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WO2023038816A1 - Procédé de traitement d'une réponse immunologique excessive à une infection par un virus respiratoire - Google Patents

Procédé de traitement d'une réponse immunologique excessive à une infection par un virus respiratoire Download PDF

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WO2023038816A1
WO2023038816A1 PCT/US2022/041721 US2022041721W WO2023038816A1 WO 2023038816 A1 WO2023038816 A1 WO 2023038816A1 US 2022041721 W US2022041721 W US 2022041721W WO 2023038816 A1 WO2023038816 A1 WO 2023038816A1
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patient
influenza
prodrugs
group
acid
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Vadim Markovtsov
Esteban Masuda
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Rigel Pharmaceuticals Inc
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Rigel Pharmaceuticals Inc
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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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • Severe influenza is defined as influenza with a severe symptom or syndrome such as respiratory distress or decreased consciousness or accompanying a severe complication such as encephalopathy or renal failure.
  • severe influenza requires hospital admission in most cases or intensive treatment in the intensive care unit in some cases.
  • the elderly, infants, and chronic patients are known to be at high risk for severe influenza because they may have accompanying complications such as exacerbation of an underlying disease, development of pneumonia, and another organ dysfunction or they may die.
  • This disclosure provides, among other things, a method for treating an excessive immunological response to an infection by a respiratory virus, e.g., influenza, by administering fostamatinib, an active component thereof or a pharmaceutically acceptable salt thereof to the patient.
  • a respiratory virus e.g., influenza
  • the patient may have acute respiratory distress syndrome, thrombosis, or organ failure, for example.
  • the method may comprise administering fostamatinib, an active component thereof or a pharmaceutically acceptable salt thereof to a patient that is infected by a respiratory virus having, suspected of having or expected to develop symptoms associated with an excessive immunological response, e.g., a cytokine storm, where a cytokine storm is caused by the overproduction of inflammatory cytokines, e.g., in the lungs and/or kidneys.
  • a respiratory virus having, suspected of having or expected to develop symptoms associated with an excessive immunological response, e.g., a cytokine storm, where a cytokine storm is caused by the overproduction of inflammatory cytokines, e.g., in the lungs and/or kidneys.
  • FIG. 1 shows embodiments of targets of fostamatinib.
  • FIG. 2 shows embodiments of targets (*) of fostamatinib including CLEC -dependent cytokine release by innate immune cells, immune complex driven Fc receptor mediated monocyte or endothelial cell activation, and neutrophil activation and NETosis.
  • FIG. 3 shows the design for a clinical trial.
  • dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
  • ARDS acute respiratory distress syndrome
  • ARDS refers to a syndrome characterized by a severe shortness of breath, labored and unusually rapid breathing, low blood pressure, confusion and extreme tiredness. This syndrome can be diagnosed based on a PaO2/FiO2 ratio of less than 300 mmHg despite a PEEP of more than 5 cm H2O (Fan et al JAMA. 319: 698-71).
  • ARDS occurs when fluid builds up in lung alveoli.
  • the fluid prevents the lungs from filling with enough air, limiting the amount of oxygen that reaches the bloodstream which, in turn, deprives the organs of the oxygen they need to function.
  • the symptoms of ARDS can vary in intensity, depending on its cause and severity. Severe shortness of breath — the hallmark of ARDS — usually develops within a few hours to a few days after the influenza infection. Many people who develop ARDS do not survive, and the risk of death increases with age and severity of illness. Of the patients that survive ARDS, some completely recover while others have lasting damage to their lungs. ARDS may be referred to as Acute Lung Injury (ALI) in some publications.
  • ALI Acute Lung Injury
  • AKI acute kidney injury
  • AKI acute renal injury
  • ARI acute renal failure
  • AKI acute renal failure
  • AKI is characterized by a decline of glomerular filtration rate, urine output, or both. This loss of filtration capacity results in retention of nitrogenous (urea and creatinine) and non-nitrogenous waste products that are normally excreted by the kidney, a reduction in urine output, or both.
  • AKI may be categorized as prerenal, intrinsic renal, or postrenal in causation.
  • Intrinsic renal disease can be further divided into glomerular, tubular, interstitial, and vascular abnormalities.
  • AKI is accompanied by an inflammatory response that if unchecked can lead to renal fibrosis and chronic renal failure.
  • AKI usually occurs over a period of hours or days and is potentially reversible.
  • AKI may be characterized as an abrupt (i.e., for example, within 14 Days, within 7 Days, within 72 hours, or within 48 hours) reduction in kidney function identified by an absolute increase in serum creatinine of greater than or equal to 0.3 mg/dl ( ⁇ 26.4 pmol/1), a percentage increase in serum creatinine of greater than or equal to 50% (1.5-fold from baseline), or a reduction in urine output (documented oliguria of less than 0.5 ml/kg per hour for at least 6 hours).
  • Risk factors include, for example, a subject undergoing or having undergone major vascular surgery, coronary artery bypass, or other cardiac surgery; a subject having pre-existing congestive heart failure, preeclampsia, eclampsia, diabetes mellitus, hypertension, coronary artery disease, proteinuria, renal insufficiency, glomerular filtration below the normal range, cirrhosis, serum creatinine above the normal range, or sepsis; or a subject exposed to NSAIDs, cyclosporines, tacrolimus, aminoglycosides, foscamet, ethylene glycol, hemoglobin, myoglobin, ifosfamide, heavy metals, methotrexate, radiopaque contrast agents, or streptozotocin. This list is not meant to be limiting.
  • kidney malfunction as used herein is intended to include kidney disorders, kidney disease, kidney dysfunction, kidney cancer, absence of at least one kidney due to accidents, surgical removal or genetic disorders, or other conditions where one or both of the kidneys are not properly functioning.
  • kidney malfunction may include acute kidney injury.
  • thrombosis refers to a clotting disorder to which an excess of platelets contributes.
  • Thrombosis may refer to the formation of a thrombus (blood clot) inside a blood vessel.
  • the term encompasses, without limitation, arterial and venous thrombosis, including deep vein thrombosis, portal vein thrombosis, jugular vein thrombosis, renal vein thrombosis, stroke, myocardial infarction, Budd-Chiari syndrome, Paget-Schroetter disease, and cerebral venous sinus thrombosis.
  • the patient is at heightened risk relative to the general population (e.g., as measured by recognized risk factors) of a thrombotic event.
  • a patient has one or more risk factors that make the patient have a high risk of developing thrombosis relative to the general population.
  • Risk factors for thrombosis include, e.g., classical cardiovascular disease risk factors: hyperlipidemia, smoking, diabetes, hypertension, and abdominal obesity; strong classical venous thromboembolism risk factors: trauma or fractures, major orthopedic surgery, and oncological surgery; moderate classical venous thromboembolism risk factors: non-oncological surgery, oral contraceptives and hormone replacement therapy, pregnancy and puerperium, hypercoagulability, and previous venous thromboembolism; and weak classical venous thromboembolism risk factors: age, bed rest (> 3 days), prolonged travel, and metabolic syndrome.
  • classical cardiovascular disease risk factors hyperlipidemia, smoking, diabetes, hypertension, and abdominal obesity
  • strong classical venous thromboembolism risk factors trauma or fractures, major orthopedic surgery, and oncological surgery
  • moderate classical venous thromboembolism risk factors non-oncological surgery, oral contraceptives and hormone replacement therapy, pregnancy and puerperium, hypercoagulability, and previous venous thromboembolism
  • Additional risk factors include inherited, acquired and mixed coagulation or metabolic risk factors for thrombosis such as, e.g., inherited: antithrombin deficiency, protein C deficiency, Protein S deficiency, Factor V Leiden, Prothrombin G20210A; acquired: antiphospholipid syndrome; mixed: hyperhomocysteinaemia, increased fibrinogen levels, increased factor VIII levels, increased factor IX levels.
  • heparin may increase the risk of thrombosis including, e.g., heparin-induced thrombocytopenia (HIT).
  • thrombosis Diseases and conditions associated with thrombosis include, without limitation, acute venous thrombosis, pulmonary embolism, thrombosis during pregnancy, hemorrhagic skin necrosis, acute or chronic disseminated intravascular coagulation (DIC), sepsis induced coagulopathy (SIC), clot formation from surgery, long bed rest, long periods of immobilization, venous thrombosis, fulminant meningococcemia, acute thrombotic stroke, acute coronary occlusion, acute peripheral arterial occlusion, massive pulmonary embolism, axillary vein thrombosis, massive iliofemoral vein thrombosis, occluded arterial cannulae, occluded venous cannulae, cardiomyopathy, venoocclusive disease of the liver, hypotension, decreased cardiac output, decreased vascular resistance, pulmonary hypertension, diminished lung compliance, leukopenia, thrombocytopenia (e.g.
  • Examples of methods for monitoring patients at risk of thrombosis included, without limitation, digital subtraction angiography, in vitro assays or non-invasive methods.
  • Examples of in vitro assays useful for identifying and monitoring subjects at risk for thrombosis and for treatment using the present methods include, without limitation, functional assays and antibody detection assays.
  • thrombotic event includes, but is not limited to, thrombotic disorders such as myocardial infarction, unstable angina, stroke, pulmonary embolism, transient ischemic attack, deep vein thrombosis, thrombotic re-occlusion and peripheral vascular thrombosis.
  • a thrombotic event also includes thrombotic re-occlusion which occurs subsequent to a coronary intervention procedure or thrombolytic therapy.
  • thrombotic event means any disorder which involves a blockage or partial blockage of an artery or vein with a thrombosis.
  • the term “sepsis” refers to a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated immune response to infection. The more severe form of sepsis “septic shock” is characterized by a critical reduction in tissue perfusion; acute failure of multiple organs, including the lungs, kidneys, and liver. Common causes in immunocompetent patients include many different species of gram-positive and gram-negative bacteria.
  • Immunocompromised patients may have uncommon bacterial or fungal species as a cause. Signs include fever, hypotension, oliguria, and confusion. Diagnosis is primarily clinical combined with culture results showing infection; early recognition and treatment is critical. Treatment is aggressive fluid resuscitation, antibiotics, surgical excision of infected or necrotic tissue and drainage of pus, and supportive care.
  • Influenza refers to a disease generally known to as the “flu”. Influenza is caused by a group of viruses that can be broken down into 4 separate groups: Influenza A, Influenza B, Influenza C and Influenza D which are separated based on their nuceloproteins and matrix proteins. Influenza causes viral respiratory infection resulting in fever, coryza, cough, headache, and malaise. Influenza A, B, and C all infect humans while there have been no documented cases of human Influenza D infection. Influenza C on the other hand does not cause typical influenza illness seen in individuals infected with Influenza A, B or C.
  • Influenza A strains are further classified based on two surface proteins, hemagglutinin (H) and neuraminidase (N). There are 18 different hemagglutinin subtypes and 11 different neuraminidase subtypes (Hl through H18 and N1 through Ni l, respectively). While there are potentially 198 different influenza A subtype combinations, only 131 subtypes have been detected in nature. Current subtypes of influenza A viruses that routinely circulate in people include: A(H1N1) and A(H3N2).
  • excessive immunological response to influenza refers to any condition associated with influenza that leads to high levels of cytokine release in the lungs and/or kidneys. Excessive immunological responses include without limitation, influenza-associated ARDS, influenza- associated AKI, influenza-associated thrombosis, influenza-associated sepsis, influenza- associated septic shock, etc.
  • influenza-associated ARDS refers to ARDS that is caused by influenza infection. Patients having influenza- associated ARDS may have been diagnosed as having an influenza infection, may have been exposed to another person having an influenza infection, or may be suspected of having an influenza infection based on their symptoms.
  • influenza-associated AKI refers to AKI that is caused by influenza infection. Patients having influenza- associated AKI may have been diagnosed as having an influenza infection, may have been exposed to another person having an influenza infection, or may be suspected of having an influenza infection based on their symptoms. In some cases, influenza- associated AKI includes AKI with the symptoms described, e.g., in Batlle et al. J. AM. SOC. NEPHROL. 2020, 31(7): 1380-1383 and Gabarre et al. Intensive Care Med. 2020, 46(7): 1339-1348, the disclosures of which are incorporated herein by reference in their entireties.
  • influenza-associated thrombosis refers to thrombosis that is caused by influenza infection. Patients having influenza-associated thrombosis may have been diagnosed as having an influenza infection, may have been exposed to another person having an influenza infection, or may be suspected of having a influenza infection based on their symptoms. In some cases, influenza-associated thrombosis includes any of the symptoms described in, e.g., Connors et al. Blood 2020, 135(23): 2033-2040 and Bikdeli et al. J. Am. Coll. Cardiol. 2020, 75(23): 2950-73, the disclosures of which are incorporated herein by reference in their entireties.
  • influenza-associated sepsis refers to sepsis that is caused by influenza infection. Patients having influenza- associated sepsis may have been diagnosed as having an influenza infection , may have been exposed to another person having an influenza infection, or may be suspected of having an influenza infection based on their symptoms. In some cases, influenza- associated thrombosis includes any of the symptoms described in, e.g., Florescu et al. Virulence. 2014 Jan 1; 5(1): 137-142.and Gu et al. Eur Respir Rev. 2020 Jul 21;29(157):200038, the disclosures of which are incorporated herein by reference in their entireties.
