WO2020256739A1 - Procédés de traitement de troubles myéloprolifératifs - Google Patents

Procédés de traitement de troubles myéloprolifératifs Download PDF

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WO2020256739A1
WO2020256739A1 PCT/US2019/038506 US2019038506W WO2020256739A1 WO 2020256739 A1 WO2020256739 A1 WO 2020256739A1 US 2019038506 W US2019038506 W US 2019038506W WO 2020256739 A1 WO2020256739 A1 WO 2020256739A1
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less
pharmaceutically acceptable
blood
compound
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PCT/US2019/038506
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Adrian SENDEROWICZ
Michael Cooper
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Constellation Pharmaceuticals, Inc.
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Priority to PCT/US2019/038506 priority Critical patent/WO2020256739A1/fr
Priority to PCT/US2020/038727 priority patent/WO2020257644A1/fr
Publication of WO2020256739A1 publication Critical patent/WO2020256739A1/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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • Myelofibrosis is part of a collection of progressive blood cancers known as myeloproliferative neoplasms and is associated with significantly reduced quality of life and shortened survival.
  • myeloproliferative neoplasms As the disease progresses, the bone marrow produces fewer red blood cells.
  • This disease has several important features: severe constitutional symptoms, splenomegaly (enlargement of spleen) and defects in the structure and function of the bone marrow.
  • thrombocytopenia a condition characterized by low platelet counts in the blood.
  • Patients may also have severe anemia (a condition characterized by low red-blood-cell counts) leading to red-blood-cell transfusion requirements.
  • transplantation can be curative, it is associated with its own morbidity and mortality, which limit its use to those eligible patients whose prognosis is worse ( ⁇ 5 years) than the risk of moving forward with the transplant.
  • the remaining treatments are palliative in nature, either due to their mechanism of action (e.g., treatments specifically focused on the anemia that is frequently associated with myelofibrosis) or due to the restricted effects that the treatment can elicit (e.g., the standard of care ruxolitinib).
  • the major cell responsible for MF is the megakaryocyte and preventing megakaryocyte proliferation may lead to improvement in the disease due to decrease in cytokines and decrease in fibrosis.
  • Ruxolitinib is the current standard of care and the only approved drug treatment for intermediate- and high-risk MF patients. Ruxolitinib inhibits dysregulated janus kinase 1 and 2, or JAK1/JAK2, signaling that is associated with MF. Ruxolitinib produces spleen reduction and symptom improvement in MF patients. However, its side effects include increased anemia and transfusion dependence. Indeed, in the SIMPLIFY- 1 clinical trial of ruxolitinib in JAK-narve patients, transfusion dependence increased from 24.0% to 40.1% after 24 weeks of treatment with ruxolitinib.
  • ruxolitinib has not been shown to have a significant effect on bone marrow fibrosis reversion, which has been documented as a primary cause of morbidity and mortality in MF.
  • many patients (such as those with anemia) cannot initiate ruxolitinib therapy and many other patients may not tolerate treatment with ruxolitinib or will have an insufficient response or no response at all.
  • These disadvantages coupled with the lack of alternative therapies, provide an unmet medical need for improving the survival rates for subjects with MF.
  • compositions comprising 2-((4S)-6-(4- chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide, or a
  • FIG. 1 shows the effects of Compound 1 on IL6 and IL10 mRNA transcript levels.
  • FIG. 2 depicts histograms of Compound 1 effect on megakaryocyte
  • a method for treating myelofibrosis in a subject comprising administering to the subject an effective amount of 2-((4S)-6-(4-chlorophenyl)-l- methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide, or a pharmaceutically acceptable salt thereof, and an effective amount of a JAK inhibitor.
  • a first embodiment is an effective amount of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4- yljacetamide, or a pharmaceutically acceptable salt thereof, and an effective amount of a JAK inhibitor for treating myelofibrosis in a subject.
  • a janus kinase inhibitor or JAK inhibitor are agents which inhibit the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2) and interfere with the JAK-STAT signaling pathway.
  • JAK inhibitors described herein include biological and chemical agents.
