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WO2009055932A1 - Acides phénylpropioniques substitués utiles comme stimulateurs de l'hématopoïèse et de l'érythropoïèse - Google Patents

Acides phénylpropioniques substitués utiles comme stimulateurs de l'hématopoïèse et de l'érythropoïèse Download PDF

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Publication number
WO2009055932A1
WO2009055932A1 PCT/CA2008/001929 CA2008001929W WO2009055932A1 WO 2009055932 A1 WO2009055932 A1 WO 2009055932A1 CA 2008001929 W CA2008001929 W CA 2008001929W WO 2009055932 A1 WO2009055932 A1 WO 2009055932A1
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Prior art keywords
patient
effective amount
anemia
therapeutically effective
administration
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PCT/CA2008/001929
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English (en)
Inventor
Lyne Gagnon
Mouna Lagraoui
Brigitte Grouix
Alan D. Cameron
Mustapha Allam
Christopher Penney
Boulos Zacharie
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Prometic Biosciences Inc.
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Publication of WO2009055932A1 publication Critical patent/WO2009055932A1/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the present invention relates to the treatment of anemia. This includes the treatment of anemia associated with the use of chemotherapy and radiotherapy as well as the treatment of anemia arising from chronic renal failure or treatment of HIV- infected patients with AZT (zidovudine).
  • the present invention also relates to reducing drug toxicity and enhancing drug efficiency.
  • the present invention relates to the use of substituted phenylpropionic acids as a stimulator of the production of erythrocyte progenitors, in particular Burst Forming Unit-Erythroid (Erythrocyte) cells or BFU-E cells.
  • Chemotherapy refers to the use of cytotoxic agents such as, but not limited to, cyclophosphamide, doxorubicin, daunorubicin, vinblastine, vincristine, bleomycin, etoposide, topotecan, irinotecan, taxotere, taxol, 5-fluorouracil, methotrexate, gemcitabine, cisplatin, carboplatin, or chlorambucil in order to eradicate cancer cells and tumors.
  • cytotoxic agents such as, but not limited to, cyclophosphamide, doxorubicin, daunorubicin, vinblastine, vincristine, bleomycin, etoposide, topotecan, irinotecan, taxotere, taxol, 5-fluorouracil, methotrexate, gemcitabine, cisplatin, carboplatin, or chlorambucil in order to eradicate cancer cells and tumors.
  • Myelosuppression a severe reduction of blood cell production in bone marrow, is one such side effect. It is characterized by anemia, leukopenia, neutropenia, agranulocytosis, and thrombocytopenia. Severe chronic neutropenia is also characterized by a selective decrease in the number of circulating neutrophils and an enhanced susceptibility to bacterial infections.
  • the essence of treating cancer with chemotherapeutic drugs is to combine a mechanism of cytotoxicity with a mechanism of selectivity for highly proliferating tumor cells over host cells. But it is rare for chemotherapeutic drugs to have such selectivity.
  • the cytotoxicity of chemotherapeutic agents may limit administrable doses, may affect treatment cycles, and may seriously jeopardize the quality of life for the cancer patient.
  • bone marrow is particularly sensitive to proliferation-specific treatments such as chemotherapy or radiotherapy.
  • Acute and chronic bone marrow toxicity is a common side effect of cancer therapies which leads to decreases in blood cell counts and anemia, leukopenia, neutropenia, agranulocytosis, and thrombocytopenia.
  • One cause of such effects is a decrease in the number of replicating hematopoietic cells (e.g., pluripotent stem cells and other progenitor cells) caused by both a lethal effect of cytotoxic agents or radiation on these cells and by differentiation of stem cells provoked by a feedback mechanism induced by the depletion of more mature marrow compartments.
  • the second cause is a reduction in self-renewal capacity of stem cells, which is also related to both direct (mutation) and indirect (aging of stem cell population) effects (Tubiana et al., Radiotherap. Oncol. 29: 1-17, 1993).
  • cancer treatments often result in a decrease in red blood cells or erythrocytes in the general circulation.
  • Erythrocytes are non-nucleated, biconcave, disk-like cells which contain hemoglobin and are essential for the transport of oxygen. Hemoglobin is a tetrapeptide which contains four binding sites for oxygen.