  • associated with influenza refers to a symptom or indication that develops within 28 days of hospitalization/signs of influenza infection.
  • treatment refers to a reduction in symptoms.
  • successful treatment may include a decrease in shortness of breath, less labored or less rapid breathing, higher blood pressure, decreased confusion and/or a decrease tiredness.
  • a treatment may be administered prophylactically, i.e., before the onset of ARDS.
  • a prophylactic treatment prevents ARDS and can be administered to patients that have or are suspected of having an influenza infection, but without the severe symptoms of ARDS.
  • prophylactic treatment can be administered to patients that have a cough without the other symptoms of ARDS.
  • successful treatment may include increased kidney function. Kidney function may be assessed by measuring serum creatinine levels, serum creatinine clearance, or blood urea nitrogen levels. In some cases, the successful treatment includes a reduction in metabolic acidosis, hyperkalaemia, oliguria or anuria, azotemia, restoration in body fluid balance, and improved effects on other organ systems.
  • a treatment may be administered prophylactically, i.e., before the onset of AKI.
  • a prophylactic treatment prevents AKI and can be administered to patients that have or are suspected of having an influenza infection, but without the severe symptoms of AKI.
  • prophylactic treatment can be administered to patients that have one or more of increased serum or urine creatinine, hematuria, hypoproteinemia, decreased antithrombin III levels, hypalbuminaemia, leucozyturia, or proteinuria without the other symptoms of AKI.
  • successful treatment may include improvement in the subject's coagulation profile, or preventing, slowing, delaying, or arresting, a worsening of the coagulation profile for which the subject is at risk.
  • a coagulation profile may be assessed by measurement of one or more coagulation parameters including, e.g., a subject’s serum level of one or more of D-dimer, Factor II, Factor V (e.g., Factor V Leiden), Factor VII, Factor VIII, Factor IX, Factor XI, Factor XII, Factor XIII, F/fibrin degradation products, thrombinantithrombin 111 complex, fibrinogen, plasminogen, prothrombin, and von Willebrand factor.
  • Additional coagulation parameters that may be measured for the coagulation profile include, e.g., prothrombin time, thromboplastin time, activated partial thromboplast time (aPTT), antithrombin activity, platelet count, protein C levels, and protein S levels.
  • prothrombin time e.g., prothrombin time, thromboplastin time, activated partial thromboplast time (aPTT), antithrombin activity, platelet count, protein C levels, and protein S levels.
  • aPTT activated partial thromboplast time
  • antithrombin activity e.g., platelet count, protein C levels, and protein S levels.
  • the levels of C reactive protein may also be assessed in the patient prior to treatment and if elevated this may be used as a further indicator as to an increased risk of thrombosis in the patient.
  • successful treatment may include a reduction in fever, a reduction in high or moderately-high heartbeat (e.g. tachycardia), a reduction in sweating (i.e. diaphoresis), decreased confusion and/or a decrease tiredness, and/or a decrease in shortness of breath, less labored or less rapid breathing.
  • a treatment may be administered prophylactically, i.e., before the onset of sepsis or septic shock.
  • a prophylactic treatment prevents sepsis or septic shock and can be administered to patients that have or are suspected of having an influenza infection, but without the severe symptoms of sepsis or septic shock.
  • prophylactic treatment can be administered to patients that have a cough without the other symptoms of sepsis or septic shock.
  • Alkyl by itself or as part of another substituent refers to a saturated or unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having the stated number of carbon atoms (i.e., C1-C6 means one to six carbon atoms) that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne.
  • Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan- 1-yl, propan-2-yl, cyclopropan-l-yl, prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl, cycloprop- 1-en-l-yl; cycloprop-2-en-l-yl, prop-l-yn-l-yl , prop-2-yn-l-yl, etc.; butyls such as butan-l-yl, butan-2-yl, 2-methyl-propan-l-yl, 2-methyl-propan-2-yl, cyclobutan-l-yl, but- 1-en-l-yl, but-l-en-2-yl, 2-methyl-prop- 1-en-l-yl, but-2-en-l-
  • alkanyl alkenyl and/or “alkynyl” is used, as defined below.
  • lower alkyl means (C1-C8) alkyl.
  • Alkanyl by itself or as part of another substituent refers to a saturated branched, straight-chain or cyclic alkyl derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-l-yl, propan-2-yl (isopropyl), cyclopropan-l-yl, etc.; butanyls such as butan-l-yl, butan-2-yl (sec-butyl), 2-methyl-propan-l-yl (isobutyl), 2-methyl-propan-2-yl (/-butyl), cyclobutan-l-yl, etc.; and the like.
  • "lower alkanyl” means (C1-C8) alkanyl.
  • Alkenyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
  • the group may be in either the cis or trans conformation about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-l-en-l-yl , prop-l-en-2-yl, prop-2-en-l-yl, prop-2-en-2-yl, cycloprop- 1-en-l-yl; cycloprop-2-en-l-yl ; butenyls such as but- 1-en-l-yl, but-l-en-2-yl, 2-methyl-prop- 1-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl, cyclobut- 1-en-l-yl, cyclobut- l-en-3-yl, cyclobuta-l,3-dien-l-yl, etc.; and the like.
  • "lower alkenyl” means (C2-C2-C
  • Alkynyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-l-yn-l-yl , prop-2-yn-l-yl, etc.; butynyls such as but-l-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl , etc.; and the like.
  • lower alkynyl means (C2-C8) alkynyl.
  • Alkyldiyl by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon group having the stated number of carbon atoms (z.e., C1-C6 means from one to six carbon atoms) derived by the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene or alkyne, or by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne.
  • Typical alkyldiyl groups include, but are not limited to, methandiyl; ethyldiyls such as ethan- 1,1 -diyl, ethan- 1,2-diyl, ethen- 1,1 -diyl, ethen- 1,2-diyl; propyldiyls such as propan- 1,1 -diyl, propan- 1,2-diyl, propan-2, 2-diyl, propan- 1,3-diyl, cyclopropan- 1,1 -diyl, cyclopropan- 1,2-diyl, prop- 1-en- 1,1 -diyl, prop- 1-en- 1,2-diyl, prop-2-en- 1,2-diyl, prop-l-en-l,3-diyl, cycloprop- 1- 1-en- 1,1 -diyl, prop- 1-en- 1,2-diyl, prop-2-en
  • alkanyldiyl alkenyldiyl and/or alkynyldiyl
  • alkylidene alkylidene
  • Specific embodiments include saturated acyclic alkanyldiyl groups in which the radical centers are at the terminal carbons, e.g., methandiyl (methano); ethan- 1,2-diyl (ethano); propan- 1,3-diyl (propano); butan- 1,4-diyl (butano); and the like (also referred to as alky lenos, defined infra).
  • Alkyleno by itself or as part of another substituent refers to a straight-chain saturated or unsaturated alkyldiyl group having two terminal monovalent radical centers derived by the removal of one hydrogen atom from each of the two terminal carbon atoms of straight-chain parent alkane, alkene or alkyne.
  • the locant of a double bond or triple bond, if present, in a particular alkyleno is indicated in square brackets.
  • Typical alkyleno groups include, but are not limited to, methano; ethyleno s such as ethano, etheno, ethyno; propyleno s such as propano, prop[l]eno, propa[l,2]dieno, prop[l]yno, etc.; butylenos such as butano, but[l]eno, but[2]eno, buta[l,3]dieno, but[l]yno, but[2]yno, buta[l,3]diyno, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkano, alkeno and/or alkyno is used.
  • the alkyleno group is (C1-C8) or (C1-C3) alkyleno.
  • Specific embodiments include straight-chain saturated alkano groups, e.g., methano, ethano, propano, butano, and the like.
  • Heteroalkyl Heteroalkanyl
  • Heteroalkenyl Heteroalkynyl
  • Heteroalkyldiyl Hetero alkyleno by themselves or as part of another substituent refer to alkyl, alkanyl, alkenyl, alkynyl, alkyldiyl and alkyleno groups, respectively, in which one or more of the carbon atoms are each independently replaced with the same or different heteratoms or heteroatomic groups.
  • Typical heteroatoms and/or heteroatomic groups which can replace the carbon atoms include, but are not limited to, -O-, -S-, -S-O-, -NR’-, -PH-, -S(O)-, -S(O) 2 -, -S(O) NR’-, -S(O) 2 NR’-, and the like, including combinations thereof, where each R’ is independently hydrogen or (C1-C8) alkyl.
  • “Cycloalkyl” and “Heterocycloalkyl” by themselves or as part of another substituent refer to cyclic versions of “alkyl” and “heteroalkyl” groups, respectively.
  • a heteroatom can occupy the position that is attached to the remainder of the molecule.
  • Typical cycloalkyl groups include, but are not limited to, cyclopropyl; cyclobutyls such as cyclobutanyl and cyclobutenyl; cyclopentyls such as cyclopentanyl and cyclopentenyl; cyclohexyls such as cyclohexanyl and cyclohexenyl; and the like.
  • Typical heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, etc.), piperidinyl (e.g., piperidin-l-yl, piperidin-2-yl, etc.), morpholinyl (e.g., morpholin-3-yl, morpholin-4-yl, etc.), piperazinyl (e.g., piperazin-l-yl, piperazin-2-yl, etc.), and the like.
  • tetrahydrofuranyl e.g., tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, etc.
  • piperidinyl e.g., piperidin-l-yl, piperidin-2-yl, etc.
  • morpholinyl e.g., morpholin-3-yl
  • Acyclic Heteroatomic Bridge refers to a divalent bridge in which the backbone atoms are exclusively heteroatoms and/or heteroatomic groups.
  • Typical acyclic heteroatomic bridges include, but are not limited to, -O-, -S-, -S-O-, -NR’-, -PH-, -S(O)-, -S(O) 2 -, -S(O) NR’-, -S(O) 2 NR’-, and the like, including combinations thereof, where each R’ is independently hydrogen or (Cl -C 8) alkyl.
  • Parent aromatic ring system refers to an unsaturated cyclic or polycyclic ring system having a conjugated 7t electron system.
  • parent aromatic ring system fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, tetrahydronaphthalene, etc.
  • Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, tetrahydronaphthalene, triphenylene, trinaphthalene, and the like.
  • Aryl by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon group having the stated number of carbon atoms (z.e., C6-C15 means from 6 to 15 carbon atoms) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, a.s-indaccnc, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like, as well as the various hydro isomers thereof.
  • Arylaryl by itself or as part of another substituent refers to a monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a ring system in which two or more identical or non-identical parent aromatic ring systems are joined directly together by a single bond, where the number of such direct ring junctions is one less than the number of parent aromatic ring systems involved.
  • Typical arylaryl groups include, but are not limited to, biphenyl, triphenyl, phenyl-naphthyl, binaphthyl, biphenyl-naphthyl, and the like.
  • arylaryl is an arylaryl group in which each aromatic ring comprises from 6 to 15 carbons, e.g., biphenyl, triphenyl, binaphthyl, phenylnaphthyl, etc.
  • each parent aromatic ring system of an arylaryl group is independently a (C6-C15) aromatic, more preferably a (C6-C10) aromatic.
  • Specific exemplary arylaryl groups include those in which all of the parent aromatic ring systems are identical, e.g., biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.
  • Biaryl by itself or as part of another substituent refers to an arylaryl group having two identical parent aromatic systems joined directly together by a single bond.
  • Typical biaryl groups include, but are not limited to, biphenyl, binaphthyl, bianthracyl, and the like.
  • the aromatic ring systems are (C6-C15) aromatic rings, more typically (C6-C10) aromatic rings.
  • a particular exemplary biaryl group is biphenyl.
  • Arylalkyl by itself or as part of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl group.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 2-phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2-naphthylethen-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like.
  • arylalkyl group is (C7-C21) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C6) and the aryl moiety is (C6-C15).
  • the arylalkyl group is (C7-C13), e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C3) and the aryl moiety is (C6-C10).
  • Parent Heteroaromatic Ring System refers to a parent aromatic ring system in which one or more carbon atoms are each independently replaced with the same or different heteroatoms or heteroatomic groups.
  • Typical heteroatoms or heteroatomic groups to replace the carbon atoms include, but are not limited to, N, NH, P, O, S, S(O), S(O)2, Si, etc.
  • parent heteroaromatic ring systems fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc.
  • parent heteroaromatic ring system include common substituents, such as, for example, benzopyrone and 1 -methyl- 1,2, 3, 4-tetrazole.
  • parent heteroaromatic ring system benzene rings fused to cyclic polyalkylene glycols such as cyclic polyethylene glycols.