  • Pacritinib refers the JAK inhibitor (22Z,23E,8E)-44-(2-(pyrrolidin-l-yl)ethoxy)- 21 ,22-dihydro-6, 11 -dioxa-3-aza-2(4,2)-pyrimidina- 1 ,4( 1 ,3)-dibenzenacyclododecaphan-8- ene, having the following structural formula:
  • Momelotinib refers the JAK inhibitor N-(cyanomethyl)-4-(2-((4- morpholinophenyl)amino)pyrimidin-4-yl)benzamide, having the following structural formula:
  • Baricitinib refers the JAK inhibitor 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- lH-pyrazol-l-yl)-l-(ethylsulfonyl)azetidin-3-yl)acetonitrile, having the following structural formula:
  • Itacitinib refers to the JAK inhibitor 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- lH-pyrazol-l-yl)-l-(l-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3- yl)acetonitrile, having the following structural formula:
  • Fedratinib refers the JAK inhibitor N-(l,l-dimethylethyl)-3-[[5-methyl-2-[[4-[2- ( 1 -pyrrolidinyl)ethoxy]phenyl] amino] -4-pyrimidinyl] amino] -benzenesulfonamide, having the following structural formula:
  • NS-018 refers the JAK inhibitor (S)-N2-[l-(4-fluorophenyl)ethyl]-4-(l-methyl- lH-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2, 6-diamine, having the following structural formula:
  • the terms“subject” and“patient” may be used interchangeably, and mean a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • the subject is a human in need of treatment.
  • treatment refers to reversing, alleviating, reducing the likelihood of developing, or inhibiting the progress of myelofibrosis, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. Symptoms specific to
  • myelofibrosis include, but are not limited to, abdominal discomfort, dyspnea on exertion, early satiety, fatigue, headaches, night sweats, dizziness, fever, chills, insomnia, pruritus, or bone pain.
  • a subject who is characterized as progressed/relapsed is one who at one time responded to treatment with a JAK inhibitor, but who no longer responds.
  • a subject who is characterized as refractory/resistant is one who is unresponsive or demonstrates worsening of disease while on treatment with a JAK inhibitor.
  • the administrations described herein include administering Compound 1 prior to, concurrently with, or after administration of a disclosed JAK inhibitor to treat MF.
  • simultaneous administration is not necessary for therapeutic purposes.
  • Compound 1 is administered concurrently with the JAK inhibitor.
  • an effective amount or“therapeutically effective amount” are used interchangeably and include an amount of a compound described herein that will elicit a desired medical response in a subject having myelofibrosis, e.g., reducing the symptoms of and/or slowing the progression of the disease.
  • pharmaceutically acceptable carrier refers to a non-toxic carrier, adjuvant, or vehicle that does not adversely affect the pharmacological activity of the compound with which it is formulated, and which is also safe for human use.
  • compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, sodium lauryl sulfate, and crosscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
  • the compounds described herein may be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds described herein refer to non-toxic“pharmaceutically acceptable salts.”
  • Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts where possible.
  • JAK inhibitors of the present methods and compositions are selected from those having the following formulae: 1) pharmaceutically acceptable salt thereof, wherein, X, R 1 , R 2 , R 3 , and R 4 are as defined in US 2011/0288065, the contents of which are incorporated herein by reference;
  • R 2 , Ar 1 , Ar 2 , Z 2 , and L are as defined in WO 2007/058627, the contents of which are incorporated herein by reference;
  • Y, Z, L, A, n, and R 1 are as defined in WO 2011/112662, the contents of which are incorporated herein by reference
  • the JAK of the present methods and compositions are selected from pacritinib, itacitinib, momelotinib, baricitinib, fedratinib, and NS -018, or a pharmaceutically acceptable salt thereof.
  • the subjects described in the present methods are characterized as progressed/relapsed to a JAK inhibitor.
  • the subjects described in the present methods are characterized is refractory/resistant to a JAK inhibitor.
  • the subjects described in the present methods are cytopenic.
  • Cytopenic refers to subjects in which the production of one or more blood cell types ceases or is greatly reduced.
  • Types of cytopenia include e.g., anemia (a deficiency of red blood cells), leukopenia or neutropenia (a deficiency of white blood cells), thrombocytopenia (a deficiency in the platelets), and pancytopenia (a deficiency in all three of red blood cells, white blood cells, and platelet counts).