  • Anemia refers to that condition which exists when there is a reduction below normal in the number of erythrocytes, the quantity of hemoglobin, or the volume of packed red blood cells in the blood as characterized by a determination of the hematocrit. The hematocrit or "red blood cell volume" is considered to be a particularly reliable indicator of anemia.
  • red blood cell count millions/mm 3
  • hemoglobin g/100 mL
  • hematocrit or volume packed red blood cells mL/100 tnL
  • erythrocytes are produced by the bone marrow and released in the circulation, where they survive approximately 120 days, They are subsequently removed by the monocyte-phagocyte system.
  • Anemia is a symptom of various diseases and disorders. Therefore, anemia may be classified in terms of its etiology. For example, aplastic anemia is characterized by absence of regeneration of erythrocytes and is resistant to therapy. In such patients, there is a marked decrease in the population of myeloid, erythroid, and thrombopoietic stem cells, which results in pancytopenia. Hemolytic anemia arises from shortened survival of erythrocytes and the inability of the bone marrow to compensate for their decreased life span. It may be hereditary or may result from chemotherapy, infection, or an autoimmune process.
  • Iron deficiency anemia refers to a form of anemia characterized by low or absent iron stores, low serum iron concentration, low hemoglobin concentration, or decreased hematocrit. Iron deficiency is the most common cause of anemia. Pernicious anemia, which most commonly affects adults, arises from a failure of the gastric mucosa to secrete adequate intrinsic factor, resulting in malabsorption of vitamin B 12. Sickle cell anemia arises from a genetically determined defect in hemoglobin synthesis. It is characterized by the presence of sickle-shaped erythrocytes in the blood. The above are only exemplary of the many different anemias known to medicine. Of particular interest to the inventors is addressing anemia associated with the use of chemotherapy or radiotherapy in the treatment of cancer.
  • EPO Erythropoietin
  • BFU-E cells committed erythroid progenitors in the bone marrow
  • CFU-E cells cell viability (inhibition of apoptosis of BFU-E and CFU-E cells).
  • the biological effects of EPO are receptor mediated. Amino acid identity amongst different animals is 92% between human EPO and monkey EPO and 80% between human EPO and mouse EPO.
  • the primary stimulus for the biosynthesis of EPO is tissue hypoxia. As may be seen from the above, however, EPO has significant therapeutic potential for the treatment of certain anemias.
  • EPO can be used to treat anemia arising from a diminished endogenous production of EPO, which may result from a damaged or nonfunctional kidney (e.g., chronic renal failure as discussed above).
  • EPO can be used to treat anemia arising from damaged bone marrow and subsequently diminished proliferation of erythrocyte progenitors (e.g., BFU-E cells), which results from treatment of cancer patients with cytotoxic chemotherapy or radiotherapy (as also discussed above).
  • erythrocyte progenitors e.g., BFU-E cells
  • Various forms of recombinant EPO are available on the market. They differ by their expression system used for their manufacture and by their sites and degree of glycosylation of the protein.
  • Epoetin alpha is expressed in CHO cells and is available under the trade name of Procrit ® , Epogen ® or Eprex ® . Like EPO, Epoetin alpha has three N-linked glycosylation sites at asparagine (Asn) residues; Asn 19, Asn 33 and Asn 78. Epoietin beta is N-glycosylated at three sites but epoetin omega is N- glycosylated at Asn 24, Asn 28, Asn 83 and partially O-glycosylated at serine (Ser 126). Recently, a hyperglycosylated version of EPO has been approved which contains five N-linked glycosylation sites.
  • the present invention satisfies the need for treating anemia by providing a novel method for the stimulation of the hematopoietic system in a mammal, including a human patient, in need of such treatment. It also provides a novel method for treating the myelosuppressive effects of chemotherapy and/or radiotherapy and any other situation in which stimulation of the hematopoietic system can be of therapeutic value such as, but not limited to, anemia.
  • a composition containing a therapeutically effective amount of one or more substituted phenylpropionic acids and a pharmaceutically acceptable carrier is administered to a mammal, including a human patient, to significantly reduce the adverse effects of chemotherapy and/or radiotherapy.
  • compositions containing one or more substituted phenylpropionic acids for the production of chemoprotectives as a single agent or as a combination of two or more agents with and/or without other chemotherapeutic agents or such drugs which induce a state of myelosuppression are provided.