  • Typical parent heteroaromatic ring systems include, but are not limited to, acridine, benzimidazole, benzisoxazole, benzodioxan, benzodioxole, benzofuran, benzopyrone, benzothiadiazole, benzothiazole, benzotriazole, benzoxaxine, benzoxazole, benzoxazoline, carbazole, P-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyr
  • Heteroaryl by itself or as part of another substituent refers to a monovalent heteroaromatic group having the stated number of ring atoms (e.g., “5-14 membered” means from 5 to 14 ring atoms) derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
  • Typical heteroaryl groups include, but are not limited to, groups derived from acridine, benzimidazole, benzisoxazole, benzodioxan, benzodiaxole, benzofuran, benzopyrone, benzothiadiazole, benzothiazole, benzotriazole, benzoxazine, benzoxazole, benzoxazoline, carbazole, P-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine
  • Heteroaryl-Heteroaryl by itself or as part of another substituent refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a ring system in which two or more identical or non-identical parent heteroaromatic ring systems are joined directly together by a single bond, where the number of such direct ring junctions is one less than the number of parent heteroaromatic ring systems involved.
  • Typical heteroaryl-heteroaryl groups include, but are not limited to, bipyridyl, tripyridyl, pyridylpurinyl, bipurinyl, etc.
  • each parent heteroaromatic ring system refers to the number of atoms comprising each parent heteroaromatic ring systems.
  • 5-15 membered heteroaryl-heteroaryl is a heteroaryl-heteroaryl group in which each parent heteroaromatic ring system comprises from 5 to 15 atoms, e.g., bipyridyl, tripuridyl, etc.
  • each parent heteroaromatic ring system is independently a 5-15 membered heteroaromatic, more typically a 5-10 membered heteroaromatic.
  • Specific exemplary heteroaryl-heteroaryl groups include those in which all of the parent heteroaromatic ring systems are identical.
  • “Biheteroaryl” by itself or as part of another substituent refers to a heteroaryl-heteroaryl group having two identical parent heteroaromatic ring systems joined directly together by a single bond.
  • Typical biheteroaryl groups include, but are not limited to, bipyridyl, bipurinyl, biquinolinyl, and the like.
  • the heteroaromatic ring systems are 5-15 membered heteroaromatic rings, more typically 5-10 membered heteroaromatic rings.
  • Hetero arylalkyl by itself or as part of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylakenyl and/or hetero ary lalkynyl is used.
  • the hetero arylalkyl group is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the hetero arylalkyl is (C1-C6) alkyl and the heteroaryl moiety is a
  • heteroarylalkyl is a
  • heteroarylalkyl e.g., the alkanyl, alkenyl or alkynyl moiety is (C1-C3) alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.
  • Halogen or “Halo” by themselves or as part of another substituent, unless otherwise stated, refer to fluoro, chloro, bromo and iodo.
  • Haloalkyl by itself or as part of another substituent refers to an alkyl group in which one or more of the hydrogen atoms is replaced with a halogen.
  • haloalkyl is meant to include monohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls.
  • (C1-C2) haloalkyl includes fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1 -trifluoroethyl, perfluoroethyl, etc.
  • alkyloxy or “alkoxy” refers to a group of the formula -OR
  • alkylamine refers to a group of the formula -NHR”
  • dialkylamine refers to a group of the formula -NR”R”, where each R” is independently an alkyl.
  • haloalkoxy or “haloalkyloxy” refers to a group of the formula -OR’ ”, where R” ’ is a haloalkyl.
  • Substituted when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent(s).
  • substituent groups useful for substituting for hydrogens on unsaturated carbon atoms in the specified group or radical include, but are not limited to, -R 60 , halo, -O’ M + , -OR 70 , -SR 70 , -S’M + , -NR 80 R 80 , trihalomethyl, °C(S)R 70 , -NR 70 C(O)O’M + , -NR 70 C(O)OR 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(O)R 70 and -NR 70 C(NR 70 )NR 80 R 80 , where R 60 , R 70 , R 80 and M + are as previously defined.
  • Substituent groups, other than R p , useful for substituting for hydrogens on nitrogen atoms in heteroalkyl and cycloheteroalkyl groups include, but are not limited to, -R 60 , -O’ M + , -OR 70 , -SR 70 , -S’M + , -NR 80 R 80 , trihalomethyl, -CF 3 , -CN, -NO, -NO 2 , -S(O) 2 R 70 , -S(O) 2 O’M + , -S(O) 2 OR 70 , -OS(O) 2 R 70 , -OS(O) 2 O’M + , -OS(O) 2 OR 70 , -P(O)(O’) 2 (M + ) 2 , -P(O)(OR 70 )O’ M + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 , -
  • Protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group.
  • a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY.
  • Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), terZ-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2- trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9- fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like.
  • hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups) and allyl ethers.
  • pharmaceutically acceptable salt means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, and the like.
  • salt thereof means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like.
  • the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient.
  • salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.
  • solvent refers to a complex formed by combination of solvent molecules with molecules or ions of the solute.
  • the solvent can be an organic compound, an inorganic compound, or a mixture of both.
  • Some examples of solvents include, but are not limited to, methanol, AW-di methyl formamide, tetrahydrofuran, dimethylsulfoxide, and water. When the solvent is water, the solvate formed is a hydrate.
  • Stereoisomers refer to compounds that have same atomic connectivity but different atomic arrangement in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers.
  • pyrazoles imidazoles, benzimidazoles, triazoles, and tetrazoles.
  • “or a salt or solvate or stereoisomer thereof’ is intended to include all permutations of salts, solvates and stereoisomers, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of subject compound.
  • “Pharmaceutically effective amount” and “therapeutically effective amount” refer to an amount of a compound sufficient to treat a specified disorder or disease or one or more of its symptoms and/or to prevent the occurrence of the disease or disorder.
  • This disclosure provides, among other things, a method for treating an excessive immunological response to an infection by a respiratory virus, e.g., ARDS, AKI, thrombosis, sepsis or septic shock.
  • a respiratory virus e.g., ARDS, AKI, thrombosis, sepsis or septic shock.
  • the present method can also be used to treat other influenza- associated diseases such as pneumonia because some of the symptoms of pneumonia infections (e.g. bacterial pneumonia caused by Streptococcus pneumoniae') have the same underlying cause (e.g., a cytokine storm in the lungs and/or kidneys).
  • the present method can also be used to treat other viral infections including, without limitation, Ebola virus (i.e. Zaire ebolavirus), Dengue virus, human rhinoviruses, Respiratory Syncytial virus, parainfluenza viruses, adenoviruses, paramyxoviruses (i.e.
  • the patient may be infected by a coronavirus and may have MERS, SARS, or other similar symptoms.
  • the method may be used to treat ventilator-induced ARDS, which is a mechanical lung injury that triggers an extensive biological response, including activation of a proinflammatory and pro-injurious cytokine cascade termed biotrauma.
  • the method may comprise administering fostamatinib, an active component thereof or a pharmaceutically acceptable salt thereof to a patient that has or is expected to develop ventilator- induced ARDS. These patients may or may not infected by a virus.
  • the method may comprise administering fostamatinib, an active component thereof or a pharmaceutically acceptable salt thereof to a patient having or suspected of having an influenza infection, e.g., an Influenza A, Influenza B, or Influenza C infection.
  • an Influenza A e.g., an Influenza A, Influenza B, or Influenza C infection.
  • the Influenza A subtype may be any known Influenza A subtype.
  • influenza A subtype may be HINT, H1N2, H1N3, H1N4, H1N5, H1N6, H1N7, H1N8, H1N9, H1N10, H1N11, H2N1, H2N2, H2N3, H2N4, H2N5, H2N6, H2N7, H2N8, H2N9, H2N10, H2N11, H3N1, H3N2, H3N3, H3N4, H3N5, H3N6, H3N7, H3N8, H3N9, H3N10, H3N11, H4N1, H4N2, H4N3, H4N4, H4N5, H4N6, H4N7, H4N8, H4N9, H4N10, H4N11, H5N1, H5N2, H5N3, H5N4, H5N5, H5N6, H5N7, H5N8, H5N9, H5N10, H5N11, H6N11, H5N1,
  • fostamatinib modulates, e.g., increases or decreases or inhibits, signaling pathways associated with influenza infection.
  • fostamatinib a SYK inhibitor
  • DAMP tissue damage
  • PAMP pathogen
  • FcRs Fc receptors
  • fostamatinib modulates a CLEC-driven cytokine storm associated with influenza infection (FIG. 2).
  • fostamatinib modulates FcyR driven ARDS associated with influenza infection (FIG. 2). In some cases, fostamatinib modulates FcyRIIA, CLEC2 and GPVI signaling involved in influenza-associated thrombosis. In some cases, fostamatinib modulates FcyRIIA-mediated NETosis of neutrophils in influenza-associated thrombosis. In some cases, fostamatinib modulates influenza associated thrombosis without affecting normal hemostasis, and in such embodiments, fostamatinib may target receptors involved in thrombosis but non-essential for hemostasis.
  • fostamatinib may inhibit FcyRIIa-mediated platelet aggregation, GPVI-mediated platelet aggregation, and/or CLEC2-mediated platelet aggregation and may not affect ADP-mediated platelet aggregation.
  • the patient may have or may be expected to have or develop acute respiratory distress syndrome. In some cases, however, the patient may have signs of respiratory distress, e.g., a cough, but does not have acute respiratory distress syndrome. In these embodiments, the patient may not be in intensive care.
  • the patient may have or may be expected to have or develop acute kidney injury.
  • the patient may have signs of kidney damage or injury including, e.g., proteinuria, hematuria, kaliuresis, albuminuria, oliguria, increased blood urea nitrogen, and/or an increase in serum creatinine.
  • the patient may have signs of reduced kidney function or kidney malfunction such as, e.g., proteinuria, hematuria, changes (e.g., increase) in serum creatinine (sCr) and/or blood urea nitrogen, decreased urine output, etc.
  • the patient may have signs of reduced kidney function or kidney malfunction but does not have acute kidney injury. In these embodiments, the patient may not be in intensive care.
  • the patient may have or may be expected to have or develop thrombosis.
  • the patient may have signs of thrombosis including, e.g., pain and swelling, warm skin, red or darkened skin, cyanosis, swollen veins, shortness of breath, irregular heartbeat, chest pain, lightheadedness, sweating, coughing (e.g., cough that produces blood), and/or low blood pressure.
  • the patient may have a prothrombotic coagulation profile but does not have thrombosis.
  • the patient may have a prothrombotic coagulation profile and has or is expected to have thrombosis.
  • the prothrombotic coagulation profile may include a worsening, e.g., an increase or decrease in the level or activity, of one or more of any of the coagulation parameters as described herein, e.g., compared to a control.
  • the prothrombotic coagulation profile may include increased levels of D-dimer.
  • the control may be, e.g., the coagulation profile of an asymptomatic individual with a influenza infection, an individual with a mild influenza infection, or a healthy individual. In these embodiments, the patient may not be in intensive care.
  • the patient may be at least 60 years old, at least 70 years old, or at least 80 years old.
  • the patient may have or may have had one or more other lung diseases in the past.
  • the patient has or has a history of having asthma, pneumothorax, atelectasis, bronchitis, chronic obstructive pulmonary disease, lung cancer or pneumonia.
  • kidney diseases comprise acromegaly, acute renal failure (ARF) amyloidosis, autosomal dominant polycystic kidney disease, kidney stones, kidney cysts, autosomal recessive polycystic kidney disease, chronic renal failure (CRF), chronic renal disease, coffin-Lowry syndrome, cor pulmonale, cryoglobulinemia, diabetic nephropathy, dyslipidemia, Gaucher disease, glomerulonephritis, goodpasture syndrome, hemolytic uremic syndrome, hepatitis, kidney cancer, kidney stones, leukemia, lipoproteinemia, lupus, multiple myeloma, nephritis, polyartekidney cysts, post streptococcal glomerulonephritis, glomerulonephritis, kidney pain, preeclampsia, renal tuberculosis,
  • APF acute renal failure
  • CRF chronic renal failure
  • the kidney disease or disorder is acute, or in another embodiment, chronic.
  • the phrase “predisposed to a kidney disease or disorder” with respect to a subject is synonymous with the phrase “subject at risk”, and includes a subject at risk of acute or chronic renal failure, or at risk of the need for renal replacement therapy, if the subject is reasonably expected to suffer a progressive loss of renal function associated with progressive loss of functioning nephron units. Whether a particular subject is at risk is a determination which may routinely be made by one of ordinary skill in the relevant medical or veterinary art. In some cases, the patient has or has a history of having dialysis treatments. In some cases, the patient has had a kidney transplant.
  • the patient may have or may have had thrombosis or a thrombotic event in the past.
  • the patient has or has a history of having any of the risk factors, diseases, or conditions associated with thrombosis described herein including, e.g., deep vein thrombosis, pulmonary embolism, etc.
  • the patient has one or more risk factors for developing thrombosis relative to the general population.
  • the administering can be done any convenient way.
  • the administration may be systemic, e.g., orally (via injection of tablet, pill or liquid) or intravenously (by injection or via a drip, for example).
  • the administering can be done by pulmonary administration, e.g., using an inhaler or nebulizer.
