WO2014164658A1 - Methods of inhibiting leukotriene a4 hydrolase - Google Patents

Methods of inhibiting leukotriene a4 hydrolase Download PDF

Info

Publication number
WO2014164658A1
WO2014164658A1 PCT/US2014/023138 US2014023138W WO2014164658A1 WO 2014164658 A1 WO2014164658 A1 WO 2014164658A1 US 2014023138 W US2014023138 W US 2014023138W WO 2014164658 A1 WO2014164658 A1 WO 2014164658A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
compound
condition
administered
dose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2014/023138
Other languages
English (en)
French (fr)
Inventor
Eric B. SPRINGMAN
Margaret McCrann PUGH
Lopa Bhatt
Ralph GROSSWALD
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Celtaxsys Inc
Original Assignee
Celtaxsys Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU2014249168A priority Critical patent/AU2014249168B2/en
Priority to ES14779776T priority patent/ES2864862T3/es
Priority to JP2016501158A priority patent/JP6527851B2/ja
Priority to CA2905340A priority patent/CA2905340C/en
Priority to EP14779776.5A priority patent/EP2968359B1/en
Priority to RU2015137978A priority patent/RU2686101C2/ru
Application filed by Celtaxsys Inc filed Critical Celtaxsys Inc
Publication of WO2014164658A1 publication Critical patent/WO2014164658A1/en
Priority to US14/850,061 priority patent/US9820974B2/en
Anticipated expiration legal-status Critical
Priority to US15/801,482 priority patent/US10350197B2/en
Priority to US16/443,338 priority patent/US10898471B2/en
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/504—Pyridazines; Hydrogenated pyridazines forming part of bridged ring systems
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P11/12—Mucolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • LTA4-I1 is a monomeric, soluble 69 kD zinc metalloenzyme. It catalyses two reactions: the stereospecific epoxide hydrolase reaction to convert LTA4 to leukotriene B4 (LTB 4 ) and a peptidase cleavage of chromogenic substrates. Leukotriene B 4 (LTB 4 ) is a major pro-inflammatory mediator. LTA4-I1 and receptors to LTB4 are known to be elevated in a number of human lung diseases including cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). Additionally, elevated levels of LTA4-H have been located at active demyelinating lesions in the brains of patients with multiple sclerosis (MS).
  • MS multiple sclerosis
  • LTA4-I1 inhibitors have been described, for example, in U.S. Patent No. 7,737, 145 and U.S. Patent Application Publication No. 20100210630A1, the contents of each of which are incorporated by reference herein.
  • a specific LTA4-I1 inhibitor described in these patent publications is 4- ⁇ [(l S,4S)-5-( ⁇ 4-[4-oxazol-2-yl-phenoxy]phenyl ⁇ methyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]methyl ⁇ benzoic acid. In preclinical studies, this compound was shown to reduce the progression of chronic inflammation in several animal models.
  • the present invention is directed to methods of inhibiting LTA4-I1 in a human patient and methods of treating a condition ameliorated by the inhibition of leukotriene A4 hydrolase activity in a human patient comprising administering to said human patient the compound, wherein the compound is 4- ⁇ [(lS,4S)-5-( ⁇ 4-[4-oxazol-2-yl-phenoxy]phenyl ⁇ methyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]methyl ⁇ benzoic acid, at a dose of about 100 mg or less, and wherein the compound is administered orally.
  • the compound is administered at a dose between about 1 mg and about 100 mg, a dose between about 1 mg and about 75 mg, a dose between about 1 mg and about 50 mg, a dose between about 1 mg and about 30 mg, or a dose between about 5 mg and about 25 mg. In some embodiments, the compound is administered at a dose between about 5 mg and about 15 mg. In certain aspects, the compound is administered at a dose of about 5 mg.
  • the invention also encompasses a pharmaceutical composition
  • a pharmaceutical composition comprising the compound, 4- ⁇ [(lS,4S)-5-( ⁇ 4-[4-oxazol-2-yl-phenoxy]phenyl ⁇ methyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]methyl ⁇ benzoic acid, wherein the amount of the compound present in the composition is about 100 mg or less, and wherein the composition is an oral dosage form.
  • the amount of the compound is between about 1 mg and about 100 mg, between about 1 mg and about 75 mg, between about 1 mg and about 50 mg, between about 1 mg and about 30 mg, or between about 5 mg and about 25 mg.
  • the compound is present in the composition in an amount between about 5 mg and about 15 mg.
  • the compound is present in the composition in an amount of about 5 mg.
  • FIG. 1 shows a plot of plasma concentration (ng/ml) over time (hours) of 50 mg, 15 mg and 5 mg of 4- ⁇ [(lS,4S)-5-( ⁇ 4-[4-oxazol-2-yl-phenoxy]phenyl ⁇ methyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]methyl ⁇ benzoic acid.
  • the two sets of dashed, horizontal lines indicate the plasma concentration that is three-times (3x) the IC5 0 and the plasma
  • FIG. 2 shows the x-ray powder diffraction pattern of 4- ⁇ [(lS,4S)-5-( ⁇ 4-[4-oxazol-2- yl-phenoxy]phenyl ⁇ methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]methyl ⁇ benzoic acid.
  • an additional therapeutic agent encompasses both a single additional therapeutic agent and a combination of two or more additional therapeutic agents.
  • range of the dose or amount of the compound is described as “between” a low end of the range and “between” a high end of the range, the range is meant to include both, the low end and the high end as well as doses in between the low and high ends.
  • a dose between about 1 mg and about 100 mg it is to be understood that the range includes the low end of the range, 1 mg, and the high end of the range, 100 mg, as well as the doses in between.
  • the present invention is based on the discovery that a low dose oral formulation of 4- ⁇ [(l S,4S)-5-( ⁇ 4-[4-oxazol-2-yl-phenoxy]phenyl ⁇ methyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl]methyl ⁇ benzoic acid is therapeutically effective.
  • Preclinical research conducted in mouse, rat, and dog models projected an effective oral dose of the compound for humans of at least 100 to 200 mg.
  • pharmacokinetic studies (the results of which are described in more detail below) have demonstrated that an oral formulation containing less than 100 mg is effective. These studies have shown that a dose as low as 5 mg can achieve therapeutic levels of the compound in the blood.