  • the subjects described in the present methods are anemic.
  • a subject of the present disclosure e.g., as in any one of the first through fifth embodiments
  • a subject e.g., as in any one of the first through fifth embodiments
  • Subjects treatable by the present methods therefore include those having hemoglobin values less than 13.0 g/dL, less than 12.5 g/dL, less than 12.0 g/dL, less than 11.5 g/dL, less than 11.0 g/dL, less than 10.5 g/dL, less than 10.0 g/dL, less than 9.5 g/dL, less than 9.0 g/dL, or less than 8.5 g/dL for male subjects and less than 11.5 g/dL, less than 11.0 g/dL, less than 10.5 g/dL, less than 10.0 g/dL, less than 9.5 g/dL, less than 9.0 g/dL, or less than 8.5 g/dL for female subjects.
  • a subject e.g., as in any one of the first through fifth
  • a subject e.g., as in any one of the first through fifth embodiments
  • a subject is defined herein as being anemic if their hemoglobin value ranges from 7.5 g/dL of blood to 10.5 g/dL of blood for a male subject or from 7.5 g/dL of blood to 10.5 g/dL of blood for a female subject.
  • a subject (e.g., as in any one of the first through fifth embodiments) is defined herein as being anemic if their hemoglobin value ranges from 7.5 g/dL of blood to 10.0 g/dL of blood for a male subject or from 7.5 g/dL of blood to 10.0 g/dL of blood for a female subject.
  • a subject (e.g., as in any one of the first through fifth embodiments) is defined herein as being anemic if their hemoglobin value ranges from 7.7 g/dL of blood to 10.7 g/dL of blood for a male subject or from 7.7 g/dL of blood to 10.5 g/dL of blood for a female subject.
  • a subject e.g., as in any one of the first through fifth embodiments
  • a subject is defined herein as being anemic if their hemoglobin value ranges from 7.7 g/dL of blood to 10.0 g/dL of blood for a male subject or from 7.7 g/dL of blood to 10.0 g/dL of blood for a female subject.
  • subjects treated by the methods described herein are thrombocytopenic.
  • a subject of the present disclosure e.g., as in any one of the first through sixth embodiments
  • subjects treatable by the present methods therefore include those having platelet levels less than 140,000 platelets ⁇ L, less than
  • subjects treated by the methods described herein are thrombocythemic.
  • a subject of the present disclosure subjects treated by the methods described herein is said to be thrombocythemic if their platelet count is more than 400,000 platelets ⁇ L of blood.
  • Subjects treatable by the present methods therefore include those having platelet levels more than 450,000 platelets ⁇ L, more than 500,000 platelets ⁇ L, more than 550,000 platelets ⁇ L, or more than 600,000 platelets ⁇ L, alone or in combination with one or more of the hemoglobin values described above.
  • subjects treated by the methods described herein are leukopenic.
  • a subject e.g., as in any one of the first through eighth embodiments
  • WBC white blood cell
  • subjects treatable by the present methods include those having WBC counts of less than 3,500 WBCs ⁇ L, 3,200 WBCs ⁇ L, 3,000 WBCs ⁇ tL, or 2,500 WBCs ⁇ L, alone or in combination with one or more of the hemoglobin and/or platelet values described above.
  • subjects treated by the methods described herein is (e.g., as in any one of the first through ninth embodiments) are neutropenic.
  • a subject of the present disclosure e.g., as in any one of the first through ninth embodiments is said to be neutropenic if their neutrophil count is less than 1500 neutrophils ⁇ L of blood.
  • subjects treatable by the present methods include those having neutrophil counts of less than 1250 neutrophils ⁇ L, 1000 neutrophils ⁇ L, 750 neutrophils ⁇ L, or 500 neutrophils ⁇ L, alone or in combination with one or more of the hemoglobin, platelet, and/or WBC values described above.
  • subjects treatable by the present methods include those having an enlarged spleen or liver.
  • subjects treatable by the present methods may also be experiencing one or more additional symptoms. These symptoms include, but are not limited to, abdominal discomfort, dyspnea on exertion, early satiety, fatigue, headaches, night sweats, dizziness, insomnia, pruritus, or bone pain.