  • Compounds that find use in the invention are generally 2,4-pyrimidinediamine compounds according to structural formula (I): including salts (e.g., pharmaceutically acceptable salts), hydrates, solvates and N- oxides thereof, wherein:
  • L 1 and L 2 are each, independently of one another, selected from the group consisting of a direct bond and a linker;
  • R 2 and R 4 are as described in the following embodiments and examples;
  • R 5 is selected from the group consisting of R 6 , (C1-C6) alkyl optionally substituted with one or more of the same or different R 8 groups, (C1-C4) alkanyl optionally substituted with one or more of the same or different R 8 groups, (C2-C4) alkenyl optionally substituted with one or more of the same or different R 8 groups and (C2-C4) alkynyl optionally substituted with one or more of the same or different R 8 groups; each R 6 independently is selected from the group consisting of hydrogen, an electronegative group, -OR dl , -SR dl , (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, -NR C R C , halogen, (C1-C3) haloalkyl,(Cl-C3) perhaloalkyl, -CF 3 , -CH2CF3, -CF2CF3, -CN, -NC, -OCN, -
  • L 1 and L 2 represent, independently of one another, a direct bond or a linker.
  • the substituents R 2 and/or R 4 may be bonded either directly to their respective nitrogen atoms or, alternatively, spaced away from their respective nitrogen atoms by way of a linker.
  • the identity of the linker is not critical and typical suitable linkers include, but are not limited to, (C1-C6) alkyldiyls, (C1-C6) alkanos and (C1-C6) heteroalkyldiyls, each of which may be optionally substituted with one or more of the same or different R 8 groups, where R 8 is as previously defined for structural formula (I).
  • L 1 and L 2 are each, independently of one another, selected from the group consisting of a direct bond, (C1-C3) alkyldiyl optionally substituted with one or more of the same or different R a , suitable R b or R 9 groups and 1-3 membered heteroalkyldiyl optionally substituted with one or more of the same or different R a , suitable R b or R 9 groups, wherein R 9 is selected from the group consisting of (C1-C3) alkyl, -OR a , -C(O)OR a , (C5-C10) aryl optionally substituted with one or more of the same or different halogens, phenyl optionally substituted with one or more of the same or different halogens, 5-10 membered heteroaryl optionally substituted with one or more of the same or different halogens and 6 membered heteroaryl optionally substituted with one or more of the same or different halogens; and R a
  • R 9 groups that may be used to substitute L 1 and L 2 include -OR a , -C(O)OR a , phenyl, halophenyl and 4-halophenyl, wherein R a is as previously defined for structural formula (I).
  • L 1 and L 2 are each, independently of one another, selected from the group consisting of methano, ethano and propano, each of which may be optionally monosubstituted with an R 9 group, where R 9 is as previously defined above.
  • R a groups that may be included in R 9 groups are selected from the group consisting of hydrogen, (C1-C6) alkyl, phenyl and benzyl.
  • L 1 and L 2 are each a direct bond such that the 2,4- pyrimidinediamine compounds of the invention are compounds according to structural formula (la): including salts, hydrates, solvates and N-oxides thereof, wherein R 2 , R 4 , R 5 and R 6 are as previously defined for structural formula (I). Additional specific embodiments of the 2,4- pyrimidinediamine compounds of the invention are described below.
  • R 5 , R 6 , R 8 , R a , R b , R c , R dl , m and n are as previously defined, , wherein each selected from the group consisting of N and CH, Y is selected from the group consisting of O, S, SO, SO2, SONR 36 , NH, NR 35 and NR 37 ,Z is selected from the group consisting of O, S, SO, SO2, SONR 36 , NH, NR 35 and NR 37 .
  • Each R 36 is independently selected from the group consisting of hydrogen and (C1-C6) alkyl.
  • Each R 37 is independently selected from the group consisting of hydrogen and a progroup.
  • R 38 is selected from the group consisting of (C1-C6) alkyl and (C5-C14) aryl.
  • Y is O
  • Z is NH
  • X is N
  • R 5 can be halogen and R 6 is a hydrogen.
  • R 5 , R 6 , R 8 , R a , R b , R c , R dl , m, n, R 35 , R 36 , R 37 , R 38 , X, Y and Z are as previously defined, R 2 is , wherein each R 31 , independently of the others, is methyl or (C1-C6) alkyl and R 4 .
  • R 31 independently of the others, is methyl or (C1-C6) alkyl and R 4 .
  • Y is O
  • Z is NH and X is N.
  • R 5 can be halogen and R 6 is a hydrogen.
  • Y is O
  • Z is NH
  • X is N and each R 31 is methyl.
  • L 1 , L 2 , R 5 , R 6 , R 8 , R a , R b , R c , R dl , m, n, R 31 , R 35 , R 36 , R 37 , R 38 , X, Y and Z are as previously defined, R 2
  • Z is NH and X is N.
  • R 5 can be halogen and R 6 is a hydrogen.
  • R 5 , R 6 , R 8 , R a , R b , R c , R dl , m, n, R 35 , R 36 , R 37 , R 38 , X, Y and Z are as previously defined, R 2 is
  • Substitution about the R 2 phenyl ring can be at the 2, 3, 4, 5 or 6 positions.
  • Y is O
  • Z is NH
  • X is N.
  • R 5 can be halogen and R 6 is a hydrogen.
  • L 1 , L 2 , R 5 , R 6 , R 8 , R a , R b , R c , R dl , m, n, R 35 , R 36 , R 37 , R 38 , X, Y and Z are as previously defined
  • R 2 is a phenyl group disubstituted with two R b groups Substitution about the
  • R 2 phenyl ring can be at the 2,3, 2,4, 2, 5, 2,6, 3,4, 3,5, 3,6, 4,5, 4,6 or 5,6 positions, with the proviso that the following compounds are not included:
  • each R b independently is selected from (C1-C6) alkoxy, (Cl-16) alkyl, (C1-C6) perhaloalkyls, halogens, carboxylic acid, carboxylic ester, carboxamides, sulfonamides and imidazoles.
  • L 1 , L 2 , R 5 , R 6 , R 8 , R a , R b , R c , R dl , m, n, R 35 , R 36 , R 37 , R 38 , X, Y and Z are as previously defined
  • R 2 is a phenyl group trisubstituted with three R b groups and R 4 is .
  • Substitution about the R 2 phenyl ring can be at the 2,3,4, 2,3,5, 2,3,6, 2,4,5, 2,4,6, 2,5,6, 3,4,5, 3,4,6, 3,5,6, or 4,5,6 positions, with the proviso that the following compounds are not included:
  • each R b independently is selected from (C1-C6) alkoxy, (Cl-16) alkyl, (C1-C6) perhaloalkyls, halogens, carboxylic acid, carboxylic esters, carboxamides, sulfonamides
  • R 5 of the pyrimidine ring is a halogen atom, such as fluorine
  • R 6 of the pyrimidine ring is a hydrogen atom
  • L 1 and L 2 are covalent bonds for the above-identified embodiments.
  • the compound is N4-(2,2-Dimethyl-3-oxo-4H-5- pyrid[l,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine, or a pharmaceutically acceptable salt thereof.
  • aspects of the present invention include the 2,4-pyrimidinediamine compounds described herein, which may include functional groups that can be masked with progroups to create prodrugs. Such prodrugs are usually, but need not be, pharmacologically inactive until converted into their active drug form. Indeed, many of the active 2,4-pyrimidinediamine compounds include promoieties that are hydrolyzable or otherwise cleavable under conditions of use. Prodrugs of the present invention may include an active component, where the active component is a 2,4-pyrimidinediamine compound as described herein.
  • any available functional moiety may be masked with a progroup to yield a prodrug.
  • Functional groups within the 2,4-pyrimidinediamine compounds that may be masked with progroups for inclusion in a promoiety include, but are not limited to, amines (primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, etc.
  • Myriad progroups suitable for masking such functional groups to yield promoieties that are cleavable under the desired conditions of use are known in the art. All of these progroups, alone or in combinations, may be included in the prodrugs of the invention.
  • the prodrugs generally comprise a biologically active 2,4-pyrimidinediamine compound that is substituted at the nitrogen atom of one or more primary or secondary amine groups with a progroup R p that metabolizes or otherwise transforms under conditions of use to yield the active 2,4-pyrimidinediamine.
  • the progroup R p is a phosphorous-containing progroup.
  • the progroup includes a group or moiety that is metabolized under the conditions of use to yield an unstable a-hydroxymethyl, a-aminomethyl or a-thiomethyl intermediate, which then further metabolized in vivo to yield the active 2,4- pyrimidinediamine drug.
  • the progroup includes an a-hydroxyalkyl, a-aminoalkyl or a-thioalkyl moiety, for example an a-hydroxymethyl, a-aminomethyl, a-thiomethyl moiety, that metabolizes under the conditions of use to yield the active 2,4 pyrimidinediamine drug.
  • the progroup R p is of the formula -CR d R d -AR 3 , where each R d is, independently of the other, selected from hydrogen, cyano, optionally substituted (C1-C20) alkyl, (C1-C20) perfluoroalkyl, optionally substituted (C7-C30) arylalkyl and optionally substituted 6-30 membered heteroarylalkyl, where each optional substituent is, independently of the others, selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl and heteroalkyl, or, alternatively, the two R d are taken together with the carbon atom to which they are bonded to form a cycloalkyl containing from 3 to 8 carbon atoms ;
  • A is selected from O, S and NR 50 , where R 50 is selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and cycloheteroal
  • R 3 is not critical, provided that it can be metabolized under the desired conditions of use, for example under the acidic conditions found in the stomach and/or by enzymes found in vivo, to yield a group of the formula -CR d R d -AH, where A and R d are as previously defined.
  • R 3 can comprise virtually any known or later-discovered hydroxyl, amine or thiol protecting group.
  • Non-limiting examples of suitable protecting groups can be found, for example, in Protective Groups in Organic Synthesis, Greene & Wuts, 2nd Ed., John Wiley & Sons, New York, 1991 (especially pages 10-142 (alcohols, 277-308 (thiols) and 309-405 (amines) the disclosure of which is incorporated herein by reference).
  • R 3 includes, together with A, an ether, a thioether, a silyl ether, a silyl thioether, an ester, a thioester, an amide, a carbonate, a thiocarbonate, a carbamate, a thiocarbamate, or a urea linkage, -OCH2SO3R, where R is hydrogen, alkyl, aryl, arylalkyl or a metal salt (e.g., sodium, lithium, potassium); -GCH2 + N(R 51 )3M”, where G is absent, -OPO3-, OSO3- or -CO2-, R 51 is hydrogen, alkyl, aryl, arylalkyl, cyclohetero alkyl or cycloheteroalkylalkyl and M- is a counterion, usually a halide ion or the like (acetate, sulfate), a metal salt (e.g
  • R f is selected from R f , -C(O)R f ,-C(O)OR f ,-C(O)NR f R f and -SiR f R f R f , where each R f is, independently of the others, selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower heteroalkyl, optionally substituted lower cycloalkyl, optionally substituted lower heterocycloalkyl, optionally substituted (C6-C10) aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted (C7-C18) arylalkyl and optionally substituted 6-18 membered heteroarylalkyl.
  • each R f is the same.
  • the identity of the progroup(s) R p can be selected to tailor the water-solubility and other properties of the underlying active 2,4-pyrimidinediamine compound to be optimized for a particular mode of administration. It can also be selected to provide for removal at specified organs and/or tissues within the body, such as, for example, in the digestive tract, in blood and/or serum, or via enzymes residing in specific organs, such as the liver.
  • progroups R p that are phosphorous -containing progroups include phosphate moieties that can be cleaved in vitro by enzymes such as esterases, lipases and/or phosphatases. Such enzymes are prevalent throughout the body, residing in, for example, the stomach and digestive tract, blood and/or serum, and in virtually all tissues and organs.
  • Such phosphate-containing progroups R p will generally increase the water-solubility of the underlying active 2,4-pyrimidinediamine compound, making such phosphate-containing prodrugs ideally suited for modes of administration where water-solubility is desirable, such as, for example, oral, buccal, intravenous, intramuscular and ocular modes of administration.
  • each phosphate-containing progroup R p in the prodrug is of the formula -(CR d R d ) O-P(O)(OH)(OH), or a salt thereof, wherein R d is as previously defined and y is an integer ranging from 1 to 3, typically 1 or 2.
  • each R d is, independently of the others, selected from hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted methyl and substituted or unsubstituted benzyl.
  • each R d is, independently of the others, selected from hydrogen and unsubstituted lower alkyl.
  • Specific exemplary phosphate-containing progroups R p include -CH 2 -O-P(O)(OH)(OH) and -CH 2 CH 2 -O-P(O)(OH)(OH) and/or the corresponding salts.
  • phosphate-containing prodrugs are converted in vivo by enzymes such as phosphatases, lipases and/or esterases to the corresponding hydroxymethylamines, which are then further metabolized in vivo by the elimination of formaldehyde to yield the active 2,4-pyrimidinediamine drug compound.
  • the phosphate and formaldehyde metabolic by-products are innocuous.
  • prodrugs are metabolized to the active 2,4-pyrimidinediamine drug compound in vivo by elimination of enol phosphate, which further metabolizes to acetaldehyde and phosphate.
  • the phosphate and acetaldehyde metabolic by-products are innocuous.
  • precursors can be converted in vivo to phosphate groups.
  • Such precursors include, by way of example and not limitation, phosphate esters, phosphites and phosphite esters.
  • phosphites can be oxidized in vivo to phosphates.
  • Phosphate esters can be hydrolyzed in vivo to phosphates.