  • the invention is directed to the administration of an effective oral dose of 4- ⁇ [(l S,4S)-5-( ⁇ 4-[4-oxazol-2-yl-phenoxy]phenyl ⁇ methyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl]methyl ⁇ benzoic acid.
  • This compound and methods for the preparation thereof have been described in detail in U.S. Patent No. 7,737, 145 and U.S. Patent Application Publication No.
  • the methods of the invention relate to inhibiting LTA 4 hydrolase activity in human patients, and thus are useful in treating conditions which are ameliorated by the inhibition of LTA 4 hydrolase activity.
  • diseases and conditions include inflammatory conditions and autoimmune diseases.
  • Exemplary inflammatory conditions are pulmonary and respiratory tract inflammation.
  • the condition that is treated is a chronic condition.
  • chronic conditions are cystic fibrosis, idiopathic pulmonary fibrosis, multiple sclerosis, inflammatory bowel disease, and interstitial lung disease associated with systemic sclerosis (scleroderma).
  • the condition that is treated is an acute condition.
  • acute conditions are allergic rhinitis and myocardial infarction.
  • the invention can also be used in the treatment of mild, non-life threatening conditions such as acne and gingivitis.
  • the human patient is a pediatric patient.
  • a pediatric patient can, for example, be a patient less than 16 years of age, less than 12 years of age, less than 10 years of age, less than 8 years of age, less than 6 years of age, less than 5 years of age, less than 2 years of age, or an infant.
  • the pediatric patient is suffering from cancer.
  • the pediatric patient is suffering from a respiratory or pulmonary inflammation.
  • Conditions that can be ameliorated by LTA 4 -h inhibition and that can be treated according to the methods of the invention include, for example, acute or chronic
  • Atherosclerosis aneurysm, critical leg ischemia, peripheral arterial occlusive disease and Reynaud's syndrome
  • complications of diabetes including diabetic nephropathy, neuropathy and retinopathy
  • ocular disorders including macular degeneration and glaucoma
  • neurodegenerative disorders including delayed neurodegeneration in stroke, Alzheimer's disease, Parkinson's disease, encephalitis and HIV dementia
  • inflammatory and neuropathic pain including arthritic pain, periodontal disease including gingivitis, ear infections, migraine, benign prostatic hyperplasia, and cancers (including, but not limited to, leukemias and lymphomas, prostate cancer, breast cancer, lung cancer, malignant melanoma, renal carcinoma, head and neck tumors and colorectal cancer).
  • the methods of the invention also encompass treating folliculitis induced by inhibitors of epidermal growth factor (EGF) or epidermal growth factor receptor (EGFR) kinase used in the treatment of solid tumors.
  • EGF epidermal growth factor
  • EGFR epidermal growth factor receptor
  • the methods described herein can be used to inhibit neutrophil or eosinophil-mediated inflammation, and therefore encompass the treatment of folliculitis, thereby improving the quality of life of the treated cancer patients but also allowing for the increase of the dosage of the EGF inhibitor or EGFR kinase inhibitor or the extension of the duration of the treatment, resulting in improved efficacy of the desired inhibitor.
  • the methods also encompass the treatment of pulmonary and respiratory
  • inflammation disorders in humans including, but not limited to, asthma, chronic bronchitis, bronchiolitis, bronchiolitis obliterans (including such with organizing pneumonia), allergic inflammation of the respiratory tract (including rhinitis and sinusitis), eosinophilic granuloma, pneumonias, pulmonary fibroses, pulmonary manifestations of connective tissue diseases, acute or chronic lung injury, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), and non- infectious inflammatory disorders of the lung characterized by eosinophil infiltration.
  • the inflammation is eosinophil- mediated inflammation of the lung or tissues; neutrophil-mediated inflammation of the lung; lymphocyte-mediated inflammation of the lung; airway hyper-responsiveness; and airway and vascular inflammation.
  • the methods also encompass the treatment of myocardial infarction or susceptibility to myocardial infarction in humans, transient ischemic attack, transient monocular blindness, stroke or susceptibility of stroke, claudication, peripheral arterial occlusive disease or susceptibility to peripheral arterial occlusive disease, and acute coronary syndrome (such as unstable angina, non-ST-elevation myocardial infarction or ST-elevation myocardial infarction).
  • the methods also encompass methods for reducing the risk of myocardial infarction, stroke or peripheral arterial occlusive disease in mammals and reducing the risk of a second myocardial infarction or stroke.
  • Atherosclerosis in humans who require treatment (such as angioplasty, stents, coronary artery bypass graft) in order to restore blood flow in the arteries (such as in the coronary arteries).
  • treatment such as angioplasty, stents, coronary artery bypass graft
  • Non-limiting examples of neurodegenerative diseases that can be treated according to a method of the invention are amyotrophic lateral sclerosis (ALS), Parkinson's disease and Huntington's disease.
  • ALS amyotrophic lateral sclerosis
  • Parkinson's disease Huntington's disease.
  • the methods also encompass the treatment of cancer.
  • the cancer is leukemia.
  • Specific exemplary leukemias that can be treated by administering a compound of the invention are Chronic Granulocytic Leukemias, Chronic B-Cell Leukemias and Chronic Myelogenous Leukemias.
  • the invention also encompasses a method of treating a solid tumor in a subject in need thereof.
  • Non-limiting examples of solid tumors that can be treated according to the methods described herein are ovarian, esophageal and hepatocellular tumors.
  • the invention is directed to a method of treating a condition selected from the group consisting of cystic fibrosis, idiopathic pulmonary fibrosis, interstitial lung disease associated with systemic sclerosis, atherosclerosis, osteoarthritis, Alzheimer's disease, osteoporosis, and type II diabetes, allergic rhinitis, acne, and gingivitis.
  • a condition selected from the group consisting of cystic fibrosis, idiopathic pulmonary fibrosis, interstitial lung disease associated with systemic sclerosis, atherosclerosis, osteoarthritis, Alzheimer's disease, osteoporosis, and type II diabetes, allergic rhinitis, acne, and gingivitis.