  • Another object relates to the use of a substituted phenylpropionic acid as a hematopoiesis and/or erythropoiesis stimulating factor.
  • compositions containing one or more substituted phenylpropionic acids and the use of such compounds for the treatment of myelosuppression and subsequent anemia, and immunosuppression are provided.
  • Still another object is to provide a method effective for reducing or eliminating chemotherapy-induced anemia in a mammal, including a human patient.
  • Another object is to provide a method for treating anemia arising from chronic renal failure, especially in those human patients with end-stage renal disease.
  • Yet another object is to provide a method for treating anemia arising from other medical procedures such as orthopedic surgery or the use of other drugs such as AZT.
  • Another object is to provide a method that minimizes or avoids adverse effects to the recipient.
  • the mammal including a human patient, may be selected as in need of treatment prior to such treatment.
  • Figure 1 shows the effect of compound II on white blood cell count.
  • Figure 2 shows the effect of compound II on red blood cell count.
  • Figure 3 shows the effect of compound IX on white blood cell count.
  • Figure 4 shows the effect of compound IX on total bone marrow cell count.
  • Figure 5 shows the effect of compound I on white cell count.
  • Figure 6 shows the effect of compound III on spleen white cell count.
  • Figure 7 shows the effect of compound III on white blood cell count.
  • Figure 8 shows the effect of compound II on neutrophil mobilization.
  • the present invention includes compounds or therapeutically acceptable derivatives thereof of the following general formula:
  • n 0-4
  • any minor modification of the formula such as homologation of the propionic acid (e.g., the corresponding substituted phenylbutanoic acid or phenylacetic acid) constitutes a permitted modification. Therefore, such a minor modification will only result in modulation of biological activity, for example, on hematopoiesis or erythropoiesis.
  • alteration of the spatial arrangement of the propionic acid moiety and the other (Y-(CH 2 ) n -X-) substituent from a para relationship about the core phenyl ring to a meta relationship constitutes a permitted modification.
  • High-dose chemotherapy and radiotherapy destroy hematopoietic cells in bone marrow. Subsequently, the patient can be severely depleted in erythrocytes, platelets, and neutrophils. Anemia results in fatigue, a lack of energy, and shortness of breath. Thrombocytopenia leads to prolonged clotting time and bleeding disorders. Neutropenia places the patient at increased risk of infection. Myelosuppression is a dose-limiting factor in cancer treatment.
  • a method of restoring a patient's hematopoietic system is provided.
  • Current methods employed to do the same make use of cytokines or glycoprotein growth factors.
  • erythropoietin can be used to stimulate the proliferation and maturation of responsive bone marrow erythroid cells.
  • Erythropoietin is approved for human use for the treatment of anemia where appropriate: e.g., anemia arising from the inability to produce a sufficient number of erythrocytes.
  • anemia e.g., anemia arising from the inability to produce a sufficient number of erythrocytes.
  • EMP is a polypeptide which contains twenty amino acids in each monomer. More importantly, EMP is significantly less active than erythropoietin.
  • WO 02/19963 describes synthetic erythropoiesis protein (SEP) as a synthetic stabilized polypeptide with erythropoietin-like biological activity.
  • SEP synthetic erythropoiesis protein
  • the reported advantage of SEP is that it is a stabilized, relatively longer, half-life molecule which is made by chemical synthesis and not by relatively more expensive recombinant technology. Stabilization is achieved by the introduction of ethylene glycol units (e.g., PEG) and so this introduces an additional level of complexity into the preparation of SEP.
  • PEG ethylene glycol units
  • a substituted phenylpropionic acid may be used as a hematopoiesis activation or growth factor and, more particularly, as a stimulator of the production of erythrocyte progenitor cells.
  • an appropriately substituted propionic acid is administered before, during, and/or after the treatment in order to shorten the period of anemia and to accelerate the replenishment of the hematopoietic system.
  • an appropriately substituted phenylpropionic acid is used as the therapeutic agent.
  • An appropriately substituted phenylpropionic acid can also be used after bone marrow transplantation in order to stimulate bone marrow stem cells thus shortening the time period for recovery from anemia.
  • a “therapeutically effective amount” of the compound(s) is used. Such an effective amount may be determined by varying its dose to achieve the desired therapeutic affect(s) such as, for example, treating myelosuppressive effects of chemotherapy and/or radiotherapy, stimulating the production of erythrocyte or other blood cell precursors, reducing the number and/or severity of symptoms of anemia, or any combination thereof.