  • Phosphite esters can be oxidized in vivo to phosphate esters, which can in turn be hydrolyzed in vivo to phosphates.
  • the prodrugs can also include progroups that comprise such phosphate precursors.
  • the phosphate precursor groups may be directly metabolized to the active 2,4-pyrimidinediamine drug, without first being converted into a phosphate prodrug.
  • prodrugs comprising progroups that include such phosphate precursors are first metabolized into the corresponding phosphate prodrug, which then metabolizes to the active 2,4-pyrimidinediamine drug via a hydroxymethylamine, as discussed above.
  • such phosphate precursor groups are phosphate esters.
  • the phosphate esters can be acyclic or cyclic, and can be phosphate triesters or phosphate diesters.
  • Such esters are generally less water-soluble than the corresponding phosphate acid prodrugs and the corresponding active 2,4-pyrimidinediamine compounds, and are therefore typically suitable for modes of delivering prodrugs of active 2,4-pyrimidinediamine compounds where low watersolubility is desired, including, by way of example and not limitation, administration via inhalation.
  • the solubility of the prodrug can be specifically tailored for specific modes of administration by appropriate selection of the number and identity(ies) of the esterifying groups in the phosphate ester.
  • the mechanism by which the phosphate ester group metabolizes to the corresponding phosphate group can be controlled by appropriate selection of the esterifying moieties.
  • certain esters are acid (or base) labile, generating the corresponding phosphate under the acidic conditions found in the stomach and digestive tract.
  • phosphate ester progroups that are acid-labile can be selected.
  • phosphate esters are acid and base stable, being converted into the corresponding phosphates via enzymes found in certain tissues and organs of the body (see, e.g., the various cyclic phosphate esters described in Erion et al., 2004, J. Am. Chem. Soc. 126:5154-5163, incorporated herein by reference).
  • phosphate esters having the desired metabolic properties can be selected.
  • each phosphate ester-containing progroup R p in the prodrug is an acyclic phosphate ester of the formula -(CR d R d ) O-P(O)(OH)(OR e ) or -(CR d R d ) O-P(O)(OR e )(OR e ), or a salt thereof, wherein each R e is, independently of the others, selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted (C6- C14) aryl (e.g., phenyl, naphthyl, 4-loweralkoxyphenyl, 4-methoxyphenyl), substituted or unsubstituted (C7-C20) arylalkyl (e.g., benzyl, 1-phenylethan-l-yl, 2-phenylethan-l- wherein R d , R f and y are as defined above
  • each R d is selected from hydrogen and unsubstituted lower alkyl and/or each R e is an unsubstituted lower alkanyl or benzyl.
  • Specific exemplary phosphate ester progroups include, but are not limited to, -CH 2 -O-P(O)(OH)(OR e ), -CH 2 CH 2 -O-P(O)(OH)(OR e ), -CH 2 -O-P(O)(OR e )(OR e ) and -CH 2 CH 2 -O-P(O)(OR e )(OR e ), where R e is selected from lower alkanyl, z-propyl and /-butyl.
  • each phosphate ester-containing progroup R p is a cyclic phosphate ester of the formula each R g is, independently of the others, selected from hydrogen and lower alkyl; each R h is, independently of the others, selected from hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloheteroalkyl, substituted or unsubstituted (C6-C14) aryl, substituted or unsubstituted (C7-C20) arylalkyl and substituted or unsubstituted 5-14 membered heteroaryl; z is an integer ranging from 0 to 2; and R d and y are as previously defined.
  • each phosphate ester-containing progroup R p is a cyclic phosphate ester of the formula are as previously defined.
  • cyclic phosphate ester prodrugs including such cyclic phosphate ester progroups metabolize in vivo to the active drug compound depends, in part, on the identity of the R h substitutent.
  • cyclic phosphate ester progroups in which each R h is, independently of the others, selected from hydrogen and lower alkyl are cleaved in vivo by esterases.
  • the cyclic phosphate ester progroups are selected such that they are cleavable in vivo by esterases.
  • Specific examples of such cyclic phosphate ester progroups include, but are not limited to, progroups selected from
  • cyclic phosphate ester prodrugs having progroups in which the R h substituents are substituted or unsubstituted aryl, arylalkyl and heteroaryl groups are not typically cleaved by esterases, but are instead metabolized to the active prodrug by enzymes, such as cytochrome P450 enzymes, that reside in the liver.
  • enzymes such as cytochrome P450 enzymes
  • a series of cyclic phosphate ester nucleotide prodrugs that undergo an oxidative cleavage reaction catalyzed by a cytochrome P450 enzyme (CYP) expressed predominantly in the liver are described in Erion el al., 2004, J. Am. Chem. Soc. 126:5154-5163.
  • the cyclic phosphate ester progroups are selected such that they are cleavable by CYP enzymes expressed in the liver. Specific exemplary embodiments of such cyclic phosphate ester-containing progroups R
  • Q ph -(CR d R d ) y -O-P" y include, but are not limited to, progroups having the formula O' — ' , where
  • R h is selected from phenyl, 3 -chlorophenyl, 4-pyridyl and 4-methoxyphenyl.
  • phosphites and phosphite esters can undergo oxidation in vivo to yield the corresponding phosphate and phosphate ester analogs. Such reactions can be carried out in vivo by, for example, oxidase enzymes, oxoreductase enzymes and other oxidative enzymes.
  • the phosphorous-containing progroups R p can also include phosphite and phosphite ester analogs of any of the phosphate and phosphate ester progroups described above.
  • the phosphorous-containing progroups R p include, but are not limited to, groups of the formula -(CR d R d ) O-P(OH)(OH), -(CR d R d ) O-P(OH)(OR e ) and -(CR d R d ) O-P(OR e )(R e ), or salts thereof, where R d , R e and y are as previously defined.
  • Specific exemplary embodiments include groups in which each R d is, independently of the others, selected from hydrogen and unsubstituted lower alkyl and/or each R e is, independently of the others, selected from unsubstituted lower alkanyl and benzyl.
  • Specific exemplary acyclic phosphite and phosphite-ester progroups include, but are not limited to, -CH 2 -O-P(OH)(OH), -CH 2 CH 2 -O-P(OH)(OH), -CH 2 -O-P(OH)(OR e ), and -CH 2 CH 2 -O-P(OR e )(OR e ), where each R e is selected from lower alkanyl, z-propyl and t- butyl.
  • Specific exemplary cyclic phosphite ester prodrugs include phosphite analogs of the above-described cyclic phosphate ester progroups.
  • prodrug compounds including such phosphite and/or phosphite ester progroups can be thought of as prodrugs of the corresponding phosphate and phosphate ester prodrugs.
  • each hydroxyalkyl-containing progroup R p of such prodrugs is of the formula -CR d R d -OH, where R d is as previously defined.
  • a specific exemplary hydroxyalkyl-containing progroup R p is -CH 2 OH.
  • Suitable active 2,4-pyrimidinediamine compounds are described, for example, in U.S. application Serial No. 10/355,543 filed January 31, 2003 (US2004/0029902A1), international application Serial No. PCT/US03/03022 filed January 31, 2003 (WO 03/063794), U.S. application Serial No. 10/631,029 filed July 29, 2003, international application Serial No.
  • the progroup(s) R p can be attached to any available primary or secondary amine, including, for example, the N2 nitrogen atom of the 2,4-pyrimidinediamine moiety, the N4 nitrogen atom of the 2,4-pyrimidinediamine moiety, and/or a primary or secondary nitrogen atom included in a substituent on the 2,4-pyrimidinediamine compound.
  • phosphate-containing progroups R p is especially useful for 2,4-pyrimidinediamine compounds that exhibit poor water solubility under physiological conditions (for example, solubilities of less than about 10 pg/ml). While not intending to be bound by any theory of operation, it is believed that the phosphate- containing progroups aid the solubility of the underlying active 2,4-pyrimidinediamine compound, which in turn increases its bioavailability when administered orally. It is believed that the phosphate progroups R p are metabolized by phosphatase enzymes found in the digestive tract, permitting uptake of the underlying active drug.
  • the solubility of the active drug (Compound 1) is in the range of about 1-2 pg/ml in aqueous buffer under physiological conditions
  • the solubility of the corresponding phosphate prodrug (Compound 4) is greater than 5 mg/ml under the same conditions, or approximately 2000 times greater. This increased water-solubility allows for better dissolution in the gut, thereby facilitating oral administration.
  • Other active 2,4- pyrimidinediamine compounds having similarly poor water solubilities are expected to exhibit similar increases in water solubility and oral bioavailability when formulated as phosphate prodrugs.
  • phosphate ester prodrugs are generally less water-soluble than the corresponding phosphate prodrugs, and are therefore generally useful in applications where low water-solubility is desired, such as, for example, administration via inhalation. The same holds true for the relative water- solubility of phosphite ester and phosphite prodrugs.
  • the prodrugs described herein are 2, 4 -pyrimidinediamine compounds that are substituted at the N4 nitrogen of the 2,4-pyrimidinediamine moiety with a substituted or unsubstituted nitrogen-containing bicyclic ring that includes at least one progroup R p as described herein at one or more of: the nitrogen atom(s) of the bicyclic ring, the N2 nitrogen of the 2,4-pyrimidinediamine moiety and/or the N4 nitrogen of the 2,4- pyrimidinediamine moiety.
  • the prodrug is a compound according to structural formula (I): including salts, solvates, hydrates and N-oxides thereof, wherein:
  • Y is selected from CH2, NR 24 , O, S, S(O) and S(O)2;
  • Z 1 and Z 2 are each, independently of one another, selected from CH and N;
  • R 2 is an optionally substituted lower alkyl, lower cycloalkyl, lower heteroalkyl, lower cycloheteroalkyl, aryl, phenyl, or heteroaryl group;
  • R 5 is an electronegative group, such as, for example, a halo, fluoro, cyano, nitro, trihalomethyl or trifluoromethyl group;
  • R 21 , R 22 and R 23 are each, independently of one another, selected from hydrogen and a progroup R p as described herein;
  • R 24 is selected from hydrogen, lower alkyl and a progroup R p as described herein, with the proviso that at least one of R 21 , R 22 , R 23 and R 24 must be a progroup R p .
  • each of R 21 , R 22 and R 23 is one of the specific progroups exemplified above and R 24 is hydrogen.
  • R 21 is one of the specific progroups exemplified above and R 22 , R 23 and R 24 are each hydrogen.
  • R 21 , R 22 and R 23 are each one of the specific progroups exemplified above and R 24 is lower alkyl.
  • compositions comprising one or more of the prodrugs described herein and an appropriate carrier, excipient or diluent.
  • carrier, excipient or diluent will depend upon the desired use for the composition, and may range from being suitable or acceptable for veterinary uses to being suitable or acceptable for human use.
  • the composition may optionally include one or more additional compounds.
  • the present disclosure provides intermediates useful for synthesizing the prodrugs described herein.
  • the intermediates generally comprise prodrugs in which the oxygen atoms of the phosphate- and/or phosphite-containing progroups are masked with protecting groups that are selectively removable under specified conditions.
  • the protecting groups are selectively removable under mildly acidic conditions.
  • the intermediates are phosphate or phosphite esters which are themselves prodrugs that can be metabolized into active 2,4-pyrimidinediamine compounds.
  • the intermediates include prodrugs in which each R p progroup is, independently of the others, of the formula -(CR d R d ) O-P(O)(OR i )(OR i ), -(CR d R d )y-O-P(O)(OR i )(OH), -(CR ⁇ y-O-P/OR ⁇ OR 1 ) or -(CR d R d )y-O-P(OR 1 )(OH), where each R 1 is, independently of the others, selected from lower unsubstituted alkanyl, substituted or unsubstituted phenyl and substituted or unsubstituted benzyl, and R d and y are as previously defined.
  • the intermediates include phosphate and/or phosphite esters in which each R 1 is, independently of the others, selected from lower linear alkanyl, lower branched alkanyl, z-propyl, /-butyl and lower cyclic alkanyl.
  • the intermediates comprise an active 2,4-pyrimidinediamine that is substituted at a nitrogen atom of a primary or secondary amine group with a group of the formula -CR d R d -AH, where R d and A are as previously defined.
  • Phosphate-containing prodrugs can be synthesized by reacting an active 2,4-pyrimidinediamine compound with a phosphate ester halide, for example, a phosphate ester halide of the formula X-(CR tl R tl )i-O-P(O)(OR J )(OR J ) or X-(CR d R d ) O-P(O)(OR’)(OH), where each R J is, independently of the others, a selectively removable protecting group; X is a halide, such as, for example, chloride; and R d and y are as previously defined.
  • a phosphate ester halide for example, a phosphate ester halide of the formula X-(CR tl R tl )i-O-P(O)(OR J )(OR J ) or X-(CR d R d ) O-P(O)(OR’)(OH), where each R
  • each R j is R e , as previously defined. Removal of the selectively removable protecting groups R j yields a phosphate prodrug.
  • each R J is the same and is selected from lower linear alkyl, lower branched alkyl and lower cycloalkyl.
  • each R j is isopropyl or t-butyl.
  • the desired intermediate can be isolated from the mixture using standard separation and/or isolation techniques (e.g., column chromatography).