  • eosinophilic disorders are eosinophilic esophagitis, eosinophilic gastroenteritis, eosinophilic colitis, eosinophilic fasciitis, eosinophilic pneumonia, eosinophilic cystitis, hypereosinophilic syndrome and Churg Strauss Syndrome.
  • the eosinophilic disorder is eosinophilic esophagitis.
  • the invention encompasses methods wherein 4- ⁇ 5-[4-(4-Oxazol-2-yl-phenoxy)- benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl ⁇ -benzoic acid is co-administered with at least one additional therapeutic agent.
  • the condition is cancer and 4- ⁇ 5-[4-(4-Oxazol-2-yl-phenoxy)-benzyl]-2,5-diaza-bicyclo[2.2. l]hept-2- ylmethyl ⁇ -benzoic acid is administered with a chemotherapeutic agent.
  • the human patient is suffering from chronic obstructive pulmonary disease (COPD) and the additional therapeutic agent is a drug used in the treatment of COPD, such as a
  • the condition is COPD and the at least one additional therapeutic agent is selected from the group consisting of a beta-agonist, an anticholinergic, a glucocorticoid, or a combination thereof.
  • the human patient is suffering from cystic fibrosis and the additional therapeutic agent is a drug used in the treatment of cystic fibrosis, for example, an antibiotic, a mucolytic, a surfactant, a pancreatic enzyme replacement drug, or a combination thereof.
  • the condition is interstitial lung disease (ILD), a frequent complication of systemic sclerosis
  • the additional therapeutic agent is a therapeutic agent used in the treatment of interstitial lung disease including, for example, glucocorticoids, cyclophosphamide, azathioprine, methotrexate, and mycophenolate mofetil.
  • the condition is multiple sclerosis and the additional therapeutic agent is a therapeutic agent used in the treatment of multiple sclerosis including, for example, teriflunomide (sold under the tradename AUBAGIO®), interferon-beta-la (sold under the tradenames AVONEX® and REBIF®), interferon-beta-lb (sold under the tradenames BETASERON® and EXTAVIA®), glatiramer acetate (sold under the tradename
  • COPAXONE® COPAXONE®
  • fingolimod sold under the tradename GILENYA®
  • mitoxantrone sold under the tradename (NOVANTRONE®)
  • natalizumab sold under the tradename TYSABRI®
  • 4- ⁇ 5-[4-(4-Oxazol-2-yl-phenoxy)-benzyl]-2,5-diaza- bicyclo[2.2.1]hept-2-ylmethyl ⁇ -benzoic acid is co-administered with a beta-agonist.
  • beta-agonists are salbutamol, levalbuterol, formoterol, fenoterol, salmeterol, bambuterol, brocaterol, clenbuterol, terbutalin, tulobuterol, epinephrin, isoprenalin, and hexoprenalin.
  • the compound is co-administered with an
  • the compound is co-administered with a mucolytic and/or a surfactant.
  • exemplary mucolytics and surfactants are acetylcystein, ambroxol, carbocystein, tyloxapol, dipalmytoylphosphatidylcholin, recombinant surfactant proteins, and DNase.
  • the compound is co-administered with an antibiotic agent.
  • antibiotics are beta-lactam antibiotics, including amoxycillin, piperacillin, clavulan acid, and sulbactam, cephalosporines, including cefaclor, cefazedon, Cefuroxim, Cefoxitin, cefodizim, cefsulodin, cefpodixim, and cefixim, carbapenemes such as imipenem and cilastatin, monbactames, such as, aztrenonam, aminoglycosides, including streptomycin, neomycin, paromomycin, kanamycin, gentamycin, amicacin, tobramycin, and spectinomycine, tetracyclines, such as doxycyclin and minocycline, macrolides including erythromycine, clarithromycine, roxithromycine, azithromycine, josamycine, and spiramycine, gyrase inhibitors or quinolones such as
  • the compound is co-administered with an anti-inflammatory drug.
  • anti-inflammatory drugs include romoglycate and nedocromil.
  • the compound is co-administered with a corticosteroid.
  • corticosteroids are beclomethasone, betamethasone, budesonide, ciclesonide, flunisolide, fluticasone, icomethasone, mometasone, rofleponide, triamcinolone, bradykinine, prostaglandine, leucotriene and platelet activating factor antagonists.
  • a compound when a compound is co-administered with at least one additional therapeutic agent, the compound can be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents.
  • Such combination therapy includes administration of a single pharmaceutical dosage formulation which contains the compound and one or more additional active agents, as well as administration of the compound and each active agent in its own separate pharmaceutical dosage formulation.
  • the compound and the other therapeutic agent can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent can be administered in separate oral dosage formulations.
  • the compound and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e.,
  • combination therapy is understood to include all these regimens.
  • the invention also encompasses pharmaceutical compositions.
  • the pharmaceutical compositions of the invention can be prepared by combining 4- ⁇ [(l S,4S)-5-( ⁇ 4-[4-oxazol-2- yl-phenoxy]phenyl ⁇ methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]methyl ⁇ benzoic acid with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into preparations in solid, semi-solid, or liquid forms, such as tablets, capsules, powders, granules, solutions, and the like.
  • Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet can be a single dosage unit or a tablet can be one-half of single dosage unity.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000) and Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences, 2012).
  • the composition to be administered will, in any event, contain an effective amount of a compound as described herein (for example, 100 mg or less), or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings of this invention.
  • a pharmaceutical composition of the invention can be in the form of a solid or liquid.
  • the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form.
  • the carrier(s) can be liquid, with the compositions being, for example, an oral syrup.
  • the pharmaceutical composition can be in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
  • the pharmaceutical composition can be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers.
  • binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.
  • excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like
  • lubricants such as magnesium stearate or Sterotex
  • glidants such as colloidal silicon dioxide
  • sweetening agents such as sucrose or saccharin
  • a flavoring agent such as peppermint, methyl sal
  • the pharmaceutical composition when in the form of a capsule, for example a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.
  • a liquid carrier such as polyethylene glycol or oil.