  • One or more compounds as the active pharmaceutical ingredient(s) can be formulated in a pharmaceutical composition with a pharmaceutically acceptable carrier.
  • the term "pharmaceutically acceptable carrier” refers to a substance that does not interfere with the physiological effects of the substituted phenylpropionic acid composition, and that is not toxic to a mammal, including a human patient.
  • a pharmaceutical composition may be formulated using an appropriately substituted phenylpropionic acid and pharmaceutically acceptable carriers by methods known to those skilled in the art (see, e.g., The Merck Index, Merck, 14 th Ed., 2006 and Remington: The Science and Practice of Pharmacy, 21 st Ed., Lippincott, 2005). These compositions include, but are not limited to, solids, liquids, oils, emulsions, gels, aerosols, inhalants, capsules, pills, patches, and suppositories.
  • a method to produce a pharmaceutical composition comprises bringing into contact one or more active ingredients into association with the carrier which constitutes one or more accessory ingredients.
  • chemotherapy refers to a process of killing proliferating cells using a cytotoxic agent.
  • the phrase “during the chemotherapy” refers to the period in which the effect of the administered cytotoxic agent lasts.
  • the phrase “after the chemotherapy” is meant to cover all situations in which a composition is administered after the administration of a cytotoxic agent regardless of any prior administration of the same, and also regardless of the persistence of the effect of the administered cytotoxic agent.
  • the substituted phenylpropionic acid composition can be administered prior to, during, or subsequent to the chemotherapy (i.e., prior to, during, or subsequent to the administration of a cytotoxic agent).
  • cytotoxic agent an agent which kills highly proliferating cells: e.g., tumors cells, virally infected cells, or hematopoietic cells.
  • a cytotoxic agent include, but are not limited to, cyclophosphamide, doxorubicin, daunorubicin, vinblastine, vincristine, bleomycin, etoposide, topotecan, irinotecan, taxotere, taxol, 5- fluorouracil, methotrexate, gemcitabine, cisplatin, carboplatin, or chlorambucil, and an agonist of any of the above compounds.
  • a cytotoxic agent can also be an antiviral agent: e.g., AZT (i.e., 3'-azido-3'-deoxythymidine) or 3TC/lamivudine (i.e., 3- thiacytidine).
  • AZT i.e., 3'-azido-3'-deoxythymidine
  • 3TC/lamivudine i.e., 3- thiacytidine
  • Such drugs can induce anemia in a mammal, including a human patient.
  • the term "chemoprotection” refers to protection provided to a mammal from the toxic effects arising from treatment of the mammal with a chemotherapeutic agent. Most often, the latter is a cytotoxic agent whose therapeutic effect arises from its ability to interfere with or inhibit some aspect of DNA replication, RNA transcription, or subsequent translation of protein. Therefore, a chemoprotective agent refers to any compound administered to a mammal which would protect the ma
  • Anemia can be diagnosed and its severity can be determined by a person skilled in the art.
  • the term "anemia” may refer to that condition which exists when there is a reduction below normal in the number of erythrocytes, the quantity of hemoglobin, or the volume (hematocrit) of packed red blood cells. Such clinical criteria are subject to variability. Without limitation, anemia may be the result of a reduction in the mass of circulating red blood cell. Efficacy of treatment (including a palliative effect) can be determined by a person skilled in the art.
  • the pharmaceutical composition may be provided in a form suitable for oral, sublingual, rectal, topical administration or inhalation (nasal spray), intramuscular, intradermal, intraperitoneal, subcutaneous, or intravenous administration for use in the treatment (see, e.g., Ansel's Pharmaceutical Dosage Forms and Drug Delivery
  • the amount of a compound required for use in the treatment will vary with the route of administration, the nature of the condition being treated, the age and condition of the patient, and will ultimately be at the discretion of the attending physician.
  • the desired dose may be conveniently presented in a single dose or as divided doses taken at appropriate intervals, for example as two, three, or more doses per day as necessary to effect or bring about treatment.
  • treatment or “treating” includes any therapy of existing disease or condition and prophylaxis of the disease or condition (e.g., anemia) in a mammal.