  • a desired prodrug can be isolated from a mixture of different prodrugs using standard separation and/or isolation techniques.
  • Acyclic phosphate ester prodrugs can be obtained in an analogous manner by reacting the active 2,4-pyrimidinediamine with a phosphate ester halide, for example a phosphate ester halide of the formula where X, R d , y and R e are as previously defined. In this instance, removal of the esterifying groups R e is not necessary.
  • a phosphate ester halide for example a phosphate ester halide of the formula where X, R d , y and R e are as previously defined. In this instance, removal of the esterifying groups R e is not necessary.
  • Acyclic phosphite and phosphite ester prodrugs can be prepared in an analogous manner from the corresponding phosphite ester halides, for example phosphite ester halides of the formula X-(CR d R d ) O-P(OR j )(OR j ), X-(CR d R d ) O-P(OR e )(OH), X-(CR d R d ) O-P(OR e )(OR e ), where X, R d , y, R e and R j are as previously defined.
  • Cyclic phosphate ester and phosphite ester prodrugs can be prepared by reacting the active 2,4-pyrimidinediamine compound with the corresponding cyclic phosphate ester or phosphite ester halide, for example, a cyclic phosphate ester halide of the formula cyclic phosphite ester halide of the formula are as previously defined.
  • Embodiments in which R p is -CR d R d -AR 3 can be prepared from the corresponding 2,4-pyrimidinediamine drug using conventional methods.
  • the intermediates can be synthesized by reacting an active 2,4-pyrimidinediamine compound, with an aldehyde or ketone of the formula R d -C(O)-R d , where R d is as previously defined, to yield a corresponding hydroxymethylamine intermediate (where R p is -CR d R d -OH).
  • the hydroxymethylamine intermediate can then be converted into the prodrug using standard techniques.
  • the hydroxymethylamine intermediate is also a prodrug of the invention.
  • other drug substances containing secondary amines have been added to formaldehyde to afford their corresponding isolable hydroxymethylamine adducts, Bansal et al., J. Pharmaceutical Sci. 1981, 70: (8), 850-854;
  • hydroxyalkyl-containing prodrugs can be prepared in two steps by first reacting the active 2,4-pyrimidinediamine with a bis-functional electrophile, such as a halide of the formula X 1 -CR d R d -X 2 , where X 1 represents a first halide, X 2 represents a second halide and R d is as previously defined.
  • a bis-functional electrophile such as a halide of the formula X 1 -CR d R d -X 2 , where X 1 represents a first halide, X 2 represents a second halide and R d is as previously defined.
  • the halide is of the formula I-CR d R d -Cl.
  • the unreacted halide is then hydroxylated to yield the hydroxyalkyl-containing prodrug using standard techniques.
  • Prodrugs in which A is O, S or NR 50 can be synthesized from corresponding N- methyl phosphate esters.
  • the phosphate ester groups can be displaced with a group of the formula R 3 -AH, where R 3 and A are as previously defined, to yield the prodrug, as discussed in further detail below.
  • R 21 , R 22 and R 23 each represent either hydrogen or a progroup R p .
  • R 24 represents hydrogen, a lower alkyl or a progroup R p .
  • the prodrugs can include a single R p progroup, two R p progroups, three R p progroups, or even more R p progroups, depending, in part, on the identity of Y and whether the R 2 substituent includes any R p progroups.
  • prodrugs including more than one R p progroup may metabolize at different rates.
  • Prodrugs including a single R p progroup would avoid such differential metabolic kinetics.
  • a specific embodiment of prodrugs according to structural formula (I) that include a single progroup R p are compounds according to structural formula (la): wherein Y 1 is selected from CH2, NR 24 , O, S, S(O) and S(O)2; and Z 2 , R 2 , R 5 , R 17 , R 18 , R 19 , R 20 , R 24 and R p are as previously defined, with the proviso that R 2 does not include any R p groups.
  • Such hydroxymethylamine compound are known to be unstable under physiological conditions and various pH ranges where they hydrolyze in vivo to yield formaldehyde and the active drug substance. Based on this observation, it is believed that prodrugs that include hydroxyl “protecting” groups that can be metabolized in vivo, for example by the acidic conditions of the stomach and/or by enzymes present in the digestive tract or other organs and/or tissues or fluids with the body, to yield the hydroxymethylamine intermediate illustrated above will likewise metabolize to the active 2,4 pyrimidinediamine drug.
  • the progroup(s) R p in the prodrugs of structural formulae (I) and (la) are of the formula -CR d R d -A-R 3 , where each R d is, independently of the other, selected from hydrogen, cyano, -C(O)R e , -C(O)OR e , -C(O)NR e R e , -C(OR e )(OR e ), optionally substituted (C1-C20) alkyl, (C1-C20) perfluoroalkyl, optionally substituted (C7-C30) arylalkyl and optionally substituted 6-30 membered heteroarylalkyl, where each R e is, independently of the others, selected from hydrogen, alkyl (for example lower alkyl), aryl (for example phenyl or naphthyl, arylalkyl (for example benzyl), heteroaryl and heteroaryl and heteroaryl and heteroaryl and
  • the mechanism by which the R 3 group metabolizes to yield intermediate group -CR d R d -A-H is not critical, and can be caused by, for example, hydrolysis under the acidic conditions of the stomach, and/or by enzymes present in the digestive tract and/or tissues or organs of the body. Indeed, the R 3 group(s) can be selected to metabolize at a particular site within the body. For example, many esters are cleaved under the acidic conditions found in the stomach. Prodrugs designed to cleave chemically in the stomach to the active 2,4- pyrimidinediamine can employ progroups including such esters.
  • the progroups may be designed to metabolize in the presence of enzymes such as esterases, amidases, lipolases, phosphatases including ATPases and kinase etc., to yield the intermediate group of formula - CR d R d -A-H.
  • Progroups including linkages capable of metabolizing in vivo to yield such an intermediate group are well-known, and include, by way of example and not limitation, ethers, thioethers, silylethers, silylthioethers, esters, thioesters, carbonates, thiocarbonates, carbamates, thiocarbamates, ureas, thioureas, carboxamides, etc.
  • a “precursor” group that is oxidized by oxidative enzymes such as, for example, cytochrome P450 of the liver, to a metabolizable group can be selected.
  • the identity of the R 3 group can also be selected so as to impart the prodrug with desirable characteristics.
  • lipophilic groups can be used to decrease water solubility and hydrophilic groups can be used to increase water solubility. In this way, prodrugs specifically tailored for selected modes of administration can be obtained.
  • the R 3 group can also be designed to impart the prodrug with other properties, such as, for example, improved passive intestinal absorption, improved transport-mediated intestinal absorption, protection against fast metabolism (slow-release prodrugs), tissue- selective delivery, passive enrichment in target tissues, targeting-specific transporters, etc.
  • Groups capable of imparting prodrugs with these characteristics are well-known, and are described, for example, in Ettmayer et al., 2004, J. Med. Chem. 47(10:2393-2404), the disclosure of which is incorporated by reference. All of the various groups described in these references can be utilized in the prodrugs described herein.
  • R 3 is selected from -R f , -C(O)R f , -C(O)NR f R f and -SiR f R f R f , where the R f groups are selected so as to impart the prodrugs with desired bioavailability, cleavage and/or targeting properties.
  • the R f groups are selected to impart the prodrug with higher water-solubility than the underlying active 2,4- pyrimidinediamine drug.
  • the R f groups are selected such that they, taken together with the heteroatom or group to which they are bonded, are hydrophilic in character.
  • R f groups may be selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower heteroalkyl, optionally substituted lower cycloalkyl, optionally substituted lower heterocycloalkyl, optionally substituted (C6-C10) aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted (C7-C18) arylalkyl and optionally substituted 6-18 membered heteroarylalkyl.
  • C6-C10 aryl optionally substituted 5-10 membered heteroaryl
  • C7-C18 optionally substituted arylalkyl
  • 6-18 membered heteroarylalkyl optionally substituted heteroarylalkyl.
  • the progroups on the prodrugs of formula (I) and/or (la) are of the formula -CR d R d -A-R 3 , where R 3 is selected from -(CH 2 )i-R b , -C(O)R a , -C(O)-(CH 2 )i-R b , -C(O)O-R a and -C(O)O-(CH 2 )i-R b , where X, R a , R b and R d are as previously defined, and z is an integer ranging from 0 to 6.
  • exemplary water- solubility increasing progroups include by the way of example and not limitation, hydrophilic groups such as alkyl, arylk, arylalkyl, or cycloheteroalkyl groups substituted with one or more of an amine, alcohol, a carboxylic acid, a phosphorous acid, a sulfoxide, a sugar, an amino acid, a thiol, a polyol, a ether, a thioether and a quaternary amine salt.
  • hydrophilic groups such as alkyl, arylk, arylalkyl, or cycloheteroalkyl groups substituted with one or more of an amine, alcohol, a carboxylic acid, a phosphorous acid, a sulfoxide, a sugar, an amino acid, a thiol, a polyol, a ether, a thioether and a quaternary amine salt.
  • progroups that contain a phosphate group, for example, phosphate-containing progroups of the formula -(R d R d ) O-P(O)(OH)2, where R d is as defined above and y is an integer ranging from 1 to 3, typically 1 or 2.
  • each R d is, independently of the others, selected from hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted (C6-C14) aryl and substituted or unsubstituted (C7-C20) arylalkyl.
  • phosphate-containing progroups R p act as substrates for both alkaline and acid phosphatase enzymes, leading to their removal from the prodrugs under physiological conditions of use.
  • alkaline phosphatases are abundant in the digestive tract of humans, phosphate-containing progroups R p that can be cleaved in the presence of alkaline phosphatases are particularly suitable for formulating phosphate-containing prodrugs intended for oral administration.
  • phosphate-containing progroups R p suitable for use in prodrugs intended for oral administration include, but are not limited to, groups of the formula -(R d R d ) O-P(O)(OH)2 in which each R d is, independently of the others, selected from hydrogen and unsubstituted lower alkanyl.
  • exemplary embodiments of such phosphate- containing progroups include, but are not limited to, -CH2-O-P(O)(OH)2 and -CH 2 CH 2 -O-P(O)(OH)2.
  • the phosphorous-containing progroup R p comprises a phosphite group.
  • a specific exemplary embodiment of such phosphite-containing prodrugs includes prodrug compounds in which the progroup R p is of the formula -(CR d R d ) O-P(OH)(OH), where R d and y are as previously defined.
  • the phosphorous-containing progroup R p comprises an acyclic phosphate ester or phosphite ester group.
  • acyclic phosphate ester and phosphite ester prodrugs include progroups R p of the formula -(CR d R d ) O-P(O)(OH)(OR e ), -(CR d R d ) O-P(O)(OR e ) 2 , -(CR d R d ) O-P(OH)(OR e ) and -(CR d R d ) O-P(OR e )2, where R e is selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted (C6-C14) aryl (e.g., phenyl, naphthyl, 4-lower alkoxyphenyl, 4- methoxypheny
  • each R f is, independently of the others, selected from hydrogen, unsubstituted or substituted lower alkyl, substituted or unsubstituted (C6-C14) aryl, and substituted or unsubstituted (C7-C20) arylalkyl, and R d and y are as previously defined.
  • phosphorous -containing prodrugs that include phosphate precursors are prodrugs in which the phosphorous-containing progroup R p comprises a cyclic phosphate ester of the formula each R g is, independently of the others, selected from hydrogen and lower alkyl; each R h is, independently of the others, selected from hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloheteroalkyl, substituted or unsubstituted (C6-C14) aryl, substituted or unsubstituted (C7-C20) arylalkyl and substituted or unsubstituted 5-14 membered heteroaryl; z is an integer ranging from 0 to 2; and R d and y are as previously defined.
  • phosphorous-containing prodrugs that include phosphate precursors are prodrugs in which the phosphorous-containing progroup R p comprises a cyclic phosphite ester of the formula , where R g , R h , R d , y and z are as previously defined.
  • the substituents R h on such cyclic phosphate ester and phosphite ester prodrugs are selected such that the progroup is metabolized in vitro by esterase enzymes.
  • Specific examples of such phosphate ester and phosphite ester progroups include those in which each R h is, independently of the others, selected from hydrogen, lower alkyl, methyl, ethyl and propyl. In some embodiments, such progroups are selected from
  • phosphate esters and phosphite esters are acid label and, when administered orally, metabolize to the corresponding phosphates and phosphites under the acidic conditions of the stomach and/or gut.
  • the identity of the particular phosphorous-containing progroups R p employed can be selected to tailor the prodrugs for particular modes of delivery, etc.
  • any particular progroup R p for a desired mode of administration can be confirmed in biochemical assays.
  • a prodrug is to be administered by injection into a particular tissue or organ, and the identities of the various phosphatases expressed in the tissue or organ are known
  • the particular prodrug can be tested for metabolism in biochemical assays with the isolated phosphatase(s).
  • the particular prodrug can be tested for metabolism to the active 2,4-pyrimidinediamine compound with tissue and/or organ extracts.
  • tissue and/or organ extracts can be of particular convenience when the identity(ies) of the phosphatases expressed in the target tissues or organs are unknown, or in instances when the isolated phosphatases are not conveniently available.