  • the pharmaceutical composition can be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension.
  • the composition can contain, in addition to combining 4- ⁇ [(lS,4S)-5-( ⁇ 4-[4-oxazol-2-yl-phenoxy]phenyl ⁇ methyl)-2,5- diazabicyclo[2.2. l]heptan-2-yl]methyl ⁇ benzoic acid, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
  • the liquid pharmaceutical compositions of the invention can include one or more of the following adjuvants: sterile diluents, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • adjuvants sterile diluents, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents
  • antibacterial agents such as benzyl alcohol or methyl paraben
  • antioxidants such as ascorbic acid or sodium bisulfit
  • the pharmaceutical composition of the invention can include various materials, which modify the physical form of a solid or liquid dosage unit.
  • the composition can include materials that form a coating shell around the active ingredients.
  • the materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
  • the active ingredients can be encased in a gelatin capsule.
  • the compound, 4- ⁇ [(lS,4S)-5-( ⁇ 4-[4-oxazol-2-yl- phenoxy]phenyl ⁇ methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]methyl ⁇ benzoic acid is a milled solid.
  • the milled solid has a monodisperse particle size distribution having a D90 of about 50 microns or less.
  • the milled solid has a monodisperse particle size distribution having a D90 of about 15 microns or less.
  • the milled solid has a monodisperse particle size distribution having a D90 between 10 and 15 microns. D90 refers to a particle size where 90 volume percent of the particles are smaller than the indicated diameter.
  • the compound is a solid that is amorphous or crystalline in physical structure. In certain aspects, the compound is a solid that is crystalline. In yet additional embodiments, the compound is crystalline, wherein the crystalline form is characterized by the x-ray powder diffraction pattern substantially as shown in FIG. 2. In this context, the term “substantially” refers variations in intensity and 2-theta values typically observed in the art depending on instrument and sample preparation.
  • the compound, 4- ⁇ [(lS,4S)-5-( ⁇ 4-[4-oxazol-2-yl- phenoxy]phenyl ⁇ methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]methyl ⁇ benzoic acid is a powder.
  • the pharmaceutical composition comprises the compound as a powder and an excipient selected from the group consisting of a carrier, an emulsifier, a disintegrants, a lubricant, a glidants or flow aid, or a combination of any thereof.
  • carriers are mannitol and lactose.
  • a non-limiting example of an emulsifier is methylcellulose.
  • Non-limiting examples of disintegrants are croscarmellose or crospovidone.
  • a non-limiting example of a lubricant is magnesium stearate.
  • a non-limiting example of a glidant or flow aid is silicon dioxide. In certain embodiments, the
  • composition comprises the compound as a solid powder and the composition further comprises lactose, methylcellulose, crospovidone, and magnesium stearate.
  • pharmaceutical composition comprises the compound as a solid powder and the composition further comprises mannitol, methylcellulose, croscarmellose and/or magnesium stearate.
  • pharmaceutical composition comprises the compound as a solid powder and the composition further comprises lactose,
  • the pharmaceutical composition comprises the compound as a solid powder and the composition further comprises mannitol,
  • methylcellulose, croscarmellose and/or magnesium stearate and further comprises a glidants of flow aid.
  • the glidants or flow aid is silicon dioxide.
  • the pharmaceutical composition comprises the compound as a solid powder or powder blend and wherein the pharmaceutical composition is in the form of a capsule or a tablet.
  • the pharmaceutical composition is capsule containing the compound as a solid powder or powder blend.
  • the pharmaceutical composition is a gelatin capsule containing compound as a solid powder or powder blend.
  • the ICso of 4- ⁇ [(lS,4S)-5-( ⁇ 4-[4-oxazol-2-yl-phenoxy]phenyl ⁇ methyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]methyl ⁇ benzoic acid in human whole blood has been determined using an ex vivo assay.
  • the human whole blood assay has been described in Penning et al (2000), Structure and Activity Relationship Studies on l-[2-(4- Phenylphenoxy)ethyl]pyrrolidone (SC-22716), a Potent Inhibitor of Leukotriene A4 (LTA4) hydrolase, J. Med. Chem.
  • LTB4 production is stimulated by addition of calcium ionophone (A23187) in the absence or presence of varied concentrations of 4- ⁇ [(lS,4S)-5- ( ⁇ 4-[4-oxazol-2-yl-phenoxy]phenyl ⁇ methyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl]methyl ⁇ benzoic acid.
  • LTB4 production is determined by ELISA.
  • This ELISA assay was performed using the Leukotriene B4 EIA Kit available from Cayman Chemical (Item No. 5201 1 1) and the assay was performed according to the manufacturer's instructions.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Biomedical Technology (AREA)
  • Endocrinology (AREA)
  • Cardiology (AREA)
  • Oncology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Emergency Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Vascular Medicine (AREA)
  • Obesity (AREA)
  • Communicable Diseases (AREA)
  • Transplantation (AREA)
  • Otolaryngology (AREA)
PCT/US2014/023138 2013-03-12 2014-03-11 Methods of inhibiting leukotriene a4 hydrolase Ceased WO2014164658A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
ES14779776T ES2864862T3 (es) 2013-03-12 2014-03-11 Métodos de inhibición de la leucotrieno A4 hidrolasa
JP2016501158A JP6527851B2 (ja) 2013-03-12 2014-03-11 ロイコトリエンａ４加水分解酵素を阻害する方法
CA2905340A CA2905340C (en) 2013-03-12 2014-03-11 Low dose oral formulations of acebilustat
EP14779776.5A EP2968359B1 (en) 2013-03-12 2014-03-11 Methods of inhibiting leukotriene a4 hydrolase
RU2015137978A RU2686101C2 (ru) 2013-03-12 2014-03-11 Способы ингибирования лейкотриен- а4-гидролазы
AU2014249168A AU2014249168B2 (en) 2013-03-12 2014-03-11 Methods of inhibiting leukotriene A4 hydrolase
US14/850,061 US9820974B2 (en) 2013-03-12 2015-09-10 Methods of inhibiting leukotriene A4 hydrolase
US15/801,482 US10350197B2 (en) 2013-03-12 2017-11-02 Methods of inhibiting leukotriene A4 hydrolase
US16/443,338 US10898471B2 (en) 2013-03-12 2019-06-17 Methods of inhibiting leukotriene A4 hydrolase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361776981P 2013-03-12 2013-03-12
US61/776,981 2013-03-12