  • a nontoxic composition is formed by the incorporation of any of the normally employed excipients such as, for example but not limited to, mannitol, lactose, trehalose, starch, magnesium stearate, talcum, cellulose, carboxymethyl cellulose, glucose, gelatin, sucrose, glycerol, magnesium carbonate, sodium citrate, sodium acetate, sodium chloride, sodium phosphate, and glycine.
  • excipients such as, for example but not limited to, mannitol, lactose, trehalose, starch, magnesium stearate, talcum, cellulose, carboxymethyl cellulose, glucose, gelatin, sucrose, glycerol, magnesium carbonate, sodium citrate, sodium acetate, sodium chloride, sodium phosphate, and glycine.
  • the pharmaceutical composition is in a form suitable for enteral, mucosal (including sublingual, pulmonary, and rectal), or parenteral (including intramuscular, intradermal, intraperitoneal, subcutaneous, and intravenous) administration.
  • the formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. Methods may include bringing into association the active pharmaceutical ingredient with liquid carriers (e.g., buffered saline, water for injection, etc.) or finely divided solid carriers or both and then, if necessary, shaping the product into the desired form (e.g., gel capsule, tablet, inhalation device, etc.).
  • liquid carriers e.g., buffered saline, water for injection, etc.
  • finely divided solid carriers or both e.g., finely divided solid carriers or both
  • shaping the product e.g., gel capsule, tablet, inhalation device, etc.
  • Sustained release formulations well known to the art include the
  • An appropriately substituted phenylpropionic acid can also be used in combination with other therapeutically active agents such as growth factors (e.g., granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-colony stimulating factor (GM-CSF), erythropoietin (EPO), etc.); cytotoxic agents or other anticancer agents (e.g., immune modulating or regulating drugs, therapeutic vaccines, or anti-angiogenesis drugs, etc.); or immune suppressive drugs (including antiinflammatory drugs).
  • growth factors e.g., granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-colony stimulating factor (GM-CSF), erythropoietin (EPO), etc.
  • cytotoxic agents or other anticancer agents e.g., immune modulating or regulating drugs, therapeutic vaccines, or anti-angiogenesis drugs, etc.
  • immune suppressive drugs including antiinflammatory drugs
  • the crude product was purified on a BIOTAGE 12S column (silica, 10% ethyl acetate/ hexanes) to give 3-[4-(4-fluorobenzyloxy)- phenylj-propionic acid methyl ester (0.15 g, 91 %) as a white solid.
  • the aldehyde (5.4 g, 22.3 mmol) was dissolved in toluene (17.0 mL) and treated with 2,2-dimethyl-l,3-dioxane- 4,6-dione (3.2 g, 22.3 mmol), concentrated acetic acid (0.7 mL) and piperidine (0.4 mL). The mixture was heated in an oil bath for 3 h at 135 0 C to remove the water. The solution was then cooled in an ice bath for few hours and the precipitate was filtered, washed with cold toluene, and dried under high vacuum.
  • This compound (1.0 g, 2.8 mmol) was dissolved in anhydrous tetrahydrofuran (9.3 mL) under nitrogen atmosphere and was added slowly to a solution of 1 -propynylmagnesium bromide (0.5M, 7.3 mL). The resulting mixture was stirred for 20 min at room temperature and then quenched with a saturated solution of ammonium chloride and water. The aqueous layer was extracted three times with ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. The yellow solid obtained was treated with pyridine (21 ,6 mL) and distilled water (4.3 mL).
  • the above compound was prepared as in Example 9 except 1 - propynylmagnesium bromide was replaced by methylmagnesium bromide.
  • Example 10 In vivo induction of immune cell proliferation or chemoprotection by compound II (3-(4-(3 ⁇ phenoxy-benzylamino)-phenyl)propionic acid).
  • mice Female C57BL/6 mice, 6- to 8-week old, were immunosuppressed by treatment with 200 mg/kg of cyclophosphamide administered intravenously at day 0.
  • mice were pre- treated orally at day -3, -2 and -1 at day 0 with the compound.
  • Mice were sacrificed at day +5 by cardiac puncture and cervical dislocation. Then, a gross pathological observation of the femurs (as a source of bone marrow cells) was recorded. After sacrifice, tissues were crushed in phosphate buffered saline and cells were counted with a hemacytometer.
  • Compound I also induces an increase in white blood cell count in cyclophosphamide treated mice (Fig. 5).