  • subjects treated by the present methods are transfusion dependent prior to treatment with Compound 1.
  • “transfusion dependent” means that a subject requires red blood cell (RBC) transfusions in order to maintain an acceptable level of hemoglobin.
  • RBC red blood cell
  • An acceptable level of hemoglobin is determined by those skill in the art and can range from e.g., from 13.5 to 17.5 g/dL of blood for men and from 12.0 to 15.5 g/dL of blood in women. It will be understood that subjects undergoing treatment with a JAK inhibitor may have lower hemoglobin levels than those described above and still be deemed an“acceptable” level in order for treatment to continue.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof; and a JAK inhibitor (e.g., as in the second embodiment); and optionally a pharmaceutically acceptable carrier.
  • compositions and administered to a subject such as a human, in a variety of forms adapted to the chosen route of administration.
  • routes of administering such pharmaceutical compositions include, without limitation, oral, topical, buccal, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrathecal, intrasternal injection or infusion techniques. Methods of formulating pharmaceutical compositions are well known in the art, for example, as disclosed in“Remington: The Science and Practice of Pharmacy,” University of the Sciences in Philadelphia, ed., 21st edition, 2005, Lippincott, Williams & Wilkins, Philadelphia, PA.
  • compositions of the invention can be prepared by combining a compound of the methods described herein with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi- solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • an inert diluent or an assimilable edible carrier such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound described herein in the composition will also depend upon the particular compound in the composition. In one aspect, however, Compound 1, or a pharmaceutically acceptable salt thereof, may be formulated at a dose of from 50 mg to 500 mg for e.g., administration once, twice, or three times daily.
  • Compound 1 may be administered at a dosage of from 100 mg to 300 mg/day, from 100 mg to 200 mg/day, or at 100 mg/day, 125 mg/day, 150 mg/day, 175 mg/day, or 200 mg/day.
  • Compound 1 can be obtained following the procedures describe in U.S. Patent No. 8,796,261 and WO 2015/195862, both of which are incorporated herein by reference.
  • Compound 1 was assessed for its ability to suppress the expression of NF-KB target genes in two experiments.
  • THP-1 acute leukemia cell lines were exposed to lipopolysaccharide treatment and then Compound 1 for 16 hours.
  • IL6 release from the THP-1 acute leukemia cells was inhibited, with an IC 50 of 0.069 mM.
  • the ability of Compound 1 to suppress both IL6 and IL10 expression in TMD8 ABC-DLBCL cells was investigated (data on file).
  • TMD8 cells were incubated with DMSO or 1.6 pM Compound 1 for 6 or 24 hours.
  • RNA was then extracted from the cells and quantified using qRT-PCR.
  • Compound 1 substantially suppressed mRNA transcription of both IL6 and IL10 after 6 and 24 hours of treatment. Effect of Compound 1 as a Single Agent on Megakaryocyte Differentiation
  • CD34+ cells isolated from healthy donor bone marrow (data on file).
  • the CD34+ cells were grown in megakaryocyte differentiation serum-free stem cell differentiation base medium with a megakaryocyte-driving cytokine cocktail for 14 days with DMSO or Compound 1 at concentrations ranging from 3 nM to 500 nM.
  • the cells were then stained for CD34 (progenitor marker), CD45 (leukocyte marker) and CD41a (mature megakaryocyte marker) and assessed by FACS for viability and marker expression.
  • CD41a expression and cell size were used as markers of megakaryocyte differentiation.
  • Compound 1 reduced the number of cells with high CD41a expression in a concentration-dependent manner.

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Abstract

La présente invention concerne l'utilisation de 2-((4S)-6-(4-chlorophényl)-1-méthyl-4H-benzo[c]isoxazolo [4,5-e]azépin-4-yl) acétamide en association avec des inhibiteurs de JAK pour traiter la myélofibrose.
PCT/US2019/038506 2019-06-21 2019-06-21 Procédés de traitement de troubles myéloprolifératifs WO2020256739A1 (fr)

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PCT/US2020/038727 WO2020257644A1 (fr) 2019-06-21 2020-06-19 Méthodes de traitement de troubles myéloprolifératifs

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