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US14/850,061 Continuation US9820974B2 (en) 2013-03-12 2015-09-10 Methods of inhibiting leukotriene A4 hydrolase

Publications (1)

Publication Number Publication Date
WO2014164658A1 true WO2014164658A1 (en) 2014-10-09

Family

ID=51658933

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2014/023138 Ceased WO2014164658A1 (en) 2013-03-12 2014-03-11 Methods of inhibiting leukotriene a4 hydrolase

Country Status (8)

Country Link
US (3) US9820974B2 (enExample)
EP (1) EP2968359B1 (enExample)
JP (1) JP6527851B2 (enExample)
AU (1) AU2014249168B2 (enExample)
CA (1) CA2905340C (enExample)
ES (1) ES2864862T3 (enExample)
RU (1) RU2686101C2 (enExample)
WO (1) WO2014164658A1 (enExample)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020144604A1 (en) 2019-01-11 2020-07-16 Novartis Ag Lta4h inhibitors for the treatment of hidradenitis suppurativa
WO2021044351A1 (en) 2019-09-06 2021-03-11 Novartis Ag Methods of treating liver disease using lta4h inhibitors
WO2022034529A1 (en) 2020-08-14 2022-02-17 Novartis Ag Heteroaryl substituted spiropiperidinyl derivatives and pharmaceutical uses thereof
RU2821362C2 (ru) * 2019-01-11 2024-06-21 Новартис Аг Ингибиторы lta4h для лечения гнойного гидраденита

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUE031972T2 (en) 2005-12-29 2017-08-28 Celtaxsys Inc Diamine derivatives as inhibitors of leukotriene a4 hydrolase
CA2905340C (en) * 2013-03-12 2022-05-31 Celtaxsys, Inc. Low dose oral formulations of acebilustat
KR20150131211A (ko) 2013-03-14 2015-11-24 켈탁시스, 인코퍼레이티드 류코트라이엔 a4 가수분해효소의 저해제
BR112015022226A2 (pt) 2013-03-14 2017-07-18 Celtaxsys Inc inibidores de leucotrieno a4 hidrolase
BR112015022864A8 (pt) 2013-03-14 2019-11-26 Celtaxsys Inc composto, composição farmacêutica e uso dos mesmos
US11426399B2 (en) * 2018-05-15 2022-08-30 Alkahest, Inc. Treatment of aging-associated disease with modulators of leukotriene A4 hydrolase
JP7386815B2 (ja) * 2018-05-31 2023-11-27 セルタクシー、エルエルシー 呼吸器疾患患者の肺増悪を軽減する方法
US11957671B2 (en) 2021-11-01 2024-04-16 Alkahest, Inc. Benzodioxane modulators of leukotriene A4 hydrolase (LTA4H) for prevention and treatment of aging-associated diseases
CA3239752A1 (en) * 2021-12-09 2023-06-15 Stanley Glenn Rockson Methods of treating lymphedema
WO2024254377A2 (en) * 2023-06-09 2024-12-12 Celltaxis, Llc Methods of treating lipedema and lymphatic disease of the subcutaneous tissue

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060211729A1 (en) * 2005-03-16 2006-09-21 Meda Pharma Gmbh & Co. Kg Combination of anticholinergics and leukotriene receptor antagonists for the treatment of respiratory diseases
US7597897B2 (en) * 2003-12-30 2009-10-06 3M Innovative Properties Company Medicinal compositions and method for the preparation thereof
WO2010015818A1 (en) * 2008-08-07 2010-02-11 Argenta Discovery Limited Respiratory disease treatment
US20100210630A1 (en) * 2005-12-29 2010-08-19 Estrellita Pharmaceuticals, Llc Diamine Derivatives as Inhibitors of Leukotriene A4 Hydrolase
US20100260859A1 (en) * 2009-04-09 2010-10-14 Elan Pharma International Limited Controlled-release clozapine compositions
US7915298B2 (en) * 2007-09-27 2011-03-29 Merck Sharp & Dohme Corp. Compounds and methods for leukotriene biosynthesis inhibition
US8246935B2 (en) * 2003-11-14 2012-08-21 Jagotec Ag Dry powder formulations
US20120263680A1 (en) * 2011-04-12 2012-10-18 Moerae Matrix, Inc. Compositions And Methods For Preventing Or Treating Diseases, Conditions, Or Processes Characterized By Aberrant Fibroblast Proliferation And Extracellular Matrix Deposition