  • Skilled artisans will be able to readily select progroups R p having metabolic properties (such as kinetics) suitable for particular applications using such in vitro tests.
  • specific prodrugs could also be tested for suitable metabolism in in vitro animal models.
  • the prodrugs are prodrugs according to structural formula (I) or (la) that have one or more features selected from:
  • R 5 is fluoro
  • R 2 is a phenyl optionally substituted with one or more of the same or different R 8 groups;
  • R 2 is 3,4,5-tri(loweralkoxy)phenyl
  • R 2 is 3,4,5-trimethoxyphenyl
  • Y or Y 1 is O; Z 1 is CH, Z 2 is N; R 17 and R 18 are each methyl; and R 19 and R 20 are taken together to form an oxogroup; and
  • R p is a hydroxyalkyl-containing progroup of the formula -CH2OH, or a phosphate-containing progroup of the formula -(CR d R d ) O-P(O)(OH)2, or a phosphate ester, phosphite or phosphite ester analog thereof, wherein y is 1 or 2 and each R d is, independently of the others, selected from hydrogen and unsubstituted lower alkyl, or
  • R p is selected from -CH2OH
  • the prodrugs of structural formulae (I) and (la) have two or three of the above-delineated features.
  • the prodrugs have features (i), (iii) and (v).
  • the prodrugs have features (i), (iv) and (v).
  • the prodrugs have features (i), (iii), (v) and (vi) or (vii).
  • the prodrugs have features (i), (iv), (v) and (vi) or (vii).
  • R p is a phosphate-containing progroup of the formula -(CR d R d ) O-P(O)(OH) 2 .
  • substitutions are typically, independently of one another, selected from amongst the R b groups described in connection with structural formula (I).
  • any present substitutions are, independently of one another, selected from hydroxyl, lower alkoxy, (C6-C14) aryloxy, lower alkoxyalkyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl and halogen.
  • prodrugs described herein may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or optical isomerism.
  • the prodrugs may include one or more chiral centers and/or double bonds and as a consequence may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers and diasteromers and mixtures thereof, such as racemic mixtures.
  • the prodrugs may exist in several tautomeric forms, including the enol form, the keto form and mixtures thereof.
  • the prodrugs described herein may be in the form of salts.
  • Such salts include salts suitable for pharmaceutical uses (“pharmaceutically-acceptable salts”), salts suitable for veterinary uses, etc.
  • Such salts may be derived from acids or bases, as is well-known in the art.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts are those salts that retain substantially one or more of the desired pharmacological activities of the parent compound and which are suitable for administration to humans.
  • Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids.
  • Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalide acids (e.g., hydrochloric acid, hydrobromic acid, hydriodic, etc.), sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenes
  • compositions also include salts formed when an acidic proton present in the parent compound is either replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion or an aluminum ion) or coordinates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, etc.).
  • a metal ion e.g., an alkali metal ion, an alkaline earth metal ion or an aluminum ion
  • organic base e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, etc.
  • the prodrugs described herein, as well as the salts thereof may also be in the form of hydrates, solvates and N-oxides, as are well-known in the art.
  • prodrug is intended to encompass such salts, hydrates, solvates and/or N-oxides.
  • Specific exemplary salts include, but are not limited to, mono- and di-sodium salts, mono- and di-potassium salts, mono- and di-lithium salts, mono- and di-alkylamino salts, mono-magnesium salts, mono-calcium salts and ammonium salts.
  • the present disclosure provides pharmaceutical compositions that include a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound or prodrug of the present disclosure or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.
  • a pharmaceutical composition that includes a subject compound may be administered to a patient alone, or in combination with other supplementary active agents.
  • one or more compounds according to the present disclosure can be administered to a patient with or without supplementary active agents.
  • the pharmaceutical compositions may be manufactured using any of a variety of processes, including, but not limited to, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing, and the like.
  • the pharmaceutical composition can take any of a variety of forms including, but not limited to, a sterile solution, suspension, emulsion, spray dried dispersion, lyophilisate, tablet, microtablets, pill, pellet, capsule, powder, syrup, elixir or any other dosage form suitable for administration.
  • a subject compound or prodrug may be administered to a subject using any convenient means capable of resulting in the desired reduction in disease condition or symptom.
  • a subject compound or prodrug can be incorporated into a variety of formulations for therapeutic administration. More particularly, a subject compound can be formulated into pharmaceutical compositions by combination with appropriate pharmaceutically acceptable carriers or diluents, 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, aerosols, and the like.
  • a subject compound or prodrug may be formulated as a pharmaceutical composition, where the pharmaceutical composition is an oral dosage formulation, such as a tablet.
  • oral dosage formulations e.g., tablets
  • Additional aspects of oral dosage formulations suitable for the invention are described in U.S. Patent No. 8,771,648, the disclosure of which is incorporated herein by reference.
  • Formulations for pharmaceutical compositions are described in, for example, Remington’s Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, Pa., 19th Edition, 1995, which describes examples of formulations (and components thereof) suitable for pharmaceutical delivery of disclosed compounds or prodrugs.
  • Pharmaceutical compositions that include at least one of the subject compounds or prodrugs can be formulated for use in human or veterinary medicine. Particular formulations of a disclosed pharmaceutical composition may depend, for example, on the mode of administration and/or on the location of the subject to be treated.
  • formulations include a pharmaceutically acceptable carrier in addition to at least one active ingredient, such as a subject compound or prodrug.
  • other medicinal or pharmaceutical agents for example, with similar, related or complementary effects on the disease or condition being treated can also be included as active ingredients in a pharmaceutical composition.
  • parenteral formulations may include injectable fluids, such as, but not limited to, pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • injectable fluids such as, but not limited to, pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
  • compositions to be administered can optionally contain minor amounts of non-toxic auxiliary substances (e.g., excipients), such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like; for example, sodium acetate or sorbitan monolaurate.
  • excipients include, nonionic solubilizers, such as cremophor, or proteins, such as human serum albumin or plasma preparations.
  • Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydro
  • the disclosed pharmaceutical compositions may be formulated as a pharmaceutically acceptable salt of a disclosed compound or prodrug.
  • pharmaceutically acceptable salts include non-toxic salts of a free base form of a compound that possesses the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids. Non-limiting examples of suitable inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydroiodic acid, and phosphoric acid.
  • Non-limiting examples of suitable organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, methyl sulfonic acid, salicylic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, asparagic acid, aspartic acid, benzenesulfonic acid, para-toluenesulfonic acid, naphthalenesulfonic acid, combinations thereof, and the like.
  • the pharmaceutically acceptable salt includes formic acid.
  • Other examples of pharmaceutically acceptable salts include non-toxic salts of a free acid form of compounds or prodrugs according to the present disclosure. Such salts are derived from inorganic or organic bases
  • Pharmaceutically acceptable base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, combinations thereof, and the like. Examples of salts are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts of the presently disclosed compounds or prodrugs can be derived from pharmaceutically acceptable organic non-toxic bases including, but not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- dimethylaminoethanol, 2-diethylaminoethanol, 2-amino-2-hydroxymethyl-propane- 1 ,3 -diol (“Tris” salt), dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, combinations thereof, and the like .
  • a subject compound or prodrug is formulated as a pharmaceutically acceptable salt, where the pharmaceutically acceptable salt is a disodium hexahydrate form of the subject compound or prodrug. Additional aspects of salts and hydrates of the subject compounds and prodrugs suitable for the invention are described in U.S. Patent No. 8,163,902 and U.S. Patent No. 8,445,485, the disclosures of which are incorporated herein by reference.
  • a subject compound or prodrug can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, com starch or gelatins; with disintegrators, such as com starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.
  • Such preparations can be used for oral administration.
  • a subject compound or prodmg can be formulated into preparations for injection by dissolving, suspending or emulsifying the compound in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • the preparation may also be emulsified or the active ingredient encapsulated in liposome vehicles.
  • Formulations suitable for injection can be administered by an intravitreal, intraocular, intramuscular, subcutaneous, sublingual, or other route of administration, e.g., injection into the gum tissue or other oral tissue. Such formulations are also suitable for topical administration.
  • a subject compound or prodrug can be utilized in aerosol formulation to be administered intrapulmonarily (e.g., via inhalation).
  • a subject compound or prodrug can be formulated into pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen and the like.
  • a subject compound or prodrug can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • a subject compound or prodrug can be administered rectally via a suppository.
  • the suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are substantially solid at room temperature.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of a subject compound or prodrug calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle.
  • the specifications for a subject compound or prodrug depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound or prodrug in the host.
  • the dosage form of a disclosed pharmaceutical composition may be determined by the mode of administration chosen.
  • topical or oral dosage forms may be employed.
  • Topical preparations may include eye drops, ointments, sprays and the like.
  • Oral formulations may be liquid (e.g., syrups, solutions or suspensions), or solid (e.g., powders, pills, tablets, or capsules).
  • the subject compounds or prodrugs may be formulated for intrapulmonary administration.
  • intrapulmonary formulations of the subject prodrugs may include, but are not limited to, dry powder or solution formulations
  • intrapulmonary formulations of the subject compounds may include, but are not limited to, dry powder or suspension formulations.
  • compositions that include a subject compound or prodrug may be formulated in unit dosage form suitable for individual administration of precise dosages.
  • the amount of active ingredient administered may depend on the subject being treated, the severity of the affliction, and the manner of administration, and is known to those skilled in the art.
  • the formulation to be administered contains a quantity of the compounds or prodrugs disclosed herein in an amount effective to achieve the desired effect in the subject being treated.
  • Each therapeutic compound or prodrug can independently be in any dosage form, such as those described herein, and can also be administered in various ways, as described herein.
  • the compounds or prodrugs may be formulated together, in a single dosage unit (that is, combined together in one form such as capsule, tablet, powder, or liquid, etc.) as a combination product.
  • an individual subject compound or prodrug may be administered at the same time as another therapeutic compound or prodrug or sequentially, in any order thereof.
  • a disclosed compound or prodrug can be administered alone, as the sole active pharmaceutical agent, or in combination with one or more additional compounds or prodrugs of the present disclosure or in conjunction with other agents.
  • the therapeutic agents can be formulated as separate compositions that are administered simultaneously or at different times, or the therapeutic agents can be administered together as a single composition combining two or more therapeutic agents.
  • the pharmaceutical compositions disclosed herein containing a compound of the present disclosure optionally include other therapeutic agents. Accordingly, certain embodiments are directed to such pharmaceutical compositions, where the composition further includes a therapeutically effective amount of an agent selected as is known to those of skill in the art.
  • the present compound may be is administered in combination with one or more other therapeutic agents, the other therapeutic agents may target Influenza virus or any of the symptoms of Influenza infection.
  • the agents include (a) inhibitors of cell entry of Influenza virus, (b) inhibitors of replication, assembly, and release of Influenza viruses (c) immunomodulators.
  • the present therapy may be combined with plasma therapy in some cases. Inhibitors of cell entry of Influenza viruses
  • Inhibitors of cell entry of Influenza viruses include inhibitors of Influenza HA induced membrane fusion.
  • Influenza HA induced membrane fusion inhbitors include, but are not limited to:
  • C20-Jp-Hp is a preclinical drug that is the result of the hybridization of two short peptides.
  • C20-Jp-Hp may inhibit the viral infection in the early stage by interacting with the fusogenic region of HA2 subunit. This process involves the block of conformational rearrangements of HA2, thereby interfering with the membrane fusion of virus with targeting host cells.
  • C20-Jp-Hp is described in Lin et al. Sci Rep. 2016 Mar 8;6:22790.
  • MBX2329 and MBX2546 are preclinical drugs with aminoalkyl phenol ether and aminoacetamide sulfonamide scaffolds, respectively, that inhibit multiple Influenza A viruses, including the 2009 pandemic influenza virus A/H1N1, high pathogenic avian influenza (HPAI) virus A/H5N1, and oseltamivir-resistant A/H1N1 strains, in a potent (IC50 of 0.47 to 5.8 pM) and selective (CC50 of >100 pM) manner in vitro.
  • IC50 0.47 to 5.8 pM
  • CC50 of >100 pM CC50 of >100 pM
  • agents include produgs, neuraminidase inhibitors, endonuclease inhibitors, M2 protein proton channel inhibitors and other compounds, examples of which are described below.
  • Baloxavir marboxil (Xofluza) [00190] Baloxavir marboxil was developed as a prodrug strategy, with its metabolism releasing the active agent, baloxavir acid (BXA). BXA then functions as enzyme inhibitor, targeting the Influenza virus' cap-dependent endonuclease activity, used in "cap snatching" by the virus' polymerase complex, a process essential to its life-cycle. Baloxavir interferes with viral replication by blocking viral RNA transcription.
  • Peramivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells.
  • Zanamivir works by binding to the active site of the neuraminidase protein, rendering the influenza virus unable to escape its host cell and infect others.
  • the enzyme cleaves the sialic acid which is found on glycoproteins on the surface of human cells that helps new virions to exit the cell.
  • Zanamivir prevents new viral particles from being released.
  • Oseltamivir (GS-4104) is a neuraminidase inhibitor, a competitive inhibitor of influenza's neuraminidase enzyme. The enzyme cleaves the sialic acid which is found on glycoproteins on the surface of human cells that helps new virions to exit the cell. Thus oseltamivir prevents new viral particles from being released.