  • Example 1 1 7 « vivo induction of neutrophil mobilization by compound II.
  • mice Female C57BL/6 mice, 6- to 8-week old, were treated with 200 mg/kg of compound III administered orally at day 0. To examine the neutrophil mobilization effect of compound III, mice were treated orally at day 0 with the compound. Mice were sacrificed at time 0, 0.5, 1, 2 and 4 hr by cardiac puncture and cervical dislocation. Then, blood was collected. Blood cells were counted on a Coulter counter and stained with Wright/Giemsa staining for a differential cell count analysis.
  • Figure 8 indicates that compound II induces a significant increase in neutrophil mobilization as seen by an enhancement of the number of neutrophils in blood after 30 and 60 min. The neutrophil count then returns to baseline at 2 hr.

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Abstract

L'invention concerne des composés, ou leurs dérivés acceptables pharmaceutiquement, de formule générale n = 0-4, X = O, NH, S, Z = H, C1-C4 (alkyIe, alcényle, alkynyle), Y = OH, C1-C4 (alkyle, à chaîne droite ou ramifiée), Y = OH, C1-C4 (alkyle, à chaîne droite ou ramifiée), A = Oalkyle à chaîne droite ou ramifiée), OH, Oaryle, halogène (F, Cl, Br), CF3, phényle, B = halogène (F, Cl, Br), CF3, phényle pouvant être utilisés au moins pour traiter l'anémie ou la nitropénie. Ces composés peuvent être utilisés comme stimulateurs d'au moins l'hématopoïèse ou l'érythropoïèse. Ils peuvent être également utilisés en thérapie combinatoire.
PCT/CA2008/001929 2007-11-02 2008-11-03 Acides phénylpropioniques substitués utiles comme stimulateurs de l'hématopoïèse et de l'érythropoïèse WO2009055932A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012097427A1 (fr) * 2010-10-27 2012-07-26 Prometic Biosciences Inc. Composés et compositions pour le traitement du cancer
US9938221B2 (en) 2009-05-04 2018-04-10 Prometic Pharma Smt Limited Substituted aromatic compounds and pharmaceutical uses thereof

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WO2005086661A2 (fr) * 2004-02-27 2005-09-22 Amgen Inc. Composes, compositions pharmaceutiques et procedes d'utilisation dans le traitement de troubles metaboliques

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WO2005086661A2 (fr) * 2004-02-27 2005-09-22 Amgen Inc. Composes, compositions pharmaceutiques et procedes d'utilisation dans le traitement de troubles metaboliques

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Title
GAGNON, L ET AL.: "PBI-1402: A new candidate for the treatment of anemia", BLOOD, vol. 108, 2006 *
GROUIX, B ET AL.: "PBI-1402: A low molecular wight synthetic hematopoietic growth stimulant", BLOOD, vol. 108, 2006 *
LAGRAOUI, M ET AL.: "PBI-1403: A non-toxic immunorestorative small molecule for the treatment of anemia", BLOOD, vol. 108, 2006 *
MORIN, M-J ET AL.: "Oral administration ofPBI-1402 significantly reduces erythropenia and accelerates peripheral blood recovery in myeloablated mice post transplantation", BLOOD, vol. 108, 2006 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9938221B2 (en) 2009-05-04 2018-04-10 Prometic Pharma Smt Limited Substituted aromatic compounds and pharmaceutical uses thereof
US10815183B2 (en) 2009-05-04 2020-10-27 Prometic Pharma Smt Limited Substituted aromatic compounds and pharmaceutical uses thereof
WO2012097427A1 (fr) * 2010-10-27 2012-07-26 Prometic Biosciences Inc. Composés et compositions pour le traitement du cancer
US9114118B2 (en) 2010-10-27 2015-08-25 Prometic Biosciences Inc. Compounds and compositions for the treatment of cancer
US9439882B2 (en) 2010-10-27 2016-09-13 Prometic Biosciences Inc. Compounds and compositions for the treatment of cancer
KR101821646B1 (ko) 2010-10-27 2018-01-25 프로메틱 파마 에스엠티 리미티드 암을 치료하기 위한 화합물 및 조성물
EA030038B1 (ru) * 2010-10-27 2018-06-29 Прометик Фарма Смт Лимитед Применение соединений для лечения рака и способ лечения рака

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