Family Cites Families (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL6815872A (enExample) 1967-11-22 1969-05-27
JPS5614663B2 (enExample) 1971-08-21 1981-04-06
US4582833A (en) 1984-04-16 1986-04-15 American Cyanamid Company 2-(substituted-1-piperazinyl)[1,2,4]triazolo[1,5-a]pyrimidines
US4576943A (en) 1984-10-09 1986-03-18 American Cyanamid Company Pyrazolo[1,5-a]pyrimidines
US5308852A (en) 1992-06-29 1994-05-03 Merck Frosst Canada, Inc. Heteroarylnaphthalenes as inhibitors of leukotriene biosynthesis
US6506876B1 (en) 1994-10-11 2003-01-14 G.D. Searle & Co. LTA4 hydrolase inhibitor pharmaceutical compositions and methods of use
WO1997029774A1 (en) 1996-02-13 1997-08-21 G.D. Searle & Co. Combinations, having immunosuppressive effects, containing a cyclooxygenase-2 inhibitor and a leukotriene a4 hydrolase inhibitor
US5952349A (en) 1996-07-10 1999-09-14 Schering Corporation Muscarinic antagonists for treating memory loss
JP2000516611A (ja) 1996-08-14 2000-12-12 ワーナー―ランバート・コンパニー Ｍｃｐ―１アンタゴニストとしての２―フェニルベンズイミダゾール誘導体
US6309561B1 (en) 1997-12-24 2001-10-30 3M Innovative Properties Company Liquid crystal compounds having a chiral fluorinated terminal portion
US6380203B1 (en) 1998-01-14 2002-04-30 Merck & Co., Inc. Angiogenesis inhibitors
GB9815880D0 (en) 1998-07-21 1998-09-16 Pfizer Ltd Heterocycles
GB9919776D0 (en) 1998-08-31 1999-10-27 Zeneca Ltd Compoujnds
AR023659A1 (es) 1998-09-18 2002-09-04 Vertex Pharma Un compuesto inhibidor de p38, una composicion farmaceutica que lo comprende y el uso de dicha composicion en el tratamiento y prevencion de estados patologicos
US6699873B1 (en) 1999-08-04 2004-03-02 Millennium Pharmaceuticals, Inc. Melanocortin-4 receptor binding compounds and methods of use thereof
US6924313B1 (en) 1999-09-23 2005-08-02 Pfizer Inc. Substituted tertiary-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity
AU2001234420A1 (en) 2000-02-03 2001-08-14 Eli Lilly And Company Potentiators of glutamate receptors
US6552023B2 (en) 2000-02-22 2003-04-22 Cv Therapeutics, Inc. Aralkyl substituted piperazine compounds
US6451798B2 (en) 2000-02-22 2002-09-17 Cv Therapeutics, Inc. Substituted alkyl piperazine derivatives
JP2001354657A (ja) 2000-06-09 2001-12-25 Sds Biotech:Kk 置換ピペラジン誘導体及び農園芸用殺菌剤
DE60114518T2 (de) 2000-07-06 2006-08-10 Fuji Photo Film Co. Ltd., Minamiashigara Flüssigkristallzusammensetzung, die Flüssigkristallmoleküle und Ausrichtungsmittel enthält
WO2002064211A1 (en) 2001-02-09 2002-08-22 Merck & Co., Inc. Thrombin inhibitors
WO2002069901A2 (en) 2001-03-02 2002-09-12 Merck Frosst Canada & Co. Cathepsin cysteine protease inhibitors
AUPR362001A0 (en) 2001-03-08 2001-04-05 Fujisawa Pharmaceutical Co., Ltd. New compound
FR2826011B1 (fr) 2001-06-14 2004-12-10 Oreal Nouveaux derives de la 7-oxo-dhea et utilisation cosmetique
SE0102616D0 (sv) 2001-07-25 2001-07-25 Astrazeneca Ab Novel compounds
IL160845A0 (en) 2001-09-14 2004-08-31 Tularik Inc Linked biaryl compounds
AU2002363236A1 (en) 2001-10-30 2003-05-12 Millennium Pharmaceuticals, Inc. Compounds, pharmaceutical compositions and methods of use therefor
AU2003270291A1 (en) 2002-10-04 2004-04-23 Ucb 4-aminopiperidine derivatives, processes for their preparation and their use as medicaments
US7851486B2 (en) 2002-10-17 2010-12-14 Decode Genetics Ehf. Susceptibility gene for myocardial infarction, stroke, and PAOD; methods of treatment
CA2502359A1 (en) 2002-10-17 2004-04-29 Decode Genetics Ehf. Susceptibility gene for myocardial infarction
WO2004058683A2 (en) 2002-12-20 2004-07-15 Migenix Corp. Ligands of adenine nucleotide translocase (ant) and compositions and methods related thereto
CA2521000A1 (en) 2003-04-03 2004-10-21 Kyowa Hakko Kogyo Co., Ltd. Preventive and/or therapeutic agent for neuropathic pain
US7115642B2 (en) 2003-05-02 2006-10-03 Rigel Pharmaceuticals, Inc. Substituted diphenyl isoxazoles, pyrazoles and oxadiazoles useful for treating HCV infection
JP2005008581A (ja) 2003-06-20 2005-01-13 Kissei Pharmaceut Co Ltd 新規なピラゾロ［１，５−ａ］ピリミジン誘導体、それを含有する医薬組成物およびそれらの用途
CN100591679C (zh) 2003-07-28 2010-02-24 詹森药业有限公司 苯并咪唑、苯并噻唑和苯并唑衍生物及其作为lta4h调节剂的应用
US20050272051A1 (en) 2003-09-17 2005-12-08 Decode Genetics Ehf. Methods of preventing or treating recurrence of myocardial infarction
US7932272B2 (en) 2003-09-30 2011-04-26 Eisai R&D Management Co., Ltd. Antifungal agent containing heterocyclic compound
DE10356579A1 (de) 2003-12-04 2005-07-07 Merck Patent Gmbh Aminderivate
SE0303480D0 (sv) 2003-12-19 2003-12-19 Biovitrum Ab Benzofuranes
EP1713809B1 (en) 2004-02-04 2009-07-29 Neurosearch A/S Dimeric azacyclic compounds and their use
WO2006033795A2 (en) 2004-09-17 2006-03-30 Wyeth Substituted pyrazolo [1, 5-a] pyrimidines for inhibiting abnormal cell growth
CN101189012A (zh) 2005-03-31 2008-05-28 詹森药业有限公司 苯基和吡啶基lta4h调节剂
GB0514018D0 (en) 2005-07-07 2005-08-17 Ionix Pharmaceuticals Ltd Chemical compounds
UA101943C2 (ru) 2005-09-21 2013-05-27 Декод Дженетикс Ехф Биарилзамещенные гетероциклические ингибиторы lta4h для лечения воспаления
CN1947717B (zh) 2005-10-14 2012-09-26 卓敏 选择性抑制腺苷酸环化酶1的化合物在制备用于治疗神经性疼痛和炎性疼痛的药物中的应用
DE102005049954A1 (de) 2005-10-19 2007-05-31 Sanofi-Aventis Deutschland Gmbh Triazolopyridin-derivate als Inhibitoren von Lipasen und Phospholipasen
JP5188988B2 (ja) 2006-02-10 2013-04-24 トランステック ファーマ，インコーポレイティド ベンゾアゾール誘導体、組成物、及びオーロラキナーゼ阻害剤としての使用方法
EP2058309A4 (en) 2006-08-04 2010-12-22 Takeda Pharmaceutical CONDENSED HETEROCYCLIC COMPOUND
CN101528709B (zh) 2006-10-19 2012-02-01 弗·哈夫曼-拉罗切有限公司 对痕量胺相关受体有亲和性的氨基甲基-2-咪唑类
CA2672661C (en) 2006-12-14 2015-04-28 Janssen Pharmaceutica N.V. Process for the preparation of piperazinyl and diazepanyl benzamide derivatives
FR2911139A1 (fr) 2007-01-05 2008-07-11 Sanofi Aventis Sa Nouveaux derives de phenyl-(4-phenyl-pyrimidin-2-yl)amines, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk
FR2911140B1 (fr) 2007-01-05 2009-02-20 Sanofi Aventis Sa Nouveaux derives de 2-anilino 4-heteroaryle pyrimides, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk
FR2911138B1 (fr) 2007-01-05 2009-02-20 Sanofi Aventis Sa Nouveaux derives de n, n'-2,4-dianilinopyrimidines, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk
AU2008270438B2 (en) 2007-07-02 2013-10-10 F. Hoffmann-La Roche Ag Imidazole derivatives as CCR2 receptor antagonists
US7902181B2 (en) 2007-12-12 2011-03-08 Astrazeneca Ab Compounds 010
AU2009218515A1 (en) 2008-02-26 2009-09-03 Novartis Ag Heterocyclic compounds as inhibitors of CXCR2
FR2928070A1 (fr) 2008-02-27 2009-09-04 Sumitomo Chemical Co Composition agricole, utilisation d'un compose pour sa production et procede pour matriser ou prevenir les maladies des plantes.
US20100029657A1 (en) 2008-02-29 2010-02-04 Wyeth Bridged, Bicyclic Heterocyclic or Spiro Bicyclic Heterocyclic Derivatives of Pyrazolo[1, 5-A]Pyrimidines, Methods for Preparation and Uses Thereof
MX2010011154A (es) 2008-04-11 2010-12-21 Janssen Pharmaceutica Nv Tiazolopiridin-2-iloxi-fenilo y tiazolopirazin-2-iloxifenilaminas como moduladores de la leucotrieno a4 hidrolasa.
EP2110374A1 (en) 2008-04-18 2009-10-21 Merck Sante Benzofurane, benzothiophene, benzothiazol derivatives as FXR modulators
WO2010011912A1 (en) 2008-07-25 2010-01-28 Smithkline Beecham Corporation Trpv4 antagonists
CN102030700B (zh) 2009-09-30 2016-06-01 中国医学科学院药物研究所 苯甲酰胺基羧酸类化合物及其制法和药物用途
WO2011053706A1 (en) 2009-10-30 2011-05-05 Janssen Pharmaceutica Nv 4-substituted-2-phenoxy-phenylamine delta opioid receptor modulators
SG181109A1 (en) 2009-12-07 2012-07-30 Targacept Inc 3,6-diazabicyclo[3.1.1]heptanes as neuronal nicotinic acetylcholine receptor ligands
KR101764952B1 (ko) 2010-07-29 2017-08-03 리겔 파마슈티칼스, 인크. Ａｍｐｋ-활성화 헤테로시클릭 화합물 및 그의 사용 방법
WO2012067822A1 (en) 2010-11-16 2012-05-24 Abbott Laboratories Pyrazolo [1, 5 -a] pyrimidin potassium channel modulators
CN103415513B (zh) 2011-03-14 2016-01-20 勃林格殷格翰国际有限公司 白三烯产物的苯并二氧杂环己烷抑制剂
AU2012229127A1 (en) 2011-03-15 2013-10-03 Rib-X Pharmaceuticals, Inc. Antimicrobial agents
DK2714661T3 (en) 2011-05-23 2015-10-19 Janssen Pharmaceutica Nv PICOLINAMIDO - propanoic APPLICABLE TO glucagon receptor antagonists
CN103159742B (zh) 2011-12-16 2015-08-12 北京韩美药品有限公司 5-氯嘧啶类化合物及其作为egfr酪氨酸激酶抑制剂的应用
US9006235B2 (en) 2012-03-06 2015-04-14 Bristol-Myers Squibb Company Inhibitors of human immunodeficiency virus replication
EP2827849A4 (en) 2012-03-23 2015-11-18 Univ Leland Stanford Junior TREATMENT OF PULMONARY HYPERTONIA WITH LEUKOTRIENHEMMERN
CA2905340C (en) * 2013-03-12 2022-05-31 Celtaxsys, Inc. Low dose oral formulations of acebilustat
KR20150131211A (ko) 2013-03-14 2015-11-24 켈탁시스, 인코퍼레이티드 류코트라이엔 a4 가수분해효소의 저해제
BR112015022226A2 (pt) 2013-03-14 2017-07-18 Celtaxsys Inc inibidores de leucotrieno a4 hidrolase
BR112015022864A8 (pt) 2013-03-14 2019-11-26 Celtaxsys Inc composto, composição farmacêutica e uso dos mesmos