  • Dexamethasone is a corticosteroid and an immunomodulator/immunosuppressant that has been used to treat various inflammatory conditions, including but not limited to, rheumatoid arthritis, bronchospasm, lupus, etc.
  • Dexamethasone is an agonist of the glucocorticoid receptor and upon binding activates glucocorticoid signaling leading to the suppression of immune responses.
  • Prednisone is a corticosteroid and an immunomodulator/immunosuppressant that has been used to treat various inflammatory conditions, including but not limited to, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, etc.
  • Prednisone is an agonist of the glucocorticoid receptor and upon binding activates glucocorticoid signaling leading to the suppression of immune responses.
  • Methylprednisone is a synthetic glucocorticoid primarily used for anti-inflammatory and immunosuppression. Methylprednisone is an agonist of the glucocorticoid receptor and upon binding activates glucocorticoid signaling leading to the suppression of immune responses.
  • Hydrocortisone is a glucocorticoid and is the medication form of the hormone cortisol. Hydrocortisone is used for the treatment of autoimmune disorders and immune suppression. . Hydrocortisone is an agonist of the glucocorticoid receptor and upon binding activates glucocorticoid signaling leading to the suppression of immune responses.
  • Baricitinib is an inhibitor of janus kinase (JAK) that is often used in the treatment of rheumatoid arthritis in addition to other autoimmune diseases. Baricitinib has been permitted EUA by the FDA to be used only in combination with remdesivir when, in rare circumstances, corticosteroids can be used. Baricitinib has been shown to specifically inhibit the activity of Janus kinase 1 and 2.
  • immunomodulators include ocilizumab and sarilumab, monoclonal antibodies that target cytokines or their receptors, and other JAK inhibitors (e.g., tofacitinib, upadacitinib nd ruxolitinib, etc.).
  • JAK inhibitors e.g., tofacitinib, upadacitinib nd ruxolitinib, etc.
  • the present therapy may also be used in conjunction with plasma therapy.
  • the route of administration may be selected according to a variety of factors including, but not limited to, the condition to be treated, the formulation and/or device used, the patient to be treated, and the like.
  • Routes of administration useful in the disclosed methods include but are not limited to oral and parenteral routes, such as intravenous (iv), intraperitoneal (ip), rectal, topical, ophthalmic, nasal, and transdermal. Formulations for these dosage forms are described herein.
  • An effective amount of a subject compound may depend, at least, on the particular method of use, the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic composition.
  • a “therapeutically effective amount” of a composition is a quantity of a specified compound or prodrug sufficient to achieve a desired effect in a subject (e.g., patient) being treated. For example, this may be the amount of a subject compound or prodrug necessary to prevent, inhibit, reduce or relieve a disease or disorder in a subject.
  • a therapeutically effective amount of a compound is an amount sufficient to prevent, inhibit, reduce or relieve a disease or disorder in a subject without causing a substantial cytotoxic effect on host cells in the subject.
  • Therapeutically effective doses of a subject compound or prodrug or pharmaceutical composition can be determined by one of skill in the art, with a goal of achieving local (e.g., tissue) concentrations that are at least as high as the EC50 of an applicable compound disclosed herein.
  • a dosage range is from 0.1 to 200 mg/kg body weight orally in single or divided doses.
  • a dosage range is from 1.0 to 100 mg/kg body weight orally in single or divided doses, including from 1.0 to 50 mg/kg body weight, from 1.0 to 25 mg/kg body weight, from 1.0 to 10 mg/kg body weight (assuming an average body weight of approximately 70 kg; values may be adjusted accordingly for persons weighing more or less than average).
  • the compositions are, for example, provided in the form of a tablet containing from about 10 to about 1000 mg of the active ingredient, such as 25 to 750 mg, or 50 to 500 mg, for example 75 mg, 100 mg, 200 mg, 250 mg, 400 mg, 500 mg, 600 mg, 750 mg, or 1000 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject being treated.
  • a tablet containing from 500 mg to 1000 mg active ingredient is administered once (e.g., a loading dose) followed by administration of 1/2 (i.e., half) dosage tablets (e.g., from 250 to 500 mg) each 6 to 24 hours for 3 days or more.
  • the specific dose level and frequency of dosage for any particular subject may be varied and may depend upon a variety of factors, including the activity of the subject compound or prodrug, the metabolic stability and length of action of that compound, the age, body weight, general health, sex and diet of the subject, mode and time of administration, rate of excretion, drug combination, and severity of the condition of the host undergoing therapy.
  • Embodiments of the present disclosure also include combinations of one or more disclosed compounds or prodrugs with one or more other agents or therapies useful in the treatment of a disease or disorder.
  • administration in combination with refers to both concurrent and sequential administration of the active agents.
  • influenza infection may lead to downstream events such as cytokine storm, NETosis, and platelet activation culminating in ALI, ARDS, and thrombosis.
  • Fostamatinib is a reversible, oral SYK inhibitor, that has been evaluated in >3500 patients with different diseases. Fostamatinib was approved in 2018 in the US and subsequently in Canada and Europe for the treatment of chronic immune thrombocytopenia (ITP), and two randomized studies showed increased platelet counts and decreased bleeding episodes in ITP patients. Fostamatinib has consistently demonstrated a manageable safety profile across a spectrum of diseases. In rheumatoid arthritis (RA) patients, fostamatinib was shown to reduce plasma levels of IE-6 within the first week of treatment (Weinblatt et al. Arth Rheum 2008;58:3309-18).
  • RA rheumatoid arthritis
  • the active metabolite, R406, was shown to be protective in mice with LPS-induced ALI (Nadeem A et al. Int Immunopharm 2019;68:39-47).
  • SYK inhibition through platelet receptors have been shown to decrease the incidence of thrombosis in mouse models of thromboembolism (Van Eeuwijk JMM et al. Arterioscler Thromb Vase Biol., 2016;36:1247-53.)
  • Fostamatinib has also been shown to block NETosis in human neutrophils in in vitro studies (Strich JR et al. J infect Dis. 2020;jiaa789).
  • MUC1 mucin-1
  • a high-content imaging screen identified fostamatinib as a drug with potential to reduce MUC1 levels in ARDS, and R406 reduced MUC1 in a mouse model of ALI (Kost- Alimova M et al. Cell Rep Med. 2020; 1(8): 100137).
  • a clinical study is conducted to test fostamatinib in hospitalized Inluenza patients.
  • the design for this clinical study is provided in FIG. 3.
  • a double-blind, randomized, placebo-controlled, adaptive design, multi-center, Phase 3 study is conducted to evaluate the safety and efficacy of fostamatinib in adult patients with influenza.
  • Inclusion criteria must satisfy all of the following: age of more than 18 years and less than 100 years; hospitalized influenza subjects without respiratory failure who are either not receiving any oxygen therapy or are receiving supplemental oxygen via mask or nasal prongs; male or non-pregnant, non-lactating female with influenza infection documented by a hospital approved diagnostic test (e.g., a Food and Drug Administration authorized test in the US) within 7 days prior to randomization.
  • a hospital approved diagnostic test e.g., a Food and Drug Administration authorized test in the US
  • Exclusion criteria must not have any of the following: pregnant or lactating female of childbearing potential; use of extracorporeal membrane oxygenation (ECMO) or ARDS; uncontrolled hypertension (systolic blood pressure [BP] >160 mmHg and/or diastolic BP >100 mmHg); unstable angina; congestive heart failure of New York Heart Association classification III or IV; serious cardiac arrhythmia requiring treatment; history of myocardial infarction within 3 months prior to screening.
  • ECMO extracorporeal membrane oxygenation
  • ARDS uncontrolled hypertension (systolic blood pressure [BP] >160 mmHg and/or diastolic BP >100 mmHg); unstable angina; congestive heart failure of New York Heart Association classification III or IV; serious cardiac arrhythmia requiring treatment; history of myocardial infarction within 3 months prior to screening.
  • each fostamatinib dose is between 100 to 200 mg, thereby administering between 200 and 400 mg of fostamatinib per day.
  • each fostamatinib dose is 125 mg, 150 mg, 175 mg, or 200 mg.
  • Fostamatinib is administered orally. Other routes of administration are also tested.
  • Fostamatinib is administered as TAVALISSETM, which contains fostamatinib disodium hexahydrate.
  • TAVALISSETM oral tablet can contain 100 mg or 150 mg fostamatinib, which is equivalent to 126.2 mg or 189.3 mg fostamatinib disodium hexahydrate, respectively.
  • the inactive ingredients in the tablet core are mannitol, sodium bicarbonate, sodium starch glycolate, povidone, and magnesium stearate.
  • the inactive ingredients in the film coating are polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, iron oxide yellow, and iron oxide red.
  • the primary outcome measure is the progression to severe/critical disease within 29 days of first dose of study treatment.
  • fostamatinib Compared to the placebo group, in the fostamatinib group, a significantly smaller percentage of patients is expected to develop severe or critical disease within 29 days of first dose of study treatment. The following outcomes are expected: 1) fostamatinib is expected to significantly reduce the percentage of influenza infected patients that develop severe disease that requires intensive care; 2) within the patients that develop severe disease that requires intensive care, fostamatinib is expected to significantly reduce the percentage of patients that develop ARDS; and 3) within the patients that develop ARDS, fostamatinib is expected to significantly reduce the number of patients that die.
  • fostamatinib is expected to significantly reduces certain specific symptoms of influenza. Particularly, compared to the placebo group, in the fostamatinib group, the occurrence of several severe symptoms of influenza is expected to be significantly reduced. For example, smaller percentage of patients are expected to develop one or more of the following symptoms: AKI; Kidney malfunction; acute lung injury, etc.; thrombosis; and coagulopathy.
  • a study is conducted generally as described in Example 1 with additional arms that include a combination of fostamatinib with one or more other therapeutic agents.
  • These other therapeutic agents include those described above under the section header “Combination therapies” above.
  • one arm in such study comprises administering fostamatinib in combination with an additional therapeutic plus standard of care and other arm comprises administering placebo in combination with the additional therapeutic plus standard of care.

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Abstract

La présente invention concerne, entre autres, un procédé de traitement d'une réponse immunologique excessive à une infection par un virus respiratoire, en particulier la grippe, par l'administration de fostamatinib, d'un composant actif de celui-ci ou d'un sel pharmaceutiquement acceptable de celui-ci au patient. Dans certains modes de réalisation, le patient peut par exemple avoir un syndrome de détresse respiratoire aiguë, une thrombose ou une défaillance d'organe.
PCT/US2022/041721 2021-09-08 2022-08-26 Procédé de traitement d'une réponse immunologique excessive à une infection par un virus respiratoire Ceased WO2023038816A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN117838697A (zh) * 2024-01-09 2024-04-09 暨南大学 巴瑞替尼在制备治疗流感病毒感染的药物中的应用
CN119587554A (zh) * 2024-12-31 2025-03-11 中国医学科学院医学实验动物研究所 福坦替尼在治疗重症登革热肝损伤中的应用

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Publication number Priority date Publication date Assignee Title
US20160054320A1 (en) * 2013-04-04 2016-02-25 The Board Of Trustees Of The Leland Stanford Junior University Markers for Determination of Patient Responsiveness
WO2019014624A1 (fr) * 2017-07-14 2019-01-17 The Johns Hopkins University Tsc2 modifié
WO2020146625A1 (fr) * 2019-01-09 2020-07-16 The Johns Hopkins University Polypeptides du complexe 2 de la sclérose tubéreuse modifiés
US20200377518A1 (en) * 2019-05-29 2020-12-03 Rigel Pharmaceuticals, Inc. Method of preventing and treating thrombosis
US20210128557A1 (en) * 2019-10-30 2021-05-06 Massachusetts Institute Of Technology Methods and compositions for predicting and preventing relapse of acute lymphoblastic leukemia

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160054320A1 (en) * 2013-04-04 2016-02-25 The Board Of Trustees Of The Leland Stanford Junior University Markers for Determination of Patient Responsiveness
WO2019014624A1 (fr) * 2017-07-14 2019-01-17 The Johns Hopkins University Tsc2 modifié
WO2020146625A1 (fr) * 2019-01-09 2020-07-16 The Johns Hopkins University Polypeptides du complexe 2 de la sclérose tubéreuse modifiés
US20200377518A1 (en) * 2019-05-29 2020-12-03 Rigel Pharmaceuticals, Inc. Method of preventing and treating thrombosis
US20210128557A1 (en) * 2019-10-30 2021-05-06 Massachusetts Institute Of Technology Methods and compositions for predicting and preventing relapse of acute lymphoblastic leukemia

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117838697A (zh) * 2024-01-09 2024-04-09 暨南大学 巴瑞替尼在制备治疗流感病毒感染的药物中的应用
CN119587554A (zh) * 2024-12-31 2025-03-11 中国医学科学院医学实验动物研究所 福坦替尼在治疗重症登革热肝损伤中的应用
CN119587554B (zh) * 2024-12-31 2025-08-12 中国医学科学院医学实验动物研究所 福坦替尼在治疗重症登革热肝损伤中的应用

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