearate.
  • a typical composition for delivery as a topical ointment includes 1.0 g of a compound of formula I, together with white soft paraffin to 100.0 g, dispersed to produce a smooth, homogeneous product.

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Abstract

La présente invention porte sur un procédé pour inhiber la production de HIF chez un sujet. Ce procédé comprend l'administration au sujet d'une quantité efficace d'un composé choisi dans le groupe constitué par un carbamate de benzimidazole, un 2-aminobenzimidazole, un benzoxazole ou toute combinaison de ceux-ci.
PCT/AU2008/001454 2007-10-04 2008-10-02 Inhibition de hif Ceased WO2009043093A1 (fr)

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US7811595B2 (en) 2006-06-26 2010-10-12 Warner Chilcott Company, Llc Prolyl hydroxylase inhibitors and methods of use
US8050873B2 (en) 2006-03-07 2011-11-01 Warner Chilcott Company Crystal of hypoxia inducible factor 1 alpha prolyl hydroxylase
US8309537B2 (en) 2009-11-06 2012-11-13 Aerpio Therapeutics Inc. Compositions and methods for treating colitis
CN103054858A (zh) * 2013-01-21 2013-04-24 杭州雷索药业有限公司 奥苯达唑在制备抗血管生成类药物中的应用
US8865748B2 (en) 2011-06-06 2014-10-21 Akebia Therapeutics Inc. Compounds and compositions for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer
US9987262B2 (en) 2013-11-15 2018-06-05 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US10150734B2 (en) 2015-01-23 2018-12-11 Akebia Therapeutics, Inc. Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof
US10246416B2 (en) 2011-06-06 2019-04-02 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides
US10881656B2 (en) 2008-12-10 2021-01-05 The General Hospital Corporation HIF inhibitors and use thereof
CN113648308A (zh) * 2021-09-14 2021-11-16 东莞市人民医院 奥芬达唑作为抗卵巢癌药物的应用
US11324734B2 (en) 2015-04-01 2022-05-10 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US11524939B2 (en) 2019-11-13 2022-12-13 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid
CN116421602A (zh) * 2023-04-25 2023-07-14 中国人民解放军总医院 氟苯达唑或其衍生物的新用途
US11713298B2 (en) 2018-05-09 2023-08-01 Akebia Therapeutics, Inc. Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid
US11857543B2 (en) 2013-06-13 2024-01-02 Akebia Therapeutics, Inc. Compositions and methods for treating anemia

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US8512972B2 (en) 2006-03-07 2013-08-20 Akebia Therapeutics, Inc. Crystal of hypoxia inducible factor 1 alpha prolyl hydroxylase
US8050873B2 (en) 2006-03-07 2011-11-01 Warner Chilcott Company Crystal of hypoxia inducible factor 1 alpha prolyl hydroxylase
US9598370B2 (en) 2006-06-26 2017-03-21 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US8940773B2 (en) 2006-06-26 2015-01-27 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US8343952B2 (en) 2006-06-26 2013-01-01 Akebia Therapeutics Inc. Prolyl hydroxylase inhibitors and methods of use
US12478615B2 (en) 2006-06-26 2025-11-25 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
USRE47437E1 (en) 2006-06-26 2019-06-18 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US10729681B2 (en) 2006-06-26 2020-08-04 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US8598210B2 (en) 2006-06-26 2013-12-03 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US8722895B2 (en) 2006-06-26 2014-05-13 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and method of use
US11426393B2 (en) 2006-06-26 2022-08-30 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US11883386B2 (en) 2006-06-26 2024-01-30 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US8323671B2 (en) 2006-06-26 2012-12-04 Akebia Therapeutics Inc. Prolyl hydroxylase inhibitors and methods of use
US7811595B2 (en) 2006-06-26 2010-10-12 Warner Chilcott Company, Llc Prolyl hydroxylase inhibitors and methods of use
US10881656B2 (en) 2008-12-10 2021-01-05 The General Hospital Corporation HIF inhibitors and use thereof
US8883774B2 (en) 2009-11-06 2014-11-11 Aerpio Therapeutics Inc. Methods for increasing the stabilization of hypoxia inducible factor-1 alpha
US9045495B2 (en) 2009-11-06 2015-06-02 Aerpio Therapeutics Inc. Prolyl hydroxylase inhibitors
US9278930B2 (en) 2009-11-06 2016-03-08 Aerpio Therapeutics, Inc. Methods for increasing the stabilization of hypoxia inducible factor-α
US9540326B2 (en) 2009-11-06 2017-01-10 Aerpio Therapeutics, Inc. Prolyl hydroxylase inhibitors
US10562854B2 (en) 2009-11-06 2020-02-18 Aerpio Therapeutics, Inc. Prolyl hydroxylase inhibitors
US8999971B2 (en) 2009-11-06 2015-04-07 Aerpio Therapeutics Inc. Methods for increasing the stabilization of hypoxia inducible factor-1 alpha
US8778412B2 (en) 2009-11-06 2014-07-15 Aerpio Therapeutics Inc. Methods for increasing the stabilization of hypoxia inducible factor-1 alpha
US8536181B2 (en) 2009-11-06 2013-09-17 Aerpio Therapeutics Inc. Prolyl hydroxylase inhibitors
US8309537B2 (en) 2009-11-06 2012-11-13 Aerpio Therapeutics Inc. Compositions and methods for treating colitis
US8865748B2 (en) 2011-06-06 2014-10-21 Akebia Therapeutics Inc. Compounds and compositions for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer
US11267785B2 (en) 2011-06-06 2022-03-08 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides
US10246416B2 (en) 2011-06-06 2019-04-02 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides
US10738010B2 (en) 2011-06-06 2020-08-11 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides
CN103054858A (zh) * 2013-01-21 2013-04-24 杭州雷索药业有限公司 奥苯达唑在制备抗血管生成类药物中的应用
US11857543B2 (en) 2013-06-13 2024-01-02 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US9987262B2 (en) 2013-11-15 2018-06-05 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US11065237B2 (en) 2013-11-15 2021-07-20 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US10149842B2 (en) 2013-11-15 2018-12-11 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US11690836B2 (en) 2013-11-15 2023-07-04 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US12419877B2 (en) 2013-11-15 2025-09-23 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US10596158B2 (en) 2013-11-15 2020-03-24 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US10150734B2 (en) 2015-01-23 2018-12-11 Akebia Therapeutics, Inc. Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof
US11324734B2 (en) 2015-04-01 2022-05-10 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US11844756B2 (en) 2015-04-01 2023-12-19 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US11713298B2 (en) 2018-05-09 2023-08-01 Akebia Therapeutics, Inc. Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid
US12269802B2 (en) 2018-05-09 2025-04-08 Akebia Therapeutics, Inc. Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino] acetic acid
US11524939B2 (en) 2019-11-13 2022-12-13 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid
CN113648308A (zh) * 2021-09-14 2021-11-16 东莞市人民医院 奥芬达唑作为抗卵巢癌药物的应用
CN116421602B (zh) * 2023-04-25 2024-01-30 中国人民解放军总医院 氟苯达唑或其衍生物的新用途
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