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8246935B2 (en) * 2003-11-14 2012-08-21 Jagotec Ag Dry powder formulations
US7597897B2 (en) * 2003-12-30 2009-10-06 3M Innovative Properties Company Medicinal compositions and method for the preparation thereof
US20060211729A1 (en) * 2005-03-16 2006-09-21 Meda Pharma Gmbh & Co. Kg Combination of anticholinergics and leukotriene receptor antagonists for the treatment of respiratory diseases
US20100210630A1 (en) * 2005-12-29 2010-08-19 Estrellita Pharmaceuticals, Llc Diamine Derivatives as Inhibitors of Leukotriene A4 Hydrolase
US7915298B2 (en) * 2007-09-27 2011-03-29 Merck Sharp & Dohme Corp. Compounds and methods for leukotriene biosynthesis inhibition
WO2010015818A1 (en) * 2008-08-07 2010-02-11 Argenta Discovery Limited Respiratory disease treatment
US20100260859A1 (en) * 2009-04-09 2010-10-14 Elan Pharma International Limited Controlled-release clozapine compositions
US20120263680A1 (en) * 2011-04-12 2012-10-18 Moerae Matrix, Inc. Compositions And Methods For Preventing Or Treating Diseases, Conditions, Or Processes Characterized By Aberrant Fibroblast Proliferation And Extracellular Matrix Deposition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2968359A4 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020144604A1 (en) 2019-01-11 2020-07-16 Novartis Ag Lta4h inhibitors for the treatment of hidradenitis suppurativa
RU2821362C2 (ru) * 2019-01-11 2024-06-21 Новартис Аг Ингибиторы lta4h для лечения гнойного гидраденита
EP4442315A2 (en) 2019-01-11 2024-10-09 Novartis AG Lta4h inhibitor for the treatment or prevention of hidradenitis suppurativa
WO2021044351A1 (en) 2019-09-06 2021-03-11 Novartis Ag Methods of treating liver disease using lta4h inhibitors
WO2022034529A1 (en) 2020-08-14 2022-02-17 Novartis Ag Heteroaryl substituted spiropiperidinyl derivatives and pharmaceutical uses thereof

Also Published As

Publication number Publication date
US9820974B2 (en) 2017-11-21
US20200138791A1 (en) 2020-05-07
CA2905340C (en) 2022-05-31
RU2015137978A (ru) 2017-04-13
US20180117014A1 (en) 2018-05-03
RU2686101C2 (ru) 2019-04-24
AU2014249168B2 (en) 2018-07-12
EP2968359A4 (en) 2016-11-23
US20160067226A1 (en) 2016-03-10
US10898471B2 (en) 2021-01-26
US10350197B2 (en) 2019-07-16
EP2968359A1 (en) 2016-01-20
CA2905340A1 (en) 2014-10-09
RU2015137978A3 (enExample) 2018-03-21
JP6527851B2 (ja) 2019-06-05
AU2014249168A1 (en) 2015-10-01
JP2016512517A (ja) 2016-04-28
ES2864862T3 (es) 2021-10-14
EP2968359B1 (en) 2021-01-20

Similar Documents

Publication Publication Date Title
US10898471B2 (en) Methods of inhibiting leukotriene A4 hydrolase
CN103945848B (zh) 被取代的喹唑啉酮的口服即释制剂
JP7697885B2 (ja) 化合物の製剤およびそれらの使用
JP6825574B2 (ja) ２−｛４−［ｎ−（５，６−ジフェニルピラジン−２−イル）−ｎ−イソプロピルアミノ］ブチルオキシ｝−ｎ−（メチルスルホニル）アセトアミドを含有する医薬組成物
JP2016512517A5 (enExample)
US20220233550A1 (en) Parp inhibitor pellet preparation and preparation process therefor
JP7771316B2 (ja) 組成物
US20250281480A1 (en) Pharmaceutical dry powder inhalation formulation
EP2008658A1 (en) Synergistic combination of anthranilamide pyridinureas and benzamide derivatives
JP2023070165A (ja) アザビシクロ環化合物の結晶
TW201028155A (en) New combination of active ingredients containing a non steroidal anti inflammatory drug and a colchicoside derivative
US20090306024A1 (en) Combination preparations of o-acetylsalicylic acid salts
CA2805766A1 (en) Phenylalkyl n-hydroxyureas for treating leukotriene related pathologies
CN113214206B (zh) 橙皮素与甜菜碱共晶物b及制备方法和其组合物与用途
WO2024040125A1 (en) Crystalline forms of a pcsk9 inhibitor, compositions and uses
CN116392465A (zh) 一种复方多廿烷醇普伐他汀组合物及其制备方法
CN106420759B (zh) 一种替吉奥组合物的制备方法
CN117050029A (zh) 卡巴拉汀酒石酸盐与缬沙坦共无定型合物及制备方法和其组合物与用途
HK40062460A (en) Parp inhibitor pellet preparation and preparation process therefor

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14779776

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2016501158

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2905340

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2014779776

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2014249168

Country of ref document: AU

Date of ref document: 20140311

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2015137978

Country of ref document: RU

Kind code of ref document: A